Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Checkpoint inhibitors for gastroesophageal cancers: dissecting heterogeneity to better understand their role in first-line and adjuvant therapy.

Gastroesophageal adenocarcinoma (GEA) and squamous esophageal cancer (ESCC) are responsible for >1 million deaths annually globally. Until now, patients with metastatic GEA and ESCC could anticipate survival of <1 year. Anti- programmed cell death protein 1 (anti-PD-1) monotherapy has demonstrated modest efficacy in previously treated GEA and ESCC. In 2020, four pivotal trials have established anti-PD-1 therapy as a new standard of care for selected GEA and ESCC patients as first-line advanced and adjuvant therapy. In this review, we discuss the recent results of the CheckMate 649, ATTRACTION-4, KEYNOTE-590 and CheckMate 577 trials. We consider these results in the context of current standards of care and historical trials of immune checkpoint blockade in GEA and ESCC. We explore biomarker selection for anti-PD-1 therapy and appraise the future of combination therapies. In CheckMate 649, treatment with oxaliplatin-fluoropyrimidine chemotherapy plus nivolumab in patients with combined positive score ≥5 GEA tumors provided a clinically meaningful and statistically significant improvement in overall survival. The ATTRACTION-4 trial did not see a similar overall survival benefit, despite a clear improvement in progression-free survival. We review potential explanations for this result. KEYNOTE-590 showed profoundly improved survival when pembrolizumab was added to cisplatin-fluoropyrimidine chemotherapy in ESCC patients with combined positive score ≥10 tumors; this benefit was less convincing in unselected ESCC. Finally, CheckMate 577 provides proof-of-concept for the improvement in disease-free survival with adjuvant nivolumab in high-risk resected GEA and ESCC following trimodality therapy. Immune checkpoint blockade has come of age in GEA and ESCC, and will now be integrated into first-line and earlier lines of therapy, providing benefit for a larger proportion of patients. Biomarker standardization will be critical to select the patients most likely to benefit from treatment. For patients with immune evasive tumors, novel combinations under development show promise; however, global trials are needed.

Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas.

BACKGROUND: Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers where immune checkpoint inhibitors have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr virus (EBV)-positive subtypes. Immune checkpoint inhibitor responses are markedly lower in diffuse/genome stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies. PATIENTS AND METHODS: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (N = 453 GEAs) and archival GEA resection specimen (N = 71). The Cancer Genome Atlas RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristics within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses. RESULTS: Our results confirmed substantial heterogeneity in the tumor microenvironment between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+ T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8+ T cells predominantly at the invasive margin while tumor-associated macrophages showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1. CONCLUSIONS: These results reveal the diversity of immune phenotypes of GEA. Half of GS gastric cancers have tertiary lymphoid structures and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.

The role of tumor-associated macrophages in gastric cancer development and their potential as a therapeutic target.

Gastric cancer (GC) represents the fifth cause of cancer-related death worldwide. Molecular biology has become a central area of research in GC and there are currently at least three major classifications available to elucidate the mechanisms that drive GC oncogenesis. Further, tumor microenvironment seems to play a crucial role, and tumor-associated macrophages (TAMs) are emerging as key players in GC development. TAMs are cells derived from circulating chemokine- receptor-type 2 (CCR2) inflammatory monocytes in blood and can be divided into two main types, M1 and M2 TAMs. M2 TAMs play an important role in tumor progression, promoting a pro-angiogenic and immunosuppressive signal in the tumor. The diffuse GC subtype, in particular, seems to be strongly characterized by an immuno-suppressive and pro-angiogenic phenotype. No molecular targets in this subgroup have yet been identified. There is an urgent need to understand the molecular pathways and tumor microenvironment features in the GC molecular subtypes. The role of anti-angiogenics and checkpoint inhibitors has recently been clinically validated in GC. Both ramucirumab, a fully humanized IgG1 monoclonal anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, and checkpoint inhibitors in Epstein Bar Virus (EBV) and Microsatellite Instable (MSI) subtypes, have proved beneficial in advanced GC. Nevertheless, there is a need to identify predictive markers of response to anti-angiogenics and immunotherapy in clinical practice for a personalized treatment approach. The importance of M2 TAMs in development of solid tumors is currently gaining increasing interest. In this literature review we analyze immune microenvironment composition and signaling related to M1 and M2 TAMs in GC as well as its potential role as a therapeutic target.

Targeted next-generation sequencing of circulating-tumor DNA for tracking minimal residual disease in localized colon cancer.

BACKGROUND: A high percentage of patients diagnosed with localized colon cancer (CC) will relapse after curative treatment. Although pathological staging currently guides our treatment decisions, there are no biomarkers determining minimal residual disease (MRD) and patients are at risk of being undertreated or even overtreated with chemotherapy in this setting. Circulating-tumor DNA (ctDNA) can to be a useful tool to better detect risk of relapse. PATIENTS AND METHODS: One hundred and fifty patients diagnosed with localized CC were prospectively enrolled in our study. Tumor tissue from those patients was sequenced by a custom-targeted next-generation sequencing (NGS) panel to characterize somatic mutations. A minimum variant allele frequency (VAF) of 5% was applied for variant filtering. Orthogonal droplet digital PCR (ddPCR) validation was carried out. We selected known variants with higher VAF to track ctDNA in the plasma samples by ddPCR. RESULTS: NGS found known pathological mutations in 132 (88%) primary tumors. ddPCR showed high concordance with NGS (r = 0.77) for VAF in primary tumors. Detection of ctDNA after surgery and in serial plasma samples during follow-up were associated with poorer disease-free survival (DFS) [hazard ratio (HR), 17.56; log-rank P = 0.0014 and HR, 11.33; log-rank P = 0.0001, respectively]. Tracking at least two variants in plasma increased the ability to identify MRD to 87.5%. ctDNA was the only significantly independent predictor of DFS in multivariable analysis. In patients treated with adjuvant chemotherapy, presence of ctDNA after therapy was associated with early relapse (HR 10.02; log-rank P < 0.0001). Detection of ctDNA at follow-up preceded radiological recurrence with a median lead time of 11.5 months. CONCLUSIONS: Plasma postoperative ctDNA detected MRD and identified patients at high risk of relapse in localized CC. Mutation tracking with more than one variant in serial plasma samples improved our accuracy in predicting MRD.

Towards precision oncology for HER2 blockade in gastroesophageal adenocarcinoma.

Gastroesophageal adenocarcinoma (GEA) represents a very heterogeneous disease and patients in advanced stages have a very poor prognosis. Although several molecular classifications have been proposed, precision medicine for HER2-amplified GEA patients still represents a challenge. Despite improvement in clinical outcomes obtained by adding trastuzumab to first-line platinum-based chemotherapy, no other anti-HER2 agents used first-line or beyond progression have demonstrated any benefit. Several factors contribute to this failure. Among them, variable HER2 amplification assessment, tumour heterogeneity, molecular mechanisms of resistance and microenvironmental factors could limit the effectiveness of anti-HER2 blockade. Identifying the factors responsible for both primary and acquired resistance is a priority for providing an improved, personalised approach. In this review, we examine current treatments for HER2-amplified GEA, their potential mechanisms of resistance and the ways to overcome them, investigating the most relevant translational studies with anti-HER2 agents in GEA, as well as novel agents under development in this field.

VEGF and TSP1 levels correlate with prognosis in advanced non-small cell lung cancer.

PURPOSE: There is a need for biomarkers that may help in selecting the most effective anticancer treatments for each patient. We have investigated the prognostic value of a set of angiogenesis, inflammation and coagulation markers in patients treated for advanced non-small cell lung cancer. PATIENTS AND METHODS: Peripheral blood samples were obtained from 60 patients before first line platinum-based chemotherapy ± bevacizumab, and after the third cycle of treatment. Blood samples from 60 healthy volunteers were also obtained as controls. Angiogenesis, inflammation and coagulation markers vascular endothelial growth factor (VEGF), their soluble receptors 1 (VEGFR1) and 2 (VEGFR2), thrombospondin-1 (TSP-1), interleukin-6 (IL6), sialic acid (SA) and tissue factor (TF) were quantified by ELISA. RESULTS: Except for TSP-1, pre- and post-treatment levels of all markers were higher in patients than in controls (p < 0.05). There was a positive and significant correlation between VEGF and VEGFR2 before treatment. VEGF also correlated with inflammatory markers IL-6 and SA. Moreover, there was a positive and significant correlation between levels of VEGFR1 and TF. Decreased levels of TSP-1 and increased levels of VEGF were associated with shorter survival. Bevacizumab significantly modified angiogenesis parameters and caused a decrease of VEGF and an increase of TSP-1. CONCLUSION: Angiogenesis, inflammation and coagulation markers were increased in NSCLC patients. Increased levels of VEGF and low levels of TSP-1 correlated with a poor prognosis.

Conocimiento y Práctica sobre enfermedad periodontal de los pacientes que acudieron a la cátedra de Periodoncia de la Facultad de Odontología de la Universidad Nacional de Asunción en el año 2010 / Knowledge and Practice of periodontal disease patients attending the department of Periodontology, Faculty of Dentistry, National University of Asuncion in 2010

La enfermedad periodontal es una enfermedad de carácter infeccioso que afecta a los tejidos que rodean y sostienen a los dientes. Se caracteriza por pasar durante la mayor parte de su existencia desapercibida para quien la sufre. El gran problema que acarrea esta condición es que, si no existen medidas preventivas y de autodiagnóstico, cuando sus síntomas se hacen evidentes ya es probable que existan piezas dentales muy comprometidas con la infección, corriendo el riesgo de perderlas. Se realizó un estudio observacional descriptivo de corte transversal con muestreo no probabilístico de casos consecutivos que tuvo como objetivo determinar el conocimiento y práctica sobre enfermedad periodontal de los pacientes que acudieron a la cátedra de Periodoncia de la Facultad de Odontología de la Universidad Nacional de Asunción en el año 2010, para lo cual se aplicó un cuestionario estructurado autocumplimentado con preguntas de opciones múltiples sobre conocimientos y prácticas relacionados con la enfermedad periodontal. La muestra estuvo constituida por 94 pacientes de ambos sexos. Los resultados del estudio demostraron que el 96,8% de los pacientes posee conocimiento suficiente y que el 67% de ellos realiza prácticas inadecuadas.

Repercusion neonatal de la toxemia gravidica. / Neonatal repercusion of pregnancy toxemia

Reiterados estudios han senalado la repercusion de la gestosis sobre el recien nacido. En este trabajo se analizan retrospectivamente 68 fichas perinatales precodificadas de recien nacidos cuyas madres presentaron toxemia, comparandolos con 200 recien nacidos producto de embarazos normales. Se encontraron diferencias significativas en la duracion del embarazo, el puntaje de Apgar a los cinco minutos, en el estado nutricional de los recien nacidos y en la frecuencia de las alteraciones neurologicas. Se encontro tambien una diferencia en la frecuencia de sindrome de dificultad respiratoria idiopatica, aunque no fue significativa. No hubo diferencias en la mortalidad entre los dos grupos. Se sugiere que la falta de control de las madres gestosicas es uno de los factores determinantes de los resultados obtenidos