Publications by authors named "Paolo Verderio"

121 Publications

Exploring the association with disease recurrence of miRNAs predictive of colorectal cancer.

Int J Biol Markers 2021 Dec 21:17246008211064915. Epub 2021 Dec 21.

Genetic Epidemiology and Pharmacogenomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Introduction: Disease recurrence after surgery is a crucial predictor of poor prognosis in colorectal cancer, where disseminated disease at the time of intervention can also be observed in localized early-stage cases. We evaluated the ability to predict disease recurrence of miRNAs from two signatures that we have found linked to the presence of colorectal cancer (CL signature) or adenoma (HgA signature) in higher-risk subjects.

Methods: miRNAs from the signatures were studied longitudinally by quantitative real-time polymerase chain reaction in plasma from 24 patients with resectable colorectal cancer collected at the time of surgery and during scheduled follow-up across 36 months. Patients either showed relapse within 36 months (alive with disease (AWD)), or remained disease-free (no evidence of disease (NED)) for the same period.

Results: Although the signatures did not predict recurrence, expression of the miRNAs from the CL signature decreased 1 year after surgery, and one miRNA of the signature, miR-378a-3p, almost reached significance in the NED subgroup (Wilcoxon signed-rank test: -value = 0.078). Also, miR-335-5p from the HgA signature was higher in AWD patients before surgery (Kruskal-Wallis test: -value = 0.019).

Conclusions: These data, although from a small cohort of patients, support the possible use of miRNAs as non-invasive biomarkers in liquid biopsy-based tests to identify patients at risk of relapse and to monitor them during follow-up.
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http://dx.doi.org/10.1177/17246008211064915DOI Listing
December 2021

What if the future of HER2-positive breast cancer patients was written in miRNAs? An exploratory analysis from NeoALTTO study.

Cancer Med 2022 01 17;11(2):332-339. Epub 2021 Dec 17.

Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Neoadjuvant therapy with dual HER2 blockade improved pathological complete response (pCR) rate in HER2-positive breast cancer patients. Nevertheless, it would be desirable to identify patients exquisitely responsive to single agent trastuzumab to minimize or avoid overtreatment. Herein, we evaluated the predictive and prognostic value of basal primary tumor miRNA expression profile within the trastuzumab arm of NeoALTTO study (ClinicalTrials.gov Identifier: NCT00553358).

Methods: RNA samples from baseline biopsies were randomized into training (n = 45) and testing (n = 47) sets. After normalization, miRNAs associated with Event-free survival (EFS) and pCR were identified by univariate analysis. Multivariate models were implemented to generate specific signatures which were first confirmed, and then analyzed together with other clinical and pathological variables.

Results: We identified a prognostic signature including hsa-miR-153-3p (HR 1.831, 95% CI: 1.34-2.50) and hsa-miR-219a-5p (HR 0.629, 95% CI: 0.50-0.78). For two additional miRNAs (miR-215-5p and miR-30c-2-3p), we found a statistically significant interaction term with pCR (p.interaction: 0.017 and 0.038, respectively). Besides, a two-miRNA signature was predictive of pCR (hsa-miR-31-3p, OR 0.70, 95% CI: 0.53-0.92, and hsa-miR-382-3p, OR: 1.39, 95% CI: 1.01-1.91). Notably, the performance of this predictive miRNA signature resembled that of the genomic classifiers PAM50 and TRAR, and did not improve when the extended models were fitted.

Conclusion: Analyses of primary tumor tissue miRNAs hold the potential of a parsimonious tool to identify patients with differential clinical outcomes after trastuzumab based neoadjuvant therapy.
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http://dx.doi.org/10.1002/cam4.4449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729061PMC
January 2022

Management of Dietary Habits and Diarrhea in Fap Individuals: A Mediterranean Low-Inflammatory Dietary Intervention.

Nutrients 2021 Nov 9;13(11). Epub 2021 Nov 9.

Bioinformatics and Biostatistics Unit, Department of Applied Research and Technological Development, Fondazione IRCSS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

Background: A total colectomy and a frequent life-long endoscopic surveillance are guaranteed to patients with Familial Adenomatous Polyposis (FAP) to reduce their risk of duodenal and rectal stump cancers. However, after surgery, individuals with FAP suffer from an increased number of diarrheal discharges that force them to dietary restrictions. A non-randomized pilot study was conducted to assess whether a three-month low-inflammatory Mediterranean dietary intervention reduces gastro-intestinal markers of inflammation in FAP individuals. The aim of the present work is to evaluate the participant's adherence to the proposed dietary recommendations and the change in their number of diarrheal discharges.

Methods: 26 FAP individuals aged >18 years, who underwent a total colectomy with ileo-rectal anastomosis and were involved in the surveillance program at the Fondazione IRCCS Istituto Nazionale Tumori of Milan, were included in the present analysis.

Results: FAP individuals significantly reduced the foods (-value: 0.002) and increased the consumption of the ones (-value: 0.075). The adherence to the proposed dietary recommendations was accompanied by a significant decrease in the number of diarrheal discharges (-value: 0.008).

Conclusions: This study suggests that adhering to a low-inflammatory Mediterranean diet has a potential protective effect on the number of diarrheal discharges in FAP individuals.
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http://dx.doi.org/10.3390/nu13113988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623170PMC
November 2021

Use of PEAK PlasmaBlade in implant-based breast reconstruction and radiotherapy: new strategy to reduce complications.

Tumori 2021 Oct 31:3008916211056072. Epub 2021 Oct 31.

Plastic and Reconstructive Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Background: Implant-based breast reconstruction in the setting of radiotherapy often leads to higher complications rates (mainly capsular contracture and wound dehiscence) and poor cosmetic outcomes. We hypothesized that the combination of pulsed-electron avalanche knife (PEAK) PlasmaBlade (a pulsed radiofrequency electrosurgery) and acellular dermal matrix Veritas® in postmastectomy radiotherapy implant-based breast reconstruction could result in lower complications rate, better reconstructive results, and patient satisfaction.

Methods: A prospective observational study focused on the use of PEAK PlasmaBlade in implant-based breast reconstruction and radiotherapy was carried out in the Plastic Reconstructive Surgery Unit at Fondazione IRCCS Istituto Nazionale Tumori Milano between December 2017 and 2019 (2017-2018: enrollment; 2018-2019: follow-up). Patient demographics were queried and complication rates and patient and surgeon satisfaction were assessed.

Results: A total of 88 patients were enrolled; 2 patients received bilateral reconstruction, leading to a total of 90 procedures. Sixty-two women received contralateral symmetrization. Seroma was the most frequent minor complication (8.8%); implant exposure was the most recorded among major complications (5.5%). Preoperative lipofilling was the most substantial protective factor for preventing complications ( < 0.001). A significant association between capsular thermal damage thickness and the type of electrosurgery used (traditional electrosurgery vs PEAK PlasmaBlade) was observed, with lower values with PEAK PlasmaBlade ( < 0.0001).

Conclusions: Our protocol results in low rates of surgical complications and a high level of patient and surgeon satisfaction although longer follow-up is needed.
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http://dx.doi.org/10.1177/03008916211056072DOI Listing
October 2021

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 2021 Oct 14. 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
October 2021

Contrast-enhanced digital mammography and magnetic resonance imaging: reproducibility compared to pathologic anatomy.

Tumori 2021 Oct 9:3008916211050124. Epub 2021 Oct 9.

Breast Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Lombardia, Italy.

Purpose: To compare the reproducibility between contrast-enhanced digital mammography (CEDM) and magnetic resonance imaging (MRI) with the postsurgical pathologic examination. In addition, the applicability of the Breast Imaging-Reporting and Data System (BI-RADS) lexicon of MRI to CEDM was evaluated for mass lesions.

Methods: A total of 62 patients with a histologically proven diagnosis of breast cancer were included in this study, for a total of 67 lesions. Fifty-nine patients underwent both methods. The reproducibility between MRI vs CEDM and the reference standard (postoperative pathology) was assessed by considering the lesion and breast size as pivotal variables. Reproducibility was evaluated by computing the concordance correlation coefficient (CCC). Bland-Altman plots were used to depict the observed pattern of agreement as well as to estimate the associated bias. Furthermore, the pattern of agreement between the investigated methods with regard to the breast lesion characterization (i.e. mass/nonmass; shape; margins; internal enhanced characteristics) was assessed by computing the Cohen kappa and its 95% confidence interval (CI).

Results: The reproducibility between MRI and the reference standard and between CEDM and the reference standard showed substantial agreement, with a CCC value of 0.956 (95% CI, 0.931-0.972) and 0.950 (95% CI, 0.920-0.969), respectively. By looking at the Bland-Altman analysis, bias values of 2.344 and 1.875 mm were observed for MRI and CEDM vs reference evaluation, respectively. The agreement between MRI and CEDM is substantial with a CCC value of 0.969 (95% CI, 0.949-0.981). The Bland-Altman analysis showed bias values of -0.469 mm when comparing CEDM vs MRI. Following the Landis and Koch classification criteria, moderate agreement was observed between the two methods in describing BI-RADS descriptors of mass lesions.

Conclusion: CEDM is able to measure and describe tumor masses comparably to MRI and can be used for surgical planning.
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http://dx.doi.org/10.1177/03008916211050124DOI Listing
October 2021

Integrated Molecular and Immune Phenotype of HER2-Positive Breast Cancer and Response to Neoadjuvant Therapy: A NeoALTTO Exploratory Analysis.

Clin Cancer Res 2021 12 21;27(23):6307-6313. Epub 2021 Sep 21.

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

Purpose: Little is known about the efficacy of HER2-targeted therapy in patients with breast cancer showing different HER2-pathway dependence and immune phenotypes. Herein, we report a NeoALTTO exploratory analysis evaluating the clinical value of 22 types of tumor-infiltrating immune cells by CIBERSORT and 5 immune-related metagenes in the overall patient population, and in subgroups defined by the TRAR classifier as HER2-addicted (TRAR-low) or not (TRAR-high).

Patients And Methods: Association of baseline TRAR, immune-related metagenes, and CIBERSORT data with pathologic complete response (pCR) and event-free survival (EFS) were assessed using logistic and Cox regression models. Corrections for multiple testing were performed by the Bonferroni method.

Results: A total of 226 patients were analyzed: 80 (35%) achieved a pCR, and 64 (28%) experienced a relapse with a median follow-up of 6.7 (interquartile range 6.1-6.8) years; 108 cases were classified as TRAR-low, and 118 TRAR-high. Overall, γδ T-cell fraction [OR = 2.69; 95% confidence interval (CI), 1.40-5.18], and no immune-related metagenes were predictive of pCR. Notably, lymphocyte-specific kinase (LCK) predicted pCR to combination (OR = 2.53; 95% CI, 1.12-5.69), but not to single-agent trastuzumab or lapatinib [OR = 0.74; 95% CI, 0.45-1.22 ( = 0.01)]. Integrating LCK with γδ T cells in a multivariate model added to the discriminatory capability of clinical and molecular variables with a shift in AUC from 0.80 (95% CI, 0.74-0.86) to 0.83 (95% CI, 0.78-0.89). In TRAR-low cases, activated mast cells, IFN and MHCII were reduced, and STAT1, HCK1, and γδ T cells were associated with pCR. STAT1 was broadly associated with improved EFS regardless of pCR, and nodal status in overall (HR = 0.68; 95% CI, 0.49-0.94) and in TRAR-low cases (HR = 0.50; 95% CI, 0.30-0.86).

Conclusions: Immuno-phenotyping holds the promise to complement current predictive models in HER2-positive breast cancer and to assist in new therapeutic development.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1600DOI Listing
December 2021

Circulating miRNAs as Novel Non-Invasive Biomarkers to Aid the Early Diagnosis of Suspicious Breast Lesions for Which Biopsy Is Recommended.

Cancers (Basel) 2021 Aug 10;13(16). Epub 2021 Aug 10.

Bioinformatics and Biostatistics Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

In population-based screens, tissue biopsy remains the standard practice for women with imaging that suggests breast cancer. We examined circulating microRNAs as minimally invasive diagnostic biomarkers to discriminate malignant from benign breast lesions. miRNAs were analyzed by OpenArray in a retrospective cohort of plasma samples including 100 patients with malignant (T), 89 benign disease (B), and 99 healthy donors (HD) divided into training and testing sets and a prospective cohort (BABE) of 289 women with suspicious imaging findings who underwent tissue biopsy. miRNAs associated with disease status were identified by univariate analysis and then combined into signatures by multivariate logistic regression models. By combining 16 miRNAs differentially expressed in the T vs. HD comparison, 26 signatures were also able to significantly discriminate T from B disease. Seven of them, involving 5 specific miRNAs (miR-625, miR-423-5p, miR-370-3p, miR-181c, and miR-301b), were statistically validated in the testing set. Among the 7 signatures, the discriminatory performances of 5 were confirmed in the prospective BABE Cohort. This study identified 5 circulating miRNAs that, properly combined, distinguish malignant from benign breast disease in women with a high likelihood of malignancy.
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http://dx.doi.org/10.3390/cancers13164028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391908PMC
August 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

Magnetic resonance imaging patterns of tumor response to chemotherapy in desmoid-type fibromatosis.

Cancer Med 2021 07 8;10(13):4356-4365. Epub 2021 Jun 8.

Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: We aimed to investigate changes in volume and MRI T2-weighted intensity in desmoid-type fibromatosis (DF) receiving methotrexate plus vinca-alkaloids (MTX-VA) at Istituto Nazionale dei Tumori, Milan.

Methods: All cases of sporadic DF treated with MTX-VA from 1999 to 2019 were reviewed. MRIs at baseline, 6 and 12 months of chemotherapy and at treatment withdrawal were retrospectively reviewed, contouring the tumor lesion and measuring diameters, volume, and mean T2-signal intensity (normalized to muscle) changes. These parameters were also evaluated according to clinical variables.

Results: Thirty-two DF patients were identified. Best RECIST response was: 25% partial response, 69% stable disease, 6% progression. A ≥65% tumor volume reduction was observed in 38%, <65% reduction in 53%, an increase in 9%. 22% had RECIST stable disease with a ≥65% tumor volume reduction. T2-signal intensity decreased by ≥50% in 47%, <50% in 41% and increased in 12%. In patients with symptomatic improvement while on therapy and in patients maintaining symptomatic improvement during follow-up, median T2-signal intensity showed a reduction along the time points (3.0, 1.9, 1.2, 1.1; 2.9, 2.0, 1.2, 1.2, respectively); in patients without symptomatic improvement and in those clinically progressing during follow-up, a reduction was not observed. High T2-signal intensity at baseline was observed in patients showing RECIST progression during follow-up.

Conclusions: In this series, RECIST detected a lower proportion of responses as compared to volumetric and T2-signal changes. T2-signal reduction seemed to better reflect symptomatic improvement. High T2-signal intensity at baseline was related to a higher proportion of further progression.
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http://dx.doi.org/10.1002/cam4.3973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267164PMC
July 2021

Prediction of Grade Reclassification of Prostate Cancer Patients on Active Surveillance through the Combination of a Three-miRNA Signature and Selected Clinical Variables.

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

Active surveillance (AS) has evolved as a strategy alternative to radical treatments for very low risk and low-risk prostate cancer (PCa). However, current criteria for selecting AS patients are still suboptimal. Here, we performed an unprecedented analysis of the circulating miRNome to investigate whether specific miRNAs associated with disease reclassification can provide risk refinement to standard clinicopathological features for improving patient selection. The global miRNA expression profiles were assessed in plasma samples prospectively collected at baseline from 386 patients on AS included in three independent mono-institutional cohorts (training, testing and validation sets). A three-miRNA signature (, and ) was found to predict reclassification in all patient cohorts (training set: AUC 0.74, 95% CI 0.60-0.87, testing set: AUC 0.65, 95% CI 0.51-0.80, validation set: AUC 0.68, 95% CI 0.56-0.80). Importantly, the addition of the three-miRNA signature improved the performance of the clinical model including clinicopathological variables only (AUC 0.70, 95% CI 0.61-0.78 vs. 0.76, 95% CI 0.68-0.84). Overall, we trained, tested and validated a three-miRNA signature which, combined with selected clinicopathological variables, may represent a promising biomarker to improve on currently available clinicopathological risk stratification tools for a better selection of truly indolent PCa patients suitable for AS.
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http://dx.doi.org/10.3390/cancers13102433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157371PMC
May 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

Retrospective study of late radiation-induced damages after focal radiotherapy for childhood brain tumors.

PLoS One 2021 26;16(2):e0247748. Epub 2021 Feb 26.

Pediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Purpose: To study a robust and reproducible procedure to investigate a relation between focal brain radiotherapy (RT) low doses, neurocognitive impairment and late White Matter and Gray Matter alterations, as shown by Diffusion Tensor Imaging (DTI), in children.

Methods And Materials: Forty-five patients (23 males and 22 females, median age at RT 6.2 years, median age at evaluations 11.1 years) who had received focal RT for brain tumors were recruited for DTI exams and neurocognitive tests. Patients' brains were parceled in 116 regions of interest (ROIs) using an available segmented atlas. After the development of an ad hoc, home-made, multimodal and highly deformable registration framework, we collected mean RT doses and DTI metrics values for each ROI. The pattern of association between cognitive scores or domains and dose or DTI values was assessed in each ROI through both considering and excluding ROIs with mean doses higher than 75% of the prescription. Subsequently, a preliminary threshold value of dose discriminating patients with and without neurocognitive impairment was selected for the most relevant associations.

Results: The workflow allowed us to identify 10 ROIs where RT dose and DTI metrics were significantly associated with cognitive tests results (p<0.05). In 5/10 ROIs, RT dose and cognitive tests were associated with p<0.01 and preliminary RT threshold dose values, implying a possible cognitive or neuropsychological damage, were calculated. The analysis of domains showed that the most involved one was the "school-related activities".

Conclusion: This analysis, despite being conducted on a retrospective cohort of children, shows that the identification of critical brain structures and respective radiation dose thresholds is achievable by combining, with appropriate methodological tools, the large amount of data arising from different sources. This supported the design of a prospective study to gain stronger evidence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247748PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909688PMC
August 2021

Analysis of Italian Pathogenic Variants Identifies a Private Spectrum in the Population from the Bergamo Province in Northern Italy.

Cancers (Basel) 2021 Jan 30;13(3). Epub 2021 Jan 30.

Genome Diagnostics Program, IFOM, FIRC Institute for Molecular Oncology, 20139 Milan, Italy.

Germline pathogenic variants (PVs) in the or genes cause high breast cancer risk. Recurrent or founder PVs have been described worldwide including some in the Bergamo province in Northern Italy. The aim of this study was to compare the PV spectra of the Bergamo and of the general Italian populations. We retrospectively identified at five Italian centers 1019 PVs carrier individuals affected with breast cancer and representative of the heterogeneous national population. Each individual was assigned to the Bergamo or non-Bergamo cohort based on self-reported birthplace. Our data indicate that the Bergamo PV spectrum shows less heterogeneity with fewer different variants and an average higher frequency compared to that of the rest of Italy. Consistently, four PVs explained about 60% of all carriers. The majority of the Bergamo PVs originated locally with only two PVs clearly imported. The Bergamo PV spectrum appears to be private. Hence, the Bergamo population would be ideal to study the disease risk associated with local PVs in breast cancer and other disease-causing genes. Finally, our data suggest that the Bergamo population is a genetic isolate and further analyses are warranted to prove this notion.
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http://dx.doi.org/10.3390/cancers13030532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866799PMC
January 2021

A combination of extracellular matrix- and interferon-associated signatures identifies high-grade breast cancers with poor prognosis.

Mol Oncol 2021 05 19;15(5):1345-1357. Epub 2021 Feb 19.

Unit of Immunotherapy and Anticancer Innovative Therapeutics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Breast cancer (BC) is a heterogeneous disease in which the tumor microenvironment (TME) seems to impact the clinical outcome. Here, we investigated whether a combination of gene expression signatures relating to both the structural and immune TME aspects can help predict prognosis in women with high-grade BC (HGBC). Thus, we focused on a combined molecular biomarker variable that involved extracellular matrix (ECM)-associated gene expression (ECM3 signature) and interferon (IFN)-associated metagene (IFN metagene) expression. In 97 chemo-naive HGBCs from the METABRIC dataset, the dichotomous ECM3/IFN (dECIF) variable identified a group of high-risk patients (ECM3 /IFN vs other; hazard ratio = 3.2, 95% confidence interval: 1.5-6.7). Notably, ECM3 /IFN tumors showed low tumor-infiltrating lymphocytes, high levels of CD33-positive cells, absence of PD-1 expression, or low expression of PD-L1, as suggested by immune profiles and immune-histochemical analysis on an independent cohort of 131 HGBCs. To make our results transferable to clinical use, we refined the dECIF biomarker using reduced ECM3 and IFN signatures; notably, the prognostic value of this reduced dECIF was comparable to that of the original dECIF. After validation in a new BC cohort, reduced dECIF was translated into a robust qPCR classifier for real-world clinical use.
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http://dx.doi.org/10.1002/1878-0261.12912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096783PMC
May 2021

Analysis of the mutational status of SIX1/2 and microRNA processing genes in paired primary and relapsed Wilms tumors and association with relapse.

Cancer Gene Ther 2021 09 6;28(9):1016-1024. Epub 2020 Dec 6.

Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Whereas 90% of patients with Wilms tumor (WT) reach cure, approximately half of patients developing a recurrent tumor die of the disease. Therefore, to disclose events leading to recurrence represents a clinical need. To study paired primary/recurrent tumor samples, being aware of the intra-tumoral heterogeneity, might help finding these answers. We previously suggested that mutations in SIX1 and DROSHA underlie WT recurrence. With the aim to better investigate this scenario, we collected 19 paired primary/recurrent tumors and 10 primary tumors from relapsing patients and searched for mutations in the SIX1/2 genes and microRNA processing genes (miRNAPGs). We found SIX1 mutation in one case, miRNAPGs mutations in seven cases, and the co-occurrence of SIX1 and miRNAPG mutations in one case. We could observe that, whereas in primary tumors the mutations could be heterogeneously present, in all cases they were positively selected and homogeneously present in the recurrent disease, as also indicated by a "moderate" and "almost perfect" agreement (according to the Landis and Koch classification criteria) between paired samples. Analysis of SIX1/2 genes and miRNAPGs in 50 non-relapsing WTs disclosed SIX2 mutation in one case and miRNAPGs mutations in seven. A borderline statistically significant association was observed between miRNAPGs mutations and the occurrence of relapse (p value: 0.05). These data suggest that SIX1 and miRNAPGs mutations may provide an advantage during tumor progression to recurrence and can represent oncogenic drivers in WT development.
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http://dx.doi.org/10.1038/s41417-020-00268-3DOI Listing
September 2021

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

κ and λ urine free light chains: a new method for quantification.

Tumori 2020 Dec 20;106(6):457-463. Epub 2020 Jan 20.

Laboratory Medicine Unit, Diagnostic Pathology and Laboratory Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Immunofixation electrophoresis of urinary proteins, coupled with densitometric analysis, is the gold standard method for determining urinary monoclonal free light chains (FLCs), i.e. Bence Jones protein. Recently, immunochemical methods have been developed for Bence Jones protein quantification, but no such method has been widely adopted. This study evaluated a new antibody-based immunoturbidimetry method for urinary FLC quantification, using immunofixation electrophoresis as reference.

Methods: κ and λ FLCs were measured in urine specimens from 95 (training cohort) and 103 (testing cohort) patients by both immunofixation electrophoresis and immunoturbidimetry.

Results: There was almost perfect concordance in the training cohort between the new immunoturbidimetry assay and immunofixation electrophoresis and substantial agreement, with Cohen kappa of 0.85 and 0.75, for κ and λ FLC determination, respectively. Results were confirmed in the testing cohort, where Cohen kappa was 0.86 for κ and 0.94 for λ FLCs. The κ FLC assay had 88% sensitivity and 98%-100% specificity; the λ FLC assay had 94% and 96% sensitivity and 91% and 99% specificity in the training and testing cohorts, respectively.

Conclusions: The new immunochemical method has a satisfactory performance and almost perfect agreement with immunofixation electrophoresis and gives the advantage of FLC quantification.
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http://dx.doi.org/10.1177/0300891619898533DOI Listing
December 2020

Short-term and long-term outcomes after preventive surgery in adolescent patients with familial adenomatous polyposis.

Pediatr Blood Cancer 2020 03 5;67(3):e28110. Epub 2019 Dec 5.

Pediatric Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: APC gene pathogenic variants are characterized by a lifetime risk of nearly 100% to develop a colorectal carcinoma. International guidelines suggest a prophylactic surgery in the second decade.

Methods: A descriptive analysis was performed evaluating a surgical series of adolescent patients with familial adenomatous polyposis (FAP) enrolled in the prospectively maintained hereditary polyposis registry.

Results: Thirty-eight adolescent patients (median age 16 years; range, 7-19) underwent laparoscopic prophylactic surgery. APC gene pathogenic variants were detected in all patients, and six patients were proband. No patients were converted to open surgery. Median postoperative stay was five days (4-16). Early postoperative complications were one dural puncture and one anastomotic leakage. Regarding late complications, we observed one patient having small bowel obstruction 56 months after surgery. Pathological reports showed one patient with pTis adenocarcinoma in two separate sites; 33 patients with low-grade dysplasia, four with high-grade dysplasia. One patient developed a desmoid tumor 37 months after surgery. After a median follow-up of 40.5 months, no patients died or had a second abdominal surgery because of cancer in rectal stump.

Conclusions: Rectal sparing surgery was the first choice in the major respect of patients' quality of life. Laparoscopic prophylactic surgery for FAP is well accepted from adolescents. It represents a safe option due to the low incidence of post-surgical desmoids and quick postoperative recovery.
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http://dx.doi.org/10.1002/pbc.28110DOI Listing
March 2020

Plasma miRNA-based signatures in CRC screening programs.

Int J Cancer 2020 02 5;146(4):1164-1173. Epub 2019 Aug 5.

Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607-0.682), 0.670 (0.626-0.714) and 0.682 (0.580-0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.
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http://dx.doi.org/10.1002/ijc.32573DOI Listing
February 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

High-dose-rate brachytherapy for high-grade vaginal intraepithelial neoplasia: a dosimetric analysis.

J Contemp Brachytherapy 2019 Apr 29;11(2):146-151. Epub 2019 Apr 29.

Radiotherapy 2 Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Purpose: Due to the rarity of vaginal intraepithelial neoplasia (VAIN), it is impossible to define the best treatment approach or to assess vaginal morbidity. However, brachytherapy (BT) could be a valuable choice for VAIN grade 3 (VAIN3). The aim of this paper was to report a single-institution study of the application of high-dose-rate BT and to evaluate clinical outcomes as well as to investigate the dose-effect relationship for vaginal stenosis.

Material And Methods: We retrospectively collected hospital records and treatment plans of 14 consecutive women treated in our department from August 2010 to August 2016, with HDR-BT delivered using iridium-192 by a remote after-loading system. Doses in 3D-planned treatment based on computed tomography (CT) were prescribed in high-risk clinical target volume (HR-CTV) at the vaginal wall. Vaginal stenosis was defined as vaginal shortening/narrowing according to CTCAE4.1. The International Commission on Radiation Units & Measurements (ICRU) bladder and rectal points were used for dose report analysis. The posterior-inferior border of the symphysis points was used to derive reference points. The median age of the enrolled women was 60 years, and the median total radiation dose delivered was 35 Gy.

Results: During a median period of 15 days, the treatment was well tolerated, and no interruption was necessary. Acute toxicity was minimal, whereas late toxicity appeared in 4 patients as G2 and in 3 patients as G3 vaginal stenosis. Patients with stenosis G ≥ 2 received a higher median dose to the rectal point and were mainly over 60 years old.

Conclusions: Patients with VAIN3 seemed to benefit from BT. It is generally assumed that the vagina is radio-resistant, and no constraints have yet been set, but sexual dysfunction after BT is an important cause of long-term distress. Finding applicable dose limits to the vagina could improve patients' quality of life.
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http://dx.doi.org/10.5114/jcb.2019.84696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536149PMC
April 2019

Monitoring Vitamin B in Women Treated with Metformin for Primary Prevention of Breast Cancer and Age-Related Chronic Diseases.

Nutrients 2019 May 7;11(5). Epub 2019 May 7.

Epidemiology and Prevention Unit-Department of Research, Fondazione IRCSS Istituto Nazionale dei Tumori di Milano, 20133 Milano, Italy.

Metformin (MET) is currently being used in several trials for cancer prevention or treatment in non-diabetics. However, long-term MET use in diabetics is associated with lower serum levels of total vitamin B. In a pilot randomized controlled trial of the Mediterranean diet (MedDiet) and MET, whose participants were characterized by different components of metabolic syndrome, we tested the effect of MET on serum levels of B, holo transcobalamin II (holo-TC-II), and methylmalonic acid (MMA). The study was conducted on 165 women receiving MET or placebo for three years. Results of the study indicate a significant overall reduction in both serum total B and holo-TC-II levels according with MET-treatment. In particular, in the MET group 26 of 81 patients and 10 of the 84 placebo-treated subjects had B below the normal threshold (<221 pmol/L) at the end of the study. Considering jointly all B, Holo-TC-II, and MMA, 13 of the 165 subjects (10 MET and 3 placebo-treated) had at least two deficits in the biochemical parameters at the end of the study, without reporting clinical signs. Although our results do not affect whether women remain in the trial, B monitoring for MET-treated individuals should be implemented.
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http://dx.doi.org/10.3390/nu11051020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567263PMC
May 2019

Methodological and statistical issues in developing an External Quality Assessment scheme in laboratory medicine: Focus on biomarker research.

N Biotechnol 2019 Sep 3;52:54-59. Epub 2019 May 3.

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

External Quality Assessment (EQA) schemes are well-established tools with which to evaluate, monitor and improve the output quality of clinical laboratories, recognising that high quality laboratory medicine is essential for patient care. EQA programs involve the testing of multiple laboratories and the statistical comparison of their results, according to a multistep workflow. New clinical laboratory activities, such as biomarker research, require new EQA schemes. Critical elements in designing EQA programs are choosing the statistical methods and defining reference values and control limits. This article summarizes the key features of an EQA scheme, including designing the study, identifying reference values and control limits for qualitative and quantitative data, and graphically reporting laboratory performance statistics. These steps are illustrated with examples taken from the authors' experience in national and international quality assessment schemes for biomarker research.
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http://dx.doi.org/10.1016/j.nbt.2019.05.001DOI Listing
September 2019

A Pilot Low-Inflammatory Dietary Intervention to Reduce Inflammation and Improve Quality of Life in Patients With Familial Adenomatous Polyposis: Protocol Description and Preliminary Results.

Integr Cancer Ther 2019 Jan-Dec;18:1534735419846400

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

Patients with familial adenomatous polyposis (FAP) depend on a lifelong endoscopic surveillance programme and prophylactic surgery, and usually suffer nutritional problems. Intestinal inflammation has been linked to both FAP and colorectal cancer. Epidemiological studies show a relationship between diet and inflammation. Preventive dietary recommendations for FAP patients are so far lacking. We have designed a nonrandomized prospective pilot study on FAP patients to assess whether a low-inflammatory diet based on the Mediterranean diet principles and recipes, by interacting with the microbiota, reduces gastrointestinal markers of inflammation and improves quality of life. This report describes the scientific protocol of the study and reports the participants' adherence to the proposed dietary recommendations. Thirty-four FAP patients older than 18 years, bearing the APC pathogenic variant, who underwent prophylactic total colectomy with ileo-rectal anastomosis were eligible into the study. During the 3-month dietary intervention, they reported improvements in their consumption of Mediterranean foods (vegetables, fruits, fish, and legumes), and a reduction in pro-inflammatory foods (red/processed meat and sweets); this led to a significant increase in their adherence to the Mediterranean diet. The improvement was accompanied by a decrease in the number of diarrhoeal discharges. These preliminary results are encouraging with regard to feasibility, dietary outcome measures, and safety.
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http://dx.doi.org/10.1177/1534735419846400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505234PMC
December 2019

Plasma miRNA Levels for Predicting Therapeutic Response to Neoadjuvant Treatment in HER2-positive Breast Cancer: Results from the NeoALTTO Trial.

Clin Cancer Res 2019 07 27;25(13):3887-3895. Epub 2019 Feb 27.

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

Purpose: To investigate the potential of circulating-miRNAs (ct-miRNA) as noninvasive biomarkers to predict the efficacy of single/dual HER2-targeted therapy in the NeoALTTO study.

Experimental Design: Patients with plasma samples at baseline (T0) and/or after 2 weeks (T1) of treatment were randomized into training ( = 183) and testing ( = 246) sets. RT-PCR-based high-throughput miRNA profiling was employed in the training set. After normalization, ct-miRNAs associated with pathologic complete response (pCR) were identified by univariate analysis. Multivariate logistic regression models were implemented to generate treatment-specific signatures at T0 and T1, which were evaluated by RT-PCR in the testing set. Event-free survival (EFS) according to ct-miRNA signatures was estimated by Kaplan-Meier method and Cox regression model.

Results: In the training set, starting from 51 ct-miRNAs associated with pCR, six signatures with statistically significant predictive capability in terms of area under the ROC curve (AUC) were identified. Four signatures were confirmed in the testing set: lapatinib at T0 and T1 [AUC 0.86; 95% confidence interval (CI), 0.73-0.98 and 0.71 (0.55-0.86)], respectively; trastuzumab at T1 (0.81; 0.70-0.92); lapatinib + trastuzumab at T1 (0.67; 0.51-0.83). These signatures were confirmed predictive after adjusting for known variables, including estrogen receptor status. ct-miRNA signatures failed to correlate with EFS. However, the levels of ct-miR-140-5p, included in the trastuzumab signature, were associated with EFS (HR 0.43; 95% CI, 0.22-0.84).

Conclusions: ct-miRNAs discriminate patients with and without pCR after neoadjuvant lapatinib- and/or trastuzumab-based therapy. ct-miRNAs at week two could be valuable to identify patients responsive to trastuzumab, to avoid unnecessary combination with other anti-HER2 agents, and finally to assist deescalating treatment strategies.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2507DOI Listing
July 2019

Combination of Baseline LDH, Performance Status and Age as Integrated Algorithm to Identify Solid Tumor Patients with Higher Probability of Response to Anti PD-1 and PD-L1 Monoclonal Antibodies.

Cancers (Basel) 2019 Feb 14;11(2). Epub 2019 Feb 14.

Medical Oncology Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori di Milano, Via Giacomo Venezian 1, 20133 Milan, Italy.

Predictive biomarkers of response to immune-checkpoint inhibitors (ICIs) are an urgent clinical need. The aim of this study is to identify manageable parameters to use in clinical practice to select patients with higher probability of response to ICIs. Two-hundred-and-seventy-one consecutive metastatic solid tumor patients, treated from 2013 until 2017 with anti- Programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) ICIs, were evaluated for baseline lactate dehydrogenase (LDH) serum level, performance status (PS), age, neutrophil-lymphocyte ratio, type of immunotherapy, number of metastatic sites, histology, and sex. A training and validation set were used to build and test models, respectively. The variables' effects were assessed through odds ratio estimates (OR) and area under the receive operating characteristic curves (AUC), from univariate and multivariate logistic regression models. A final multivariate model with LDH, age and PS showed significant ORs and an AUC of 0.771. Results were statistically validated and used to devise an Excel algorithm to calculate the patient's response probabilities. We implemented an interactive Excel algorithm based on three variables (baseline LDH serum level, age and PS) which is able to provide a higher performance in response prediction to ICIs compared with LDH alone. This tool could be used in a real-life setting to identify ICIs in responding patients.
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http://dx.doi.org/10.3390/cancers11020223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406250PMC
February 2019

The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial.

Eur J Cancer 2019 03 25;109:51-60. Epub 2019 Jan 25.

Sarcoma Service, Department of Surgery, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy. Electronic address:

Background: This study was aimed at determining whether patients with high-risk soft tissue sarcoma (STS), as identified using the nomogram Sarculator, benefitted from adjuvant chemotherapy in the EORTC-STBSG 62931 randomised controlled trial (RCT), which failed to detect an impact for adjuvant doxorubicin plus ifosfamide (Adj) over observation (Obs).

Methods: Patients with extremity and trunk wall STS in the EORTC-STBSG 62931 RCT were analysed (N = 290/351). Ten-year predicted probability of overall survival (pr-OS) was calculated using the prognostic nomogram Sarculator. Patients were grouped into three categories of predicted pr-OS: high (pr-OS>66%), intermediate (51
Results: Nomogram pr-OS was dispersed (median 72%, interquartile range 57-83%) and had prognostic value for OS and DFS (log-rank test: P < 0.001). One hundred seventy, 68 and 52 patients had high (58.6%, 90 Obs/80 Adj), intermediate (23.5%, 34 Obs/34 Adj) and low pr-OS (17.9%, 24 Obs/28 Adj), respectively. Adjuvant chemotherapy halved the risk of recurrence (hazard ratio [HR] = 0.46, 95% confidence interval [CI] 0.24-0.89) and death (HR = 0.46, 95% CI 0.23-0.94) in the low pr-OS category, while no effect was detected in intermediate and high pr-OS categories. To strengthen these findings, study participants with pr-OS<60% were combined (N = 80, 27.6%, 39 Obs/41 Adj), and a significant DFS (HR = 0.49, 95% CI 0.28-0.85) and OS (HR = 0.50, 95% CI 0.30-0.90) benefit was detected.

Conclusion: Patients of the EORTC-STBSG 62931 RCT with extremity and trunk wall STS and a low predicted pr-OS (high-risk patients) had better outcomes when treated with adjuvant chemotherapy. This may help reconcile the disparate results of clinical studies on adjuvant/neoadjuvant chemotherapy in STS.
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http://dx.doi.org/10.1016/j.ejca.2018.12.009DOI Listing
March 2019

Constitutive Promoter Hypermethylation Can Be a Predisposing Event in Isolated Early-Onset Breast Cancer.

Cancers (Basel) 2019 Jan 9;11(1). Epub 2019 Jan 9.

Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

Early age at onset of breast cancer (eoBC) is suggestive of an increased genetic risk. Although genetic testing is offered to all eoBC-affected women, in isolated cases the detection rate of pathogenic variants is <10%. This study aimed at assessing the role of constitutive promoter methylation at BC-associated loci as an underlying predisposing event in women with eoBC and negative family history. Promoter methylation at 12 loci was assessed by the MassARRAY technology in blood from 154 negative patients with eoBC and negative family history, and 60 healthy controls. Hypermethylation was determined, within each promoter, by comparing the patient's mean methylation value with thresholds based on one-sided 95% bootstrap confidence interval of the controls' mean. Three patients had hypermethylated results, two at and one at . Analyses on tumor tissue from the patient exceeding the highest threshold at revealed a mean methylation >60% and loss of heterozygosity at chromosome 17q. The patient hypermethylated at showed low methylation in the tumor sample, ruling out a role for methylation-induced silencing in tumor development. In isolated eoBC patients, constitutive promoter methylation may be a predisposing event. Further studies are required to define the impact of methylation changes occurring at BC-predisposing genes and their role in tumorigenesis.
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http://dx.doi.org/10.3390/cancers11010058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356733PMC
January 2019
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