Publications by authors named "Pablo L Ortiz-Romero"

64 Publications

Primary Cutaneous Lymphoma: Recommendations for Clinical Trial Design and Staging Update from the ISCL, USCLC, and EORTC.

Blood 2021 Nov 10. Epub 2021 Nov 10.

Leiden University Medical Center, Leiden, Netherlands.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome (MF/SS), the most common type of PCL, none exist for the other PCLs. In addition, staging in the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.
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http://dx.doi.org/10.1182/blood.2021012057DOI Listing
November 2021

Randomized phase 3 ALCANZA study of brentuximab vedotin vs physician's choice in cutaneous T-cell lymphoma: final data.

Blood Adv 2021 Sep 10. Epub 2021 Sep 10.

Peter MacCallum Cancer Centre, Melbourne, Australia.

The primary analysis of the phase 3 ALCANZA trial showed significantly-improved objective responses lasting ≥4 months (ORR4; primary endpoint) and progression-free survival (PFS) with brentuximab vedotin vs physician's choice (methotrexate or bexarotene) in CD30-expressing mycosis fungoides (MF) or primary cutaneous anaplastic large-cell lymphoma (C-ALCL). Cutaneous T-cell lymphomas often cause pruritus and pain; brentuximab vedotin improved skin symptom burden with no negative effects on quality of life. We report final data from ALCANZA (median follow-up 45.9 months). Adults with previously treated CD30-expressing MF/C-ALCL were randomized to brentuximab vedotin (n = 64) or physician's choice (n = 64). Final data demonstrated improved responses per independent review facility with brentuximab vedotin vs physician's choice: ORR4, 54.7% vs 12.5% (P < .001); complete response, 17.2% vs 1.6% (P = .002). Median PFS with brentuximab vedotin vs physician's choice was 16.7 months vs 3.5 months (P< .001). Median time to next treatment was significantly longer with brentuximab vedotin than with physician's choice (14.2 vs 5.6 months; hazard ratio, 0.27; 95% CI, 0.17-0.42; P < .001). Of 44 patients in the brentuximab vedotin arm who experienced any-grade peripheral neuropathy (PN), (grade 3, n = 6; grade 4, n = 0), 86% (38/44) had complete resolution (26/44) or improvement to grade 1-2 (12/44). PN was ongoing in 18 patients (all grade 1-2). These final analyses confirm improved, clinically meaningful, durable responses and longer PFS with brentuximab vedotin vs physician's choice in CD30-expressing MF or C-ALCL. This trial was registered at https://www.clinicaltrials.gov/ct2/show/NCT01578499 as #NCT01578499.
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http://dx.doi.org/10.1182/bloodadvances.2021004710DOI Listing
September 2021

Primary cutaneous anaplastic large-cell lymphoma successfully treated with intralesional brentuximab vedotin: a case report.

Int J Dermatol 2021 Aug 7. Epub 2021 Aug 7.

Department of Dermatology, 12 de Octubre Hospital, Institute i+12, CIBERONC, Medical School, University Complutense, Madrid, Spain.

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http://dx.doi.org/10.1111/ijd.15834DOI Listing
August 2021

Lymphomatoid papulosis mimicking distal embolism.

Int J Dermatol 2021 Jul 14. Epub 2021 Jul 14.

Department of Dermatology, Hospital Universitario 12 de Octubre, Madrid, Spain.

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http://dx.doi.org/10.1111/ijd.15795DOI Listing
July 2021

Romidepsin-induced sterile folliculitis in a patient with Sézary syndrome.

Int J Dermatol 2021 May 5. Epub 2021 May 5.

Department of Dermatology, Hospital Universitario 12 de Octubre, I+12 Research Institute, Universidad Complutense, Madrid, Spain.

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http://dx.doi.org/10.1111/ijd.15646DOI Listing
May 2021

UVA-Degradable Collagenase Nanocapsules as a Potential Treatment for Fibrotic Diseases.

Pharmaceutics 2021 Apr 6;13(4). Epub 2021 Apr 6.

Departamento de Química en Ciencias Farmacéuticas, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria, Hospital 12 de Octubre i+12, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.

Peyronie and Dupuytren are pathologies characterized by the appearance of localized fibrotic lesions in an organ. These disorders originate from an excessive production of collagen in the tissue provoking dysfunction and functional limitations to the patients. Local administration of collagenase is the most used treatment for these fibrotic-type diseases, but a high lability of the enzyme limits its therapeutic efficacy. Herein, we present a novel methodology for the preparation of collagenase nanocapsules without affecting its enzymatic activity and capable of releasing the enzyme in response to an ultraviolet A (UVA) light stimulus. Polymeric coating around collagenase was formed by free-radical polymerization of acrylamide-type monomers. Their degradation capacity under UVA irradiation was provided by incorporating a novel photocleavable acrylamide-type crosslinker within the polymeric framework. This property allowed collagenase release to be triggered in a controlled manner by employing an easily focused stimulus. Additionally, UVA irradiation presents considerable benefits by itself due to its capacity to induce collagenase production in situ. An expected synergistic effect of collagenase nanocapsules in conjunction with UVA effect may present a promising treatment for these fibrotic diseases.
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http://dx.doi.org/10.3390/pharmaceutics13040499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067494PMC
April 2021

Dermoscopy and reflectance confocal microscopy features of acquired lymphangiectasias following surgery and radiotherapy of breast cancer.

Int J Dermatol 2021 Oct 19;60(10):e429-e431. Epub 2021 Apr 19.

Department of Dermatology, Hospital Universitario 12 de Octubre, I+12 Research Institute, Universidad Complutense, Madrid, Spain.

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http://dx.doi.org/10.1111/ijd.15596DOI Listing
October 2021

Response to brentuximab vedotin versus physician's choice by CD30 expression and large cell transformation status in patients with mycosis fungoides: An ALCANZA sub-analysis.

Eur J Cancer 2021 05 29;148:411-421. Epub 2021 Mar 29.

Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, 40 Landsdowne Street, 02139, Cambridge, MA, USA. Electronic address:

Introduction: Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study.

Methods: Baseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30 < 10% (≥1 biopsy with <10% CD30 expression), or CD30 ≥ 10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS).

Results: Clinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician's choice in patients: with CD30 < 10% (40.9% versus 9.5%), with CD30 ≥ 10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician's choice in patients: with CD30 < 10% (16.7 versus 2.3 months), with CD30 ≥ 10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups.

Conclusion: These exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician's choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status.

Clinical Trial Registration: Clinicaltrials.gov, NCT01578499.
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http://dx.doi.org/10.1016/j.ejca.2021.01.054DOI Listing
May 2021

Behçet-ähnliche Erkrankung unter Secukinumab-Behandlung: neue paradoxe Reaktion?

J Dtsch Dermatol Ges 2021 Jan;19(1):116-118

Department of Dermatology, Hospital Universitario 12 de Octubre, I+12 Research Institute, Universidad Complutense, Madrid, Spain.

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http://dx.doi.org/10.1111/ddg.14196_gDOI Listing
January 2021

Usefulness of Patch Testing With Patient's Own Products in the Diagnosis of Allergic Contact Dermatitis.

Dermatitis 2021 Jan-Feb 01;32(1):38-41

From the Department of Dermatology, Hospital 12 de Octubre, Madrid, Spain.

Background: The usefulness of using patient's own products in patch tests for the diagnosis of allergic contact eczema is well known. However, most of the literature is based on case series published decades ago, and they are focused on cosmetics and fragrances.

Objective: The aim of the study was to evaluate the usefulness of using patient's own products in patch tests for the diagnosis of contact eczema in a contact dermatitis unit, describing the most frequently positive own products, as well as the most frequently responsible allergens.

Methods: In a 17-year period, 3514 patients were patch tested in our department. In 2429 patients, patch testing with the patients' own products was performed.

Results: We found that 363 patients (10.33%) reacted to their own products. In 131 cases (3.81%), reacting to their own product was the only clue for detecting the responsible allergen for allergic contact eczema. Most reactions were found for topical medications, moisturizers, and adhesives. Fragrance mix I, methylchloroisothiazolinone/methylisothiazolinone, ketoprofen, and colophony were found to be the allergens most often responsible.

Conclusions: It is essential to include patient's own products in the study of allergic contact eczema to make a correct diagnosis. In our series, 3.81% of the patients would not have been correctly diagnosed if their own products had not been included in patch tests.
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http://dx.doi.org/10.1097/DER.0000000000000654DOI Listing
October 2021

Lack of Systemic Absorption of Topical Mechlorethamine Gel in Patients with Mycosis Fungoides Cutaneous T-Cell Lymphoma.

J Invest Dermatol 2021 06 8;141(6):1601-1604.e2. Epub 2021 Jan 8.

Department of Dermatology, Hospital 12 de Octubre, Institute i+12, CIBERONC, Medical School, University Complutense, Madrid, Spain.

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http://dx.doi.org/10.1016/j.jid.2020.12.009DOI Listing
June 2021

The changing therapeutic landscape, burden of disease, and unmet needs in patients with cutaneous T-cell lymphoma.

Br J Haematol 2021 02 23;192(4):683-696. Epub 2020 Oct 23.

Department of Dermatology, University Complutense, Hospital 12 de Octubre, Medical School, Institute i+12, Madrid, Spain.

Cutaneous T-cell lymphomas (CTCLs) have a chronic, relapsing course, and the most common subtypes are mycosis fungoides and Sézary syndrome. The disease causes visible skin alterations and can also cause alopecia, pruritus and pain, all of which can impact patients' health-related quality of life (HRQoL). The goal of treatment is to reduce symptoms and prevent disease progression. However, treatment recommendations are often based on low levels of evidence due to the lack of well-designed randomised clinical trials and treatment guidelines, and approved drugs vary considerably across different countries and regions. Currently, available treatments rarely lead to durable remissions and eventually become less effective, meaning patients often require multiple therapy changes. Skin-directed therapies (SDTs) are first-line treatments for early-stage CTCL, whereas systemic therapies may be needed for early-stage disease that does not respond to SDT or for advanced-stage disease. However, patients can experience significant side-effects with these treatments or may be unable to tolerate them. Hence, there is an unmet need for effective therapies with good safety profiles for the treatment of early- and late-stage CTCL. Here, we review current treatment guidelines, investigational and approved treatments, the impact of CTCL on patients' HRQoL, and the treatment of pruritus.
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http://dx.doi.org/10.1111/bjh.17117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894136PMC
February 2021

The Course of Mycosis Fungoides under Cytokine Pathway Blockers: A Multicentre Analysis of Real-life Clinical Data.

Acta Derm Venereol 2020 09 30;100(16):adv00277. Epub 2020 Sep 30.

Literature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or anti-interleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stage-progression in 8 patients after a median of 8 months' treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.
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http://dx.doi.org/10.2340/00015555-3642DOI Listing
September 2020

Behçet's-like disease during secukinumab treatment: new paradoxical reaction?

J Dtsch Dermatol Ges 2021 Jan 10;19(1):116-118. Epub 2020 Aug 10.

Department of Dermatology, Hospital Universitario 12 de Octubre, I+12 Research Institute, Universidad Complutense, Madrid, Spain.

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http://dx.doi.org/10.1111/ddg.14196DOI Listing
January 2021

Patient-reported quality of life in patients with relapsed/refractory cutaneous T-cell lymphoma: Results from the randomised phase III ALCANZA study.

Eur J Cancer 2020 07 2;133:120-130. Epub 2020 Jun 2.

University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1452, Houston, TX, USA. Electronic address:

Background: Brentuximab vedotin was approved for adult patients with CD30-expressing cutaneous T-cell lymphoma treated with prior systemic therapy based on improved response rates and progression-free survival with brentuximab vedotin (1.8 mg/kg once every 3 weeks; ≤16 cycles) versus physician's choice (methotrexate/bexarotene; ≤48 weeks) in the phase III ALCANZA study. Quality of life (QoL) in ALCANZA patients was also examined.

Methods: QoL measures in ALCANZA were based on the Skindex-29, Functional Assessment of Cancer Therapy-General (FACT-G) and European QoL 5-dimension (EQ-5D) questionnaires.

Results: Mean maximum reduction from the baseline Skindex-29 symptom domain score (key secondary end-point) was greater with brentuximab vedotin than physician's choice (-27.96 versus -8.62); the difference, -18.9 (95% confidence interval -26.6, -11.2; adjusted p < 0.001), exceeded the study-defined minimally important difference (9.0-12.3). Mean changes from baseline to end-of-treatment visit total FACT-G scores were similar with brentuximab vedotin and physician's choice (0.15 versus -2.29). EQ-5D changes were also comparable between arms. Among brentuximab vedotin-treated patients with peripheral neuropathy (PN), mean maximum reduction in Skindex-29 symptom domain was -35.54 versus -11.11 in patients without PN. PN had no meaningful effect on FACT-G and EQ-5D QoL scores.

Conclusions: In summary, brentuximab vedotin produced superior reductions in symptom burden compared with physician's choice, without adversely impacting QoL. QoL was unaffected by the presence of PN in brentuximab vedotin-treated patients.

Clinical Trial Registration: NCT01578499.
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http://dx.doi.org/10.1016/j.ejca.2020.04.010DOI Listing
July 2020

Rapidly-developing alopecic nodules in a young man.

Int J Dermatol 2020 Oct 17;59(10):1219-1221. Epub 2020 Mar 17.

Department of Dermatology, Hospital Universitario 12 de Octubre, Madrid, Spain.

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http://dx.doi.org/10.1111/ijd.14847DOI Listing
October 2020

State of the art of Mohs surgery for rare cutaneous tumors in the Spanish Registry of Mohs Surgery (REGESMOHS).

Int J Dermatol 2020 Mar 28;59(3):321-325. Epub 2019 Nov 28.

Hospital La Paz, Madrid, Spain.

Background: The use of Mohs micrographic surgery (MMS) for rare cutaneous tumors is poorly defined. We aim to describe the demographics, tumor presentation and topography, surgery characteristics and complications of MMS for rare cutaneous tumors in a national registry.

Methods: Prospective cohort study of patients treated with MMS in Spain between July 2013 and June 2018. The inclusion criteria were patients with cutaneous tumors with final diagnosis different from basal cell carcinoma, squamous cell carcinoma, dermatofibrosarcoma protuberans, or any kind of melanoma.

Results: Five thousand and ninety patients were recorded in the registry, from which only 73 tumors (1.4%) fulfilled the inclusion criteria: atypical fibroxanthoma (18), microcystic adnexal carcinoma (10), extramammary Paget's disease (7), Merkel cell carcinoma (5), dermatofibroma (4), trichilemmal carcinoma (4), desmoplastic trichoepithelioma (4), sebaceous carcinoma (3), leiomyosarcoma (2), porocarcinoma (2), angiosarcoma (2), trichoblastoma (1), superficial acral fibromyxoma (1), and others (10). No intra-surgery morbidity was registered. Postsurgery complications appeared in six patients (9%) and were considered mild. Median follow-up time was 0.9 years during which three Merkel cell carcinomas, one angiosarcoma, one microcystic adnexal carcinoma, and four others recurred (12.3%).

Conclusion: This national registry shows that rare cutaneous tumors represent a negligible part of the total MMS performed in our country with a low complication rate.
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http://dx.doi.org/10.1111/ijd.14732DOI Listing
March 2020

Use of extracellular vesicles from lymphatic drainage as surrogate markers of melanoma progression and mutation.

J Exp Med 2019 05 11;216(5):1061-1070. Epub 2019 Apr 11.

Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center, Madrid, Spain

Liquid biopsies from cancer patients have the potential to improve diagnosis and prognosis. The assessment of surrogate markers of tumor progression in circulating extracellular vesicles could be a powerful non-invasive approach in this setting. We have characterized extracellular vesicles purified from the lymphatic drainage also known as exudative seroma (ES) of stage III melanoma patients obtained after lymphadenectomy. Proteomic analysis showed that seroma-derived exosomes are enriched in proteins resembling melanoma progression. In addition, we found that the mutation can be detected in ES-derived extracellular vesicles and its detection correlated with patients at risk of relapse.
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http://dx.doi.org/10.1084/jem.20181522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504207PMC
May 2019

Psoriatic alopecia-like paradoxical reaction to certolizumab pegol.

Int J Dermatol 2019 Jun 1;58(6):e118-e120. Epub 2019 Mar 1.

Department of Dermatology, Hospital Universitario, Madrid, Spain.

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http://dx.doi.org/10.1111/ijd.14417DOI Listing
June 2019

The Circulating Transcriptome as a Source of Biomarkers for Melanoma.

Cancers (Basel) 2019 Jan 10;11(1). Epub 2019 Jan 10.

Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain.

The circulating transcriptome is a valuable source of cancer biomarkers, which, with the exception of microRNAs (miRNAs), remains relatively unexplored. To elucidate which RNAs are present in plasma from melanoma patients and which could be used to distinguish cancer patients from healthy individuals, we used next generation sequencing (NGS), and validation was carried out by qPCR and/or ddPCR. We identified 442 different microRNAs in samples, eleven of which were differentially expressed ( < 0.05). Levels of and were significantly down-regulated ( < 0.001) in melanoma samples ( = 96) compared to healthy controls ( = 28). Differentially expressed protein-encoding mRNA 5'-fragments were enriched for the angiopoietin, p21-activated kinase (PAK), and EIF2 pathways. Levels of , , , and gene fragments were up-regulated ( < 0.001) in melanoma samples ( = 144) compared to healthy controls ( = 41) (AUC = 0.825). Over 40% of mapped reads were YRNAs, a class of non-coding RNAs that to date has been little explored. Expression levels of , , and were significantly higher in patients with stage 0 disease than either healthy controls or more advanced stage disease ( < 0.001). In conclusion, we have identified a number of novel RNA biomarkers, which, most importantly, we validated in multi-center retrospective and prospective cohorts, suggesting potential diagnostic use of these RNA species.
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http://dx.doi.org/10.3390/cancers11010070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356785PMC
January 2019

p62/SQSTM1 Fuels Melanoma Progression by Opposing mRNA Decay of a Selective Set of Pro-metastatic Factors.

Cancer Cell 2019 01 20;35(1):46-63.e10. Epub 2018 Dec 20.

Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain. Electronic address:

Modulators of mRNA stability are not well understood in melanoma, an aggressive tumor with complex changes in the transcriptome. Here we report the ability of p62/SQSTM1 to extend mRNA half-life of a spectrum of pro-metastatic factors. These include FERMT2 and other transcripts with no previous links to melanoma. Transcriptomic, proteomic, and interactomic analyses, combined with validation in clinical biopsies and mouse models, identified a selected set of RNA-binding proteins (RBPs) recruited by p62, with IGF2BP1 as a key partner. This p62-RBP interaction distinguishes melanoma from other tumors where p62 controls autophagy or oxidative stress. The relevance of these data is emphasized by follow-up analyses of patient prognosis revealing p62 and FERMT2 as adverse determinants of disease-free survival.
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http://dx.doi.org/10.1016/j.ccell.2018.11.008DOI Listing
January 2019

Association of APOA5 and APOC3 Genetic Polymorphisms With Severity of Hypertriglyceridemia in Patients With Cutaneous T-Cell Lymphoma Treated With Bexarotene.

JAMA Dermatol 2018 12;154(12):1424-1431

Dermatology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain.

Importance: Hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors.

Objectives: To analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile.

Design, Setting, And Participants: This case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed.

Main Outcomes And Measures: Primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied.

Results: Among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02).

Conclusions And Relevance: These results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile.
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http://dx.doi.org/10.1001/jamadermatol.2018.3679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583311PMC
December 2018

Subcutaneous panniculitis-like T-cell lymphoma: Clinical features, therapeutic approach, and outcome in a case series of 16 patients.

J Am Acad Dermatol 2018 Nov 17;79(5):892-898. Epub 2018 Aug 17.

Hospital Clínic, Barcelona, Spain.

Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous lymphoma of mature cytotoxic T cells. Initially, patients with SPTCL were treated with doxorubicin-based polychemotherapy.

Objective: To analyze clinical, biologic, immunophenotypical, molecular, imaging, treatment, and outcome data reflecting the current state of knowledge.

Methods: A retrospective multicenter study of 16 patients with SPTCL that was diagnosed between 1996 and 2016.

Results: The female-to-male ratio was 1.7. The median age at diagnosis was 46.5 years. Patients presented with multiple nodular or plaque-like lesions preferentially affecting the legs and/or trunk. Histopathology typically showed a lobular panniculitis with individual adipocytes surrounded by atypical lymphocytes, usually with a CD3, CD4, CD8, CD56, TIA1 cytotoxic granule associated RNA binding protein 1-positive phenotype and high proliferation rate. SPTCL was associated with autoimmune diseases in 25% of patients, and with the development of hemophagocytic syndrome in 18% of patients. Oral steroids alone or in combination with low-dose methotrexate or cyclosporine A were the most common initial treatment, achieving a complete response in 85% of the treated patients. The median follow-up time was 14 months. The 5-year disease-specific survival rate was 85.7%.

Limitations: This was a retrospective study.

Conclusions: SPTCL has an excellent prognosis. Immunosuppressive agents can be considered for first-line treatment.
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http://dx.doi.org/10.1016/j.jaad.2018.05.1243DOI Listing
November 2018

Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial.

Lancet Oncol 2018 09 9;19(9):1192-1204. Epub 2018 Aug 9.

Columbia University Medical Center, New York, NY, USA.

Background: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.

Methods: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.

Findings: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.

Interpretation: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.

Funding: Kyowa Kirin.
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http://dx.doi.org/10.1016/S1470-2045(18)30379-6DOI Listing
September 2018

Mycosis fungoides progression could be regulated by microRNAs.

PLoS One 2018 12;13(6):e0198477. Epub 2018 Jun 12.

Pathology Department, Fundación Jiménez Díaz, UAM, Madrid, CIBERONC, Madrid, Spain.

Differentiating early mycosis fungoides (MF) from inflammatory dermatitis is a challenge. We compare the differential expression profile of early-stage MF samples and benign inflammatory dermatoses using microRNA (miRNA) arrays. 114 miRNAs were found to be dysregulated between these entities. The seven most differentially expressed miRNAs between these two conditions were further analyzed using RT-PCR in two series comprising 38 samples of early MFs and 18 samples of inflammatory dermatitis. A series of 51 paraffin-embedded samples belonging to paired stages of 16 MF patients was also analyzed. MiRNAs 26a, 222, 181a and 146a were differentially expressed between tumoral and inflammatory conditions. Two of these miRNAs (miRNA-181a and miRNA-146a) were significantly deregulated between early and advanced MF stages. Bioinformatic analysis showed FOXP3 expression to be regulated by these miRNAs. Immunohistochemistry revealed the level of FOXP3 expression to be lower in tumoral MFs than in plaque lesions in paraffin-embedded tissue. A functional study confirmed that both miRNAs diminished FOXP3 expression when overexpressed in CTCL cells. The data presented here suggest that the analysis of a restricted number of miRNAs (26a, 222, 181a and 146a) could be sufficient to differentiate tumoral from reactive conditions. Moreover, these miRNAs seem to be involved in MF progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997347PMC
December 2018
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