Search

The change towards intensive agriculture has led to an increase in the use of pesticides. In addition, legacy pesticides, such as organochlorines are still present in the environment. Ten Franciscana dolphins were accidentally killed by netting in a coastal area of Argentina in Buenos Aires province. From these animals, organochlorine, organophosphate and pyrethroid pesticides were analyzed in liver, bubbler and melon tissues. The concentrations of Σendosulfan ranged from not detectable values (nd) to 3539 ng g−1 lw, with the maximum level in melon tissue. DDE was present in 60% of all samples at concentrations from nd to 6672 ng g−1 lw, indicating historical DDT contamination. The presence of endosulfan and heptachlor in a nursling calf indicated a transfer of these pesticides through lactational and placental transport. The concentrations of organophosphates and pyrethroids were below the limit of detection, reflecting the low persistence of these compounds. Fil: Romero, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina Fil: Polizzi, Paula Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: Chiodi, L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: Medici, Sandra Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina Fil: Blando, M.. Laboratorio Bioquimico Mar del Plata Sa; Argentina Fil: Gerpe, Marcela Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina

488 Background: Immune checkpoint therapy can produce durable anti-tumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of immune checkpoint therapy in mUCC, we lack predictive biomarkers to guide patient selection. Therefore, there is a critical need to develop clinically useful biomarkers to refine patient selection. The single biomarker studies either focused on tumor mutations or immune response biomarkers, which may limit predictive power due to lack of integration between cancer cell biology and immune cell responses. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Methods: We performed retrospective multi-platform immuno-genomic analyses of pre-treatment tumor tissues in a discovery cohort (n = 31). Next, we tested the clinical relevance of ARID1A mutation and pre-treatment CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). Additionally, we performed reverse translational studies using murine model of bladder cancer to demonstrate direct association of the biomarkers in anti-PD-(L)-1 mediated anti-tumor immunity. Results: We identified genomic mutation of AT-rich interactive domain-containing protein 1A ( ARID1A) in tumor cells and expression of immune cytokine CXCL13 in the pre-treatment tumor tissues as two predictors of clinical responses. We found that ARID1A mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data, n = 217; ARID1A data, n = 139, and IMvigor210, CXCL13 data, n = 348; ARID1A data, n = 275). Further, reverse translational studies revealed that CXCL13−/− tumor-bearing mice were resistant to immune checkpoint therapy whereas ARID1A knockdown enhanced sensitivity to immune checkpoint therapy in a murine model of bladder cancer. We then interrogated CXCL13 expression plus ARID1A mutation as a combination biomarker in predicting response to immune checkpoint therapy in CheckMate275 and IMvigor210. Combination of the 2 biomarkers in baseline tumor tissues showed improved OS compared to either single biomarker. Conclusions: Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A mutation may improve patient selection in mUCC for immune checkpoint therapy.

4098 Background: In HCC, surgical resection is associated with high recurrence rate, and no effective neoadjuvant or adjuvant therapies currently exist. On the basis of of previous reports on the efficacy and safety of anti–PD-1 (nivolumab) and anti–CTLA-4 (ipilimumab) antibodies against HCC, we initiated a randomized pilot trial of perioperative immunotherapy for resectable HCC. Methods: This is a randomized, phase II pilot trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as pre-operative treatment for patients (pt) with HCC who are eligible for surgical resection. Pt are given nivolumab 240 mg every 2 weeks (wk) for a total of 6 wk. Pt in Arm B are treated concurrently with ipilimumab 1 mg/kg every 6 wk. Surgical resection occurs within 4 weeks after last cycle of therapy. Pt continue adjuvant immunotherapy for up to 2 years after resection. Primary objective is the safety and tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, complete response rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: 17 pt were enrolled at the time of interim analysis (8 in Arm A, 9 in Arm B) and 14 were evaluable. Most pt (53%) were 60-70yo, and males (70%). 6 pt were HCV-positive and 4 had chronic hepatitis B. 14 pt proceeded with resection as planned; surgery was aborted for 2 pt (1 for frozen abdomen and 1 for development of contralateral liver nodule). One is still receiving preoperative therapy. Pathologic complete response (pCR) was observed in 4/14 evaluable pt – 2 in Arm A and 2 Arm B (29% pCR rate). 4 pt in Arm B and 1 in Arm A experienced grade 3 or higher toxicity prior to surgery. Conclusions: We report a pCR rate of 29% in an interim analysis of a phase II pilot trial of perioperative immunotherapy for resectable HCC. Treatment was safe and surgical resection was not delayed. The study is ongoing and results may contribute to a paradigm shift in the perioperative treatment of HCC. Clinical trial information: NCT03222076.

4501 Background: Cytoreductive surgery (CS) including cytoreductive nephrectomy and metastasectomy provides clinical benefits to patients with MRCC. However, CS has not been evaluated in the setting of immune checkpoint (IC) therapy. We performed a pre-surgical/biopsy trial to evaluate biological and clinical activity of nivo +/- (bev or ipi) in patients with MRCC. Methods: In this open-label, randomized trial (NCT02210117), patients with MRCC w/o prior IC therapy and anti-VEGF therapy were randomized 2:3:2 to receive nivo (3mg/kg q2wks x3), nivo + bev (10mg/kg q2wks x3) or nivo + ipi (1mg/kg q3wks x2), followed by CS or Bx, and then nivo maintenance therapy up to 2 yrs. Clinical response per RECIST criteria was assessed at ≥12 wks. Pre- and post-treatment blood and tumors were obtained for correlative studies. Results: All of 105 patients have been accrued and 104 are evaluable for response. For all patients, best overall response (BOR = complete response [CR] + partial response [PR]) including surgery effect was 55% nivo, 44% nivo + bev, 43% nivo + ipi. Median PFS (95% confidence interval) was 14.5 months (5.5, not reached [NR]) nivo, 7.6 (4.8, 8.9) months nivo + bev, 7.5 (2.0, 12.4) months nivo + ipi. Overall survival (OS) at one year was 86% nivo, 73% nivo + bev, 83% nivo + ipi. Grade 3 or higher toxicities related to therapy were 38% for nivo, 42% for nivo + bev (including 18% hypertension), and 47% for nivo + ipi. For patients with CS, BOR including surgery effect was: 86% nivo, 88% nivo + bev, and 69% nivo + ipi. Median PFS was 17.3 months (6.1, NR) nivo, 7.6 (5.7, 10.3) months nivo + bev, 8.9 (2.9, 23.0) months nivo + ipi. OS at one year was 100% nivo, 94% nivo + bev, 92% nivo + ipi. Median OS has not yet reached with a median follow-up of 24.6 months. Immune and gene profiling analyses demonstrate: 1) tumor infiltrating CD8 T cells correlate with clinical responses to nivo or nivo + bev, but not to nivo + ipi; 2) tumor IFN pathway gene expression correlates with responses; and 3) PD-L1 status, tumor mutation or mutation burden, neoantigens did not correlate with response. Conclusions: IC therapy plus CS is safe and beneficial to patients with MRCC and therefore, warrants testing, along with a few correlative biomarkers, in a larger phase 3 trial. Clinical trial information: NCT 02210117.

Numerose evidenze scientifiche incoraggiano il consumo di frutta e verdura per prevenire malattie cardiovascolari e tumori. Tuttavia il loro consumo rimane sotto il limite consigliato dall'Organizzazione Mondiale della Sanità. Per questo motivo i consumatori e le aziende alimentari sono alla ricerca di bevande salutistiche "ready-to-drink". I frutti di P. mahaleb, ricchi di composti salutistici (antocianine, flavonoli e cumarine) non sono commestibili a causa del loro sapore amaro, ma l'impiego biotecnologico della fermentazione controllata, utilizzata per migliorare le qualità organolettiche, salutistiche e di serbevolezza di frutta e verdura, potrebbe consentirne l'utilizzo come nuova fonte di probiotici e phytochemicals.

Cancer stem cells (CSCs) are proposed to play a key role in development and survival of many tumor types. In this study, we have isolated a population of cells that possess characteristics of CSC both in-vitro and in-vivo from prostate tumors of one-year-old Hi-Myc mice. These cells, called HMVP2, are LinnegSca-1highCD49f high by flow cytometry (FC) analyses, with high CD44 and CD29 expression. Immunofluorescence (IF) analysis of HMVP2 cells showed positive staining for CK14, Sca-1 and CD49f while staining negative for CK8, suggesting basal-epithelial characteristics. HMVP2 cells were able to form spheroids and both cells and spheres were able to generate allograft tumors following s.c injection. After four days of culture, FC analysis of the spheres revealed a gradual transition from LinnegSca-1highCD49f high expression to LinnegSca-1lowCD49f low indicative of possible differentiation to a more luminal-epithelial cell-type, while a part of the cells retained the original Linneg Sca-1highCD49f high expression. Moreover, additional cell subpopulations expressing Linpos markers, and changes on the levels of CD34, CD44 and CD29 on LinnegSca-1highCD49f high and LinnegSca-1lowCD49f low cells were also confirmed by FC, suggesting a differentiation to a hematopoietic/vessel and pre-adipocyte cell-subtypes. IF staining of the spheroids and grafted tumors revealed staining for Sca-1, CD49f, CK8 and CK14 also verifying the presence of two or more cell subpopulations. Two additional cell lines (HMVP2-A1 and HMVP2-A2) were isolated from the original grafted tumors following in vivo passage also showing CSC characteristics. Concurrently, we also isolated cells from the VP of 6 months old Hi-Myc mice (HMVP1) and FVB/N NTg mice (NMVP) having less aggressive growth properties compared to the other three cell lines. Expression of the AR was lower in HMVP2, HMVP2A1 and HMVP2A2 cells compared to NMVP and HMVP1 cells. The expression of vimentin was increased in cells from Hi-Myc mice compared to the NMVP cells. Collectively, our data suggest that single cells derived from prostate tumors in Hi-Myc mice, showing basal-epithelial progenitor characteristics, can differentiate to mixed cell populations and form tumors. These cells provide novel tools for studying tumor development as wells for analysis of novel preventive and/or therapeutic agents for prostate cancer. Citation Format: Jorge M. Blando, Achinto Saha, Irina Fernandez, Kaoru Kiguchi, John DiGiovanni. Lin neg Sca-1high CD49f high prostate cancer cells derived from Hi-Myc mice are tumor-initiating cells with basal-epithelial characteristics and differentiation potential in vitro and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2044. doi:10.1158/1538-7445.AM2014-2044

The antimicrobial resistance patterns and plasmid profile analyses for 30 Shigella spp. isolated in Cordoba, Argentina, were determined. Most strains were resistant to multiple antibiotics, particularly traditional agents such as ampicillin, chloramphenicol and trimethoprim. All isolates harboured at least one plasmid (range 1-12), the plasmid profiles differing in every case. Nineteen strains transferred all or some of their resistance determinants by conjugation.