Alteraciones genómicas en carcinoma epidermoide de ano localizado: secuenciación del exoma completo

El carcinoma epidermoide de ano es una neoplasia poco frecuente con una incidencia creciente a nivel global. Aunque es más frecuente en la mujer, la población de mayor riesgo son los varones que mantienen relaciones sexuales con varones, especialmente en la población infectada por el virus de la inmunodeficiencia humana. En el 85% de los casos la base etiopatogénica se fundamenta en la persistencia de infección por genotipos de alto riesgo del virus del papiloma humano, favorecida por la inmunodepresión y el consumo de tabaco. Las oncoproteínas virales E6 y E7 promueven la degradación de p53 yRb, respectivamente, en la célula huésped, favoreciendo la transformación a carcinoma infiltrante. Algunos factores clínicos de mal pronóstico son el sexo masculino, la afectación ganglionar, el tamaño mayor a 5 cm, o la presencia de ulceración cutánea. Menos evidencia existe acerca de los factores pronósticos moleculares. El tratamiento de la enfermedad localizada se basa en la administración de radioterapia concurrente con mitomicina y fluoropirimidinas desde la década de los 70. A pesar de esta aproximación terapéutica, uno de cada tres pacientes presentará una recaída, habitualmente local

Epidermal growth factor receptor (EGFR) activation induces the expression of multidrug resistance associated protein 4 (MRP4/ABCC4) in a pancreatic cancer human cell line

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of pancreatic cancer and has one of the worse prognosis. The poor overall survival is associated with the overexpression of epidermal growth factor receptor (EGFR), a known member of the ErbB family of receptor tyrosine kinases and multidrug resistance associated protein 4 (MRP4/ABCC4). Our previous results show that high levels MRP4 are associated with increase in tumor cell proliferation, metastatic invasion and up-regulation of EGFR protein levels in PDACs cell lines. The aim of our study was to evaluate the regulation of MRP4 by EGFR activation in a pancreatic cancer cell model. To accomplish our objective, we treated the pancreatic cancer cell line BxPC-3 with EGF (0.1ng/ul). EGFR activation was confirmed by ERK phosphorylation at 5, 10, 20, 30, and 40 min after EGF treatment. MRP4 protein expression was evaluated by western blot using whole cell extracts following incubation with EGF for 0, 24 and 48 h, using histone as loading control. MRP4 expression levels were also assessed 48 h after treatment with EGF alone or in combination with the EGFR inhibitor CL 387-785 (1µM). Our results confirm that EGFR is quickly activated upon incubation with EGF, as evidenced by a 4-fold increase in the pERK/total ERK ratio detected (P<0.001) at 5 min and normalized at 40 min. Maximal induction of MRP4 expression (86%, P<0.001) was observed in cells treated with EGF for 48 h. Furthermore, EGF-mediated MRP4 induction was abolished by co-treatment with CL387-785 (P<0.05), while its expression does not change by treatment with this EGFR inhibitor alone. These data demonstrate that EGFR activation produces increments in MRP4 protein levels in a PDAC cell line. In summary, it is possible that MRP4 and EGFR, both PDAC poor prognosis markers, are co-regulated by a positive feed-back which ultimately enhances their effect upon each other.Fil: Lago, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Barosso, Ismael Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Sahores, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Imperiale, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Manautou, José E.. University of Connecticut; Estados UnidosFil: Davio, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Ghanem, Carolina Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaReunión Anual de la Sociedad Argentina de FisiologíaRosarioArgentinaSociedad Argentina de Fisiologí

Role of sex on psychological distress, quality of life, and coping of patients with advanced colorectal and non-colorectal cancer

Patients with advanced gastrointestinal cancer must cope with the negative effects of cancer and complications. However, data on psychological distress, quality of life, and coping strategies in patients with advanced colorectal cancer compared to non-colorectal cancer based on sex is lacking. This was a multicenter study conducted in 203 patients that completed questionnaires evaluating psychological distress, quality of life, and coping strategies before starting systemic cancer treatment. Based on these data, the degree of disease acceptance in gastrointestinal malignancies may depend on sex and location of the primary digestive neoplasm

Cytokines and lymphoid populations as potential biomarkers in locally and borderline pancreatic adenocarcinoma

Despite its relative low incidence, PDAC is one of the most aggressive and lethal types of cancer, being currently the seventh leading cause of cancer death worldwide, with a 5-year survival rate of 10.8%. Taking into consideration the necessity to improve the prognosis of these patients, this research has been focused on the discovery of new biomarkers. For this purpose, patients with BL and resectable disease were recruited. Serum cytokines and growth factors were monitored at different time points using protein arrays. Immune cell populations were determined by flow cytometry in peripheral blood as well as by immunohistochemistry (IHC) in tumor tissues. Several cytokines were found to be differentially expressed between the study subgroups. In the BL disease setting, two different scores were proven to be independent prognostic factors for progression-free survival (PFS) (based on IL-10, MDC, MIF, and eotaxin-3) and OS (based on eotaxin-3, NT-3, FGF-9, and IP10). In the same context, CA19-9 was found to play a role as independent prognostic factor for OS. Eotaxin-3 and MDC cytokines for PFS, and eotaxin-3, NT-3, and CKβ8-1 for OS, were shown to be predictive biomarkers for nab-paclitaxel and gemcitabine regimen. Similarly, oncostatin, BDNF, and IP10 cytokines were proven to act as predictive biomarkers regarding PFS, for FOLFIRINOX regimen. In the resectable cohort, RANTES, TIMP-1, FGF-4, and IL-10 individually differentiated patients according to their cancer-associated survival. Regarding immune cell populations, baseline high levels of circulating B lymphocytes were related to a significantly longer OS, while these levels significantly decreased as progression occurred. Similarly, baseline high levels of helper lymphocytes (CD4+), low levels of cytotoxic lymphocytes (CD8+), and a high CD4/CD8 ratio, were related to a significantly longer PFS. Finally, high levels of CD4+ and CD8+ intratumoural infiltration was associated with significantly longer PFS. In conclusion, in this study we were able to identify several prognostic and predictive biomarker candidates in patients diagnosed of resectable or BL PDAC.This work was funded by grants from the Department of Health from the Government of Navarra (Ref. 008-2018), REFBIO II Pyrenees Biomedical Network from Programa INTERREG V-A España-Francia-Andorra (Ref. BMK_PANC) and Sociedad Española de Oncología Médica (SEOM) to A.V. I.G.B was supported by a predoctoral fellowship from the Department of Economic Development Government of Navarre Ayudas para la contratación de doctorandos y doctorandas por empresas y organismos de investigación y difusión de conocimientos: doctorados industriales 2018–2020. Intensification Programme Navarrabiomed 2017–2021 Obra Social La Caixa Fundación Caja Navarra. Work by JPC received funds from Spanish Ministry of Economy (MINECO; BFU2016–80360-R) and Ministry of Science and Innovation (MICINN; PID2019-105201RB-I00), Junta de Andalucía (BIO- 0139), Universidad de Córdoba-FEDER (UCO-202099901918904), GETNE2019 Research grant; and CIBERobn Fisiopatología de la Obesidad y Nutrición (CIBER is an initiative of Instituto de Salud Carlos III, co-funded by European Union: ERDF/ESF, “Investing in your future”). EAP was funded by a Predoctoral contract FI17/00282 Instituto de Salud Carlos III

Estoicismo frente al cáncer: riesgo o protección.

Detectar una actitud de afrontamiento estoica en los pacientes con cáncer es importante porque puede favorecer o dificultar el tratamiento oncológico. Objetivo: En este trabajo, analizamos si en función de la edad, el género, la presencia de dolor y el tiempo transcurrido desde que empezaron los síntomas hasta el diagnóstico del cáncer, podemos asignar a las conductas estoicas un valor positivo o negativo, como factor de protección o de riesgo en los pacientes. Material y Métodos: evaluamos 540 pacientes que acudieron a la consulta de Oncología Médica para valoración de tratamiento adyuvante tras una cirugía oncológica, entre junio del 2015 y diciembre del 2016.Los datos clínicos y demográficos se obtuvieron a través de la entrevista médica y fueron: género, edad, estado civil, nivel educativo, área ocupacional, localización del tumor, estadio y tiempo trascurrido desde la presencia de los síntomas y la consulta al médico. Se administraron en papel y presencialmente los siguientes cuestionarios: Inventario de Dolor Breve, Brief Symptom Inventory y Liverpool Stoicism Scale. Resultados: Los hombres de la muestra mostraron casi 5 veces más probabilidad de presentar altas puntuaciones en estoicismo que las mujeres y 7 veces más si se asocia un estado de ánimo decaído y edad avanzada. El estoicismo fue mayor en los pacientes de más edad. No se ha hallado relación entre el estoicismo y las escalas de dolor. Conclusión: Las tres características que discriminan mejor entre los pacientes con altas y/o bajas puntuaciones en estoicismo son el género, la edad y el estado de ánimo depresivo. El hecho de que el estoicismo esté asociado a hombres ancianos con depresión nos hace pensar que el estoicismo debe ser considerado más como un factor de riesgo que de protección. La madurez relacionada con la edad conlleva inevitablemente una mayor aceptación de las pérdidas y una propensión a ocultar el dolor, o a no buscar ayuda para evitar mostrar debilidad. Ante esta situación es importante contar con la información que nos proporciona la familia y reconocer la importancia del apoyo familiar sobre a estas personas que pueden ser de entrada más vulnerables

Clinico-pathological characteristics and outcomes of patients with early-onset colorectal cancer

[Background]: The rising incidence of colorectal cancer (CRC) among young patients is alarming. We aim to characterize the clinico-pathological features and outcomes of patients with early-onset CRC (EOCRC). [Methods]: We included all of the patients with pathologically confirmed diagnosis of CRC at Hospital Universitario La Paz from October 2016 to September 2020. EOCRC age cut-off was 50 years. All statistical analyses were carried out using SPSS v.25. [Results]: A total of 1152 patients were diagnosed with CRC, fifty-nine (5,1%) of them were After a median follow-up of 24 months, 279 patients have died. Median overall survival (OS) was not reached in either group (p = 0,06). Three-year OS was 80% (95%CI: 73-87) and 67 (95%CI: 65-69) in the younger and older group, respectively. In patients with localized disease that underwent surgery or other antineoplastic treatment ( n = 856), 159 events for disease-free survival (DFS) were observed. Median DFS was [Conclusions]: Patients with EOCRC are diagnosed at a more advanced stage and display distinct biological features (more prevalence of dMMR and WT tumors among others). Studies focusing on screening in this population and deeper molecular profiling are needed

Clinico-pathological characteristics and outcomes of patients with early-onset colorectal cancer

[Background]: The rising incidence of colorectal cancer (CRC) among young patients is alarming. We aim to characterize the clinico-pathological features and outcomes of patients with early-onset CRC (EOCRC).[Methods]: We included all of the patients with pathologically confirmed diagnosis of CRC at Hospital Universitario La Paz from October 2016 to September 2020. EOCRC age cut-off was 50 years. All statistical analyses were carried out using SPSS v.25. [Results]: A total of 1152 patients were diagnosed with CRC, fifty-nine (5,1%) of them were After a median follow-up of 24 months, 279 patients have died. Median overall survival (OS) was not reached in either group (p ¼ 0,06). Three-year OS was 80% (95% CI: 73-87) and 67 (95%CI: 65-69) in the younger and older group, respectively. In patients with localized disease that underwent surgery or other antineoplastic treatment ( n ¼ 856), 159 events for disease-free survival (DFS) were observed. Median DFS was not reached in either group (p ¼0,144). Three-year DFS was 86% (95%CI: 79-93) and 73% (95%CI: 71-75, respectively). In patients with metastatic disease (n ¼ 332; synchronous or metachronic), median OS was not reach in the EOCRC group vs 18,1 (95%CI: 13,8-22,4), p ¼ 0,05). In those patients with metastatic EOCRC with mutational status assessed (n ¼23), no difference in OS according to RAS was observed (p ¼ 0,55).[Conclusions]: Patients with EOCRC are diagnosed at a more advanced stage and display distinct biological features (more prevalence of dMMR and WT tumors among others). Studies focusing on screening in this population and deeper molecular profiling are needed.Peer reviewe

VITAL phase 2 study: Upfront 5-fluorouracil, mitomycin-C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09-02)

Aim: VITAL, a phase II single-arm study, aimed to evaluate efficacy and safety of panitumumab addition to 5-fluorouracil (5-FU), mitomycin-C (MMC) and radiotherapy (RT) in patients with localized squamous cell carcinoma of the anal canal (SCCAC). Methods: Adult, treatment-naïve SCCAC patients (Stage T2-T4, any N, M0) and ECOG-PS ≤2, received panitumumab (6 mg/kg, day 1 and Q2W; 8 weeks), 5-FU (1000 mg/m2/d, days 1-4 and 29-32), MMC (10 mg/m2, days 1 and 29) and RT 45 Gy (1.8 Gy/fraction) to the primary tumor and mesorectal, iliac and inguinal lymph nodes, plus 10-15 Gy boost dose to the primary tumor and affected lymph nodes. The primary objective was disease free survival rate (DFS) at 3-years (expected 3-year DFS rate: 73.7 ± 12%). Results: Fifty-eight patients (31 women; median age: 59 years; ECOG-PS 0-1:98%; TNM II [29%] (T2 or T3/N0/M0)/IIIA (T1-T3/N1/M0 or T4/N0/M0) [21%]/IIIB (T4/N1/M0 or any T/N2 or N3/M0) [47%]/nonevaluable [4%]) were included. The median follow-up was 45 months. The 3-year DFS rate was 61.1% (95% CI: 47.1, 72.4). The 3-year overall survival rate was 78.4% (95% CI: 65.1, 87.1). Eighteen patients (31.0%) required a colostomy within 2 years posttreatment. Grade 3-4 toxicities were experienced by 53 (91%) patients. Most common grade 3-4 treatment-related events were radiation skin injury (40%) and neutropenia (24%). No toxic deaths occurred. Improved efficacy in colostomy-free survival and complete response rate was observed in human papilloma virus positive patients. Conclusions: Panitumumab addition to MMC-5FU regimen in SCCAC patients increases toxicity and does not improve patients’ outcomes. RT plus MMC-5FU remains the standard of care for localized SCCAC patients.This work was supported by Amgen S.A

Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma

Background: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. Methods: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. Results: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p <.0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7–24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p =.02, HR = 3.6; 95% CI, 1.1–5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. Conclusions: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. Plain Language Summary: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacyIdiPAZ, Grant/Award Number: Jesús Antolín Garciarena Fellowship; European Proteomics Infrastructure Consortium, Grant/Award Number: 823839, Horizon 2020 Programm

Psychometric properties of the Shared Decision-Making Questionnaire (SDM-Q-9) in oncology practice

Background/Objective: This study sought to assess the psychometric properties of the 9-item Shared Decision-Making Questionnaire (SDM-Q-9) in patients with resected, non-metastatic cancer and eligible for adjuvant chemotherapy. Method: A total of 568 patients were recruited from a multi-institutional, prospective, transversal study. Patients answered the SDM-Q-9 after visiting their medical oncologist who, in turn, completed the SDM-Q---Physician version. Reliability, factorial structures [exploratory factor analysis (EFA), confirmatory factor analysis (CFA)], and convergent validity of the SDM-Q-9 scores were explored. Results: SDM-Q-9 showed a clear factorial structure, compatible with a strong and replicable general factor and a secondary group factor, in patients with resected, non-metastatic cancer. Total sum scores derived from the general factor showed good reliability in terms of omega coefficient: .90. The association between patient and physician perception of SDM was weak and failed to reach statistical significance. Males and patients over 60 years of age displayed the greatest satisfaction with SDM. Conclusions: SDM-Q-9 can aid in evaluating SDM from the cancer patients' perspective. SDM-Q-9 is helpful in studies examining patient perspectives of SDM and as an indicator of the degree of quality and satisfaction with health care and patient-physician relationship