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Funding Information: This work was supported by the National Key Research and Development Program (2020YFA0707900, 2018YFE0201100, 2019YFA0110800 to W.L., 2018YFA0108400, 2019YFA0903800 to Q.Z.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030403 to W.L.), the National Natural Science Foundation of China (31621004 to Q.Z. and W.L.), and the CAS Project for Young Scientists in Basic Research (YSBR-012 to W.L.). We thank Xia Yang and Jinxin Yang for their help with fluorescence activated cell sorting and cell culture. Publisher Copyright: Copyright © 2022 Pinto and Neves. Primary immunodeficiencies (PID) are rare, complex diseases that can be characterised by a spectrum of phenotypes, from increased susceptibility to infections to autoimmunity, allergy, auto-inflammatory diseases and predisposition to malignancy. With the introduction of genetic testing in these patients and wider use of next-Generation sequencing techniques, a higher number of pathogenic genetic variants and conditions have been identified, allowing the development of new, targeted treatments in PID. The concept of precision medicine, that aims to tailor the medical interventions to each patient, allows to perform more precise diagnosis and more importantly the use of treatments directed to a specific defect, with the objective to cure or achieve long-term remission, minimising the number and type of side effects. This approach takes particular importance in PID, considering the nature of causative defects, disease severity, short- and long-term complications of disease but also of the available treatments, with impact in life-expectancy and quality of life. In this review we revisit how this approach can or is already being implemented in PID and provide a summary of the most relevant treatments applied to specific diseases. publishersversion published

BackgroundVaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective. Nevertheless, immunocompromised participants were excluded from randomized controlled clinical trials. This study evaluates the efficacy and safety of the Pfizer/BioNTech BNT162b2 (BNT162b2) vaccine in patients with breast and gynecological cancer treated with active anticancer therapy versus a control cohort of healthy participants.MethodsImmune responses to the BNT162b2 vaccine in patients with breast cancer (n = 44) or a gynecological malignancy (n = 6) on active anticancer therapy (28 on chemotherapy, mostly anthracycline- or taxane-based, and 22 on target therapy) and in a control cohort of participants without cancer (n = 67) were investigated by SARS-CoV-2 neutralizing antibody titers measured by S1-binding immunoglobulin G (IgG) concentrations assessed using the LIAISON XL tools (DiaSorin S.p.A.). Response was assessed after a second dose of the BNT162b2 vaccine administered before and at least 3 weeks after the vaccine dose.ResultsOverall, 43/50 (86%) patients of the cancer cohort (74% in the breast cancer group and 100% in the gynecological malignancy group) developed IgG antibodies after the second dose of the BNT162b2 vaccine. There were no statistically significant differences in responder rates between patients treated with chemotherapy and those on target therapy. The majority of patients who received chemotherapy with or without target therapy, 21/28 (75%), developed a reliable antibody titer after a vaccine. All seven non-responder patients were undergoing an anthracycline-based regimen. Based on IgG levels (0–400 AU/ml), patients were classified as negative (‘non-responders’), weakly positive, or strongly positive (‘responders’). No delay in cancer therapy schedule or reported side effects were recorded after BNT162b2 vaccine administration. All healthy participants were strongly positive. Responder rates differed significantly between the two study cohorts (p < 0.001).ConclusionsMost patients develop antibody titers after the second immunization. However, given the persistence of non-responders or weak responders, additional immunization booster seems to be required, along with proactive planning in the vaccination schedule, with vaccine administration spaced out over time with respect to chemotherapy.

Traballo Fin de Grao en Medicina. Curso 2021-2022 Introducción: Los tumores endometriales constituyen la neoplasia ginecológica más frecuente en mujeres occidentales, mientras que el cáncer ovárico es la de mayor tasa de mortalidad. El desarrollo de nuevos modelos preclínicos tridimensionales (organoides) que reproduzcan las características específicas del tumor permite llevar a cabo estudios de caracterización molecular y screening farmacológico, lo que podría orientar la selección de tratamientos y el pronóstico de las pacientes, de especial importancia en casos de alto riesgo, recidiva o progresión de la enfermedad a varias líneas de tratamiento. El principal objetivo de este trabajo es presentar un procedimiento del desarrollo de organoides a partir de muestras mínimamente invasivas de pacientes de cáncer de endometrio y ovario. Materiales y métodos: Se obtuvieron muestras de pacientes de cáncer endometrial (n=6) y cáncer ovárico (n=1). Se desarrolló un método de procesamiento para obtener una suspensión de célula única epitelial. Se compararon cualitativamente distintos protocolos descritos en la literatura, tanto a nivel de eficiencia de generación y rendimiento de los cultivos (BME droplet y BME bilayer organoid culture), como de mantenimiento (químico, mecánico y enzimático). Se llevó a cabo una caracterización preliminar de los organoides de tumor ovárico mediante inmunofluorescencia. Resultados: El método desarrollado permitió obtener una suspensión de células tumorales con una viabilidad >75% en todas las muestras. Se identificaron diferentes patrones morfológicos en las estructuras generadas. El método de cultivo BME droplets y el mecánico resultaron ser los más eficientes. La caracterización de los organoides de ovario demostró la expresión de PAX8, vimentina y citoqueratinas. Conclusiones: La tasa de éxito en la generación de organoides y el rendimiento sufrieron gran variabilidad, no pudiendo ser esta atribuida a las diferencias de viabilidad de la suspensión celular de partida. Se destaca la necesidad de estandarizar protocolos y desarrollar estudios que avalen su implementación en la clínica Introdución: Os tumores endometriais constitúen a neoplasia xinecolóxica máis frecuente nas mulleres occidentais, namentres que o cancro ovárico é a de maior taxa de mortalidade. O desenvolvemento de novos modelos preclínicos tridimensionais (organoides) que reproduzan as características específicas do tumor permite levar a cabo estudos de caracterización molecular e cribado farmacolóxico, o que podería orientar a selección de tratamentos e o pronóstico das pacientes, de especial importancia nos casos de alto risco, recidiva ou progresión da enfermidade a varias liñas de tratamento. O principal obxectivo deste traballo é presentar un procedemento da xeración de organoides a partir de mostras minimamente invasivas de pacientes de cancro de endometrio e ovario. Materiais e métodos: Obtivéronse mostras de pacientes de cancro endometrial (n=6) e cancro ovárico (n=1). Desenvolveuse un método de procesamento para obter unha suspensión de célula única epitelial. Comparáronse cualitativamente distintos protocolos descritos na literatura, tanto a nivel de eficiencia de xeración e rendemento dos cultivos (BME droplet e BME bilayer organoid culture), como de mantemento dos mesmos (químico, mecánico e encimático). Levouse a cabo unha caracterización preliminar dos organoides de tumor ovárico mediante inmunofluorescencia. Resultados: O método desenvolvido permitiu obter unha suspensión de células tumorais cunha viabilidade >75% en todas as mostras. Identificáronse diferentes patróns morfolóxicos nas estruturas xeradas. O método de cultivo de BME droplets e o mecánico resultaron ser os de maior eficiencia. A caracterización dos organoides de ovario demostrou a expresión de PAX8, vimentina e citoqueratinas. Conclusións: A taxa de éxito na xeración de organoides e no rendemento do cultivo sufriu unha grande variabilidade, non podendo ser atribuida ás diferenzas de viabilidade da suspensión celular de partida. Destácase a necesidade de estandarizar protocolos e desenvolver estudos que avalen a súa implementación na clínica Background: Endometrial tumors constitute the most frequent gynecological neoplasia in occidental women, whereas ovarian cancer is the one with the highest mortality rate. New 3D preclinical models (organoids) development that recapitulate specific characteristics of the original tumor allows to drive molecular characterization tests and drug screening, which could lead treatment selection and patient’s prognosis, especially important in high-risk cases, relapse or illness progression to several lines of therapy. The main objective of this project is to show a development organoid procedure from minimally invasive samples of endometrial and ovarian cancer patients. Methods: Endometrial cancer (n=6) and ovarian cancer (n=1) samples were obtained. A method for processing samples to achieve an epithelial single-cell suspension was developed. Several protocols described in literature were qualitatively compared, in terms of efficiency of the generation of structures comparing two techniques (BME droplet and BME bilayer organoid culture), and in terms of culture maintenance (chemical, mechanic and enzymatic). A preliminary characterization of ovarian organoids was conducted by immunofluorescence. Results: The developed method allowed to obtain a tumoral single-cell suspension with a viability >75% in all the samples. Different morphological patterns in the generated structures were observed. BME droplets culture and mechanic method showed to be the most efficient ones. Ovarian organoid characterization revealed PAX8, vimentin and cytokeratins expression. Conclusions: The success rate of organoids generation suffered high variability, which could not be attributed to differences in the suspension cell viability. It is highlighted the need of standardized protocols and studies to support clinical implementation

Carbon nanotubes (CNTs) were discovered in 1991, and since then, have been one of the most intensely studied nanomaterials due to their improved functionalities and diversity of applications. Specifically, CNTs are entirely composed of carbon atoms connected through sp2 bonds structured in several condensed benzene rings rolled up into a cylinder form. Depending on the number of graphitic layers, CNTs can be classified into single-walled carbon nanotubes (SWCNTs) or multi-walled carbon nanotubes (MWCNTs). The specific structural properties of CNTs, leading to a strong loading capacity, high surface area, high strength, and enhanced chemical and thermal stability, make these nanomaterials very promising for biomedical applications. In this sense, this book chapter overviews the potential applications of CNTs in the biomedical field, highlighting their usage on: (1) diagnosis, by the development of CNTs-based biosensors and imaging methods; (2) tissue engineering; (3) delivery systems of several anticancer and antihypertensive drugs, corticosteroids, genes, nucleic acids, among others; and (4) target therapies, namely photothermal and photodynamic therapies. Additionally, particular attention is given to the CNTs potential toxicity and different strategies to overcome this controversial subject, namely by the adequate CNTs functionalization. published

Periodontal disease is a chronic inflammatory condition affecting about 20–50% of people, worldwide, and manifesting clinically through the detection of gingival inflammation, clinical attachment loss, radiographically assessed resorption of alveolar bone, gingival bleeding upon probing, teeth mobility and their potential loss at advanced stages. It is characterized by a multifactorial etiology, including an imbalance of the oral microbiota, mechanical stress and systemic diseases such as diabetes mellitus. The current standard treatments for periodontitis include eliminating the microbial pathogens and applying biomaterials to treat the bone defects. However, periodontal tissue regeneration via a process consistent with the natural tissue formation process has not yet been achieved. Developmental biology studies state that periodontal tissue is composed of neural crest-derived ectomesenchyme. The aim of this review is to discuss the clinical utility of stem cells in periodontal regeneration by reviewing the relevant literature that assesses the periodontal-regenerative potential of stem cells.

Renal cell carcinoma (RCC) is an increasingly common malignancy that can progress to metastatic renal cell carcinoma (mRCC) in approximately one-third of RCC patients. The 5-year survival rate for mRCC is abysmally low, and, at the present time, there are sparingly few if any effective treatments. Current surgical and pharmacological treatments can have a long-lasting impact on renal function, as well. Thus, there is a compelling unmet need to discover novel biomarkers and surveillance methods to improve patient outcomes with more targeted therapies earlier in the course of the disease. Circulating biomarkers, such as circulating tumor DNA, noncoding RNA, proteins, extracellular vesicles, or cancer cells themselves potentially represent a minimally invasive tool to fill this gap and accelerate both diagnosis and treatment. Here, we discuss the clinical relevance of different circulating biomarkers in metastatic renal cell carcinoma by clarifying their potential role as novel biomarkers of response or resistance to treatments but also by guiding clinicians in novel therapeutic approaches.

People living with HIV (PLWH) with advanced immunosuppression who initiate antiretroviral therapy (ART) are susceptible to the occurrence of an immune reconstitution inflammatory syndrome (IRIS). Although ART is responsible for AIDS- associated Kaposi sarcoma (KS) improvement and resolution, new onset (unmasking KS-IRIS) or sudden progression of preexisting KS (paradoxical KS-IRIS) can occur after a time delay of between a few days and 6 months after the initiation or resumption of ART, even in patients with a low degree of immunocompromise. KS-IRIS incidence varies from 2.4% to 39%, depending on study design, populations, and geographic regions. Risk factors for developing KS-IRIS include advanced KS tumor stage (T1), pre-treatment HIV viral load >5 log10 copies/mL, detectable pre-treatment plasma-KSHV, and initiation of ART alone without concurrent chemotherapy. Both paradoxical and unmasking KS-IRIS have been associated with significant morbidity and mortality, and thrombocytopenia (

ROS proto-oncogene 1 (ROS1) rearrangements are reported in about 1–2% of non-squamous non-small-cell lung cancer (NSCLC). After efficacy of crizotinib was demonstrated, identification of ROS1 translocations in advanced disease became fundamental to give patients the chance of specific and effective treatment. Different methods are available for detection of rearrangements, and probably the real prevalence of ROS1 rearrangements is higher than that reported in literature, as our capacity to detect gene rearrangements is improving. In particular, with next generation sequencing (NGS) techniques, we are currently able to assess multiple genes simultaneously with increasing sensitivity. This is leading to overcome the “single oncogenic driver” paradigm, and in the very near future, the co-existence of multiple drivers will probably emerge more frequently and represent a therapeutic issue. Since recently, crizotinib has been the only available therapy, but today, many other tyrosine kinase inhibitors (TKI) are emerging and seem promising both in first and subsequent lines of treatment. Indeed, novel inhibitors are also able to overcome resistance mutations to crizotinib, hypothesizing a possible sequential strategy also in ROS1-rearranged disease. In this review, we will focus on ROS1 rearrangements, dealing with diagnostic aspects, new therapeutic options, resistance issues and the coexistence of ROS1 translocations with other molecular alterations.

Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4–8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1–10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies.

BackgroundHepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. Although the diagnostic scheme of HCC is currently undergoing refinement, the prognosis of HCC is still not satisfactory. In addition to certain factors, such as tumor size and number and vascular invasion displayed on traditional imaging, some histopathological features and gene expression parameters are also important for the prognosis of HCC patients. However, most parameters are based on postoperative pathological examinations, which cannot help with preoperative decision-making. As a new field, radiomics extracts high-throughput imaging data from different types of images to build models and predict clinical outcomes noninvasively before surgery, rendering it a powerful aid for making personalized treatment decisions preoperatively.ObjectiveThis study reviewed the workflow of radiomics and the research progress on magnetic resonance imaging (MRI) radiomics in the diagnosis and treatment of HCC.MethodsA literature review was conducted by searching PubMed for search of relevant peer-reviewed articles published from May 2017 to June 2021.The search keywords included HCC, MRI, radiomics, deep learning, artificial intelligence, machine learning, neural network, texture analysis, diagnosis, histopathology, microvascular invasion, surgical resection, radiofrequency, recurrence, relapse, transarterial chemoembolization, targeted therapy, immunotherapy, therapeutic response, and prognosis.ResultsRadiomics features on MRI can be used as biomarkers to determine the differential diagnosis, histological grade, microvascular invasion status, gene expression status, local and systemic therapeutic responses, and prognosis of HCC patients.ConclusionRadiomics is a promising new imaging method. MRI radiomics has high application value in the diagnosis and treatment of HCC.

Background: Breast cancer is the most common malignancy in women worldwide. Patients with triple negative breast cancer represent a subgroup with unfavorable prognosis especially in advanced stages of the disease. Several first-line therapeutic agents have been described. Objective: To perform a systematic review and meta-analysis to compare target therapies plus chemotherapy with chemotherapy in the treatment of patients with triple negative breast cancer Stage IV or recurrent. Material and Methods: A systematic search identified randomized clinical studies for the treatment of triple negative breast cancer in Stage IV or recurrent. The outcomes of interest were overall survival (OS) and progression-free survival (PFS). Data from each clinical study were recorded for the outcomes and the relative risk was estimated. Results: 10 studies were included and participants ranged from 53 to 902 per study. Regarding overall survival, we observed that target therapy plus chemotherapy in patients with triple-negative Stage IV or recurrent breast cancer was associated with a 15% decrease in the risk of mortality with a RR (95% CI): 0.85 (0.70 to 1.03). In relation to the level of progression-free risk, we observed that the intervention showed a 16% decrease in the risk of progression with a RR (95% CI): 0.84 (0.74 to 0.95). Progression-free survival in patients with the intervention ranged from 2.8 to 9.7 months, while in conventional therapy it ranged from 1.5 to 6.2 months. Conclusion: Patients with Stage IV or recurrent triple negative breast cancer who received target therapy plus chemotherapy showed a trend towards decreased risk of disease progression (PFS) and mortality (OS), however, more clinical studies are required to validate its significance. Objetivo: Realizar una revisión sistemática y metaanálisis para comparar terapias target más quimioterapia con quimioterapia en el tratamiento de pacientes con cáncer de mama triple negativo EC IV o recurrente. Material y Métodos: Una búsqueda sistemática de estudios clínicos aleatorizados para el tratamiento de cáncer de mama triple negativo en EC IV o recurrente. Los desenlaces de interés fueron Sobrevida Global (SG) y sobrevida libre de progresión (SLP). Se registró datos de cada estudio clínico para los desenlaces y se estimó RR. Resultados: 10 estudios fueron incluidos y los participantes oscilaron entre 53 a 902 por estudio. La sobrevida global observamos que la terapia target más quimioterapia en las pacientes con cáncer de mama triple negativo EC IV o recurrente estuvo asociado a una disminución del 15% del riesgo de mortalidad con un RR (IC 95%): 0,85 (0,70 a 1,03). En relación al nivel de riesgo libre de progresión observamos que en la intervención se presentó una disminución del 16% en el riesgo de progresión con un RR (IC 95%): 0,84 (0,74 a 0,95). La sobrevida libre de progresión en las pacientes con la intervención oscilo entre 2,8 a 9,7 meses, mientras que en la terapia convencional osciló entre 1,5 a 6,2 meses. Conclusión: Las pacientes con cáncer de mama EC IV o recurrente triple negativo que recibieron terapia target más quimioterapia presentaron tendencia a la disminución en el riesgo de progresión de enfermedad (SLP) y mortalidad (OS), sin embargo, ­­­­se requieren más estudios clínicos para validar su significancia.

The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionised the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children; and they are either rare tumours with common NTRK fusions that may be diagnostic, or more prevalent tumours with rare NTRK fusions. To assess currently available evidence on this matter, three key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathological Anatomy (SEAP), and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical, and therapeutic aspects of NTRK-fusion tumours. This document also discusses the challenges related to the routine detection of these genetic alterations in a mostly public Health Care System., SEOM, SEAP and SEHOP have received financial support for this project in the form of unrestricted collaboration in the logistics of expert meeting from Bayer and Roche.

Triple-negative breast cancer (TNBC) is characterized by the absence of hormone receptor and HER2 expression, and therefore a lack of therapeutic targets. Anthracyclines and taxane-based neoadjuvant chemotherapy have historically been the cornerstone of treatment of early TNBC. However, genomic and transcriptomic analyses have suggested that TNBCs include various subtypes, characterized by peculiar genomic drivers and potential therapeutic targets. Therefore, several efforts have been made to expand the therapeutic landscape of early TNBC, leading to the introduction of platinum and immunomodulatory agents into the neoadjuvant setting. This review provides a comprehensive overview of the currently available evidence regarding platinum agents and immune-checkpoint-inhibitors for the neoadjuvant treatment of TNBC, as well as the novel target therapies that are currently being evaluated in this setting. Taking into account the economic issues and the side effects of the expanding therapeutic options, we focus on the potential efficacy biomarkers of the emerging therapies, in order to select the best therapeutic strategy for each specific patient.

Malignant pleural mesothelioma (MPM) is a clinical emergency of our time. Being strongly associated with asbestos exposure, incidence of this cancer is ramping up these days in many industrialized countries and it will soon start to increase in many developing areas where the use of this silicate derivate is still largely in use. Deficiency of reliable markers for the early identification of these tumors and the limited efficacy of the currently available therapeutic options are the basis of the impressive mortality rate of MPM. These shortcomings reflect the very poor information available about the molecular basis of this disease. Results of the recently released deep profiling studies point to the epigenome as a central element in MPM development and progression. First, MPM is characterized by a low mutational burden and a highly peculiar set of mutations that hits almost exclusively epigenetic keepers or proteins controlling chromatin organization and function. Furthermore, asbestos does not seem to be associated with a distinctive mutational signature, while the precise mapping of epigenetic changes caused by this carcinogen has been defined, suggesting that alterations in epigenetic features are the driving force in the development of this disease. Last but not least, consistent evidence also indicates that, in the setting of MPM, chromatin rewiring and epigenetic alterations of cancer cells heavily condition the microenvironment, including the immune response. In this review we aim to point to the relevance of the epigenome in MPM and to highlight the dependency of this tumor on chromatin organization and function. We also intend to discuss the opportunity of targeting these mechanisms as potential therapeutic options for MPM.

There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type I IFN, the ‘so-called’ type I IFN signature, is present in peripheral blood mononuclear cells, and that this finding is associated with the development of systemic extra-glandular manifestations, and a substantial production of autoantibodies and inflammatory cytokines. In contrast, the absence or a milder expression of type I IFN signature and low level of inflammatory cytokines characterizes patients with a different clinical phenotype, where the disease is limited to glandular involvement and often marked by the presence of widespread pain and depression. The role of type II (IFNγ) in this subset of pSS patients, together with the potentially related activation of completely different immunological and metabolic pathways, are emerging issues. Expression of both types of IFNs has also been shown in target tissues, namely in minor salivary glands where a predominance of type II IFN signature appeared to have a certain association with the development of lymphoma. In view of the role played by IFN overexpression in the development and progression of pSS, inhibition or modulation of IFN signaling has been regarded as a potential target for the therapeutic approach. A number of therapeutic compounds with variable mechanisms of action have been tested or are under consideration for the treatment of patients with pSS.

ROS proto-oncogene 1 (ROS1) rearrangements are reported in about 1–2% of non-squamous non-small-cell lung cancer (NSCLC). After efficacy of crizotinib was demonstrated, identification of ROS1 translocations in advanced disease became fundamental to give patients the chance of specific and effective treatment. Different methods are available for detection of rearrangements, and probably the real prevalence of ROS1 rearrangements is higher than that reported in literature, as our capacity to detect gene rearrangements is improving. In particular, with next generation sequencing (NGS) techniques, we are currently able to assess multiple genes simultaneously with increasing sensitivity. This is leading to overcome the “single oncogenic driver” paradigm, and in the very near future, the co-existence of multiple drivers will probably emerge more frequently and represent a therapeutic issue. Since recently, crizotinib has been the only available therapy, but today, many other tyrosine kinase inhibitors (TKI) are emerging and seem promising both in first and subsequent lines of treatment. Indeed, novel inhibitors are also able to overcome resistance mutations to crizotinib, hypothesizing a possible sequential strategy also in ROS1-rearranged disease. In this review, we will focus on ROS1 rearrangements, dealing with diagnostic aspects, new therapeutic options, resistance issues and the coexistence of ROS1 translocations with other molecular alterations.

BACKGROUND/AIM We evaluated local control and toxicity in patients receiving radiotherapy associated with immune check point inhibitors and analyzed which oligometastatic disease setting benefits the most from local ablation in terms of advantage in overall survival. PATIENTS AND METHODS We retrospectively identified 60 oligoprogressive patients treated with a PD-1 inhibitor in association with radiotherapy on the site of progression (119 lesions). RESULTS After a median follow-up of 11.7 months (range=1-39 months), we observed complete response (CR) in 45/119, partial response (RP) in 42/119, and stable disease (SD) in 30/119 patients. Nine radionecrotic events occurred. Two patients experienced grade 3 toxicities and 32 patients reported grade 2 toxicities. The number of radiologically evident metastatic organs in patients who received concomitant PD-1 inhibitors and radiotherapy showed a significant increase in survival (respectively, 73% after 12 months and 47% after 24 months) in patients with 0-3 metastatic organs compared to those with more than 3 organ sites involved (p

Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, indeed, the treatment armamentarium for advanced HCC has broadened tremendously, with targeted- and immune-therapies, and probably the combination of both, playing pivotal roles. Together with new established knowledge, many issues are emerging, with the role of neoadjuvant/adjuvant settings, the definition of the best transitioning time from loco-regional treatments to systemic therapy, the identification of potential predictive biomarkers, and radiomics being just some of the topics that will have to be further explored in the next future. Clearly, the current COVID-19 pandemic has influenced the management of HCC patients and some considerations about this topic will be elucidated.

Malignant mesothelioma is a locally aggressive and highly lethal neoplasm. Dysregulation and activation of Gas6/AXL tyrosine kinase signaling are associated with mesothelioma progression, but the mechanisms of these AXL tumorigenic roles are poorly understood. p53 mutants in lung carcinoma upregulate AXL expression by binding and acetylating the AXL promoter. Although TP53 mutations are uncommon in mesothelioma, we hypothesized that these tumors might have alternative feedback mechanisms between AXL and p53. In the current report, we investigated AXL regulation of TP53 transcription, expression, and biological function in mesothelioma. AXL expression was stronger in mesothelioma than most of the other tumor types from the TCGA gene expression profile dataset. AXL knockdown by shRNA induced wild-type and mutant p53 expression in mesothelioma cell lines, suggesting that AXL pro-tumorigenic roles result in part from the suppression of p53 function. Likewise, induced AXL inhibited expression of wild type p53 in COS-7 cells and 293T cells. Immunofluorescence staining showed nuclear colocalization of AXL and p53, however, association of AXL and p53 was not demonstrated in immunoprecipitation complexes. The AXL effects on p53 expression resulted from the inhibition of TP53 transcription, as demonstrated by qRT-PCR after AXL silencing and TP53 promotor dual luciferase activity assays. Chromatin immunoprecipitation-qPCR and sequencing showed that AXL bound to the initial 600 bp sequence at the 5&prime, end of the TP53 promoter. AXL inhibition (shRNA or R428) reduced mesothelioma cell viability, migration, and invasion, whereas TP53 shRNA knockdown attenuated antiproliferative, migration, and invasive effects of AXL silencing or AXL inactivation in these cells. These studies demonstrate a novel feedback regulation loop between AXL and p53, and provide a rationale for mesothelioma therapies targeting AXL/p53 signaling.

T-cell acute lymphoblastic leukemia/lymphoma is an aggressive hematological neoplasm whose classification is still based on immunophenotypic findings. Frontline treatment encompass high intensity combination chemotherapy with good overall survival; however, relapsing/refractory patients have very limited options. In the last years, the understanding of molecular physiopathology of this disease, lead to the identification of a subset of patients with peculiar genetic profile, namely "early T-cell precursors" lymphoblastic leukemia, characterized by dismal outcome and indication to frontline allogeneic bone marrow transplant. In general, the most common mutations occur in the NOTCH1/FBXW7 pathway (60% of adult patients), with a positive prognostic impact. Other pathogenic steps encompass transcriptional deregulation of oncogenes/oncosuppressors, cell cycle deregulation, kinase signaling (including IL7R-JAK-STAT pathway, PI3K/AKT/mTOR pathway, RAS/MAPK signaling pathway, ABL1 signaling pathway), epigenetic deregulation, ribosomal dysfunction, and altered expression of oncogenic miRNAs or long non-coding RNA. The insight in the genomic landscape of the disease paves the way to the use of novel targeted drugs that might improve the outcome, particularly in relapse/refractory patients. In this review, we analyse available literature on T-ALL pathogenesis, focusing on molecular aspects of clinical, prognostic, and therapeutic significance.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score &ge, 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0&ndash, 4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5% of the ACCs demonstrated a strong SOAT1 protein expression (score &gt, 2), while 62.5% demonstrated a weak or absent protein expression (score &le, 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95% 1.26&ndash, 3.66, p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95% 1.09&ndash, 4.06, p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC.

Currently, the only curative treatment for cholangiocarcinoma (CCA) is surgical resection, though this treatment is possible in less than 40% of patients. However, recent improvements in preoperative management have led to a higher number of patients who are candidates for this procedure. For unresectable patients, progress is ongoing in terms of locoregional and chemoradiation treatments and target therapies, especially in the definition of patient selection criteria. This is the second part of the Italian CCA guidelines, dealing with CCA treatment, that have been formulated in accordance with Italian National Institute of Health indications and developed according to the GRADE method and related advancements.

Eleni Res,1 Stella Maria Kyvelou,2 Charalambos Vlachopoulos,2 Kyriaki Manousou,1 Dimitris Tousoulis,3 Christodoulos Stefanadis,2 Dimitris Pektasides3 1Third Department of Medical Oncology, Agioi Anargyroi General Oncology Hospital of Kifissia, 2Cardiology Department, First Cardiology Clinic, Athens Medical School, Hippokration Hospital, 3Second Department of Internal Medicine, School of Medicine, University of Athens, Athens, Greece Background: The aim of the prospective study was to evaluate blood pressure (BP) and the arterial stiffness before and after chemotherapy in three subgroups of patients with metastatic colorectal, renal cell, and gastrointestinal carcinoma and exploit, if possible, the effect of chemotherapy and biological agents in the event of cardiotoxicity.Methods: A total of 171 patients were included in the study: 60 with kidney cancer, 18 with gastrointestinal stromal tumors (GISTs), and 93 with metastatic colorectal cancer. All patients were subjected to full clinical and laboratory evaluation before and after chemotherapy. Arterial-stiffness indices were assessed before the initiation and after the completion of chemotherapy by means of pulse wave velocity (PWV; Complior) and augmentation index (AIx; SphygmoCor).Results: Patients in all three cancer cohorts exhibited significantly (P

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, we demonstrated the overexpression of both DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) in RMS tumour biopsies and cell lines compared to normal skeletal muscle. Radiotherapy may often fail due to the abnormal expression of some molecules able to drive resistance mechanisms. The aim of this study was to analyse the involvement of DNMT3A and DNMT3B in radioresistance in RMS. RNA interference experiments against DNMT3A/3B were performed in embryonal RMS cells, upon ionizing radiation (IR) exposure and the effects of the combined treatment on RMS cells were analysed. DNMT3A and DNMT3B knocking down increased the sensitivity of RMS cells to IR, as indicated by the drastic decrease of colony formation ability. Interestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular senescence program by up-regulating p16 and p21, whilst DNMT3B depletion induces significant DNA damage and impairs the DNA repair machinery (ATM, DNA-PKcs and Rad51 reduction). Our findings demonstrate for the first time that DNMT3A and DNMT3B overexpression may contribute to radiotherapy failure, and their inhibition might be a promising radiosensitizing strategy, mainly in the treatment of patients with metastatic or recurrent RMS tumours.

Next-generation sequencing (NGS) is progressively being used in clinical practice. However, several barriers preclude using this technology for precision oncology in most Latin American countries. To overcome some of these barriers, we have designed a 25-gene panel that contains predictive biomarkers for most current and near-future available therapies in Chile and Latin America. Library preparation was optimized to account for low DNA integrity observed in formalin-fixed paraffin-embedded tissue. The workflow includes an automated bioinformatic pipeline that accounts for the underrepresentation of Latin Americans in genome databases. The panel detected small insertions, deletions, and single nucleotide variants down to allelic frequencies of 0.05 with high sensitivity, specificity, and reproducibility. The workflow was validated in 272 clinical samples from several solid tumor types, including gallbladder (GBC). More than 50 biomarkers were detected in these samples, mainly in BRCA1/2, KRAS, and PIK3CA genes. In GBC, biomarkers for PARP, EGFR, PIK3CA, mTOR, and Hedgehog signaling inhibitors were found. Thus, this small NGS panel is an accurate and sensitive method that may constitute a more cost-efficient alternative to multiple non-NGS assays and costly, large NGS panels. This kind of streamlined assay with automated bioinformatics analysis may facilitate the implementation of precision medicine in Latin America.

Gliomas are the most prevalent primary malignant brain tumors associated with poor prognosis. NAMPT, a rate-limiting enzyme that boosts the nicotinamide adenine dinucleotide (NAD) regeneration in the salvage pathway, is commonly expressed in these tumors. NAD metabolism is required to maintain tissue homeostasis. To maintain metabolism, cancer cells require a stable NAD regeneration circuit. However, high levels of NAD confer resistance to therapy to these tumors, usually treated with Temozolomide (TMZ). We report that NAMPT overexpression in glioma cell lines increases tumorigenic properties controlling stem cell pathways and enriching the cancer-initiating cell (CIC) population. Furthermore, NAMPT expression correlated with high levels of Nanog, CD133 and CIC-like cells in glioblastoma directly extracted from patients. Meta-analysis reveals that NAMPT is also a key factor inducing cancer stem pathways in glioma cells. Furthermore, we report a novel NAMPT-driven signature which stratify prognosis within tumor staging. NAMPT signature also correlates directly with EGFR positive and IDH negative tumors. Finally, NAMPT inhibition increases sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres. Therefore, NAMPT represents a novel therapeutic target in Glioma progression and relapse.

Small cell lung cancer is a highly aggressive, difficult to treat neoplasm. Among all lung tumors, small cell lung cancers account for about 20%. Patients typically include heavy smokers in 70s age group, presenting with symptoms such as intrathoracic tumors growth, distant spread or paraneoplastic syndromes at the time of diagnosis. A useful and functional classification divides small cell lung cancers into limited disease and extensive disease. Concurrent chemo-radiotherapy is the standard treatment for limited disease, with improved survival when combined with prophylactic cranial irradiation. Platinum compounds (cisplatin/carboplatin) plus etoposide remain the cornerstone for extensive disease. Nevertheless, despite high chemo- and radio-sensitivity of this cancer, nearly all patients relapse within the first two years and the prognosis is extremely poor. A deeper understanding about small cell lung cancer carcinogenesis led to develop and test a considerable number of new and targeted agents but the results are currently weak or insufficient. To date, small cell lung cancer is still a challenge for researchers. In this review, key aspects of small cell lung cancer management and controversial points of standard and new treatments will be discussed.

microRNAs (miRNAs) regulate gene expression by modulating the translation of protein-coding RNAs. Their aberrant expression is involved in various human diseases, including cancer. Here, we summarize the experimental pieces of evidence that proved how dysregulated miRNA expression can lead to RAS (HRAS, KRAS, or NRAS) activation irrespective of their oncogenic mutations. These findings revealed relevant pathogenic mechanisms as well as mechanisms of resistance to target therapies. Based on this knowledge, potential approaches for the control of RAS oncogenic activation can be envisioned.

Introduction: Innate immune response and bone remodeling are key factors contributing to the pathogenesis of psoriatic arthritis (PsA). Moreover, the evidence of autoantibodies in patients' sera suggests an autoimmune side in PsA. Besides the immune pathways, studies strongly support the role of genetic risk alleles in affecting the clinical heterogeneity of PsA as well as the response to therapy. A good clinical response to treatment, indeed, represents a challenge in PsA patients and the identification of patient-targeted therapies is still a critical issue. Areas covered: We performed a systematic review aiming at describing new evidence on PsA pathogenesis and treatments. Reported items for systematic reviews (PRISMA checklist) were analyzed. Studies included from the PubMed database addressed the following items: innate immunity, autoimmunity, bone remodeling, and therapeutic targets in PsA; time frame of research 1970-2019. Specifically, we reviewed data on IL-17 inhibitors, abatacept, JAK inhibitors, ABT 122, and A (3) adenosine receptors agonist, CF101. Expert opinion: In PsA an intriguing pathogenetic network has been documented. Several biological and synthetic drugs are promising in terms of efficacy and safety profile.

Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity in cardiac hypertrophy. ERK signaling produces beneficial effects during the early phase of chronic pressure overload in response to G protein-coupled receptors (GPCRs) and integrin stimulation. These functions comprise (i) adaptive concentric hypertrophy and (ii) cell death prevention. On the other hand, ERK participates in maladaptive hypertrophy during hypertension and chemotherapy-mediated cardiac side effects. Specific ERK-associated scaffold proteins are implicated in either cardioprotective or detrimental hypertrophic functions. Interestingly, ERK phosphorylated at threonine 188 and activated ERK5 (the big MAPK 1) are associated with pathological forms of hypertrophy. Finally, we examine the connection between ERK activation and hypertrophy in (i) transgenic mice overexpressing constitutively activated RTKs (receptor tyrosine kinases), (ii) animal models with mutated sarcomeric proteins characteristic of inherited hypertrophic cardiomyopathies (HCMs), and (iii) mice reproducing syndromic genetic RASopathies. Overall, the scientific literature suggests that during cardiac hypertrophy, ERK could be a “good” player to be stimulated or a “bad” actor to be mitigated, depending on the pathophysiological context.

The development of effective nanosystems for drug delivery represents a key challenge for the improvement of most current anticancer therapies. Recent progress in the understanding of structure and function of extracellular vesicles (EVs)—specialized membrane-bound nanocarriers for intercellular communication—suggests that they might also serve as optimal delivery systems of therapeutics. In addition to carrying proteins, lipids, DNA and different forms of RNAs, EVs can be engineered to deliver specific bioactive molecules to target cells. Exploitation of their molecular composition and physical properties, together with improvement in bio-techniques to modify their content are critical issues to target them to specific cells/tissues/organs. Here, we will discuss the current developments in the field of animal and plant-derived EVs toward their potential use for delivery of therapeutic agents in different pathological conditions, with a special focus on cancer.

The development of drug-resistance by neoplastic cells is recognized as a major cause of targeted therapy failure and disease progression. The mechanistic (previously mammalian) target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that acts as the catalytic subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. Both mTORC1 and mTORC2 play key roles in a variety of healthy cell types/tissues by regulating physiological anabolic and catabolic processes in response to external cues. However, a body of evidence identified aberrant activation of mTOR signaling as a common event in many human tumors. Therefore, mTOR is an attractive target for therapeutic targeting in cancer and this fact has driven the development of numerous mTOR inhibitors, several of which have progressed to clinical trials. Nevertheless, mTOR inhibitors have met with a very limited success as anticancer therapeutics. Among other reasons, this failure was initially ascribed to the activation of several compensatory signaling pathways that dampen the efficacy of mTOR inhibitors. The discovery of these regulatory feedback mechanisms greatly contributed to a better understanding of cancer cell resistance to mTOR targeting agents. However, over the last few years, other mechanisms of resistance have emerged, including epigenetic alterations, compensatory metabolism rewiring and the occurrence of mTOR mutations. In this article, we provide the reader with an updated overview of the mechanisms that could explain resistance of cancer cells to the various classes of mTOR inhibitors.

Cancer treatment with either standard chemotherapy or targeted agents often results in the emergence of drug-refractory cell populations, ultimately leading to therapy failure. The biological features of drug resistant cells are largely overlapping with those of cancer stem cells and include heterogeneity, plasticity, self-renewal ability, and tumor-initiating capacity. Moreover, drug resistance is usually characterized by a suppression of proliferation that can manifest as quiescence, dormancy, senescence, or proliferative slowdown. Alterations in key cellular pathways such as autophagy, unfolded protein response or redox signaling, as well as metabolic adaptations also contribute to the establishment of drug resistance, thus representing attractive therapeutic targets. Moreover, a complex interplay of drug resistant cells with the micro/macroenvironment and with the immune system plays a key role in dictating and maintaining the resistant phenotype. Recent studies have challenged traditional views of cancer drug resistance providing innovative perspectives, establishing new connections between drug resistant cells and their environment and indicating unexpected therapeutic strategies. In this review we discuss recent advancements in understanding the mechanisms underlying drug resistance and we report novel targeting agents able to overcome the drug resistant status, with particular focus on strategies directed against dormant cells. Research on drug resistant cancer cells will take us one step forward toward the development of novel treatment approaches and the improvement of relapse-free survival in solid and hematological cancer patients.

Upper tract urothelial carcinoma (UTUC) accounts for 5% of urothelial carcinomas (UCs), the estimated annual incidence being 1–2 cases per 100,000 inhabitants. Similarly to bladder UC, divergent differentiations and histologic variants confer an adverse risk factor in comparison with pure UTUC. Molecular and genomic characterization studies on UTUC have shown changes occurring at differing frequencies from bladder cancer, with unique molecular and clinical subtypes, potentially with different responses to treatment. Systemic chemotherapy is the standard approach for patients with inoperable locally advanced or metastatic UCs. Although initial response rates are high, the median survival with combination chemotherapy is about 15 months. In first-line chemotherapy several cisplatin-based regimens have been proposed. For patients with advanced UC who progress to first-line treatment, the only product licensed in Europe is vinflunine, a third-generation, semisynthetic, vinca alkaloid. Better response rates (15–60%), with higher toxicity rates and no overall survival (OS) benefit, are generally achieved in multidrug combinations, which often include taxanes and gemcitabine. The US FDA has recently approved five agents targeting the programmed death-1 and programmed death ligand-1 pathway as a second-line therapy in patients with locally advanced or metastatic UC with disease progression during or following platinum-containing chemotherapy. Potential therapeutic targets are present in 69% of tumours analyzed. Specific molecular alterations include those involved in the RTK/Ras/PI(3)K, cell-cycle regulation and chromatin-remodeling pathways, many of them have either targeted therapies approved or under investigation. Angiogenic agents, anti-epidermal growth factor receptor therapy, phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathway inhibitors and immunotherapeutic drugs are being successfully investigated.

Several new biological agents have been investigated as second line of treatment in advanced Hepatocellular Cancer (HCC). We performed a meta -analysis to assess the effect of targeted therapies in advanced HCC patients beyond the first line of treatment. A literature-based metaanalysis of randomized controlled trials was undertaken. The primary outcome was the overall survival. The secondary endpoints were the progression-free survival (PFS), the response rate (RR) and disease control rate (DCR) and the safety. Pooled analysis of targeted agents revealed a modest increase in overall survival compared with control arm (Hazard Ratio (HR) = 0.93, 95%CI: 0.83-1.04; P = 0.21). On the counterpart, all the secondary endpoints were in favoured to the targeted agents-based treatment (PFS: HR = 0.68, 95% CI:0.56–0.83; P = 0.0002; RR: 3.50,95% CI 1.81–6.76; P = 0.0002, DCR: RR:1.19, 95% CI 1.06–1.32; P = 0.002). To date, there is a clinical need of a more efficacious second line of therapy in treatment of the advanced HCC. This study showed some activity of the new targeted therapies in second line of treatment in advanced HCC.

The prognosis of patients affected by ovarian cancer has not substantially changed in the last decades and improving survival still remains a challenge. In the promising era of 'personalized therapy' several new biologic therapies are currently being investigated: in this setting, targeting the folate receptor (FR) has been considered a new potential strategy for biologic therapy. Areas covered: The aim of the current review is to summarize, giving a critical overview,promising folate receptor alpha antagonists under preclinical or early clinical development for ovarian cancer. Expert opinion: Two categories of therapeutics are included in this class: FRα targeted mAbs and FRα-binding-ADC (Antibody drug conjugates); both share the interesting possibility of selecting patients via a biomarker which is already available. In the first class, farletuzumab has reached the most advanced stage in clinical evaluation and results of a Phase II randomized trial are awaited to assess its efficacy in a specific patients' setting. MOv18 IgE represents a novel strategy to target FRα expressing cells, which has shown encouraging results in preclinical studies: further evaluation is needed in the clinical setting. IMGN 853 is an innovative FRα-binding ADC under development, with only preliminary results of a Phase I trial available.

The presence of mutations in the KRAS gene is a predictor of a poor clinical response to EGFR-targeted agents in patients affected by colorectal cancer (CRC), but its significance as a global prognostic factor remains unclear. The aim of the present study was to evaluate the impact of the KRAS mutational status on time to first metastasis (TTM) and overall survival (OS) in a cohort of Sardinian CRC patients. A total of 551 patients with metastatic CRC at the time of enrolment were included. Clinical and pathological features of the disease, including follow-up information, were obtained from medical records and cancer registry data. For mutational analysis formalin-fixed paraffin-embedded tissue samples were processed using a standard protocol. The coding sequence and splice junctions of exons 2 and 3 of the KRAS gene were screened for mutations by direct automated sequencing. Overall, 186 KRAS mutations were detected in 183/551 (33%) patients: 125 (67%) were located in codon 12, 36 (19%) in codon 13, and 18 (10%) in codon 61. The remaining mutations (7; 4%) were detected in uncommonly-affected codons. No significant correlation between KRAS mutations and gender, age, anatomical location and stage of the disease at the time of diagnosis was identified. Furthermore, no prognostic value of KRAS mutations was found considering either TTM or OS. When patients were stratified by KRAS mutational status and gender, males were significantly associated with a longer TTM. The results of the present study indicate that KRAS mutation correlated with a slower metastatic progression in males with CRC from Sardinia, irrespective of the age at diagnosis and the codon of the mutation.

With the ever-expanding therapeutic indications and ongoing clinical trials with Poly(adenosine diphosphate-ribose) Polymerase (PARP) inhibitors, it is of outmost importance to stop and rethink what we know and still do not know concerning one of the major revolutions in target therapies in the last decades. Indeed, many PARP inhibitors (PARPi) are able to bind multiple targets, with a plethora of potential interactions with cancer cell signaling, metabolism and the tumor microenvironment (TME). These interactions can mediate both response and resistance to PARPi, but also represent an opportunity for sequential and/or combinatorial therapies. Here we advocate a "look before you leap" approach in reviewing available clinical and preclinical evidence concerning PARPi, delving into this complex entanglement, trying to unravel the potential for innovative therapeutic strategies revolving on PARP inhibition.

Inflammatory Bowel Diseases (IBD), whose denomination comprehends Crohn's Disease (CD) and Ulcerative Colitis (UC), are intestinal chronic diseases that often require lifelong medical therapy. In the last two decades monoclonal antibodies against the cytokine TNF have become integral parts in the treatment of IBD patients, however there are unwanted side-effects and one third of patients show primary non-response while another subgroup loses response over time. Finding novel drugs which could act as therapies against precise pro-inflammatory molecular targets to avoid unwanted systemic side effects and additionally the process of immunization, represents an important aim for subsequent therapeutic approaches. Oligonucleotide based therapies represent a promising novel concept for the treatment of IBD. The molecular action of oligonucleotides ranges from inhibition of the translational process of mRNA transcripts of pro-inflammatory molecules, to mimicking bacterial DNA which can activate cellular targets for immunomodulation. Alicaforsen, selectively targets ICAM-1 mRNA. ICAM-1 is an adhesion molecule which is upregulated on endothelial cells during IBD, thereby mediating the adhesion and migration of leucocytes from blood to sites of active inflammation. In CD parenteral application of alicaforsen did not show therapeutic efficacy in phase II trials, but it demonstrated an improved efficacy as a topical enema in distal UC. Topical application of alicaforsen might represent a therapeutic perspective for refractory pouchitis as well. SMAD7 is a protein that inhibits the signaling of TGFβ, which is the mainstay of a regulatory counterpart in cellular immune responses. An antisense oligonucleotide against SMAD7 mRNA (mongersen) demonstrated pre-clinical and phase II efficacy in CD, but a phase III clinical trial was stopped due to lack of efficacy. Cobitolimod is a single strand oligonucleotide, which mimics bacterial DNA as its CpG dinucleotide sequences can be recognized by the Toll-like receptor 9 on different immune cells thereby causing induction of different cytokines, for example IL10 and IFNα. Topical application of cobitolimod was studied in UC patients. We will also discuss two other novel oligonucleotides which act on the GATA3 transcription factor (SB012) and on carbohydrate sulfotransferase 15 (STNM01), which could both represent novel promising therapeutic options for the treatment of UC.

Peripheral T cell lymphomas (PTCLs) are highly heterogeneous tumors, displaying distinct clinical and biological features. The pathogenesis and normal counterpart of such entities have been elusive for decades. Recent studies have, however, disclosed key mechanisms of peripheral T cell transformation, including (a) the deregulation of signaling pathways controlling T cell development, differentiation, and maturation; (b) the remodeling of the peritumor microenvironment; and (c) the virus-mediated rewiring of T cell biology. Uncovering the molecular mechanisms of T cell transformation will help elucidate the peculiar clinical and pathological features of each PTCL entity and will lead to the characterization of novel antitumor therapies. These therapies will combine conventional and new-generation compounds with immune-modulating agents to ablate both the neoplastic cells and the tumor-supporting microenvironment. This review addresses the pathogenic mechanisms of PTCLs, with special attention paid to novel therapeutic strategies for the clinical management of such aggressive tumors.

Schneiderian papillomas are uncommon tumors which may develop within the nasal cavity and comprise three well-defined histological types: sinonasal inverted papilloma (SNIP), exophytic papilloma, and oncocytic papilloma. It is well known the rate of Schneiderian papilloma may also present a malignant degeneration and SNIP represents the most important subgroup in consideration of its frequency and malignant propensity. Although HPV infection is always considered the first event favoring the development of SNIP, however, it is not established as an eventual connection between viral actions and malignant transformation. In fact, different molecular mechanisms are suspected to play a crucial role in this process and, currently, many authors agree that only by improving our knowledge about these mechanisms it will be possible to achieve new and effective targeted therapies. So the aim of this study was firstly to systematically review the literature focusing on different biomarkers that could be implicated in the stages of SNIP malignant degeneration. Secondly, a systematic review with meta-analysis was performed to better define the incidence of sinonasal malignancies originating from Schneiderian papilloma (SNIP, exophytic papilloma, and oncocytic papilloma). Twenty-nine studies comprising a total of 3177 patients were statistically analyzed. Results showed a 9% (95% CI = 7–11) overall rate of malignant transformation from Schneiderian papilloma. In conclusion, this analysis confirmed that the potential malignancy of Schneiderian papilloma should not be underestimated. On the other hand, our review showed the paucity of studies investigating the molecular alterations which may be related with the malignant transformation of SNIP.

The objective of this review is to summarize results from clinical trials that tested cytotoxic drugs and target strategies for the treatment of platinum resistant (PR) recurrent ovarian cancer (ROC) with particular attention to Phase III and ongoing trials. Areas covered: Since platinum free interval (PFI) represents the most important predictive factor for response to platinum re-treatment in ROC, non-platinum regimens are conventionally considered the most appropriate approaches. Impressive progress has been made in recent decades, resulting in the identification of most effective cytotoxic agents and in the development of new target strategies. However, the efficacy of most of these drugs for the treatment of PR disease is still limited. Expert opinion: The most favorable benefit for the treatment of PR disease, has been described by the AURELIA trial that showed a 3.3 months increase in progression free survival (PFS) when bevacizumab was combined with non-platinum single agent chemotherapy in bevacizumab-naïve patients. Nevertheless, the use of novel agents is associated to important costs for just little gains in survival. Thus, in our opinion the economic evaluation, such as the incorporation of quality of life into the clinical studies is crucial for the development of future trials for PR-ROC.

Micro-Abstract Neoadjuvant chemoradiation represents the mainstay of the treatment of locally advanced rectal cancer (LARC). However, despite substantial improvements in previous years, patients still develop relapses and eventually die of metastatic disease. In the present phase Ib dose-escalation trial, everolimus added to standard chemoradiation did not seem to worsen toxicity. The activity of this combination warrants further evaluation in larger clinical trials. Background During the past 20 years, considerable improvement has occurred in the treatment of patients with locally advanced rectal cancer (LARC). With the introduction of multimodal treatment, refinements in preclinical staging and improvements in surgical skills, local relapse is no longer the major problem for patients with LARC. However, many patients die of metastatic disease. The present phase Ib study aimed to establish the maximum tolerated dose of everolimus combined with 5-fluorouracil and radiotherapy in patients with LARC. Patients and Methods Patients were sequentially assigned to 4 cohorts with an increasing dose of everolimus, starting from 14 days before 5-fluorouracil and radiotherapy and continuing throughout concomitant treatment. The secondary endpoints were the Dworak tumor regression grade, pathologic complete response rate, neoadjuvant rectal score, biomarker assessment (phosphorylated mTOR [mammalian target of rapamycin] protein and phosphorylated-p70S6K protein). Results At the time of this report, 12 patients had been treated, and no dose-limiting toxicity was recorded. The most frequently reported acute toxicities were rectal tenesmus, skin rash, diarrhea, and dysuria. All 12 patients underwent curative R0 resection. Two patients had Dworak tumor regression grade 4 (pathologic complete response). No everolimus-related postoperative complications were observed. No relationship was found between biomarker expression and the clinicopathologic outcomes. Conclusion Although the addition of everolimus did not appear to worsen the toxicity of chemoradiation in patients with LARC, evaluation of its activity deserves further investigation in larger clinical trials.

The treatment of advanced disease (stage IIIb and IV) of non-small cell lung cancer (NSCLC) is based on systemic treatment with platinum-based chemotherapy or biological compounds depending on the disease molecular profile. In the last few years, intensive investigational efforts in anticancer therapy have led to the registration of new active chemotherapeutic agents, combination regimens, and biological drugs, expanding choices for customizing individual treatment. However, the introduction of new drugs in the clinical setting has led to several new toxicities, creating some difficulties in daily management. Among these, ocular toxicity is generally overlooked as more common toxicities such as myelosuppression, stomatitis, diarrhea, vomiting, “hand–foot syndrome”, and neurological alterations attract greater attention. Ophthalmic complications from cytotoxic chemotherapeutics are rare, transient, and of mild/moderate intensity but irreversible acute disorders are possible. The best way to prevent potential irreversible visual complications is an awareness of the potential for ocular toxicity because dose reductions or early drug cessation can prevent serious ocular complications in the majority of cases. However, given the novelty of many therapeutic agents and the complexity of ocular pathology, oncologists may be unfamiliar with these adverse effects of anticancer therapy. Although toxicities from chemotherapy are generally intense but short lasting, toxicities related to targeted drugs are often milder but longer lasting and can persist throughout treatment. Here we review the principal clinical presentations of ocular toxicity arising from chemotherapy [1–3], target therapies [4], and newly developed drugs and provide some recommendations for monitoring and management of ocular toxicity.

The integration between radiotherapy and drugs, from chemotherapy to recently available target therapies, continues to have a relevant role in the treatment of locally advanced and metastatic Non-small cell lung cancer (NSCLC). Aim of the present review is to evaluate the promising and emerging application of the best interaction between new drugs and new modalities of radiotherapy. Areas covered: We searched Medline, Google Scholar, PubMed, ProQuest Dissertation, and Theses databases for reports published in English. A study was included when it reported on cancer-related radiotherapy and included patients with NSCLC treated with chemo and/or target therapies. Review articles were excluded from the analysis. Expert commentary: Chemo-radiotherapy still represents the standard of choice in locally advanced NSCLC, while to date the addition of target therapies to chemo-radiotherapy did not demonstrate any robust advantage in this stage of disease. Considering the absence of randomized controlled trials, the role of target therapies in early stage adjuvant NSCLC is not yet recommended in clinical practice. On the contrary, in the setting of oligometastatic and oligoprogressive disease, new molecules demonstrated to be safe and effective, opening to a promising and emerging application of the best interaction between new drugs and new modalities of radiotherapy.

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.

Tumor heterogeneity is associated with the therapeutic failures of targeted therapies. To overcome such heterogeneity, a novel targeted therapy is proposed that could kill tumor populations with diverse phenotypes by delivering nonselective cytotoxins to target‐positive cells as well as to the surrounding tumor cells via a recurrent bystander killing effect. A representative prodrug is prepared that targets integrin αvβ3 and releases cytotoxins upon entering cells or by caspase‐3. This allows the prodrug to kill integrin αvβ3‐positive cells and upregulate caspase‐3, which in turn, activates the prodrug to release a cytotoxin that could subsequently diffuse into and kill the neighboring tumor cells. Apoptotic cells further upregulate and release caspase‐3, which activate more prodrugs leading to another round of adjacent cell death and caspase‐3 release. Thus, the bystander killing effect could occur repeatedly, leading to augmented and widespread anticancer activity. This strategy provides an avenue that could advance the current targeted therapy.

Cholangiocarcinoma (CC) is a primary malignancy that arises from cholangiocytes, the epithelial cells lining the bile duct livers. The worldwide incidence of CC is increasing and despite of combined therapeutic strategies, its prognosis remains poor. Till now surgery remains the only curative treatment modality. Over the past years, several important studies have yielded new insights into the molecular mechanisms of cholangiocarcinoma. This review focused on critical molecular player during the development from inflammation and cellular and molecular pathogenesis of this disease. The novel prophylactic and therapeutic approach deals especially the molecules involved in inflammation of cholangiocite or those related to promotion and progression of CC. The elucidation of their specific effects and interaction of this complex mechanism will accelerate the development of new biomarker for early detection and predictor factors outcome in CC.