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To present our real-life experience with dabrafenib and trametinib (D-T) treatment in patients with BRAF V600E-mutated ATC in Argentina.We included five patients from four different hospitals. The median age was 70 years, and 60% were male. The performance status at diagnosis was grade 0 in 60% and grade 2 in 40% of patients. Four patients could undergo total thyroidectomy; in one of them, surgical treatment was amenable due to the indication of D-T as neoadjuvant therapy. From the total cohort, the best response to treatment was complete response in 40%, partial response in 20%, and stable disease in 20%. The median duration of response was 20 weeks, ranging from 16 to 92 weeks. All patients experienced at least one adverse event (AE). Grade ≥3 AEs were observed in two (40%) patients. They were upper gastrointestinal bleeding and subclavian vein thrombosis. The median follow-up was 20 weeks (range: 16 to 92).This report contributes to illustrate the feasibility and effectiveness of D-T treatment in five patients with loco-regionally advanced and metastatic BRAF V600E-mutated ATC in a real-life setting. A multidisciplinary approach and rapid molecular-tailored testing are essential to begin this therapeutic option.

Background: Breast cancer is a highly heterogeneous disease with large differences in the risk of recurrence. An elevated neutrophil-to-lymphocyte ratio (NLR) is correlated with a poor prognosis in a variety of tumors, and although it is still controversial in breast cancer, there are multiple studies, including meta-analysis, suggesting this. The purpose of this study was to analyze the prognostic value of preoperative NLR in an Argentine population of patients with nonmetastatic breast cancer, not exposed to neoadjuvant treatment. Methods: Retrospective multicenter cohort study that includes patients over 18 years of age from three centers in the city and province of Buenos Aires who have had surgery for early breast cancer between January 1, 1999, and December 31, 2014. Based on the previous literature, a cutoff value of 2.0 was defined. Results: A total of 791 patients were eligible for the analysis. Median age was 55 years (IQR 45–65). Median NLR was 1.92 (IQR 1.50–2.56). The distribution of groups according to the 8th edition of the AJCC was 54.1% for stage I, 35.6% stage II, and 10.4% stage III. Among the different tumor phenotypes, 79.0% were HR+/HER2−, 11.4% were HR+ or−/HER2+, and 9.2% were HR−/HER2−. With a median follow-up of 5.3 years, 112 patients (14.2%) had disease recurrence. Stage III patients had a higher NLR than stage I and stage II patients (p = 0.002). The rest of the clinical and pathological characteristics did not show differences in the groups according to NLR. There were no differences in relapse-free survival according to the NLR (p = 0.37), and itdid not change after adjusting for other prognostic variables. Conclusion: We consider it is important to determine the efficacy of prognostic markers that are easily accessible and of simple, systematic application. However, NLR does not appear to be an independent prognostic factor for recurrence in our population. In this sense, we consider it is important to publish negative results in order to avoid publication bias.

Purpose: Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden.Experimental Design: IL8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis.Results: IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non–small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract.Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance. Clin Cancer Res; 20(22); 5697–707. ©2014 AACR.

Supplementary Figure 4. Comparison of IL-8 serum concentrations with the serum concentration of IL-6 and c-reactive protein (CRP) in available samples from 14 melanoma and 19 RCC patients from Figure 2A. (**, p

Supplementary Figure 1B. Time course of the serum concentrations of IL-8 (lower panels) and tumor volume (upper panels) in Rag2-/-IL2Rγc-/- mice xenografted with the indicated cell lines. Individual mice are represented and at the time point indicated by the arrow the tumor was surgically removed. Serum IL-8 concentrations are depicted at 2h and 24h after surgery.

Supplementary Figure 2. Serum IL-8 levels before (day -1) and after (day 5-7) disease-reduction surgery of 7 patients: 1 hepatocellular carcinoma (HCC); 2 colorectal carcinoma (CRC); 1 pancreatic cancer (PC); 3 renal cell carcinoma (RCC).

Supplementary Figure 3. Quantitative RT-PCR analyses of the mRNA encoding IL-8 in malignant cells from the biopsy of three melanoma patients. The serum IL-8 levels at the time of the biopsy from each patient is provided under the graph.

Supplementary Table 2. Surgical patient description 2

Supplemental Legend

Supplementary Table 1. Patient description 1

La mayoría de los pacientes con cáncer de pulmón de células no pequeñas (NSCLC) progresan o recaen luego del tratamiento con taxanos-platinos. En el microambiente tumoral (TME) las cancer stem cells (CSCs), que expresan CD133, están involucradas en la recurrencia. El ácido hialurónico (HA) del TME regula, en parte, la función de las CSCs. Analizamos HA en el TME y si su modulación con la cumarina 4-Methylumbelliferona (4Mu) modifica las propiedades de las CSCs. Utilizamos líneas murinas (Lewis Lung Carcinoma; LLC) y humanas (A549) para evaluar viabilidad luego de la exposición al paclitaxel, pemetrexed o cisplatino, o combinados con 4Mu. Analizamos sintasas HAS y hialuronidasas HYAL y factores de transcripción de CSCs a partir de datos de pacientes (TCGA) y por qPCR. Aislamos células CD133+ y estudiamos la expresión de HA y la capacidad clonogénica y tumorigénica. Observamos que los tumores de LLC producen HA, generado en parte por estas células. El 8.53 ± 0.35% de LLC son CD133+, y expresan más HA y CD44 en comparación a las CD133- (p

Purpose: To present our real-life experience with dabrafenib and trametinib (D-T) treatment in patients with BRAF V600E-mutated ATC in Argentina. Patients y methods: We included five patients from four different hospitals. The median age was 70 years, and 60% were male. The performance status at diagnosis was grade 0 in 60% and grade 2 in 40% of patients. Four patients could undergo total thyroidectomy; in one of them, surgical treatment was amenable due to the indication of D-T as neoadjuvant therapy. From the total cohort, the best response to treatment was complete response in 40%, partial response in 20%, and stable disease in 20%. The median duration of response was 20 weeks; ranging from 16 to 92 weeks. All patients experienced at least one adverse event (AE). Grade ≥3 AEs were observed in two (40%) patients. They were upper gastrointestinal bleeding and subclavian vein thrombosis. The median follow-up was 20 weeks (range: 16 to 92). Conclusion: This report contributes to illustrate the feasibility and effectiveness of D-T treatment in five patients with loco-regionally advanced and metastatic BRAF V600E-mutated ATC in a real-life setting. A multidisciplinary approach and rapid molecular tailored testing are essential to begin this therapeutic option.

PURPOSE Multiple studies have reported that breast cancer in young patients is associated with aggressive characteristics, and it is suggested that prognosis is worse independently of pathologic variables. PATIENTS AND METHODS We performed a retrospective analysis of the Breast Cancer Registry of the Argentinian Society of Mastology, including public and private centers. Patients ≤ 40 years of age at diagnosis were classified as “young,” and patients ≤ 35 years of age at diagnosis were classified as “very young.” Univariate and multivariate analyses were performed to detect differences between groups. RESULTS Patients ≤ 40 years of age comprised 10.40% (739/7,105) of the participants, with an average age of 35.61 ± 4.04 years. Multivariate analysis showed that human epidermal growth factor receptor 2 (HER2)-positive tumor phenotype (odds ratio [OR], 1.82), nodal involvement (OR, 1.69), histologic grade (grade 3 OR, 1.41), and tumor size (T2 OR, 1.37; T3-T4, 1.47) were independently associated with younger age at diagnosis. Patients ≤ 35 years of age (n = 286), compared with patients 36 to 40 years of age, had a higher proportion of HER2 tumors (24.58% v 16.94%; P = .021), absence of progesterone receptor expression (29.85% v 22.95%; P = .043), and stage 3 cancer (29.34% v 18.52%; P < .001). Fewer breast-conserving surgeries (75.37% v 62.89%; P < .001) and more adjuvant chemotherapy (59.04% v 36.66%; P < 0.001) were reported in patients ≤ 40 years of age. CONCLUSION In the population studied, breast cancer in young women was associated with aggressive pathologic features and locally advanced disease at the time of diagnosis. Moreover, tumor characteristics in very young patients with breast cancer nested in the population ≤ 40 years of age showed differences in important prognostic factors. More high-quality evidence is needed to improve treatment strategies in these patients.

The clinical outcome of patients with human epidermal growth factor receptor 2 (HER2) amplified breast carcinoma (BC) has improved with the development of anti-HER2 targeted therapies. However, patients can experience disease recurrence after curative intent and disease progression in the metastatic setting. In the current era of evolving immunotherapy agents, the understanding of the immune response against HER2 tumor cells developed by anti-HER2 antibodies (Abs) is rapidly evolving. Trastuzumab therapy promotes Natural Killer (NK) cell activation in patients with BC overexpressing HER2, indicating that the efficacy of short-term trastuzumab monotherapy, albeit direct inhibition of HER, could also be related with antibody-dependent cell-mediated cytotoxicity (ADCC). Currently, dual HER2 blockade using trastuzumab and pertuzumab is the standard of care in early and advanced disease as this combination could confer an additive effect in ADCC. In patients with disease relapse or progression, ADCC may be hampered by several factors such as FcγRIIIa polymorphism and an immunosuppressive environment, among others. Hence, new drug development strategies are being investigated aiming to boost the ADCC response triggered by anti-HER2 therapy. In this review, we summarize these strategies and the rationale, through mAbs engineering and combinatorial strategies, focusing on clinical results and ongoing trials., Highlights • Efficacy of short-term trastuzumab monotherapy could also be related with ADCC. • ADCC involves the activation of NK cells by Abs that bind to FcRs. • Different strategies to augment NK cell activation may be combined to enhance ADCC. • Margetuximab, an Fc optimized antiHER2 Ab, has a significant improvement in PFS. • Engineered mAbs are the most promising tools for tailored therapy in cancer treatment.

Background & Aims A causal link has recently been established between epigenetic alterations and hepatocarcinogenesis, indicating that epigenetic inhibition may have therapeutic potential. We aimed to identify and target epigenetic modifiers that show molecular alterations in hepatocellular carcinoma (HCC). Methods We studied the molecular-clinical correlations of epigenetic modifiers including bromodomains, histone acetyltransferases, lysine methyltransferases and lysine demethylases in HCC using The Cancer Genome Atlas (TCGA) data of 365 patients with HCC. The therapeutic potential of epigenetic inhibitors was evaluated in vitro and in vivo. RNA sequencing analysis and its correlation with expression and clinical data in the TCGA dataset were used to identify expression programs normalized by Jumonji lysine demethylase (JmjC) inhibitors. Results Genetic alterations, aberrant expression, and correlation between tumor expression and poor patient prognosis of epigenetic enzymes are common events in HCC. Epigenetic inhibitors that target bromodomain (JQ-1), lysine methyltransferases (BIX-1294 and LLY-507) and JmjC lysine demethylases (JIB-04, GSK-J4 and SD-70) reduce HCC aggressiveness. The pan-JmjC inhibitor JIB-04 had a potent antitumor effect in tumor bearing mice. HCC cells treated with JmjC inhibitors showed overlapping changes in expression programs related with inhibition of cell proliferation and induction of cell death. JmjC inhibition reverses an aggressive HCC gene expression program that is also altered in patients with HCC. Several genes downregulated by JmjC inhibitors are highly expressed in tumor vs. non-tumor parenchyma, and their high expression correlates with a poor prognosis. We identified and validated a 4-gene expression prognostic signature consisting of CENPA, KIF20A, PLK1, and NCAPG. Conclusions The epigenetic alterations identified in HCC can be used to predict prognosis and to define a subgroup of high-risk patients that would potentially benefit from JmjC inhibitor therapy. Lay summary In this study, we found that mutations and changes in expression of epigenetic modifiers are common events in human hepatocellular carcinoma, leading to an aggressive gene expression program and poor clinical prognosis. The transcriptional program can be reversed by pharmacological inhibition of Jumonji enzymes. This inhibition blocks hepatocellular carcinoma progression, providing a novel potential therapeutic strategy.

BACKGROUNDThe association of platinum, taxanes, and cetuximab has proven to be an effective and safe strategy for head and neck cancer treatment. Here we present a multi-institutional real-world experience of the TPEx schema as first-line therapy in advanced squamous cell carcinoma of the head and neck (SCCHN).METHODS This retrospective multicenter cohort study included patients with histologically confirmed recurrent or metastatic SCCHN treated with first-line TPEx regimen at five medical centers in Argentina between January 1, 2017, and April 31, 2020. Chemotherapy consisted of four cycles of docetaxel, cisplatin, and cetuximab, followed by cetuximab maintenance. Clinical outcomes and toxicity profiles were evaluated. RESULTSTwenty-four patients were included. Median age at diagnosis was 58 years (range 36-77). The majority of patients (83.3%) received at least four chemotherapy cycles in the initial part. In the included group, overall response rate was 62.5%, and three patients achieved a complete response (12.5%). The median time to response was 2.4 months (95% CI 1.3-3.5). With a median follow-up of 12.7 months (95% CI 8.8-16.6), the median progression-free survival was 6.9 months (95% CI: 6.5-7.3), and the overall survival rate at 12 months was 82.4%. Two-thirds of patients reported at least one treatment-related adverse event, and 25% presented grade 3-4 toxicities.CONCLUSIONSTPEx was an adequately tolerated regimen in our population. Median progression-free survival and overall response rates were consistent with recent reports in clinical trials evaluating this treatment combination.

Purpose Breast cancer (BC) is a highly heterogeneous disease presenting a broad range of clinical and molecular characteristics. In the past years, a growing body of evidence demonstrated that immune response plays a significant role in cancer outcome. However, immune prognostic markers are not completely validated in clinical practice in BC patients. Materials and methods With the aim to characterize immune features, several parameters were analyzed in peripheral blood at diagnosis of 85 nonmetastatic BC patients between April 2011 and July 2014. Results With a median follow-up of 38.6 months, peripheral blood analysis of BC patients (stages I, II, and III) showed that total lymphocyte and T lymphocyte counts were augmented in nonrelapsed patients. Also, a higher neutrophil-to-lymphocytes ratio was associated with prolonged disease-free survival. Natural killer cell receptor analysis revealed that early activation receptor CD69 was associated with a better outcome. Conclusion This preliminary evidence is in accordance with the concept of immune surveillance. We suggest an "immune phenotype" that provides relevant prognostic information in early-stage BC patients and which could be useful in the decision-making process.

Introduction: ESR1 mutations were described for the first time in 1996 when different tyrosine 537 mutations were found to confer constitutive activation of the receptor, describing this region as a key factor in the ligand regulation of ER transcriptional activity. However, due to the low prevalence of this mutation in primary breast tumors its clinical significance maintained unknown. With the advent of large scale genomic analysis, a new understanding of breast cancer molecular characteristics has gained relevance. The low prevalence of ESR1 mutations in primary breast cancer has been confirmed but mutations in metastatic ER-positive breast cancers has been proved to be a completely different scenario. Nevertheless, information regarding real prevalence of ESR1 mutation in metastatic breast cancer is not known as selection of patients and molecular technique used are heterogeneous. Sources: Search was carried by corresponding clinical oncologists of the Breast Cancer Unit of Alexander Fleming Institute. In March 2017, key words “ESR1 mutations”, “Estrogen receptor mutations” and “Breast cancer” were used as search strategy for the present meta-analysis in PubMed. Furthermore, abstracts from congress presentations were analyzed and hand searching from reference list of obtained articles was executed. Online search retrieved 60 articles published, 3 abstracts related were found and 3 further studies were detected by hand search. Articles were excluded if they only included primary tumors and not metastatic cases and if they were undertaken before 2000 due to important technical differences of mutation detection, including finally 23 cohorts. Study Selection: Studies considered were prospective or retrospective cohorts of metastatic breast cancer patients with mutation analysis of tissue or circulating DNA. A data form was used by the primary reviewer to extract equivalent information from each article. Information extracted included population sampled, prevalence estimates, clinical characteristics of cohort, sample analyzed and technical procedure for mutation detection. A second reviewer blinded to the primary reviewer's decisions checked the article selection and data extraction. Any differences of opinion were discussed, and a third reviewer was available to arbitrate any issues. Meta-analysis was undertaken using a random-effects model conducted using the metaprop function in Meta package of R studio Version 1.0.136 (© 2009-2016 RStudio, Inc.). PRISMA guidelines were followed in conducting and reporting the results. Results and Discussion: Results show a prevalence of ESR1 mutation of 24% (CI95% 19-30%) in the 3607 patients included. Nevertheless, important heterogeneity (I2 =90%) is observed due to great differences in the articles published of this topic. This heterogeneity is attributed to the type of cohorts presented, the selection of patients, the technique used and type of sample studied, but another source of heterogeneity must be present as it still persists after grouping studies according to this variables. The importance of this analysis resides in the fact that it is the most complete information of the prevalence of this mutation that may have future importance in therapeutic decisions in metastatic breast cancer. Citation Format: Mandó P, Rizzo MM, Perez de la Puente C, Costanzo MV, Nervo A, Nadal J, Colo F, Loza CM, Loza J, Fabiano V, Ponce C, Chacon R. Meta-analysis of ESR1 mutation prevalence in metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-09.

Non-small cell lung cancer (NSCLC) is the most common cause of cancer death worldwide. Taxane-platin chemotherapy is widely used for NSCLC treatment; however, the majority of patients will ultimately progress or relapse. In the tumor microenvironment (TME) cancer cells co-exist with cellular and non-cellular components that drive tumor processes such as chemotherapy resistance. A small group of tumor cells called cancer stem cells (CSCs) that express some markers such as CD133, CD44 and ALHD1 have particularly different proliferative, differentiation and self-renewal potential. In fact, CD133+ NSCLC cells showed significantly higher abilities of self-renewal and drug resistance characteristics when compared to CD133- cells. It has been partly described how the TME component hyaluronan (HA) regulates CSCs function. We have previously demonstrated that 4-Methylumbelliferone (4Mu), a modulator of HA synthesis, reduces CSCs properties in hepatocarcinoma. Here, we observed that HA was present Lewis Lung Carcinoma (LLC) tumors from mice. We found HA+ LLC cells; thus cancer cells produced, at least in part, the HA observed in tumors. We also observed about 6.58 ± 0.83 % of CD133+ CSCs on in vitro cultured LLC cells. Isolated CD133+ cells showed higher expression of HA and CD44 in comparison with non-CSCs population (p Citation Format: Ana L. Bezazian, Maria Amanda Escribano, Marco A. Diaz Gutierrez, Mariel Fusco, Paula Roselló, Juan Braga Menendez, Esteban J. Fiore, Juan M. Bayo Fina, Manglio M. Rizzo, Mariana Malvicini. 4-Methylumbelliferone (4Mu) turns CD133+ lung cancer stem cells (CSCs) more susceptible to conventional chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3105.

Introduction: Breast cancer is the tumor with highest incidence and mortality in women in Argentina. Hormonal receptors (HR) and HER2 are the most important prognostic and predictive factors. It is suggested that estrogen receptors (ER), progesterone receptors (PR) and HER2 expression can vary during tumor progression and metastases development. Published evidence has reported discordance between primary tumors and its metastases ranging from 15-54% for HR and HER2 overexpression. A similar discordance situation may exist among primary tumor (PT) and its axillary nodal metastases (NM) Objective: To describe the expression and discordance of ER, PR and HER2 in PT and its synchronic NM Material and methods: Prospective analysis of surgical breast cancer patients (pts) at Instituto Alexander Fleming (Sept 2013 to Feb 2016). HR were analyzed by immunohistochemistry (IHC) according to CAP protocols; values ≥ 10% were considered positive. HER2 overexpression was defined by 3+ IHC or positive FISH. Paired t test was used to compare mean using Prims 5 software. Results: In 587 breast cancer surgeries, 190 pts presented NM. HR and HER2 analysis was performed in 101 paired samples. Median age was 51 years (r 25-83). Mean tumor size was 3,3 ± 0,2 cm. 0,99% (1) were stage I, 68,3% (69) stage II and 30,7% (31) stage III. Most frequent histologic subtype was ductal carcinoma (66.3%). 78.2% presented lymphovascular invasion. Median positive nodes were 2 (r 1-21). Paired samples allowed ER analysis in 99 cases, PR in 98 and HER2 in 96; 8 NM were Her2++; FISH analysis was inconclusive in 4 of them due to insufficient tissue. No differences were observed on ER between PT and NM (72% vs 71.1%, OR: 0,91, IC95 -3.2-5.1; p>0,05), nor PR expression (52.1% vs 54,5%, OR: -2.1, IC95 -7.1-3.01; p>0,05). PT were ER+ in 86.1% of the cases; NM were ER+ in 82.2%. Regarding PR, PT were 74.3% PR+ and NM were 76.2% PR+. 28 of the 101 pts (27.7%) were discordant. 5 pts with ER+ PT had ER- NM, and 3 pts had PT ER- but ER+ NM, representing a 7.9% of discordance. 4 of 75 pts with PR+ in PT were PR- in NM, while 8 of 26 pts were PR- in PT but PR+ in NM. Of the 13 HER2+ pts, 2 (15%) did not present overexpression in NM. On the other hand, 6 (7%) of the 83 HER2- PT were HER2+ in NM. 4 of 9 pts had PT RH and Her2- (TN), but NM RH and/or Her2+. Discussion: Tumor heterogeneity is an important issue that may affect clinical decisions. Axillary nodes are the first metastatic site for breast cancer and different studies have shown discrepancy between PT and NM. We described a discordant expression in ER, PR and HER2 of 8%, 12% and 9% respectively. These differences could be due to technical reasons, intratumor heterogeneity and/or a different cellular phenotype. Although the clinical importance of these changes are not completely understood, NM status could bring important prognostic and therapeutic information defining a particular group of patients in which a specific therapeutic strategy could influence long term results. In fact, in our series 44% of TN tumors presented NM with a therapeutic target, either HR or HER2. We therefore confirm that pathological analysis of NM may bring up additional information that could be useful in a prognostic or therapeutic point of view. Citation Format: Rizzo MM, Mando P, Perez de la Puente C, Maino M, Ponce C, Fabiano V, Pombo MT, Loza CM, Costanzo MV, Nervo A, Nadal J, Colo F, Chacon RD. Her2 and hormonal receptor analysis in breast cancer synchronic node metastases could add therapeutic information [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-40.

Nivolumab was the first anti-programmed cell death 1 drug approved in Argentina for non-small-cell lung cancer treatment in the second-line setting.The present study was a multicenter, observational, retrospective study of patients with progression to stage IV NSCLC during platinum-based chemotherapy who had received nivolumab monotherapy in a drug-expanded access program in Argentina.The data from 109 patients were assessed retrospectively for safety and clinical outcomes. The follow-up period was 8.83 months (interquartile range, 3.4-12.67); 57.8% were men, 29.4% were current smokers, and 78.0% had a diagnosis of nonsquamous cell cancer. The median number of chemotherapy lines before nivolumab was 2 (range, 1-4). Also, 59.6% had received radiotherapy and 89% had received platinum-based chemotherapy. The drug-related toxicity rate was 78.9%, the grade 2-3 toxicity rate was 28.4%, and 33.9% of patients had required corticosteroids. The treatment response was evaluated in 104 patients. The best response was a complete response in 2 (2%), partial response in 28 (27%), stable disease in 33 (32%), and progressive disease in 41 (39%). Univariate analysis revealed that the absence of corticosteroid use (P = .034), toxicity grade 1-3 (P = .0025), and performance status of ≤ 1 (P = .049) were associated with longer disease-free survival, performance status of ≤ 1 (P .001), and toxicity grade 1-3 (P = .001) were associated with longer overall survival. On multivariate Cox regression analysis, toxicity grade 1-3 (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.24-0.81; P = .008) and age ≤ 50 years (HR, 0.28; 95% CI, 0.13-0.61; P = .001) were associated with longer progression-free survival and corticosteroid use was associated with shorter progression-free survival (HR, 2.06; 95% CI, 1.22-3.48; P = .007).The use of nivolumab in the real world setting in patients with heavily pretreated NSCLC was well tolerated and showed promising clinical efficacy. The performance status, use of corticosteroids, and immune-mediated toxicity seem to be the conditions that can affect the clinical outcomes.

Patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) have shown benefit from anti-PD-1 therapies. However, not all patients experience tumor shrinkage, durable responses or prolonged survival, demonstrating the need to find response markers. In blood samples from NSCLC and RCC patients obtained before and after anti-PD-1 treatment, we studied leukocytes by complete blood cell count, lymphocyte subsets using flow cytometry and plasma concentration of nine soluble mediators, in order to find predictive biomarkers of response and to study changes produced after anti-PD-1 therapy. In baseline samples, discriminant analysis revealed a combination of four variables that helped differentiate stable disease-response (SD-R) from progressive disease (PD) patients: augmented frequency of central memory CD4+ T cells and leukocyte count was associated with response while increased percentage of PD-L1+ natural killer cells and naive CD4+ T cells was associated with lack of response. After therapy, differential changes between responders and non-responders were found in leukocytes, T cells and TIM-3+ T cells. Patients with progressive disease showed an increase in the frequency of TIM-3 expressing CD4+ and CD8+ T cells, whereas SD-R patients showed a decrease in these subsets. Our findings indicate that a combination of immune variables from peripheral blood (PB) could be useful to distinguish response groups in NSCLC and RCC patients treated with anti-PD-1 therapy. Frequency of TIM-3+ T cells showed differential changes after treatment in PD vs SD-R patients, suggesting that it may be an interesting marker for monitoring progression during therapy.

En el carcinoma de pulmón de células no pequeñas (CPCNP), la activación de ALK se produce por la formación de genes de fusión. El perfil clínico donde ocurre con más frecuencia corresponde a pacientes jóvenes, mayormente mujeres, no fumadores, histología de adenocarcinoma y ausencia de mutaciones de EGFR y KRAS. Su presencia se describe en el 3-10% de los CPCNP. La importancia de la determinación de ALK radica en que identifica un subgrupo de pacientes con un comportamiento biológico diferente, en los cuales el tratamiento con inhibidores específicos, como el crizotinib, ceritinib o alectinib, es más eficaz que los convencionales. Las alteraciones moleculares de ALK pueden identificarse por hibridación in situ (ISH), por inmunohistoquímica (IHQ) y por RT-PCR, aunque el FISH es el procedimiento diagnóstico de referencia a nivel clínico. Se examinaron 308 casos de CPCNP y se compararon los resultados por FISH e IHQ. De los 8 (3%) identificados con expresión positiva, sólo 6 presentaron el rearreglo de ALK. Se presentan dos casos clínicos con ALK positivo por IHC y FISH negativo, uno presentó respuesta al tratamiento dirigido y otro no. A pesar de que el FISH es el gold standard, se acepta el uso de IHQ ya sea para definir conducta como único test o para screening y ulterior confirmación por FISH en los casos positivos. Estos dos casos con distinta respuesta al tratamiento con IHQ positiva pero FISH negativo, indican la ausencia de pautas, requiriendo de más conocimiento en el futuro para optimizar las conductas médicas.

Purpose: Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden. Experimental Design: IL8 levelsweremonitored by sandwich ELISAs incultured tumor cells supernatants, tumor-xenograftedmice serum, and in samples from126 patients with cancer. Wecorrelated IL8 serumlevels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis. Results: IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non-small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract. Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance. Fil: Sanmamed, Miguel F.. Universidad de Navarra; España Fil: Carranza Rua, Omar. Universidad de Navarra; España Fil: Alfaro, Carlos. Universidad de Navarra; España Fil: Oñate, Carmen. Universidad de Navarra; España Fil: Martín Algarra, Salvador. Universidad de Navarra; España Fil: Perez, Guiomar. Universidad de Navarra; España Fil: Landazuri, Sara F.. Universidad de Navarra; España Fil: Gonzalez, Alvaro. Universidad de Navarra; España Fil: Gross, Stefanie. University Hospital Erlangen; Alemania Fil: Rodriguez, Inmaculada. Universidad de Navarra; España Fil: Muñoz Calleja, Cecilia. Universidad Autonoma de Madrid. Hospital Universitario de la Princesa; España Fil: Rodríguez Ruiz, María. Universidad de Navarra; España Fil: Sangro, Bruno. Universidad de Navarra; España Fil: López Picazo, José M.. Universidad de Navarra; España Fil: Rizzo, Manglio Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pascual, Juan I.. Universidad de Navarra; España Fil: Andueza, Maria Pilar. Universidad de Navarra; España Fil: Perez Gracia, Jose Luis. Universidad de Navarra; España Fil: Melero, Ignacio. Universidad de Navarra; España

e20637 Background: To compare survival outcomes of patients with advanced or metastatic NSCLC who received immunotherapy at first, second or beyond versus matched patients receiving standard chemotherapy. Methods: A retrospective multicenter international cohort study of 296 patients with unresectable/ metastatic NSCLC treated with immunotherapy either as first, second, third or fourth line was conducted. A matched comparison with a historical cohort of first line chemotherapy was conducted. Results: Median age was 64 years (Range 34-90) and 40.2% were female patients. 91.2% of patients had an ECOG performance score ≤ 1. Immunotherapy as first line was given to 39 patients (13.7%), second line to 140 (48.8%), and as third line and beyond to 108 (37.6%). Median overall survival was 12.7 months (95% CI 9.67-14 months) and progression-free survival was 4.27 months (95% CI 3.97-5.0). Factors associated with increased survival included treatment as first-line (p < 0.001), type of response (p < 0.001) and PD-L1 status (p = 0.0039). Compared to the historical cohort, immunotherapy proved to be superior in terms of OS (p = 0.05) but not PFS (p = 0.2). Conclusions: Patients who receive immune checkpoint inhibitors as part of their treatment for NSCLC have better OS compared with matched patients treated with standard chemotherapy, regardless treatment line.

El cáncer de mama es una de las enfermedades más frecuentes en todo el mundo. La amplificación del proto-oncogén HER2 se presenta en 20-25% de los tumores de mama. TDM-1 es un conjugado anticuerpo-quimioterápico. Se realizó en forma retrospectiva, observacional y descriptiva un análisis de los datos de pacientes con diagnóstico de cáncer de mama metastásico HER2 positivo, que realizaban y/o habían realizado tratamiento con dicho fármaco. Se evaluaron 27 mujeres. La indicación de TDM-1 fue en 7.4% (2) en primera línea, 37% (10) en segunda línea, y 55.5% (15) en líneas posteriores, con un tiempo a la progresión de 7.44 meses (IC: 4.33-NC) para el global de pacientes, tasa de respuesta objetiva de 44% y se constataron 7 (26%) toxicidades G3-4.

In recent years immunotherapy has revolutionized the treatment of patients with advanced cancer. The increased knowledge in the tumor immune-biology has allowed developing rational treatments by manipulation of the immune system with significant clinical impact. This rapid development has significantly changed the prognosis of many tumors without treatment options up to date. Other strategies have explored the use of therapeutic vaccines based on dendritic cells (DC) by inducing antitumor immunity. DC are cells of hematopoietic origin, constitutively expressing molecules capable to present antigens, that are functionally the most potent inducers of the activation and proliferation of antigen specific T lymphocytes. The CD8+ T cells proliferate and acquire cytotoxic capacity after recognizing their specific antigen presented on the surface of DC, although only some types of DC can present antigens internalized from outside the cell to precursors of cytotoxic T lymphocytes (this function is called cross-presentation) requiring translocation mechanisms of complex antigens. The induction of an effective adaptive immune response is considered a good option given its specificity, and prolonged duration of response. The DC, thanks to its particular ability of antigen presentation and lymphocyte stimulation, are able to reverse the poor antitumor immune response experienced by patients with cancer. The DC can be obtained from various sources, using different protocols to generate differentiation and maturation, and are administered by various routes such as subcutaneous, intravenous or intranodal. The wide variety of protocols resulted in heterogeneous clinical responses.

We have recently shown that systemic administration of low molecular weight hyaluronan (LMW HA) significantly reduces colorectal carcinoma (CRC) growth in vivo. The elicited response is partially mediated by activated dendritic cells (DC). To potentiate the ability of DC loaded with whole tumor lysate (DC/TL) to induce immunity against CRC in mice, we aimed to study the effects of preconditioning DC with LMW HA for therapeutic vaccination. LMW HA improved maturation of ex vivo generated DC, increased IL-12, decreased IL-10 production, and enhanced a MLR activity in vitro. Although TNF-α showed a similar capacity to mature DC, preconditioning of DC/TL with LMW HA increased their ability to migrate in vitro toward CCL19 and CCL-21 in a CD44- and a TLR4-independent manner; this effect was superior to Poly(I:C), LPS, or TNF-α and partially associated with an increase in the expression of CCR7. Importantly, LMW HA dramatically enhanced the in vivo DC recruitment to tumor-regional lymph nodes. When these LMW HA-treated CRC tumor lysate-pulsed DC (DC/TL/LMW HA) were administered to tumor-bearing mice, a potent antitumor response was observed when compared to DC pulsed with tumor lysate alone and matured with TNF-α. Then, we showed that splenocytes isolated from animals treated with DC/TL/LMW HA presented a higher proliferative capacity, increased IFN-γ production, and secreted lower levels of the immunosuppressive IL-10. Besides, increased specific CTL response was observed in DC/TL/LMW HA-treated animals and induced long-term protection against tumor recurrence. Our data show that LMW HA is superior to other agents at inducing DC migration; therefore, LMW HA could be considered a new adjuvant candidate in the preparation of DC-based anticancer vaccines with potent immunostimulatory properties.

Oncological and ophthalmological diseases are increasingly treated with antiangiogenic agents. These agents have different intensities and duration of effects that should be considered to choose the most suitable therapy. Our purpose was to evaluate the synergistic effect of two drugs, jointly administered as a pharmaceutical compound, in two animal models. Corneal neovascularization was induced in three groups of nine white New Zealand rabbits, applying a filter paper disk soaked in 1 M NaOH on the central cornea (Ormerod et al., Invest Ophthalmol Vis Sci 30:2148–2153, 1989). Group one was treated immediately after injury with intravenous Suramab, compound of Bevacizumab + Suramin, and group two with intravenous Bevacizumab. A third group of non-treated rabbits was included as control group. Digital photographs were taken at days 9, 15, 21, and 35. Neovessel index (NVI) was calculated using the Image J Program. Neovessels formation was quantified and given a score from 0 to 4 to each quadrant according to the centripetal growth of the longest vessel. Colorectal animal model: 6- to 8-week-old male BALB/c mice were inoculated with cancer cells. Seven days after tumor inoculation, four groups of BALB/c mice were treated with intravenous Bevacizumab (n = 9); intravenous Suramin (n = 10); intravenous Suramab (n = 10); and intravenous saline solution (n = 4). Tumor growth was assessed twice weekly by caliper measurement. The NVI was remarkably inferior in the group of rabbits treated with intravenous Suramab compared with controls after 35 days of follow-up. A greater inhibitory effect was obtained with Suramab compared to that obtained with Bevacizumab. Suramab significantly reduced tumor volume and prolonged survival of mice compared to controls. Suramab strongly reduced neovascularization in a rabbit model of corneal angiogenesis and induced a potent antitumoral effect in mice.

Cirrhosis is characterized by an excessive accumulation of extracellular matrix components including hyaluronic acid (HA) and is widely considered a pre-neoplastic condition for hepatocellular carcinoma (HCC). 4-methylumbelliferone (4MU) is an inhibitor of HA synthesis and has anti-cancer activity in an orthotopic HCC model with underlying fibrosis. Our aim was to explore the effects of HA inhibition by 4MU orally administered on tumour microenvironment. Hepa129 tumour cells were inoculated orthotopically in C3H/HeJ male mice with fibrosis induced by thioacetamide. Mice were orally treated with 4MU. The effects of 4MU on angiogenesis were evaluated by immunostaining of CD31 and quantification of proangiogenic factors (VEGF, IL-6, CXCL12). IL-6 was also quantified in Hepa129 cells in vitro after treatment with 4MU. Migration of endothelial cells and tube formation were also analyzed. As a result, 4MU treatment decreases tumour growth and increased animal survival. Systemic levels of VEGF were significantly inhibited in 4MU-treated mice. Expression of CD31 was reduced after 4MU therapy in liver parenchyma in comparison with control group. In addition, mRNA expression and protein levels of IL-6 and VEGF were inhibited both in tumour tissue and in non-tumoral liver parenchyma. Interestingly, IL-6 production was dramatically reduced in Kupffer cells isolated from 4MU-treated mice, and in Hepa129 cells in vitro. Besides, 4MU was able to inhibit endothelial cell migration and tube formation. In conclusion, 4MU has antitumour activity in vivo and its mechanisms of action involve an inhibition of angiogenesis and IL-6 production. 4MU is an orally available molecule with potential for HCC treatment. Fil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bayo Fina, Juan Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Tirado González, Irene. Universität zu Berlin; Alemania Fil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Purpose Several studies have shown that estrogen receptor (ER) and progesterone receptor (PR) expression and human epidermal growth factor receptor 2 (HER2) expression may vary during tumoral progression. We aimed to describe and compare ER, PR, and HER2 expressions in primary breast tumors and synchronic axillary nodal metastases, and evaluate phenotypic correlations between them. Methods Patients were identified prospectively through surgical procedures between September 2013 and July 2016. The status of ER, PR, HER2, and Ki-67 were pathologically analyzed in breast cancers and axillary nodal metastases; these patients were classified based on the breast cancer phenotypes into five subgroups. Results Synchronic axillary nodal metastases were observed in 127 patients. In breast cancers and nodal metastases, correlation analyses of ER, PR, and Ki-67 expression showed a statistical dependence and concordance between these samples was unambiguously demonstrated through Bland-Altman plots for each determination. Primary breast tumors were classified as follows: luminal A, 41.6%; luminal B, 40.0%; luminal B/HER2, 9.6%; HER2, 2.4%; triple negative, 6.4%. Alterations in phenotype were observed in 28% of patients. The most frequent phenotypic alteration was from luminal B to A (36.4%). Ten cases (30.3%) showed alterations with therapeutic implications; six gained HER2 overexpression, and four, hormonal receptor (HR) expression. A moderate strength of agreement (Cohen's κ coefficient, 0.59; 95% confidence interval, 0.48–0.71) was observed. In multivariate analyses, high histologic grade (odds ratio [OR], 2.79; p