Publications by authors named "Francesca Consoli"

32 Publications

Supportive therapies in patients with advanced adrenocortical carcinoma submitted to standard EDP-M regimen.

Endocrine 2022 May 14. Epub 2022 May 14.

Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Brescia, Italy.

Purpose: The management of patients with advanced/metastatic adrenocortical carcinoma (ACC) is challenging, EDP-M (etoposide, doxorubicin, cisplatin combined with mitotane) is the standard regimen. However, it is quite toxic, so an adequate supportive therapy is crucial to reduce as much as possible the side effects and maintain the dose intensity of cytotoxic agents.

Methods: We describe the main side effects of the EDP-M scheme and the best way to manage them based on the experience of the Medical Oncology Unit of the Spedali Civili of Brescia. We also deal with the administration of EDP-M in specific frail patients, such as those with huge disease extent and poor performance status (PS) and those with mild renal insufficiency.

Results: In patients with hormone secreting ACC the rapid control of Cushing syndrome using adrenal steroidogenesis inhibitors such as metyrapone or osilodrostat is mandatory before starting EDP-M. Primary prophylaxis of neutropenia with Granulocyte-Colony Stimulating Factors is crucial and should be introduced at the first chemotherapy cycle. Possible mitotane induced hypoadrenalism should be always considered in case of persistent nausea and vomiting and asthenia in the interval between one cycle to another. In case of poor PS. A 24 h continuous infusion schedule of cisplatin could be an initial option in patients with poor PS as well as to reduce the risk of nefrotoxocity in patients with mild renal impairment.

Conclusion: A careful and accurate supportive care is essential to mitigate EDP-M side effects as much as possible and avoid that, due to toxicity, patients have to reduce doses and or postpone cytotoxic treatment with a negative impact on efficacy of this chemotherapy regimen.
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http://dx.doi.org/10.1007/s12020-022-03075-yDOI Listing
May 2022

Retrospective Chart Review of Dabrafenib Plus Trametinib in Patients with Metastatic BRAF V600-Mutant Melanoma Treated in the Individual Patient Program (DESCRIBE Italy).

Target Oncol 2021 11 10;16(6):789-799. Epub 2021 Nov 10.

Oncology Division, Policlinico San Martino IRCCS, Genoa, Italy.

Background: Real-world data on extended follow-up of patients with BRAF V600-mutant metastatic melanoma are limited. We investigated dabrafenib plus trametinib (dab + tram) outside of a clinical trial setting (Individual Patient Program; DESCRIBE Italy).

Objective: To describe the baseline features, treatment patterns, efficacy, and safety outcomes in patients with BRAF V600-mutant unresectable or metastatic melanoma who had received dab + tram as part of the Managed Access Program (MAP) in Italy.

Patients And Methods: An observational, retrospective chart review was conducted in Italian patients with BRAF V600-mutant unresectable stage III/IV melanoma receiving dab + tram as part of the MAP. Baseline features, treatment patterns, efficacy, and safety outcomes were evaluated.

Results: Overall, 499 patients were included in this analysis. BRAF V600E mutation was seen in 81.4% of patients. Overall response rate achieved in 243 of the 390 evaluable patients was 62.3% (95% CI 57.5-67.1). Median progression-free survival (PFS) was 9.3 months (95% CI 8.6-10.6). Subgroup analyses revealed that patients with normal lactate dehydrogenase (LDH) and ≤ three metastatic sites without brain metastases at baseline had better outcomes. With normal LDH at baseline, median PFS for patients with one or two metastatic sites other than cerebral was 18 months. No new safety signals were observed. Treatment was permanently discontinued because of treatment-emergent adverse events (TEAEs) in 9.2% of patients, and pyrexia (27.3%) was the most common TEAE, with a lower incidence than that in the phase 3 studies of dab + tram.

Conclusion: Treatment of BRAF V600E-mutant metastatic melanoma with dab + tram in the real-world setting was effective and safe, including the unselected population with several patients having a high tumor burden - concordant with the results of the pivotal phase 3 studies of dab + tram.
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http://dx.doi.org/10.1007/s11523-021-00850-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613139PMC
November 2021

Accurate Triage of Oncological Patients for Safely Continuing Cancer Therapy During the SARS-CoV-2 Pandemic.

Front Oncol 2021 14;11:707346. Epub 2021 Oct 14.

Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at the Azienda Socio Sanitaria Territoriale (ASST)-Spedali Civili, Brescia, Italy.

Objective: To evaluate the efficacy of clinical triage of oncological patients for safe continuation of cancer therapy implemented during the first SARS-CoV-2 outbreak.

Methods: Between 25 February and 21 April 2020, patients attending the Medical Oncology Unit, Spedali Civili Hospital, Brescia (Italy) for cancer therapy underwent triage to identify those with no signs and symptoms suspicious for SARS-CoV-2 infection in which antineoplastic treatment could be continued as scheduled. Triage questions investigated common symptoms (e.g., fever, cough, dyspnea, anosmia, dysgeusia, headache, nasal congestion, conjunctival congestion, sore throat, diarrhea, nausea and vomiting); body temperature and pulse oximetry were also recorded. All patients were followed-up for overt SARS-CoV-2 through to 18 May 2020.

Results: Overall, 1180 patients (median age 65 years) underwent triage during the study period. The most frequent primary malignances were breast (32%), gastrointestinal (18%), and lung (16.5%) cancer. Thirty-one (2.5%) presented with clinically evident SARS-CoV-2 infection and tested positive on nasopharyngeal swab testing and/or radiological imaging. Triage identified 69 (6%) grey zone patients with symptoms suspicious for SARS-CoV-2; 5 (7.2%) subsequently developed symptomatic disease. Neither the symptomatic nor the grey zone patients received their scheduled treatment; instead, they were referred for hospitalization or home quarantine.

Conclusion: Triage of oncological patients at our Unit provided for safe continuation of scheduled cancer treatment in 91.5% of patients during the initial SARS-CoV-2 outbreak.
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http://dx.doi.org/10.3389/fonc.2021.707346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552044PMC
October 2021

Efficacy of Immune Checkpoint Inhibitors in Rare Tumours: A Systematic Review.

Front Immunol 2021 20;12:720748. Epub 2021 Sep 20.

Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili of Brescia, Brescia, Italy.

Background: Rare cancers, as defined by the European Union, occur in fewer than 15 out of 100,000 people each year. The International Rare Cancer Consortium defines rare cancer incidence as less than six per 100,000 per year. There is a growing number of reports of the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with rare tumours, and hence, we conducted a comprehensive review to summarise and analyse the available literature.

Methods: A literature search of PubMed was performed on January 31, 2021, using the following ICI names as keywords: ipilimumab, tremelimumab, cemiplimab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab. Studies on patients with rare tumours who were being treated with ICIs were included. We plotted the overall response rate against the corresponding median survival across a variety of cancer types using linear regression.

Results: From 1,255 publications retrieved during the primary search, 62 publications were selected (with a total of 4,620 patients). Only four were randomised trials. A minority were first-line studies, while the remaining were studies in which ICIs were delivered as salvage therapy in pretreated patients. There was a good correlation between response rate and overall survival (Spearman R >0.9) in skin cancers, mesothelioma, and sarcomas.

Conclusions: Treatment of advanced-stage rare tumours with ICI therapy was found to be associated with significant activity in some orphan diseases (e.g., Merkel cell carcinoma) and hepatocellular carcinoma. Several ongoing prospective clinical trials will expand the knowledge on the safety and efficacy of ICI therapy in patients with these rare cancers.
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http://dx.doi.org/10.3389/fimmu.2021.720748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488393PMC
December 2021

What to Do and What Not to Do in the Management of Cancer Pain: A Physician Survey and Expert Recommendations.

Cancer Manag Res 2021 30;13:5203-5210. Epub 2021 Jun 30.

Unit Department Medical Oncology, AORN Cardarelli, Napoli, Italy.

Background: Despite the prevalence of pain among patients with cancer and the availability of pertinent guidelines, the clinical management of oncological pain is decisively insufficient. To address this issue, we evaluated current trends in clinical practice and subsequently generated a list of ten corrective actions-five things to do and five things not to do-for the diagnosis, management, and monitoring of cancer pain.

Methods: The survey included 18 questions about clinical practice surrounding background pain and breakthrough cancer pain (BTcP). Survey questions were developed by a scientific board of 10 physician experts and communicated via email to an expanded panel of physicians in Italy. Responses were tabulated descriptively for analysis.

Results: Of 51 invited physicians, 32 (63%) provided complete survey responses. The responses revealed several incongruencies with current guideline recommendations: physicians did not always diagnose or monitor pain using diagnostically validated or disease-specific instruments; frequently based clinical decision-making on time availability or convenience; and pharmacological therapy was often inappropriate (eg, prescribing NSAIDs or corticosteroids for BTcP). The list of corrective actions generated by the scientific board favored a guideline-oriented approach that systematically characterizes oncological pain and implements treatment based on pain characteristics (eg, fast-acting transmucosal opioids for BTcP) and evidence-based recommendations.

Conclusion: Oncologists require better education and training about the diagnosis, treatment, and monitoring of oncological pain. Physicians should be aware of current guideline recommendations as well as available pharmacological tools for BTcP.
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http://dx.doi.org/10.2147/CMAR.S310651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256821PMC
June 2021

Outcome of patients with intrathyroidal thymic carcinoma: a pooled analysis.

Endocr Relat Cancer 2021 07 5;28(8):593-604. Epub 2021 Jul 5.

Medical Oncology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University of Brescia, ASST-Spedali Civili, Brescia, Italy.

Intrathyroidal thymic carcinoma (ITC) is a rare thyroid tumor that resembles thymic carcinoma, for which there are no recommendations on diagnostic and therapeutic approaches. We performed a pooled analysis of published ITC cases to describe the natural history of this disease and identify prognostic factors. We performed a systematic review of histopathological-confirmed ITC cases published in the literature in English. The following keywords were used: 'intrathyroidal thymic carcinoma', 'carcinoma showing thymus-like differentiation', 'CASTLE tumor', 'thyroid carcinoma showing thymus like differentiation'. Fifty eligible publications were identified, providing data from 132 patients, plus a case diagnosed at our institution. Median disease-free survival (DFS) of this patient series was 144 months (range 91-197), while median overall survival (OS) was not reached. Upfront surgery was performed in 97% of patients and 24% of them experienced disease recurrence after a median of 19 months (range 13-25). Complaining of major symptoms, as a sign of more advanced local stage, was the only prognostic factor significantly associated with a higher risk of death at multivariate analysis (HR 4.903, 95% CI: 1.092-22.008, P = 0.038). Postoperative radiation therapy was not associated with prognosis, while not enough data were available to assess the efficacy of chemotherapy. ITC is a rather indolent disease and ITC patients have a relatively good prognosis. Surgery is the mainstay of therapy. Survival outcome of patients depends on tumor burden and complete surgical resection. Postoperative radiation effect seems to be negligible. Data on the efficacy of chemotherapy in advanced patients are lacking.
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http://dx.doi.org/10.1530/ERC-21-0123DOI Listing
July 2021

A Retrospective Analysis of Dabrafenib and/or Dabrafenib Plus Trametinib Combination in Patients with Metastatic Melanoma to Characterize Patients with Long-Term Benefit in the Individual Patient Program (DESCRIBE III).

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

Medical Oncology, Universitair Ziekenhuis Brussel, 1090 Brussels, Belgium.

The dabrafenib plus trametinib (dab + tram) combination has demonstrated durable long-term efficacy in patients with V600-mutant metastatic melanoma. However, real-world data characterizing patients with long-term benefit are limited. DESCRIBE III was a global, observational, retrospective, chart review study in patients with unresectable or metastatic melanoma treated with dab monotherapy and/or dab + tram combination therapy as part of the Named Patient Program or Individual Patient Program. Overall, 509 patients were enrolled. Patients were categorized into three groups based on their observed treatment duration: long-term (on therapy ≥12 months), intermediate (on therapy ≥6 months and <12 months), and short-term (on therapy <6 months) duration of benefit. More patients in the short-term duration of benefit group had baseline characteristics associated with poor prognosis compared with the other two groups. Median lactate dehydrogenase (LDH) levels (368 U/L) at baseline were also higher in the short-term duration of benefit group. No new safety signals were identified. DESCRIBE III identified baseline characteristics associated with long-term benefit of dab + tram. Lower LDH level and <3 metastatic sites at baseline were associated with a longer duration of benefit, confirming that the findings from COMBI-d and COMBI-v are relevant to patients treated in a real-world setting.
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http://dx.doi.org/10.3390/cancers13102466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158680PMC
May 2021

The Spread of SARS-CoV-2 Infection Among the Medical Oncology Staff of ASST Spedali Civili of Brescia: Efficacy of Preventive Measures.

Front Oncol 2020 18;10:1574. Epub 2020 Aug 18.

Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at ASST Spedali Civili, Brescia, Italy.

Patients with cancer are at a higher risk of developing serious disease-related complications in case of contracting SARS-CoV-2. Oncology units should implement all possible preventive measures to reduce the risk of viral transmission by healthcare professionals (HCPs) to patients. We conducted a surveillance for SARS-CoV-2 infection among the staff members of the Medical Oncology Unit of ASST Spedali Civili in Brescia, one of the Italian areas most affected by the SARS-CoV-2 pandemic. The aim of this study was to demonstrate whether the recommended preventive measures, promptly implemented by the unit, have been effective in reducing the spread of the virus among the HCPs. Between February 24 and May 19, 2020, SARS-CoV-2 infection was detected in 10 out of 76 healthy HCPs (13%). Six of them developed a symptomatic disease, leading to home quarantine, and four remained asymptomatic. The infection was revealed when a serology test was performed on all staff members of the unit. In seven HCPs, in which it was possible to trace the person-to-person infection, the contagion occurred as a result of unprotected contacts or partially protected with surgical masks. In particular, four asymptomatic HCPs did not stop working, but a widespread outbreak in the unit was avoided. Adherence to the recommended preventive strategies, in particular, wearing of surgical masks by both the HCPs and the patients, is effective in reducing and preventing the viral spread.
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http://dx.doi.org/10.3389/fonc.2020.01574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462005PMC
August 2020

A Rare Complex BRAF Mutation Involving Codon V600 and K601 in Primary Cutaneous Melanoma: Case Report.

Front Oncol 2020 10;10:1056. Epub 2020 Jul 10.

Unit of Medical Oncology, Spedali Civili di Brescia, Brescia, Italy.

BRAF is one of the most common mutated kinases detected in human cancer, particularly in cases of primary cutaneous melanomas (PCM). Mutations of the BRAF proto-oncogene, at the p.V600 codon, has been detected in more than 50% of primary and metastatic melanoma cells in clinical samples. In addition to the most frequent BRAF p.V600E mutation, corresponding to the single base pair substitution c.1799T>A, rarer mutations, within and outside the V600 codon, have been described. Expectedly, BRAF and MEK inhibitors (or their combination) have been poorly explored as potential therapeutic strategies in metastatic melanomas harboring this rare mutation. By using a set of sequencing techniques and immunohistochemistry, this work reports the genomic and clinical features of two melanoma patients showing a rare complex mutation affecting codon V600 and K601 of the BRAF gene, leading to a V600E2; K601I change. Specifically, these two patients show a distinct clinical behavior and significantly differ in their responses to BRAF and MEK inhibitors. Indeed, although this treatment has proven to be effective and safe in both cases, the observed variability between the two patients resulted as a direct consequence of the baseline extent of brain involvement, intracranial treatment failure as well as on the PTEN status.
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http://dx.doi.org/10.3389/fonc.2020.01056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367153PMC
July 2020

Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis.

Cancers (Basel) 2020 Jul 28;12(8). Epub 2020 Jul 28.

Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.

The introduction of targeted therapies and immunotherapies has significantly improved the outcome of metastatic melanoma (MM) patients. These approaches rely on immune functions for their anti-melanoma response. Plasmacytoid dendritic cells (pDCs) exhibit anti-tumor function by production of effector molecules, type I interferons (I-IFNs), and cytokines. Tissue and blood pDCs result compromised in MM, although these findings are still partially conflicting. This study reports that blood pDCs were dramatically depleted in MM, particularly in patients with high lactate dehydrogenase (LDH) and high tumor burden; the reduced pDC frequency was associated with poor overall survival. Circulating pDCs resulted also in significant impairment in interferon alpha (IFN-α) and C-X-C motif chemokine 10 (CXCL10) production in response to toll-like receptor (TLR)-7/8 agonists; on the contrary, the response to TLR-9 agonist remained intact. In the BRAF subgroup, no recovery of pDC frequency could be obtained by BRAF and MEK inhibitors (BRAFi; MEKi), whereas their function was partially rescued. Mechanistically, in vitro exposure to lactic acidosis impaired both pDC viability and function. In conclusion, pDCs from MM patients were found to be severely impaired, with a potential role for lactic acidosis. Short-term responses to treatments were not associated with pDC recovery, suggesting long-lasting effects on their compartment.
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http://dx.doi.org/10.3390/cancers12082085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463681PMC
July 2020

Reply to E. Hindié.

J Clin Oncol 2020 09 23;38(27):3238-3240. Epub 2020 Jul 23.

Andrea Maurichi, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Rosalba Miceli, PhD, Medical Statistics, Biometry and Bioinformatics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Hanna Eriksson, MD, PhD, Department of Oncology, Theme Cancer, Karolinska University Hospital, and Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Julia Newton-Bishop, MD, FRCP; Jérémie Nsengimana, PhD; and May Chan, PGD, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom; Andrew J. Hayes, MA, MBBS, MD, PhD and Kara Heelan, MB, BCH, BAO, MRCPI, MD, Sarcoma and Melanoma Units and Skin Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London, United Kingdom; David Adams, PhD, Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Roberto Patuzzo, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Francesco Barretta, MS, PhD, Medical Statistics, Biometry and Bioinformatics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Gianfranco Gallino, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Catherine Harwood, MA, MD, PhD, FRCP and Daniele Bergamaschi, PhD, Queen Mary University of London, London, United Kingdom; Dorothy Bennett, FMedSci, PhD, Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom; Konstantinos Lasithiotakis, MD, PhD, York Teaching Hospital NHS Foundation Trust, York, United Kingdom and Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Paola Ghiorzo, MD, PhD and Bruna Dalmasso, MD, University Hospital of Genoa, Genoa, Italy; Ausilia Manganoni, MD and Francesca Consoli, MD, University Hospital of Brescia, Brescia, Italy; Ilaria Mattavelli, MD; Consuelo Barbieri, MD; and Andrea Leva, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Umberto Cortinovis, MD, Plastic and Reconstructive Surgical Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Vittoria Espeli, MD and Cristina Mangas, MD, PhD, Istituto Oncologico Svizzera Italiana, Ospedale Regionale Bellinzona e Valli, Bellinzona, Switzerland; Pietro Quaglino, MD; Simone Ribero, MD, PhD; and Paolo Broganelli, MD, University Hospital of Turin, Turin, Italy; Giovanni Pellacani, MD, University Hospital of Modena, Modena, Italy; Caterina Longo, MD, Arcispedale S. Maria Nuova, Reggio Emilia, Italy; Corrado Del Forno, MD, University Hospital of Pavia, Pavia, Italy; Lorenzo Borgognoni, MD and Serena Sestini, MD, Ospedale S. Maria Annunziata, Tuscan Cancer Institute, Florence, Italy; Nicola Pimpinelli, MD, PhD and Sara Fortunato, MD, Division of Dermatology, University of Florence, Florence, Italy; Alessandra Chiarugi, MD and Paolo Nardini, MD, Institute for Cancer Research and Prevention, Florence, Italy; Elena Morittu, PhD and Antonio Florita, PhD, Scientific Director's Office, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Mara Cossa, MD, PhD; Barbara Valeri, MD; Massimo Milione, MD, PhD; and Giancarlo Pruneri, MD, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Odysseas Zoras, MD, PhD, University Hospital of Heraklion, Heraklion, Greece; Andrea Anichini, PhD and Roberta Mortarini, PhD, Immunobiology of Human Cancers Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; and Mario Santinami, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

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http://dx.doi.org/10.1200/JCO.20.01460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499609PMC
September 2020

Should everolimus be stopped after radiological progression in metastatic insulinoma? A "cons" point of view.

Endocrine 2020 09 2;69(3):481-484. Epub 2020 Jun 2.

Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, University of Brescia at ASST Spedali Civili, Brescia, Italy.

Insulinoma is a rare pancreatic neuroendocrine tumor (pNET) potentially associated with severe hypoglycaemic crisis. The great majority of these tumors are benign. In patients with metastatic malignant insulinoma, systemic therapies aim to control both the syndrome and tumor growth. Everolimus is a drug approved for the management of advanced pNETs that can achieve both these goals. According to international guidelines and regulatory authorities, everolimus in patients with pNET should be continued until the demonstration of disease progression with standard radiologic imaging techniques. The drug is neither recommended nor authorized beyond progression. This could not be the case of advanced insulinoma patients since the antineoplastic and the glycaemic effects of everolimus seem to follow independent mechanisms. The authors present here their point of view in favor of continuing everolimus beyond progression in symptomatic insulinoma patients on the basis of a robust rationale and describing a case.
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http://dx.doi.org/10.1007/s12020-020-02368-4DOI Listing
September 2020

Factors Affecting Sentinel Node Metastasis in Thin (T1) Cutaneous Melanomas: Development and External Validation of a Predictive Nomogram.

J Clin Oncol 2020 05 13;38(14):1591-1601. Epub 2020 Mar 13.

University Hospital of Modena, Modena, Italy.

Purpose: Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB.

Patients And Methods: The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram.

Results: Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines.

Conclusion: We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.
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http://dx.doi.org/10.1200/JCO.19.01902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213590PMC
May 2020

Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma.

Cells 2020 02 11;9(2). Epub 2020 Feb 11.

Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy.

The prognosis of metastatic melanoma (MM) patients has remained poor for a long time. However, the recent introduction of effective target therapies (BRAF and MEK inhibitors for BRAFV600-mutated MM) and immunotherapies (anti-CTLA-4 and anti-PD-1) has significantly improved the survival of MM patients. Notably, all these responses are highly dependent on the fitness of the host immune system, including the innate compartment. Among immune cells involved in cancer immunity, properly activated plasmacytoid dendritic cells (pDCs) exert an important role, bridging the innate and adaptive immune responses and directly eliminating cancer cells. A distinctive feature of pDCs is the production of high amount of type I Interferon (I-IFN), through the Toll-like receptor (TLR) 7 and 9 signaling pathway activation. However, published data indicate that melanoma-associated escape mechanisms are in place to hijack pDC functions. We have recently reported that pDC recruitment is recurrent in the early phases of melanoma, but the entire pDC compartment collapses over melanoma progression. Here, we summarize recent advances on pDC biology and function within the context of melanoma immunity.
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http://dx.doi.org/10.3390/cells9020417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072514PMC
February 2020

The density and spatial tissue distribution of CD8 and CD163 immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors.

J Immunother Cancer 2019 11 15;7(1):308. Epub 2019 Nov 15.

Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy.

Background: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors.

Methods: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received.

Results: Patients with high intratumoral, but not peritumoral, CD8 T cells and concomitantly low CD163 myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8 T cells and high CD163 myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068).

Conclusions: Analysis of the spatially constrained distribution of CD8 and CD163 cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.
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http://dx.doi.org/10.1186/s40425-019-0797-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858711PMC
November 2019

Panniculitis and vitiligo occurring during BRAF and MEK inhibitors combination in advanced melanoma patients: Potential predictive role of treatment efficacy.

PLoS One 2019 2;14(4):e0214884. Epub 2019 Apr 2.

Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, University of Brescia at ASST-Spedali Civili, Brescia, Italy.

Panniculitis and vitiligo-like lesions have been recently identified as rare cutaneous side effects of the combination of BRAF and MEK inhibitors, a standard of care in metastatic and locally advanced BRAF V600 mutated melanoma. An immune-mediated mechanism has been advocated in the pathogenesis of these skin lesions. Herein we retrospectively reviewed our institutional experience with the aim to explore the association between the occurrence of panniculitis and vitiligo-like lesions during combination therapy with dabrafenib (D) and trametinib (T) and outcome of advanced melanoma patients. Among 52 consecutive BRAF V600 mutated melanoma patients submitted to DT in our center, 12 (23%) developed immune related skin lesions (IRSLs): 8 panniculitis and 4 vitiligo. Patients with IRSLs diagnosis obtained a better disease response (83% versus 25%) (p = 0.001) than their counterpart and had a longer progression free survival and overall survival. The association of IRSLs and lower risk of disease progression (HR 0.19; CI 95% 0.04-0.90; p = 0.043) was confirmed after adjusting for major prognostic factors in multivariate analysis. IRSLs might represent an easy predictive surrogate marker for treatment response and favourable outcome in melanoma patients submitted to DT combination therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214884PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445428PMC
January 2020

The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper.

Crit Rev Oncol Hematol 2019 Feb 19;134:39-45. Epub 2018 Dec 19.

Women Cancer Center, Azienda Socio Sanitaria Territoriale di Cremona, University of Trieste, Italy.

Background: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease.

Methods: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IV, those with < 5 CTCs as Stage IV Survival was analyzed using Kaplan-Meier curves and the log rank test.

Results: For all patients, Stage IV patients had longer median overall survival than those with Stage IV (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IV vs. 18.7 months Stage IV, p < 0.0001). Moreover, patients with Stage IV disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location.

Conclusions: We confirm the identification of two subgroups of MBC, Stage IV and Stage IV, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials.
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http://dx.doi.org/10.1016/j.critrevonc.2018.12.004DOI Listing
February 2019

Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome.

Cancer Immunol Res 2019 01 6;7(1):12-28. Epub 2018 Nov 6.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in locoregional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8 T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the p.Q61 codon. Compared with what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by analysis. In contrast, in metastatic melanoma patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34 progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR agonist-based trials.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0141DOI Listing
January 2019

A solitary cutaneous metastasis from colon adenocarcinoma: Dermoscopic and confocal microscopy features.

Indian J Dermatol Venereol Leprol 2018 Sep-Oct;84(5):589-591

Department of Dermatology, University Hospital ASST Spedali Civili of Brescia, Brescia, Italy.

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http://dx.doi.org/10.4103/ijdvl.IJDVL_304_17DOI Listing
August 2019

Hepatoprotective effect of N-acetylcysteine in trabectedin-induced liver toxicity in patients with advanced soft tissue sarcoma.

Support Care Cancer 2018 Aug 15;26(8):2929-2935. Epub 2018 Mar 15.

Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy.

Purpose: Trabectedin is one of the few active agents in soft tissue sarcoma (STS) but hepatotoxicity is frequent and represents a dose-limiting factor. Protective strategies aiming at counteracting this important side effect have a crucial clinical impact. Due to its antioxidant properties, N-acetylcysteine (NAC) has a recognized hepatoprotective effect and this provides the rationale for testing NAC in the management of trabectedin-induced hepatotoxicity.

Methods: Patients with recurrent or metastatic soft tissue sarcoma, consecutively observed at our institution, who were considered eligible to trabectedin, received concomitant NAC if they had impaired hepatic or renal function at baseline or developed hepatotoxicity during treatment. The study aim was to retrospectively explore trabectedin administration in terms of number of cycles, mean dose, and dose intensity (DI) in patients who received NAC as compared with those who did not. Secondary end points were progression-free survival (PFS) and overall survival (OS).

Results: A total number of 18 patients were enrolled in this study. Nine received NAC and nine did not. The median number of administered trabectedin cycles, mean trabectedin dose/cycles, and median DI was comparable in the two groups (p = 0.450, p = 0.534, and p = 0.450, respectively). The PFS and OS curves overlapped.

Conclusion: This explorative study suggests that NAC can have a hepatoprotective activity in patients receiving trabectedin allowing to maintain an adequate dose intensity and continuative administration in patients with impaired liver and renal function or developing treatment-induced hepatotoxicity. A prospective randomized trial is warranted.
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http://dx.doi.org/10.1007/s00520-018-4129-xDOI Listing
August 2018

Melanoma in the elderly.

G Ital Dermatol Venereol 2017 Jun 16;152(3):203-207. Epub 2017 Feb 16.

Department of Dermatology, ASST Spedali Civili, Brescia, Italy.

Background: Among older patients, melanoma in general presents biological features related to a more aggressive biology, such as more locally advanced tumor. Management of melanoma in elderly may be difficult, mainly due to comorbidities. We report the experience of the Melanoma Unit of ASST Spedali Civili in Brescia, Italy.

Methods: Study subjects were drawn from 3444 patients with histological confirmed melanoma. Data were extracted from electronic database of the Melanoma Unit of ASST Spedali Civili in Brescia, Italy. Patients who received diagnosis of cutaneous melanoma at age of 65 years or older were retrospectively evaluated. For each diagnosed melanoma, histological characteristics, treatment, and outcomes were evaluated.

Results: Of the 805 patients described in this study, 444 were males and 361 females. Statistically significant differences were found between patients aged 65-80 years and those aged >80 years considering melanoma prognostic factors, such as Breslow thickness, number of mitoses/mm2 and ulceration.

Conclusions: Older age is recognized as an independent poor prognostic factor in melanoma patients, and melanoma in older patients have a distinct natural history. It was found that management of cancer in old person represents a major challenge to medical practice. We believe that the choice of therapy should be individualized and based upon the individual's overall health and that, particularly in these cases, management often requires interdisciplinary cooperation between dermatologist, surgical specialist, oncologist and geriatrician.
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http://dx.doi.org/10.23736/S0392-0488.17.05609-7DOI Listing
June 2017

Second line treatment of recurrent glioblastoma with sunitinib: results of a phase II study and systematic review of literature.

J Neurosurg Sci 2019 Aug 28;63(4):458-467. Epub 2016 Sep 28.

Department of Medical Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.

Introduction: Second line treatment of recurrent or progressive glioblastoma multiforme (GBM) is not standardized. Anti-angiogenic strategies with tyrosine-kinase inhibitors have been tested with conflicting results. We tested the association of sunitinib plus irinotecan (CPT-11) in a phase II trial in terms of response rate (RR) and 6-months progression-free survival (6-PFS). We also reviewed the clinical evidence from all the trials with sunitinib in this setting published to date and summarized it in a meta-analysis.

Evidence Acquisition: Patients with GBM recurrent or progressive after surgery and standard chemo-radiotherapy were treated with sunitinib 37.5 mg/day for 14 days + CPT-11 125 mg/sqm every 14 days in a Simon's two-stage phase II study. A summary data meta-analysis was performed to establish the 6-PFS in patients with ascertained histological diagnosis of GBM treated with sunitinib.

Evidence Synthesis: Six patients were enrolled in the stage I of the trial and only one had a stable disease. The overall response rate was 17% and 6-PFS was not reached. Therefore, the trial was stopped early for insufficient activity. All toxicities were grade 1-2. Systematic review of the literature identified 9 studies (including the present one) for a total of 221 patients. Pooled 6-PFS was 15.1% (95% CI: 9.0-24.4). Subgroup analysis by different schedule revealed a 6-PFS of 17.5% (95% CI: 10.3-28.1) in the weekly setting which was consistent across all the studies (I2=0%, P=0.66) and a pooled 6-PFS of 12.7% (95% CI: 4.9-29.1) in the daily setting with a substantial amount of heterogeneity (I2=65%, P=0.01).

Conclusions: Results of this trial and those of the systematic review indicate that, compared to conventional chemotherapy or bevacizumab, sunitinib has insufficient activity in the setting of recurrent GBM. Better patient's molecular stratification for second-line treatment in GBM is warranted.
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http://dx.doi.org/10.23736/S0390-5616.16.03874-1DOI Listing
August 2019

Circulating tumor cells in patients with recurrent or metastatic head and neck carcinoma: prognostic and predictive significance.

PLoS One 2014 8;9(8):e103918. Epub 2014 Aug 8.

Medical Oncology Unit, University of Brescia and Spedali Civili Hospital, Brescia, Italy.

Introduction: We investigated the frequency of detection and the prognostic and predictive significance of circulating tumor cells (CTCs) in patients with recurrent/metastatic (R/M) head and neck carcinoma (HNC) before starting systemic therapy.

Patients And Methods: Using the CellSearch technology, CTCs were assessed prospectively in peripheral blood of 53 R/M-HNC patients. We performed spiking experiments to test the diagnostic performance of the CellSearch platform in identifying squamous carcinoma cells.

Results: CTCs were identified in 14 (26%) and 22 (41%) patients at baseline and at any time point, respectively. In univariate analysis ≥2 CTCs had a poorer prognostic role than 0-1 CTC. In multivariate analysis, the presence of one CTC or more was associated with a poor prognosis both in terms of progression-free survival (PFS) [Hazard Ratio (HR): 3.068, 95% confidence interval (CI): 1.53-6.13, p 0.002] and overall survival (OS) [HR: 3.0, 95% CI: 1.48-6.0, p 0.002]. A disease control after systemic therapy was obtained in 8% of CTC-positive patients as opposed to 45% in CTC-negative ones (p 0.03). The epidermal growth factor receptor (EGFR) expression was identified in 45% of CTC-positive patients.

Discussion: In conclusion, CTCs are detected in one out of three patients with RM-HNC. CTC detection is a strong prognostic parameter and may be predictive of treatment efficacy. The frequency of EGFR expression in CTCs seems to be lower than that expected in the primary tumor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103918PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126745PMC
April 2015

Testosterone serum levels and prostate cancer prognosis: the double face of Janus.

Future Oncol 2014 May;10(7):1113-5

Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, Medical Oncology, University of Brescia, Spedali Civili Hospital, Piazzale Spedali Civili 1, 25123 Brescia, Italy.

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http://dx.doi.org/10.2217/fon.14.1DOI Listing
May 2014

Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data.

Lancet Oncol 2014 Apr 11;15(4):406-14. Epub 2014 Mar 11.

Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.

Background: We aimed to assess the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with metastatic breast cancer by undertaking a pooled analysis of individual patient data.

Methods: We contacted 51 European centres and asked them to provide reported and unreported anonymised data for individual patients with metastatic breast cancer who participated in studies between January, 2003, and July, 2012. Eligible studies had participants starting a new line of therapy, data for progression-free survival or overall survival, or both, and CTC quantification by the CellSearch method at baseline (before start of new treatment). We used Cox regression models, stratified by study, to establish the association between CTC count and progression-free survival and overall survival. We used the landmark method to assess the prognostic value of CTC and serum marker changes during treatment. We assessed the added value of CTCs or serum markers to prognostic clinicopathological models in a resampling procedure using likelihood ratio (LR) χ(2) statistics.

Findings: 17 centres provided data for 1944 eligible patients from 20 studies. 911 patients (46·9%) had a CTC count of 5 per 7·5 mL or higher at baseline, which was associated with decreased progression-free survival (hazard ratio [HR] 1·92, 95% CI 1·73-2·14, p<0·0001) and overall survival (HR 2·78, 95% CI 2·42-3·19, p<0·0001) compared with patients with a CTC count of less than 5 per 7·5 mL at baseline. Increased CTC counts 3-5 weeks after start of treatment, adjusted for CTC count at baseline, were associated with shortened progression-free survival (HR 1·85, 95% CI 1·48-2·32, p<0·0001) and overall survival (HR 2·26, 95% CI 1·68-3·03) as were increased CTC counts after 6-8 weeks (progression-free survival HR 2·20, 95% CI 1·66-2·90, p<0·0001; overall survival HR 2·91, 95% CI 2·01-4·23, p<0·0001). Survival prediction was significantly improved by addition of baseline CTC count to the clinicopathological models (progression-free survival LR 38·4, 95% CI 21·9-60·3, p<0·0001; overall survival LR 64·9, 95% CI 41·3-93·4, p<0·0001). This model was further improved by addition of CTC change at 3-5 weeks (progression-free survival LR 8·2, 95% CI 0·78-20·4, p=0·004; overall survival LR 11·5, 95% CI 2·6-25·1, p=0·0007) and at 6-8 weeks (progression-free survival LR 15·3, 95% CI 5·2-28·3; overall survival LR 14·6, 95% CI 4·0-30·6; both p<0·0001). Carcinoembryonic antigen and cancer antigen 15-3 concentrations at baseline and during therapy did not add significant information to the best baseline model.

Interpretation: These data confirm the independent prognostic effect of CTC count on progression-free survival and overall survival. CTC count also improves the prognostication of metastatic breast cancer when added to full clinicopathological predictive models, whereas serum tumour markers do not.

Funding: Janssen Diagnostics, the Nuovo-Soldati foundation for cancer research.
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http://dx.doi.org/10.1016/S1470-2045(14)70069-5DOI Listing
April 2014

Idiopathic intracranial hypertension: a possible complication in the natural history of advanced prostate cancer.

Int J Urol 2014 Mar 22;21(3):335-7. Epub 2013 Sep 22.

Department of Medical Oncology, University of Brescia, Spedali Civili Hospital, Brescia, Italy.

Idiopathic intracranial hypertension is a variety of intracranial hypertension that is extremely rare in men. Obesity and hypogonadism are the most important predictive factors. Etiological hypotheses include increased central venous pressure, and various hormonal and metabolic changes commonly found in obese patients. We described the case of an obese man with prostate cancer who showed a consistent bodyweight increase during treatment with taxanes and prednisone. He was hospitalized because of a severe loss of vision as a consequence of idiopathic intracranial hypertension. A complete symptom remission was obtained after 3 weeks of anti-edema therapies (steroids, acetazolamide). Castration-resistant prostate cancer is a risk factor for idiopathic intracranial hypertension. Long-term androgen deprivation therapy, bodyweight increase, and fluid retention during chronic steroid administration and taxane chemotherapy might favor the disease onset. This severe complication has a good outcome, and should be suspected in the presence of symptoms and signs of intracranial hypertension.
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http://dx.doi.org/10.1111/iju.12273DOI Listing
March 2014

Circulating tumour cells in locally advanced head and neck cancer: preliminary report about their possible role in predicting response to non-surgical treatment and survival.

Eur J Cancer 2012 Nov 7;48(16):3019-26. Epub 2012 Jun 7.

Radiation Oncology Department, Brescia University, Italy.

Background And Purpose: The mechanism of dissemination of locally advanced head and neck cancer (LAHNC) is far to be resolved. Circulating tumour cells (CTC) have been identified as a prognostic factor in metastatic breast and prostate cancer. This prospective multi-centric analysis studied the possible role of CTC identification in LAHNC.

Materials And Methods: CTC were searched in 73 patients with LAHNC (oropharynx, n=39; nasopharynx, n=10; larynx, n=10; paranasal sinuses, n=6, of whom 3 with sinonasal undifferentiated carcinoma, SNUC; hypopharynx, n=5; oral cavity, n=3). All of them (apart from SNUC) had squamous cell cancers. The relationship between CTC positivity and other clinical prognostic factors has been investigated. Response to treatment and survival has been related with changes in CTC number during the treatment.

Results: CTC were frequently identified in oro- and hypopharyngeal cancer and in SNUC. They were more frequent in stage IV than in stages I-III disease (18% versus 6%, p=NS (not significant)). Partial or complete response (CR) was related with the absence or disappearance of CTC during treatment (p=0.017). A decrease in the CTC number or their absence throughout the treatment seems also related with non-progressive disease, after both complete or incomplete remission and with the proportion of patients alive and NED (no evidence of disease) (p=0.009).

Conclusions: These preliminary data suggest a possible role of CTC determination in head and neck cancer. Additional and longer follow up data need to be collected to confirm these findings.
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http://dx.doi.org/10.1016/j.ejca.2012.05.007DOI Listing
November 2012

Involvement of target gene polymorphisms in 5-Fluorouracil toxicity: a case report.

Pharmacology 2012 15;89(1-2):99-102. Epub 2012 Feb 15.

Division of Oncology, AO Spedali Civili, University of Brescia Medical School, Brescia, Italy.

Personalized medicine is becoming an important tool in oncology, both in preventing disease and in optimizing the treatment of existing cancers. Here we describe the cases of 2 patients with relevant systemic toxicity following 5-fluorouracil (5-FU) therapy and we study the more frequent polymorphisms in the target genes, in particular: (1) the variability in the number of 28-base repetitions present in the 5'-untranslated sequence of the thymidine synthase gene; (2) the presence of single-nucleotide polymorphisms in the methylene tetrahydrofolate reductase gene, and (3) the presence of mRNA splicing in intron 14 of the hepatic enzyme dihydropyrimidine dehydrogenase. The 5-FU gene profile of our patients strongly suggested that the polymorphisms expressed may contribute to the adverse effects seen during the therapy. To what extent these polymorphisms induced adverse effects cannot be established at present; however, our results strengthen the relevance of the 5-FU-related pharmacogenomic profile to predict the response outcome and the chemotherapy toxicity.
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http://dx.doi.org/10.1159/000335784DOI Listing
July 2012

Circulating tumor cells as predictors of prognosis in metastatic breast cancer: clinical application outside a clinical trial.

Tumori 2011 Nov-Dec;97(6):737-42

Medical Oncology Unit, Beretta Foundation, Azienda Spedali Civili, Piazzale Spedali Civili 1, Brescia, Italy.

Aims And Background: Circulating tumor cells have a prognostic role in metastatic breast cancer. The aim of the study was to confirm the ability of circulating tumor cells, detected by the US Food and Drug Administration approved Cell Search assay, to predict the outcome of patients treated in a community general hospital.

Patients And Methods: A prospective mono-institutional study was conducted at the Department of Medical Oncology at Spedali Civili, Brescia, Italy, from January 2009 to September 2010. A total of 93 consecutive patients with metastatic breast cancer were enrolled. Patients underwent a blood sample collection to detect circulating tumor cells at baseline and, subsequently, at the first follow-up examination (after 3-4 weeks from the beginning of a systemic therapy). A third sample was drawn at disease progression (at the beginning of a subsequent new course of therapy). The prognostic cutoff value of circulating tumor cells was fixed at 5 cells/7.5 ml of blood.

Results: At baseline, median overall survival and progression-free survival in the subgroup ≥5 circulating tumor cells/7.5 ml of blood were significantly shorter (5 months and 3 months, respectively) than in the subgroup with <5 circulating tumor cells (8 months and 7 months, respectively) (P = 0.003 and P <0.001). At the first follow-up, the subgroup with more than 5 circulating tumor cells/7.5 ml of blood had a median overall survival of 4 months versus 8 months in the subgroup with <5 circulating tumor cells (P <0.001) and a median progression-free survival of 3 months versus 7 months respectively (P <0.001). At multivariate analysis, the level of circulating tumor cells at the first follow-up and at baseline remained significant as a predictor of progression-free and overall survival. The number of metastatic sites was significantly associated with overall and progression-free survival and correlated with the number of circulating tumor cells.

Conclusions: Our study confirms the role of circulating tumor cells as predictors of prognosis in metastatic breast cancer patients treated in general clinical practice.
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http://dx.doi.org/10.1700/1018.11090DOI Listing
April 2012

Circulating tumor cells and cardiac metastasis from esophageal cancer: a case report.

Case Rep Oncol 2011 May 28;4(2):299-303. Epub 2011 May 28.

Department of Medical Oncology, Beretta Foundation, Azienda Spedali Civili, Brescia, Italy.

We report the case of a 67-year-old man affected by metastatic esophageal cancer. The patient developed a symptomatic heart metastasis presenting as mimicking ST-segment elevation myocardial infarction. Cardiac magnetic resonance imaging (MRI) documented the presence of a mass in the apex and septum of the left ventriculum. The dissemination of cancer was confirmed by the detection of circulating tumor cells (CTCs) in the peripheral blood, measured by the CellSearch System (Veridex, LLC, Raritan, N.J., USA). The blood sample drawn at cardiac disease progression revealed the presence of 2 CTCs per 7.5 ml of blood. This report highlights the potential role of CTCs as markers of metastatic spread.
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http://dx.doi.org/10.1159/000329021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124464PMC
May 2011
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