Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC.

The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients.

Colorectal liver metastases patients prognostic assessment: prospects and limits of radiomics and radiogenomics.

In this narrative review, we reported un up-to-date on the role of radiomics to assess prognostic features, which can impact on the liver metastases patient treatment choice. In the liver metastases patients, the possibility to assess mutational status (RAS or MSI), the tumor growth pattern and the histological subtype (NOS or mucinous) allows a better treatment selection to avoid unnecessary therapies. However, today, the detection of these features require an invasive approach. Recently, radiomics analysis application has improved rapidly, with a consequent growing interest in the oncological field. Radiomics analysis allows the textural characteristics assessment, which are correlated to biological data. This approach is captivating since it should allow to extract biological data from the radiological images, without invasive approach, so that to reduce costs and time, avoiding any risk for the patients. Several studies showed the ability of Radiomics to identify mutational status, tumor growth pattern and histological type in colorectal liver metastases. Although, radiomics analysis in a non-invasive and repeatable way, however features as the poor standardization and generalization of clinical studies results limit the translation of this analysis into clinical practice. Clear limits are data-quality control, reproducibility, repeatability, generalizability of results, and issues related to model overfitting.

Randomized phase II study of valproic acid in combination with bevacizumab and oxaliplatin/fluoropyrimidine regimens in patients with RAS-mutated metastatic colorectal cancer: the REVOLUTION study protocol.

BACKGROUND: Despite effective treatments, metastatic colorectal cancer (mCRC) prognosis is still poor, mostly in RAS-mutated tumors, thus suggesting the need for novel combinatorial therapies. Epigenetic alterations play an important role in initiation and progression of cancers, including CRC. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with chemotherapy in the treatment of solid tumors. Owing to its HDACi activity and its safe use for epileptic disorders, valproic acid (VPA) is a good candidate for anticancer therapy that we have largely explored preclinically translating our findings in currently ongoing clinical studies. We have shown in CRC models that HDACi, including VPA, induces synergistic antitumor effects in combination with fluoropyrimidines. Furthermore, unpublished results from our group demonstrated that VPA induces differentiation and sensitization of CRC stem cells to oxaliplatin. Moreover, preclinical and clinical data suggest that HDACi may prevent/reverse anti-angiogenic resistance. METHODS/DESIGN: A randomized, open-label, two-arm, multicenter phase-II study will be performed to explore whether the addition of VPA to first line bevacizumab/oxaliplatin/fluoropyrimidine regimens (mFOLFOX-6/mOXXEL) might improve progression-free survival (PFS) in RAS-mutated mCRC patients. A sample size of 200 patients was calculated under the hypothesis that the addition of VPA to chemotherapy/bevacizumab can improve PFS from 9 to 12 months, with one-sided alpha of 0.20 and a power of 0.80. Secondary endpoints are overall survival, objective response rate, metastases resection rate, toxicity, and quality of life. Moreover, the study will explore several prognostic and predictive biomarkers on blood samples, primary tumors, and on resected metastases. DISCUSSION: The "Revolution" study aims to improve the treatment efficacy of RAS-mutated mCRC through an attractive strategy evaluating the combination of VPA with standard cancer treatment. Correlative studies could identify novel biomarkers and could add new insight in the mechanism of interaction between VPA, fluoropyrimidine, oxaliplatin, and bevacizumab. TRIAL REGISTRATION: EudraCT: 2018-001414-15; ClinicalTrials.gov identifier: NCT04310176.

Double-Wall Nanotubes and Graphene Nanoplatelets for Hybrid Conductive Adhesives with Enhanced Thermal and Electrical Conductivity.

Improving the electrical and thermal properties of conductive adhesives is essential for the fabrication of compact microelectronic and optoelectronic power devices. Here we report on the addition of a commercially available conductive resin with double-wall carbon nanotubes and graphene nanoplatelets that yields simultaneously improved thermal and electrical conductivity. Using isopropanol as a common solvent for the debundling of nanotubes, exfoliation of graphene, and dispersion of the carbon nanostructures in the epoxy resin, we obtain a nanostructured conducting adhesive with thermal conductivity of ∼12 W/mK and resistivity down to 30 µΩ cm at very small loadings (1% w/w for nanotubes and 0.01% w/w for graphene). The low filler content allows one to keep almost unchanged the glass-transition temperature, the viscosity, and the curing parameters. Die shear measurements show that the nanostructured resins fulfill the MIL-STD-883 requirements when bonding gold-metalized SMD components, even after repeated thermal cycling. The same procedure has been validated on a high-conductivity resin characterized by a higher viscosity, on which we have doubled the thermal conductivity and quadrupled the electrical conductivity. Graphene yields better performances with respect to nanotubes in terms of conductivity and filler quantity needed to improve the resin. We have finally applied the nanostructured resins to bond GaN-based high-electron-mobility transistors in power-amplifier circuits. We observe a decrease of the GaN peak and average temperatures of, respectively, ∼30 °C and ∼10 °C, with respect to the pristine resin. The obtained results are important for the fabrication of advanced packaging materials in power electronic and microwave applications and fit the technological roadmap for CNTs, graphene, and hybrid systems.

Gastrointestinal non colorectal cancer. Do elderly patients need a specific management?

BACKGROUND: Elderly patients (65 years and over) develop often, sometimes predominantly , esophageal, gastro esophageal junction, gastric and pancreatic cancer (gastrointestinal non colorectal cancer). Most clinical trials exclude elderly patients from accrual considering aging a potential risk factor. In fact an elderly patient can develop greater toxicity than a younger patient from oncologic treatments (chemotherapy, radiotherapy, target therapies) due to a worse function of vital organs. METHODS: We analyzed the current scientific literature, searching articles since 1990, about gastrointestinal non colorectal cancer in elderly patients, to establish if they need a specific management, different from younger patients. RESULTS: Data from analyzed studies, both gastro esophageal and pancreatic cancer, are contradictory. In some reports elderly patients don't seem to bring greater toxicity than younger. Other trials consider that dose-adjustment to renal function is need in elderly patients, but these trials are very few. Other trials may include several biases such as accrual of "only fit" elderly patients. CONCLUSIONS: It is very important in elderly patients with higher risk of toxicity, to distinguish the aim of cancer treatment: is it curative or palliative? Furthermore, in this type of patients the most important target is probably maintaining the quality of life especially in gastric and pancreatic cancer that often started as advanced disease. For these valuation chronological age alone is not sufficient. Another very important factor in elderly cancer patients is the geriatric assessment including not only age but also functional, social and mental status.

Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma.

BACKGROUND: The aim of the current randomized Phase II study was to investigate the efficacy and safety of capecitabine combined with irinotecan as first-line treatment in metastatic colorectal carcinoma (CRC). METHODS: A total of 140 patients received capecitabine at a dose of 1250 mg/m(2) twice daily on Days 2-15 and irinotecan at a dose of either 300 mg/m(2) on Day 1 (Arm A) or 150 mg/m(2) on Days 1 and 8 (Arm B) every 3 weeks. During the course of the study, enrollment was continued using lower doses of capecitabine (1000 mg/m(2) twice daily) and irinotecan (Arm A: 240 mg/m(2); Arm B: 120 mg/m(2)) to improve the safety profile of the combinations. RESULTS: Efficacy was evaluable in 134 patients (68 in Arm A, 66 in Arm B). Objective responses were observed in 46% of the patients (8% complete response [CR]), including 47% in Arm A (9% CR; 38% partial response [PR]) and 44% in Arm B (8% CR; 36% PR). The median progression-free survival was 8.3 months in Arm A and 7.6 months in Arm B. Among the first 52 patients treated with the higher doses, the most frequent Grade 3-4 adverse event was diarrhea (27%). The lower doses adopted in the subsequent 88 patients led to better diarrhea control, particularly in Arm A, and significant reductions in the incidence of all-grade hand-foot syndrome and abdominal pain. CONCLUSIONS: The capecitabine and irinotecan combination was a highly active first-line therapy in metastatic CRC. An acceptable safety profile was observed after dose reduction, particularly when irinotecan was administered on 1 day.