Efficacy and safety of lurbinectedin and doxorubicin in relapsed small cell lung cancer: results from an expansion cohort of a phase I study

Lurbinectedin; Phase I study; Small cell lung cancerLurbinectedina; Estudio fase I; Cáncer de pulmón de células pequeñasLurbinectedina; Estudi de fase I; Càncer de pulmó de cèl·lules petitesBackground A phase I study found remarkable activity and manageable toxicity for doxorubicin (bolus) plus lurbinectedin (1-h intravenous [i.v.] infusion) on Day 1 every three weeks (q3wk) as second-line therapy in relapsed small cell lung cancer (SCLC). An expansion cohort further evaluated this combination. Patients and methods Twenty-eight patients with relapsed SCLC after no more than one line of cytotoxic-containing chemotherapy were treated: 18 (64%) with sensitive disease (chemotherapy-free interval [CTFI] ≥90 days) and ten (36%) with resistant disease (CTFI <90 days; including six with refractory disease [CTFI ≤30 days]). Results Ten patients showed confirmed response (overall response rate [ORR] = 36%); median progression-free survival (PFS) = 3.3 months; median overall survival (OS) = 7.9 months. ORR was 50% in sensitive disease (median PFS = 5.7 months; median OS = 11.5 months) and 10% in resistant disease (median PFS = 1.3 months; median OS = 4.6 months). The main toxicity was transient and reversible myelosuppression. Treatment-related non-hematological events (fatigue, nausea, decreased appetite, vomiting, alopecia) were mostly mild or moderate. Conclusion Doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2 on Day 1 q3wk has shown noteworthy activity in relapsed SCLC and a manageable safety profile. The combination is being evaluated as second-line therapy for SCLC in an ongoing, randomized phase III trial. Clinical trial registration www.ClinicalTrials.gov code: NCT01970540. Date of registration: 22 October, 2013.This work was supported by Pharma Mar, S.A

Recommendations for the use of biomarkers for head and neck cancer, including salivary gland tumours: a consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology

Epstein Barr virus; Prognosis; Response to treatmentVirus de Epstein Barr; Pronóstico; Respuesta al tratamientoVirus d'Epstein Barr; Pronòstic; Resposta al tractamentThe treatment of head and neck and salivary gland tumours is complicated and evolves constantly. Prognostic and predictive indicators of response to treatment are enormously valuable for designing individualized therapies, which justifies their research and validation. Some biomarkers, such as p16, Epstein–Barr virus, PD-L1, androgen receptors and HER-2, are already used routinely in clinical practice. These biomarkers, along with other markers that are currently under development, and the massively parallel sequencing of genes, ensure future advances in the treatment of these neoplasms. In this consensus, a group of experts in the diagnosis and treatment of tumours of the head and neck and salivary glands were selected by the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica—SEAP) and the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica—SEOM) to evaluate the currently available information and propose a series of recommendations to optimize the determination and daily clinical use of biomarkers.SEOM and SEAP acknowledge the financial support for this project in the form of unrestricted collaboration in the logistics from AstraZeneca

ICO-ICS Praxis para el tratamiento médico y con irradiación del cáncer de orofaringe, hipofaringe, laringe y nasofaringe

Tractament mèdic; Tractament amb irradiació; Càncer de cap i coll; Carcinoma de nasofaringeTratamiento médico; Tratamiento con irradiación; Cáncer de cabeza y cuello; Carcinoma de nasofaringeMedical treatment; Irradiation treatment; Head and neck cancer; Nasopharyngeal carcinomaL’anomenat càncer de cap i coll engloba un grup de tumors malignes localitzats en diverses zones de les vies aerodigestives superiors: sins paranasals, nasofaringe, orofaringe (amígdala, paladar tou, base de la llengua), hipofaringe, laringe, cavitat oral (mucosa oral, geniva, paladar dur, llengua i terra de la boca) i glàndules salivals. L'objectiu d'aquest document és - Desenvolupar, difondre, implementar i avaluar resultats de la ICO-ICSPraxi per al tractament del càncer d’orofaringe, hipofaringe, laringe i nasofaringe. - Disminuir la variabilitat terapèutica entre els pacients tractats en els diversos centres d’aquesta institució. - Implementar els resultats de la terapèutica en els pacients amb càncer de càvum, orofaringe, hipofaringe o laringe tractats d’acord amb les recomanacions d’aquesta guia

LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy

Càncer; Macròfags associats al tumor: LIF; CD8Cáncer; Macrófagos asociados al tumor; CD8Cancer; Tumor-associated macrophages; CD8Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival

Anticancer targeted agent combination

Las toxicidades limitantes de dosis fuero una neutropenia febril grado 4 (en el brazo de docetaxel) y una neutropenia grado 3 en el brazo de gemcitabina. La combinación de carlumab no tuvo un impacto El cáncer es una enfermedad altamente frecuente y con alta mortalidad. El desarrollo de fármacos contra el cáncer se ha caracterizado por su ineficiencia, con una de las tasas de aprobación de fármacos más baja entre las diferentes especialidades médicas. El principal motivo de esta baja tasa de éxito es la falta de eficacia de los nuevos fármacos que entran al desarrollo clínico. Se han planteado diferentes estrategias para mejorar la eficiencia del desarrollo de fármacos, incluyendo la combinación de fármacos antitumorales, el desarrollo en paralelo de biomarcadores y la optimización del diseño de los ensayos clínicos usando modelización basada en farmacocinética y farmacodinamia Esta tesis es un compendio de dos artículos que evalúan estrategias para optimizar el desarrollo de fármacos mediante la combinación de agentes antitumorales. El primer proyecto es la evaluación preclínica en xenoinjertos derivados de pacientes (PDX) la combinación de inhibidores de PI3K-mTOR con diferentes agentes antitumorales y el segundo es el ensayo clínico fase I evaluando carlumab, un anticuerpo anti CCL2, en combinación con diferentes quimioterapias en pacientes con tumores sólidos avanzados. Proyecto 1: se seleccionaron tres modelos de PDX con deficiencia en PTEN: un PDX de cáncer de mama triple negativo (TNBC), otro de carcinoma de ovario de bajo grado KRAS G12R mutado y otro de adenocarcinoma de pulmón con mutaciones en KRAS G12C y TP53 R181P. En estos modelos se evaluaron dos inhibidores de PI3K-mTOR—PF-04691502 and PF-05212384— en combinación con cisplatino, paclitaxel o dacomitinib. La adición de los inhibidores de PI3K-mTOR a cisplatino o paclitaxel aumentó la actividad de la quimioterapia en los modelos de TNBC y LGSOC; sin embargo, no se objetivó este efecto en modelo de adenocarcinoma de pulmón con mutación de KRAS y TP53. Se objetivó modulación farmacodinámica de pAKT y pS6 en los grupos tratados con inhibidores de PI3K-mTOR. Nuestra investigación sugiere que añadir un inhibidor de PI3K-mTOR puede aumentar el efecto inhibitorio sobre el crecimiento de la quimioterapia en modelos PDX con deficiencia en PTEN. Sin embargo, este beneficio no se observó en el modelo de adenocarcinoma KRAS y TP53 mutado. En el futuro se deberá ahondar en el papel de la pérdida de PTEN en la actividad de estas combinaciones. Proyecto 2: se trata de un ensayo clínico fase Ib evaluando carlumab, un anticuerpo monoclonal contra CCL-2, en combinación con cuatro regímenes de quimioterapia (docetaxel, gemcitabina, carboplatino + paclitaxel y doxorrubicina liposomal pegilda (PLD). En este estudio participaron 53 pacientes en los que o bien los agentes quimioterápicos eran parte del tratamiento convencional o no tenían otras opciones de tratamiento convencional: docetaxel (n=15), gemcitabina (n=12), carboplatino + paclitaxel (n=12) y PLD (n=14). Las toxicidades limitantes de dosis incluyeron una neutropenia febril grado 4 (en el brazo de docetaxel) y una neutropenia grado 3 (en el brazo de gemcitabina). De acuerdo a los brazos de tratamiento, las toxicidades grado 3 o mayores más frecuentes fueron: neutropenia (6/15) y neutropenia febril (4/15) en el brazo de docetaxel, neutropenia (2/12) en el brazo de gemcitabina, neutropenia (4/12), trombocitopenia (4/12) y anemia (2/12) en el brazo de carboplatino-paclitaxel y anemia (3/14) y mucositis (2/14) en el brazo de PLD. Se objetivo una respuesta parcial y 18 estabilizaciones de la enfermedad (38%). La adición de carlumab no tuvo cambios relevantes en el perfil farmacocinético de ninguna de las quimioterapias evaluadas. Los niveles de CCL2 libres descendieron inmediatamente tras el tratamiento con carlumab, pero aumentaron con las administraciones posteriores, sugiriendo que carlumab secuestraba CCL2 de manera temporal. No se objetivaron anticuerpos anti-droga que justificasen dicho efecto. No se objetivaron cambios en las células tumorales circulantes ni en las células circulantes endoteliales. En 3 de 19 pacientes evaluables se objetivó una reducción del 30% en los niveles de N-telopeptido de colágeno tipo I en orina (uNTx). Carlumab es seguro administrado a dosis de 10 o 15 mg/kg en combinación con quimioterapia convencional y tiene buena tolerancia. Sin embargo, no se alcanza una inhibición sostenida de CCL2, ni se han objetivado un número de respuestas significativas.Cancer is a highly frequent disease associated to high mortality. Drug development in Oncology has shown to be inefficient, having one of the lowest success rate of drugs entering in phase I trials that finally achieves marketed authorization. The main reason for this high failure rate is lack of efficacy. Different strategies have been adopted to improved anti-cancer drug development with the aim of improving patient care. This strategies include the combinatorial use of agents, biomarker co-development, and optimization of clinical trial design with the use of pharmacokinetic-pharmacodynamic modeling. This thesis is presented as compendium of work integrating two projects; the first project preclinically evaluates the combination of two PI3K-mTOR inhibitors and chemotherapy or the pan-HER inhibitor dacomitinib in patient derived xenografts. The second project evaluates de monoclonal antibody anti-CCL2 carlumab in patient derived xenografts. Project 1: Three PDXs were selected for their lack of PTEN expression by immunohistochemistry: a triple-negative breast cancer (TNBC), a KRAS G12R low-grade serous ovarian cancer (LGSOC), and KRAS G12C and TP53 R181P lung adenocarcinoma (LADC). Two dual PI3K-mTOR inhibitors were evaluated—PF-04691502 and PF-05212384—in combination with cisplatin, paclitaxel, or dacomitinib. The addition of PI3K-mTOR inhibitors to cisplatin or paclitaxel increased the activity of chemotherapy in the TNBC and LGSOC models; whereas no added activity was observed in the LADC model. Pharmacodynamic modulation of pS6 and pAKT was observed in the group treated with PI3K-mTOR inhibitor. Our research suggests that the addition of a PI3K-mTOR inhibitor may enhance tumor growth inhibition when compared to chemotherapy alone in PTEN-deficient PDXs. However, this benefit was absent in the KRAS and TP53 mutant LADC model. The role of PTEN deficiency in the antitumor activity of these combinations should be further investigated in the clinic. Project 2 is a first-in-human phase 1b study of carlumab with one of four chemotherapy regimens (docetaxel, gemcitabine, paclitaxel+carboplatin, and pegylated liposomal doxorubicin HCl [PLD]). Fifty-three patients with advanced solid tumors for which ≥1 of these regimens was considered standard of care or for whom no other treatment options existed participated in the study: docetaxel (n=15), gemcitabine (n=12), paclitaxel or carboplatin (n=12), or PLD (n=14). Dose-limiting toxicities included one grade 4 febrile neutropenia (docetaxel arm) and one grade 3 neutropenia (gemcitabine arm). The most common drug-related grade ≥3 adverse events were docetaxel arm—neutropenia (6/15) and febrile neutropenia (4/15); gemcitabine arm—neutropenia (2/12); paclitaxel+carboplatin arm—neutropenia, thrombocytopenia (4/12 each), and anemia (2/12); and PLD arm—anemia (3/14) and stomatitis (2/14). One partial response and 18 (38 %) stable disease responses were observed. Combination treatment with carlumab had no clinically relevant pharmacokinetic effect on any of the chemotherapeutic agents tested. Free CCL2 declined immediately post-treatment with carlumab but increased with further chemotherapy administrations in all arms, suggesting that carlumab could sequester CCL2 for only a short time. Neither antibodies against carlumab nor consistent changes in circulating tumor cells (CTCs) or circulating endothelial cells (CECs) enumeration were observed. Three of 19 evaluable patients showed a 30 % decrease from baseline urinary cross-linked N-telopeptide of type I collagen (uNTx). Carlumab could be safely administered at 10 or 15 mg/kg in combination with standard-of-care chemotherapy and was well-tolerated, although no long-term suppression of serumCCL2 or significant tumor responses were observed

The inhibition of flower bud differentiation in ‘Crimson Gold’ nectarine with GA3 as an alternative to hand thinning

14 pag., 9 fig. The definitive version is available at: http://www.sciencedirect.com/science/journal/03044238The reduction of flower bud density by gibberellin sprays, to adjust the cropping level, is a novel approach to fruit thinning of peach and nectarine. A linear reduction in the number of flowers developed per unit of shoot length was found following the spray application of increasing concentrations of GA3, in the nectarine cultivar ‘Crimson Gold’. These reductions in flower number led to reductions in yield at harvest, and increases in mean fruit weight. Flowering was slightly delayed by the GA3 treatments, but no differences in ripening were detected at harvest, this depending rather on fruit size. The yield obtained by the application of 200 mg l−1 GA3 corresponded to that obtained with a very good thinning level, as established by hand thinning. No secondary effects on vegetative growth followed either the application of GA3 or the reductions in crop load by means of hand thinning. Decreasing crop-loads have resulted in an increase in fruit size and an advance of fruit ripening, measured by greater levels of soluble solids and lower flesh firmness. A good commercial quality fruit size was obtained for crop-loads of 300 fruits per tree or less.Work carried out under research project CONSID (DGA) PCA1294.Peer reviewe

Actividad de la vía PI3K-AKT-FOXOp27 como factor pronóstico en tumores astrocitarios

Els tumors astrocitaris són entitats poc freqüents i el seu pronòstic és pobre. Recentment s'ha descrit l'alta freqüència d'alteració de la via de PI3K a aquests tumors. L'objectiu d'aquest estudi és valorar la possible correlació entre la supervivència lliure de progressió d'una sèrie de pacients intervinguts per tumors astrocitarios en el nostre centre i l'activació de la via de PI3K definida mitjançant expressió inmunohistoquímica. Es van analitzar un total de 83 pacients. A més dels factors correlacionats en la literatura amb la supervivència lliure de progressió (grau, cirurgia i edat), l'estudi mostra una correlació directament proporcional amb els nivells de pFOXO i inversament proporcional amb p27. El valor d'aquestes troballes haurà de ser validat posteriorment.Los tumores astrocitarios son entidades poco frecuentes y su pronóstico es pobre. Existen pocos factores pronósticos en estos tumores Recientemente se ha descrito una alta frecuencia de alteraciones en la vía PI3K en estos tumores. El objetivo de este estudio es valorar la posible correlación entre la supervivencia libre de progresión de una serie de pacientes intervenidos por tumores astrocitarios en nuestro centro y la activación de la vía PI3K definida por la expresión inmunohistoquímica de alguno de sus componentes. Se analizaron 83 pacientes (55 gliomastomas, 13 astrocitomas anaplásicos, 13 astrocitomas difusos, 2 astrocitoma de bajo grado no definido). Además de los factores correlacionado en la literatura con la supervivencia libre de progresión (grado, cirugía y edad), el estudio muestra una correlación directamente proporcional con los niveles de pFOXO e inversamente proporcional con p27. El posible valor pronóstico de estos hallazgos deberá ser validado en estudios posteriore

Overview of Oral Potentially Malignant Disorders:From Risk Factors to Specific Therapies

SIMPLE SUMMARY: Oral potentially malignant disorders (OPMDs) include a group of oral mucosal diseases with different morphological characteristics that are able to progress to oral squamous cell carcinoma (OSCC). Given OSCC’s poor prognosis and high mortality, early diagnosis is a priority step in OSCC. Extrinsic and intrinsic risk factors and etiologies are involved in developing and malignant transformation of oral lesions, and different molecular alterations have been described in early lesions associated with a potential malignant behavior. This review summarizes the information about clinical, morphological and molecular features of OPMDs, with an emphasis on the early detection techniques and an overview of the surgical and systemic therapies’ effectiveness. ABSTRACT: Oral squamous cell carcinoma (OSCC) is a very aggressive cancer, representing one of the most common malignancies worldwide. Oral potentially malignant disorders (OPMDs) regroup a variegate set of different histological lesions, characterized by the potential capacity to transform in OSCC. Most of the risk factors associated with OSCC are present also in OPMDs’ development; however, the molecular mechanisms and steps of malignant transformation are still unknown. Treatment of OSCC, including surgery, systemic therapy and radiotherapy (alone or in combination), has suffered a dramatic change in last years, especially with the introduction of immunotherapy. However, most cases are diagnosed during the advanced stage of the disease, decreasing drastically the survival rate of the patients. Hence, early diagnosis of premalignant conditions (OPMDs) is a priority in oral cancer, as well as a massive education about risk factors, the understanding of mechanisms involved in malignant progression and the development of specific and more efficient therapies. The aim of this article is to review epidemiological, clinical, morphological and molecular features of OPMDs, with the purpose to lay the foundation for an exhaustive comprehension of these lesions and their ability of malignant transformation and for the development of more effective and personalized treatments

LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy

Cancer response to immunotherapy depends on the infiltration of CD8 T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8 T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8 T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival