Publications by authors named "Giovanni Apolone"

115 Publications

Timeline of SARS-CoV-2 Spread in Italy: Results from an Independent Serological Retesting.

Viruses 2021 Dec 30;14(1). Epub 2021 Dec 30.

Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.

The massive emergence of COVID-19 cases in the first phase of pandemic within an extremely short period of time suggest that an undetected earlier circulation of SARS-CoV-2 might have occurred. Given the importance of this evidence, an independent evaluation was recommended by the World Health Organization (WHO) to test a subset of samples selected on the level of positivity in ELISA assays (positive, low positive, negative) detected in our previous study of prepandemic samples collected in Italy. SARS-CoV-2 antibodies were blindly retested by two independent centers in 29 blood samples collected in the prepandemic period in Italy, 29 samples collected one year before and 11 COVID-19 control samples. The methodologies used included IgG-RBD/IgM-RBD ELISA assays, a qualitative micro-neutralization CPE-based assay, a multiplex IgG protein array, an ELISA IgM kit (Wantai), and a plaque-reduction neutralization test. The results suggest the presence of SARS-CoV-2 antibodies in some samples collected in the prepandemic period, with the oldest samples found to be positive for IgM by both laboratories collected on 10 October 2019 (Lombardy), 11 November 2019 (Lombardy) and 5 February 2020 (Lazio), the latter with neutralizing antibodies. The detection of IgM and/or IgG binding and neutralizing antibodies was strongly dependent on the different serological assays and thresholds employed, and they were not detected in control samples collected one year before. These findings, although gathered in a small and selected set of samples, highlight the importance of harmonizing serological assays for testing the spread of the SARS-CoV-2 virus and may contribute to a better understanding of future virus dynamics.
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http://dx.doi.org/10.3390/v14010061DOI Listing
December 2021

Living systematic review to assess the analgesic undertreatment in cancer patients.

Pain Pract 2022 Jan 11. Epub 2022 Jan 11.

Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background And Aims: This living and systematic review aimed to provide an updated summary of the available evidence on pain undertreatment prevalence in patients with cancer; correlations with some potential determinants and confounders were also carried out.

Materials And Methods: We updated a systematic review published on 2014, including observational and experimental studies reporting the use of the pain management index (PMI) in adults with cancer and pain, from 2014 to 2020. We conducted searches in PubMed/MEDLINE, Embase, and Google Scholar. We performed univariate and multivariable regression analyses to describe the relationship between PMI and a list of potential explanatory variables.

Results: Twenty new papers were identified, yielding a total sample size of 66 studies. The proportion of patients classified as undertreated according to the year of study publication shows a higher decrease from 1994 to 2013 (-13% as relative change) than the most recent years 2014-2020 (-11%). The quality of the included studies has increased over the years (from 80% to 93%). At the multivariable analysis, a statistically significant relationship was confirmed between undertreatment and the year of the publication of the study and with a low-medium economic level of the countries, where the studies were conducted.

Discussion: Despite the improvement when compared to the period 1994-2000, still about 40% of the cases identified received an analgesic treatment inadequate to the intensity of pain, according to the PMI. Despite its intrinsic limitations, PMI continues to be widely used, and it could allow a continuous monitoring of pain management across a different mix of studies and patients.
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http://dx.doi.org/10.1111/papr.13098DOI Listing
January 2022

Evaluation and correlation between SARS-CoV-2 neutralizing and binding antibodies in convalescent and vaccinated subjects.

J Immunol Methods 2022 01 26;500:113197. Epub 2021 Nov 26.

VisMederi srl, Siena, Italy; VisMederi Research Srl, Siena, Italy; Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

Since the first detection of a novel Coronavirus (SARS-CoV-2) in December 2019 in Wuhan (China), it has become crucial to assess and quantize the human humoral immune response after SARS-CoV-2 natural infection and/or vaccination. Having well standardized and reliable serological assays able to accurately measure the total IgG antibodies response as well as the neutralization dynamics, play a pivotal role for the evaluation of "second" and "third" vaccines generation and in monitoring the effect in case of reinfection in the human population caused by the original strains or new SARS-CoV-2 variants. In the present study we reported that both symptomatic convalescent and vaccinated donors showed the presence of different levels of neutralizing antibodies. In addition, vaccinated subjects presented high levels of anti-S antibodies, whereas the complete absence of anti-N antibodies, whereas convalescent patients presented high levels of both anti-S and anti-N antibodies. The evaluation of the correlation between SARS-CoV-2 neutralizing and binding antibodies in convalescent and vaccinated subjects revealed that the IgG anti-S log-values were significantly higher in the vaccinated group respect to convalescent subjects. In addition, the level of binding antibodies recognizing the S protein shows a positive linear regression when compared to neutralizing titres in both the two groups evaluated.
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http://dx.doi.org/10.1016/j.jim.2021.113197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619878PMC
January 2022

Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer.

Cancer Discov 2022 Jan 17;12(1):90-107. Epub 2021 Nov 17.

Molecular Immunology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

In tumor-bearing mice, cyclic fasting or fasting-mimicking diets (FMD) enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. Here we conducted a clinical trial to investigate the safety and biological effects of cyclic, five-day FMD in combination with standard antitumor therapies. In 101 patients, the FMD was safe, feasible, and resulted in a consistent decrease of blood glucose and growth factor concentration, thus recapitulating metabolic changes that mediate fasting/FMD anticancer effects in preclinical experiments. Integrated transcriptomic and deep-phenotyping analyses revealed that FMD profoundly reshapes anticancer immunity by inducing the contraction of peripheral blood immunosuppressive myeloid and regulatory T-cell compartments, paralleled by enhanced intratumor Th1/cytotoxic responses and an enrichment of IFNγ and other immune signatures associated with better clinical outcomes in patients with cancer. Our findings lay the foundations for phase II/III clinical trials aimed at investigating FMD antitumor efficacy in combination with standard antineoplastic treatments. SIGNIFICANCE: Cyclic FMD is well tolerated and causes remarkable systemic metabolic changes in patients with different tumor types and treated with concomitant antitumor therapies. In addition, the FMD reshapes systemic and intratumor immunity, finally activating several antitumor immune programs. Phase II/III clinical trials are needed to investigate FMD antitumor activity/efficacy..
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http://dx.doi.org/10.1158/2159-8290.CD-21-0030DOI Listing
January 2022

T-cell immune response after mRNA SARS-CoV-2 vaccines is frequently detected also in the absence of seroconversion in patients with lymphoid malignancies.

Br J Haematol 2022 02 14;196(3):548-558. Epub 2021 Oct 14.

School of Medicine, University of Milano, Italy.

Patients affected by lymphoid malignancies (LM) are frequently immune-compromised, suffering increased mortality from COVID-19. This prospective study evaluated serological and T-cell responses after complete mRNA vaccination in 263 patients affected by chronic lymphocytic leukaemia, B- and T-cell lymphomas and multiple myeloma. Results were compared with those of 167 healthy subjects matched for age and sex. Overall, patient seroconversion rate was 64·6%: serological response was lower in those receiving anti-cancer treatments in the 12 months before vaccination: 55% vs 81·9% (P < 0·001). Anti-CD20 antibody plus chemotherapy treatment was associated with the lowest seroconversion rate: 17·6% vs. 71·2% (P < 0·001). In the multivariate analysis conducted in the subgroup of patients on active treatment, independent predictors for seroconversion were: anti-CD20 treatment (P < 0·001), aggressive B-cell lymphoma diagnosis (P = 0·002), and immunoglobulin M levels <40 mg/dl (P = 0·030). The T-cell response was evaluated in 99 patients and detected in 85 of them (86%). Of note, 74% of seronegative patients had a T-cell response, but both cellular and humoral responses were absent in 13·1% of cases. Our findings raise some concerns about the protection that patients with LM, particularly those receiving anti-CD20 antibodies, may gain from vaccination. These patients should strictly maintain all the protective measures.
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http://dx.doi.org/10.1111/bjh.17877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653177PMC
February 2022

A Low-Dose CT-Based Radiomic Model to Improve Characterization and Screening Recall Intervals of Indeterminate Prevalent Pulmonary Nodules.

Diagnostics (Basel) 2021 Sep 3;11(9). Epub 2021 Sep 3.

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milan, Italy.

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 radiomics for improving the characterization and optimizing screening recall intervals of indeterminate PNs.
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http://dx.doi.org/10.3390/diagnostics11091610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471292PMC
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

Hereditary colorectal cancer syndromes and the COVID-19 pandemic: results from a survey conducted in patients enrolled in a dedicated registry.

Qual Life Res 2021 Aug 23. Epub 2021 Aug 23.

Unit of Hereditary Digestive Tract Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, Italy.

Purpose: The coronavirus 2019 (COVID-19) pandemic has had profound consequences also for non-infected patients. This study aimed to evaluate the impact of the pandemic on the quality of life of a population with hereditary gastrointestinal cancer predisposition syndromes and on the surveillance/oncological care program of patients enrolled in a dedicated registry.

Methods: The study was conducted by means of an online self-report survey during the first Italian national lockdown. The survey comprised four sections: demographics; perception/knowledge of COVID-19; impact of the COVID-19 pandemic on surveillance and cancer care; health status (SF-12 questionnaire).

Results: 211 complete questionnaires were considered. 25.12% of respondents reported being not at all frightened by COVID-19, 63.98% felt "not at all" or "a little" more fragile than the healthy general population, and 66.82% felt the coronavirus to be no more dangerous to them than the healthy general population. 88.15% of respondents felt protected knowing they were monitored by a team of dedicated professionals.

Conclusion: Patients with hereditary gastrointestinal cancer predisposition syndromes reported experiencing less fear related to COVID-19 than the healthy general population. The study results suggest that being enrolled in a dedicated registry can reassure patients, especially during health crises.
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http://dx.doi.org/10.1007/s11136-021-02973-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381716PMC
August 2021

Preventive Anti-inflammatory Diet to Reduce Gastrointestinal Inflammation in Familial Adenomatous Polyposis Patients: A Prospective Pilot Study.

Cancer Prev Res (Phila) 2021 10 12;14(10):963-972. Epub 2021 Jul 12.

Unit of Hereditary Digestive Tract Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Familial adenomatous polyposis (FAP) is an autosomal-dominant hereditary condition associated with germline mutations in the adenomatous polyposis coli gene. Patient management involves prophylactic surgery and intensive life-long endoscopic surveillance. Diet is a major concern for patients with FAP, who are generally free of symptoms before surgery but tend to have issues related to bowel function postoperatively. We hypothesized that a low-inflammatory diet based on the principles and recipes of the Mediterranean diet would reduce markers of local and systemic inflammation. Twenty-eight patients with FAP over 18 years of age who underwent rectum-sparing prophylactic colectomy and were included in our surveillance program participated in a pilot dietary intervention study. Blood and stool samples at baseline (T0), at the end of the dietary intervention (T1, three months), and at the end of the study (T2, six months after T0) were collected. Gastrointestinal inflammation markers including fecal calprotectin, cyclooxygenase-2, and 15-hydroxyprostaglandin dehydrogenase were evaluated. Serum calprotectin, insulin, insulin-like growth factor-1, C-reactive protein, and glycated hemoglobin were also assessed. Significant changes in serum calprotectin, insulin, and insulin-like growth factor-1 levels occurred over time. Borderline significant changes were observed in the neutrophil-lymphocyte ratio. These changes were noticeable immediately at the end of the 3-month active dietary intervention (T1). A significant increase in 15-hydroxyprostaglandin dehydrogenase expression in the normal crypts of matched samples was also observed between T0 and T2. This pilot study supports the hypothesis that a low-inflammatory diet can modulate gastrointestinal markers of inflammation in individuals with FAP. PREVENTION RELEVANCE: Cancer is known to be related to inflammatory conditions. This study suggests that anti-inflammatory dietary intervention may potentially prevent adenomas and cancer in FAP patients by reducing systemic and tissue inflammatory indices.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0076DOI Listing
October 2021

A focused ethnography in the context of a European cancer research hospital accreditation program.

BMC Health Serv Res 2021 May 11;21(1):446. Epub 2021 May 11.

Azienda USL - IRCCS di Reggio Emilia, viale Umberto I, 50, 42123, Reggio Emilia, Italy.

Background: A quality accreditation program (AP) is designed to guarantee predefined quality standards of healthcare organizations. Evidence of the impact of quality standards remains scarce and somewhat challenging to document. This study aimed to investigate the accreditation of a cancer research hospital (Italy), promoted by the Organization of European Cancer Institutes (OECI), by focusing on the individual, group, and organizational experiences resulting from the OECI AP.

Methods: A focused ethnography study was carried out to analyze the relevance of participation in the accreditation process. Twenty-nine key informants were involved in four focus group meetings, and twelve semistructured interviews were conducted with professionals and managers. Inductive qualitative content analysis was applied to examine all transcripts.

Results: Four main categories emerged: a) OECI AP as an opportunity to foster diversity within professional roles; b) OECI AP as a possibility for change; c) perceived barriers; and d) OECI AP-solicited expectations.

Conclusions: The accreditation process is an opportunity for improving the quality and variety of care services for cancer patients through promoting an interdisciplinary approach to care provision. Perceiving accreditation as an opportunity is a prerequisite for overcoming the barriers that professionals involved in the process may report. Critical to a positive change is sharing the values and the framework, which are at the basis of accreditation programs. Improving the information-sharing process among managers and professionals may limit the risk of unmet expectations and prevent demotivation by future accreditation programs. Finally, we found that positive changes are more likely to happen when an accreditation process is considered an activity whose results depend on managers' and professionals' joint work.
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http://dx.doi.org/10.1186/s12913-021-06466-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111912PMC
May 2021

Conquer cancer for everyone.

Lancet Oncol 2021 05;22(5):583-584

European Association for Palliative Care Research Network, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy; Organisation of European Cancer Institutes, Fondation Universitaire, Brussels, Belgium.

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http://dx.doi.org/10.1016/S1470-2045(21)00059-0DOI Listing
May 2021

Reply to comments on: Unexpected detection of SARS-CoV-2 antibodies in the prepandemic period in Italy.

Tumori 2021 10 20;107(5):472-473. Epub 2021 Apr 20.

Scientific Direction, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

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http://dx.doi.org/10.1177/03008916211009688DOI Listing
October 2021

SARS-CoV-2 Serology Monitoring of a Cancer Center Staff in the Pandemic Most Infected Italian Region.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

Biomarker Unit, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy.

Since the beginning of the COVID-19 outbreak, Cancer Centers adopted specific procedures both to protect patients and to monitor the possible spread of SARS-CoV-2 among healthcare personnel (HCP). In April 2020 at Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, one of the three oncologic hubs in Lombardy where the Health Regional Authorities referred all the cancer patients of the region, we implemented a prospective longitudinal study aimed at monitoring the serological response to SARS-Cov-2 in HCP. One hundred and ten HCP answered a questionnaire and were screened by nasopharyngeal swabs as well as for IgM/IgG levels; seropositive HCPs were further screened every 40-45 days using SARS-CoV-2-specific serology. We identified a fraction of HCP with long-term anti-SARS-CoV-2 antibody responses, though negative for viral RNA, and thus probably able to safely approach fragile cancer patients. Monitoring asymptomatic HCP might provide useful information to organize the healthcare service in a Cancer Center, while waiting for the effectiveness of the active immunization by SARS-CoV-2 vaccines, which will provide protection from infection.
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http://dx.doi.org/10.3390/cancers13051035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957867PMC
March 2021

Unexpected detection of SARS-CoV-2 antibodies in the prepandemic period in Italy.

Tumori 2021 Oct 11;107(5):446-451. Epub 2020 Nov 11.

Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

There are no robust data on the real onset of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and spread in the prepandemic period worldwide. We investigated the presence of SARS-CoV-2 receptor-binding domain (RBD)-specific antibodies in blood samples of 959 asymptomatic individuals enrolled in a prospective lung cancer screening trial between September 2019 and March 2020 to track the date of onset, frequency, and temporal and geographic variations across the Italian regions. SARS-CoV-2 RBD-specific antibodies were detected in 111 of 959 (11.6%) individuals, starting from September 2019 (14%), with a cluster of positive cases (>30%) in the second week of February 2020 and the highest number (53.2%) in Lombardy. This study shows an unexpected very early circulation of SARS-CoV-2 among asymptomatic individuals in Italy several months before the first patient was identified, and clarifies the onset and spread of the coronavirus disease 2019 (COVID-19) pandemic. Finding SARS-CoV-2 antibodies in asymptomatic people before the COVID-19 outbreak in Italy may reshape the history of pandemic.
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http://dx.doi.org/10.1177/0300891620974755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529295PMC
October 2021

Impact of COVID-19 in gynecologic oncology: a Nationwide Italian Survey of the SIGO and MITO groups.

J Gynecol Oncol 2020 11;31(6):e92

Department of Gynecology, San Camillo-Forlanini Hospital, Rome, Italy.

Objective: Coronavirus disease 2019 (COVID-19) has caused rapid and drastic changes in cancer management. The Italian Society of Gynecology and Obstetrics (SIGO), and the Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) promoted a national survey aiming to evaluate the impact of COVID-19 on clinical activity of gynecologist oncologists and to assess the implementation of containment measures against COVID-19 diffusion.

Methods: The survey consisted of a self-administered, anonymous, online questionnaire. The survey was sent via email to all the members of the SIGO, and MITO groups on April 7, 2020, and was closed on April 20, 2020.

Results: Overall, 604 participants completed the questionnaire with a response-rate of 70%. The results of this survey suggest that gynecologic oncology units had set a proactive approach to COVID-19 outbreak. Triage methods were adopted in order to minimize in-hospital diffusion of COVID-19. Only 38% of gynecologic surgeons were concerned about COVID-19 outbreak. Although 73% of the participants stated that COVID-19 has not significantly modified their everyday practice, 21% declared a decrease of the use of laparoscopy in favor of open surgery (19%). However, less than 50% of surgeons adopted specific protection against COVID-19. Additionally, responders suggested to delay cancer treatment (10%-15%), and to perform less radical surgical procedures (20%-25%) during COVID-19 pandemic.

Conclusions: National guidelines should be implemented to further promote the safety of patients and health care providers. International cooperation is of paramount importance, as heavily affected nations can serve as an example to find out ways to safely preserve clinical activity during the COVID-19 outbreak.
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http://dx.doi.org/10.3802/jgo.2020.31.e92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593217PMC
November 2020

Cardiovascular Risk After Adjuvant Trastuzumab in Early Breast Cancer: An Italian Population-Based Cohort Study.

Oncologist 2020 10 29;25(10):e1492-e1499. Epub 2020 Aug 29.

National Centre for Healthcare Research and Pharmacoepidemiology, Milan, Italy.

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 low and limited to the treatment period. The findings suggest that developing tools that would be adequately able to predict cardiac toxicity at an early stage remains an important area in which additional research efforts are needed.
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http://dx.doi.org/10.1634/theoncologist.2020-0216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543336PMC
October 2020

PATIENT VOICES, a project for the integration of the systematic assessment of patient reported outcomes and experiences within a comprehensive cancer center: a protocol for a mixed method feasibility study.

Health Qual Life Outcomes 2020 Jul 28;18(1):252. Epub 2020 Jul 28.

Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Listening to "patient voices" in terms of symptoms, emotional status and experiences with care, is crucial for patient empowerment in clinical practice. Despite convincing evidence that routine patient reported outcomes and experience measurements (PRMs) with rapid feed-back to oncologists can improve symptom control, patient well-being and cost effectiveness, PRMs are not commonly used in cancer care, due to barriers at various level. Part of these barriers may be overcome through electronic PRMs collection (ePRMs) integrated with the electronic medical record (EMR). The PATIENT VOICES initiative is aimed at achieving a stepwise integration of ePRMs assessment into routine cancer care. The feasibility project presented here is aimed at assessing the knowledge, use and attitudes toward PRMs in a comprehensive cancer centre; developing and assessing feasibility of a flexible system for ePRM assessment; identifying barriers to and developing strategies for implementation and integration of ePRMs clinical practice.

Methods: The project has been organized into four phases: a) pre-development; b) software development and piloting; c) feasibility assessment; d) post-development. A convergent mixed method design, based on concurrent quantitative and qualitative data collection will be applied. A web-survey on health care providers (HCPs), qualitative studies on patients and HCPs (semi-structured interviews and focus groups) as well as longitudinal and cross-sectional quantitative studies will be carried out. The quantitative studies will enroll 600 patients: 200 attending out-patient clinics (physical symptom assessement), 200 attending inpatient wards (psychological distress assessment) and 200 patients followed by multidisciplinary teams (patient experience with care assessment). The Edmonton symptom assessment scale, the Distress Thermometer, and a tool adapted from existing patient reported experience with cancer care questionnaires, will be used in quantitative studies. A multi-disciplinary stakeholder team including researchers, clinicians, health informatics professionals, health system administrators and patients will be involved in the development of potentially effective implementation strategies in the post development phase.

Discussion: The documentation of potential advantages and implementation barriers achieved within this feasibility project, will serve as a starting point for future and more focused interventions aimed at achieving effective ePRMs routine assessment in cancer care.

Trial Registration: ClinicalTrials.gov ( NCT03968718 ) May 30th, 2019.
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http://dx.doi.org/10.1186/s12955-020-01501-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388528PMC
July 2020

A moonshot approach toward the management of cancer patients in the COVID-19 time: what have we learned and what could the Italian network of cancer centers (Alliance Against Cancer, ACC) do after the pandemic wave?

J Exp Clin Cancer Res 2020 Jun 11;39(1):109. Epub 2020 Jun 11.

Alliance Against Cancer, Rome, Italy.

If we focus our attention on seven main features of COVID-19 infection (heterogeneity, fragility, lack of effective treatments and vaccines, "miraculous cures", psychological suffering, deprivation, and globalization), we may establish parallelism with the challenges faced in the steep road to the understanding and treatment of neoplastic diseases. How the similarities between these two conditions can help us cope with the emergency effort represented by the management of cancer patients in the COVID-19 era, today and in the future? In a manner similar to the Cancer Moonshot initiative in the United States, we can hypothesize a multinational moonshot project towards the management of cancer patients during COVID-19 pandemic. In particular, we believe that the main road to elaborate meaningful scientific evidence is represented by the collection of all the data on COVID-19 and cancer comorbidity that are and will become available in cancer centers, coupled with the design of large clinical studies. To address this goal, it is essential to identify the entity that can produce this scientific evidences and the potentially most successful research strategy to undertake. The largest Italian organization for cancer research, Alliance Against Cancer (Alleanza Contro il Cancro, ACC), is called to play a scientific leadership in addressing these challenges, which requires the coordination of oncology teams at regional, national, and international levels. To fulfill this commitment, ACC will create a liaison with health government agencies in order to develop "dynamic" indications able to fight such an unpredictable pandemic.
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http://dx.doi.org/10.1186/s13046-020-01614-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286743PMC
June 2020

Caring for patients with cancer in the COVID-19 era.

Nat Med 2020 05 16;26(5):665-671. Epub 2020 Apr 16.

Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

The current COVID-19 pandemic challenges oncologists to profoundly re-organize oncological care in order to dramatically reduce hospital visits and admissions and therapy-induced immune-related complications without compromising cancer outcomes. Since COVID-19 is a novel disease, guidance by scientific evidence is often unavailable, and impactful decisions are inevitably made on the basis of expert opinions. Here we report how the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations 'pandemic proof'. We identify and discuss many commonalities, but also important local differences, and pinpoint critical research priorities to enable evidence-based remodeling of cancer care during the COVID-19 pandemic. Also, we discuss how the current situation offers a unique window of opportunity for assessing the effects of de-escalating anticancer regimens, which may fast-forward the development of more-refined and less-toxic treatments. By sharing our joint experiences, we offer a roadmap for proceeding and aim to mobilize the global research community to generate the data that are critically needed to offer the best possible care to patients.
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http://dx.doi.org/10.1038/s41591-020-0874-8DOI Listing
May 2020

Response of a comprehensive cancer center to the COVID-19 pandemic: the experience of the Fondazione IRCCS-Istituto Nazionale dei Tumori di Milano.

Tumori 2020 May 4:300891620923790. Epub 2020 May 4.

Scientific Director, Fondazione IRCCS Istituto Tumori di Milano, Milan, Italy.

Background: The rapid spread of coronavirus disease (COVID-19) is affecting many countries. While healthcare systems need to cope with the need to treat a large number of people with different degrees of respiratory failure, actions to preserve aliquots of the healthcare system to guarantee treatment to patients are mandatory.

Methods: In order to protect the Fondazione IRCCS-Istituto Nazionale dei Tumori di Milano from the spread of COVID-19, a number of to-hospital and within-hospital filters were applied. Among others, a triage process to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity in patients with cancer was developed consisting of high-resolution low-dose computed tomography (CT) scan followed by reverse transcription polymerase chain reaction (RT-PCR) detection of SARS-CoV-2 in nose-throat swabs whenever CT was suggestive of lung infection. To serve symptomatic patients who were already admitted to the hospital or in need of hospitalization while waiting for RT-PCR laboratory confirmation of infection, a COVID-19 surveillance zone was set up.

Results: A total of 301 patients were screened between March 6 and April 3, 2020. Of these, 47 were hospitalized, 53 needed a differential diagnosis to continue with their cancer treatment, and 201 were about to undergo surgery. RT-PCR was positive in 13 of 40 hospitalized patients (32%), 14 of 52 day hospital patients (27%), and 6 of 201 surgical patients (3%).

Conclusion: Applying filters to protect our comprehensive cancer center from COVID-19 spread contributed to guaranteeing cancer care during the COVID-19 crisis in Milan. A surveillance area and surgical triage allowed us to protect the hospital from as many as 33 patients infected with SARS-CoV-2.
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http://dx.doi.org/10.1177/0300891620923790DOI Listing
May 2020

Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19.

N Engl J Med 2020 06 1;382(25):2431-2440. Epub 2020 May 1.

From the University of Milano-Bicocca (G.M.), the National Center of Healthcare Research and Pharmacoepidemiology (F.R., G.C.) and the Unit of Biostatistics, Epidemiology, and Public Health, Department of Statistics and Quantitative Methods (F.R., G.C.), University of Milano-Bicocca, Azienda Regionale per l'Innovazione e gli Acquisti (M.L.), and Fondazione IRCCS Istituto Nazionale dei Tumori (G.A.), Milan, and Policlinico di Monza, Monza (G.M.) - all in Italy.

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 affected the risk of COVID-19.
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http://dx.doi.org/10.1056/NEJMoa2006923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206933PMC
June 2020

Early Modulation of Circulating MicroRNAs Levels in HER2-Positive Breast Cancer Patients Treated with Trastuzumab-Based Neoadjuvant Therapy.

Int J Mol Sci 2020 Feb 18;21(4). Epub 2020 Feb 18.

Biomarker Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20100 Milan, Italy.

Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2-targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after trastuzumab. Increased levels of ct-miR-148a-3p and ct-miR-374a-5p were significantly associated with pathological complete response (pCR) ( = 0.008 and 0.048, respectively). At a threshold ≥ the upper limit of the 95%CI of the mean difference, pCR resulted 45% (95%CI 24%-68%), and 44% (95%CI 22%-69%) for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95%CI 1.23-9.46, = 0.018) in bivariate analysis along with estrogen receptor status. Combined information from ct-miR-148a-3p and ct-miR140-5p, which we previously reported to identify trastuzumab-responsive patients, resulted in greater predictive capability over each other, with pCR of 54% (95%CI 25%-81%) and 0% (95%CI 0%-31%) in ct-miR-148a/ct-miR-140-5p high/present and low/absent, respectively. GO and KEGG analyses showed common enriched terms between the targets of these ct-miRNAs, including cell metabolism regulation, AMPK and MAPK signaling, and HCC progression. In conclusion, early modulated ct-miR-148-3p may inform on the functional processes underlying treatment response, integrate the information from already available predictive biomarkers, and identify patients likely to respond to single agent trastuzumab-based neoadjuvant therapy.
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http://dx.doi.org/10.3390/ijms21041386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073028PMC
February 2020

Health technology assessment-based approach to flow cytometric immunophenotyping of acute leukemias: a literature classification.

Tumori 2020 Feb 14:300891620904412. Epub 2020 Feb 14.

Fondazione IRCCS Istituto Nazionale dei Tumori, Direzione Scientifica, Milan, Italy.

Objective: Acute leukemia (AL) is a broad, heterogeneous group of malignant diseases. The diagnostic workup of AL is based on several clinical and laboratory findings, including flow cytometric immunophenotyping. However, the role of this assay in the diagnosis of AL has not been systematically investigated. The aim of this study was to determine the accuracy and utility of flow cytometric immunophenotyping in the identification, characterization, and staging of AL.

Methods: We performed a systematic selection and classification of the literature since 1980, focused on flow cytometric immunophenotyping of AL. We applied a 6-variables model to cover both the technical capabilities and the clinical value of flow cytometric immunophenotyping in the diagnosis of AL.

Results: Using 3 key words (acute leukemia, immunophenotyping, flow cytometry), we screened the literature from January 1985 to April 2015 in PubMed and Embase databases and found 1010 articles. A total of 363 were selected and submitted to the expert panel, which selected a final data set of 248 articles to be analyzed. Of these, 160 were focused on clinical and biological issues, 55 were technical articles, and 31 were reviews. These 248 articles were then analyzed according to the 6-variables model and definitively classified.

Conclusions: We assessed the literature on flow cytometric immunophenotyping of AL over 3 decades as the first step toward an evidence-based analysis of the impact of this technology on the clinical management of patients with AL.
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http://dx.doi.org/10.1177/0300891620904412DOI Listing
February 2020

Number of lung resections performed and long-term mortality rates of patients after lung cancer surgery: evidence from an Italian investigation.

Eur J Cardiothorac Surg 2020 07;58(1):70-77

National Centre for Healthcare Research and Pharmacoepidemiology, Milan, Italy.

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.
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http://dx.doi.org/10.1093/ejcts/ezaa031DOI Listing
July 2020

Neoadjuvant eribulin mesylate following anthracycline and taxane in triple negative breast cancer: Results from the HOPE study.

PLoS One 2019 7;14(8):e0220644. Epub 2019 Aug 7.

Fondazione IRCCS Istituto Nazionale dei Tumori-Milano, Italy.

Background: Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy.

Methods: Patients with primary triple negative breast cancer ≥2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study.

Results: In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2-5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR.

Conclusions: Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial-mesenchymal transition, claims for further investigation.

Trial Registration: EU Clinical Trial Register, EudraCT number 2012-004956-12.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220644PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685628PMC
March 2020

The 41-gene classifier TRAR predicts response of HER2 positive breast cancer patients in the NeoALTTO study.

Eur J Cancer 2019 09 5;118:1-9. Epub 2019 Jul 5.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. Electronic address:

Background: Dual HER2-inhibition combined with neoadjuvant chemotherapy allows increased pathological complete response (pCR) rate. However, with the addition of new agents, there is a growing need to select patients to minimise overtreatment. Herein, we evaluated the 41-gene classifier TRAR to predict pCR to anti-HER2 therapies in the NeoALTTO trial.

Patients And Methods: Gene expression data were obtained using RNA from 226 pretreatment tumour biopsies. Logistic regression analysis and the area under the receiver operating characteristic (ROC) curve (AUC) were used to evaluate TRAR predictive and discriminatory capabilities.

Results: TRAR levels were associated with pCR (odds ratio, OR: 0.25, 95% confidence interval, CI: 0.15-0.42). The ROC analysis showed AUC values of 0.73 (95% CI: 0.67-0.80) overall; 0.70 (0.59-0.81) and 0.71 (0.62-0.80) for positive and negative oestrogen receptor cases and 0.74 (0.60-0.88), 0.76 (0.65-0.87) and 0.71 (0.59-0.83) for trastuzumab, lapatinib and combined treatment arms, respectively. TRAR provided reliable predictive information beyond established clinicopathological variables (OR: 0.26, 95% CI: 0.14-0.47). Furthermore, addition of TRAR to these variables provided greater predictive capability than the addition of PAM50: AUC 0.78 (0.72-0.84) versus 0.74 (0.67-0.81), p = 0.04.

Conclusion: TRAR represents a promising tool to refine the ability to identify patients sensitive to anti-HER2 (including trastuzumab-only)-based therapy and eligible for de-escalated treatment strategies.
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http://dx.doi.org/10.1016/j.ejca.2019.06.001DOI Listing
September 2019
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