Publications by authors named "Diana Giannarelli"

333 Publications

Distinctive Role of the Systemic Inflammatory Profile in Non-Small-Cell Lung Cancer Younger and Elderly Patients Treated with a PD-1 Immune Checkpoint Blockade: A Real-World Retrospective Multi-Institutional Analysis.

Life (Basel) 2021 Nov 15;11(11). Epub 2021 Nov 15.

Medical Oncology Unit, Grand Metropolitan Hospital "Bianchi-Melacrino-Morelli", 89124 Reggio Calabria, Italy.

An immune checkpoint blockade with mAbs to PD-1 and PD-L1 is an expanding therapeutic option for mNSCLC patients. This treatment strategy is based on the use of mAbs able to restore the anti-tumor activity of intratumoral T cells inhibited by PD-1 binding to PD-L1/2 on tumor and inflammatory cells. It has been speculated that a chronic status of systemic inflammation as well as the immunosenescence physiologically occurring in elderly patients may affect the efficacy of the treatment and the occurrence of irAEs. We performed a multi-institutional retrospective study aimed at evaluating the effects of these mAbs (nivolumab or atezolizumab) in 117 mNSCLC patients younger (90 cases) and older (27 cases) than 75 years in correlation with multiple inflammatory parameters (NLR, CRP, ESR, LDH and PCT). No differences were observed when the cohorts were compared in terms of the frequency of PFS, OS, inflammatory markers and immune-related adverse events (irAEs). Similarly, the occurrence of irAEs was strictly correlated with a prolonged OS survival in both groups. On the contrary, a negative correlation between the high baseline levels of inflammatory markers and OS could be demonstrated in the younger cohort only. Overall, PD-1/PD-L1-blocking mAbs were equally effective in young and elderly mNSCLC patients; however, the detrimental influence of a systemic inflammation at the baseline was only observed in young patients, suggesting different aging-related inflammation immunoregulative effects.
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http://dx.doi.org/10.3390/life11111235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8621400PMC
November 2021

A Prospective Study Assessing the Post-Prostatectomy Detection Rate of a Presumed Local Failure at mpMR with Either CuCl or CuPSMA PET/CT.

Cancers (Basel) 2021 Nov 6;13(21). Epub 2021 Nov 6.

Department of Radiation Oncology, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

Background: We aimed assess the detection rate (DR) of positron emission tomography/computed tomography with two novel tracers in patients referred for salvage radiotherapy (sRT) with a presumed local recurrence at multiparametric magnetic resonance (mpMR) after radical prostatectomy (RP).

Methods: The present prospective study was conducted at a single institution between August 2017 and June 2020. Eligibility criteria were undetectable PSA after RP; subsequent biochemical recurrence (two consecutive PSA rises to 0.2 ng/mL or greater); a presumed local failure at mpMR; no distant metastases at F-fluorocholine PET/CT (CH/PET); no previous history of androgen deprivation therapy. Patients were offered both CuCl PET/CT (CU/PET) and Cu-PSMA PET/CT (PSMA/PET) before sRT. After image co-registration, PET findings were compared to mpMR ones in terms of DR and independent predictors of DR investigated at logistic regression.

Results: A total of 62 patients with 72 nodules at mpMR were accrued. Compared to mpMR (DR = 100%, 95%CI: 94.9-100%), DRs were 47.2% (95%CI: 36.1-58.6%) and 54.4% (95%CI: 42.7-65.7%) for CU/PET and PSMA/PET, respectively ( < 0.001 for both). Both experimental PET/CT performed particularly poorly at PSA levels consistent with early sRT.

Conclusions: The two novel radiotracers are inferior to mpMR in restaging the prostatic fossa for sRT planning purposes, particularly in the context of early salvage radiotherapy.
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http://dx.doi.org/10.3390/cancers13215564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582802PMC
November 2021

Antibody Persistence 6 Months Post-Vaccination with BNT162b2 among Health Care Workers.

Vaccines (Basel) 2021 Oct 3;9(10). Epub 2021 Oct 3.

Department Otolaryngology Head and Neck Surgery, IRCCS Regina Elena National Cancer Institute, Istituti Fisioterapici Ospitalieri (IFO), 00144 Rome, Italy.

Background: We present immunogenicity data 6 months after the first dose of BNT162b2 in correlation with age, gender, BMI, comorbidities and previous SARS-CoV-2 infection.

Methods: An immunogenicity evaluation was carried out among health care workers (HCW) vaccinated at the Istituti Fisioterapici Ospitalieri (IFO). All HCW were asked to be vaccine by the national vaccine campaign at the beginning of 2021. Serum samples were collected on day 1 just prior to the first dose of the vaccine and on day 21 just prior to the second vaccination dose. Thereafter sera samples were collected 28, 49, 84 and 168 days after the first dose of BNT162b2. Quantitative measurement of IgG antibodies against S1/S2 antigens of SARS-CoV-2 was performed with a commercial chemiluminescent immunoassay.

Results: Two hundred seventy-four HWCs were analyzed, 175 women (63.9%) and 99 men (36.1%). The maximum antibody geometric mean concentration (AbGMC) was reached at T2 (299.89 AU/mL; 95% CI: 263.53-339.52) with a significant increase compared to baseline ( < 0.0001). Thereafter, a progressive decrease was observed. At T5, a median decrease of 59.6% in COVID-19 negative, and of 67.8% in COVID-19 positive individuals were identified with respect to the highest antibody response. At T1, age and previous COVID-19 were associated with differences in antibody response, while at T2 and T3 differences in immune response were associated with age, gender and previous COVID-19. At T4 and T5, only COVID-19 positive participants demonstrated a greater antibody response, whereas no other variables seemed to influence antibody levels.

Conclusions: Overall our study clearly shows antibody persistence at 6 months, albeit with a certain decline. Thus, the use of this vaccine in addressing the COVID-19 pandemic is supported by our results that in turn open debate about the need for further boosts.
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http://dx.doi.org/10.3390/vaccines9101125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538824PMC
October 2021

Cross-sectional study to develop and describe psychometric characteristics of a patient-reported instrument (PROFFIT) for measuring financial toxicity of cancer within a public healthcare system.

BMJ Open 2021 10 20;11(10):e049128. Epub 2021 Oct 20.

Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy

Objectives: To measure and explain financial toxicity (FT) of cancer in Italy, where a public healthcare system exists and patients with cancer are not expected (or only marginally) to pay out-of-pocket for healthcare.

Setting: Ten clinical oncological centres, distributed across Italian macroregions (North, Centre, South and Islands), including hospitals, university hospitals and national research institutes.

Participants: From 8 October 2019 to 11 December 2019, 184 patients, aged 18 or more, who were receiving or had received within the previous 3 months active anticancer treatment were enrolled, 108 (59%) females and 76 (41%) males.

Intervention: A 30-item prefinal questionnaire, previously developed within the qualitative tasks of the project, was administered, either electronically (n=115) or by paper sheet (n=69).

Primary And Secondary Outcome Measures: According to the protocol and the International Society for Pharmacoeconomics and Outcomes Research methodology, the final questionnaire was developed by mean of explanatory factor analysis and tested for reliability, internal consistency (Cronbach's α test and item-total correlation) and stability of measurements over time (test-retest reliability by intraclass correlation coefficient and weighted Cohen's kappa coefficient).

Results: After exploratory factor analysis, a score measuring FT (FT score) was identified, made by seven items dealing with outcomes of FT. The Cronbach's alpha coefficient for the FT score was 0.87 and the item-total correlation coefficients ranged from 0.53 to 0.74. Further, nine single items representing possible determinants of FT were also retained in the final instrument. Test-retest analysis revealed a good internal validity of the FT score and of the 16 items retained in the final questionnaire.

Conclusions: The Patient-Reported Outcome for Fighting FInancial Toxicity (PROFFIT) instrument consists of 16 items and is the first reported instrument to assess FT of cancer developed in a country with a fully public healthcare system.

Trial Registration Number: NCT03473379.
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http://dx.doi.org/10.1136/bmjopen-2021-049128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529986PMC
October 2021

Immunogenicity and Safety of COVID-19 Vaccine BNT162b2 for Patients with Solid Cancer: A Large Cohort Prospective Study from a Single Institution.

Clin Cancer Res 2021 Sep 28. Epub 2021 Sep 28.

Medical Oncology 1 Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Purpose: We assessed the immunogenicity and safety of the BNT162b2 vaccine in a large cohort of patients with cancer (CP).

Experimental Design: From March 1, 2021 to March 20, 2021, this prospective cohort study included 816 CP afferent to our institution and eligible for the vaccination. A cohort of 274 health care workers (HCW) was used as age- and sex-matched control group. BNT162b2 was administered as a two-dose regimen given 21 days apart. Blood samples to analyze anti-Spike (S) IgG antibodies (Ab) were collected prevaccination [timepoint (TP) 0], and at 3 weeks (TP1) and 7 weeks (TP2) after the first dose.

Results: Patients characteristics: median age 62 (range, 21-97); breast/lung cancer/others (31/21/48%); active treatment/follow-up (90/10%). In the whole CP cohort, the serologic response rate (RR) and the titre of anti-S IgG significantly increased across the TPs; at TP2, the responders (IgG >15 AU/mL) were 94.2%. Active chemotherapy and chronic use of steroids were independent predictors of lower RR. Adverse events (AE) after the booster predicted higher likelihood of response (OR, 4.04; 95% confidence interval, 1.63-9.99; = 0.003). Comparing the matched cohorts, the responders were significantly lower in CP than in HCW at TP1 (61.2% vs. 93.2%) and TP2 (93.3% vs. 100%), while the geometric mean concentration of IgG did not significantly differ at TP2 being significantly lower in CP (23.3) than in HCW (52.1) at TP1. BNT162b2 was well tolerated in CP; severe-grade AEs were 3.5% and 1.3% after the first and second doses, respectively.

Conclusions: BNT162b2 assures serologic immunization without clinically significant toxicity in CP. The second dose is needed to reach a satisfactory humoral response.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2439DOI Listing
September 2021

COVID-19 Vaccination in Fragile Patients: Current Evidence and an Harmonized Transdisease Trial.

Front Immunol 2021;12:704110. Epub 2021 Aug 10.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

Patients diagnosed with malignancy, neurological and immunological disorders, , 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.
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http://dx.doi.org/10.3389/fimmu.2021.704110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383886PMC
September 2021

Neutrophil-to-lymphocyte ratio, Factor VIII and Antithrombin III: inflammatory-clotting biomarkers in glioma.

EXCLI J 2021 8;20:1152-1169. Epub 2021 Jul 8.

Department of Clinical Experimental Oncology, IRCCS Regina Elena National Cancer Institute, IFO, Via Elio Chianesi 53, 00144, Rome, Italy.

One of the key difficulties in glioma treatment is our limited ability to consistently assess cancer response or progression either by neuroimaging or specific blood biomarkers. An ideal biomarker could be measured through non-invasive methods such as blood-based biomarkers, aiding both early diagnosis and monitoring disease evolution. This is a single-center, case-control, 10-year retrospective, longitudinal study. We evaluated routine coagulation factors in 138 glioma patients (45 Females/93 Males; median [range] age, 56.4 [27-82] years; 64 non-recurrent/74 recurrent) and, for comparison, in 56 relapsing-remitting MS patients (41 Females/15 Males; 40.8 [25-62] years, 35 stable/21 active) and 23 controls (16 Females/7 Males; 41.7 [24-62] years) as well as Neutrophil-to-lymphocyte ratio (NLR) in subgroups of 127 glioma patients, 33 MS patients and 23 healthy controls. Secondly, we assessed whether these indicators could be predictive of overall (OS) and progression-free survival (PFS) in glioma patients. NLR, d-dimer, Antithrombin III and Factor VIII were significantly higher in glioma patients compared to both MS patients and controls (p<0.0001 for all). ROC curves confirmed that either NLR, Antithrombin III or Factor VIII were moderately accurate biomarkers (0.7
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http://dx.doi.org/10.17179/excli2021-3831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326499PMC
July 2021

Early DMO: a predictor of poor outcomes following cataract surgery in diabetic patients. The DICAT-II study.

Eye (Lond) 2021 Aug 3. Epub 2021 Aug 3.

Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: The prospective DIabetes and CATaract Study II (DICAT II) was performed to characterise the risks of cataract surgery to the retinae of patients with early diabetic macular oedema (E-DMO).

Methods: DICAT II was a prospective, comparative, multicentre, observational study involving six Italian clinics. Patients were aged ≥55 years, had type 1 or 2 diabetes with spectral-domain optical coherence tomography evidence of ESASO classification Early DMO. Group 1 eyes (78 eyes, 78 patients) underwent phacoemulsification-based cataract surgery. Group 2 eyes (65 eyes, 65 patients) had E-DMO and either clear media or had undergone uncomplicated cataract surgery ≥1 year previously. Central subfield thickness (CST) and best-corrected visual acuity (BCVA) were assessed in both groups.

Results: The negative impact of surgery on CST was evident after the first postoperative week; CST peaked during the first month, then rapidly decreased. CST worsening ≥10 µm was observed in 63/78 eyes (80.7%) and 29/65 eyes (44.6%) in Groups 1 and 2, respectively (p < 0.0001). CST worsening of ≥50 µm was observed in 51 eyes (65.4%) and 10 eyes (15.4%) in Groups 1 and 2, respectively (p < 0.0001). Mean CST worsening was lower in Group 2 than in Group 1 (38.6 ± 30.4 µm vs 85.5 ± 55.3 µm, p < 0.0001) with a lower BCVA loss (-2.6 ± 3.5 letters vs -8.2 ± 6.2 letters, p < 0.0001). Higher glycaemic levels and HBA1c levels were significantly associated with the risk of >50 μm CST worsening in eyes from both groups.

Conclusion: Early DMO is associated with poorer outcomes after cataract surgery and requires close pre- and postoperative monitoring.
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http://dx.doi.org/10.1038/s41433-021-01718-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330474PMC
August 2021

Lower response to BNT162b2 vaccine in patients with myelofibrosis compared to polycythemia vera and essential thrombocythemia.

J Hematol Oncol 2021 07 29;14(1):119. Epub 2021 Jul 29.

Hematology Unit, Department of Research and Clinical Oncology, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

In a population of 42 Philadelphia negative myeloproliferative neoplasm patients, all on systemic active treatment, the likelihood of responding to anti-SARS-CoV-2 BNT162b2 vaccine at 2 weeks after the second dose was significantly lower in the ten patients with myelofibrosis compared to the 32 with essential thrombocythemia (n = 17) and polycythemia vera (n = 15) grouped together, both in terms of neutralizing anti-SARS-CoV-2 IgG titers and seroprotection rates (32.47 AU/mL vs 217.97 AU/mL, p = 0.003 and 60% vs 93.8%, p = 0.021, respectively). Ruxolitinib, which was the ongoing treatment in five patients with myelofibrosis and three with polycythemia vera, may be implicated in reducing vaccine immunogenicity (p = 0.076), though large prospective study is needed to address this issue.
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http://dx.doi.org/10.1186/s13045-021-01130-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319901PMC
July 2021

Pembrolizumab for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer: Analysis of Prognostic Factors of Outcomes.

Anticancer Agents Med Chem 2021 Jul 26. Epub 2021 Jul 26.

Department of Oncology, S.Luca Hospital, Lucca, Italy.

Background: In advanced non-small-cell lung cancer, without activating mutations and with PD-L1≥50%, Pembrolizumab monotherapy is the therapeutic standard in Europe.

Objective: to evaluate retrospectively the safety and the efficacy of this drug and to investigate potential prognostic factors in daily clinical practice.

Methods: From September 2017 to September 2019, 205 consecutive patients from 14 Italian Medical Oncology Units were enrolled in the study. Gender, Age (> or <70 years), ECOG-PS (0-1 or 2), histology (squamous or non-squamous), presence of brain, bone and liver metastases at baseline, PD-L1 score (>90% or <90%), smoking status (never or former or current) were applied to the stratified log-rank. Cox's proportional hazards model was used for multivariate analysis.

Results: At a median follow-up of 15.2 months, median progression-free and overall survival (mPFS and mOS) were 9.2 months (95% C.I., 4.8-13.5) and 15.9 months (95% C.I., not yet evaluable), respectively. Patients with Eastern Cooperative Oncology Group performance status (ECOG-PS) 2 had mPFS of 2.8 months (95% C.I., 2.1-3.4) and mOS of 3.9 months (95% C.I., 2.5-5.3). Patients with liver metastases at diagnosis had an mPFS of 3.2 months (95% C.I., 0.6-5.8) and an mOS of 6.0 months (95% C.I., 3.7-8.4). At multivariate analysis for OS gender, ECOG-PS 2, and presence of liver metastases were independent prognostic factors.

Conclusion: Patients with ECOG-PS 2 derived little benefit from the use of first-line pembrolizumab. In patients with liver metastases the association of pembrolizumab with platinum-based chemotherapy could be a better option than pembrolizumab alone.
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http://dx.doi.org/10.2174/1871520621666210727112212DOI Listing
July 2021

Safety of outpatient stem cell mobilization with low- or intermediate-dose cyclophosphamide in newly diagnosed multiple myeloma patients.

Eur J Haematol 2021 Nov 4;107(5):566-572. Epub 2021 Aug 4.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Objectives: Autologous stem cell transplantation is the gold standard for eligible newly diagnosed multiple myeloma patients. Patients are usually hospitalized for administration of mobilization chemotherapy. We aimed to assess safety and efficacy of mobilization therapy with low-dose (2 g/m ) and intermediate-dose (3-4 g/m ) cyclophosphamide administered as outpatient.

Methods: A total of 176 consecutive newly diagnosed transplant-eligible myeloma patients receiving outpatient mobilization were retrospectively evaluated. Induction therapy was mainly performed with new drugs (91%).

Results: Chemotherapy was very well tolerated with 16.6% of patients having all-grade adverse events (AEs) and only 1.2% having severe AEs. The most frequently reported AEs were nausea and vomiting grade 1-2 (6.8%). Only 5.7% of patients required hospitalization for AEs. Stem cell collection was successful in 93.1% of patients, with a median CD34 harvest of 8.7 × 10 /kg. Target for 2 autologous stem cell transplantation (at least 6 CD34  × 10 /kg) was reached by 76.3% of patients. Administration of plerixafor on demand was necessary in 12.1% of patients.

Conclusions: Outpatient mobilization with low- and intermediate-dose cyclophosphamide appears an efficient and safe procedure, with minimal and manageable AEs and low rate of hospitalization.
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http://dx.doi.org/10.1111/ejh.13693DOI Listing
November 2021

Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib.

Cancers (Basel) 2021 Jun 29;13(13). Epub 2021 Jun 29.

Hematology, Department of Translational and Precision Medicine, "Sapienza" University, 00161 Rome, Italy.

Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free ( < 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections-PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments-identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.
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http://dx.doi.org/10.3390/cancers13133240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269042PMC
June 2021

Early Progression in Non-Small Cell Lung Cancer (NSCLC) with High PD-L1 Treated with Pembrolizumab in First-Line Setting: A Prognostic Scoring System Based on Clinical Features.

Cancers (Basel) 2021 Jun 11;13(12). Epub 2021 Jun 11.

Division of Thoracic Oncology, European Institute of Oncology IRCCS, 20141 Milano, Italy.

Background: Pembrolizumab is approved in monotherapy for the first-line (1L) of advanced or metastatic NSCLC patients with high PD-L1 (≥50%). Despite a proportion of patients achieve long-term survival, about one-third of patients experience detrimental survival outcomes, including early death, hyperprogression, and fast progression. The impact of clinical factors on early progression (EP) development has not been widely explored.

Methods: We designed a retrospective, multicenter study involving five Italian centers, in patients with metastatic NSCLC with PD-L1 ≥ 50%, treated with Pembrolizumab in a 1L setting. EP was defined as a progressive disease within three months from pembrolizumab initiation. Baseline clinical factors of patients with and without EP were collected and analyzed. Logistic regression was performed to identify clinical factors associated with EP and an EP prognostic score was developed based on the logistic model.

Results: Overall, 321 out of 336 NSCLC patients treated with 1L pembrolizumab provided all the data for the analysis. EP occurred in 137 (42.7%) patients; the median PFS was 3.8 months (95% CI: 2.9-4.7), and median OS was not reached in the entire study population. Sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), steroids, metastatic sites ≥2, and the presence of liver/pleural metastasis were confirmed as independent factors for EP by multivariate analysis. By combining these factors, we developed an EP prognostic score ranging from 0-13, with three-risk group stratification: 0-2 (good prognosis), 3-6 (intermediate prognosis), and 7-13 (poor prognosis). The area under the curve (AUC) of the model was 0.76 (95% CI: 0.70-0.81).

Conclusions: We identified six clinical factors independently associated with EP. We developed a prognostic score model for EP-risk to potentially improve clinical practice and patient selection for 1L pembrolizumab in NSCLC with high PD-L1, in the real-world clinical setting.
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http://dx.doi.org/10.3390/cancers13122935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230881PMC
June 2021

Early Onset of SARS-COV-2 Antibodies after First Dose of BNT162b2: Correlation with Age, Gender and BMI.

Vaccines (Basel) 2021 Jun 22;9(7). Epub 2021 Jun 22.

Scientific Direction, IRCCS Regina Elena National Cancer Institute, Istituti Fisioterapici Ospitalieri (IFO), 00144 Rome, Italy.

Background: The first goal of the study was to analyse the antibody titre 21 days after the first dose of the BNT162b2 vaccine in a group of 252 healthcare workers (HCW). The second goal was to analyse how the antibody titre changes in correlation with age, gender and body mass index (BMI).

Methods: Participants had a nasopharyngeal swab for SARS-CoV-2 and were assessed for the presence of SARS-CoV-2 antibodies at baseline and 21 days after the BNT162b2 priming dose.

Results: First dose of BNT162b2 activated immune responses in 98% of the participants. Five HWC had no increase in antibody titre 21 days after the first dose. Antibody titre was greater in young (<38 years) vs. older participants (<38 vs. 47-56 = 0.002; <38 vs. >56 = 0.001). Higher antibody levels were detected in underweight vs. pre-obesity group ( = 0.026) and in normal-weight vs. pre-obesity group ( = 0.007). This association was confirmed after adjusting for age ( = 0.0001) and gender ( = 0.00001).

Conclusions: Our study demonstrates that a single dose of BNT162b2 activates the immune response, and being young and normal-weight correlate positively with this response. Larger specifically designed clinical trials are needed to validate these results.
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http://dx.doi.org/10.3390/vaccines9070685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310011PMC
June 2021

Inflammatory Markers and Procalcitonin Predict the Outcome of Metastatic Non-Small-Cell-Lung-Cancer Patients Receiving PD-1/PD-L1 Immune-Checkpoint Blockade.

Front Oncol 2021 14;11:684110. Epub 2021 Jun 14.

Medical Oncology Unit, Grand Metropolitan Hospital "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.

Peripheral-immune-checkpoint blockade (P-ICB) with mAbs to PD-1 (nivolumab and pembrolizumab) or PD-L1 (atezolizumab, durvalumab, avelumab) alone or combination with chemotherapy represents a novel active treatment for mNSCLC patients. However, this therapy can be associated to immune-related adverse events (irAEs) and high cost. Therefore, finding reliable biomarkers of response and irAEs is strongly encouraged to accurately select patients who may potentially benefit from the immuno-oncological treatment. This is a retrospective multi-institutional analysis performed on ninety-five mNSCLC patients who received real-world salvage therapy with nivolumab or atezolizumab between December 2015 and April 2020. The outcome of these patients in term of PFS and OS was evaluated in comparison with different serum levels of C-reactive protein (CRP), Erythrocyte Sedimention Rate (ESR) and Procalcitonin (PCT) by performing Kaplan-Meier and Log-rank test and multivariate analysis. We found that high baseline levels of CRP, ESR, and PCT were strongly predictive of poor outcome (P <0.05) with the worse prognosis detected in those patients with a baseline levels of both ESR and PCT over the pre-established cut off (median OS recorded in patients with no marker over the cut off . those with just one marker over the cut off . those with both markers over the cut off: 40 ± 59 . 15.5 ± 5.5 . 5.5 ± 1.6 months, respectively; P <0.0001). Our results suggest the predictive value of systemic inflammation and suggest a potential role of PCT in predicting a poor outcome in mNSCLC receiving PD-1/PD-L1 blocking mAbs. This finding also suggests a potential role of subclinical bacterial infections in defining the response to PD-1/PD-L1 blocking mAbs that deserves further and more specific investigations.
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http://dx.doi.org/10.3389/fonc.2021.684110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236817PMC
June 2021

The first report on coronavirus disease 2019 (COVID-19) vaccine refusal by patients with solid cancer in Italy: Early data from a single-institute survey.

Eur J Cancer 2021 08 26;153:260-264. Epub 2021 May 26.

Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome, Italy; Dipartimento di Medicina Clinica e Molecolare, Università La Sapienza di Roma, Rome, Italy. Electronic address:

Introduction: Patients with cancer have an increased risk of complications from coronavirus disease 2019 (COVID-19) infection, including death, and thus, they were considered as high-priority subjects for COVID-19 vaccination. We report on the compliance with the COVID-19 vaccine of patients affected by solid tumours.

Materials And Methods: Patients with cancer afferent to Medical Oncology 1 Unit of Regina Elena National Cancer Institute in Rome were considered eligible for vaccination if they were receiving systemic immunosuppressive antitumor treatment or received it in the last 6 months or having an uncontrolled advanced disease. The Pfizer BNT162b2 vaccine was proposed to all candidates via phone or during a scheduled visit. The reasons for refusal were collected by administrating a 6-item multiple-choice questionnaire.

Results: From 1st March to 20th March 2021, of 914 eligible patients, 102 refused vaccination (11.2%, 95% confidence interval [CI] 9.1-13.2). The most frequent (>10%) reasons reported were concerns about vaccine-related adverse events (48.1%), negative interaction with concomitant antitumor therapy (26.7%), and the fear of allergic reaction (10.7%). The refusal rate (RR) after 15th March (date of AstraZeneca-AZD1222 suspension) was more than doubled compared with the RR observed before (19.7% versus 8.6%, odds ratio [OR] 2.60, 95% CI 1.69-3.99; P < 0.0001). ECOG-PS 2 was associated with higher RR compared with ECOG-PS 0-1 (OR 2.94, 95% CI 1.04-8.34; P = 0.04). No statistically significant differences in RR according to other clinical characteristics were found.

Conclusions: Our experience represents the first worldwide report on the adherence of patients with cancer to COVID-19 vaccination and underlines how regulatory decisions and media news spreading could influence the success of the campaign.
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http://dx.doi.org/10.1016/j.ejca.2021.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149194PMC
August 2021

Major Differences in Lymphocyte Subpopulations Between Cerebrospinal Fluid and Peripheral Blood in Non-Hodgkin Lymphoma Without Leptomeningeal Involvement: Flow Cytometry Evidence of a Cerebral Lymphatic System.

Front Oncol 2021 3;11:685786. Epub 2021 Jun 3.

Department of Research and Clinical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Cerebrospinal fluid (CSF) flow cytometry has a crucial role in the diagnosis of leptomeningeal disease in onco-hematology. This report describes the flow cytometry characterization of 138 CSF samples from patients affected by non-Hodgkin lymphoma, negative for disease infiltration. The aim was to focus on the CSF non-neoplastic population, to compare the cellular composition of the CSF with paired peripheral blood samples and to document the feasibility of flow cytometry in hypocellular samples. Despite the extremely low cell count (1 cell/µl, range 1.0-35) the study was successfully conducted in 95% of the samples. T lymphocytes were the most abundant subset in CSF (77%; range 20-100%) with a predominance of CD4-positive over CD8-positive T cells (CD4/CD8 ratio = 2) together with a minority of monocytes (15%; range 0-70%). No B cells were identified in 90% of samples. Of relevance, a normal, non-clonal B-cell population was documented in 5/7 (71%) patients with primary central nervous system lymphoma at diagnosis (<0.0001), suggesting a possible involvement of blood-brain barrier cell permeability in the pathogenesis of cerebral B-cell lymphomas. The highly significant differences between CSF and paired peripheral blood lymphoid phenotype (<0.0001) confirms the existence of an active mechanism of lymphoid migration through the meninges.
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http://dx.doi.org/10.3389/fonc.2021.685786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210665PMC
June 2021

Italian nursing students' attitudes towards care of the dying patient: A multi-center descriptive study.

Nurse Educ Today 2021 Sep 1;104:104991. Epub 2021 Jun 1.

Research Unit of Nursing Science, Campus Bio-Medico di Roma University, Via Alvaro del Portillo 21, Rome, Italy.. Electronic address:

Background: International literature reports that nursing students feel unprepared when facing patients and families within dying care. They consider their curricula inadequate in teaching end-of-life care and promoting the attitudes required to care for dying patients. Findings of recent studies exploring nursing students' attitudes towards care of the dying patient are often contradictory.

Objectives: To explore Italian nursing students' attitudes towards caring for dying patients.

Design: A multicenter cross-sectional study was conducted.

Settings: The Bachelor's Degree in Nursing courses of four Universities of the Lazio Region.

Participants: The sample included 1193 students.

Methods: Data were collected between September 2017 and March 2018 using the Italian version of FATCOD-B-I. The differences between the mean scores were compared through t-test or ANOVA. Associations between scores and participant characteristics were evaluated through generalized linear regression.

Results: The mean score of FATCOD-B-I was 115.3 (SD = 9.1). Higher scores were significantly associated with training in palliative care (p < 0.0001) and experience with terminally ill patients (p < 0.0001). Students manifested more negative attitudes when they perceived patients losing hope of recovering, and patient's family members interfering with health professionals' work. Uncertainties emerged around knowledge of opioid drugs, decision-making, concepts of death and dying, management of mourning, and relational aspects of patient care.

Conclusions: Italian nursing students seem to have more positive attitudes towards care of dying patients than most other countries. They believe that caring for a terminal patient is a formative, useful experience but they do not feel adequately prepared in practice. Deeper palliative care education, integrated with practical training, would prepare students better, enabling them to discover their own human and professional capacity to relieve suffering.
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http://dx.doi.org/10.1016/j.nedt.2021.104991DOI Listing
September 2021

Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases.

Clin Cancer Res 2021 Sep 10;27(17):4737-4745. Epub 2021 Jun 10.

Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy.

Purpose: Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases.

Patients And Methods: This phase III study recruited patients 18 years of age and older with wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS).

Results: From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8-12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2-14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59-1.99; = 0.78), and 29.2 months (95% CI, 0-65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22-0.87; = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6-61.4) vs. 10.9% (95% CI, 0-24.4; = 0.015)], and was 10.3% (95% CI, 0-22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths.

Conclusions: Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1046DOI Listing
September 2021

Initial observations on age, gender, BMI and hypertension in antibody responses to SARS-CoV-2 BNT162b2 vaccine.

EClinicalMedicine 2021 Jun 4;36:100928. Epub 2021 Jun 4.

Scientific Direction, IRCCS Regina Elena National Cancer Institute, Istituti Fisioterapici Ospitalieri (IFO), Rome, Italy.

Background: Literature data suggests that age, gender and body mass index (BMI) could be associated with difference in immune responses to vaccines. The first goal of the study was to analyze the antibody titre seven days after the second dose of BNT162b2 vaccine in a group of 248 healthcare workers (HCWs). The second goal was to analyze how antibody titre changes in correlation with age, gender, BMI and hypertension.

Methods: An immunogenicity evaluation was carried out among HCWs vaccinated at the Istituti Fisioterapici Ospitalieri (IFO), Rome, Italy. All HCWs were asked to be vaccinated by the Italian national vaccine campaign at the beginning of 2021. 260 vaccinated HCWs were enrolled in the study. All eligible participants were assigned to receive the priming dose in two weeks' time and the booster dose exactly 21 days thereafter. Blood and nasopharyngeal swabs were collected at baseline and 7 days after second dose of vaccine. Quantitative measurements of IgG antibodies against S1/S2 antigens of SARS-CoV-2 were performed with a commercial chemiluminescent immunoassay. Presence of SARS-Cov-2 in nasopharyngeal swab was determined by commercial RT-PCR testing.

Findings: 248 HWCs were analyzed, 158 women (63.7%) and 90 men (36.3%). After the second dose of BNT162b2 vaccine, 99.5% of participants developed a humoral immune response. The geometric mean concentration of antibodies among the vaccinated subjects after booster dose (285.9 AU/mL 95% CI: 249.5-327.7) was higher than that of human convalescent sera (39.4 AU/mL, 95% CI: 33.1-46.9), with <0.0001. Multivariate linear regression analysis of AU/mL by age, gender and BMI multivariate was performed by the inclusion of covariates. This analysis demonstrated that age (<0.0001) and gender ( = 0.038) are statistically associated with differences in antibody response after vaccination, whereas BMI and hypertension have no statistically significant association ( = 0.078 and  = 0.52 respectively).

Interpretation: 99.5% of HCW developed a humoral immune response and female and young participants seem to have an increased capacity to mount humoral immune responses. BMI and hypertension seem not associated with difference in immune response to the vaccine.

Funding: None.
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http://dx.doi.org/10.1016/j.eclinm.2021.100928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177433PMC
June 2021

Efficacy and tolerability of very low-volume bowel preparation in patients with inflammatory bowel diseases.

Eur J Gastroenterol Hepatol 2021 07;33(7):977-982

Gastroenterology Unit, Department of Systems Medicine, University of Rome "Tor Vergata".

Objectives: An adequate bowel preparation is essential for a quality colonoscopy. Patients with inflammatory bowel disease (IBD) show low compliance with bowel preparation due to the large volume of lavage solution to be ingested, especially if active symptoms are present, and the frequency of having a colonoscopy. We evaluated the efficacy and tolerability of a very low-volume (VLV) polyethylene glycol (PEG)-based solution in patients with IBD.

Methods: A cohort of 103 consecutive patients, 56 with Crohn's disease and 47 with ulcerative colitis, received a 1-L PEG-based bowel preparation divided into two 500-mL doses taken the evening before and the morning of the colonoscopy, each dose followed by at least another 500-mL of clear fluids. Colon cleansing was scored according to the Boston Bowel Preparation Scale (BBPS) and evaluated in relation to influencing variables.

Results: Bowel cleansing was adequate (BBPS ≥ 6) in 88 patients (85.4%). The time interval between the end of bowel preparation and the beginning of colonoscopy and the disease activity significantly affected colon cleansing. Most patients declared a complete intake of lavage solution (99%), the willingness to repeat the same bowel preparation in a future colonoscopy (86.4%), and a good taste assessment.

Conclusion: The VLV PEG-based bowel preparation is effective and well accepted by IBD patients. As minimizing the volume of lavage solution required, the VLV-bowel preparation here tested could be of choice in subjects who perform periodically colonoscopy or in those who do not tolerate a larger amount of liquids.
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http://dx.doi.org/10.1097/MEG.0000000000002167DOI Listing
July 2021

INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors: a multicenter prospective observational study (INVIDIa-2).

J Immunother Cancer 2021 05;9(5)

Medical Oncology Unit, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy.

Background: Until now, no robust data supported the efficacy, safety and recommendation for influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs).

Methods: The prospective multicenter observational INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors (INVIDIa-2) study investigated the clinical effectiveness of influenza vaccination in patients with advanced cancer receiving ICIs, enrolled in 82 Italian centers from October 2019 to January 2020. The primary endpoint was the time-adjusted incidence of influenza-like illness (ILI) until April 30, 2020. Secondary endpoints regarded ILI severity and vaccine safety.

Results: The study enrolled 1279 patients; 1188 patients were evaluable for the primary endpoint analysis. Of them, 48.9% (581) received influenza vaccination. The overall ILI incidence was 8.2% (98 patients). Vaccinated patients were significantly more frequently elderly (p<0.0001), males (p=0.004), with poor European Cooperative Oncology Group performance status (p=0.009), affected by lung cancer (p=0.01), and by other non-cancer comorbidities (p<0.0001) when compared with unvaccinated. ILI incidence was not different basing on influenza vaccination: the time-to-ILI was similar in vaccinated and unvaccinated patients (p=0.62). ILI complications were significantly less frequent for patients receiving the vaccination (11.8% vs 38.3% in unvaccinated, p=0.002). ILI-related intravenous therapies were significantly less frequent in vaccinated patients than in unvaccinated (11.8% 29.8%, p=0.027). ILI lethality was, respectively, 0% in vaccinated and 4.3% in unvaccinated patients. Vaccine-related adverse events were rare and mild (1.5%, grades 1-2).

Conclusion: The INVIDIa-2 study results support a positive recommendation for influenza vaccination in patients with advanced cancer receiving immunotherapy.
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http://dx.doi.org/10.1136/jitc-2021-002619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141439PMC
May 2021

Fifth-week immunogenicity and safety of anti-SARS-CoV-2 BNT162b2 vaccine in patients with multiple myeloma and myeloproliferative malignancies on active treatment: preliminary data from a single institution.

J Hematol Oncol 2021 05 17;14(1):81. Epub 2021 May 17.

Hematology Unit, Department of Research and Clinical Oncology, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: Safety and immunogenicity of BNT162b2 mRNA vaccine are unknown in hematological patients; both were evaluated prospectively in 42 patients with multiple myeloma (MM) and 50 with myeloproliferative malignancies (MPM) (20 chronic myeloid leukemias and 30 myeloproliferative neoplasms), all of them on active anti-cancer treatment, in comparison with 36 elderly controls not suffering from cancer. Subjects serologically and/or molecularly (by nasal/throat swab) positives at basal for SARS-CoV-2 were excluded. Primary endpoint was to compare titers of neutralizing anti-SARS-CoV-2 IgG and seroprotection rates among the cohorts at 3 and 5 weeks from first dose.

Methods: Titration was done using LIAISON® SARS-CoV-2 S1/S2 IgG test, a quantitative chemiluminescent immunoassay approved by FDA on the basis of robust evidences of concordance (94.4%) between the test at cutoff of 15 AU/mL and the Plaque Reduction Neutralization Test 90% at 1:40 ratio. Cutoff of 15 AU/mL was assumed to discriminate responders to vaccination with a protective titer. Cohorts were compared using Fisher' exact test and the Mann-Whitney test as appropriated. Geometric mean concentrations (GMCs), geometric mean ratios and response rates after 1st and 2nd dose were compared in each cohort by Wilcoxon and McNemar tests, respectively.

Results: At 5 weeks, GMC of IgG in elderly controls was 353.3 AU/mL versus 106.7 in MM (p = 0.003) and 172.9 in MPM patients (p = 0.049). Seroprotection rate at cutoff of 15 AU/mL was 100% in controls compared to 78.6% in MM (p = 0.003) and 88% in MPM patients (p = 0.038). In terms of logarithm of IgG titer, in a generalized multivariate linear model, no gender effect was observed (p = 0.913), while there was a significant trend toward lower titers by increasing age (p < 0.001) and in disease cohorts with respect to controls (MM: p < 0.001 and MPM: p < 0.001). An ongoing treatment without daratumumab was associated with higher likelihood of response in MM patients (p = 0.003). No swabs resulted positive on each time point. No safety concerns were observed.

Conclusions: BNT162b2 has demonstrated to be immunogenic at different extent among the cohorts. Response was 88% and robust in MPM patients. MM patients responded significantly less, particularly those on anti-CD38-based treatment. These latter patients should be advised to maintain masks and social distancing regardless of vaccination status, and their cohabiting family members need to be vaccinated in order to reduce the risk of contagion from the family. Additional boosters and titer monitoring could be considered. Trial registration Study was formally approved by the IRCCS Central Ethical Committee of Regione Lazio in January 2021 (Prot. N-1463/21).
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http://dx.doi.org/10.1186/s13045-021-01090-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128283PMC
May 2021

Ipilimumab and Stereotactic Radiosurgery with CyberKnife System in Melanoma Brain Metastases: A Retrospective Monoinstitutional Experience.

Cancers (Basel) 2021 Apr 13;13(8). Epub 2021 Apr 13.

Radiation Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy.

The median overall survival (OS) and local control (LC) of patients with melanoma brain metastases (MBMs) are poor even with immune checkpoint inhibitors and/or radiotherapy (RT). The aims of the study were to evaluate the association and timing of stereotactic radiotherapy (SRT)/radiosurgery (SRS) performed with the CyberKnife System and ipilimumab (IPI). A total of 63 MBMs patients were analyzed: 53 received RT+IPI and 10 RT alone. Therefore, the patients were divided into four groups: RT PRE-PI (>4 weeks before IPI) (18), RT CONC-IPI (4 weeks before/between first and last cycle/within 3 months of last cycle of IPI) (20), RT POST-IPI (>3 months after IPI) (15), and NO-IPI (10). A total of 127 lesions were treated: 75 with SRS (one fraction) and 24 with SRT (three to five fractions). The median follow-up was 10.6 months. The median OS was 10.6 months for all patients, 10.7 months for RT+IPI, and 3.3 months for NO-IPI ( = 0.96). One-year LC was 50% for all patients, 56% for RT+IPI, and 18% for NO-IPI ( = 0.08). The 1-year intracranial control was 45% for all patients, 44% for RT+IPI, and 51% for NO-IPI ( = 0.73). IPI with SRS/SRT in MBMs treatment could improve LC. However, the impact and timing of the two modalities on patients' outcomes are still unclear.
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http://dx.doi.org/10.3390/cancers13081857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068853PMC
April 2021

Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study.

Lancet Respir Med 2021 09 9;9(9):969-976. Epub 2021 Apr 9.

Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy; EPigenetic Immune-Oncology Consortium Airc (EPICA), Rome, Italy; Department of Medicine, Surgery, and Neuroscience, University of Siena, Siena, Italy; Fondazione Italian Network for Tumour Biotherapy (NIBIT) Onlus, Siena, Italy. Electronic address:

Background: The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [IQR 49-53]. Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy.

Methods: NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. In this follow-up study, patients with disease progression following initial clinical benefit-ie, a partial repsonse or stable disease-were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov, number NCT02588131.

Findings: 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49-53), median overall survival was 16·5 months (95% CI 13·7-19·2). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22·0-25·0), median overall survival was 12·5 months (95% CI 0·0-25·8), and survival at 12 months was 52·9%, at 18 months was 35·3%, and at 24 months was 23·5%. There were no grade 3-4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8·3 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8·3 mutations per Mb and those with TMB lower than the median in the retreated cohort (41·3 months vs 17·4 months; p=0·02).

Interpretation: Tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients.

Funding: NIBIT Foundation, Fondazione AIRC, AstraZeneca.
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http://dx.doi.org/10.1016/S2213-2600(21)00043-6DOI Listing
September 2021

Low Frequency of Acute Pancreatitis in Hospitalized COVID-19 Patients.

Pancreas 2021 03;50(3):393-398

From the Department of Systems Medicine, University of Rome "Tor Vergata".

Objective: The clinical significance of increased serum pancreatic enzymes (PEs) in coronavirus disease 2019 (COVID-19) patients has not yet been fully understood. We aimed to investigate the frequency and the impact on clinical outcome of PE elevation and acute pancreatitis in such patients.

Methods: Clinical data, laboratory tests, and cross-sectional images were analyzed from COVID-19 patients admitted to the Tor Vergata Hospital in Rome. Variables associated with PE abnormalities, intensive care unit (ICU) admission, or death were investigated through univariate and multivariate analyses and Cox proportional hazard model.

Results: Pancreatic enzymes were available in 254 of 282 COVID-19 patients. Among these, 66 patients (26%) showed mild elevation of PE, and 11 patients (4.3%) had severe elevation (>3 times of the upper limit of normal). Overall, 2 patients met the diagnostic criteria for acute pancreatitis. Hepatic and renal involvements were associated with PE elevation. Multivariate analysis showed that mild and severe PE elevations were significantly associated with ICU admission (odds ratios, 5.51 [95% confidence interval, 2.36-12.89; P < 0.0001] and 26.2 [95% confidence interval, 4.82-142.39; P < 0.0001]).

Conclusions: Increase in serum PE, but not acute pancreatitis, is frequent in hospitalized COVID-19 patients and associates with ICU admission.
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http://dx.doi.org/10.1097/MPA.0000000000001770DOI Listing
March 2021

Systemic effect of radiotherapy before or after nivolumab in lung cancer: an observational, retrospective, multicenter study.

Tumori 2021 Apr 4:3008916211004733. Epub 2021 Apr 4.

Department of Oncology, San Camillo de Lellis Hospital, Rieti, Italy.

Background: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses.

Objective: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC).

Methods: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic.

Results: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], = 0.005; median OS, 22.4 months vs 8.6 months, = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0).

Conclusions: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.
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http://dx.doi.org/10.1177/03008916211004733DOI Listing
April 2021
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