Publications by authors named "Daniele Morelli"

59 Publications

Efficacy of mRNA anti-SARS-CoV-2 vaccination and dynamics of humoral immune response in patients with solid tumors: results from the institutional registry of an Italian tertiary cancer center.

Authors:
Giovanni Fucà Mara Lecchi Chiara Maura Ciniselli Arianna Ottini Andrea Spagnoletti Laura Mazzeo Daniele Morelli Paola Frati Martina Stroscia Elisabella Ebrahem Elisa Sottotetti Giulia Galli Maria Grazia D'Elia Riccardo Lobefaro Monika Ducceschi Lorenza Di Guardo Sherrie Bhoori Salvatore Provenzano Marco Platania Monica Niger Elena Colombo Federico Nichetti Matteo Duca Licia Rivoltini Roberta Mortarini Paolo Baili Giovanni Apolone Filippo de Braud Paolo Verderio Silvia Damian

Ther Adv Med Oncol 2022 27;14:17588359221108687. Epub 2022 Jul 27.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, Milan 20133, Italy.

Background: Systemic immunosuppression characterizing cancer patients represents a concern regarding the efficacy of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, and real-world evidence is needed to define the efficacy and the dynamics of humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines.

Methods: We conducted an observational study that included patients with solid tumors who were candidates for mRNA anti-SARS-CoV-2 vaccination at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. The primary objective was to monitor the immunologic response to the mRNA anti-SARS-CoV-2 vaccination in terms of anti-spike antibody levels. All the patients received two doses of the mRNA-1273 vaccine or the BNT162b2 vaccine. Healthcare workers served as a control group of healthy subjects.

Results: Among the 243 patients included in the present analysis, 208 (85.60%) and 238 (97.94%) resulted seroconverted after the first and the second dose of vaccine, respectively. Only five patients (2.06%) had a negative titer after the second dose. No significant differences in the rate of seroconversion after two vaccine doses were observed in patients as compared with the control group of healthy subjects. Age and anticancer treatment class had an independent impact on the antibody titer after the second dose of vaccination. In a subgroup of 171 patients with available data about the third timepoint, patients receiving immunotherapy with immune checkpoint inhibitors seem to have a higher peak of antibodies soon after the second dose (3 weeks after), but a more pronounced decrease at a late timepoint (3 months after).

Conclusions: The systemic immunosuppression characterizing cancer patients did not seem to dramatically affect the humoral response to anti-SARS-CoV-2 mRNA vaccines in our population of patients with solid tumors. Further investigation is needed to dissect the interplay between immunotherapy and longitudinal dynamics of humoral response to mRNA vaccines, as well as to analyze the cellular response to mRNA vaccines in cancer patients.
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http://dx.doi.org/10.1177/17588359221108687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340426PMC
July 2022

Local synthesis of the phosphatidylinositol-3,4-bisphosphate lipid drives focal adhesion turnover.

Authors:
York Posor Charis Kampyli Benoit Bilanges Sushila Ganguli Philipp A Koch Alexander Wallroth Daniele Morelli Michalina Jenkins Samira Alliouachene Elitza Deltcheva Buzz Baum Volker Haucke Bart Vanhaesebroeck

Dev Cell 2022 Jul 8;57(14):1694-1711.e7. Epub 2022 Jul 8.

UCL Cancer Institute, University College London, London WC1E 6DD, UK. Electronic address:

Focal adhesions are multifunctional organelles that couple cell-matrix adhesion to cytoskeletal force transmission and signaling and to steer cell migration and collective cell behavior. Whereas proteomic changes at focal adhesions are well understood, little is known about signaling lipids in focal adhesion dynamics. Through the characterization of cells from mice with a kinase-inactivating point mutation in the class II PI3K-C2β, we find that generation of the phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P) membrane lipid promotes focal adhesion disassembly in response to changing environmental conditions. We show that reduced growth factor signaling sensed by protein kinase N, an mTORC2 target and effector of RhoA, synergizes with the adhesion disassembly factor DEPDC1B to induce local synthesis of PtdIns(3,4)P by PI3K-C2β. PtdIns(3,4)P then promotes turnover of RhoA-dependent stress fibers by recruiting the PtdIns(3,4)P-dependent RhoA-GTPase-activating protein ARAP3. Our findings uncover a pathway by which cessation of growth factor signaling facilitates cell-matrix adhesion disassembly via a phosphoinositide lipid switch.
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http://dx.doi.org/10.1016/j.devcel.2022.06.011DOI Listing
July 2022

COVID-19 Vaccination in Health Care Workers in Italy: A Literature Review and a Report from a Comprehensive Cancer Center.

Authors:
Chiara Maura Ciniselli Mara Lecchi Mariangela Figini Cecilia C Melani Maria Grazia Daidone Daniele Morelli Emanuela Zito Giovanni Apolone Paolo Verderio

Vaccines (Basel) 2022 May 7;10(5). Epub 2022 May 7.

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

The coronavirus disease 2019 pandemic still represents a global public health emergency, despite the availability of different types of vaccines that reduced the number of severe cases, the hospitalization rate and mortality. The Italian Vaccine Distribution Plan identified healthcare workers (HCWs) as the top-priority category to receive access to a vaccine and different studies on HCWs have been implemented to clarify the duration and kinetics of antibody response. The aim of this paper is to perform a literature review across a total of 44 studies of the serologic response to COVID-19 vaccines in HCWs in Italy and to report the results obtained in a prospective longitudinal study implemented at the Fondazione IRCCS Istituto Nazionale Tumori (INT) of Milan on 1565 HCWs. At INT we found that 99.81% of the HCWs developed an antibody response one month after the second dose. About six months after the first serology evaluation, 100% of the HCWs were still positive to the antibody, although we observed a significant decrease in its levels. Overall, our literature review results highlight a robust antibody response in most of the HCWs after the second vaccination dose. These figures are also confirmed in our institutional setting seven months after the completion of the cycle of second doses of vaccination.
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http://dx.doi.org/10.3390/vaccines10050734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9146113PMC
May 2022

Application of morphological characteristics of radiofrequency lesions to individual parameters of thermal rhizolysis for trigeminal neuralgia.

Authors:
Nicolas Massager Henri-Benjamin Pouleau Alexandre Jodaïtis Daniele Morelli

Eur J Pain 2022 Jul 12;26(6):1292-1303. Epub 2022 Apr 12.

Department of Neurological Surgery, University Hospital Tivoli, La Louvière, Belgium.

Background: Thermic rhizolysis is a reliable therapy for pharmaco-resistant trigeminal neuralgia (TN). Temperature, duration of electrocautery and needle location can influence the efficacy and complications of the therapy.

Methods: We performed experimental thermocautery on egg white with increasing parameters of time (30-120 s) and temperature (60-95°C); we analysed the shape, size and volume of the thermic lesions produced. We developed a surgical procedure to assess peroperatively the probable thermocoagulation field and its geometric relations with the trigeminal roots and other anatomical structures of Meckel's cave, and we individually adapted the parameters of rhizolysis to optimize the results. This procedure was applied on 22 patients with TN.

Results: The volume of the lesions produced by rhizolysis on egg white had a spheroidal shape and increased linearly with the level of temperature and the time of electrocautery from 1.595 mm (SD 0.38) to 54.454 mm (SD 10.41); higher temperatures induced larger thermocoagulation fields than longer time periods. The calculated volumes measured at all levels of temperature and time were applied in vivo on the patient stereotactic planning during the thermocoagulation procedure in order to select the optimal parameters for rhizolysis. The median values used were 75°C (range 70-85°C) and 60 s (range 45-60 s). At 6-month follow-up, pain outcome was Barrow-Neurological-Institute class-I for 72.7%, IIIa for 22.7% and IIIb for 4.6%; the only complication due to rhizolysis was mild facial numbness in 13 subjects (59%) at 6-month follow-up.

Conclusion: We conclude that geometric analysis of the position of the electrode before trigeminal thermocoagulation with morphometric-related individual adaptation of treatment parameters could avoid serious injuries and optimize pain control.

Significance: We have adapted the technique of radiofrequency rhizolysis for TN. Our procedure allows individual peroperative adaptation of the parameters of thermocoagulation, according to the specific position of the electrode during rhizolysis. Preliminary results on a series of 22 patients have shown promising results.
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http://dx.doi.org/10.1002/ejp.1950DOI Listing
July 2022

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

Authors:
Ciniselli Chiara Maura Bruno Eleonora Oliverio Andreina Baldassari Ivan Pastori Marta Signoroni Stefano Vitellaro Marco Ricci Maria Teresa Milione Massimo Cattaneo Laura Gariboldi Manuela Mancini Andrea Rivoltini Licia Morelli Daniele Pasanisi Patrizia Verderio Paolo

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

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

Authors:
Vincenzo Marasco Cristiana Carniti Anna Guidetti Lucia Farina Martina Magni Rosalba Miceli Ludovica Calabretta Paolo Verderio Silva Ljevar Fabio Serpenti Daniele Morelli Giovanni Apolone Giuseppe Ippolito Chiara Agrati Paolo Corradini

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

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

Authors:
Antonino Belfiore Chiara Maura Ciniselli Stefano Signoroni Manuela Gariboldi Andrea Mancini Licia Rivoltini Daniele Morelli Enzo Masci Eleonora Bruno Alessandra Macciotta Maria Teresa Ricci Elena Daveri Laura Cattaneo Giuliana Gargano Giovanni Apolone Massimo Milione Paolo Verderio Patrizia Pasanisi Marco Vitellaro

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

COVID-19 Pandemic: Huge Stress Test for Health System Could Be a Great Opportunity to Update the Workflow in a Modern Surgical Pathology.

Authors:
Antonino Belfiore Giovanni Centonze Patrick Maisonneuve Carla Riva Daniele Morelli Alessandro Mangogna Giovanna Sabella Giancarlo Pruneri Massimo Milione

Cancers (Basel) 2021 Jun 30;13(13). Epub 2021 Jun 30.

First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori Milano, 20133 Milan, Italy.

Background: On December 2019, an outbreak of atypical pneumonia, known as COVID-19, was identified in Wuhan, China. This disease, characterized by the rapid human-to-human transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly in more than 200 countries. Northern Italy's regions have been hit hard in terms of deaths. Here, we report the experience of the Pathology Department of the Fondazione IRCCS Istituto Nazionale Tumori (INT) in Milan, the first Italian public cancer center, in the period of the lockdown that took place in Lombardy from March to May 2020.

Method: The variation in terms of exams was calculated in two different timeframes: December 2019-February 2020 (pre-COVID-19) and March-May 2020 (COVID-19). During these periods, Turn-Around-Time (TAT) metrics released by the Lombardy Region were calculated to assess if changes applied to guarantee the safeguarding of workers affected the average diagnosis time.

Results: In the COVID-19 period, there was a decrease for all the performed exams. The most considerable decrease was observed for PAP tests (-81.6%), followed by biopsies (-48.8%), second opinions (-41.7%), and surgical (-31.5%), molecular (-29.4%) and cytological (-18.1%) tests. Measures applied within the Pathology Department, such as digital pathology, remote working, rotations and changes in operating procedures, improved the diagnostic performance as required by the guidelines of the Lombardy Region in terms of TAT. At the same time, the measures applied for the safeguarding of the personnel turned out to be feasible and did not affect the overall performance of the Pathology Department.

Conclusions: The sharp slowdown in cancer screening during the first wave of COVID-19 could seriously endanger cancer prevention in the near future.
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http://dx.doi.org/10.3390/cancers13133283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268969PMC
June 2021

Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy.

Authors:
Matt Lechner Volker H Schartinger Christopher D Steele Wen Long Nei Marc Lucas Ooft Liesa-Marie Schreiber Christodoulos P Pipinikas Grace Tin-Yun Chung Yuk Yu Chan Feng Wu Ka-Fai To Chi Man Tsang Wayne Pearce Daniele Morelli Martin Philpott Liam Masterson Reshma Nibhani Graham Wells Christopher G Bell Julia Koller Susanne Delecluse Yim Ling Yip Jacklyn Liu Cillian T Forde Martin D Forster Amrita Jay József Dudás Annika Krapp Simon Wan Christian Uprimny

Nat Commun 2021 01 5;12(1):117. Epub 2021 Jan 5.

Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria.

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.
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http://dx.doi.org/10.1038/s41467-020-20308-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785735PMC
January 2021

A Mediterranean Dietary Intervention in Female Carriers of BRCA Mutations: Results from an Italian Prospective Randomized Controlled Trial.

Authors:
Eleonora Bruno Andreina Oliverio Angelo Virgilio Paradiso Antonella Daniele Stefania Tommasi Antonio Tufaro Daniela Andreina Terribile Stefano Magno Alessio Filippone Elisabetta Venturelli Daniele Morelli Ivan Baldassari Maria Luisa Cravana Siranoush Manoukian Patrizia Pasanisi

Cancers (Basel) 2020 Dec 11;12(12). Epub 2020 Dec 11.

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

Women carriers of / mutations face a high lifetime risk (penetrance) of developing breast and/or ovarian cancer. Insulin-like growth factor I (IGF-I), body weight and markers of insulin resistance affect BRCA penetrance. We conducted a multicenter prospective two-armed (1:1) randomized controlled trial (NCT03066856) to investigate whether a Mediterranean dietary intervention with moderate protein restriction reduces IGF-I and other metabolic modulators of BRCA penetrance. : BRCA carriers, with or without a previous cancer, aged 18-70 years and without metastases were randomly assigned to an active dietary intervention group (IG) or to a control group (CG). The primary endpoint of the intervention was the IGF-I reduction. : 416 women (216 in the IG and 200 in the CG) concluded the six-month dietary intervention. The IG showed significantly lowered serum levels of IGF-I (-11.3 ng/mL versus -1.3 ng/mL, = 0.02), weight (-1.5 Kg versus -0.5 Kg, < 0.001), waist circumference (-2 cm versus -0.7 cm, = 0.01), hip circumference (-1.6 cm versus -0.5 cm, = 0.01), total cholesterol (-10.2 mg/dL versus -3.6 mg/dL, = 0.04) and triglycerides (-8.7 mg/dL versus + 5.5 mg/dL, = 0.01) with respect to the CG. : A Mediterranean dietary intervention with moderate protein restriction is effective in reducing IGF-I and other potential modulators of BRCA penetrance.
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http://dx.doi.org/10.3390/cancers12123732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764681PMC
December 2020

Effects of cabozantinib on bone turnover markers in real-world metastatic renal cell carcinoma.

Authors:
Raffaele Ratta Elena Verzoni Alessia Mennitto Francesco Pantano Antonia Martinetti Alessandra Raimondi Pierangela Sepe Elisa Sottotetti Roberta Mennitto Daniele Morelli Daniele Santini Filippo G de Braud Giuseppe Procopio

Tumori 2021 Dec 5;107(6):542-549. Epub 2020 Nov 5.

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

Background: Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma.

Methods: This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves.

Results: Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population ( = 0.013 and < 0.0001, respectively), as well as at paired analysis ( = 0.015 and = 0.045, respectively). No differences were observed between baseline and 6 months ( = 0.053 and = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population ( = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively ( = 0.019 and = 0.041, respectively). Changes in BTM levels were not associated with outcome.

Conclusions: Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.
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http://dx.doi.org/10.1177/0300891620969817DOI Listing
December 2021

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

Authors:
Marta Giussani Chiara Maura Ciniselli Alessandra Macciotta Rossella Panella Paolo Verderio Chiara Bonini Daniele Morelli

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

Weighing the prognostic role of hyponatremia in hospitalized patients with metastatic solid tumors: the HYPNOSIS study.

Authors:
Giovanni Fucà Luigi Mariani Salvatore Lo Vullo Giulia Galli Rossana Berardi Massimo Di Nicola Claudio Vernieri Daniele Morelli Katia Dotti Ilaria Fiordoliva Silvia Rinaldi Cecilia Gavazzi Filippo Pietrantonio Marco Platania Filippo de Braud

Sci Rep 2019 09 10;9(1):12993. Epub 2019 Sep 10.

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Previous works linked low sodium concentration with mortality risk in cancer. We aimed at weighing the prognostic impact of hyponatremia in all consecutive patients with metastatic solid tumors admitted in a two-years period at our medical oncology department. Patients were included in two cohorts based on serum sodium concentration on admission. A total of 1025 patients were included, of whom 279 (27.2%) were found to be hyponatremic. The highest prevalence of hyponatremia was observed in biliary tract (51%), prostate (45%) and small-cell lung cancer (38.9%). With a median follow-up of 26.9 months, median OS was 2 months and 13.2 months for the hyponatremia versus control cohort, respectively (HR, 2.65; P < 0.001). In the multivariable model, hyponatremia was independently associated with poorer OS (HR, 1.66; P < 0.001). According to the multivariable model, a nomogram system was developed and validated in an external set of patients. We weighed over time the influence of hyponatremia on survival of patients with metastatic solid tumors and pointed out the possibility to exploit serum sodium assessment to design integrated prognostic tools. Our study also highlights the need for a deeper characterization of the biological role of extracellular sodium levels in tumor development and progression.
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http://dx.doi.org/10.1038/s41598-019-49601-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736887PMC
September 2019

Invisible hemolysis in serum samples interferes in NSE measurement.

Authors:
Antonio Mastroianni Rossella Panella Daniele Morelli

Tumori 2020 Feb 9;106(1):79-81. Epub 2019 Aug 9.

Laboratory Medicine Unit, IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.

Introduction: The accuracy of serum neuron-specific enolase (NSE) measurements is critical, particularly in neurologic diseases and cancer. NSE measurements are compromised by slight, even invisible, hemolysis, which can produce apparently higher NSE levels, leading to inappropriate clinical decisions. In this article, we describe this issue and propose a solution for avoiding incorrect results.

Methods: Twenty blood samples from donors with NSE values that were within the reference interval were considered. Experimental hemolysis was induced in vitro to examine the relationship between the degree of hemolysis and the increase in serum NSE. The data were then subjected to statistical analysis.

Results: There was excellent correlation ( 0.953) between the degree of hemolysis and the rise in NSE concentration. Each hemolysis unit (equal to 1 mg/dL of free hemoglobin) corresponded to a mean value of 0.29 ± 0.09 ng/mL NSE that was released from red blood cells.

Conclusion: The hemolysis index must be measured in every sample with no evident hemolysis before assaying it for NSE. Moreover, if the degree of hemolysis is between 5 and 30 units, the increase in NSE (from 1.5 to 9.0 ng/mL) must be calculated, and the laboratory results should be appended with comments that suggest the approximate rise in NSE.
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http://dx.doi.org/10.1177/0300891619867836DOI Listing
February 2020

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

Authors:
Antonio Mastroianni Chiara Maura Ciniselli Rossella Panella Alessandra Macciotta Adalberto Cavalleri Elisabetta Venturelli Francesca Taverna Arabella Mazzocchi Eleonora Bruno Paola Muti Franco Berrino Paolo Verderio Daniele Morelli Patrizia Pasanisi

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

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.

Authors:
Patrizia Pasanisi Manuela Gariboldi Paolo Verderio Stefano Signoroni Andrea Mancini Licia Rivoltini Massimo Milione Enzo Masci Chiara Maura Ciniselli Eleonora Bruno Alessandra Macciotta Antonino Belfiore Maria Teresa Ricci Giuliana Gargano Daniele Morelli Giovanni Apolone Marco Vitellaro

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

Differential diagnosis between bone relapse of breast cancer and lambda light chain multiple myeloma: role of the clinical biochemist.

Authors:
Antonio Mastroianni Rossella Panella Daniele Morelli

Tumori 2019 Dec 24;105(6):NP17-NP19. Epub 2019 Feb 24.

Laboratory Medicine Unit-IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

Purpose: The integration of expertise between oncologist and clinical biochemist for the monitoring and diagnosis of plasma cell dyscrasia is crucial. In some cases, medical laboratory scientists can provide an original contribution using the appropriate techniques to arrive at a diagnosis.

Methods: We report a case of 67-year-old woman who was admitted to our hospital for bone pain. Imaging studies showed multiple diffuse bone lytic lesions, and a laboratory screen revealed anemia and altered creatinemia; serum capillary zone electrophoresis confirmed a monoclonal peak in the γ-zone that had been known since 2011, typed as immunoglobulin G kappa by immunosubtraction electrophoresis. The patient had undergone surgery for breast cancer in 2013, and based on her clinical history, the oncologist suspected the presence of bone metastases from the breast cancer and opted for relative therapy. Immunosubtraction, however, showed a very small reduction in lambda free light chains in the beta zone, but it was difficult to establish if was a monoclonal component, and consequently additional tests were performed.

Discussion: A monoclonal component composed of only lambda free light chains was evidenced. This result in association with multiple diffuse bone lytic lesions observed led us to suspect multiple myeloma and not bone metastases from the breast cancer. Based on these observations, we encouraged the oncologist to conduct an osteomedullary biopsy, allowing us to make a diagnosis of low-grade stage II lambda light chain multiple myeloma.

Conclusion: In this report, we show how the expertise of the clinical biochemist was instrumental in solving this case.
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http://dx.doi.org/10.1177/0300891619832521DOI Listing
December 2019

Baseline and Postoperative C-reactive Protein Levels Predict Long-Term Survival After Lung Metastasectomy.

Authors:
Ugo Pastorino Daniele Morelli Giovanni Leuzzi Luigi Rolli Paola Suatoni Francesca Taverna Elena Bertocchi Mattia Boeri Gabriella Sozzi Anna Cantarutti Giovanni Corrao Alessandro Gronchi

Ann Surg Oncol 2019 Mar 3;26(3):869-875. Epub 2019 Jan 3.

Sarcoma Service - Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Blood level of C-reactive protein (CRP) at diagnosis is a well-know prognostic bio-marker in different primary tumors, but its role has not been investigated in resectable lung metastases. The aim of our study is to assess the predictive value of baseline (CRP0) and 3rd postoperative day (CRP3) levels on long-term survival of patients undergoing lung metastasectomy.

Methods: A total of 846 consecutive patients underwent the first pulmonary resection for lung metastases between January 2003 and December 2015, including 611 (72%) single surgical procedures, 235 (28%) multiple metastasectomies, 501 (59%) epithelial primary tumors, 276 (33%) sarcomas, 66 (8%) melanomas, 286 (33.8%) with 0 risk factors (CRP0 ≤ 2 and CRP3 ≤ 84 mg/L) and 560 (66.2%) with ≥ 1 risk factor (CRP > 2 and/or CRP > 84 mg/L).

Results: Cumulative 5-year survival was 57% in patients with low CRP (0 risk factors) versus 43% in high CRP (≥ 1 risk factor, p < 0.0002), 62% versus 50% respectively for epithelial tumors (p < 0.0140), and 51% versus 34% for sarcomas (p < 0.0111). Multivariable Cox analysis confirmed a mortality hazard ratio of 2.5 at 1-year and 1.5 at 5-years in patients with high CRP.

Conclusions: Baseline and postoperative CRP levels predict survival of patients with resectable lung metastases. These data provide a rationale for prospective clinical trials testing the efficacy of anti-inflammatory or immune-modulating agents as "adjuvant" therapy after lung metastasectomy, in patients with elevated pre- and/or postoperative CRP levels.
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http://dx.doi.org/10.1245/s10434-018-07116-7DOI Listing
March 2019

Imatinib and everolimus in patients with progressing advanced chordoma: A phase 2 clinical study.

Authors:
Silvia Stacchiotti Carlo Morosi Salvatore Lo Vullo Alessandra Casale Elena Palassini Anna Maria Frezza Gabriella Dinoi Antonella Messina Alessandro Gronchi Adalberto Cavalleri Elisabetta Venturelli Daniele Morelli Silvana Pilotti Paola Collini Silvia Brich Elena Tamborini Luigi Mariani Paolo G Casali

Cancer 2018 10 14;124(20):4056-4063. Epub 2018 Sep 14.

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

Background: We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma.

Methods: In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response.

Results: Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9%), 24 with stable disease (SD) (ORR, 55.8%), and 7 with progressive disease (ORR, 16.3%). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3%), 37 stable disease (ORR, 86%), and 4 progressive disease (ORR, 9.3%). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8% and 48.1% of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5% and 30.2% of patients, respectively.

Conclusions: Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.
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http://dx.doi.org/10.1002/cncr.31685DOI Listing
October 2018

A Dietary Intervention to Lower Serum Levels of IGF-I in Mutation Carriers.

Authors:
Patrizia Pasanisi Eleonora Bruno Elisabetta Venturelli Daniele Morelli Andreina Oliverio Ivan Baldassari Francesca Rovera Giovanna Iula Monica Taborelli Bernard Peissel Jacopo Azzolini Siranoush Manoukian

Cancers (Basel) 2018 Sep 4;10(9). Epub 2018 Sep 4.

Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milano, Italy.

Background: Insulin-like growth factor I (IGF-I) and other markers of insulin resistance (IRm) might influence the penetrance of gene mutation. In a demonstration project on mutation carriers we tested the effect of the 'Mediterranean diet', with moderate protein restriction, on serum levels of IGF-I and IRm.

Methods: mutation carriers, with or without breast cancer, aged 18⁻70 years and without metastases were eligible. After the baseline examinations, women were randomized to an active dietary intervention or to a control group. The intervention group attended six full days of life-style intervention activities (cookery classes followed by lunch, sessions of walking for 45 min and nutritional conferences) over the next six months.

Results: 213 mutation carriers completed the six-month study. Women in the intervention group (110) showed major changes in all the parameters under study. They significantly lost weight ( < 0.001), fat mass ( = 0.002), with reduced hip circumference ( = 0.01), triglycerides ( = 0.02) and IGF-I ( = 0.02) compared with controls. They also had a significantly higher levels of insulin-like growth factor-binding protein 3 (IGFI-BP3) ( = 0.03) and a lower IGF-I/IGFI-BP3 ratio ( = 0.04). The reduction of serum levels of IGF-I was significantly associated with the reduction in the consumption of animal products ( = 0.04).

Conclusions: Women in the intervention group showed significant improvements in IGF-I and in other IRm that might influence the penetrance of BRCA mutations.
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http://dx.doi.org/10.3390/cancers10090309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162406PMC
September 2018

Effect of Tobacco Smoking Cessation on C-Reactive Protein Levels in A Cohort of Low-Dose Computed Tomography Screening Participants.

Authors:
Silvano Gallus Alessandra Lugo Paola Suatoni Francesca Taverna Elena Bertocchi Roberto Boffi Alfonso Marchiano Daniele Morelli Ugo Pastorino

Sci Rep 2018 08 27;8(1):12908. Epub 2018 Aug 27.

Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Smokers have higher levels of C-Reactive Protein (CRP) compared to never smokers. The role of smoking cessation on CRP is still under debate. Using data from two screening studies conducted in Italy in 2000-2010 on 3050 heavy smokers (including 777 ex-smokers), we estimated multivariate odds ratios (OR) for high CRP (i.e. ≥2 mg/L) according to smoking status. Moreover, in a longitudinal analysis based on 975 current smokers, with a second measurement of CRP after an average study period of 3.4 years, we estimated the changes in CRP according to smoking cessation. Prevalence of high CRP at baseline was 35.8% among ex-smokers and 41.1% among current smokers (significant OR for ex- vs. current smokers: 0.79). After four years since smoking cessation, CRP levels significantly decreased with increasing years of cessation (significant OR for ex-smokers since more than 8 years: 0.55). In the longitudinal analysis, no significant reduction in CRP was found for time since smoking cessation (ORs: 1.21, 1.04, and 0.91 for ex-smokers since 1 year, 2-3 years, and ≥4 years, respectively). In the largest prospective study available so far, we found that smoking cessation has a favourable effect on CRP, but this benefit is not evident in the short-term.
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http://dx.doi.org/10.1038/s41598-018-29867-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110802PMC
August 2018

Early detection of colorectal adenocarcinoma: a clinical decision support tool based on plasma porphyrin accumulation and risk factors.

Authors:
Manuela Lualdi Adalberto Cavalleri Luigi Battaglia Ambrogio Colombo Giulia Garrone Daniele Morelli Emanuele Pignoli Elisa Sottotetti Ermanno Leo

BMC Cancer 2018 Aug 22;18(1):841. Epub 2018 Aug 22.

Colorectal Cancer Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: An increase in naturally-occurring porphyrins has been described in the blood of subjects bearing different kinds of tumors, including colorectal, and this is probably related to a systemic alteration of heme metabolism induced by tumor cells. The aim of our study was to develop an artificial neural network (ANN) classifier for early detection of colorectal adenocarcinoma based on plasma porphyrin accumulation and risk factors.

Methods: We measured the endogenous fluorescence of blood plasma in 100 colorectal adenocarcinoma patients and 112 controls using a conventional spectrofluorometer. Height, weight, personal and family medical history, use of alcohol, red meat, vegetables and tobacco were all recorded. An ANN model was built up from demographic data and from the integral of the fluorescence emission peak in the range 610-650 nm. We used the Receiver Operating Characteristic (ROC) curve to assess performance in distinguishing colorectal adenocarcinoma patients and controls. A liquid chromatography-high resolution mass spectrometry (LC-HRMS) analytical method was employed to identify the agents responsible for native fluorescence.

Results: The fluorescence analysis indicated that the integral of the fluorescence emission peak in the range 610-650 nm was significantly higher in colorectal adenocarcinoma patients than controls (p < 0.0001) and was weakly correlated with the TNM staging (Spearman's rho = 0.224, p = 0.011). LC-HRMS measurements showed that the agents responsible for the fluorescence emission were mainly protoporphyrin-IX (PpIX) and coproporphyrin-I (CpI). The overall accuracy of our ANN model was 88% (87% sensitivity and 90% specificity) with an area under the ROC curve of 0.83.

Conclusions: These results confirm that tumor cells accumulate a diagnostic level of endogenous porphyrin compounds and suggest that plasma porphyrin concentrations, indirectly measured through fluorescence analysis, may be useful, together with risk factors, as a clinical decision support tool for the early detection of colorectal adenocarcinoma. Our future efforts will be aimed at examining how plasma porphyrin accumulation correlates with survival and response to therapy.
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http://dx.doi.org/10.1186/s12885-018-4754-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106935PMC
August 2018

Intratumor lactate levels reflect HER2 addiction status in HER2-positive breast cancer.

Authors:
Lorenzo Castagnoli Egidio Iorio Matteo Dugo Ada Koschorke Simona Faraci Rossella Canese Patrizia Casalini Patrizia Nanni Claudio Vernieri Massimo Di Nicola Daniele Morelli Elda Tagliabue Serenella M Pupa

J Cell Physiol 2019 02 21;234(2):1768-1779. Epub 2018 Aug 21.

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

Despite different molecular tumor profiles indicate that human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) levels mirror HER2 addiction and trastuzumab benefit in HER2-positive breast cancer (BC), the identification of noninvasive clinical predictors of trastuzumab sensitivity remains an unmet clinical need. In the current study, we investigated whether intratumor lactate levels reflect HER2 addiction and, in turn, trastuzumab susceptibility. Accordingly, the gene expression profiles of transgenic murine BC cell lines expressing the human d16HER2 variant (HER2-addicted) or human full-length HER2 (WTHER2; HER2-nonaddicted) revealed a significant enrichment of glycolysis-related gene pathways in HER2-addicted cells. We studied the metabolic content of 22 human HER2-positive BC by quantitative nuclear magnetic resonance spectroscopy and found that those cases with higher lactate levels were characterized by higher HER2 transcript levels. Moreover, gene expression analyses of HER2-positive BC samples from a TCGA data set revealed a significant enrichment in glycolysis-related pathways in high/HER2-addicted tumors. These data were confirmed by metabolic analyses of human HER2-positive BC cell lines with high or low HER2 transcript levels, which revealed significantly more active glycolytic metabolism in high HER2 transcript than in low HER2 transcript cells. Overall, our results provide evidence for noninvasive intratumor lactate detection as a potential metabolic biomarker of HER2 addiction and trastuzumab response suggesting the possibility to use in vivo imaging to assess lactate levels and, in turn, select HER2-positive BC patients who are more likely to benefit from anti-HER2 treatments.
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http://dx.doi.org/10.1002/jcp.27049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282573PMC
February 2019

Hepatocellular Carcinoma Is Associated With Gut Microbiota Profile and Inflammation in Nonalcoholic Fatty Liver Disease.

Authors:
Francesca Romana Ponziani Sherrie Bhoori Chiara Castelli Lorenza Putignani Licia Rivoltini Federica Del Chierico Maurizio Sanguinetti Daniele Morelli Francesco Paroni Sterbini Valentina Petito Sofia Reddel Riccardo Calvani Chiara Camisaschi Anna Picca Alessandra Tuccitto Antonio Gasbarrini Maurizio Pompili Vincenzo Mazzaferro

Hepatology 2019 01 10;69(1):107-120. Epub 2018 Jul 10.

Hepato-Bilio-Pancreatic Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori and University of Milan, Italy.

The gut-liver axis plays a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which is the third leading cause of hepatocellular carcinoma (HCC) worldwide. However, the link between gut microbiota and hepatocarcinogenesis remains to be clarified. The aim of this study was to explore what features of the gut microbiota are associated with HCC in patients with cirrhosis and NAFLD. A consecutive series of patients with NAFLD-related cirrhosis and HCC (group 1, 21 patients), NAFLD-related cirrhosis without HCC (group 2, 20 patients), and healthy controls (group 3, 20 patients) was studied for gut microbiota profile, intestinal permeability, inflammatory status, and circulating mononuclear cells. We finally constructed a model depicting the most relevant correlations among these features, possibly involved in hepatocarcinogenesis. Patients with HCC showed increased levels of fecal calprotectin, while intestinal permeability was similar to patients with cirrhosis but without HCC. Plasma levels of interleukin 8 (IL8), IL13, chemokine (C-C motif) ligand (CCL) 3, CCL4, and CCL5 were higher in the HCC group and associated with an activated status of circulating monocytes. The fecal microbiota of the whole group of patients with cirrhosis showed higher abundance of Enterobacteriaceae and Streptococcus and a reduction in Akkermansia. Bacteroides and Ruminococcaceae were increased in the HCC group, while Bifidobacterium was reduced. Akkermansia and Bifidobacterium were inversely correlated with calprotectin concentration, which in turn was associated with humoral and cellular inflammatory markers. A similar behavior was also observed for Bacteroides. Conclusion: Our results suggest that in patients with cirrhosis and NAFLD the gut microbiota profile and systemic inflammation are significantly correlated and can concur in the process of hepatocarcinogenesis.
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http://dx.doi.org/10.1002/hep.30036DOI Listing
January 2019

Mesothelin and osteopontin as circulating markers of diffuse malignant peritoneal mesothelioma: A preliminary study.

Authors:
Federica Bruno Dario Baratti Antonia Martinetti Daniele Morelli Elisa Sottotetti Chiara Bonini Marcello Guaglio Shigeki Kusamura Marcello Deraco

Eur J Surg Oncol 2018 06 17;44(6):792-798. Epub 2018 Feb 17.

Peritoneal Malignancy Program, National Cancer Institute, via Venezian, 1, 20133, Milan, Italy.

Background: The differential diagnosis between diffuse malignant peritoneal mesothelioma (DMPM) and other peritoneal surface malignancies (PSM) is still challenging. Serum mesothelin and osteopontin are increasingly used as markers of pleural mesothelioma, but their role in DMPM is unclear. We assessed the diagnostic and prognostic values of mesothelin, osteopontin, CEA, CA19.9, CA125, and CA15.3 in DMPM patients.

Methods: Markers were dosed before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) by enzyme-linked immunosorbent assay (ELISA) in 30 DMPM patients and 14 controls with other PSMs. Receiver-operating characteristics (ROC) curve were plotted. The performance of each marker was assessed by the area under the ROC curve (AUC-ROC).

Results: Mean mesothelin levels were 7.84 ng/dl (SD = 5.14) in DMPM group and 3.00 ng/dl (SD = 1.25) in controls (P = 0.001). Mean CEA levels were 5.3 ng/dl (SD = 4.7), and 61.96 ng/dl (SD = 112.5) in the two groups (P = 0.008). No statistical difference was seen for osteopontin (P = 0.738), CA19.9 (P = 0.081), CA125 (P = 0.600), and CA15.3 (P = 0.365). AUC-ROC was 0.836 for CA19.9, 0.812 for mesothelin, 0.793 for CEA, and lower for CA125 (0.652), osteopontin (0.531), and CA15.3 (0.481). Using diagnostic cut-offs selected by ROC methodology, sensitivity, specificity, positive and negative predictive values were 70.0%, 100.0%, 100.0%, and 60.9% for mesothelin >5.21 ng/dl, and 90.0%, 85.7%, 93.1%, and 80.0% for CA19.9 < 8.8 U/dl. At multivariate analysis, osteopontin correlated with survival (hazard rate 6.46; 95%CI 1.81-23.05; P = 0.004).

Conclusion: When assessing PSMs of unknown origin, elevated mesothelin with low CA19.9 may increase the suspicion index for DMPM. Ospeopontin warrants further investigations as a prognostic marker for DMPM.
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http://dx.doi.org/10.1016/j.ejso.2018.02.010DOI Listing
June 2018

Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism.

Authors:
Benoit Bilanges Samira Alliouachene Wayne Pearce Daniele Morelli Gyorgy Szabadkai Yuen-Li Chung Gaëtan Chicanne Colin Valet Julia M Hill Peter J Voshol Lucy Collinson Christopher Peddie Khaled Ali Essam Ghazaly Vinothini Rajeeve Georgios Trichas Shankar Srinivas Claire Chaussade Rachel S Salamon Jonathan M Backer Cheryl L Scudamore Maria A Whitehead Erin P Keaney Leon O Murphy Robert K Semple Bernard Payrastre Sharon A Tooze Bart Vanhaesebroeck

Nat Commun 2017 11 27;8(1):1804. Epub 2017 Nov 27.

UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, UK.

Vps34 PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking. The organismal impact of systemic inhibition of Vps34 kinase activity is not completely understood. Here we show that heterozygous Vps34 kinase-dead mice are healthy and display a robustly enhanced insulin sensitivity and glucose tolerance, phenotypes mimicked by a selective Vps34 inhibitor in wild-type mice. The underlying mechanism of insulin sensitization is multifactorial and not through the canonical insulin/Akt pathway. Vps34 inhibition alters cellular energy metabolism, activating the AMPK pathway in liver and muscle. In liver, Vps34 inactivation mildly dampens autophagy, limiting substrate availability for mitochondrial respiration and reducing gluconeogenesis. In muscle, Vps34 inactivation triggers a metabolic switch from oxidative phosphorylation towards glycolysis and enhanced glucose uptake. Our study identifies Vps34 as a new drug target for insulin resistance in Type-2 diabetes, in which the unmet therapeutic need remains substantial.
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http://dx.doi.org/10.1038/s41467-017-01969-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703854PMC
November 2017

Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling.

Authors:
Inma M Berenjeno Roberto Piñeiro Sandra D Castillo Wayne Pearce Nicholas McGranahan Sally M Dewhurst Valerie Meniel Nicolai J Birkbak Evelyn Lau Laurent Sansregret Daniele Morelli Nnennaya Kanu Shankar Srinivas Mariona Graupera Victoria E R Parker Karen G Montgomery Larissa S Moniz Cheryl L Scudamore Wayne A Phillips Robert K Semple Alan Clarke Charles Swanton Bart Vanhaesebroeck

Nat Commun 2017 11 24;8(1):1773. Epub 2017 Nov 24.

UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London, London, WC1E 6DD, UK.

Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome amplification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling. We also present evidence that the majority of PIK3CA mutations in the TCGA breast cancer cohort precede genome doubling. These previously unappreciated roles of PIK3CA mutation show that PI3K signalling can contribute to the generation of irreversible genomic changes in cancer. While this can limit the impact of PI3K-targeted therapies, these findings also open the opportunity for therapeutic approaches aimed at limiting tumour heterogeneity and evolution.
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http://dx.doi.org/10.1038/s41467-017-02002-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701070PMC
November 2017

Clinical implications for pro-GRP in small cell lung cancer. A single center experience.

Authors:
Stefano Cavalieri Daniele Morelli Antonia Martinetti Giulia Galli Federico Nichetti Filippo de Braud Marco Platania

Int J Biol Markers 2018 Jan;33(1):55-61

1 Medical Oncology Department - National Cancer Institute of Milan - Fondazione IRCCS Istituto Nazionale Tumori, Milan - Italy.

Background: Recently, pro-gastrin-releasing peptide (pro-GRP) became available as an alternative sensitive, specific and reliable tumor marker for patients with small cell lung cancer (SCLC), both in limited (LD) and diffuse disease (DD).

Methods: We retrospectively analyzed pro-GRP, neuron-specific enolase (NSE) and CEA in patients with SCLC and non-small cell lung cancer (NSCLC). Serum pro-GRP level was measured with electrochemiluminescence at our laboratory (cutoff 77.8 pg/mL). Continuous variables were analyzed with the Mann-Whitney test, contingency data with Fisher's exact test. Receiver operator characteristic (ROC) curve analysis was performed to identify threshold values to set the highest sensitivity (Sn) and specificity (Sp) values.

Results: A total of 65 patients were studied (49 men, median age 67 years, range 27-79). Thirty-seven patients had SCLC (29 DD, 8 LD) and 28 advanced NSCLC. Median pro-GRP level was 919 pg/mL (range 22-147,350) in SCLC and 32 pg/mL (range 10-119.2) in NSCLC (p<0.0001). NSE was 4.38-fold higher in SCLC patients (p = 0.0005); CEA did not reveal significant differences between groups. Pro-GRP Sn and Sp were 86.4% and 96.4%, respectively. With ROC curve analysis, a cutoff value of 329.3 pg/mL showed a Sn of 75.8% and Sp of 87.5% in discriminating DD from LD. Pro-GRP was not influenced by either liver metastases or renal impairment.

Conclusions: Pro-GRP is sensitive for SCLC diagnosis. Since high marker levels are related to high disease burden, pro-GRP may have a negative prognostic significance. Follow-up studies are required to define its role in clinical practice in monitoring responses to treatment and early relapses.
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http://dx.doi.org/10.5301/ijbm.5000305DOI Listing
January 2018

Adherence to Mediterranean Diet and Metabolic Syndrome in BRCA Mutation Carriers.

Authors:
Eleonora Bruno Siranoush Manoukian Elisabetta Venturelli Andreina Oliverio Francesca Rovera Giovanna Iula Daniele Morelli Bernard Peissel Jacopo Azzolini Eliana Roveda Patrizia Pasanisi

Integr Cancer Ther 2018 03 25;17(1):153-160. Epub 2017 Jul 25.

1 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Insulin resistance is associated with higher breast cancer (BC) penetrance in BRCA mutation carriers. Metabolic syndrome (MetS), an insulin resistance syndrome, can be reversed by adhering to the Mediterranean diet (MedDiet). In a dietary intervention trial on BRCA mutation carriers, we evaluated adherence to the MedDiet, and the association with the MetS, by analyzing data from the Mediterranean Diet Adherence Screener (MEDAS).

Methods: BRCA mutation carriers, with or without BC, aged 18 to 70 years, were eligible for the trial. After the baseline examinations, women were randomized to a dietary intervention or to a control group. Both groups completed the MEDAS at baseline and at the end of the dietary intervention.

Results: A total of 163 women completed the 6 months of dietary intervention. Compared with controls, the women in the intervention group significantly reduced their consumption of red meat ( P < .01) and commercial sweets ( P < .01) and their MEDAS score rose significantly (+1.3 vs +0.55, P = .02). The number of MetS parameters decreased with increasing points of adherence to the MEDAS score ( P = .01). In the intervention group, there was a significant association with the greater reduction of MetS.

Conclusion: BRCA mutation carriers in the intervention group experienced greater improvement in their MedDiet and MetS parameters.
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http://dx.doi.org/10.1177/1534735417721015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950953PMC
March 2018

Baseline and postoperative C-reactive protein levels predict mortality in operable lung cancer.

Authors:
Ugo Pastorino Daniele Morelli Giovanni Leuzzi Mara Gisabella Paola Suatoni Francesca Taverna Elena Bertocchi Mattia Boeri Gabriella Sozzi Anna Cantarutti Giovanni Corrao

Eur J Cancer 2017 07 1;79:90-97. Epub 2017 May 1.

Division of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy. Electronic address:

Background: Higher blood levels of C-reactive protein (CRP) have been associated with shorter survival in patients with cardiovascular, chronic obstructive pulmonary disease and cancer. We investigated the impact of baseline and postoperative CRP levels on survival of patients with operable lung cancer (LC).

Patients And Methods: CRP values at baseline (CRP) and 3 days after surgery (CRP) were measured in a consecutive series of 1750 LC patients who underwent complete resection between 2003 and 2015. Patients were classified as having 0 (N = 593), 1 (N = 658) or 2 (N = 553) risk factors: CRP and/or CRP values above the respective median value. The effect of higher CRP was evaluated by Kaplan-Meier mortality curves and adjusted hazard ratio (HR) with 95% confidence interval (CI), by fitting Cox proportional hazards models.

Results: Cumulative proportions of 5-year survival were 67% for 0 risk factors, 58% for 1 risk factor and 41% for 2 risk factors (P < 0.0001). The overall 5-year mortality risk was significantly higher in patients with 1 risk factor (adjusted hazard ratio [aHR] 1.43 [95% CI 1.14-1.79]), or 2 risk factors (aHR 2.49 [95% CI 1.99-3.11]). A significant impact on survival was observed in each tumour-node-metastasis stage group, and in the subset of non-smokers. Postoperative 30-day mortality was significantly higher in patients with 2 risk factors only (aHR 2.2% versus 0.6%, p < 0.0475).

Conclusions: Baseline and postoperative CRP levels predict immediate and long-term mortality in all stages of operable lung cancer. Patients with higher CRP levels could be candidate to randomised adjuvant trials with anti-inflammatory agents.
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http://dx.doi.org/10.1016/j.ejca.2017.03.020DOI Listing
July 2017
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