Publications by authors named "Luis de La Cruz-Merino"

51 Publications

Increased Blood Monocytic Myeloid Derived Suppressor Cells but Low Regulatory T Lymphocytes in Patients with Mild COVID-19.

Viral Immunol 2021 Sep 16. Epub 2021 Sep 16.

Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Clinical Biochemistry Service, Virgen Macarena University Hospital, University of Seville, Seville, Spain.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may produce a systemic disease, the coronavirus disease-19 (COVID-19), with high morbidity and mortality. Even though we do not fully understand the interaction of innate and adaptive immunity in the control and complications of the viral infection, it is well recognized that SARS-CoV-2 induces an immunodepression that impairs the elimination of the virus and favors its rapid dissemination in the organism. Even less is known about the possible participation of inhibitory cells of the innate immune system, such as the myeloid-derived suppressor cells (MDSCs), or the adaptive immune system, such as the T regulatory cells (Tregs). That is why we aimed to study blood levels of MDSCs, as well as lymphocyte subpopulations, including Tregs, and activated (OX-40+) and inhibited (PD-1) T lymphocytes in patients with mild COVID-19 in comparison with data obtained from control donors. We have found that 20 hospitalized patients with COVID-19 and no health history of immunosuppression had a significant increase in the number of peripheral monocytic MDSCs (M-MDSC), but a decrease in Tregs, as well as an increase in the number of inhibited or exhausted T cells, whereas the number of activated T cells was significantly decreased compared with that from 20 healthy controls. Moreover, there was a significant negative correlation ( = 0.496) between the number of M-MDSC and the number of activated T cells. Therefore, M-MDSC rather than Tregs may contribute to the immunosuppression observed in patients with COVID-19.
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http://dx.doi.org/10.1089/vim.2021.0044DOI Listing
September 2021

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival.

J Immunother Cancer 2021 Aug;9(8)

Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA

Background: Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial.

Methods: Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups.

Results: From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm.

Conclusion: Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident.

Trial Registration Number: NCT02388906.
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http://dx.doi.org/10.1136/jitc-2021-003188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404438PMC
August 2021

Immunometabolism Modulation in Therapy.

Biomedicines 2021 Jul 9;9(7). Epub 2021 Jul 9.

Low Prevalenc Tumors, Centro de Investigación Biomédica En Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain.

The study of cancer biology should be based around a comprehensive vision of the entire tumor ecosystem, considering the functional, bioenergetic and metabolic state of tumor cells and those of their microenvironment, and placing particular importance on immune system cells. Enhanced understanding of the molecular bases that give rise to alterations of pathways related to tumor development can open up new therapeutic intervention opportunities, such as metabolic regulation applied to immunotherapy. This review outlines the role of various oncometabolites and immunometabolites, such as TCA intermediates, in shaping pro/anti-inflammatory activity of immune cells such as MDSCs, T lymphocytes, TAMs and DCs in cancer. We also discuss the extraordinary plasticity of the immune response and its implication in immunotherapy efficacy, and highlight different therapeutic intervention possibilities based on controlling the balanced systems of specific metabolites with antagonistic functions.
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http://dx.doi.org/10.3390/biomedicines9070798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301471PMC
July 2021

Circulating immune biomarkers in peripheral blood correlate with clinical outcomes in advanced breast cancer.

Sci Rep 2021 Jul 13;11(1):14426. Epub 2021 Jul 13.

Clinical Oncology Department, Virgen Macarena University Hospital, Seville, Spain.

Identification of the different elements intervening at the tumor microenvironment seems key to explain clinical evolution in several tumor types. In this study, a set of immune biomarkers (myeloid derived suppressor cells, regulatory T cells, and OX40 + and PD-1 + T lymphocytes counts) in peripheral blood of patients diagnosed with advanced breast cancer were analyzed along of first line antineoplastic therapy. Subsequently, a comparison between groups with clinical benefit versus progression of disease and with a healthy women cohort was executed. Results reflected that patients showed higher basal levels of myeloid derived suppressor cells (35.43, IR = 180.73 vs 17.53, IR = 16.96 cells/μl; p = 0.001) and regulatory T cells (32.05, IR = 29.84 vs 22.61, IR = 13.57 cells/μl; p = 0.001) in comparison with healthy women. Furthermore, an increase in the number of activated T lymphocytes (expressing OX40), a decrease of immune inhibitory cells (MDSCs and Tregs) and inhibited T lymphocytes (expressing PD-1) were observed along the treatment in patients with clinical benefit (p ≤ 0.001). The opposite trend was observed in the case of disease progression. These findings suggest that some critical immune elements can be easily detected and measured in peripheral blood, which open a new opportunity for translational research, as they seem to be correlated with clinical evolution, at least in ABC.
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http://dx.doi.org/10.1038/s41598-021-93838-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277895PMC
July 2021

Leptin, Both Bad and Good Actor in Cancer.

Biomolecules 2021 06 20;11(6). Epub 2021 Jun 20.

Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain.

Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the last decades, obesity and leptin have been associated with the initiation, proliferation and progression of many types of cancer. Obesity is also linked with complications and mortality, irrespective of the therapy used, affecting clinical outcomes. However, some evidence has suggested its beneficial role, called the "obesity paradox", and the possible antitumoral role of leptin. Recent data regarding the immunotherapy of cancer have revealed that overweight leads to a more effective response and leptin may probably be involved in this beneficial process. Since leptin is a positive modulator of both the innate and the adaptive immune system, it may contribute to the increased immune response stimulated by immunotherapy in cancer patients and may be proposed as a good actor in cancer. Our purpose is to review this dual role of leptin in cancer, as well as trying to clarify the future perspectives of this adipokine, which further highlights its importance as a cornerstone of the immunometabolism in oncology.
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http://dx.doi.org/10.3390/biom11060913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235379PMC
June 2021

5-Year Outcomes with Cobimetinib plus Vemurafenib in Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study.

Clin Cancer Res 2021 Jun 22. Epub 2021 Jun 22.

Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Victoria, Australia.

Purpose: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.

Experimental Design: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).

Results: 495 patients were randomized to cobimetinib plus vemurafenib ( = 247) or placebo plus vemurafenib ( = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.

Conclusions: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with mutation-positive advanced melanoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0809DOI Listing
June 2021

Circulating myeloid-derived suppressor cells and regulatory T cells as immunological biomarkers in refractory/relapsed diffuse large B-cell lymphoma: translational results from the R2-GDP-GOTEL trial.

J Immunother Cancer 2021 Jun;9(6)

Medical Biochemistry and Molecular Biology and Immunology, Virgen Macarena University Hospital, Sevilla, Seville, Spain

Background: The search for immunological markers with ability of predicting clinical outcome is a priority in lymphomas, and in cancer in general. It is well known that some immunomodulatory cells, such as myeloid derived suppressor cells (MDSCs) or regulatory T cells (Tregs), are recruited by tumors, jeopardizing antitumor immunosurveillance. In this work, we have studied blood levels of these immunosuppressive cells in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), prior to and along the course of the experimental rituximab, gemcitabine, dexamethasone, and cisplatin (R2-GDP) schedule, as a translational substudy of the R2-GDP-GOTEL trial (EudraCT Number: 2014-001620-29), which included lenalidomide as an immunomodulator.

Methods: Blood samples were taken before treatment, at cycle 3 and end of induction. Samples were analyzed by flow cytometry. Non-parametric tests were used. Mann-Whitney U test was used to compare basal cells distributions, and Wilcoxon test was considered to compare cells distribution at different times. Spearman test was performed to measure the degree of association between cell populations.

Results: In this study, MDSC and Treg circulating concentration was found increased in all patients compared with a healthy control group and decreased after treatment only in patients with longest overall survival (>24 months), reaching the levels of the healthy group. Likewise, the number of inhibited T lymphocytes expressing Programmed Death-1 (PD-1) were increased in peripheral blood from patients and decreased on the treatment, whereas activated T lymphocytes increased after therapy in those with better overall survival.

Conclusions: In conclusion, blood concentration of MDSCs and Treg cells may be good prognostic markers for overall survival after 2 years in R/R DLBCL. These results point to a possible role of these elements in the immunosuppression of these patients, as assessed by the circulating activated and inhibited T lymphocytes, and therefore, they may be considered as therapeutic targets in DLBCL.
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http://dx.doi.org/10.1136/jitc-2020-002323DOI Listing
June 2021

Metabolic Classification and Intervention Opportunities for Tumor Energy Dysfunction.

Metabolites 2021 Apr 23;11(5). Epub 2021 Apr 23.

Low Prevalence Tumors, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain.

A comprehensive view of cell metabolism provides a new vision of cancer, conceptualized as tissue with cellular-altered metabolism and energetic dysfunction, which can shed light on pathophysiological mechanisms. Cancer is now considered a heterogeneous ecosystem, formed by tumor cells and the microenvironment, which is molecularly, phenotypically, and metabolically reprogrammable. A wealth of evidence confirms metabolic reprogramming activity as the minimum common denominator of cancer, grouping together a wide variety of aberrations that can affect any of the different metabolic pathways involved in cell physiology. This forms the basis for a new proposed classification of cancer according to the altered metabolic pathway(s) and degree of energy dysfunction. Enhanced understanding of the metabolic reprogramming pathways of fatty acids, amino acids, carbohydrates, hypoxia, and acidosis can bring about new therapeutic intervention possibilities from a metabolic perspective of cancer.
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http://dx.doi.org/10.3390/metabo11050264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146396PMC
April 2021

Nivolumab Plus Ipilimumab for Treatment-Naïve Metastatic Uveal Melanoma: An Open-Label, Multicenter, Phase II Trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402).

J Clin Oncol 2021 02 8;39(6):586-598. Epub 2021 Jan 8.

Medical Oncology, Complejo Hospitalario General Universitario de Valencia, Valencia, Spain.

Purpose: This study aimed to assess the efficacy of the combination of nivolumab (nivo) plus ipilimumab (ipi) as a first-line therapy with respect to the 12-month overall survival (OS) in patients with metastatic uveal melanoma (MUM) who are not eligible for liver resection.

Methods: This was a single-arm, phase II trial led by the Spanish Multidisciplinary Melanoma Group (GEM) on nivo plus ipi for systemic treatment-naïve patients of age > 18 years, with histologically confirmed MUM, Eastern Cooperative Oncology Group-PS 0/1, and confirmed progressive metastatic disease (M1). Nivo (1 mg/kg once every 3 weeks) and ipi (3 mg/kg once every 3 weeks) were administered during four inductions, followed by nivo (3 mg/kg once every 2 weeks) until progressive disease, toxicity, or withdrawal. The primary end point was 12-month OS. OS, progression-free survival (PFS), and overall response rate were evaluated every 6 weeks using RECIST (v1.1). Safety was also evaluated. Logistic regression and Cox proportional hazard models comprising relevant clinical factors were used to evaluate the potential association with response to treatment and survival. Cytokines were quantified in serum samples for their putative role in immune modulation/angiogenesis and/or earlier evidence of involvement in immunotherapy.

Results: A total of 52 patients with a median age of 59 years (range, 26-84 years) were enrolled. Overall, 78.8%, 56%, and 32% of patients had liver M1, extra-liver M1, and elevated lactate dehydrogenase. Stable disease was the most common outcome (51.9%). The primary end point was 12-month OS, which was 51.9% (95% CI, 38.3 to 65.5). The median OS and PFS were 12.7 months and 3.0 months, respectively. PFS was influenced by higher LDH values.

Conclusions: Nivo plus ipi in the first-line setting for MUM showed a modest improvement in OS over historical benchmarks of chemotherapy, with a manageable toxicity profile.
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http://dx.doi.org/10.1200/JCO.20.00550DOI Listing
February 2021

Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2020 11 19;21(11):1465-1477. Epub 2020 Sep 19.

Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.

Background: Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results.

Methods: This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906.

Findings: Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6-52·7) with nivolumab and 50·9 months (36·2-52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8-56·3) in the nivolumab group and 41·2% (36·4-45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60-0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7-81·5) with nivolumab and 76·6% (72·2-80·3) with ipilimumab (HR 0·87 [95% CI 0·66-1·14]; p=0·31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported.

Interpretation: At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab.

Funding: Bristol Myers Squibb and Ono Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(20)30494-0DOI Listing
November 2020

SOLTI-1503 PROMETEO TRIAL: combination of talimogene laherparepvec with atezolizumab in early breast cancer.

Future Oncol 2020 Aug 7;16(24):1801-1813. Epub 2020 Jul 7.

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain.

New treatment strategies such as immune checkpoint inhibitors and oncolytic viruses are opening new possibilities in cancer therapy. Preliminary results in melanoma and other tumors showed that the combination of talimogene laherparepvec with an anti-PD-1/PD-L1 or anti-CTLA4 has greater efficacy than either therapy alone, without additional safety concerns beyond those expected for each agent. The presence of residual cancer after neoadjuvant chemotherapy in early breast cancer patients is an unmet medical need. SOLTI-1503 PROMETEO is a window of opportunity trial, which evaluates the combination of talimogene laherparepvec in combination with atezolizumab in women with operable HER2-negative breast cancer who present residual disease after neoadjuvant chemotherapy. The primary end point is the rate of residual cancer burden 0/1. NCT03802604.
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http://dx.doi.org/10.2217/fon-2020-0246DOI Listing
August 2020

Integrating the Tumor Microenvironment into Cancer Therapy.

Cancers (Basel) 2020 Jun 24;12(6). Epub 2020 Jun 24.

Low Prevalence Tumors, Centro de investigación biomédica en red de cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain.

Tumor progression is mediated by reciprocal interaction between tumor cells and their surrounding tumor microenvironment (TME), which among other factors encompasses the extracellular milieu, immune cells, fibroblasts, and the vascular system. However, the complexity of cancer goes beyond the local interaction of tumor cells with their microenvironment. We are on the path to understanding cancer from a systemic viewpoint where the host macroenvironment also plays a crucial role in determining tumor progression. Indeed, growing evidence is emerging on the impact of the gut microbiota, metabolism, biomechanics, and the neuroimmunological axis on cancer. Thus, external factors capable of influencing the entire body system, such as emotional stress, surgery, or psychosocial factors, must be taken into consideration for enhanced management and treatment of cancer patients. In this article, we review prognostic and predictive biomarkers, as well as their potential evaluation and quantitative analysis. Our overarching aim is to open up new fields of study and intervention possibilities, within the framework of an integral vision of cancer as a functional tissue with the capacity to respond to different non-cytotoxic factors, hormonal, immunological, and mechanical forces, and others inducing stroma and tumor reprogramming.
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http://dx.doi.org/10.3390/cancers12061677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352326PMC
June 2020

[An integral view of cancer (III). Evaluation of new biomarkers and treatment strategies].

Rev Esp Patol 2020 Apr - Jun;53(2):88-99. Epub 2019 Nov 22.

CIBERONC, Madrid, España; Servicio de Anatomía Patológica, Hospital Verge de la Cinta, Tortosa, Tarragona, España. Electronic address:

We propose a comprehensive approach to oncological disease, based on a systemic consideration of biology, health and disease. Our two previous review articles focused on tumour microenvironment and the discovery of new biomarkers; here we discuss the practical application of these principles to pathology, through the identification, evaluation and quantitative analysis of new prognostic and predictive factors (Immunoscore, TIME). We also consider the clinical use of promising, better tolerated treatments, such as immunotherapy. The integrative pathologist now has access to the latest improved oncology stratification tools designed to identify effective treatment strategies, based on the natural evolution of clinical and scientific knowledge that transcend the gene-centric theory of cancer.
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http://dx.doi.org/10.1016/j.patol.2019.08.001DOI Listing
November 2019

Long-term complete response to intrathecal trastuzumab in a patient with leptomeningeal carcinomatosis due to her2- overexpressing breast cancer: Case report.

Medicine (Baltimore) 2020 Jan;99(1):e18298

Clinical Oncology Department, Medicine Department, Hospital Universitario Virgen Macarena, University of Seville, Seville, Spain.

Introduction: Leptomeningeal dissemination due to HER2-overexpressing breast cancer is a rare and hard to treat complication with short-term dismal prognosis.

Patient Concerns: A 34-year-old female previously treated because of HER2+ breast cancer is admitted to the Neurology Department in December 2016 due to sensory-motor neurological semiology.

Diagnosis: A wide set of diagnostic tests is performed and finally cytologic findings after repeated CSF confirm leptomeningeal infiltration by breast carcinoma (panCK+, GATA3+).

Interventions: Weekly intrathecal triple therapy with methotrexate, cytarabine and hydrocortisone plus trastuzumab is carried out during 4 months.

Outcomes: Clinical and pathological response that lasts more than 24 months.

Conclusion: Leptomeningeal carcinomatosis is an oncological situation where conventional therapies have limited activity. In HER2+ advanced breast cancer patients, intrathecal therapy with anti-HER2 therapy (trastuzumab) is feasible and may reach long-term disease control, especially in cases of low-tumor burden.
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http://dx.doi.org/10.1097/MD.0000000000018298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946348PMC
January 2020

Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.

N Engl J Med 2020 02 11;382(6):514-524. Epub 2019 Dec 11.

From the David Geffen School of Medicine at UCLA, Los Angeles (D.J.S.); Multidisciplinary Breast Center, Universitair Ziekenhuis Leuven, Leuven (P.N.), and Centre Hospitalier Universitaire Liège and Liege University, Liege (G.J.) - all in Belgium; the British Columbia Cancer Agency, Vancouver, Canada (S.C.); University Hospital Erlangen, Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, and Department of Gynecology and Obstetrics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen (P.A.F.), and the Practice for Hematology and Internal Oncology, Velbert (A.N.) - all in Germany; Istituto Nazionale Tumori Fondazione G. Pascale, Naples (M.D.L.), and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (G.V.B.) - both in Italy; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Masaryk Memorial Cancer Institute, Brno, Czech Republic (K.P.); New York University Langone Health, New York (F.J.E.); Instituto de Investigación Sanitaria Gregorio Marañon, Centro de Investigación Biomédica en Red de Cáncer, Grupo Español de Investigación en Cáncer de Mama, Universidad Complutense, Madrid (M.M.), and Hospital Universitario Virgen Macarena, Department of Medicine, Universidad de Sevilla, Seville (L.D.C.-M.) - both in Spain; Netherlands Cancer Institute-Borstkanker Onderzoek Groep Study Center, Amsterdam (G.S.S.); Highlands Oncology Group, Fayetteville, AR (J.T.B.); Institut Régional du Cancer, Strasbourg, France (X.P.); Novartis Pharmaceuticals, East Hanover, NJ (M.S., A.C., K.R.-L.); and Novartis Pharma, Basel, Switzerland (Y.W., T.T.).

Background: In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival.

Methods: Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.

Results: This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed.

Conclusions: Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).
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http://dx.doi.org/10.1056/NEJMoa1911149DOI Listing
February 2020

[An integral view of cancer (II). Fields of investigation and emerging biomarkers].

Rev Esp Patol 2019 Oct - Dec;52(4):222-233. Epub 2019 Jun 11.

CIBERONC, Madrid, España; Servicio de Anatomía Patólogica, Hospital Verge de la Cinta, Tortosa, Tarragona, España. Electronic address:

Pathology and clinical oncology work hand in hand so that techniques and treatments, biomarkers and antibodies share the common goal of identifying integral new treatment regimens that are more effective and less aggressive. Evidence shows how tissue mechanics affect carcinogenesis and that tumor heterogeneity depends on metabolic stromal alteration and the Warburg effect of malignant cells, regulated directly by PD-1, becoming a target for immunotherapy. Proliferation and apoptosis depend on mitochondrial dysfunction in tumor cells, determining the grade of chemo/radio-resistance. The status of intestinal microbiota regulates immune response, tumor microenvironment structure and oncologic treatment response, whilst the Vitamin D receptor allows reprogramming of tumor stroma. Current collaboration between basic and clinical research paves the way for future investigation into areas such as tumor microenvironment and molecular mechanotherapy, metabolism and immunotherapy, mitochondria and oncogenesis, microbiota and chemotherapy, psychoneuroendocrine axis and homeostatic imbalance, epigenetics and reprogramming possibilities of the tumor phenotype. We review new prognostic and predictive biomarkers emerging from these fields of knowledge, opening up new therapeutic possibilities.
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http://dx.doi.org/10.1016/j.patol.2019.04.005DOI Listing
June 2020

Development and validation of a sexual relations satisfaction scale in patients with breast cancer - "SEXSAT-Q".

Health Qual Life Outcomes 2019 Aug 17;17(1):143. Epub 2019 Aug 17.

Psychology Department, Universidad Autónoma de Madrid, Madrid, Spain.

Purpose: Because the currently available questionnaires to evaluate sexual changes on breast cancer women only address the sexual sphere with a few questions our purpose was to develop a questionnaire that assesses changes in sexual dysfunction and satisfaction in women treated for breast cancer.

Methods: A sample was selected of women aged between 18 and 65 who had had surgery for breast cancer, completed neoadjuvant/adjuvant chemotherapy treatment and could be receiving adjuvant hormonal treatment, with an active sex life at least 3 months before starting treatment. Metastatic disease was excluded. A questionnaire structured in 4 dimensions was developed. The MOS SF-12 and QLQ-BR23 questionnaires were also provided. The following metric properties were evaluated: item analysis; internal consistency; temporal stability; construct validity; concurrent, convergent and divergent validity; and feasibility.

Results: Three samples were recruited: a pilot sample of 20; a reduction sample of 152; and a validation sample of 148. The presence of 6 dimensions was confirmed: 1) Loss of sex drive; 2) worsening of body image; 3) psychological coping; 4) discomfort during intercourse; 5) satisfaction with sexual relations; and 6) satisfaction with breast reconstruction. Good goodness-of-fit statistics were obtained (χ/df = 1.5, GFI = 0.9, AGFI = 0.84, CFI = 0.959, RMSEA = 0.062). Reliability was good (α = 0.855), as was test-retest stability (r = 0.838). The correlation with the convergent questionnaires proved to be higher than that obtained with generic measurements.

Conclusions: We were able to develop a short questionnaire (17 items) capable of measuring sexual satisfaction in women with breast cancer with good metric properties.
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http://dx.doi.org/10.1186/s12955-019-1197-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698031PMC
August 2019

Obesity and Breast Cancer: Role of Leptin.

Front Oncol 2019 18;9:596. Epub 2019 Jul 18.

Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, Seville, Spain.

Obesity-related breast cancer is an important threat that affects especially post-menopausal women. The link between obesity and breast cancer seems to be relying on the microenvironment generated at adipose tissue level, which includes inflammatory cytokines. In addition, its association with systemic endocrine changes, including hyperinsulinemia, increased estrogens levels, and hyperleptinemia may be key factors for tumor development. These factors may promote tumor initiation, tumor primary growth, tissue invasion, and metastatic progression. Although the relationship between obesity and breast cancer is already established, the different pathophysiological mechanisms involved are not clear. Obesity-related insulin resistance is a well-known risk factor for breast cancer development in post-menopausal women. However, the role of inflammation and other adipokines, especially leptin, is less studied. Leptin, like insulin, appears to be a growth factor for breast cancer cells. There exists a link between leptin and metabolism of estrogens and between leptin and other factors in a more complex network. As a result, obesity-associated hyperleptinemia has been suggested as an important mediator in the pathophysiology of breast cancer. On the other hand, recent data on the paradoxical effect of obesity on cancer immunotherapy efficacy has brought some controversy, since the proinflammatory effect of leptin may help the effect of immune checkpoint inhibitors. Therefore, a better knowledge of the molecular mechanisms that mediate leptin action may be helpful to understand the underlying processes which link obesity to breast cancer in post-menopausal women, as well as the possible role of leptin in the response to immunotherapy in obese patients.
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http://dx.doi.org/10.3389/fonc.2019.00596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657346PMC
July 2019

The tumour microenvironment as an integrated framework to understand cancer biology.

Cancer Lett 2019 Oct 17;461:112-122. Epub 2019 Jul 17.

Departament of Pathology, Medical School, University of Valencia - INCLIVA Biomedical Health Research Institute, Valencia, Spain; CIBERONC, Madrid, Spain. Electronic address:

Cancer cells all share the feature of being immersed in a complex environment with altered cell-cell/cell-extracellular element communication, physicochemical information, and tissue functions. The so-called tumour microenvironment (TME) is becoming recognised as a key factor in the genesis, progression and treatment of cancer lesions. Beyond genetic mutations, the existence of a malignant microenvironment forms the basis for a new perspective in cancer biology where connections at the system level are fundamental. From this standpoint, different aspects of tumour lesions such as morphology, aggressiveness, prognosis and treatment response can be considered under an integrated vision, giving rise to a new field of study and clinical management. Nowadays, somatic mutation theory is complemented with study of TME components such as the extracellular matrix, immune compartment, stromal cells, metabolism and biophysical forces. In this review we examine recent studies in this area and complement them with our own research data to propose a classification of stromal changes. Exploring these avenues and gaining insight into malignant phenotype remodelling, could reveal better ways to characterize this disease and its potential treatment.
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http://dx.doi.org/10.1016/j.canlet.2019.07.010DOI Listing
October 2019

Recent Therapeutic Advances and Change in Treatment Paradigm of Patients with Merkel Cell Carcinoma.

Oncologist 2019 10 8;24(10):1375-1383. Epub 2019 Apr 8.

Medical Oncology Department, University General Hospital of Valencia, Valencia, Spain.

Merkel cell carcinoma (MCC) is a rare, aggressive, primary cutaneous neuroendocrine tumor that typically presents as an indurated nodule on sun-exposed areas of the head and neck in the white population. Major risk factors include immunosuppression, UV light exposure, and advanced age. Up to 80% of MCC are associated with Merkel cell polyomavirus. About 50% of patients present with localized disease, and surgical resection with or without adjuvant radiotherapy is generally indicated in this context. However, recurrence rates are high and overall prognosis rather poor, with mortality rates of 33%-46%. MCC is a chemosensitive disease, but responses in the advanced setting are seldom durable and not clearly associated with improved survival. Several recent trials with checkpoint inhibitors (pembrolizumab, avelumab, nivolumab) have shown very promising results with a favorable safety profile, in both chemonaïve and pretreated patients. In 2017, avelumab was approved by several regulatory agencies for the treatment of metastatic MCC, the first drug to be approved for this orphan disease. More recently, pembrolizumab has also been approved by the U.S. Food and Drug Administration in this setting. Immunotherapy has therefore become the new standard of care in advanced MCC. This article reviews current evidence and recommendations for the diagnosis and treatment of MCC and discusses recent therapeutic advances and their implications for care in patients with advanced disease. This consensus statement is the result of a collaboration between the Spanish Cooperative Group for Neuroendocrine Tumors, the Spanish Group of Treatment on Head and Neck Tumors, and the Spanish Melanoma Group. IMPLICATIONS FOR PRACTICE: Merkel cell carcinoma (MCC) is an uncommon aggressive skin cancer associated with advanced age, UV light exposure, and immunosuppression. Up to 80% are associated with Merkel cell polyomavirus. MCC is a chemosensitive disease, but tumor responses in the advanced setting are short-lived with no long-term survivors. Recent clinical trials with immune checkpoint inhibitors (i.e., pembrolizumab, avelumab, nivolumab) have shown promising results, with avelumab becoming the first drug to receive regulatory approval for this orphan indication. Further follow-up is needed, however, to define more adequately the long-term benefits of these drugs, and continued research is warranted to optimize immunotherapeutic strategies in this setting.
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http://dx.doi.org/10.1634/theoncologist.2018-0718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795164PMC
October 2019

Pneumonitis Related to Melanoma Immunotherapy.

Clin Nucl Med 2019 Jun;44(6):e392-e393

From the Department of Nuclear Medicine and.

Several regimens of immunotherapy have recently proven successful for multiple cancers, due to increased survival and quality of life. Rarely, immunotherapy with anti-programmed cell death protein 1 and programmed death-ligand 1 antibodies across cancer may cause immune-related pulmonary toxicity, with a low overall incidence, being particularly low among patients with melanoma and highest among individuals with lung cancer. In this vein, pulmonary toxicity is staged at 4 degrees according to the severity of the clinic and radiological findings, and its management is based on suppression of immunotherapy and administration of glucocorticoids. We report a case of pulmonary toxicity related to melanoma immunotherapy observed by F-FDG PET/CT.
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http://dx.doi.org/10.1097/RLU.0000000000002549DOI Listing
June 2019

[An integral view of cancer (I). The study, classification and reprogramming of the tumoral microclimate].

Rev Esp Patol 2019 Apr - Jun;52(2):92-102. Epub 2019 Feb 10.

CIBERONC, Madrid, España; Hospital Verge de la Cinta, Tortosa, Tarragona, España. Electronic address:

The group of diseases that we call cancer share a biological structure formed by a complex ecosystem, with altered intercellular communication, information fields, development and tissue function. Beyond the genetic alterations of the tumor cell, the demonstration of an altered ecosystem, with interconnections at systemic levels, opens up a new perspective on cancer biology and behavior. Different tumor facets, such as morphology, classification, clinical aggressiveness, prognosis and response to treatment now appear under a comprehensive vision that offers a new horizon of study, research and clinical management. The Somatic Mutation Theory in cancer, in force for more than one hundred years, is now completed by the study of the tumor microenvironment, the extracellular matrix, the stromal cells, the immune response, the innervation, the nutrition, the mitochondria, the metabolism, the interstitial fluid, the mechanical and electromagnetic properties of the tissue and many other areas of emerging knowledge; thus opening the door to a reprogramming exercise of the tumor phenotype through the modification of the keys offered by this new paradigm. Its recognition makes it possible to go from considering the oncological process as a cellular problem to a supracellular alteration based on the disorganization of tissues, immersed in the relationships of the complex system of the living being.
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http://dx.doi.org/10.1016/j.patol.2018.11.003DOI Listing
May 2020

Transformed follicular lymphoma in the rituximab era: A report from the Spanish Lymphoma Oncology Group.

Hematol Oncol 2019 Apr 4;37(2):143-150. Epub 2019 Apr 4.

Medical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) subtype. The histological transformation (HT) of FL is an event considered frequent in the natural history of this tumor. We studied the transformation rates, predictive factors, and treatment characteristics that may impact in the survival of patients with FL and HT. A total of 1074 patients diagnosed with FL were prospectively enrolled from 1990 to 2016 in a Spanish registry. Sixty-four HTs were recorded based on clinical criteria (55%) or histological confirmation (45%). The cumulative incidence rate of transformation at 5 years is 7.3%. The 5-year overall survival (OS) without HT was 85% (95% confidence interval [CI], 70%-90%) vs 66% (95% CI, 51%-76%; P = 0.0012) with HT. Factors associated with HT were elevated lactate dehydrogenase (LDH) (odds ratio [OR] 1.83), intermediate-high Follicular lymphoma international prognostic index (FLIPI) (OR 2.16-OR 3.21), B symptoms (OR 2.46), or Eastern Cooperative Oncology Group (ECOG) 1 (OR 2.35). Treatment options related to HT were "watch and wait" or no rituximab or anthracyclines initially. A 5-year OS for patients treated with chemotherapy before HT was 55% (95% CI, 38%-69%) versus 81% (95% CI, 53%-93%; P = 0.009) for those who had not received it. The HT rate has decreased after the introduction of rituximab, as has been previously described. The timing of this treatment had an impact on the survival of these patients.
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http://dx.doi.org/10.1002/hon.2601DOI Listing
April 2019

Unraveling transformation of follicular lymphoma to diffuse large B-cell lymphoma.

PLoS One 2019 25;14(2):e0212813. Epub 2019 Feb 25.

Lymphoma Research Group, Medical Oncology Department, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Madrid, Spain.

Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212813PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388933PMC
November 2019

Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors.

J Immunother Cancer 2019 01 24;7(1):18. Epub 2019 Jan 24.

Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI, 53226, USA.

Background: PD-L1 immunohistochemistry (IHC) has been traditionally used for predicting clinical responses to immune checkpoint inhibitors (ICIs). However, there are at least 4 different assays and antibodies used for PD-L1 IHC, each developed with a different ICI. We set to test if next generation RNA sequencing (RNA-seq) is a robust method to determine PD-L1 mRNA expression levels and furthermore, efficacy of predicting response to ICIs as compared to routinely used, standardized IHC procedures.

Methods: A total of 209 cancer patients treated on-label by FDA-approved ICIs, with evaluable responses were assessed for PD-L1 expression by RNA-seq and IHC, based on tumor proportion score (TPS) and immune cell staining (ICS). A subset of serially diluted cases was evaluated for RNA-seq assay performance across a broad range of PD-L1 expression levels.

Results: Assessment of PD-L1 mRNA levels by RNA-seq demonstrated robust linearity across high and low expression ranges. PD-L1 mRNA levels assessed by RNA-seq and IHC (TPS and ICS) were highly correlated (p < 2e-16). Sub-analyses showed sustained correlation when IHC results were classified as high or low by clinically accepted cut-offs (p < 0.01), and results did not differ by tumor type or anti-PD-L1 antibody used. Overall, a combined positive PD-L1 result (≥1% IHC TPS and high PD-L1 expression by RNA-Seq) was associated with a 2-to-5-fold higher overall response rate (ORR) compared to a double negative result. Standard assessments of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) showed that a PD-L1 positive assessment for melanoma samples by RNA-seq had the lowest sensitivity (25%) but the highest PPV (72.7%). Among the three tumor types analyzed in this study, the only non-overlapping confidence interval for predicting response was for "RNA-seq low vs high" in melanoma.

Conclusions: Measurement of PD-L1 mRNA expression by RNA-seq is comparable to PD-L1 expression by IHC both analytically and clinically in predicting ICI response. RNA-seq has the added advantages of being amenable to standardization and avoidance of interpretation bias. PD-L1 by RNA-seq needs to be validated in future prospective ICI clinical studies across multiple histologies.
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http://dx.doi.org/10.1186/s40425-018-0489-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346512PMC
January 2019

[2018 Consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary].

Rev Esp Patol 2019 Jan - Mar;52(1):33-44. Epub 2018 Oct 10.

Servicio de Oncología Médica, Institut Català d'Oncologia ICO-Hospitalet/Hospital de Sant Joan Despí - Moisès Broggi, Sant Joan Despí, Barcelona, España.

Cancer of unknown primary is defined as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They differ from other primary tumours in their biological features and how they spread, which means they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, cancer of unknown primary can account for 2-9% of all cancer patients, mostly 60-75 years old. This article reviews the main clinical, pathological and molecular studies conducted to analyse and determine the origin of cancer of unknown primary. The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed.
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http://dx.doi.org/10.1016/j.patol.2018.08.002DOI Listing
May 2020

MULTI-CRITERIA DECISION ANALYSIS AS A DECISION-SUPPORT TOOL FOR DRUG EVALUATION: A PILOT STUDY IN A PHARMACY AND THERAPEUTICS COMMITTEE SETTING.

Int J Technol Assess Health Care 2018 Jan 23;34(5):519-526. Epub 2018 Oct 23.

Department of Pharmacy,Hospital Universitario Virgen Macarena.

Objectives: The aim of this study was to develop and to assess a specific Multi-Criteria Decision Analysis (MCDA) framework to evaluate new drugs in an hospital pharmacy and therapeutics committee (P&TC) setting.

Methods: A pilot criteria framework was developed based on the EVIDEM (Evidence and Value: Impact on DEcisionMaking) framework, together with other relevant criteria, and assessed by a group of P&TC's members. The weighting of included criteria was done using a 5-point weighting technique. Two drugs were chosen by evaluation: an orphan-drug for Gaucher disease, and a nonorphan drug for the treatment of inflammatory bowel disease. Evidence matrices were developed, and value contribution of each drug was evaluated by P&TC's members. An agreed final framework was obtained through a discussion between the P&TC's members.

Results: After criteria assessment, the pilot framework included eight quantitative criteria: "disease severity," "unmet needs," "comparative efficacy/effectiveness," "comparative safety/tolerability," "comparative patient-reported outcomes," "comparative cost consequences-cost of treatment," "comparative cost consequences-other medical costs," and "quality of evidence"; and one contextual criterion: "opportunity costs and affordability." The most valued criteria were: "comparative safety/tolerability," "disease severity," and "comparative efficacy/effectiveness." When assessing the drugs most valued characteristics of the MCDA were the possibility that all team may contribute to drug assessment by means of scoring the matrices and the discussion to reach a consensus in drug positioning and value decision making.

Conclusions: The reflective MCDA would integrate quantitative and qualitative criteria relevant for a P&TC setting, allowing reflective discussions based on the criteria weighting score.
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http://dx.doi.org/10.1017/S0266462318000569DOI Listing
January 2018

Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3.

J Clin Oncol 2018 08 3;36(24):2465-2472. Epub 2018 Jun 3.

Dennis J. Slamon, University of California Los Angeles Medical Center, Santa Monica, CA; Patrick Neven, Multidisciplinary Breast Centre, Universitair Ziekenhuis, Leuven; Guy Jerusalem, Centre Hospitalier Universitaire de Liege and Liege University, Liège, Belgium; Stephen Chia, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Peter A. Fasching, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen; Arnd Nusch, Practice for Hematology and Internal Oncology, Velbert, Germany; Michelino De Laurentiis, Istituto Nazionale Tumori "Fondazione G. Pascale," Naples; Giulia Val Bianchi, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Seock-Ah Im, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; Katarina Petrakova, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Francisco J. Esteva, New York University Langone Health, New York, NY; Miguel Martín, Instituto de Investigacion Sanitaria Gregorio Marañon, Centro de Investigación Biomédica en Red de Cáncer, Grupo Español de Investigación en Cáncer de Mama, Universidad Complutense, Madrid; Luis De la Cruz-Merino, Hospital Universitario Virgen Macarena, Seville, Spain; Gabe S. Sonke, Netherlands Cancer Institute/Borstkanker Onderzoek Groep Study Center, Amsterdam, the Netherlands; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Xavier Pivot, Institut Régional du Cancer, Strasbourg, France; Gena Vidam, Karen Rodriguez Lorenc, Michelle Miller, and Tetiana Taran, Novartis Pharmaceuticals, East Hanover, NJ; and Yingbo Wang, Novartis Pharma, Basel, Switzerland.

Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting. Patients and Methods Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. Results A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naïve in the advanced setting (hazard ratio, 0.577; 95% CI, 0.415 to 0.802), as well as in patients who had received up to one line of prior endocrine therapy for advanced disease (hazard ratio, 0.565; 95% CI, 0.428 to 0.744). Among patients with measurable disease, the overall response rate was 40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant. Grade 3 adverse events reported in ≥ 10% of patients in either arm (ribociclib plus fulvestrant v placebo plus fulvestrant) were neutropenia (46.6% v 0%) and leukopenia (13.5% v 0%); the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% v 0%). Conclusion Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
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http://dx.doi.org/10.1200/JCO.2018.78.9909DOI Listing
August 2018
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