Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters

IntroductionImmunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines.MethodsHere we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation.ResultsWe show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus.DiscussionThese data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20

Il glioblastoma multiforme dalla diagnostica al trattamento; ruolo della metilazione del promotore di MGMT e dei polimorfismi di Akt nella risposta alla terapia.

Background Il glioblastoma multiforme è il tumore cerebrale più aggressivo, costituisce, infatti, il IV grado della classificazione dei gliomi, ed è anche il tumore cerebrale più frequente. Ad oggi il trattamento standard comprende: l’exeresi chirurgica più estesa possibile, la radiochemioterapia postoperatoria con un massimo di 60 Gy e temozolomide (TMZ) e 6 cicli di chemioterapia adiuvante con TMZ. Nonostante questo approccio combinato, l’outcome dei pazienti e la loro sopravvivenza media (15 mesi) risultano insoddisfacenti. Per questo si continuano a studiare le diverse alternative terapeutiche e il ruolo della genetica e della epigenetica nella risposta alla terapia. Molteplici studi clinici hanno correlato il livello di espressione dell’enzima O6-metilguanina-DNA metiltransferasi (MGMT) e la metilazione del promotore del suo gene con la risposta alla terapia (in particolare agli agenti alchilanti, quale la temozolomide) e la sopravivenza. Altri studi hanno associato il polimorfismo del gene Akt con risposte differenti alla radioterapia e alla chemioterapia. L’enzima MGMT è deputato alla riparazione del DNA, tramite la rimozione di gruppi alchilici dalla posizione 6 della guanina; il gene Akt codifica per una chinasi coinvolta in numerosi processi cellulari, come la regolazione dell’apoptosi e la crescita cellulare. Obiettivo Lo scopo di questo lavoro è quello di valutare il ruolo della metilazione del promotore di MGMT e dei polimorfismi di Akt nella risposta alla terapia nei pazienti con glioblastoma. Questo lavoro si prefigge, inoltre, di effettuare una stratificazione dei pazienti con promotore di MGMT metilato in base al PMR (percentuale di metilazione del promotore), per evidenziare la correlazione tra valore di PMR e sopravvivenza. Metodi Per questo studio è stata impiegata una coorte di 36 pazienti affetta da neoplasia cerebrale maligna gliale, sottoposta prima a chirurgia ed in seguito a radioterapia e chemioterapia con temozolomide, tra il Novembre 2000 e il Settembre 2010. Per indagare la correlazione tra la metilazione del promotore di MGMT e i polimorfismi di Akt nella risposta alla terapia, dopo aver estratto il DNA dal tessuto, abbiamo eseguito la Real Time Polymerase Chain Reaction (PCR) con specifici primers e sonde per l’analisi della metilazione del promotore di MGMT e del gene di riferimento e la Real Time Polymerase Chain Reaction con specifiche sonde per la discriminazione allelica del gene Akt. Istologia, sesso, estensione della rimozione chirurgica, ripetitività della rimozione chirurgica, metilazione del promotore di MGMT e polimorfismo di Akt sono stati analizzati come fattori prognostici. Risultati E’ stata rilevata una differenza di sopravvivenza tra i pazienti con PMR >30% e quelli con PMR ≤30% (p=0,01); in particolare, la correlazione tra valori crescenti di PMR e sopravvivenza risultava ancora più evidente distinguendo i pazienti con PMR ≤30%, quelli con 30%77% (p=0,02). Per quanto riguarda lo SNP di Akt rs2498804, da noi studiato, è stato osservato un DFS di 36 mesi nei pazienti con genotipo omozigote wild-type, di 16 mesi nei pazienti eterozigoti e di 9 mesi nei pazienti omozigoti per la variante contenente la citosina. Prendendo in considerazione contemporaneamente i valori di PMR e il polimorfismo di Akt, il DFS mediana dei pazienti con genotipo “favorevole” (omozigoti per lo SNP rs2498804 di Akt wild type e con PMR > 77%) era di 36 mesi e di 7 mesi nei pazienti con genotipo “sfavorevole” (omozigoti per lo SNP rs2498804 di Akt mutato e con PMR < 77%). La sopravvivenza mediana è risultata essere di 16 mesi nei pazienti con GBM I e di 67 mesi nei pazienti con GBM II. Il DFS mediano è risultato essere di 7 mesi nei pazienti con GBM I e di 20 mesi nei pazienti con GBM II. Conclusioni Il presente lavoro conferma il ruolo della metilazione del promotore di MGMT come marker predittivo di risposta al trattamento con agenti alchilanti e di più lunga sopravvivenza. Dalla stratificazione dei pazienti con promotore metilato effettuata sulla base del PMR è stato individuato che valori di PMR superiori al 30% sono sufficienti per garantire un aumento di overall survival (OS) e che valori di PMR superiori al 77% sono correlati ad un OS mediano ancora maggiore. Per quanto riguarda lo SNP di Akt rs2498804, da noi studiato, è stato osservato un DFS maggiore nei pazienti con genotipo omozigote wild-type, rispetto ai pazienti eterozigoti ed ai pazienti omozigoti per la variante contenente la citosina. Confrontando - quindi - il DFS mediano dei pazienti con genotipo “favorevole” (omozigoti per lo SNP rs2498804 di Akt wild type e con PMR > 77%) e quello dei pazienti con genotipo “sfavorevole” (omozigoti per lo SNP rs2498804 di Akt mutato e con PMR 77%) che nei pazienti con genotipo “sfavorevole” (omozigoti per lo SNP rs2498804 di Akt mutato e con PMR < 77%)

Novità in tema di discinesia ciliare primaria

Numerosi sono ancora i problemi aperti che ritardano o rendono difficile l’inquadramento diagnostico della discinesia ciliare primaria e poco si conosce sulle reali necessità dei soggetti affetti in termini di monitoraggio e di appropriatezza delle cure.Vengono, pertanto, riferiti i risultati delle ricerche più recenti riguardanti rispettivamente gli elementi che possono farne sospettare la diagnosi (in particolare la presenza di una mancata o ridotta pneumatizzazione dei seni paranasali), il significato della misurazione dell’ossido nitrico nasale (utilizzata come test di screening), i progressi nelle tecniche diagnostiche (in particolare la possibilità di eseguire colture dell’epitelio respiratorio ciliato anche utilizzando campioni prelevati mediante brushing nasale), le nuove conoscenze sull’evoluzione della funzione respiratoria, sulle necessità del suo monitoraggio ed infine le prospettive di sviluppo di terapie geniche mirate al ripristino della funzione ciliar

Dry Pharmaceutical Composition for Inhalation

Vaccine administration is usually performed via intramuscular or subcutaneous injection. However, there are few challenges associated with this mode of delivery, such as a poor physico-chemical stability of the vaccine solution, which requires transportation and storage under temperature controlled conditions. This significantly increases vaccine (and health) cost as it dramatically limits vaccine availability, especially in developing countries. A dry- powder vaccine formulation is thermostable and easy to transport. Vaccine administration by injection can be painful, it may generate adverse psychosomatic effects (so called ‘lipothymic reaction’) and it must be performed by trained healthcare personnel. A dry-powder vaccine, instead, can be filled into monodose capsules and administered via ready-to-use inhalers. The technology uses a new formulation for the manufacturing of a respirable, dry-powder vaccine (i.e., containing both a recombinant antigen and an immune-stimulant) suitable for pulmonary administration. In addition to a greatly facilitated (i.e., unassisted) administration, this mode of delivery enhances immunogenicity and ultimately the efficacy of vaccination

Reduced Time CT Perfusion Acquisitions Are Sufficient to Measure the Permeability Surface Area Product with a Deconvolution Method

Objective. To reduce the radiation dose, reduced time CT perfusion (CTp) acquisitions are tested to measure permeability surface (PS) with a deconvolution method. Methods and Materials. PS was calculated with repeated measurements (n=305) while truncating the time density curve (TDC) at different time values in 14 CTp studies using CTp 4D software (GE Healthcare, Milwaukee, WI, US). The median acquisition time of CTp studies was 59.35 sec (range 49–92 seconds). To verify the accuracy of the deconvolution algorithm, a variation of the truncated PS within the error measurements was searched, that is, within 3 standard deviations from the mean nominal error provided by the software. The test was also performed for all the remaining CTp parameters measured. Results. PS maximum variability happened within 25 seconds. The PS became constant after 40 seconds for the majority of the active tumors (10/11), while for necrotic tissues it was consistent within 1% after 50 seconds. A consistent result lasted for all the observed CTp parameters, as expected from their analytical dependance. Conclusion. 40-second acquisition time could be an optimal compromise to obtain an accurate measurement of the PS and a reasonable dose exposure with a deconvolution method

A solitary uterine relapse in T-cell Acute Lymphoblastic Leukaemia: CT features and pathologic correlation

T-cell Acute Lymphoblastic Leukemia (T-cell ALL) is a rare haematological neoplasia, that affects children and less commonly adults. Female genital tract and particularly uterus involvement in acute ALL is rare. This report presents the CT features of a 64-year-old woman with uterine relapse of T-cell ALL, occurring 11 months after the diagnosis, as a second, unique relapse of disease. The patient was asymptomatic when a CT examination showed a homogenous thickness of the uterine wall in comparison with the previous CT examination. Histology from biopsy specimens, obtained through hysteroscopy, confirmed T-cell ALL localisation (TdT+, CD10+, CD3c+ and CD2+). The uterus could be a site of relapse in patients suffering from ALL. Even though an MRI examination could better demonstrate the disease in cases of suspected female genital tract involvement by ALL, the comparison of differences between a present and a previous CT examination is sufficient to suspect the diagnosis

Diagnosis of idiopathic pulmonary fibrosis by virtual means using “IPFdatabase”- a new software

Background: The diagnostic algorithm for idiopathic pulmonary fibrosis (IPF) guidelines has some shortcomings. The aim of the present study was to develop a novel software, “IPFdatabase” that could readily apply the diagnostic criteria per IPF guidelines and make a ‘virtual’ diagnosis of IPF. Methods: Software was developed as a step-by-step compilation of necessary information according to guidelines to enable a diagnosis of IPF. Software accuracy was validated primarily by comparing software diagnoses to those previously made at a Center for Interstitial Lung Diseases. Results: Clinical validation on 98 patients (68 male, age 61.0 ± 8.5 years), revealed high software accuracy for IPF diagnosis when compared to historical diagnoses (sensitivity 95.5%, specificity 96.2%; positive predictive value 95.5%, negative predictive value 96.2%). A general radiologist and a general pathologist reviewed relevant data with and without the new software: interobserver agreement increased when they used the IPFdatabase (kappa 0.18 to 0.64 for radiology, 0.13 to 0.59 for pathology). Conclusion: IPFdatabase is a useful diagnostic tool for typical cases of IPF, and potentially restricts the need for MDDs to atypical and complex cases. We propose this web-designed software for instant accurate diagnosis of IPF by virtual means and for educational purposes; the software is readily accessed with mobile apps, allows incorporation of updated version of guidelines, can be utilized for gathering data useful for future studies and give physicians rapid feedback in daily practice

Listening Understanding and acting (lung): focus on communicational issue in thoracic oncology

Background: In the field of oncological assistance, nowadays we have to deal with a complex scenario where patients got used to obtain a huge amount of information through internet or social media and to apply them in performing their health-related decisions. This landscape requires that clinicians become able to handle therapeutical approaches and adequate skills in communication tools to satisfy the current needs. Our project aimed to build a communication model based on clinical oncologists’ real experiences in order to find a simple way to share with patients all the innovative therapeutical opportunities today available in lung cancer. The final goal is to design a flexible and personalized model adaptable to clinician’s personal characteristics and to the specific patient he is facing. We applied both traditional educational tools and innovative techniques in order to make the results effective and applicable to support peer learning. Methods: The first step consisted in a Board synthesized the definition of the diagnostic process, the identification of treatment strategies and any potential communication barrier clinicians may face dealing with patients. The second step consisted in teamwork including a theoretical part and a training part. In the third step we produce five training videos and video interviews regarding communication praxis and a “Small communication manual”. The last step consisted in the publication of the produced material on website and its diffusion through the social media. Results: In medicine, the universal application of a single model of communication does not represent the optimal solution. By contrary, the availability of simple and practical suggestions to improve the communicative style could allow clinicians to abandon stereotyped formulas identically repurposed to all patients. The “from bottom to top” training, starting from real-life to take advantage of the clinician’s experience, give the clinicians the possibility to meditate about their own communicative style and to train in the context of a protected environment. Applying these rules, we design an effective communication model, based on healthcare humanization, which could represent a fundamental support for the patient in order to be gently driven by the clinician to the most appropriate therapeutical choice, balancing efficacy and quality of life. The relational training may improve the quality of clinician-patient communication and could be widespread to other clinicians through the media. Conclusions: Considering the innovative therapeutical options available, particularly for lung cancer patients, and the increasing access of health-related information through internet or social media the clinician-patient communication has become crucial to support the achievement of the most appropriate therapeutical choice for the patient, facing the intricate illness experience. Building a shareable and easy-toapply communication model represents a challenge aimed to help clinicians and including technology not as a threat, but as a positive tool