SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023).

Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, the incidence is lower and GC represents the tenth most frequent tumor and the seventh cause of cancer mortality. Molecular biology knowledge allowed to better profile patients for a personalized therapeutic approach. In the localized setting, the multidisciplinary team discussion is fundamental for planning the therapeutic approach. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors, and chemoradiation + surgery + adjuvant immunotherapy for the GEJ are current standards. For the metastatic setting, biomarker profiling including Her2, PD-L1, MSS status is needed. Chemotherapy in combination with checkpoint inhibitors had improved the outcomes for patients with PD-L1 expression. Her2 positive patients should receive antiHer2 therapy added to chemotherapy. We describe the different evidences and recommendations based on the literature.

Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma represents one of the solid tumors showing the worst prognosis worldwide, with a high recurrence rate after adjuvant or neoadjuvant therapy. Circulating tumor DNA analysis raised as a promising non-invasive tool to characterize tumor genomics and to assess treatment response. In this study, surgical tumor tissue and sequential blood samples were analyzed by next-generation sequencing and were correlated with clinical and pathological characteristics. Thirty resectable/borderline pancreatic ductal adenocarcinoma patients treated at the Hospital Universitario de Navarra were included. Circulating tumoral DNA sequencing identified pathogenic variants in KRAS and TP53, and in other cancer-associated genes. Pathogenic variants at diagnosis were detected in patients with a poorer outcome, and were correlated with response to neoadjuvant therapy in borderline pancreatic ductal adneocarcinoma patients. Higher variant allele frequency at diagnosis was associated with worse prognosis, and thesum of variant allele frequency was greater in samples at progression. Our results build on the potential value of circulating tumor DNA for non-metastatic pancreatic ductal adenocarcinoma patients, by complementing tissue genetic information and as a non-invasive tool for treatment decision. Confirmatory studies are needed to corroborate these findings.

Automated Monitoring of Human-Computer Interaction for Assessing Teachers' Digital Competence Based on LMS Data Extraction.

The fast-paced evolution of technology has compelled the digitalization of education, requiring educators to interact with computers and develop digital competencies relevant to the teaching-learning process. This need has prompted various organizations to define frameworks for assessing digital competency emphasizing teachers' interaction with computer technologies in education. Different authors have presented assessment methods for teachers' digital competence based on the video analysis of recorded classes using sensors such as cameras, microphones, or electroencephalograms. The main limitation of these solutions is the large number of resources they require, making it difficult to assess large numbers of teachers in resource-constrained environments. This article proposes the automation of teachers' digital competence evaluation process based on monitoring metrics obtained from teachers' interaction with a Learning Management System (LMS). Based on the Digital Competence Framework for Educators (DigCompEdu), indicators were defined and extracted that allow automatic measurement of a teacher's competency level. A tool was designed and implemented to conduct a successful proof of concept capable of automating the evaluation process of all university faculty, including 987 lecturers from different fields of knowledge. Results obtained allow for drawing conclusions on technological adoption according to the teacher's profile and planning educational actions to improve these competencies.

Stillbirth mortality by Robson ten-group classification system: A cross-sectional registry of 80 663 births from 16 hospital in sub-Saharan Africa.

OBJECTIVE: To assess stillbirth mortality by Robson ten-group classification and the usefulness of this approach for understanding trends. DESIGN: Cross-sectional study. SETTING: Prospectively collected perinatal e-registry data from 16 hospitals in Benin, Malawi, Tanzania and Uganda. POPULATION: All women aged 13-49 years who gave birth to a live or stillborn baby weighting >1000 g between July 2021 and December 2022. METHODS: We compared stillbirth risk by Robson ten-group classification, and across countries, and calculated proportional contributions to mortality. MAIN OUTCOME MEASURES: Stillbirth mortality, defined as antepartum and intrapartum stillbirths. RESULTS: We included 80 663 babies born to 78 085 women; 3107 were stillborn. Stillbirth mortality by country were: 7.3% (Benin), 1.9% (Malawi), 1.6% (Tanzania) and 4.9% (Uganda). The largest contributor to stillbirths was Robson group 10 (preterm birth, 28.2%) followed by Robson group 3 (multipara with cephalic term singleton in spontaneous labour, 25.0%). The risk of dying was highest in births complicated by malpresentations, such as nullipara breech (11.0%), multipara breech (16.7%) and transverse/oblique lie (17.9%). CONCLUSIONS: Our findings indicate that group 10 (preterm birth) and group 3 (multipara with cephalic term singleton in spontaneous labour) each contribute to a quarter of stillbirth mortality. High mortality risk was observed in births complicated by malpresentation, such as transverse lie or breech. The high mortality share of group 3 is unexpected, demanding case-by-case investigation. The high mortality rate observed for Robson groups 6-10 hints for a need to intensify actions to improve labour management, and the categorisation may support the regular review of labour progress.

Current Indications and Future Landscape of Bispecific Antibodies for the Treatment of Lung Cancer.

Bispecific antibodies are a promising type of therapy for the treatment of cancer due to their ability to simultaneously inhibit different proteins playing a role in cancer progression. The development in lung cancer has been singularly intense because of the increasingly vast knowledge of the underlying molecular routes, in particular, in oncogene-driven tumors. In this review, we present the current landscape of bispecific antibodies for the treatment of lung cancer and discuss potential scenarios where the role of these therapeutics might expand in the near future.

Scalable Early Detection of Grapevine Viral Infection with Airborne Imaging Spectroscopy.

The U.S. wine and grape industry loses $3B annually due to viral diseases including grapevine leafroll-associated virus complex 3 (GLRaV-3). Current detection methods are labor-intensive and expensive. GLRaV-3 has a latent period in which the vines are infected but do not display visible symptoms, making it an ideal model to evaluate the scalability of imaging spectroscopy-based disease detection. The NASA Airborne Visible and Infrared Imaging Spectrometer Next Generation was deployed to detect GLRaV-3 in Cabernet Sauvignon grapevines in Lodi, CA in September 2020. Foliage was removed from the vines as part of mechanical harvest soon after image acquisition. In September of both 2020 and 2021, industry collaborators scouted 317 hectares on a vine-by-vine basis for visible viral symptoms and collected a subset for molecular confirmation testing. Symptomatic grapevines identified in 2021 were assumed to have been latently infected at the time of image acquisition. Random forest models were trained on a spectroscopic signal of noninfected and GLRaV-3 infected grapevines balanced with synthetic minority oversampling of noninfected and GLRaV-3 infected grapevines. The models were able to differentiate between noninfected and GLRaV-3 infected vines both pre- and postsymptomatically at 1 to 5 m resolution. The best-performing models had 87% accuracy distinguishing between noninfected and asymptomatic vines, and 85% accuracy distinguishing between noninfected and asymptomatic + symptomatic vines. The importance of nonvisible wavelengths suggests that this capacity is driven by disease-induced changes to plant physiology. The results lay a foundation for using the forthcoming hyperspectral satellite Surface Biology and Geology for regional disease monitoring in grapevine and other crop species. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

State of the Art: ctDNA in Upper Gastrointestinal Malignancies.

Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive source to characterize genetic alterations related to the tumor. Upper gastrointestinal cancers, including gastroesophageal adenocarcinoma (GEC), biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PADC) are poor prognostic malignancies, usually diagnosed at advanced stages when no longer amenable to surgical resection and show a poor prognosis even for resected patients. In this sense, ctDNA has emerged as a promising non-invasive tool with different applications, from early diagnosis to molecular characterization and follow-up of tumor genomic evolution. In this manuscript, novel advances in the field of ctDNA analysis in upper gastrointestinal tumors are presented and discussed. Overall, ctDNA analyses can help in early diagnosis, outperforming current diagnostic approaches. Detection of ctDNA prior to surgery or active treatment is also a prognostic marker that associates with worse survival, while ctDNA detection after surgery is indicative of minimal residual disease, anticipating in some cases the imaging-based detection of progression. In the advanced setting, ctDNA analyses characterize the genetic landscape of the tumor and identify patients for targeted-therapy approaches, and studies show variable concordance levels with tissue-based genetic testing. In this line, several studies also show that ctDNA serves to follow responses to active therapy, especially in targeted approaches, where it can detect multiple resistance mechanisms. Unfortunately, current studies are still limited and observational. Future prospective multi-center and interventional studies, carefully designed to assess the value of ctDNA to help clinical decision-making, will shed light on the real applicability of ctDNA in upper gastrointestinal tumor management. This manuscript presents a review of the evidence available in this field up to date.

Current developments in gastric cancer: from molecular profiling to treatment strategy.

Gastric cancer and gastro-oesophageal junction cancer represent a global health-care challenge. Despite the efficacy of improved chemotherapy and surgical options, these patients still have a poor prognosis. In advanced disease, only trastuzumab and some immune checkpoint inhibitors, such as nivolumab and pembrolizumab in addition to chemotherapy, have demonstrated consistent and reliable efficacy in patients with HER2-positive and PDL1-positive tumours, respectively. In this Review, we discuss the intrinsic characteristics of gastric and gastro-oesophageal cancer from the molecular and clinical perspectives and provide a comprehensive review of previously reported and ongoing phase II and III clinical trials with targeted agents and immunotherapy in advanced and localized settings. Finally, we suggest alternative strategies to help overcome current challenges in precision medicine and to improve outcomes for these patients.

A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer.

BACKGROUND: This Phase 1b study (B2151002) evaluated the PI3K/mTOR inhibitor gedatolisib (PF-05212384) in combination with other anti-tumour agents in advanced solid tumours. METHODS: Patients with various malignancies were administered gedatolisib (90‒310 mg intravenously every week [QW]) plus docetaxel (arm A) or cisplatin (arm B) (each 75 mg/m2 intravenously Q3W) or dacomitinib (30 or 45 mg/day orally). The safety and tolerability of combination therapies were assessed during dose escalation; objective response (OR) and safety were assessed during dose expansion. RESULTS: Of 110 patients enrolled, 107 received gedatolisib combination treatment. Seven of 70 (10.0%) evaluable patients had dose-limiting toxicities; the most common was grade 3 oral mucositis (n = 3). Based upon reprioritisation of the sponsor's portfolio, dose expansion focused on arm B, gedatolisib (180 mg QW) plus cisplatin in patients (N = 22) with triple-negative breast cancer (TNBC). OR (95% CI) was achieved in four of ten patients in first-line (overall response rate 40.0% [12.2-73.8%]) and four of 12 in second/third-line (33.3% [9.9-65.1%]) settings. One patient in each TNBC arm (10%, first-line; 8.3%, second/third-line) achieved a complete response. CONCLUSIONS: Gedatolisib combination therapy showed an acceptable tolerability profile, with clinical activity at the recommended Phase 2 dose in patients with TNBC. CLINICAL TRIAL: ClinicalTrial.gov: NCT01920061.

Recent progress and current challenges of immunotherapy in advanced/metastatic esophagogastric adenocarcinoma.

The new era of immunotherapy is successfully implemented in the treatment of metastatic/locally advanced esophagogastric adenocarcinoma (EGAC), as it has been investigated in combinations with/without chemotherapy in human epidermal growth factor receptor 2 (Her2)-positive and Her2-negative tumors. Recent approvals of immune checkpoint inhibitors (ICI) enrich the therapeutic landscape in nearly every therapeutic line. Based on CHECKMATE-649, the combination of nivolumab and chemotherapy in first-line therapy of programmed cell death protein 1 (PD-L1)-positive patients with advanced gastroesophageal junction cancer (GEJC), esophageal cancer (EC), and gastric cancer (GC) was approved in Europe for PD-L1 combined positivity score (CPS) ≥ 5 patients and independently from PD-L1 score in the USA and Asia. Based on KEYNOTE-590, patients with advanced GEJC and EC qualify for the combination of pembrolizumab plus chemotherapy in Europe (CPS ≥ 10) and the USA. For Her2-positive patients, trastuzumab with first-line chemotherapy plus pembrolizumab has beneficial response rates and resulted in approval in the USA (KEYNOTE-811). In third-line therapy, superior overall survival (OS) was achieved by the administration of nivolumab (approval in Japan, ATTRACTION-02), and pembrolizumab shows a positive effect on the duration of response (KEYNOTE-059). Questions of resistance to immunotherapy or the role of gender in response to ICI need to be clarified. This review provides an overview of the current approvals of ICI in advanced EGAC and reflects results of relevant phase II/III trials with focus on possible biomarkers, including PD-L1 CPS and microsatellite-instability (MSI) status.

Effects of meteorological and land surface modeling uncertainty on errors in winegrape ET calculated with SIMS.

Characterization of model errors is important when applying satellite-driven evapotranspiration (ET) models to water resource management problems. This study examines how uncertainty in meteorological forcing data and land surface modeling propagate through to errors in final ET data calculated using the Satellite Irrigation Management Support (SIMS) model, a computationally efficient ET model driven with satellite surface reflectance values. The model is applied to three instrumented winegrape vineyards over the 2017-2020 time period and the spatial and temporal variation in errors are analyzed. We illustrate how meteorological data inputs can introduce biases that vary in space and at seasonal timescales, but that can persist from year to year. We also observe that errors in SIMS estimates of land surface conductance can have a particularly strong dependence on time of year. Overall, meteorological inputs introduced RMSE of 0.33-0.65 mm/day (7-27%) across sites, while SIMS introduced RMSE of 0.55-0.83 mm/day (19-24%). The relative error contribution from meteorological inputs versus SIMS varied across sites; errors from SIMS were larger at one site, errors from meteorological inputs were larger at a second site, and the error contributions were of equal magnitude at the third site. The similar magnitude of error contributions is significant given that many satellite-driven ET models differ in their approaches to estimating land surface conductance, but often rely on similar or identical meteorological forcing data. The finding is particularly notable given that SIMS makes assumptions about the land surface (no soil evaporation or plant water stress) that do not always hold in practice. The results of this study show that improving SIMS by eliminating these assumptions would result in meteorological inputs dominating the error budget of the model on the whole. This finding underscores the need for further work on characterizing spatial uncertainty in the meteorological forcing of ET. Supplementary Information: The online version contains supplementary material available at 10.1007/s00271-022-00808-9.

Evaluation of satellite Leaf Area Index in California vineyards for improving water use estimation.

Remote sensing estimation of evapotranspiration (ET) directly quantifies plant water consumption and provides essential information for irrigation scheduling, which is a pressing need for California vineyards as extreme droughts become more frequent. Many ET models take satellite-derived Leaf Area Index (LAI) as a major input, but how uncertainties of LAI estimations propagate to ET and the partitioning between evaporation and transpiration is poorly understood. Here we assessed six satellite-based LAI estimation approaches using Landsat and Sentinel-2 images against ground measurements from four vineyards in California and evaluated ET sensitivity to LAI in the thermal-based two-source energy balance (TSEB) model. We found that radiative transfer modeling-based approaches predicted low to medium LAI well, but they significantly underestimated high LAI in highly clumped vine canopies (RMSE ~ 0.97 to 1.27). Cubist regression models trained with ground LAI measurements from all vineyards achieved high accuracy (RMSE ~ 0.3 to 0.48), but these empirical models did not generalize well between sites. Red edge bands and the related vegetation index (VI) from the Sentinel-2 satellite contain complementary information of LAI to VIs based on near-infrared and red bands. TSEB ET was more sensitive to positive LAI biases than negative ones. Positive LAI errors of 50% resulted in up to 50% changes in ET, while negative biases of 50% in LAI caused less than 10% deviations in ET. However, even when ET changes were minimal, negative LAI errors of 50% led to up to a 40% reduction in modeled transpiration, as soil evaporation and plant transpiration responded to LAI change divergently. These findings call for careful consideration of satellite LAI uncertainties for ET modeling, especially for the partitioning of water loss between vine and soil or cover crop for effective vineyard irrigation management.

Improving the spatiotemporal resolution of remotely sensed ET information for water management through Landsat, Sentinel-2, ECOSTRESS and VIIRS data fusion.

Robust information on consumptive water use (evapotranspiration, ET) derived from remote sensing can significantly benefit water decision-making in agriculture, informing irrigation schedules and water management plans over extended regions. To be of optimal utility for operational usage, these remote sensing ET data should be generated at the sub-field spatial resolution and daily-to-weekly timesteps commensurate with the scales of water management activities. However, current methods for field-scale ET retrieval based on thermal infrared (TIR) imaging, a valuable diagnostic of canopy stress and surface moisture status, are limited by the temporal revisit of available medium-resolution (100 m or finer) thermal satellite sensors. This study investigates the efficacy of a data fusion method for combining information from multiple medium-resolution sensors toward generating high spatiotemporal resolution ET products for water management. TIR data from Landsat and ECOSTRESS (both at ~ 100-m native resolution), and VIIRS (375-m native) are sharpened to a common 30-m grid using surface reflectance data from the Harmonized Landsat-Sentinel dataset. Periodic 30-m ET retrievals from these combined thermal data sources are fused with daily retrievals from unsharpened VIIRS to generate daily, 30-m ET image timeseries. The accuracy of this mapping method is tested over several irrigated cropping systems in the Central Valley of California in comparison with flux tower observations, including measurements over irrigated vineyards collected in the GRAPEX campaign. Results demonstrate the operational value added by the augmented TIR sensor suite compared to Landsat alone, in terms of capturing daily ET variability and reduced latency for real-time applications. The method also provides means for incorporating new sources of imaging from future planned thermal missions, further improving our ability to map rapid changes in crop water use at field scales.

Application of a remote-sensing three-source energy balance model to improve evapotranspiration partitioning in vineyards.

Improved accuracy of evapotranspiration (ET) estimation, including its partitioning between transpiration (T) and surface evaporation (E), is key to monitor agricultural water use in vineyards, especially to enhance water use efficiency in semi-arid regions such as California, USA. Remote-sensing methods have shown great utility in retrieving ET from surface energy balance models based on thermal infrared data. Notably, the two-source energy balance (TSEB) has been widely and robustly applied in numerous landscapes, including vineyards. However, vineyards add an additional complexity where the landscape is essentially made up of two distinct zones: the grapevine and the interrow, which is often seasonally covered by an herbaceous cover crop. Therefore, it becomes more complex to disentangle the various contributions of the different vegetation elements to total ET, especially through TSEB, which assumes a single vegetation source over a soil layer. As such, a remote-sensing-based three-source energy balance (3SEB) model, which essentially adds a vegetation source to TSEB, was applied in an experimental vineyard located in California's Central Valley to investigate whether it improves the depiction of the grapevine-interrow system. The model was applied in four different blocks in 2019 and 2020, where each block had an eddy-covariance (EC) tower collecting continuous flux, radiometric, and meteorological measurements. 3SEB's latent and sensible heat flux retrievals were accurate with an overall RMSD ~ 50 W/m2 compared to EC measurements. 3SEB improved upon TSEB simulations, with the largest differences being concentrated in the spring season, when there is greater mixing between grapevine foliage and the cover crop. Additionally, 3SEB's modeled ET partitioning (T/ET) compared well against an EC T/ET retrieval method, being only slightly underestimated. Overall, these promising results indicate 3SEB can be of great utility to vineyard irrigation management, especially to improve T/ET estimations and to quantify the contribution of the cover crop to ET. Improved knowledge of T/ET can enhance grapevine water stress detection to support irrigation and water resource management. Supplementary Information: The online version contains supplementary material available at 10.1007/s00271-022-00787-x.

Immune Profiling Uncovers Memory T-Cell Responses with a Th17 Signature in Cancer Patients with Previous SARS-CoV-2 Infection Followed by mRNA Vaccination.

It is unclear whether patients with cancer present inherently impaired responses to COVID-19 and vaccination due to their treatments, neoplastic diseases or both. To address this question, immune profiling was performed in three cohorts of healthy donors and oncologic patients: infected with SARS-CoV-2, BNT162b2-vaccinated, and with previous COVID-19 disease and subsequently vaccinated. Cancer patients showed good antibody responses to vaccination, but poor induction of T-cell responses towards the S protein when compared to infection. Following natural infection, the major targets for T-cells were the SARS-CoV-2 structural proteins M and S, but not the N protein. Similar to antibody titers, the T-cell responses quickly decayed after six months post-vaccination. Significant memory T-cell expansion was observed in vaccinated donors only if previously diagnosed with COVID-19 before undergoing vaccination. Oncologic patients with previous COVID-19 followed by vaccination exhibited potent IL-17+ CD4 and CD8 T-cell responses and elevated numbers of circulating neutrophils in peripheral blood.

The LEGACy study: a European and Latin American consortium to identify risk factors and molecular phenotypes in gastric cancer to improve prevention strategies and personalized clinical decision making globally.

BACKGROUND: Gastric Cancer (GC) is the fourth most deadly cancer worldwide. Enhanced understanding of its key epidemiological and molecular drivers is urgently needed to lower the incidence and improve outcomes. Furthermore, tumor biology in European (EU) and Latin American (LATAM) countries is understudied. The LEGACy study is a Horizon 2020 funded multi-institutional research approach to 1) detail the epidemiological features including risk factors of GC in current time and 2) develop cost-effective methods to identify and integrate biological biomarkers needed to guide diagnostic and therapeutic approaches with the aim of filling the knowledge gap on GC in these areas. METHODS: This observational study has three parts that are conducted in parallel during 2019-2023 across recruiting centers from four EU and four LATAM countries: Part 1) A case-control study (800 cases and 800 controls) using questionnaires on candidate risk factors for GC, which will be correlated with clinical, demographic and epidemiological parameters. Part 2) A case-control tissue sampling study (400 cases and 400 controls) using proteome, genome, microbiome and immune analyses to characterize advanced (stage III and IV) GC. Patients in this part of the study will be followed over time to observe clinical outcomes. The first half of samples will be used as training cohort to identify the most relevant risk factors and biomarkers, which will be selected to propose cost-effective diagnostic and predictive methods that will be validated with the second half of samples. Part 3) An educational study, as part of our prevention strategy (subjects recruited from the general public) to test and disseminate knowledge on GC risk factors and symptoms by a questionnaire and informative video. Patients could be recruited for more than one of the three LEGACy studies. DISCUSSION: The LEGACy study aims to generate novel, in-depth knowledge on the tumor biological characteristics through integrating epidemiological, multi-omics and clinical data from GC patients at an EU-LATAM partnership. During the study, cost-effective panels with potential use in clinical decision making will be developed and validated. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: Part 1: NCT03957031 . Part 2: NCT04015466 . Part 3: NCT04019808 .

Highlights from the 2022 ASCO gastrointestinal cancer symposium: An overview by the EORTC gastrointestinal tract cancer group.

Recently, we have witnessed impressive diagnostic and therapeutic changes for gastrointestinal cancer patients. New challenges brought by the COVID-19 pandemic have led us to re-evaluate our work priorities. Thanks to the commendable resilience of both investigators and patients, however, clinical research never stopped. In addition to conducting cutting-edge research and serving patients' needs, as EORTC Gastrointestinal Tract Cancer Group, we are committed to pursuing educational initiatives beneficial to the entire European oncology community and beyond. In this regard, we have been providing critical discussions of new data from major international meetings. In this article, we discuss results of important selected studies presented at the 2022 ASCO Gastrointestinal Cancer Symposium, putting them in perspectives and highlighting potential implications for routine practice. With the number of in-person attendees and practice-changing/informing trials presented, this meeting represented a milestone in the return to normality as well as in the fight against cancer.

Chemorefractory Gastric Cancer: The Evolving Terrain of Third-Line Therapy and Beyond.

Gastric and gastro-oesophageal junction cancer (GC) represent a global healthcare problem being the fifth most common tumour type and the fourth cause of cancer mortality. Extremely poor median survival of approximately 10 months is normally reported within advanced GC patients, mainly secondary to two factors, i.e., the fragility of these patients and the aggressiveness of this disease. In this context, the correct treatment of GC patients requires not only a multidisciplinary team with special attention to palliative and nutritional care but also a close follow-up with regular monitoring of disease symptoms and tumour evaluation. Sequential treatment lines with few toxic adverse events have emerged as the best therapeutic approach, and a third line of therapy could further improve survival and quality of life of GC patients. Chemotherapy, immunotherapy, and targeted agents -when indicated- constitute the treatment armamentarium of these patients. In this review, we discuss treatment options in the refractory setting as well as novel approaches to overcome the poor prognosis of GC.