Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

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.

Towards texture accurate slice interpolation of medical images using PixelMiner.

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.

PEOPLE (NCT03447678), a first-line phase II pembrolizumab trial, in negative and low PD-L1 advanced NSCLC: clinical outcomes and association with circulating immune biomarkers.

BACKGROUND: The PEOPLE trial aimed to identify new immune biomarkers in negative and low programmed death-ligand 1 (PD-L1) (0%-49%) advanced non-small-cell lung cancer (aNSCLC) patients treated with first-line pembrolizumab. Here we report the main outcomes and the circulating immune biomarkers analysis. PATIENTS AND METHODS: The primary endpoint of this phase II trial was the identification of immune biomarkers associated with progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety were secondary endpoints. Absolute cell counts for 36 subsets belonging to innate and adaptive immunity were determined by multiparametric flow cytometry in peripheral blood at baseline and at first radiologic evaluation. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyze immune variables and their correlation with clinical endpoints. RESULTS: From May 2018 to October 2020, 65 patients were enrolled. After a median follow-up of 26.4 months, the median PFS was 2.9 months [95% confidence interval (CI) 1.8-5.6 months] and median OS was 12.1 months (95% CI 8.7-17.1 months). The ORR was 21.5%, DCR was 47.7% and median DoR was 14.5 months (95% CI 6.4-24.9 months). Drug-related grade 3-4 adverse events were 9.2%. Higher T cell and natural killer (NK) cell count at baseline and at the first radiologic evaluation were associated with improved PFS, DCR and OS. On the contrary, higher myeloid cell count at baseline or at the first radiologic evaluation was significantly associated with worse OS and DCR. CONCLUSIONS: Circulating immune biomarkers can contribute to predict outcomes in negative and low PD-L1 aNSCLC patients treated with first-line single-agent pembrolizumab.

KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Prevention by metformin of alterations induced by chronic exposure to high glucose in human islet beta cells is associated with preserved ATP/ADP ratio.

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 24h with or without high glucose (16.7mM) 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.

[Ocra Method: development of a new procedure for analysis of multiple tasks subject to infrequent rotation]. / Metodo Ocra: messa a punto di una nuova procedura per l'analisi di compiti multipli con rotazioni infrequenti.

In the Ocra methods (Ocra index and Ocra Checklist), when computing the final indices (Ocra index or checklist score), in the case of more than one repetitive task a "traditional" procedure was already proposed, the results of which could be defined as "time-weighted average". This approach appears to be appropriate when considering rotations among tasks that are performed very frequently, for instance almost once every hour (or for shorter periods). However, when rotation among repetitive tasks is less frequent (i.e. once every 1 1/2 or more hours), the "time-weighted average" approach could result in an underestimation of the exposure level (as it practically flattens peaks of high exposures). For those scenarios an alternative approach based on the "most stressful task as minimum" might be more realistic. This latter approach has already been included in the NIOSH approach for multiple sequential lifting tasks and, given the recent availability in the Ocra method of more detailed duration multipliers (practically one different Du(M) for each different step of one hour of duration of the repetitive task), it is now possible to define a particular procedure to compute the complex Ocra Multitask Index (cOCRA) and the complex Checklist Score (cCHESCO) for the analysis of two or more repetitive tasks when rotations are infrequent (rotations every 1 1/2 hours or more). The result of this approach will be at least equal to the index of the most stressful task considered for its individual daily duration and at the most equal to the index of the most stressful task when it is (only theoretically) considered as lasting for the overall daily duration of all examined repetitive tasks. The procedure is based on the following formula: Complex Ocra Multitask Index = Ocra(1(Dum1) + (Delta ocra1xK) where 1,2,3,...,N = repetitive tasks ordered by ocra index values (1 = highest; N = lowest) computed considering respective real duration multipliers (Dum(i)). ocra1 = ocra index of task, considering Dum(1). Dum(i) = duration multiplier for task(i) real duration. Dum(tot) = duration multiplier for total duration of all repetitive tasks. delta ocra1 = highest ocra index among N tasks considering Dum(tot) (ocra(i max)) - ocra index of task1 considering Dum1. K = (ocra(1 max)*FT1) + (ocra(2 max)*FT2) + ... + (ocra (N)*FT(N)) over (ocra(i max)). ocral,Nm(1,N MAX) = index of tasks 1 to Ncons idering Dum,, (tot)7=Fr(i) c tion of Time (values from 0 to 1) of task; wi(i)h respect to the total repetitive time.

[Fraley's syndrome. A nephron-sparing laparoscopic surgical procedure. Case report].

16-year-old girl with Fraley's syndrome, which caused right flank pain and urinary infection. The radiologic exam showed a distended calyx and an infundibular obstruction caused by compression of normal renal vessels. Retroperitoneal laparoscopic calycectomy and closure of infundibulum with calyx exclusion were performed.

[Multiple metachronous metastasis of adenocarcinoma of the kidneys in crossed ectopy with fusion]. / Metastatizzazione multipla metacrona da adenocarcinoma di rene in ectopia crociata con fusione.

The A.A. report the clinic history of patient that showed up their examination with multiple metachronous arose fifteen months ago after a widening nephrectomy, by adenocarcinoma of ectopic-crossed kidney with fusion. They resume the pathogenetic and therapeutics hypothesis; in agreement on the prognostic difficulty and on the variability line of conduct by the kidney adenocarcinoma.

Concentrations of 24,25-dihydroxyvitamin D and 25-hydroxyvitamin D in paired maternal-cord sera.

Mean serum concentrations of 24,25-dihydroxyvitamin D (24,25(OH)2D) and 25-hydroxyvitamin D (25OHD), measured by competitive radioassays, were significantly higher in maternal serum than in cord serum of term infants in both black and white subjects. There were positive correlations between maternal and cord levels of both metabolites of vitamin D. Serum concentrations of 24,25(OH)2D and 25OHD were significantly lower in white pregnant subjects than in nonpregnant women. In utero levels of 24,25(OH)2D and 25OHD probably reflect maternal stores of these metabolites.

Prostaglandins and gastrointestinal function.

Much work has been done and much remains to be done in defining the role of the prostaglandins in the physiology and pathophysiology of the gastrointestinal tract. The following statements summarize the current knowledge of the prostaglandins in human gastrointestinal function: 1. Prostaglandins of the E type have been isolated from human gastrointestinal tissue. They are naturally occurring 20 carbon hydroxy fatty acids synthesized and degraded in the same intestinal tissue by a 15-prostaglandin dehydrogenase. 2. Prostaglandins E2 and PGF2alpha have opposing, dose-related effects on the lower esophageal sphincter and lower two thirds of the esophagus. Sphincter pressure is decreased and esophageal contractions are inhibited by PGE2, whereas sphincter pressure is increased and esophageal contractions are induced by PGF2alpha. 3. Basal and stimulated gastric acid secretion is inhibited by PGE and its methyl analogues, but not by PGF, in a dose-related, nonselective manner. Oral administration of PGE methyl analogues may be an effective mode of therapy in peptic ulcer disease. 4. The prostaglandins reduce absorption and induce secretion of electrolytes and water in the jejunum and ileum but not in the colon. This secretory effect has been implicated in certain pathologic conditions. 5. The prostaglandins appear to be vasodilators of the hepatic circulation. Prostaglandin E contracts the gall bladder, relaxes the sphincter of Oddi and inhibits isosmotic fluid transport. 6. Pancreatic secretion and insulin release are inhibited by the prostaglandins in vivo and secretion is stimulated in vitro. The actual role of the prostaglandins in insulin release is not known.