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BACKGROUND: Patients with solid or hematological tumors or neurological and immune-inflammatory disorders are potentially fragile subjects at increased risk of experiencing severe coronavirus disease 2019 and an inadequate response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. METHODS: We designed a prospective Italian multicenter study to assess humoral and T-cell responses to SARS-CoV-2 vaccination in patients (n = 378) with solid tumors (ST), hematological malignancies (HM), neurological disorders (ND), and immunorheumatological diseases (ID). A group of healthy controls was also included. We analyzed the immunogenicity of the primary vaccination schedule and booster dose. RESULTS: The overall seroconversion rate in patients after 2 doses was 62.1%. Significantly lower rates were observed in HM (52.4%) and ID (51.9%) than in ST (95.6%) and ND (70.7%); a lower median antibody level was detected in HM and ID versus ST and ND (P < .0001). Similar rates of patients with a positive SARS-CoV-2 T-cell response were found in all disease groups, with a higher level observed in ND. The booster dose improved the humoral response in all disease groups, although to a lesser extent in HM patients, whereas the T-cell response increased similarly in all groups. In the multivariable logistic model, independent predictors of seroconversion were disease subgroup, treatment type, and age. Ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (P < .0001) but had no effect on T-cell responses. CONCLUSIONS: Immunosuppressive treatment more than disease type per se is a risk factor for a low humoral response after vaccination. The booster dose can improve both humoral and T-cell responses.

BACKGROUND: With the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones. MATERIALS AND METHODS: After a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA). RESULTS: By applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate. CONCLUSIONS: The use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments' value in these contexts. Its generalizabi

Background: Although trastuzumab (T) represents the standard of care for the adjuvant treatment of HER2-positive early-stage breast cancer, contrasting results are available about the cardiac toxicity associated to its use. We conducted a multiregional population-based cohort investigation aimed to assess both the short- and long-term cardiovascular (CV) outcomes in women with early breast cancer treated with T-based or standard adjuvant chemotherapy (CT). Materials and Methods: We used health care use databases of six Italian regions, overall accounting for 42% of the Italian population. The study cohort was made by all women surgically treated for breast cancer who started a first-line adjuvant T-based or CT treatment. Patients treated with T were 1:2 matched to those treated with CT based on date of treatment start, age, and presence of CV risk factors. Short- and long-term CV outcomes (heart failure and cardiomyopathy) were measured, respectively, after 1 year and at the end of follow-up. Results: Among 28,599 women who met the inclusion criteria, 6,208 T users were matched to 12,416 CT users. After a mean follow-up of 5.88 years, short- and long-term cumulative CV risk were 0.8% and 2.6% in patients treated with T and 0.2% and 2.8% in those treated with CT, respectively. Adjusted hazard ratios were 4.6 (95% confidence interval [CI], 2.6–8.0) for short-term and 1.2 (95% CI, 0.9–1.6) for long-term CV risk. Discussion: In our large real-world investigation, T-associated cardiotoxicity was limited to the treatment period. The addition of T to adjuvant CT did not result in long-term worsening of CV events. Implications for Practice: Adjuvant trastuzumab-based chemotherapy represents the backbone therapy in patients with HER2-positive early breast cancer. Although well tolerated, cardiovascular events can manifest during or after therapy because of treatment-related toxicities. In this wide multicenter and unselected cohort, long-term symptomatic cardiotoxicity was l

Current follow-up policies for early breast cancer aim to detect loco-regional recurrences and manage treatment-related adverse effects. Their "one size fits all" approach does not take into account differences in subtypes at initial diagnosis, individual prognosis and treatments received. They are derived from clinical trials conducted when early detection means - other than mammography - and treatment options were limited. Herein, we address the arguments for re-evaluating current breast cancer follow-up strategies starting from recent advances in breast cancer local and systemic treatments and discussing individual risk of recurrence prediction models, time-adapted imaging and biomarker assessment for disease diagnostic anticipation. This change in perspective would transform breast cancer follow-up into an integrated, multidisciplinary team medical practice. Hence we discuss the important role of patient-centered approaches, but also of general practitioners and other health professionals, in the final promotion of personalized surveillance programs and patient education.

Importance: Despite people with impaired immune competence due to an underlying disease or ongoing therapy, hereinafter frail patients, are (likely to be) the first to be vaccinated, they were usually excluded from clinical trials. Objective: To report adverse reactions of frail patients after receipt of the third dose (booster) administered after completion of a two-dose mRNA vaccination and to compare with those reported after the receipt of the first two doses. Design: A multicenter, observational, prospective study aimed at evaluating both the safety profile and the immune response of Pfizer-BioNTech or Moderna vaccines in frail patients. Setting: National Project on Vaccines, COVID-19 and Frail Patients (VAX4FRAIL) Participants: People consenting and included in the VAX4FRAIL trial. Exposure: A series of three doses of COVID-19 mRNA vaccination from the same manufacturer. Main outcome(s) and measure(s): Evaluation of a self-assessment questionnaire addressing a predefined list of eight symptoms on a five-item Likert scale. Symptoms were classified as severe if the patient rated them as severe or overwhelming. Results: Among 320 VAX4FRAIL participants diagnosed/treated for hematological malignancies (N=105; 32.8%), solid tumors (N=48; 15.0%), immune-rheumatological diseases (N=60; 18.8%), neurological diseases (N=107; 33.4%), and receiving the booster dose, 70.3% reported at least one loco-regional or systemic reactions. Adverse events were mostly mild or moderate, none being life-threatening. Only six of the 320 (1.9%) patients had their treatment postponed due to the vaccine. The safety profile of the booster compared to previously administered two doses showed a stable prevalence of patients with one or more adverse events (73.5%, 79.7% and 73.9% respectively), and a slightly increment of patients with one or more severe adverse events (13.4%, 13.9% and 19.2% respectively). Conclusions and relevance: The booster of the mRNA COVID-19 vaccine was safely adminis

Background: Frail patients are considered at relevant risk of complications due to coronavirus disease 2019 (COVID-19) infection and, for this reason, are prioritized candidates for vaccination. As these patients were originally not included in the registration trials, fear related to vaccine adverse events and disease worsening was one of the reasons for vaccine hesitancy. Herein, we report the safety profile of the prospective, multicenter, national VAX4FRAIL study (NCT04848493) to evaluate vaccines in a large trans-disease cohort of patients with solid or hematological malignancies and neurological and rheumatological diseases. Methods: Between March 3 and September 2, 2021, 566 patients were evaluable for safety endpoint: 105 received the mRNA-1273 vaccine and 461 the BNT162b2 vaccine. Frail patients were defined per protocol as patients under treatment with hematological malignancies (n = 131), solid tumors (n = 191), immune-rheumatological diseases (n = 86), and neurological diseases (n = 158), including multiple sclerosis and generalized myasthenia. The impact of the vaccination on the health status of patients was assessed through a questionnaire focused on the first week after each vaccine dose. Results: The most frequently reported moderate–severe adverse events were pain at the injection site (60.3% after the first dose, 55.4% after the second), fatigue (30.1%–41.7%), bone pain (27.4%–27.2%), and headache (11.8%–18.9%). Risk factors associated with the occurrence of severe symptoms after vaccine administration were identified through a multivariate logistic regression analysis: age was associated with severe fever presentation (younger patients vs. middle-aged vs. older ones), female individuals presented a higher probability of severe pain at the injection site, fatigue, headache, and bone pain; and the mRNA-1237 vaccine was associated with a higher probability of severe pain at the injection site and fever. After the first dose, patients presenting a se

Lung cancer (LC) is currently one of the main causes of cancer-related deaths worldwide. Low-dose computed tomography (LDCT) of the chest has been proven effective in secondary prevention (i.e., early detection) of LC by several trials. In this work, we investigated the potential impact of radiomics on indeterminate prevalent pulmonary nodule (PN) characterization and risk stratification in subjects undergoing LDCT-based LC screening. As a proof-of-concept for radiomic analyses, the first aim of our study was to assess whether indeterminate PNs could be automatically classified by an LDCT radiomic classifier as solid or sub-solid (first-level classification), and in particular for sub-solid lesions, as non-solid versus part-solid (second-level classification). The second aim of the study was to assess whether an LCDT radiomic classifier could automatically predict PN risk of malignancy, and thus optimize LDCT recall timing in screening programs. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, positive predictive value, negative predictive value, sensitivity, and specificity. The experimental results showed that an LDCT radiomic machine learning classifier can achieve excellent performance for characterization of screen-detected PNs (mean AUC of 0.89 ± 0.02 and 0.80 ± 0.18 on the blinded test dataset for the first-level and second-level classifiers, respectively), providing quantitative information to support clinical management. Our study showed that a radiomic classifier could be used to optimize LDCT recall for indeterminate PNs. According to the performance of such a classifier on the blinded test dataset, within the first 6 months, 46% of the malignant PNs and 38% of the benign ones were identified, improving early detection of LC by doubling the current detection rate of malignant nodules from 23% to 46% at a low cost of false positives. In conclusion, we showed the high potential of LDCT-based r

The current COVID pandemic crisis made it even clearer that the solutions to several questions that public health must face require the access to good quality data. Several issues of the value and potential of health data and the current critical issues that hinder access are discussed in this paper. In particular, the paper (i) focuses on "real-world data" definition; (ii) proposes a review of the real-world data availability in our country; (iii) discusses its potential, with particular focus on the possibility of improving knowledge on the quality of care provided by the health system; (iv) emphasizes that the availability of data alone is not sufficient to increase our knowledge, underlining the need that innovative analysis methods (e.g., artificial intelligence techniques) must be framed in the paradigm of clinical research; and (v) addresses some ethical issues related to their use. The proposal is to realize an alliance between organizations interested in promoting research aimed at collecting scientifically solid evidence to support the clinical governance of public health.

Patients diagnosed with malignancy, neurological and immunological disorders, i.e., fragile patients, have been excluded from COVID-19 vaccine trials. However, this population may present immune response abnormalities, and relative reduced vaccine responsiveness. Here we review the limited current evidence on the immune responses to vaccination of patients with different underlying diseases. To address open questions we present the VAX4FRAIL study aimed at assessing immune responses to vaccination in a large transdisease cohort of patients with cancer, neurological and rheumatological diseases.

Background: A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting-enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied. Methods: We carried out a population-based case-control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients' clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression. Results: Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex. Conclusions: In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affect

OBJECTIVES: Although it has been postulated that patients might benefit from the centralization of high-volume specialized centres, conflicting results have been reported on the relationship between the number of lung resections performed and the long-term, all-cause mortality rates among patients who underwent surgery for lung cancer. A population-based observational study was performed to contribute to the ongoing debate. METHODS: The 2613 patients, all residents of the Lombardy region (Italy), who underwent lung resection for lung cancer from 2012 to 2014 were entered into the cohort and were followed until 2018. The hospitals were classified according to the annual number of pulmonary resections performed. Three categories of lung resection cases were identified: low (≤30), intermediate (31-95) and high (>95). The outcome of interest was all-cause death. A frailty model was used to estimate the death risk associated with the categories of numbers of lung resections performed, taking into account the multilevel structure of the data. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS: The 1-year and 5-year survival rates of cohort members were 90% and 63%. Patients operated on in high-volume centres were on average younger and more often women. Compared to patients operated on in a low-volume centre, the mortality risk exhibited a significant, progressive reduction as the numbers of lung resections performed increased to intermediate (-13%; 95% confidence interval +10% to-31%) and high (-26%; 0% to-45%). Sensitivity analyses revealed that the association was consistent. CONCLUSIONS: Further evidence that the volume of lung resection cases performed strongly affects the long-term survival of lung cancer patients has been supplied.