Lung deposition of inhaled extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide in healthy volunteers and asthma: the STORM study

BACKGROUND: An extrafine formulation triple therapy combination of beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) has been developed for the maintenance treatment of asthma and chronic obstructive pulmonary disease. This study used gamma scintigraphy to evaluate the intrapulmonary and extrapulmonary in vivo deposition of BDP/FF/GB, and the intrapulmonary regional distribution of the deposited formulation. METHODS: This open-label uncontrolled nonrandomized single-dose study recruited 10 healthy volunteers and 9 patients with asthma. After a krypton-81m ((81m)Kr) ventilation scan was conducted, subjects inhaled study drug (four inhalations of BDP/FF/GB 100/6/12.5 μg radiolabeled using technetium-99 m [(99m)Tc]) through pressurized metered-dose inhaler, and a series of scintigraphic images were taken. The primary objective was to evaluate intrapulmonary drug deposition of BDP/FF/GB, determined as the percentage of nominal (i.e., metered) dose. Secondary endpoints included central/peripheral deposition ratio (C/P), and the standardized central/peripheral ratio (sC/P; (99m)Tc aerosol C/P/(81m)Kr gas C/P). RESULTS: All participants completed the study, with all scintigraphy procedures performed at one site. In patients with asthma, mean ± standard deviation intrapulmonary deposition was 25.50% ± 6.81%, not significantly different to that in healthy volunteers (22.74% ± 9.19%; p = 0.4715). Approximately half of the lung dose was deposited in the peripheral region of the lung (fraction deposited 0.52 ± 0.07 and 0.49 ± 0.06 in healthy volunteers and patients with asthma, respectively), resulting in C/P ratios of 0.94 ± 0.25 and 1.06 ± 0.25, respectively, with sC/P ratios of 1.80 ± 0.40 and 1.94 ± 0.38. Deposition patterns were similar in the two populations. BDP/FF/GB was well tolerated. CONCLUSIONS: This study confirmed that the extrafine particles delivered by BDP/FF/GB penetrate the peripheral areas of the lungs, with a similar proportion of particles deposited in the central and peripheral regions. Importantly, the deposition patterns were similar in healthy volunteers and patients with asthma, suggesting that disease characteristics are unlikely to impact drug deposition. Clinical Trial Registration number: NCT03795350

Screening tools combined with multivariate data analysis to predict or confirm virgin olive oil classification by the Panel test

A particular aspect of quality control of virgin olive oil (VOO) is the mandatory application, together with chemical and instrumental determinations, of a standardized and official method for sensory assessment. The latter, known as Panel test, is carried out by trained assessors and contributes to the classification of VOOs into three commercial categories (extra virgin, virgin, and lampante). One drawback of this method is related to the large number of samples to be analyzed, compared to the work capacity of a sensory panel, especially during the selection for purchase by companies that blend and market virgin oils and the quality control conducted by the authorities to verify the declared commercial category. For this reason, it is helpful to develop and validate robust and rapid screening methods, based on volatile fingerprints, to preclassify each sample into one of the three commercial categories. Considering the strict relation between volatile compounds and the main sensory attributes (fruity and defects), a gas-chromatographic volatile fingerprint can be the right choice. In this paper, the comparison of two emerging techniques, namely, headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) and flash-gas chromatography (FGC), applied on a sample set of 49 VOOs, using calibrations previously built with a larger number of samples, is presented. The number of correctly classified samples, with respect to the commercial category determined by the Panel test, was satisfactory and comparable (92% for HS-GC-IMS, and 94% for FGC), confirming the effectiveness of both methods and the robustness of the predictive models. Practical Applications: The demand for rapid screening tools to reduce the number of samples to be assessed by the Panel test has increased in recent years. The validation of robust models and their joint adoption by companies that market VOOs as well as official control bodies could reduce nonconformities and increase the batches of VOO being controlled, thus better protecting the consumer. Therefore, it is desirable to have different tools available to analyze volatile compounds, together with the associated calibration models, along with detailed instructions for their application, to have different alternatives that suit the equipment of individual laboratories

Preoperative Intensified Chemoradiation with Intensity-Modulated Radiotherapy and Simultaneous Integrated Boost Combined with Capecitabine in Locally Advanced Rectal Cancer: Long-Term Outcomes of a Real-Life Multicenter Study

Background: Despite the feasibility and promising activity data on intensity-modulated RT and simultaneous integrated boost (IMRT-SIB) dose escalation in preoperative chemoradiation (CRT) for locally advanced rectal cancer (LARC), few data are currently available on long-term outcomes. Patients and Methods: A cohort of 288 LARC patients with cT3-T4, cN0-2, cM0 treated with IMRT-SIB and capecitabine from March 2013 to December 2019, followed by a total mesorectal excision (TME) or an organ-preserving strategy, was collected from a prospective database of 10 Italian institutions. A dose of 45 Gy in 25 fractions was prescribed to the tumor and elective nodes, while the SIB dose was prescribed according to the clinical practice of each institution on the gross tumor volume (GTV). Concurrent capecitabine was administered at a dose of 825 mg/m2 twice daily, 7 days a week. The primary objective of the study was to evaluate long-term outcomes in terms of local control (LC), progression-free survival (PFS) and overall survival (OS). The secondary objective was to confirm the previously reported feasibility, safety and efficacy (pCR, TRG1-2 and downstaging rates) of the treatment in a larger patient population. Results: All patients received a dose of 45 Gy to the tumor and elective nodes, while the SIB dose ranged from 52.5 Gy to 57.5 Gy (median 55 Gy). Acute gastrointestinal and hematologic toxicity rates of grade 3–4 were 5.7% and 1.8%, respectively. At preoperative restaging, 36 patients (12.5%) with complete or major clinical responses (cCR or mCR) were offered an organ-preserving approach with local excision (29 patients) or a watch and wait strategy (7 patients). The complete pathologic response rate (pCR) in radically operated patients was 25.8%. In addition, 4 TME patients had pT0N1 and 19 LE patients had pT0Nx, corresponding to an overall pT0 rate of 31.3%. Of the 36 patients selected for organ preservation, 7 (19.5%) required the completion of TME due to unfavorable pathologic features after LE or tumor regrowth during W-W resulting in long-term rectal preservation in 29 of 288 (10.1%) of the total patient population. Major postoperative complications occurred in 14.2% of all operated patients. At a median follow-up of 50 months, the 5-year PFS and OS rates were 72.3% (95% CI: 66.3–77.4) and 85.9% (95% CI: 80.2–90.1), respectively. The 5-year local recurrence (LR) rate was 9.2% (95% CI: 6.0–13.2), while the distant metastasis (DM) rate was 21.3% (95% CI: 16.5–26.5). The DM rate was 24.5% in the high-risk subset compared to 16.2% in the low-intermediate risk group (p = 0.062) with similar LR rates (10% and 8%, respectively). On multivariable analysis, cT4 and TRG3–5 were significantly associated with worse PFS, OS and metastasis-free survival. Conclusions: Preoperative IMRT-SIB with the moderate dose intensification of 52.5–57.5 Gy (median 55 Gy) and the full dose of concurrent capecitabine confirmed to be feasible and effective in our real-life clinical practice. Organ preservation was shown to be feasible in carefully selected, responsive patients. The favorable long-term survival rates highlight the efficacy of this intensified treatment program. The incorporation of IMRT-SIB with a more effective systemic therapy component in high-risk patients could represent a new area of investigational interest

Validation of a Novel Three-Dimensional (3D Fusion) Gross Sampling Protocol for Clear Cell Renal Cell Carcinoma to Overcome Intratumoral Heterogeneity: The Meet-Uro 18 Study

76siWe aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3-G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity.noneBrunelli, Matteo; Martignoni, Guido; Malpeli, Giorgio; Volpe, Alessandro; Cima, Luca; Raspollini, Maria Rosaria; Barbareschi, Mattia; Tafuri, Alessandro; Masi, Giulia; Barzon, Luisa; Ammendola, Serena; Villanova, Manuela; Cerruto, Maria Angela; Milella, Michele; Buti, Sebastiano; Bersanelli, Melissa; Fornarini, Giuseppe; Rebuzzi, Sara Elena; Vellone, Valerio Gaetano; Gaggero, Gabriele; Procopio, Giuseppe; Verzoni, Elena; Bracarda, Sergio; Fanelli, Martina; Sabbatini, Roberto; Passalacqua, Rodolfo; Perrucci, Bruno; Giganti, Maria Olga; Donini, Maddalena; Panni, Stefano; Tucci, Marcello; Prati, Veronica; Ortega, Cinzia; Caliò, Anna; Eccher, Albino; Alongi, Filippo; Pappagallo, Giovanni; Iacovelli, Roberto; Mosca, Alessandra; Umari, Paolo; Montagnani, Ilaria; Gobbo, Stefano; Atzori, Francesco; Munari, Enrico; Maruzzo, Marco; Basso, Umberto; Pierconti, Francesco; Patriarca, Carlo; Colombo, Piergiuseppe; Lapini, Alberto; Conti, Giario; Salvioni, Roberto; Bollito, Enrico; Cossarizza, Andrea; Massari, Francesco; Rizzo, Mimma; Franco, Renato; Zito-Marino, Federica; Aberasturi Plata, Yoseba; Galuppini, Francesca; Sbaraglia, Marta; Fassan, Matteo; Dei Tos, Angelo Paolo; Colecchia, Maurizio; Moch, Holger; Scaltriti, Maurizio; Porta, Camillo; Delahunt, Brett; Giannarini, Gianluca; Bortolus, Roberto; Rescigno, Pasquale; Banna, Giuseppe Luigi; Signori, Alessio; Obispo, Miguel Angel Llaja; Perris, Roberto; Antonelli, AlessandroBrunelli, Matteo; Martignoni, Guido; Malpeli, Giorgio; Volpe, Alessandro; Cima, Luca; Raspollini, Maria Rosaria; Barbareschi, Mattia; Tafuri, Alessandro; Masi, Giulia; Barzon, Luisa; Ammendola, Serena; Villanova, Manuela; Cerruto, Maria Angela; Milella, Michele; Buti, Sebastiano; Bersanelli, Melissa; Fornarini, Giuseppe; Rebuzzi, Sara Elena; Vellone, Valerio Gaetano; Gaggero, Gabriele; Procopio, Giuseppe; Verzoni, Elena; Bracarda, Sergio; Fanelli, Martina; Sabbatini, Roberto; Passalacqua, Rodolfo; Perrucci, Bruno; Giganti, Maria Olga; Donini, Maddalena; Panni, Stefano; Tucci, Marcello; Prati, Veronica; Ortega, Cinzia; Caliò, Anna; Eccher, Albino; Alongi, Filippo; Pappagallo, Giovanni; Iacovelli, Roberto; Mosca, Alessandra; Umari, Paolo; Montagnani, Ilaria; Gobbo, Stefano; Atzori, Francesco; Munari, Enrico; Maruzzo, Marco; Basso, Umberto; Pierconti, Francesco; Patriarca, Carlo; Colombo, Piergiuseppe; Lapini, Alberto; Conti, Giario; Salvioni, Roberto; Bollito, Enrico; Cossarizza, Andrea; Massari, Francesco; Rizzo, Mimma; Franco, Renato; Zito-Marino, Federica; Aberasturi Plata, Yoseba; Galuppini, Francesca; Sbaraglia, Marta; Fassan, Matteo; Dei Tos, Angelo Paolo; Colecchia, Maurizio; Moch, Holger; Scaltriti, Maurizio; Porta, Camillo; Delahunt, Brett; Giannarini, Gianluca; Bortolus, Roberto; Rescigno, Pasquale; Banna, Giuseppe Luigi; Signori, Alessio; Obispo, Miguel Angel Llaja; Perris, Roberto; Antonelli, Alessandr