Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes ...immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.
KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.
On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.
This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
•Coexisting alterations in KEAP1, PBRM1, SMARCA4 and STK11 define a subset of lung adenocarcinoma unresponsive to immunotherapy.•Tumors harboring co-mutations had inferior survival outcomes compared with both single-mutant and wild-type tumors.•Tumors with co-occurring alterations are misclassified as immunoresponsive by tumor mutational burden.•An immunologically cold phenotype characterizes lung adenocarcinoma with coexisting mutations.
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.
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.
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.
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.
•TC is a rare and aggressive tumor with poor responsiveness to standard chemotherapy.•Ramucirumab, carboplatin and paclitaxel combination shows ORR of 80%, disease control rate of 100%, and median PFS of 18.1 months in untreated TC.•The combination toxicity profile is manageable and consistent with the known safety of each agent.•Ramucirumab, carboplatin and paclitaxel combination shows important activity as first-line treatment in untreated TC.
In this work we present the results of the experimental characterization of Silicon Drift Detectors (SDDs) readout by CUBE preamplifiers for X-ray spectroscopy measurements. One specific goal of the ...work was to characterize SDDs of different sizes cooled at low temperature in view of their use in the upgrade of the SIDDHARTA nuclear physics experiment. Beside the target application, the results of this work are also of interest for a more extended use of the SDDs in other X-ray spectroscopy applications. The SDDs have been designed as single units with square shape of different areas, 64 mm 2 (8 mm × 8 mm) and 144 mm 2 (12 mm × 12 mm), and also as monolithic array of 3×3 elements of the 8 mm × 8 mm unit (total area 26 mm × 26 mm). The read-out of the SDDs is based on a CMOS (Complementary Metal Oxide Semiconductor) preamplifier (CUBE) both for the single unit and for the 3×3 array. For the readout of the array, an Application Specific Integrated Circuit (ASIC) has been used. An energy resolution better than 124 eV at the Mn-Kα line has been measured with a 64 mm 2 SDD cooled at the temperature of 50 K. The energy resolution remains good (<;130 eV) also at short shaping time (250 ns) thanks to the noise feature of the CUBE preamplifier. Results of measurements on SDDs of different format and also on arrays of SDDs are presented in this work.
Quantitative image analysis models are used for medical imaging tasks such as registration, classification, object detection, and segmentation. For these models to be capable of making accurate ...predictions, they need valid and precise information. We propose PixelMiner, a convolution-based deep-learning model for interpolating computed tomography (CT) imaging slices.
PixelMiner was designed to produce texture-accurate slice interpolations by trading off pixel accuracy for texture accuracy. PixelMiner was trained on a dataset of 7829 CT scans and validated using an external dataset. We demonstrated the model's effectiveness by using the structural similarity index (SSIM), peak signal to noise ratio (PSNR), and the root mean squared error (RMSE) of extracted texture features. Additionally, we developed and used a new metric, the mean squared mapped feature error (MSMFE). The performance of PixelMiner was compared to four other interpolation methods: (tri-)linear, (tri-)cubic, windowed sinc (WS), and nearest neighbor (NN).
PixelMiner produced texture with a significantly lowest average texture error compared to all other methods with a normalized root mean squared error (NRMSE) of 0.11 (p < .01), and the significantly highest reproducibility with a concordance correlation coefficient (CCC) ≥ 0.85 (p < .01).
PixelMiner was not only shown to better preserve features but was also validated using an ablation study by removing auto-regression from the model and was shown to improve segmentations on interpolated slices.
•A novel architecture for performing interpolation of slices in CT.•A generative deep learning approach that uses an explicit density model.•Towards texture accurate slice interpolation.•Slice interpolation without common artifacts caused by traditional interpolation.•Towards improved slice interpolation for the purpose of improving downstream tasks suck as detection, classification, and segmentation.
Abstract Aim We have explored whether the insulin secretory defects induced by glucotoxicity in human pancreatic islets could be prevented by metformin and investigated some of the possible ...mechanisms involved. Methods Human pancreatic islets and INS-1E cells were cultured for 24 h with or without high glucose (16.7 mM) concentration in the presence or absence of therapeutical concentration of metformin and then glucose-stimulated insulin release, adenine nucleotide levels and mitochondrial complex I and II activities were measured. Islet ultrastructure was analyzed by electron microscopy. Results Compared to control islets, human islets cultured with high glucose showed a reduced glucose-stimulated insulin secretion that was associated with lower ATP levels and a lower ATP/ADP ratio. These functional and biochemical defects were significantly prevented by the presence of metformin in the culture medium, that was also able to significantly inhibit the activity of mitochondrial complex I especially in beta cells exposed to high glucose. Ultrastructural observations showed that mitochondrial volume density was significantly increased in high glucose cultured islets. The critical involvement of mitochondria was further supported by the observation of remarkably swollen organelles with dispersed matrix and fragmented cristae. Metformin was able to efficiently prevent the appearance of all these ultrastructural alterations in human islets exposed to high glucose. Conclusions Our results show that the functional, biochemical and ultrastructural abnormalities observed in human islet cells exposed to glucotoxic condition can be significantly prevented by metformin, further highlighting a direct beneficial effect of this drug on the insulin secreting human pancreatic beta cells.
Within the vast panorama of multimodal systems for clinical diagnosis, PET/MRI has been receiving significant attention. In parallel, new technological solutions have been paving the way to ...simultaneous SPECT/MRI systems, whose development has been so far delayed due to the challenging compatibility between MRI, gamma-ray detectors, and collimators. This paper presents an silicon photomultiplier (SiPM)-based Anger camera designed for preclinical and clinical SPECT static inserts for standard MR scanners. The gamma-ray detector is based on a continuous CsI(Tl) scintillator readout by arrays of SiPMs and custom ASICs. The design has been adapted to fit with the limited space conditions (23 mm thickness), but also considering mutual compatibility issues. Despite these constraints and thanks to the adoption of an iterative statistical event estimation method simply requiring a flood image, the detector maintains state-of-the-art performance in terms of intrinsic spatial resolution (1.0 mm FWHM within the usable field of view) and an energy resolution below 14% FWHM at 140 keV. The experimental studies here performed show that the camera, designed to operate at 0 °C to reduce the dark current of SiPMs, can operate up to 10 °C without significant worsening of imaging performance.
A new multi-modality imaging tool is under development in the framework of the INSERT (INtegrated SPECT/MRI for Enhanced Stratification in Radio-chemo Therapy) project, supported by the European ...Community. The final goal is to develop a custom SPECT apparatus, that can be used as an insert for commercially available MRI systems such as 3T MRI with 59cm bore diameter. INSERT is expected to offer more effective and earlier diagnosis with potentially better outcome in survival for the treatment of brain tumors, primarily glioma. Two SPECT prototypes will be developed, one dedicated to preclinical imaging, the second one dedicated to clinical imaging.
The basic building block of the SPECT detector ring is a small 5cm×5cm gamma camera, based on the well-established Anger architecture with a continuous scintillator readout by an array of silicon photodetectors. Silicon Drift Detectors (SDDs) and Silicon PhotoMultipliers (SiPM) are being considered as possible scintillator readout, considering that the detector choice plays a predominant role for the final performance of the system, such as energy and spatial resolution, as well as the useful field of view of the camera. Both solutions are therefore under study to evaluate their performances in terms of field of view (FOV), spatial and energy resolution. Preliminary simulations for both the preclinical and clinical systems have been carried out to evaluate resolution and sensitivity.
•We introduce INSERT, a new multi-modality SPECT/MRI instrument.•We propose two possible photodetectors (SDD, SiPM) for the scintillators readout.•We show possible results for INSERT, based on simulations.
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