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Background: Residual disease (RD) following neoadjuvant chemotherapy (NAC) in early HER2-negative breast cancer (BC) remains an unmet medical need. However, no therapies to date have tested their activity directly in chemo-resistant RD. Here, we hypothesized that combining an oncolytic virus such as T-VEC with atezolizumab may offer clinical benefit in patients (pts) with RD after standard NAC. To our knowledge, PROMETEO is the first trial that examines the activity of immunotherapy in pts with RD prior to surgery. Methods: PROMETEO (NCT03802604) is a single-arm, open-label, multicenter phase II trial. Women with triple-negative BC (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) BC with baseline (i.e., before NAC) ki67 ≥ 20% were eligible. RD was confirmed with a magnetic resonance imaging (MRI) showing a tumor diameter ≥ 10 mm and a core-biopsy detecting the presence of invasive cells. Before surgery, T-VEC was administered intratumorally on week 1 (106 pfu/mL), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) was administered intravenously every 2 weeks for 4 infusions, starting at week 4. Surgery was performed in < 3 weeks after completing the treatment. The primary objective was to evaluate the efficacy of the combination, measured by the rate of residual cancer burden (RCB) class 0/1 at surgery. Tumor samples collected at 5 timepoints (before NAC, during screening period, after first dose of T-VEC, after first dose of T-VEC and atezolizumab and at surgery) were mandatory to assess gene expression, tumor-infiltrating lymphocytes (TILs), immune cells PD-L1 IHC (SP142), tumor mutational burden (TMB) by FoundationOne and other translational endpoints. Results: Between Dec 2018 to Feb 2022, 28 pts were enrolled: 20 pts with HR+/HER2- disease and 8 pts with TNBC. Median age was 47 (range 31-71) and 71% of pts were premenopausal. At diagnosis before NAC, clinical stage II disease represented 60.7%, cN+ 60.7%, median Ki-67 was 37.5% (range 20%-95%), high TILs (≥10%) 37%, median TMB was 3 (0-19) and only 1 of 27 pts (3.7%) had a PD-L1-positive tumor. After NAC, mean tumor size by MRI was 28.3 mm (10-93). Two pts discontinued from the trial (1 withdrawal of consent and 1 COVID infection). The completion of 5 cycles of treatment was achieved by 73% of pts. The overall RCB-0/1 rate was 25% (7 of 28, 95% IC 10.7 – 44.9%), all with RCB 0 (pathologic complete response [pCR]). The pCR rate was 30% in HR+/HER2- disease and 12.5 % in TNBC. Radiological response by MRI was achieved by 3 of 28 pts (10.7%). Interestingly, none of the 7 pts with a pCR had radiological response (stable disease n=5, progressive disease [PD] n=2). Six pts (21.4%) had radiological PD and had RCB 2/3. Overall, 27 (96%) patients had at least one treatment-emergent adverse event (TEAE) of any grade. Most common grade 1 or 2 AEs were fever (11 pts, 39.3%), ALT increased (9 pts, 32.1%), AST increased (8 pts, 28.6%), arthralgia (6 pts, 21.4%) and anemia (6 pts, 21.4%). Grade 3 reversible neutropenia occurred in 1 patient. Across all pts, significant increases (p< 0.001) in TILs, immune genes and immune PDL1+ cells were observed after 1 dose of TVEC, 1 dose of the combination and at surgery. Intrinsic subtype changes at surgery occurred in 73.1% of cases, mostly (46.1%) Luminal A/B converting to Normal-like. At surgery, 19 of 26 (73.1%) of tumors were PDL1+. Conclusions: Two months of T-VEC in combination with atezolizumab induced a pCR in a subgroup of pts with chemoresistant HER2- breast cancer. This effect is probably related to the immune activation provoked by the combined treatment. Interestingly, a high discrepancy was observed between the pre-surgical radiological imaging and the actual surgical pathological report. Pre-operative window-of-opportunity trials in this context might provide important clues regarding the activity of novel treatment strategies. Citation Format: Tomás Pascual, Maria Vidal, Juan Miguel Cejalvo, Estela Vega, Esther Sanfeliu, Sergi Ganau, Ana Julve, Esther Zamora, Ignacio Miranda, Ana Delgado, Begoña Bermejo, Luis de la Cruz-Merino, Manel Juan, Patricia Galván, Xavier Gonzalez-Farré, Juan Manuel Ferrero-Cafiero, Patricia Villagrasa, Mafalda Oliveira, Aleix Prat. PD11-04 Primary results of SOLTI-1503 PROMETEO phase 2 trial of Combination of Talimogene Laherparepvec (T-VEC) with Atezolizumab in patients with residual breast cancer after standard neoadjuvant multi-agent chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-04.

La Crisis sanitaria provocada por la pandemia del COVID-19 agravo la situación económica de Ecuador, el desempleo aumento hasta 34,5% sumergiendo a los ecuatorianos a la necesidad de buscar un trabajo de forma urgente, optando por trabajos de temporada o eventuales, es aquí donde se centra la presente investigación, debido a la falta de cultura laboral para la elaboración de contratos eventuales, contratos que son manejados de manera informal, y en muchas ocasiones los empleadores desconocen este tipo de contratos, por ello la investigación consistió en el análisis de los contratos eventuales dentro del marco del derecho laboral provisto por el código de trabajo ecuatoriano, haciendo uso del método observacional, con un enfoque Critico-descriptivo, realizado a través de una revisión legal y doctrinal, además se analizaran las propuestas de flexibilización laboral, que permitan fomentar sustancialmente el empleo en Ecuador, mediante una recopilación exploratoria de fuentes secundarias con información legal, doctrinal, científica y coyuntural relacionada a la naturaleza jurídica de los contratos eventuales, la investigación permitió concluir que los pagos de un 35 por ciento adicional para contratos eventuales y ocasionales socavan la voluntad de los empresarios en optar por este medio de contratación, provocando la necesidad de que las autoridades tomen cartas en el asunto para construir proyectos de ley que permitan rescatar el derecho laboral de todos los ecuatorianos.

Background: Simultaneous liver resection and peritoneal cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial today. The aim of the study was to analyze the postoperative outcomes and survival of patients with advanced metastatic colon cancer (peritoneal and/or liver metastases). Methods: Retrospective observational study from a prospective maintained data base. Patients who underwent a simultaneous peritoneal cytoreduction and liver resection plus HIPEC were studied. Postoperative outcomes and overall and disease free survival were analyzed. Univariate and multivariate analyses were performed. Results: From January 2010 to October 2022, 22 patients operated with peritoneal and liver metastasis (LR+) were compared with 87 patients operated with peritoneal metastasis alone (LR−). LR+ group presented higher serious morbidity (36.4 vs. 14.9%; p: 0.034). Postoperative mortality did not reach statistical difference. Median overall and disease free survival was similar. Peritoneal carcinomatosis index was the only predictive factor of survival. Conclusions: Simultaneous peritoneal and liver resection is associated with increased postoperative morbidity and hospital stay, but with similar postoperative mortality and OS and disease free survival. These results reflect the evolution of these patients, considered inoperable until recently, and justify the trend to incorporate this surgical strategy within a multimodal therapeutic plan in highly selected patients.

Purpose:To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer.Patients and Methods:PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2–4 prior lines of anti-HER2–based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes.Results:Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1–2 and 3–4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3–4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003).Conclusions:Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.

Supplementary Data

PDF file, 12332K, Supplementary Figure S1. Expression of NK-1R, NK-2R and SP in normal mammary epithelium. Supplementary Figure S2. Transactivation of HER2 by human tachykinins. Supplementary Figure S3. Dose-response effect of SP on HER2 activation. Supplementary Figure S4. Contribution of HER2 signaling to SP-induced MAPK activation. Supplementary Figure S5. Representative images of NK-1R immunohistochemistry in the tumors used for primary cultures. Supplementary Figure S6. Activation of HER2 under SP treatment in each primary culture derived from 19 primary breast tumors. Supplementary Figure S7. Overexpression of NK-1R in BC cells. Supplementary Figure S8. Mitotic index for the MDA-MB-231 and MDA-MB-453 xenograft tumors growth under the continuous exposure to SP. Supplementary Figure S9. Immunohistochemical analysis of the xenograft tumors treated with the NK-1R inhibitor L-733,060. Supplementary Figure S10. Acute and chronic effects of SP on cellular responses to anti-HER2 and anti-EGFR therapies. Supplementary Table S1. Statistical analysis for the correlation of NK-1R, NK-2R and SP expression levels. Supplementary Table S2. Statistical analysis for the correlation of NK-1R, NK-2R and SP expression levels. Supplementary Table S3. Clinical information of the cohort used to investigate the levels of circulating SP in healthy donors and breast cancer patients. Supplementary Table S4. Histopathologic information of the samples used Supplementary Table S5. IC50 obtained in the drug-response studies and combination index.

PDF file, 290K.

Crohn disease; Artificial intelligence; Three-dimensional imaging Enfermedad de Crohn; Inteligencia artificial; Imagen tridimensional Malaltia de Crohn; Intel·ligència artificial; Imatge tridimensional Aim The aim of this study is to demonstrate the added value of three-dimensional (3D) reconstruction models and artificial intelligence for preoperative planning in complex perianal Crohn's disease. MRI is the gold standard for diagnosis of complex perianal fistulas and abscess due to its high sensitivity, but it lacks high specificity values. This creates the need for better diagnostic models such as 3D image processing and reconstruction (3D-IPR) with artificial intelligence (AI) algorithms. Method This is a prospective study evaluating the utility of 3D reconstruction models from MRI in four patients with perineal Crohn's disease (pCD). Results Four pCD patients had 3D reconstruction models made from pelvic MRI. This provided a more visual representation of perianal disease and made possible location of the internal fistula orifice, seton placement in fistula tracts and abscess drainage. Conclusion Three-dimensional reconstruction in CD-associated complex perianal fistulas can facilitate disease interpretation, anatomy and surgical strategy, potentially improving preoperative planning as well as intraoperative assistance. This could probably result in better surgical outcomes to control perianal sepsis and reduce the number of surgical procedures required in these patients.

Background The combination of HP and a taxane increases progression-free survival (PFS) and overall survival (OS) in patients with HER2+ ABC. PIK3CA mut can occur in 30-35% of HER2+ tumors, independently of hormone receptor (HR) status. In an exploratory analysis from CLEOPATRA, patients with a tumor harboring a PIK3CA mut had a shorter PFS. The AKT inhibitor IPAT blocks the PI3K/AKT pathway and has activity in PI3K/AKT-altered tumors. Patients and Methods IPATHER (NCT04253561) is an open-label, single-arm, phase Ib study to evaluate the safety and preliminary efficacy of IPAT plus HP in patients with HER2+ ABC with a PIK3CA-mut (detected in tissue or plasma ctDNA in a Central Laboratory) who are candidates to receive maintenance HP after taxane discontinuation in the first line setting for a reason different to progressive disease. The primary objective is to characterize the safety and tolerability of IPAT in combination with HP, and to identify a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The study has two phases: a dose safety phase and a dose expansion phase. MTD is defined as the highest dose level at which ≤1 of 6 subjects experience a dose-limiting toxicity (DLT) during the first 28 days of treatment. DLT during first 28 days of therapy is defined as grade ≥3 diarrhea lasting more than 72 hours, grade ≥2 diarrhea lasting more than 5 days, and other non-hematologic or hematologic toxicities that are ≥ grade 3 and probably or definitely related to study therapy. Given the low risk for overlapping toxicities, the first cohort of the dose safety phase tested IPAT at 400 mg orally once daily D1-21 q28d and standard dose HP. Dose level -1 and -2 of IPAT were 300 mg and 200 mg in case dose de-escalation was needed. Loperamide was given as prophylaxis for diarrhea. In HR-positive tumors, endocrine therapy could be started after the DLT period. Here, we present the results of the dose safety phase of IPATHER. Results A total of 6 female patients with PI3KCA-mut/HER2+ ABC were included in the first dose safety cohort. Median age was 52 (41-78), most patients had ECOG 0 (66.6%), and 50% were postmenopausal. Five out of six patients (83.3%) had HR-negative tumors and visceral metastases. Patients received a median of 6 treatment cycles (range 4-7) with taxane plus HP. At the time of the data cut-off (28/02/2021), all the patients remained on treatment. Median follow up is 4 months (range 2-12). Treatment was well tolerated with no DLTs or grade 3/4 adverse events (AEs) observed during the DLT period or the rest of treatment period (Table 1). The most common treatment-related AEs were diarrhea (N=5, [83.3%]) and nausea (N=2,[33.3%]), mostly grade 1. There was no dose reduction and diarrhea was controlled with prophylactic loperamide. A partial response (PR) was observed in one patient, and 5 had stable disease. Of note, the addition of IPAT to HP in the patient with a PR deepened the response achieved during the induction phase with chemotherapy plus HP. Conclusion IPAT 400 mg orally once daily D1-21 q28d in combination with HP is well tolerated and has shown preliminary signs of efficacy. Given the favourable safety profile, the dose expansion phase testing IPAT 400 mg in combination with HP has started and will include 19 additional patients. Table 1.Adverse Events during treatment period related with study treatment (IPAT and/or HP).Adverse EventN AEsN patientsGrade 1Grade 2% (N=6)Diarrhea55 (83%)5083%Nausea32 (33%)2033Vomiting21 (17%)1017Anemia11 (17%)1033Lymphopenia11 (17%)1033Gastroesophageal reflux11 (17%)0117Dyspepsia11 (17%)1017Hyporexia11 (17%)1017 Citation Format: Mafalda Oliveira, Eva Ciruelos, Serafín Morales, Joaquín Gavilá, Vanesa Quiroga, Estela Vega, Javier Salvador Bofill, Alexandra Cortegoso, Fernando Henao, Pablo Tolosa, Jordi Canes, Patricia Villagrasa, Xavier Gonzalez Farré, Tomás Pascual, Cristina Saura. Solti-1507 IPATHER - A phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with pertuzumab and trastuzumab (HP) in patients with HER2-positive (HER2+) advanced breast cancer (ABC) and a PIK3CA mutation (mut): Results from the first safety cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-34.

Improved selection of cancer patients who are most likely to respond to immune checkpoint inhibitors remains an unmet clinical need. Recently, a positive correlation between levels of

Positive and negative regulators of innate immunity work together to maintain immune homeostasis. We previously discovered that HLH-30/TFEB is a critical transcription factor that positively regulates host defense genes upon S. aureus infection in C. elegans. However, repression of host defense genes and negative regulation of immunity remain poorly understood. In this study, we identified nhr-42 as a negative regulator of host defense genes functioning downstream of HLH-30/TFEB, with major implications in host survival and metabolism after infection. nhr-42 expression is induced in an HLH-30/TFEB dependent manner mostly in the pharynx upon infection. We find that animals lacking nhr-42 have higher expression of host defense genes, which enables enhanced survival after infection. Antimicrobials expressed in the pharynx such as abf-2, function downstream of nhr-42 to confer resistance to infection by mitigating pathogen burden. Furthermore, nhr-42 deficient animals are defective in lipid mobilization, having higher lipid stores compared to wild type animals after infection. nhr-42 therefore enables C. elegans to limit the host defense response and reallocate energy resources through lipid mobilization after infection. To our knowledge, this is the first report of a transcription factor that represses host defense genes in C. elegans.

Background: A previous phase 2 study in metastatic breast cancer compared treatment with intravenously delivered oncolytic reovirus, pelareorep (pela), in combination with paclitaxel (PTX) versus PTX alone. This study demonstrated a statistically significant improvement in overall survival (OS), without differences in objective response or progression-free survival. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive immune response triggered by pela. To test this hypothesis, and examine if pela can mediate the priming of an anti-tumor immune response, we designed a study called AWARE-1 (A window-of-opportunity study of pela in Early Breast Cancer), which is currently enrolling and for which initial translational research results are presented. Methods: AWARE-1 is evaluating the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, while atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five cohorts will be examined: Cohort 1: Hormone Receptor-positive/HER2-negative (HR+/HER2-neg) (10 patients), pelareorep + letrozole. Cohort 2: HR+/HER2-neg (10 patients), pelareorep + letrozole + atezolizumab. Cohort 3: Triple Negative Breast Cancer (TNBC) (6 patients), pelareorep + atezolizumab. Cohort 4: Hormone Receptor-positive/HER2-positive (HR+/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. Cohort 5: Hormone Receptor-negative/HER2-positive (HR-/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. The primary endpoint of the study is CelTIL score, a metric for quantifying the changes in tumor cellularity and infiltration of TILs, where an increase in CelTIL is associated with a favorable response to treatment. Tumor tissue was examined for pela replication, and changes to the TME were assessed by imaging mass cytometry (IMC), immunohistochemistry, and T cell receptor sequencing (TCR-seq). Peripheral blood was also examined by TCR-seq. Results: Detailed translational research results will be presented from patients in cohort 1, who received just pelareorep and letrozole. CelTIL score increased in 5/10 patients at day 3 biopsies and 6/10 patients at day 21 biopsies. Preliminary results show high levels of viral replication (>50% of tumor cells) while immunohistochemistry and IMC analysis revealed changes to the TME, with increases in CD8+ T cells and upregulation of PD-L1 at both day 3 and day 21 biopsies. Overall, preliminary data from cohort 1 of AWARE-1 demonstrate pela-mediated priming of an adaptive immune response. (NCT04102618) Citation Format: Luis Manso, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan Miguel Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose Luis Alonso, Alejandro Martínez, Rafael Villanueva, Juan Antonio Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca González, Rita Laeufle, Gerard Nuovo, Grey Wilkinson, Matt Coffey, Azucena González, Débora Martínez, Laia Paré, Fernando Salvador, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (REO-027, AWARE-1) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-08.

Background Hormone receptor–positive/HER2-negative (HR+/HER2-) breast cancer (BC) is associated with low % of stromal tumor-infiltrating lymphocytes (sTIL) and immune gene expression and poor response to immune checkpoint inhibitors. Evaluating the effect of letrozole and ribociclib (L+R) on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches for HR+/HER2- BCs. Here, we present an exploratory correlative analysis from CORALLEEN, a trial that evaluated the efficacy of L+R (vs. chemotherapy [CHT]) in patients with high-risk PAM50 Luminal B BC (Prat et al. Lancet Oncology. 2022). Methods CORALLEEN is a randomized exploratory study in postmenopausal women with operable stage I-III breast cancer, HR+/HER2- and Luminal B by Prosigna®. Patients were randomized 1:1 to receive either 6 cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole or CHT: 4 cycles of AC followed by 12 doses of weekly paclitaxel. The primary endpoint was the rate of PAM50 Risk of Relapse (ROR)-low score at surgery in each arm. Samples were prospectively collected at baseline, day 15, and surgery. sTILs score, ki67 IHC and gene expression analysis were determined in all available samples. Complete cell cycle arrest (CCCA) was defined as Ki67≤2.7%. Gene expression profiling by mRNA sequencing (RNAseq) was evaluated. We applied a collection of 194 immune- gene expression signatures (iGES), representing multiple biological pathways and cell types, including. Results 106 patients were randomly assigned to receive neoadjuvant L+R (n=52) or CTH (n=54). Overall, Ki67, sTILs and RNA-seq was available in 95.4%, 96.7% and 83.1% of the samples across the 3 time-points. In terms of cell-cycle inhibition, L+R achieved a significant decrease in Ki67 protein expression and led to higher rates of CCCA at 2 weeks (89.6% vs. 43.2%, p< 0.001) and surgery (45.9% vs 25.5%, P=0.054) compared with CHT. Interestingly, the 11-gene PAM50 proliferative score was significantly lower in tumors with CCAA than in those with non-CCCA (p< 0.001) after L+R, but not after CTH (p = 0.682). In contrast, tumors with CCCA after CHT had a significantly lower rate of tumor cellularity compared to tumors with non-CCAA (p = 0.002). This was not observed in the L+R arm (p=0.141). Compared to baseline, no clear and significant patterns in % of sTILs were observed at week 2 and surgery. However, % of TILs at surgery in tumors with CCCA after CHT was higher than in tumors with non-CCCA (median 15% versus 1%, p=0.017). This was not observed in the L+R arm (median 1% and 5%, p=0.584). Interestingly, this inverse relationship between immune infiltration and CCAA was further confirmed by RNA- CHT compared to tumors with non-CCCA, whereas 174 (89.7%) of iGES were upregulated (FDR< 5%) in tumors with non-CCCA after L+R compared to tumors with CCCA. Finally, L+R and CTH treatment at week 2 and surgery showed an increase in adaptive immune signatures indicative of activated T-cell and B-cell phenotypes; however, CTH was uniquely associated with increased cytokine signaling, enhanced antigen presentation, dendritic, granulocyte, macrophage and NK cells and decrease in Th17, Th2 and Treg cells. Conclusion In early-stage Luminal B breast cancer, L+R induce a potent anti-proliferative effect compared to CHT. Both treatments generally increased T- and B-cell immune infiltration; however, an inverse relationship between immune infiltration and anti-proliferative response at surgery exists according to treatment, where immune infiltration is increased in residual tumors with non-CCAA when treated with L+R, but the opposite is observed with CHT. The prognostic value of immune and anti-proliferative effects of L+R in residual tumors is currently being evaluated in the prospective RIBOLARIS phase II clinical trial (NCT05296746). Citation Format: Tomás Pascual, Nuria Chic, Aranzazu Fernandez-Martinez, Blanca González-Farré, Laia Paré, Cristina Saura, Cristina Hernando, Montserrat Muñoz, Míriam Arumí, Patricia Galván, Xavier Gonzalez-Farré, Mafalda Oliveira, Miguel Gil Gil, Eva Ciruelos, Patricia Villagrasa, Joaquin Gavila Gregori, Aleix Prat, Charles M. Perou. Cell-Cycle Inhibition and Immune Microenvironment in HR+/HER2- Breast Cancer During and After preoperative ribociclib and letrozole vesus chemotherapy: A correlative analysis of the 1402-SOLTI/CORALLEEN phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-07.

Introduction Elacestrant is the first oral, non-steroidal, selective estrogen receptor degrader (SERD) to demonstrate improved efficacy compared to standard of care endocrine treatment, with greater relative benefit in ESR1-mutated tumors, and manageable safety profile in pretreated patients with metastatic breast cancer (BC) (Bidard F.C., JCO 2022). SOLTI ELIPSE trial (NCT04797728) is a prospective, multicenter, window of opportunity trial designed to assess whether a short-course of preoperative elacestrant may suppress tumor proliferation in postmenopausal women with estrogen receptor positive (ER+)/HER2-negative early BC (Vidal M., SABCS 2021). Here, we present the results of the primary efficacy and safety study analysis. Methods Eligible patients with operable, untreated ER+/HER2-negative BC that were T1c (≥1.5 cm)-T3 by ultrasound, clinically or radiologically N0 and had a locally assessed Ki67 ≥10%, received elacestrant 400 mg once a day continuously for a total of 4 weeks. At the study treatment completion, patients were treated according to local practice. Centralized assessment of post-treatment (D28) Ki67 from surgical specimen or tumor biopsy was required for the primary endpoint evaluation. Primary efficacy endpoint was complete cell cycle arrest (CCCA), defined as Ki67≤2.7%, at D28. Ki67 geometric relative change, variation in tumor infiltrating lymphocytes (TILs), switch in PAM50 subtypes and differential expression of 192 genes from baseline (D1) to D28 was also explored. Adverse events (AEs) were graded according to CTCAE v5.0. Results Between April 2021 and February 2022, 24 patients were enrolled and 22 were evaluable for the primary endpoint. Baseline characteristics were: mean age 69 years (range 50-81); ductal histology 74%; T1c 61%; T2 39%; grade 1-2 83%; median local Ki67 20% (10-70). Baseline PAM50 subtypes distribution was: Luminal A (n=12), Luminal B (n=8), Basal-like (n=1), Normal-like (n=1). At D28, CCCA was achieved in the 27% (n=6) of the patients. Fourteen patients (64%) had D28 Ki67 ≤10%. Paired centralized Ki67 was available in 19 patients. A statistically significant 41% (95% CI, -24 to -58) Ki67 relative reduction (rr) from D1 was observed (p=0.007). CCCA rate was 31% and 17% in patients with D1 Ki67 < 20% (n=13) and D1 Ki67 ≥20% (n=6), respectively. Ki67 varied consistently in both Ki67 < 20% (rr=-38%; 95% CI, -16 to -60) and Ki67 ≥20% (rr=-46%; 95% CI, -20 to -72) groups. Overall, elacestrant was associated with a shift towards a more endocrine sensitive and less proliferative phenotype based on PAM50 gene signatures. CCCA occurred in 45% of Luminal A tumors, whereas no CCCA was observed among Luminal B tumors. Levels of TILs were significantly higher at D28 (mean difference, +3.73; p=0.004). Elacestrant induced high expression of immune-response genes including IGJ, GZMB, CD4, CD8a and suppressed proliferation (e.g., UBE2T, MYBL2, BIRC5, MK67) and estrogen-signaling (e.g., ESR1, PGR, CCND1, BRCA2) genes (false discovery rate 5%). These changes in gene expression were observed both in tumors with D28 Ki67≤2.7% and in those with D28 Ki67 >10%. Overall, 87% of the patients reported any grade AEs. Treatment-related AE occurred in 1 patient (grade 3 cutaneous rash) and led to treatment discontinuation. Most frequently reported AEs (all grade 1) were hot flush (n=6), dyspepsia (n=2), anemia (n=2) and constipation (n=2). No serious AEs were reported. Conclusions In untreated ER+/HER2-negative early BC a short-course preoperative treatment with elacestrant was associated with relevant biological and molecular response and with manageable safety profile. Globally, these findings support further exploration of this highly potent, novel oral SERD in early BC. Citation Format: Maria Vidal, Tomás Pascual, Claudette Falato, Rodrigo Sanchez-Bayona, Montserrat Muñoz, Isaac Cerbrecos, Xavier Gonzalez-Farré, Tomás Cortadellas, Mireia Margelí, Miguel Angel Luna, Christian Siso, Kepa Amillano, Patricia Galván, Fernando Salvador, Alejandra Espinosa, Laia Paré, Esther Sanfeliu, Aleix Prat, Meritxell Bellet Ezquerra. PD13-01 Elacestrant in postmenopausal women with estrogen receptor positive and HER2-negative early breast cancer: primary efficacy and safety analysis of the preoperative, window of opportunity SOLTI-1905-ELIPSE trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-01.

Introduction: Sentinel lymph node biopsy (SLNB) in ductal carcinoma in situ (DCIS) is not indicated. However, in certain cases (size >3 cm, high grade, mass effect on mammography, or palpable mass), it may be possible to find incidental invasive carcinoma (IC) that requires an SLNB. We studied the correlation of the aforesaid factors with the probability of finding IC in the surgical specimen. Methods: Data was collected from 3 different institutions between 2010 and 2016, recording characteristics such as, but not limited to: high grade, size >3 cm, mass effect on mammography, and palpable mass. Results: On the whole, 468 “high-risk” DCIS cases were identified, 139 (29%) of which had IC. When the DCIS was high grade or the size was >3 cm, there was no significant difference in the probability of finding IC in the surgical specimen (OR = 1.13; 95% CI 0.84–1.51; OR = 1.2; 95% CI 0.85–1.40). Nevertheless, when a high grade and size (>3 cm) were combined, IC was more likely to exist (72.7 vs. 27.3%; p = 0.001). In addition, mass effect and palpation were independently associated with a significantly greater degree of IC (OR = 12.76; 95% CI 6.93–23.52). Conclusions: The results suggest that high-grade DCIS or DCIS with a size >3 cm, independently, does not require SLNB. Nonetheless, in the event that both factors are found in the same case, SLNB may be indicated. Additionally, SLNB is advisable for DCIS cases that are palpable or show a mass effect on mammography.

Purpose:To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer.Patients and Methods:PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2–4 prior lines of anti-HER2–based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes.Results:Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1–2 and 3–4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3–4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003).Conclusions:Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.

New treatment strategies such as immune checkpoint inhibitors and oncolytic viruses are opening new possibilities in cancer therapy. Preliminary results in melanoma and other tumors showed that the combination of talimogene laherparepvec with an anti-PD-1/PD-L1 or anti-CTLA4 has greater efficacy than either therapy alone, without additional safety concerns beyond those expected for each agent. The presence of residual cancer after neoadjuvant chemotherapy in early breast cancer patients is an unmet medical need. SOLTI-1503 PROMETEO is a window of opportunity trial, which evaluates the combination of talimogene laherparepvec in combination with atezolizumab in women with operable HER2-negative breast cancer who present residual disease after neoadjuvant chemotherapy. The primary end point is the rate of residual cancer burden 0/1.Clinical Trial Registration: NCT03802604

Stapes surgery is the gold standard surgical treatment nowadays for otosclerosis. Several controversies on the procedure have been reported; surgical techniques for most favorable outcomes are still on discussion. The objective of this study is to present an update of evidence-based medicine concerning the utilization of lasers and drilling for footplate fenestration during stapedotomy surgery. A systematic review and meta-analysis were conducted. Publications in English in the last 5 years were searched in the PubMed/MEDLINE database and were systematically reviewed. A total of three articles were included according to the inclusion criteria, obtaining a total of 1531 patients managed surgically for otosclerosis, using laser or drill for footplate fenestration. Data were systematically extracted and hearing results were compared in a meta-analysis. For the drill group, a total of 978 patients were retrieved and data were obtained as follows: mean age was 50 years old; the female proportion was 62%; mean preoperative air–bone gap (ABG) of 28 dB; mean postoperative ABG of 8 dB; mean ABG improvement of 20 dB; an ABG closure rate to

Background Type 3 tympanoplasty is the surgery of choice for middle ear reconstruction in cases where an integral stapes suprastructure and mobile footplate are present. Objective The objective of this study was to obtain functional results after endoscopic type 3 tympanoplasty in chronic otitis media. Materials and methods Prospective study including 24 patients who underwent endoscopic type 3 tympanoplasty, using PORP for ossicular chain reconstruction (OCR) and cartilage graft for tympanic membrane reconstruction. Audiograms were made preoperatively, and 6 months after surgery. Results Dry, closed, self-cleaning ears were obtained in 91.7% of the cases. Mean preoperative air-bone gap (ABG) was 30.4 dB, mean postoperative ABG was 16.7 dB, dB gain of 13.6 dB. ABG closure rate to 20 dB or less of 79.2%, and to 10 dB or less of 29.2%. Conclusion and significance Endoscopic tympanoplasty and OCR is a valid option for surgeons who are comfortable with the use of endoscopes for middle ear surgery as it allows improved visualization of the prosthesis and graft placement during middle ear reconstruction.

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries. Although most patients are diagnosed at early stages, 15-20% will relapse despite local treatment. Presently, there are no reliable markers to identify patients with worse outcomes who may benefit from adjuvant treatments, such as chemotherapy, and liquid biopsies may be of use in this setting. Peritoneal lavages are systematically performed during endometrial surgery but little data are available about their potential as liquid biopsies. We analyzed KRAS and PIK3CA mutations in paired surgical biopsies, blood and cytology-negative peritoneal lavages in a cohort of 50 EC patients. Surgical biopsies were submitted to next-generation sequencing (NGS) while circulating-free DNA (cfDNA) purified from plasma and peritoneal lavages was analyzed for KRAS and PIK3CA hotspot mutations using a sensitive quantitative polymerase chain reaction (PCR) assay. NGS of biopsies revealed KRAS, PIK3CA or concomitant KRAS + PIK3CA mutations in 33/50 (66%) EC patients. Of those, 19 cases carried hotspot mutations. Quantitative PCR revealed KRAS and/or PIK3CA mutations in the lavages of 9/19 (47.4%) hotspot EC patients. In contrast, only 2/19 (10.5%) blood samples from hotspot EC patients were positive. Mutations found in cfDNA consistently matched those in paired biopsies. One of the two patients positive in plasma and lavage died in less than 6 months. In conclusion, mutational analysis in peritoneal lavages and blood from early stage EC is feasible. Further studies are warranted to determine if it might help to identify patients with worse prognosis. Human genes discussed: KRAS, KRAS proto-oncogene, GTPase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.

Improved selection of cancer patients who are most likely to respond to immune checkpoint inhibitors remains an unmet clinical need. Recently, a positive correlation between levels of PD1 mRNA and clinical outcome in response to PD1 blockade across diverse tumor histologies has been confirmed in several datasets. ACROPOLI is a parallel cohort, non-randomized, phase II study that aims to evaluate the efficacy of the anti-PD1 immune checkpoint inhibitor spartalizumab as monotherapy in metastatic patients with solid tumors that express high levels of PD1 (cohort 1; n = 111). An additional cohort of 30 patients with tumors expressing low levels of PD1, where PD1/PD-L1 antibodies in monotherapy are standard treatment, will also be included (cohort 2). Primary end point is overall response rate in cohort 1. Considering previous data, we hypothesized that anti-PD1 monotherapy is effective across multiple cancer types in patients with PD1-high mRNA expressing tumors. Given these observations, ACROPOLI is a phase II study designed to study spartalizumab in this population. This article describes the SOLTI-1904 ACROPOLI phase II trial, `Efficacy of spartalizumab across multiple cancertypes in patients with PD1-highmRNA expressing tumors defined by a single and pre-specified cutoff.' The primary objective is to determine overall response rate (ORR) in the PD1-high population. Secondary objectives include other measures of clinical efficacy and evaluation of safety and tolerability. Spartalizumab has shown to have a manageable safety profile and preliminary clinical efficacy according to several phase I/II clinical trials [1-3].

Background: Luminal advanced breast cancer (ABC) patients eventually progress on endocrine therapy. REVERT aimed to explore whether eribulin could restore endocrine sensitivity in a randomized, non-comparative phase II trial. Methods: Aromatase inhibitor (AI)-resistant patients with luminal ABC were randomized 1:1 to receive eribulin +/− AI. Patients were stratified by prior cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) treatment. The primary endpoint was an investigator-assessed overall response rate (ORR) according to RECIST version 1.1 in the eribulin + AI arm. An interim analysis was planned with 11 evaluable patients according to a two-stage Simon design. Results: Twenty-two patients were enrolled (15 eribulin + AI arm; 7 eribulin arm). The trial was terminated early in March 2021, with eight (36.4%) patients still on treatment. ORR was 26.7% in the eribulin + AI arm (95% CI, 7.8–55.1%; p = 0.0541). In the eribulin arm, two (28.6%) patients had an objective response (95% CI, 3.7–71.0%). The difference between the study arms was not significant (p = 0.918). The addition of AI to eribulin also failed to show improvement in other efficacy endpoints. A significant interaction between the treatment arm and previous CDK4/6i treatment was observed for ORR (p = 0.018) and progression-free survival (p = 0.084). Overall, the toxicity profile was consistent with the known safety profile of eribulin. No treatment-related deaths were reported. Conclusion: Eribulin + AI does not seem to improve outcomes compared with eribulin monotherapy in patients with AI-resistant luminal ABC. This chemo–endocrine approach deserves further investigation after progression to CDK4/6i-based therapy.

The mini-SciCR is a cosmic ray detector, it is made of scintillator bars with a total volume of 20 x 20 x 20.8 $cm^{3}$. The array of scintillator bars act both as a target and as a tracker of the incident radiation. In this paper we describe the method developed with the help of a Monte Carlo simulation to distiguish the neutron signals from gamma ray signals, it is based on the different maximum energy deposited at a scintillator bar by neutrons and gamma rays. To distiguish the neutral emission signals (neutrons and gamma rays) from charged particles signals, we implemented via software a system of anti-coincidence between edge bars and internal bars of the detector. We also report the flux of neutrons and gamma rays measured by the mini-SciCR at the top of the Sierra Negra volcano at 4,600 m.a.s.l., in Eastern Mexico. The mini-SciCR was operating from October 2010 to July 2012. We also present the Forbush decrease registered by the mini-SciCR on march, 2012. The mini-SciCR is a prototype of a new cosmic ray detector called SciBar Cosmic Ray Telescope installed in the same place, which is in the process of operation parameter tuning and calibration. The SciCRT will work mainly as a Solar Neutron and Muon Telescope.

BACKGROUND: The anti-proliferative effect of mVNB alone or in combination with endocrine therapy in patients with hormone receptor-positive/HER2- breast cancer (BC) has been scarcely addressed. METHODS: Postmenopausal women with untreated stage I-III BC were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5mg/day, oral mVNB 50mg 3 days/week or the combination. The 1ary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of mVNB+LTZ was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene Proliferation Score in each arm. 2ary objectives included safety and the comparison of the anti-proliferative effect between arms. An unplanned analysis of stromal tumor infiltrating lymphocytes (sTILs) was performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360TM panel. Changes in the expression of 790 genes/signatures tracking multiple biological processes from tumor cells and the microenvironment were evaluated within each arm using paired (surgery vs. baseline) univariate analyses. P-values were corrected for multiple comparisons using false discovery rate (FDR). RESULTS: A total of 61 patients were randomized and 54 paired samples (89%) were analyzed. Main patient characteristics were mean age 67, mean tumor size 1.7 cm, stage I (55.7%) and grade 1-2 (90%). Grade 3 toxicities occurred in 3.3% of cases. Baseline samples were Luminal A (72.3%) or B (27.7%). The anti-proliferative effect of mVNB+LTZ (-73.2%) was superior to both monotherapy arms combined (-49.9%; p=0.001) and mVNB (-19.1%; p CONCLUSIONS: mVNB is well-tolerated and presents antiproliferative activity alone and in combination with LTZ. The increase of activated CD8 T-cells or TILs observed with LTZ+mVNB opens the possibility of studying combinations with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or combinations is warranted. Citation Format: Prat A, Adamo B, Pascual T, Perez Fidalgo JA, Blanch S, Martínez N, Gomez Pardo P, Lopez Gonzalez A, Murillo Jaso L, Amillano K, Vidal M, Paré L, Canes J, Galvan P, Gonzalez Farre B, Ortega Cebrián V, Gonzalez X, Bellet Ezquerra M, Villagrasa P, Ciruelos E. Anti-proliferative effect of oral metronomic vinorelbine (mVNB) in PAM50 Luminal/HER2-negative early breast cancer (SOLTI-1501 VENTANA): A randomized, three-arm, window-of-opportunity study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-04.

Animals are colonized by diverse communities that provide essential functions to the superorganism. At homeostasis, such microbiota communities are thought to benefit the healthy host. In contrast, dysbiosis can be both pathogenic and a consequence of disease. Establishing causal relationships among microbiota composition, host immune status, and disease is essential for fundamental understanding of many diseases and for their therapeutic targeting. Here we took a reductionist approach to address the potential for normal microbiota bacteria to cause disease in the immunodeficient host (i.e., the cryptic virulence of pathobionts) using C. elegans. C. elegans are known to rely on several host defense pathways to counteract intestinal infections. Although these pathways are known to play pivotal roles in defense against various human pathogenic bacteria, it is not clear what roles these pathways play for interactions with the native microbiota. To address this gap in knowledge, we determined the functional significance of p38, Wnt, and TFEB pathways in terms of gene expression and host survival of monocolonization by individual members of the C. elegans microbiota. We find that distinct host defense pathways are necessary for normal survival of animals colonized with distinct microbiota members. Our results suggest that specific microbiota members trigger specific host defense pathways, which are necessary for the host to defend against their cryptic virulence. The new insights provide the necessary foundation to characterize the molecular mechanisms by which microbiota members trigger host defense pathways specifically, including potentially novel bacterial metabolites with useful therapeutic properties in mammals. Supported by gran from NIH (R01GM101056-10) Supported by grant from NIH (Innate Immunity Training Grant (T32 AI095213))

Possible ionospheric effects of the Morelian meteoroid that passed and exploded over Mexico on 19 February 2020 (18 February 2020 local time) were estimated. The meteoroid trajectory, velocity and time of occurrence were calculated based on outdoor camera records. Modeling was used to estimate the meteoroid initial diameter, density, mass, velocity, energy and their change during its flight in the atmosphere. The ensemble of ionospheric scintillation indices calculated from the high-rate GNSS data and the filtered slant Total Electron Content data were used to reveal the presence of ionospheric disturbances generated by shock waves excited by the meteoroid flight and explosion. The first ionospheric responses to phenomena accompanying the meteoroid were detected (2.5–3.5) min after the explosion. The disturbances were attenuated quickly with distance from their source and were rarely recorded by GNSS receivers located more than 600 km from the meteoroid explosion site. The ionospheric disturbances of intermediate-scale, small-scale, shock-acoustic-wave-scale and sometimes medium-scale were revealed. The detected disturbances corresponded to the range of acoustic-gravity waves. An asymmetry of the disturbance manifestation in different directions was observed. The obtained results are in accordance with results of the observation of other meteoroids. Although the object was smaller and of less energy than other known meteoroids, it is an interesting case because, to the best of our knowledge, it isthe first known to us low-latitude meteoroid with the detected ionospheric effects.