Immune checkpoint inhibitors in pmmr metastatic colorectal cancer: A tough challenge

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of “immune-competent” TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies

Clinical, pathological, and prognostic features of rare BRAF mutations in metastatic colorectal cancer: a bi-institutional retrospective analysis (REBUS study)

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molecular characterization of immune microenvironment in colorectal cancers with microsatellite instability by digital rna counting

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Clinical and molecular determinants of extrahepatic disease progression (ePD) in initially unresectable, liver-limited metastatic colorectal cancer (mCRC)

e15511Background: In the last years, availability of active upfront systemic regimens, development of surgical techniques and diffusion of locoregional treatments (LrTx) increased the therapeutic o..

Phase II study of capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer: the PANDORA trial

Background: This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer.Patients and methods: The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (a = 0.05, power = 0.80). The proposed treatment could be considered promising if >= 13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365).Results: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation).Conclusion: This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation

La prevenzione strumentale del respiro sibilante. La funzionalità respiratoria

valutazione del ruolo della funzionalità respiratoria nell'asma bronchial

Forced oscillometry is applicable to epidemiological settings to detect asthmatic children.

Forced oscillometry (FOT) has been reported as a simple method to detect respiratory resistance (Rrs) changes. The aim of this study was to evaluate FOT capacity to detect children with clinical characteristics of asthma in a school setting. One thousand thirty children, 6-7 years old, were investigated by questionnaire. Children with wheezing symptoms in the last 12 months but without previous diagnosis of asthma were selected and underwent evaluations. FOT measurements were performed pre- and post-salbutamol administration, with a level of significant reduction of Rrs of >29\%. Patients were further investigated for atopy by skin-prick tests (SPTs) and for bronchial hyperreactivity (BHR) by exercise free-running test. Of 1030 children participating in the study, 120 were selected by questionnaire responses for respiratory symptoms. Twenty-two children had a significant reduction of Rrs of 6 Hz (p < 0.001; group 1); 98 children presented no variation of Rrs to bronchodilator (group 2). Prick test positivity and significant bronchoconstriction after exercise tests were significantly more frequent in group 1 than in group 2 (77\% and 64\% versus 8\% and 12\%, respectively; p < 0.001). In a school setting FOT changes after bronchodilator are able to detect airway obstruction in children with wheezing symptoms. Children with significant FOT variability present more significantly atopy and BHR and therefore more probable asthma

Forced oscillometry is applicable to epidemiological settings to detect asthmatic children.

Forced oscillometry (FOT) has been reported as a simple method to detect respiratory resistance (Rrs) changes. The aim of this study was to evaluate FOT capacity to detect children with clinical characteristics of asthma in a school setting. One thousand thirty children, 6-7 years old, were investigated by questionnaire. Children with wheezing symptoms in the last 12 months but without previous diagnosis of asthma were selected and underwent evaluations. FOT measurements were performed pre- and post-salbutamol administration, with a level of significant reduction of Rrs of >29%. Patients were further investigated for atopy by skin-prick tests (SPTs) and for bronchial hyperreactivity (BHR) by exercise free-running test. Of 1030 children participating in the study, 120 were selected by questionnaire responses for respiratory symptoms. Twenty-two children had a significant reduction of Rrs of 6 Hz (p < 0.001; group 1); 98 children presented no variation of Rrs to bronchodilator (group 2). Prick test positivity and significant bronchoconstriction after exercise tests were significantly more frequent in group 1 than in group 2 (77% and 64% versus 8% and 12%, respectively; p < 0.001). In a school setting FOT changes after bronchodilator are able to detect airway obstruction in children with wheezing symptoms. Children with significant FOT variability present more significantly atopy and BHR and therefore more probable asthma

Assessment of variable obstruction by forced expiratory volume in 1 second, forced oscillometry, and interrupter technique.

The aim of this study was to evaluate the presence and the degree of reversible airflow obstruction as detected by forced expiratory volume in 1 second (FEV1), forced oscillometry (FOT), and interrupter technique (resistance measured by the interrupter technique [Rint]) in mild asthmatic children compared with controls. FOT, Rint, and FEV1 were evaluated before and after albuterol (200 microg) administered by metered-dose inhaler and spacer in 28 asthmatic children (mean age +/-SD, 9.1 +/- 1.9 years) and in 20 healthy children (mean age +/-SD, 8.5 +/- 2.1 years). No correlation was found between FEV1, FOT, and Rint values either before or after albuterol. FOT and Rint values were highly correlated pre- and postbronchodilatation. An improvement in FEV1 > or =12% after albuterol was observed in 11 (39%) asthmatic subjects. As suggested using the cutoff value at R6 > or =29%, significant bronchodilatation was observed in 20 (71%) children with FOT and using a reduction > or = 0.20 kPa or 2 cm of H2O, 22 (78%) subjects showed significant bronchodilatation with Rint. No significant changes were observed after albuterol in controls. FOT and Rint techniques showed a greater sensitivity in detecting reversibility of bronchoconstriction in mild asthmatic patients. Prospective studies are needed to clarify the possible advantages of these findings in mild-moderate asthmatic children