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A cancer diagnosis is devastating for both patients and their caregivers. With high morbidity and mortality, cancer is a serious disease area with unmet medical needs. Thus, innovative anticancer drugs are in high demand worldwide but are unequally available. Our study focused on first-in-class (FIC) anticancer drugs and investigated their actual development situation in the United States (US), European Union (EU), and Japan over the last two decades to obtain fundamental information for understanding how the aforementioned demands are met, especially to eliminate drug lags among regions. We identified FIC anticancer drugs using pharmacological classes for the Japanese drug pricing system. Most FIC anticancer drugs were first approved in the US. The median approval time for anticancer drugs in new pharmacological classes during the last two decades in Japan (5072 days) was significantly different (p=0.043) from that in the US (4253 days), though it was not significantly different from that in the EU (4655 days). Submission and approval lags between the US and Japan were more than 2.1 years, and those between the EU and Japan were more than 1.2 years. However, those between the US and the EU were less than 0.8 years. The development rate of FIC anticancer drugs in Japan is slower than in other regions. Even among developed countries, FIC anticancer drug lags exist. Considering the high impact of FIC anticancer drugs on society worldwide, we should work together to reduce drug lag among regions using an improved international cooperative framework.

Lipid-based nanoparticles as drug delivery carriers have been mainly used for delivery of anti-cancer therapeutic agents. Lipid-based nanoparticles, due to their smaller particle size and similarity to cell membranes, are readily internalized into cancer cells. Interestingly, cancer cells also overexpress receptors for specific ligands including folic acid, hyaluronic acid, and transferrin on their surface. This allows the use of these ligands for surface modification of the lipid-based nanoparticle. These modifications then allow the specific recognition of these ligand-coated nanoparticles by their receptors on cancer cells allowing the targeted gradual intracellular accumulation of the functionalized nanoplatforms. These interactions could eventually enhance the internalization of desired drugs via increasing ligand-receptor mediated cellular uptake of the nanoplatforms. The cellular internalization of the nanoplatforms also varies and depends on their physicochemical properties including particle size, zeta potential, and shape. The cellular uptake is also influenced by the types of ligand internalization pathway utilized by cells such as phagocytosis, macropinocytosis, and multiple endocytosis pathways. In this review, we will classify and discuss lipid based nanoparticles engineered to express specific ligands, and are recognized by their receptors on cancer cell, and their cellular internalization pathways. Moreover, the intracellular fate of nanoparticles decorated with specific ligands and the best internalization pathways (caveolae mediated endocytosis) for safe cargo delivery will be discussed.

Introduction: The use of monoclonal antibodies has been incorporated into cancer treatment protocols, once their effectiveness has been proven. This type of therapy is costly and its acquisition is still an obstacle for the patient. Objective: To describe the use of monoclonal antibodies in the perspective of purchasing, regulation and judicialization, adverse effects and causes of therapy discontinuation. Method: Descriptive study evaluating patients (n=169) undergoing treatment for cancer in a public hospital, from August 1, 2017 to July 31, 2019. Results: The population investigated consisted mostly of females (n=115). The main neoplasms found were breast (n=64, 36.16%), lymphomas (n=53, 29.94%) and plasma cell/plasmacytoma multiple myeloma (n=25, 14.12%). The most used monoclonal antibodies were trastuzumab (n=65, 35.71%) and rituximab (n=54, 29.67%). Four forms of drug purchase were observed. The purchases through the National Health System (SUS) (n=103, 56.59%) and law-mandated (n=72, 39.56%) prevailed. Most patients had no therapy-related adverse effects (60.3%), but among those who did, the main effects were vomiting and nausea, asthenia, diarrhea, pain, neutropenia and mucositis. Adverse effects/toxicity (n=15), lack of medication (n=11) and delayed approval (n=10) were the most common causes of treatment discontinuation. Conclusion: Monoclonal antibodies are more specific and have lesser effects. For drugs unavailable at SUS, judicialization is an important tool. Introducción: El uso de anticuerpos monoclonales se ha incorporado a los protocolos de tratamiento del cáncer, una vez comprobada su eficacia. Este tipo de terapia es costosa y su adquisición sigue siendo un obstáculo para el paciente. Objetivo: Describir el uso de anticuerpos monoclonales en términos de adquisición, regulación y judicialización, efectos adversos y causas de interrupción de la terapia. Método: Estudio descriptivo que evaluó a pacientes (n=169) en tratamiento por cáncer, en un hospital público, desde el 1 de agosto de 2017 al 31 de julio de 2019. Resultados: La población estudiada fue mayoritariamente femenina (n=115). Las principales neoplasias encontradas fueron mama (n=64, 36,16%), linfomas (n=53, 29,94%) y mieloma múltiple de células plasmáticas/plasmocitomas (n=25, 14,16%). Los anticuerpos monoclonales más utilizados fueron trastuzumab (n=65, 35,71%) y rituximab (n=54, 29,67%). Se observaron cuatro formas de adquisición de fármacos. Predominaron las adquisiciones a través del Sistema Único de Salud (SUS) (n=103, 56,59%) y judiciales (n=72, 39,56%). La mayoría de los pacientes no presentaron efectos adversos a la terapia (60,3%), pero entre los que sí los tuvieron, los principales efectos fueron vómitos y náuseas, astenia, diarrea, dolor, neutropenia y mucositis. Los efectos adversos/toxicidad (n=15), la falta de medicación (n=11) y la liberación retardada (n=10) fueron las causas más frecuentes de interrupción del tratamiento. Conclusión: Los anticuerpos monoclonales son más específicos y tienen menos efectos. Para los medicamentos no disponibles en el SUS, la judicialización es una herramienta importante. Introdução: A utilização dos anticorpos monoclonais vem sendo incorporada aos protocolos de tratamento para câncer, uma vez comprovada sua eficácia. Essa modalidade de terapia é onerosa, e sua aquisição ainda constitui um obstáculo para o paciente. Objetivo: Descrever a utilização de anticorpos monoclonais no que tange à forma de aquisição, regulação e judicialização, efeitos adversos e causas de interrupção da terapia. Método: Estudo descritivo com avaliação de pacientes (n=169) em tratamento para câncer, em um hospital público, no período de 1 de agosto de 2017 a 31 de julho de 2019. Resultados: A população estudada foi majoritariamente feminina (n=115). As principais neoplasias encontradas foram de mama (n=64, 36,16%), linfomas (n=53, 29,94%) e mieloma múltiplo de plasmócito/plasmocitoma (n=25, 14,12%). Os anticorpos monoclonais mais utilizados foram o trastuzumabe (n=65, 35,71%) e rituximabe (n=54, 29,67%). Foram observadas quatro formas de aquisição dos fármacos. As aquisições por meio do Sistema Único de Saúde (SUS) (n=103, 56,59%) e judicial (n=72, 39,56%) prevaleceram. A maioria dos pacientes não apresentou efeitos adversos à terapia (60,3%); mas, entre os que apresentaram, os principais efeitos foram vômitos e náuseas, astenia, diarreia, dor, neutropenia e mucosite. Efeitos adversos/toxicidade (n=15), falta de medicamento (n=11) e atraso na liberação (n=10) foram as causas mais comuns de interrupção do tratamento. Conclusão: Os anticorpos monoclonais são mais específicos e apresentam menores efeitos. Aos fármacos indisponíveis pelo SUS, a judicialização mostra-se como uma ferramenta importante.

Plasmacytoid dendritic cells (pDCs) are multifaceted immune cells with a wide range of innate and adaptive immunological functions. They constitute the first line of defence against multiple viral infections and have also been reported to actively participate in antitumor immune responses. The clinical implication of the presence of pDCs in the tumor microenvironment (TME) is still ambiguous, but it is clear that pDCs possess the ability to modulate tumor-specific T cell responses and direct cytotoxic functions. Therapeutic strategies designed to exploit these qualities of pDCs to boost tumor-specific immune responses could represent an attractive alternative compared to conventional therapeutic approaches in the future, and promising antitumor effects have already been reported in phase I/II clinical trials. Here, we review the many roles of pDCs in cancer and present current advances in developing pDC-based immunotherapeutic approaches for treating cancer.

BACKGROUND: The CD47-signal regulatory protein alpha (SIRPα) 'don't eat me' signalling axis is perhaps the most prominent innate immune checkpoint to date. However, from initial clinical trials, it is evident that monotherapy with CD47-SIRPα blocking has a limited therapeutic effect at the maximum tolerated dose. Furthermore, treatment is associated with severe side effects, most notably anaemia, that are attributable to the ubiquitous expression of CD47. Nevertheless, promising clinical responses have been reported upon combination with the tumour-targeting antibody rituximab or azacytidine, although toxicity issues still hamper clinical application.MAIN BODY: Here, we discuss the current state of CD47-SIRPα blocking therapy with a focus on limitations of current strategies, such as depletion of red blood cells. Subsequently, we focus on innovations designed to overcome these limitations. These include novel antibody formats designed to selectively target CD47 on tumour cells as well as tumour-targeted bispecific antibodies with improved selectivity. In addition, the rationale and outcome of combinatorial approaches to improve the therapeutic effect of CD47 blockade are discussed. Such combinations include those with tumour-targeted opsonizing antibodies, systemic therapy, epigenetic drugs, other immunomodulatory T-cell-targeted therapeutics or dual immunomodulatory CD47 bispecific antibodies.CONCLUSION: With these advances in the design of CD47-SIRPα-targeting therapeutic strategies and increasing insight into the mechanism of action of this innate checkpoint, including the role of adaptive immunity, further advances in the clinical application of this checkpoint can be anticipated.

BACKGROUND: The CD47-signal regulatory protein alpha (SIRPα) 'don't eat me' signalling axis is perhaps the most prominent innate immune checkpoint to date. However, from initial clinical trials, it is evident that monotherapy with CD47-SIRPα blocking has a limited therapeutic effect at the maximum tolerated dose. Furthermore, treatment is associated with severe side effects, most notably anaemia, that are attributable to the ubiquitous expression of CD47. Nevertheless, promising clinical responses have been reported upon combination with the tumour-targeting antibody rituximab or azacytidine, although toxicity issues still hamper clinical application. MAIN BODY: Here, we discuss the current state of CD47-SIRPα blocking therapy with a focus on limitations of current strategies, such as depletion of red blood cells. Subsequently, we focus on innovations designed to overcome these limitations. These include novel antibody formats designed to selectively target CD47 on tumour cells as well as tumour-targeted bispecific antibodies with improved selectivity. In addition, the rationale and outcome of combinatorial approaches to improve the therapeutic effect of CD47 blockade are discussed. Such combinations include those with tumour-targeted opsonizing antibodies, systemic therapy, epigenetic drugs, other immunomodulatory T-cell-targeted therapeutics or dual immunomodulatory CD47 bispecific antibodies. CONCLUSION: With these advances in the design of CD47-SIRPα-targeting therapeutic strategies and increasing insight into the mechanism of action of this innate checkpoint, including the role of adaptive immunity, further advances in the clinical application of this checkpoint can be anticipated.

PURPOSE The WHO essential medicines list (EML) guides selection of drugs for national formularies. Here, we evaluate which medicines are considered highest priority by Indian oncologists and the extent to which they are available in routine practice. METHODS This is a secondary analysis of an electronic survey developed by the WHO EML Cancer Medicine Working Group. The survey was distributed globally using a hierarchical snowball method to physicians who prescribe systemic anticancer therapy. The survey captured the 10 medicines oncologists considered highest priority for population health and their availability in routine practice. RESULTS The global study cohort included 948 respondents from 82 countries; 98 were from India and 67 were from other low- and middle-income countries. Compared with other low- and middle-income countries, the Indian cohort was more likely to be medical oncologist (70% v 31%, P < .001) and work exclusively in the private health system (52% v 17%, P < .001). 14/20 most commonly selected medicines were conventional cytotoxic drugs. Universal access to these medicines was reported by a minority of oncologists; risks of significant out-of-pocket expenditures for each medicine were reported by 19%-58% of oncologists. Risk of catastrophic expenditure was reported by 58%-67% of oncologists for rituximab and trastuzumab. Risks of financial toxicity were substantially higher within the private health system compared with the public system. CONCLUSION Most high-priority cancer medicines identified by Indian oncologists are generic chemotherapy agents that provide substantial improvements in survival and are already included in WHO EML. Access to these treatments remains limited by major financial burdens experienced by patients. This is particularly acute within the private health system. Strategies are urgently needed to ensure that high-quality cancer care is affordable and accessible to all patients in India.

Contains fulltext : 283345.pdf (Publisher’s version ) (Open Access) Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8(+)/CD4(+) T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications.

The use of low-dose irradiation (LDI) for mobilizing innate and adaptive immunity is gaining interest among the scientific community. Recent evidence suggests that LDI can reprogramme the tumor microenvironment, induce inflammation and turn cold tumors susceptible to immunecheckpoint blockade therapy. Translating immuno-radiation preclinical findings in the clinic is more challenging than expected. We propose therapeutic strategies for combining LDI with immunotherapy, and emphasize the importance of pursuing clinical research to determine optimal radiation dosage, fractionation, volumes, and sequencing to stimulate immune-mediated tumor responses.

Radioimmunotherapy (RIT) is a cancer treatment that combines radiation therapy with tumor-directed monoclonal antibodies (Abs). Although RIT had been introduced for the treatment of CD20 positive non-Hodgkin lymphoma decades ago, it never found a broad clinical application. In recent years, researchers have developed theranostic agents based on Ab fragments or small Ab mimetics such as peptides, affibodies or single-chain Abs with improved tumor-targeting capacities. Theranostics combine diagnostic and therapeutic capabilities into a single pharmaceutical agent; this dual application can be easily achieved after conjugation to radionuclides. The past decade has seen a trend to increased specificity, fastened pharmacokinetics, and personalized medicine. In this review, we discuss the different strategies introduced for the noninvasive detection and treatment of hematological malignancies by radiopharmaceuticals. We also discuss the future applications of these radiotheranostic agents.

BACKGROUND: The management of patients with atrial fibrillation (AF) and malignancy is challenging given the paucity of evidence supporting their appropriate clinical management. PURPOSE: To evaluate the outcomes of patients with active or prior malignancy in a contemporary cohort of European AF patients. METHODS: Patients enrolled in the EURObservational Research Programme in AF General Long-Term Registry were categorized into 3 categories: No Malignancy (NoMal), Prior Malignancy (PriorMal) and Active Malignancy (ActiveMal). The primary outcomes were all-cause death and the composite outcome MACE. RESULTS: A total of 10 383 patients were analysed. Of these, 9597 (92.4%) were NoMal patients, 577 (5.6%) PriorMal and 209 (2%) ActiveMal. Lack of any antithrombotic treatment was more prevalent in ActiveMal patients (12.4%) as compared to other groups (5.0% vs 6.3% for PriorMal and NoMal, p

With increasing numbers of drugs tested in oncology for smaller patient populations, fewer patients are available to answer important clinical pharmacological questions in the timeframe of clinical drug development. The quality and efficiency of trials to assess the pharmacokinetics of new drugs can be improved by making better use of available resources. One approach to do this is by making more effective use of isotopic tracer techniques. With increasing sensitivity of liquid chromatography-tandem mass spectrometry analyzing equipment over the years, it has now become possible to generate much more rich, high-quality pharmacokinetic data than before. In particular we want to make a plea here for a hybrid trial approach, where both radiolabeled drug and stable isotopically labeled drug are administered to patients to assess both the absolute bioavailability and absorption, distribution, metabolism and excretion in a single clinical trial experiment.

Targeting enzymes involved in tumor metabolism is a promising way to tackle cancer progression. The inhibition of carnitine palmitoyltransferase 1 (CPT1) by etomoxir (Eto) efficiently slows down the growth of various cancers. Unfortunately, the clinical use of this drug was abandoned because of hepatotoxic effects. We report the development of pH-sensitive peptide (pHLIP)-drug conjugate to deliver Eto selectively to cancer cells exposed to acidic microenvironmental conditions. A newly designed sequence for the pHLIP peptide, named pHLIPd, was compared with a previously published reference pHLIP peptide, named pHLIPr. We showed that the conjugate between pHLIPd and Eto has a better pH-dependent insertion and structuration than the pHLIPr-based conjugate inside POPC vesicles. We observed antiproliferative effects when applied on acid-adapted cancer cells, reaching a larger inhibitory activity than Eto alone. In conclusion, this study brings the first evidence that pHLIP-based conjugates with a CPT1 inhibitor has the potential to specifically target the tumor acidic compartment and exert anticancer effects while sparing healthy tissues.

OBJECTIVE: The aim of this study was to quantify HIV-specific immunological and virological changes in people with HIV (PWH) on antiretroviral therapy (ART) with malignancy who received immune checkpoint blockade (ICB).DESIGN: An observational cohort study.METHODS: Blood samples were collected before and after four cycles of ICB in HIV-positive adults on ART. Virological assessments performed on CD4+ T cells included cell-associated unspliced HIV RNA, cell-associated HIV DNA, Tat/rev-induced limiting dilution assay (TILDA) and plasma HIV RNA using a single copy assay (SCA). Flow cytometry was used to assess the frequency of precursor exhausted T cells (Tpex) and exhausted T cells (Tex), and Gag-specific CD4+ and CD8+ T cells positive for IFN-γ, TNF-α or CD107a by intracellular cytokine staining (ICS).RESULTS: Participant (P)1 received avelumab (anti-PD-L1) for Merkel cell carcinoma. P2 and P3 received ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) for metastatic melanoma. An increase in CA-US RNA following each infusion was noted in all three participants. There were no consistent changes in HIV DNA or the proportion of cells with inducible MS HIV RNA. P2 demonstrated a striking increase in the frequency of gag-specific central and effector memory CD8+ T cells producing IFN-γ, TNF-α and CD107a following anti-PD1 and anti-CTLA-4. The frequency of CD8+ Tpex cells pre-ICB was also highest in this participant.CONCLUSION: In three PWH with cancer on ART, we found that ICB activated latent HIV and enhanced HIV-specific T cell function but with considerable variation.

O V Congresso Nacional e I Internacional de Oncologia da Associação Presente, no ano 2021, em razão da pandemia causada pela Covid-19, acontece pela segunda vez consecutiva no formato on-line. Vários são os desafios na realização do evento na forma digital e várias também as grandes oportunidades que são vivenciadas, entre as quais a participação de congressistas de todos os estados brasileiros. O Congresso visa a aprofundar discussões referentes à promoção à saúde, à prevenção, aos avanços no tratamento e aos cuidados paliativos em câncer. Reúne profissionais de saúde como médicos, acadêmicos, enfermeiros, psicólogos, dentistas, nutricionistas, fisioterapeutas, educadores físicos, entre outros, abordando temas a cerca do câncer. Com isso, os congressistas ganham tanto na mudança de práticas clínicas a partir do conhecimento científico difundido quanto na busca obstinada de todos em serem profissionais melhores. Os participantes poderão nesta nova edição ter acesso aos resumos aceitos que já estarão hospedados no site do congresso em forma de e-poster a partir do primeiro dia do evento (26/8/2021), assim como uma programação impecável com palestrantes de renome nacional e internacional abordando temas transformadores a favor da vida.

Antibody therapeutics can be associated with unwanted immune responses resulting in the development of anti‐drug antibodies (ADA). Optimal methods to evaluate the potential effects of ADA on clinical outcomes in oncology are not well established. In this study, we assessed efficacy and safety, based on ADA status, in patients from over 10 clinical trials that evaluated the immune checkpoint inhibitor atezolizumab as a single agent or as combination therapy for several types of advanced cancers. ADA can only be observed post randomization, and imbalances in baseline prognostic factors can confound the interpretation of ADA impact. We applied methodology to account for the confounding effects of baseline clinical characteristics and survivorship bias on efficacy. Adjusted meta‐analyses revealed that despite numerical differences in overall survival and progression‐free survival between ADA‐positive and ADA‐negative patients from some studies, ADA‐positive patients from studies with an overall treatment effect derived benefit from atezolizumab, compared with their adjusted controls. Based on large, pooled populations from atezolizumab monotherapy or combination studies, unadjusted descriptive analyses did not identify a clear relationship between ADA status and frequency or severity of adverse events. Data also suggested that any ADA impact is not driven by neutralizing activity. Collectively, this exploratory analysis suggests that the potential for ADA development should not impact treatment decisions with atezolizumab.

Background: Immuno-oncology (IO)–based therapies have been approved based on randomised clinical trials, yet a significant proportion of real-world patients are not represented in these trials. We sought to compare the outcomes of trial-ineligible vs. -eligible patients with advanced solid tumours treated with first-line (1L) IO therapy. Patients and methods: Using the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and the Alberta Immunotherapy Database, patients with advanced RCC, non–small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition–based therapy were included. Trial eligibility was retrospectively determined as per commonly used exclusion criteria. The outcomes of interest were overall survival (OS), overall response rate (ORR), treatment duration (TD) and time to next treatment (TTNT). Results: A total of 395 of 1241 (32%) patients were deemed trial-ineligible. The main reasons for ineligibility based on preselected exclusion criteria were Karnofsky performance status 1 (40%, 158 of 395), brain metastases (32%, 126 of 395), haemoglobin < 9 g/dL (16%, 63 of 395) and estimated glomerular filtration rate

ilustraciones, gráficas, tablas Objetivo: Realizar la traducción, adaptación transcultural y validación del componente de síntomas gastrointestinales (SGI) de la escala CTCAE Versión 4.02, en pacientes ambulatorios tratados con quimioterapia en el Instituto Nacional de Cancerología en Bogotá. Métodos: Se realizó una búsqueda manual en medios electrónicos, de escalas en idiomas inglés o español, que evaluarán la presencia, frecuencia o intensidad de SGI en pacientes oncológicos. La selección de los ítems fue efectuada por consenso informal de un comité técnico, que verificó la concordancia entre los principales SGI descritos en la literatura y los incluidos en la escala, todos los cuales podrían afectar el estado nutricional. Para la adaptación transcultural se siguieron los pasos y recomendaciones del manual ISPOR y del grupo de calidad de vida EORTC. La prueba piloto se efectuó en 25 pacientes seleccionados por conveniencia, que cumplieron los criterios de inclusión. La validez de la escala se determinó usando métodos de análisis factorial exploratorio. Para evaluar la confiabilidad se efectuaron tanto análisis de consistencia interna (se usaron coeficientes Alfa de Cronbach y GLB) como análisis de medidas repetidas (confiabilidad test-retest). Se aplicó la escala a 310 pacientes con diagnóstico confirmado de cáncer y que se sometieran a quimioterapia por primera vez como neodayuvancia o adyuvancia del tratamiento antineoplásico. Resultados: El 52% fueron hombres; la edad promedio fue 54,2 años (+/- 15,3 años). Los cánceres más frecuentes fueron: colorrectal (28%), estómago (16%) y mama (12%). Los 14 SGI incluidos en la escala fueron experimentados por todos los pacientes, por lo cual se conservaron, y no se requirió adicionar ningún otro. El tiempo promedio de aplicación del instrumento fue de 5 minutos y el 90% de los participantes lo consideró adecuado. En la validación de escala se aplico a 310 pacientes en donde el 74.8% fueron mujeres, 79,7% de procedencia urbana con un nivel educativo predominante de básica primaria (45.5%). Los cánceres más frecuentes fueron: sistema digestivo 38.4%, mama, 33.9% y aparato genital femenino 19.4%. En cuanto a validez de contenido, el resultado del test de esfericidad de Bartlett fue χ2 = 564.179, p=0.000 y el del KMO fue de 0.705. En la solución de 14 factores el primer factor explicó el 50% de la varianza y el segundo factor el 21%. Se encontraron valores bajos de alfa de Cronbach por fatores y escala total, pero valores de Glb para escala total de 0.817. La confiabilidad test-retest, se encontraron valores del coeficiente de correlación de spearman entre 0.3 y 0.7, siendo todos estadísticamente significativos, indicando estabilidad en la medición de síntomas gastrointestinales. En cuanto a la validez de criterio, dado que no se cuenta con otra escala disponible para medición de síntomas gastrointestinales, se comparó con variables antropométricas con un coeficiente de relación de 0.55 entre el domino 1 y el porcentaje pérdida de peso. Se evalúo la sensibilidad al cambio a través del subgrupo cáncer de mama, presentando una mayor intensidad y frecuencia de síntomas gastrointestinales en la sesión 4 de quimioterapia y una reducción en los mismos en sesión 6 y 7, el análisis de varianza de medidas repetidas mostró que la escala presenta la capacidad para encontrar diferentes niveles de medición de acuerdo con la variación del fenómeno. Conclusiones: Se generó un instrumento de 14 ítems para medir SGI en pacientes oncológicos ambulatorios sometidos a quimioterapia, que es de rápida aplicación y utiliza lenguaje de fácil comprensión para el paciente. Al evaluar las características clinimétricas de la escala se concluye que el instrumento es válido y confiable para la medición de la frecuencia e intensidad de los síntomas gastrointestinales en los pacientes con cáncer sometidos a quimioterapia. (Texto tomado de la fuente). Objective: To perform the translation, transcultural adaptation and validation of the gastrointestinal symptoms component (SGI) of the CTCAE Version 4.02 scale, in outpatients treated with chemotherapy at the National Institute of Cancerology in Bogota. Methods: A manual search was conducted in electronic media, of scales in English or Spanish languages, which will evaluate the presence, frequency or intensity of SGI in cancer patients. The selection of items was carried out by informal consensus of a technical committee, which verified the agreement between the main GIS described in the literature and those included in the scale, all of which could affect nutritional status. For transcultural adaptation, the steps and recommendations of the ISPOR manual and the EORTC quality of life group were followed. The pilot test was conducted on 25 patients selected for convenience, who met the inclusion criteria. The validity of the scale was determined using exploratory factor analysis methods. Both internal consistency analyses (Cronbach Alpha and GLB coefficients) and repeated action analysis (test-retest reliability) were performed to assess reliability. The scale was applied to 310 patients diagnosed with cancer and undergoing chemotherapy for the first time as neodayuvance or adjuvancy of antineoplastic treatment. Results: 52% were male; the average age was 54.2 years (+/- 15.3 years). The most common cancers were: colorectal (28%), stomach (16%) and breast (12%). The 14 SGI included in the scale were experienced by all patients, so they were retained, and no additional addition was required. The average implementation time of the instrument was 5 minutes and 90% of participants deemed it appropriate. Scale validation applied to 310 patients where 74.8% were women, 79.7% from urban sources with a predominant primary basic education level (45.5%). The most common cancers were: digestive system 38.4%, breast, 33.9% and female genital tract 19.4%. In terms of content validity, the result of Bartlett's sphericity test was χ2 = 564.179, p=0.000 and that of the KMO was 0.705. In the 14-factor solution the first factor explained 50% of the variance and the second factor 21%. Low Cronbach alpha values were found by fators and total scale, but Glb values for total scale of 0.817. The reliability test-retest, values of the correlation coefficient of spearman were found between 0.3 and 0.7, all being statistically significant, indicating stability in the measurement of gastrointestinal symptoms. As for the validity of criteria, since there is no other scale available for measuring gastrointestinal symptoms, it was compared with anthropometric variables with a ratio coefficient of 0.55 between domain 1 and the percentage weight loss. Sensitivity to change through the breast cancer subgroup was evaluated, with a higher intensity and frequency of gastrointestinal symptoms in session 4 of chemotherapy and a reduction in them in session 6 and 7, the analysis of variance of repeated measurements showed that the scale presents the ability to find different measurement levels according to the variation of the phenomenon. Conclusions: A 14-item tool was generated to measure SGI in outpatient cancer patients undergoing chemotherapy, which is fast-implementing and uses language that is easy for the patient to understand. Assessing the clinimetric characteristic of the scale concludes that the instrument is valid and reliable for measuring the frequency and intensity of gastrointestinal symptoms in cancer patients undergoing chemotherapy. Incluye anexos Maestría Magíster en Ciencias Epidemiología Clínica Metodología Selección del diseño Estudio de desarrollo y validación de escala. Escala síntomas gastrointestinales. Desarrollo escala para medición de síntomas gastrointestinales. Selección de escalas disponibles Se realizó una búsqueda manual en medios electrónicos, de diferentes escalas en idioma inglés o español, que evaluarán no sólo la presencia de síntomas gastrointestinales en el paciente oncológico sino también su frecuencia o intensidad. La mayoría de las escalas encontradas fueron diseñadas para la medición de calidad de vida en pacientes oncológicos y en general incluían pocos ítems relacionados con los síntomas de interés (EORTC QLQ-C30, ECOG, FACT-G, la escala de Karnofsky y el cuestionario Rotterdam SymptomChecklist) (15,17,18,42,43). En el proceso de búsqueda se encontró la escala desarrollada por el Instituto Nacional de Cáncer de los Estados Unidos, conocida como “Terminología común para los eventos adversos en pacientes con cáncer - CTCAE versión 4.02” (44), que se consideró la más completa ya que contenía todos los ítems asociados al sistema gastrointestinal y a desórdenes metabólicos y nutricionales, evaluando tanto presencia como frecuencia o intensidad de los mismos. Selección de los ítems El objetivo de esta etapa fue identificar y seleccionar los ítems a incluir a partir de la escala CTCAE versión 4.02, la cual permite notificar la presencia y medir la frecuencia o gravedad de eventos adversos asociados al tratamiento antineoplásico. La identificación y selección de los ítems se efectuó por medio de un consenso informal, realizado por un comité técnico conformado por seis profesionales con experiencia en el área clínica oncológica, siendo estos un médico epidemiólogo experto en validación de escalas, dos enfermeras especialistas en enfermería oncológica y tres nutricionistas dietistas. Los ítems fueron seleccionados teniendo en cuenta tres aspectos: a) La revisión de literatura sobre los principales síntomas gastrointestinales descritos en pacientes con cáncer sometidos a quimioterapia (3,4,7,8,11,13,14,45,46); b) La concordancia entre los síntomas gastrointestinales encontrados en la revisión de literatura y los existentes dentro de la escala CTCAE versión 4.02 (44); y c) La posibilidad de los síntomas de repercutir sobre el estado nutricional de los pacientes. El proceso resultó en la selección de 14 de 118 ítems o síntomas gastrointestinales secundarios o asociados al tratamiento con quimioterapia citotóxica. Los síntomas seleccionados, en orden, fueron: náusea, vómito, diarrea, estreñimiento, xerostomía, disfagia, mucositis, queilitis, disgeusia, saciedad precoz, distensión abdominal, flatulencia, dolor abdominal y anorexia. Traducción de los ítems seleccionados El proceso de la adaptación transcultural se realizó siguiendo los pasos y recomendaciones del manual ISPOR y del grupo de calidad de vida EORTC (47,48) (Figura 1). Como primer paso se contactó a los desarrolladores del instrumento, quienes informaron que éste era de uso libre, por tanto, se dio curso al proceso de traducción y adaptación de este. Traducción directa: De los 14 ítems o síntomas seleccionados del documento original CTCAE versión 4.02, se realizaron dos traducciones del inglés (idioma original de la escala) al español, de manera independiente por dos personas calificadas para este fin (un traductor certificado por el Ministerio de Educación Nacional de Colombia y un nativo de país de habla inglesa). Luego de este proceso, el comité técnico analizó la equivalencia de las dos traducciones y generó por consenso una versión del documento en idioma español. Traducción inversa: La versión del documento en español, generada en la etapa previa, se tradujo nuevamente al inglés (idioma original de la escala), de manera independiente por dos personas expertas en traducciones científicas (un traductor oficial vinculado con el Instituto Nacional de Cancerología de Colombia y un experto en traducciones científicas). Estos traductores tenían desconocimiento de la estructura de la versión original. Revisión de las versiones resultantes de la traducción inversa: El comité técnico analizó ambas traducciones y procedió teniendo en cuenta dos criterios: 1. En caso de encontrar dos traducciones idénticas, no se efectúo ningún cambio; 2. En caso de identificar diferencias en las dos traducciones, se eligió la traducción más ajustada a la versión original en inglés, para asegurar la equivalencia semántica al contexto cultural colombiano. Como resultado de este paso, se generó por consenso una nueva versión del componente de sintomatología gastrointestinal de la escala CTCAE versión 4.02, adaptada al contexto cultural colombiano y equivalente a la versión original (Figura 2). Figura 2. Proceso de Selección y traducción de Ítems. Prueba piloto al instrumento Selección de los participantes En la fase preliminar o piloto de la adaptación transcultural del componente de síntomas gastrointestinales de la escala CTCAE Versión 4.02, se trabajó con una muestra de 25 pacientes que asistieron en forma ambulatoria al programa “Hospital Día” del Instituto Nacional de Cancerología (en Bogotá, Colombia) entre noviembre de 2012 y enero de 2013. Estos fueron seleccionados con criterio no probabilístico, de conveniencia, entre quienes presentaban las siguientes características: a) Tener diagnóstico confirmado de cáncer, b) Ser mayor de edad, c) Estar en tratamiento quimioterapéutico o próximo a iniciar quimioterapia, d) Haber aceptado participar voluntariamente en este componente del estudio. Realización de la prueba piloto Los objetivos de la prueba piloto fueron: a) Verificar que los ítems seleccionados sí reflejaran los síntomas gastrointestinales experimentados por los pacientes, b) Determinar la comprensión de los ítems y la necesidad de explicación por parte del entrevistador, c) Establecer el tiempo promedio empleado para contestar el total de preguntas, d) Determinar la dificultad para responder las preguntas, e) Evaluar el eventual grado de confusión, molestia u ofensa que pudieran generar los ítems, f) Recibir sugerencias del paciente sobre la utilización de palabras más fácilmente comprensibles o el refraseo de ítems que facilitara la comprensión. Para documentar cada uno de los anteriores puntos se diseñó un formato que, para cada uno de los ítems, consideraba las respuestas y comentarios aportados por el paciente. La aplicación, tanto del instrumento de medición de síntomas gastrointestinales como del formato de comprensión, fue efectuada por un profesional en salud nutricionista-dietista. El desarrollo de la prueba piloto se efectuó en cuatro momentos diferentes, así: 1) La primera prueba de aplicación de ambos componentes se realizó en 10 pacientes y generó la primera serie de modificaciones técnicas. 2) La segunda aplicación consistió en aplicar los formatos modificados a 10 pacientes diferentes (todos ellos para primera quimioterapia) y derivó en una segunda serie de ajustes técnicos. 3) La tercera aplicación se efectuó en 5 pacientes diferentes, en quienes se utilizaron los formatos doblemente modificados, la cual evidenció problemas de comprensión en dos síntomas. 4) La cuarta aplicación, efectuada en 5 pacientes (4 diferentes y 1 repetido), verificó y ajustó los problemas de comprensión evidenciados en la fase previa. Como resultado final de los cuatro pasos realizados se logró obtener la escala definitiva. Prueba Piloto Desarrollo escala para medición de síntomas gastrointestinales. Los objetivos de la prueba piloto fueron: • Verificar que los 14 ítems seleccionados sí reflejaran los síntomas gastrointestinales experimentados por los pacientes. • Determinar la comp • rensión de los ítems y la necesidad de explicación por parte del entrevistador. • Establecer el tiempo promedio empleado para contestar el total de preguntas. • Determinar la dificultad para responder las preguntas • Evaluar el eventual grado de confusión, molestia u ofensa que pudieran generar los ítems • Recibir sugerencias del paciente sobre la utilización de palabras más fácilmente comprensibles o el refraseo de ítems que facilitara la comprensión. Para documentar cada uno de los anteriores puntos se diseñó un formato que, para cada uno de los 14 ítems, consideraba las respuestas y comentarios aportados por el paciente. La aplicación, tanto del instrumento de medición de síntomas gastrointestinales como del formato de comprensión, fue supervisada por dos profesionales en salud (nutricionistas-dietistas) Figura 3. Figura 3. Proceso aplicación de comprensión escala SGI. Validación de escala para medición de síntomas gastrointestinales. Tamaño de muestra El tamaño de la muestra fue determinado para la evaluación de cada propiedad psicométrica de acuerdo con los criterios y los estudios previos presentados en la tabla 2. Para todas las estimaciones se consideró un error tipo I =0.05 y un poder 1-=0.80. Tabla 2. Cálculo de tamaños de muestra según propiedades psicométricas a evaluar Propiedad psicométrica Criterios Tamaño de la muestra Confiabilidad test retest Hipótesis Nula: Coeficiente de correlación y concordancia de Lin=0.7 Hipótesis alterna: Coeficiente de correlación y concordancia de Lin=0.8 118 pacientes Consistencia interna Hipótesis Nula: Coeficiente alfa de Cronbach=0.6 Hipótesis alterna: Coeficiente alfa de Cronbach=0.7 Número de ítems de la escala: 14 ítems 203 pacientes Validez de contenido Para realizar el análisis factorial por medio de ecuaciones estructurales se sugiere una muestra mínima de 250 examinados cuando se emplean variables ordinales, utilizando el método de estimación de mínimos cuadrados ponderados (49). 300 pacientes Validez de criterio Hipótesis Nula: Coeficiente de correlación Pearson=0.5 Hipótesis alterna: Coeficiente de correlación Pearson=0.7 80 pacientes Sensibilidad al cambio Media y desviación antes de una intervención: 6.16 (4.4) (49) Correlación entre las mediciones: 0.8 54 pacientes Estrategia de muestreo Muestreo por conveniencia conforme asistieron los pacientes quimioterapia ambulatoria en el INC. Criterios de inclusión y exclusión Criterios de inclusión: • Hombres y mujeres con edades entre 18 y 85 años de edad con diagnóstico confirmado de cáncer (tumores malignos sólidos). • Pertenecer al programa Hospital Día del Instituto Nacional de Cancerología. • Pacientes que se encuentren en capacidad física, intelectual y cognoscitiva para participar en la investigación. • Pacientes que acepten voluntariamente participar en el estudio. • Encontrarse próximo a iniciar por primera vez su tratamiento quimioterapéutico ambulatorio. Criterios de exclusión: • Presentar más de una enfermedad neoplásica. • Mujeres en estado de embarazo o lactancia. • Presentar discapacidad relacionada con la pérdida de algún miembro corporal. • Presentar discapacidad que imposibilite la bipedestación por su propia cuenta • Tener implantes corporales electrónicos, dado que la impedancia bioeléctrica puede generar riesgo en este tipo de pacientes. • Tener enfermedades que generen modificaciones en la volemia corporal como enfermedad renal crónica, insuficiencia cardíaca congestiva y hepatopatías.

New systemic cancer therapies are increasingly oriented towards specific signaling pathways involved in carcinogenesis. However, these new treatments may lead to disorders of glycemic homeostasis ranging from glucose intolerance, diabetes or the occurrence of severe acute hyperglycemic syndrome due to blockade of certain pathways common to glucose metabolism. This article discusses the estimated frequency of new-onset diabetes, the pathophysiological mechanisms as well as the diagnostic, therapeutic, monitoring and prognostic management of glycemic dysfunction in patients treated with these novel systemic cancer therapies.

Introduction: Child cancer has a major impact on public health. The evaluation of body composition by bioelectric impedance provides the values of phase angle, causally related to functional changes in the cell membrane which have been used to evaluate nutritional status and prognosis. Objective: To evaluate the correlation between phase angle and parameters of the nutritional status of pediatric oncologic patients under treatment. Method: Cross-sectional study performed in a public university hospital. The nutritional status was evaluated by weight, height, arm circumference, triceps skin fold, body mass index and arm muscle circumference. The phase angle was determined by bioelectric impedance. Results: 13 patients were included with a mean age of 103.2±39.7 months, 61.5% males with prevalence of leukemia in the diagnoses. It was found that most (53.8%) of the patients were eutrophic. There was a strong correlation of the phase angle with the parameters of lean mass (r=0.923; p=0.000), cellular body mass (r=0.911; p=0.000), extracellular mass (r=0.897; p=0.000) and body weight (r=0.920; p=0.000). Conclusion: Expressive associations between phase angle and other anthropometric indicators were observed, reinforcing the hypothesis that it can anticipate the identification of changes in body composition, allowing early nutritional intervention and better prognosis. Introducción: El cáncer infantil tiene un gran impacto en la salud pública. La evaluación de la composición corporal por impedancia bioeléctrica proporciona los valores del ángulo de fase, directamente relacionados con los cambios funcionales de la membrana celular y que se han utilizado para evaluar el estado nutricional y el pronóstico. Objetivo: Evaluar la correlación entre el ángulo de fase y los parámetros del estado nutricional de los pacientes oncológicos pediátricos en tratamiento. Método: Estudio transversal realizado en un hospital universitario público. El estado nutricional se evaluó por peso, altura, circunferencia del brazo, pliegue de la piel del tríceps, índice de masa corporal y circunferencia muscular del brazo. El ángulo de fase fue determinado por la impedancia bioeléctrica. Resultados: Se incluyeron 13 pacientes con una edad media de 103,2±39,7 meses, de los cuales el 61,5% eran hombres con prevalencia de leucemia entre los diagnósticos. Se descubrió que la mayoría (53,8%) de los pacientes eran eutróficos. Hubo una fuerte correlación del ángulo de fase con los parámetros de masa magra (r=0,923; p=0,000), masa corporal celular (r=0,911; p=0,000), masa extracelular (r=0,897; p=0,000) y peso corporal (r=0,920; p=0,000). Conclusión: Se observaron asociaciones expresivas entre el ángulo de fase y otros indicadores antropométricos, lo que refuerza la hipótesis de que puede anticiparse a la identificación de cambios en la composición corporal, lo que permite una intervención nutricional temprana y un mejor pronóstico. Introdução: O câncer infantil gera um grande impacto para a saúde pública. A avaliação da composição corporal pela impedância bioelétrica fornece os valores de ângulo de fase, diretamente relacionados a alterações funcionais na membrana celular e que têm sido usados para avaliar o estado nutricional e o prognóstico. Objetivo: Avaliar a correlação entre o ângulo de fase e os parâmetros do estado nutricional de pacientes oncológicos pediátricos em tratamento. Método: Estudo transversal realizado em um hospital público universitário. O estado nutricional foi verificado por meio das medidas de peso, altura, circunferência do braço, dobra cutânea tricipital, índice de massa corporal e circunferência muscular do braço. O ângulo de fase foi determinado pela impedância bioelétrica. Resultados: Foram incluídos 13 pacientes com média de idade de 103,2±39,7 meses, sendo 61,5% do sexo masculino, com prevalência da leucemia entre os diagnósticos. Constatou-se que a maioria (53,8%) dos pacientes estava em eutrofia. Houve forte correlação do ângulo de fase com os parâmetros de massa magra (r=0,923; p=0,000), massa corporal celular (r=0,911; p=0,000), massa extracelular (r=0,897; p=0,000) e peso corporal (r=0,920; p=0,000). Conclusão: Observaram-se correlações expressivas entre o ângulo de fase e os indicadores antropométricos, reforçando a hipótese de que o ângulo de fase pode antecipar a identificação de alterações na composição corporal, possibilitando uma intervenção nutricional precoce e melhor prognóstico.

MiRNAs that are characterized by small non-coding RNAs orchestrate the expression of important genes involved in cancer cell development processes, including apoptosis, proliferation, angiogenesis, metastasis, and drug resistance at the post-transcriptional level. Dysregulation of miR-9 in various cancers has been reported. Recently, miR-9 has been considered as a key miRNA in various malignancies. However, its importance in the pathogenesis of different neoplasms is not yet well defined. Accordingly, this study was conducted in order to clarify the potential roles of miR-9 in the development of various cancers, prognosis, and treatment approaches. We have shown that a large number of miR-9 targets play fundamental roles in carcinogenesis, and that is dysregulated in various cancer cells. Our findings werefound aberrant miR-9 expression in a majority of cancers. This review article generally emphasizesthe critical roles of miR-9 in cancer cell progression. Additionally, we intended to investigate the effects of down-regulation or up-regulation of miR-9 in different types of cancers. It is hoped that a good understanding of the regulatory roles of miR-9 in various cancers ishelpful for using miR-9 in clinical settings, including prognosis, diagnosis, and miRNA-based target therapy. MiRNAs that are characterized by small non-coding RNAs orchestrate the expression of important genes involved in cancer cell development processes, including apoptosis, proliferation, angiogenesis, metasta-sis, and drug resistance at the post-transcriptional level. Dysregulation of miR-9 in various cancers has been re-ported. Recently, miR-9 has been considered as a key miRNA in various malignancies. However, its impor-tance in the pathogenesis of different neoplasms is not yet well defined. Accordingly, this study was conducted in order to clarify the potential roles of miR-9 in the development of various cancers, prognosis, and treatment approaches. We have shown that a large number of miR-9 targets play fundamental roles in carcinogenesis, and that is dysregulated in various cancer cells. Our findings werefound aberrant miR-9 expression in a majority of cancers. This review article generally emphasizesthe critical roles of miR-9 in cancer cell progression. Addition-ally, we intended to investigate the effects of down-regulation or up-regulation of miR-9 in different types of cancers. It is hoped that a good understanding of the regulatory roles of miR-9 in various cancers ishelpful for using miR-9 in clinical settings, including prognosis, diagnosis, and miRNA-based target therapy.

Immune checkpoint inhibitors (ICIs) are emerging as the new standard of care for treating various metastatic cancers. It is known that effective anti-tumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes (TILs) in solid tumor tissue. Cancer patients with relapsing–remitting multiple sclerosis (RRMS) are often under continuous treatment with fingolimod, an immune-modulating drug that inhibits lymphocyte egress from secondary lymphatic organs. Little is known about the effect of fingolimod on ICI cancer therapy, as fingolimod may limit the number of TILs. Here we present three patients with RRMS, who developed various cancers during fingolimod treatment. Histology of all tumors consistently showed low numbers of TILs. A second biopsy taken from one of the tumors, a melanoma, revealed a significant increase of TILs after stopping fingolimod and starting pembrolizumab, indicating a surge in the number and re-invigoration of T cells. Our study suggests that fingolimod limits the number of TILs in solid tumors and may, thus, inhibit anti-cancer immune responses.

CD44 promotes metastasis, chemoresistance, and stemness in different types of cancer and is a target for the development of new anti-cancer therapies. All CD44 isoforms share a common N-terminal domain that binds to hyaluronic acid (HA). Herein, we used a computational approach to design new potential CD44 antagonists and evaluate their target-binding ability. By analyzing 30 crystal structures of the HA-binding domain (CD44HAbd), we characterized a subdomain that binds to 1,2,3,4-tetrahydroisoquinoline (THQ)-containing compounds and is adjacent to residues essential for HA interaction. By computational combinatorial chemistry (CCC), we designed 168,190 molecules and compared their conformers to a pharmacophore containing the key features of the crystallographic THQ binding mode. Approximately 0.01% of the compounds matched the pharmacophore and were analyzed by computational docking and molecular dynamics (MD). We identified two compounds, Can125 and Can159, that bound to human CD44HAbd (hCD44HAbd) in explicit-solvent MD simulations and therefore may elicit CD44 blockage. These compounds can be easily synthesized by multicomponent reactions for activity testing and their binding mode, reported here, could be helpful in the design of more potent CD44 antagonists.