Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out. RESULTS: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts.

BACKGROUND: The search for biomarkers to evaluate ovarian cancer (OC) homologous recombination (HR) function and predict the response to therapy is an urgent clinical need to improve the selection of patients who could benefit from platinum- and olaparib (poly-ADP ribose polymerase inhibitors, PARPi)-based therapies. METHODS: We used a large collection of OC patient-derived xenografts (PDXs) (n = 47) and evaluated their HR status based on BRCA1/2 mutations, BRCA1 promoter methylation and the HRDetect score. RAD51 foci were quantified in formalin-fixed, paraffin-embedded untreated tumour specimens by immunofluorescence and the messenger RNA expression of 21 DNA repair genes by real-time PCR. RESULTS: Tumour HR deficiency predicted both platinum and olaparib responses. The basal level of RAD51 foci evaluated in geminin-positive/replicating cells strongly inversely correlated with olaparib response (p = 0.011); in particular, the lower the foci score, the greater the sensitivity to olaparib, while low RAD51 foci score seems to associate with platinum activity. CONCLUSIONS: The basal RAD51 foci score is a candidate predictive biomarker of olaparib response in OC patients as it can be easily translatable in a clinical setting. Moreover, the findings corroborate the importance of OC-PDXs as a reliable tool to identify and validate biomarkers of response to therapy.

Single-arm, open label prospective trial to assess prediction of the role of ERCC1/XPF complex in the response of advanced NSCLC patients to platinum-based chemotherapy.

BACKGROUND: Platinum-based therapy, combined or not with immune checkpoint inhibitors, represents a front-line choice for patients with non-small-cell lung cancer (NSCLC). Despite the improved outcomes in the last years for this malignancy, only a sub-group of patients have long-term benefit. Excision repair cross-complementation group 1 (ERCC1) has been considered a potential biomarker to predict the outcome of platinum-based chemotherapy in NSCLC. However, the ERCC1 gene is transcribed in four splice variants where the isoform 202 was described as the only one active and able to complex Xeroderma pigmentosum group F-complementing protein (XPF). Here, we prospectively investigated if the active form of ERCC1, as assessed by the ERCC1/XPF complex (ERCC1/XPF), could predict the sensitivity to platinum compounds. PATIENTS AND METHODS: Prospectively enrolled, patients with advanced NSCLC treated with a first-line regimen containing platinum were centrally evaluated for ERCC1/XPF by a proximity ligation assay. Overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were analyzed. RESULTS: The absence of the ERCC1/XPF in the tumor suggested a trend of worst outcomes in terms of both OS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 0.67-2.94, P = 0.373] and PFS (HR 1.61, 95% CI 0.88-3.03, P = 0.123). ORR was marginally influenced in ERCC1/XPF-negative and -positive groups [odds ratio (stable disease + progressive disease versus complete response + partial response) 0.87, 95% CI 0.25-3.07, P = 0.832]. CONCLUSION: The lack of ERCC1/XPF complex in NSCLC tumor cells might delineate a group of patients with poor outcomes when treated with platinum compounds. ERCC1/XPF absence might well identify patients for whom a different therapeutic approach could be necessary.

Carbon nanotube films as a platform to transduce molecular recognition events in metalloporphyrins.

Porphyrins have been widely used for many years as functional materials for chemical sensors. Their outstanding chemical features are balanced by some restrictions in terms of transduction techniques. In particular, porphyrin layers are barely conductive, with the consequence that the fabrication of porphyrin based chemiresistors is not possible, except in few rare cases. On the other hand, carbon nanotubes (CNTs) have superior electric properties ranging from metallic to semiconductor in character. Although the conductivity of CNTs is very sensitive to adsorbed molecules, it should be considered that the adsorption onto carbon structures is also scarcely selective and cannot be modified unless other molecular recognition systems are coupled with the CNTs. Following this approach, in this paper we investigated the sensing properties of hybrid CNT-porphyrin films to explore the possibility of transducing the adsorption events occurring in a porphyrin layer into resistance changes of the CNT layers. The results obtained indicate that the presence of the porphyrin films increases the sensitivity of the electric resistance of the CNTs to the concentration of volatile compounds. This enhancement is probably due to the catalytic effect of the metalloporphyrin in conveying the charge transfer from the adsorbate molecule to the CNTs substrate. This property of metalloporphyrins may introduce a further differentiation between porphyrin based sensors that could be positively utilized in sensor array configurations.

Platinum-gold nanoclusters as catalyst for direct methanol fuel cells.

Nanosized platinum-gold alloys clusters have been deposited on gas diffusion electrode by sputter deposition. The deposits were characterized by FE-SEM, TEM and XPS in order to verify the formation of alloy nanoparticles and to study the influence of deposition technique on the nanomorphology. The deposition by sputtering process allowed a uniform distribution of metal particles on porous surface of carbon supports. Typical island growth mode was observed with the formation of a dispersed metal nanoclusters (mean size about 5 nm). Cyclic voltammetry was used to determine the electrochemical active surface and the electrocatalytic performance of the PtAu electrocatalysts for methanol oxidation reaction. The data were re-calculated in the form of mass specific activity (MSA). The sputter-catalyzed electrodes showed higher performance and stability compared to commercial catalysts.

Metal-modified and vertically aligned carbon nanotube sensors array for landfill gas monitoring applications.

Vertically aligned carbon nanotube (CNT) layers were synthesized on Fe-coated low-cost alumina substrates using radio-frequency plasma enhanced chemical vapour deposition (RF-PECVD) technology. A miniaturized CNT-based gas sensor array was developed for monitoring landfill gas (LFG) at a temperature of 150 degrees C. The sensor array was composed of 4 sensing elements with unmodified CNT, and CNT loaded with 5 nm nominally thick sputtered nanoclusters of platinum (Pt), ruthenium (Ru) and silver (Ag). Chemical analysis of multicomponent gas mixtures constituted of CO(2), CH(4), H(2), NH(3), CO and NO(2) has been performed by the array sensor responses and pattern recognition based on principal component analysis (PCA). The PCA results demonstrate that the metal-decorated and vertically aligned CNT sensor array is able to discriminate the NO(2) presence in the multicomponent mixture LFG. The NO(2) gas detection in the mixture LFG was proved to be very sensitive, e.g.: the CNT:Ru sensor shows a relative change in the resistance of 1.50% and 0.55% for NO(2) concentrations of 3.3 ppm and 330 ppb dispersed in the LFG, respectively, with a wide NO(2) gas concentration range measured from 0.33 to 3.3 ppm, at the sensor temperature of 150 degrees C. The morphology and structure of the CNT networks have been characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and Raman spectroscopy. A forest-like nanostructure of vertically aligned CNT bundles in the multi-walled form appeared with a height of about 10 microm and a single-tube diameter varying in the range of 5-35 nm. The intensity ratio of the Raman spectroscopy D-peak and G-peak indicates the presence of disorder and defects in the CNT networks. The size of the metal (Pt, Ru, Ag) nanoclusters decorating the CNT top surface varies in the range of 5-50 nm. Functional characterization based on electrical charge transfer sensing mechanisms in the metal-modified CNT-chemoresistor array demonstrates high sensitivity by providing minimal sub-ppm level detection, e.g., download up to 100 ppb NO(2), at the sensor temperature of 150 degrees C. The gas sensitivity of the CNT sensor array depends on operating temperature, showing a lower optimal temperature of maximum sensitivity for the metal-decorated CNT sensors compared to unmodified CNT sensors. Results indicate that the recovery mechanisms in the CNT chemiresistors can be altered by a rapid heating pulse from room temperature to about 110 degrees C. A comparison of the NO(2) gas sensitivity for the chemiresistors based on disorderly networked CNTs and vertically aligned CNTs is also reported. Cross-sensitivity towards relative humidity of the CNT sensors array is investigated. Finally, the sensing properties of the metal-decorated and vertically aligned CNT sensor arrays are promising to monitor gas events in the LFG for practical applications with low power consumption and moderate sensor temperature.

Deposition of SiO2 films with high laser damage thresholds by ion-assisted electron-beam evaporation.

SiO(2) thin films (approximately 100 nm thick) with transmittivity and a laser damage threshold nearly equal to those of bulk material are deposited on silica substrates by the technique of ion-assisted electron-beam evaporation. The influence of film packing density on the laser damage threshold is investigated by the technique of photoacoustic probe beam deflection. It is shown that films with lower packing density may have a higher laser damage threshold and as a consequence better heat dissipation.