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Supplementary Table from Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis

Purpose:New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma.Patients and Methods:In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1–14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1–3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1–21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29).Results:After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3–4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells.Conclusions:R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

Supplementary Data from Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis

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.

Purpose: New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. Patients and Methods: In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1–14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1–3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1–21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). Results: After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3–4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. Conclusions: R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.

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.

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.

Resumen El grupo de enfermedades al que nos referimos como «cancer» comparte una estructura biologica conformada por un ecosistema complejo, donde se han alterado las relaciones intercelulares, los campos de informacion, el desarrollo y la funcion tisular. Mas alla de las alteraciones geneticas de la celula tumoral, la demostracion de un ecosistema alterado, con sus interconexiones a nivel sistemico, abre una nueva perspectiva de la biologia y del comportamiento del cancer. Diversas facetas del tumor, su morfologia, clasificacion, agresividad clinica, pronostico y respuesta al tratamiento aparecen ahora bajo una vision integral que ofrece un nuevo horizonte de estudio, investigacion y manejo clinico. La Teoria de la Mutacion Somatica en cancer, vigente desde hace mas de 100 anos, se ve hoy completada por el estudio del microambiente tumoral, la matriz extracelular, las celulas estromales, la respuesta inmune, la inervacion, la nutricion, la mitocondria, el metabolismo, el fluido intersticial, las propiedades mecanicas y electromagneticas del tejido, y muchas otras areas de conocimiento emergente, que abren la puerta a un ejercicio de reprogramacion del fenotipo tumoral a traves de la modificacion de las claves ofrecidas por este nuevo paradigma. Su reconocimiento permite pasar de considerar el proceso oncologico como un problema celular a una alteracion supracelular basada en la desorganizacion de los tejidos, inmersos en las relaciones del sistema complejo que conforma un ser vivo.

Pediatric cancers are rare malignancies worldwide and represent around 1% of all new cancer diagnoses [...]

© 2020 by the authors., 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., This work was supported by grants from ISCIII (FIS) and FEDER (European Regional Development Fund) PI17/01558; CIBERONC (contract CB16/12/00484); Fundación Científica de la Asociación Española contra el Cáncer (FAECC2015/006) and NEN Association (Nico contra el cancer infantil 2017—PVR00157).

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.

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.

Resumen Objetivo Comparar la supervivencia del cancer de mama en mujeres que han sido cribadas en el programa de Deteccion Precoz del Cancer de Mama (DPCM) y en las que no han participado en el. Pacientes y metodos Es un estudio descriptivo y longitudinal en el que se han estudiado todos los canceres de mama registrados en el servicio de Anatomia Patologica del Hospital de Tortosa Verge de la Cinta (Tarragona) de mujeres de 50-65 anos, que se habian detectado la enfermedad ellas mismas o que la habia detectado el programa DPCM, desde junio de 1999 hasta junio de 2003. Se registraron 101 pacientes con cancer de mama, de las que en 84 se pudieron recoger todos los datos relativos al tumor, la cirugia y el tratamiento. En el 2014, tras un seguimiento de 11,6 ± 1,8 anos, se anoto el estado actual. Resultados No hay diferencia estadisticamente significativa en la supervivencia de los 2 grupos. Pacientes con carcinoma in situ y sin ganglios metastasicos se encuentran entre las fallecidas, mientras que ninguna paciente con carcinoma bien diferenciado fallecio. Conclusiones En nuestro estudio, el cribado del cancer de mama no mejora la supervivencia y determinados factores en los que se apoyan los programas de cribado, como la deteccion de carcinomas no infiltrantes y/o de ganglios no metastasicos, no aseguran la curacion.

This study aimed to assess the differences in the cellular composition of the inflammatory reactive background around tumoral cells of classical Hodgkin's lymphomas (cHL) inside and outside the HIV settings. This retrospective study evaluates the infiltrating T lymphocytes (CD4 and CD8), natural killer cells (CD57+ cells), and more especially cytotoxic cells [granzyme B (GrB) and TIA-1+ cells] in the background of 99 EBV+ cHL. Sections from paraffin-embedded tumor samples from nine HIV-infected cHL patients were immunostained, using standard immunohistochemical protocols and were compared to a control group of 90 HIV-noninfected cHL patients. Our clinical and histological data indicate that HIV-infected cHL patients present a higher frequency of mixed cellularity (MC) histological subtypes, more advanced disease stages, a poor response to treatment, and a poor overall survival compared to control patients. In controls, CD4/CD8 and GrB/TIA-1 ratios were determined as 2:1 and 1:2, respectively. The inflammatory infiltrate of HIV-infected patients had a significant reduction of CD4+ T lymphocytes (CD4/CD8 ratio 1:23), a decrease in infiltrating GrB+ cells (activated cytotoxic cells) and an increase in infiltrating TIA+ T cells (mainly nonactivated cytotoxic cells) in these patients (GrB/TIA-1 ratio 1:12). In conclusion, this study highlights an important intratumoral loss of CD4+ T cells (striking inversion in the CD4/CD8 ratio) and a decrease in intratumoral activated cytotoxic T lymphocytes in HIV-associated cHL patients. Further studies are required to confirm these results and to determine the role of these findings on the antitumoral immune response observed in HIV-associated cHL.

The present study aimed to describe the general tissular composition of the immune infiltrate observed in Hodgkin's lymphoma (HL) and its possible relationship with clinical and survival prognostic factors. In this retrospective study of 267 HL patients, the relative proportions of infiltrating T lymphocytes (CD4+, CD8+), natural killer cells (CD 56+, CD 57+), cytotoxic cells (Granzyme B+, TIA-1+) and dendritic cells (CD 21+, S-100+) were quantified immunohistochemically with tissue microarray technology. Our results confirm the predominance of CD4 + T lymphocytes in the background of tumoral cells, in addition to a high number of cytotoxic lymphocytes (CD8, CD 57 and TIA-1). Patients with low numbers of infiltrating CD8, CD 56, CD 57+cells and high numbers of Granzyme B and TIA-1+cells presented a significantly unfavourable clinical course (presence of leukocytosis, B symptoms, advanced clinical stage (III/IV), non-responding patients). A reduced infiltration of CD4+T lymphocytes was related with the presence of Epstein - Barr virus. Significantly longer survival times were observed in patients with a high level of infiltrating CD 57, as well as a low level of Granzyme B and TIA-1+cells (log-rank test). When evaluated in a multivariate model, high levels of infiltrating TIA-1 and Granzyme B+cells were shown to be independent prognostic factors that negatively influenced overall survival. The presence of TIA-1+cells was found to be the only unfavorable prognostic factor of event-free survival and disease-free survival. The overall detection of tumor-infiltrating cells in HL confirms the importance of cytotoxic T lymphocyte infiltration (Granzyme B and TIA-1+cells) in these patients. Independently of the classical clinical and pathological features, these cells appear to be an unfavourable prognostic factor in HL and, more particularly, the presence of cytotoxic TIA-1+cells.

BACKGROUND No cytologic reports on spermatic cord sarcomas have been published. CASE A 64-year-old man presented with a slowly growing, painless, left spermatic cord enlargement. Fine needle aspiration (FNA) obtained < 1 mL of bloody fluid consisting of solitary, mark-edly anaplastic and pleomorphic tumor giant cells occasionally arranged in small fragments. Rare atypical spindle cells could be observed. Some reactive lymphocytes were observed intermingled with tumor cells. Immunohistochemistry displayed vimentin reactivity and negativity for keratins and leukocytic common antigen. The specimen removed showed a well-circumscribed, 30-mm, yellowish solid tumor. Touch imprints displayed pleomorphic tumor cells showing intense anisonucleosis; a moderate amount of clear, sometimes microvacuolated cytoplasm; and tissue fragments with a storiform pattern. Histologic examination revealed microscopic and immunohistochemical features of malignant fibrous histiocytoma (MFH) arising in soft tissues of the spermatic cord. CONCLUSION FNA of a spermatic cord lesion may reveal a pleomorphic sarcoma. A pleomorphic appearance together with some spindle elements and compatible immunocytochemistry could help diagnose spermatic cord MFH. This is one of the few reports dealing with FNA cytology of paratesticular tumors and the first report, to the best of our knowledge, showing the cytologic characteristics of a case of spermatic cord MFH.

Background Although the cytologic features of cervical cystic lesions are well established, no cytology reports on lymphangioma in adults have been published. Case A 60-year-old male presented with a slowly growing, upper laterocervical, painless enlargement. Fine needle aspiration (FNA) obtained 15 mL of yellowish fluid, consisting predominantly of a uniform population of small and round lymphocytes without mitosis or atypia and with some histiocytes intermingled with them. Some centrocytes and occasionally centroblasts and plasma cells could also be observed. Immunohistochemistry performed on cell block sections displayed polyclonal B lymphocytes mixed with T cells. The specimen showed a clearly circumscribed, 50-mm, cystic lesion with a multilocular appearance and abundant, yellowish liquid. Microscopic examination demonstrated cystic lymphangioma arising from the medullary portion of a lymph node. Conclusion FNA cytology permits a suggested diagnosis of lymphangioma. This is one of the few reports of FNA cytology of lymphangioma and, to the best of our knowledge, this entity has not previously been found as a neck mass in an adult.

Prolymphocytic leukaemia and Hodgkin's lymphoma We describe a case of B-prolymphocytic leukaemia (B-PLL) who, following a long-lasting remission with fluradabine, developed a Hodgkin's lymphoma (HL) with bone marrow involvement. A 75-yr-old male was found to have a lymphocytosis [white blood cell (WBC) count = 146 x 10(9) L-1], small volume axillary lymphadenopathy, and hepatosplenomegaly. The majority of circulating lymphocytes had a round nucleus and prominent single nucleolus. The patient did not respond to chlorambucil and then received fludarabine, achieving a good response lasting for 5 yr, when he manifested with B symptoms and pancytopenia. A diagnosis of HL in the bone marrow was made based on histology (Reed Sternberg cells) and immunohistochemistry (CD30(+), CD15(+)). Epstein-Barr virus (EBV) studies were negative. The patient was treated with chemotherapy but died 6 months later from disease progression.

Fundamento Se pretende determinar la proporcionde enfermedad de Hodgkin (EH)que expresa el virus de Epstein-Barr (VEB)en nuestro medio. Pacientes Y Metodos Se ha realizado un estudioretrospectivo sobre 49 casos de EHusando la tecnica inmunohistoquimicaLMP-1 y la tecnica de hibridacion in situpara EBER-1. Resultados Un 40,8% (20/49) de los casosexpresaba VEB (EBER-1 y/o LMP-1 positivos).ESte porcentaje fue significativamentemayor en EH diagnosticadas a pacientesmayores de 55 anos y no hubo diferenciaspor sexo, aunque fue mayor, pero no de formasignificativa, en el subtipo histologicode EH de celularidad mixta. Conclusiones El VEB se asocia a un 40,8%de las EH en las comarcas de Tarragona. Background The aim of this study is to assessthe proportion of Hodgkin disease(HD) expressing Epstein-Barr virus (EBV) inour area (Tarragona-Spain). Patients and Methods A retrospective studywas performed on paraffin embedded HDtissues from 49 patients to examine thepresence of latent membrane protein (LMP-1) by immunohistochemistry and for EBER-1 in situ hybridization. Results Overall, EBV (EBER-1 and/or LMPpositive) was expressed in 20 cases(40.8%). This percentage was higher, butnot significant, in mixted cellularity, andsignificant higher in patients over 55 yearsold. No differences between sexes were observed. Conclusions EBV is associated with 40.8%of HD in area of Tarragona.

La matriz extracelular (MEC) representa una red tridimensional que engloba todos los órganos, tejidos y células del organismo. Constituye un filtro biofísico de protección, nutrición e inervación celular y el terreno para la respuesta inmune, angiogénesis, fibrosis y regeneración tisular. Y representa el medio de transmisión de fuerzas mecánicas a la membrana basal, que a través de las integrinas soporta el sistema de tensegridad y activa los mecanismos epigenéticos celulares. La alteración de la MEC supone la pérdida de su función de filtro eficaz, nutrición, eliminación, denervación celular, pérdida de la capacidad de regeneración y cicatrización y alteración de la transmisión mecánica o mecanotransducción. También la pérdida del sustrato para una correcta respuesta inmune ante agentes infecciosos, tumorales y tóxicos. Los tumores son tejidos funcionales conectados y dependientes del microambiente. El microambiente tumoral, constituido por la MEC, células del estroma y la propia respuesta inmune, son determinantes de la morfología y clasificación tumoral, agresividad clínica, pronóstico y respuesta al tratamiento del tumor. Tanto en condiciones fisiológicas como patológicas, la comunicación recíproca entre células del estroma y el parénquima dirige la expresión génica. La capacidad oncogénica del estroma procede tanto de los fibroblastos asociados al tumor como de la celularidad de la respuesta inmune y la alteración de la tensegridad por la MEC. La transición epitelio-mesenquimal es el cambio que transforma una célula normal o «benigna» en «maligna». El citoesqueleto pseudomesenquimal otorga las propiedades de migración, invasión y diseminación. Y viceversa, el fenotipo maligno es reversible a través de la corrección de las claves que facilita el microambiente tumoral. Extracellular matrix (ECM) is a three-dimensional network that envelopes all the organs, tissues and cells of the body. A biophysical filter that provides protection, nutrition and cell innervation, it is the site for immune response, angiogenesis, fibrosis and tissue regeneration. It is also the transport medium for mechanical forces to the basal membrane through integrins that support the tensegrity system, activating cellular epigenetic mechanisms. The disruption of the ECM leads to a functional loss of nutrition, elimination, cell innervation, regenerative capacity and wound healing as well as alterations in mechanical transduction. This loss also disrupts the immune response to pathogens, tumour cells and toxins. Tumours are functionally connected tissues which depend on the microenvironment. This tumour microenvironment, made up of ECM, stromal cells and the immune response, determines the morphology and tumour histopathological classification, clinical behaviour, prognosis and immune response to the tumour. Both in physiological and pathological conditions, reciprocity in the communication between stromal and parenchymal cells determine gene expression. The oncogenic capacity of the stroma depends on tumour associated fibroblasts, immune system cellularity and disruption of tensegrity by ECM. Epithelial-mesenchymal transition is the change that transforms a normal or benign cell into a malignant cell. The «pseudo-mensenchymal» cytoskeleton is responsible for migration, invasion and dissemination, and vice-versa, the malignant phenotype is reversible through the correction of the microenvironmental factors that favour tumour growth. Noguera Salva, Rosa, Rosa.Noguera@uv.es

Rituximab is a monoclonal antibody against the CD20 molecule which is used to treat B-cell lymphomas. In 60% of low-grade B lymphomas in which rituximab was effective at first, there was no clinical response in a second treatment and a few cases of follicular lymphomas (FL) with transformation to diffuse large B-cell lymphoma (DLBCL) have been reported. We describe a new case and hypothesize about the mechanisms of transformation: a 52-year-old man, in follow-up during 8 years for FL, who after rituximab treatment and complete remission of FL showed progressive disease involving the liver and duodenal mucosa. Immunohistochemical and molecular studies were performed on paraffin-embedded tissue samples of lymph nodes, the small intestine, and liver tumors. After rituximab treatment, biopsies of a liver lesion and the small bowel both showed CD20-negative large B-cell lymphoma. Molecular study of the initial and relapse specimens shows a CDR2 IgH rearrangement with the same height and t14;18 (MBR). The rapid relapse with the same rearrangement of IgH seems to support the interpretation that the change of grade of lymphoma and loss of CD20 expression occurred before rituximab treatment. The existence of a varying proportion of a CD20-negative cell population in every B-cell lymphoma which does not respond to rituximab should therefore be considered. The reduction of CD20 expression could be a resistance mechanism to rituximab retreatment in DLBCL as a consequence of the progression of low-grade B-cell non-Hodgkin's lymphoma (B-NHL). It is necessary to perform new biopsies to evaluate CD20 expression in relapse or the progression of B-cell lymphoma after rituximab treatment.