NOVA2 regulates the properties of liver cancer stem cells and lenvatinib resistance in hepatocellular carcinoma via the Wnt pathway.

Background: The regulation of cancer stem cells (CSCs) is influenced by RNA-binding proteins (RBPs). The present study sought to investigate the role of NOVA2 in the processes of self-renewal, carcinogenesis, and lenvatinib resistance in liver CSCs. Methods: Neuro-oncological ventral antigen 2 (NOVA2) expression in liver CSCs was examined by real-time polymerase chain reaction (PCR). In vitro experiments were used to assess the effects of NOVA2 on liver CSC expansion and lenvatinib resistance. Results: In our study, the expression of the RBP NOVA2 was higher in CSCs. NOVA2 also increased the capacity for self-renewal and carcinogenesis of the liver CSCs via the Wnt pathway. Further, suppressing the Wnt pathway leads to desensitization of the hepatocellular carcinoma (HCC) cells that overexpress NOVA2 to apoptosis caused by lenvatinib. Analyzing patient data confirmed reduced levels of NOVA2 and therefore we speculate that NOVA2 may serve as a potential indicator for response to lenvatinib in patients with HCC. Methyltransferase-like 3 (METTL3) and YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1)-dependent N6-methyladenosine (m6A) methylation were linked to upregulation of NOVA2 in HCC. Furthermore, it was shown that the expression of METTL3 was elevated in cellular models of type 2 diabetes mellitus (T2DM). Conclusions: NOVA2 is involved in the process of liver CSC self-renewal and carcinogenesis. In addition, NOVA2 expression may help identify patients with a higher chance of benefiting from lenvatinib treatment and can be a promising therapeutic target for HCC.

Support Through Remote Observation and Nutrition Guidance (STRONG), a digital health intervention to reduce malnutrition among pancreatic cancer patients: A study protocol for a pilot randomized controlled trial.

Background: Malnutrition is a common and distressing condition among pancreatic cancer patients. Fewer than a quarter of pancreatic cancer patients receive medical nutrition therapy (MNT), important for improving nutritional status, weight maintenance, quality of life and survival. System, provider, and patient level barriers limit access to MNT. We propose to examine the feasibility of a 12-week multi-level, digital health intervention designed to expand MNT access among pancreatic cancer patients. Methods: Individuals with advanced pancreatic cancer starting chemotherapy (N = 80) will be 1:1 randomized to the intervention or usual care. The Support Through Remote Observation and Nutrition Guidance (STRONG) intervention includes system-level (e.g., routine malnutrition and screening), provider-level (e.g., dietitian training and web-based dashboard), and patient-level strategies (e.g., individualized nutrition plan, self-monitoring of dietary intake via Fitbit, ongoing goal monitoring and feedback). Individuals receiving usual care will be referred to dietitians based on their oncologists' discretion. Study assessments will be completed at baseline, 4-, 8-, 12-, and 16-weeks. Results: Primary outcomes will be feasibility (e.g., recruitment, retention, assessment completion) and acceptability. We will collect additional implementation outcomes, such as intervention adherence, perceived usability, and feedback on intervention quality via an exit interview. We will collect preliminary data on outcomes that may be associated with the intervention including malnutrition, quality of life, treatment outcomes, and survival. Conclusion: This study will advance our knowledge on the feasibility of a digital health intervention to reduce malnutrition among individuals with advanced pancreatic cancer. Trial registration: NCT05675059, registered on December 9, 2022.

Efficacy and safety of Zolbetuximab plus chemotherapy for advanced CLDN18.2-positive gastric or gastro-oesophageal adenocarcinoma: a meta-analysis of randomized clinical trials.

BACKGROUND: The benefit of adding Zolbetuximab to the treatment in patients with Claudin-18 isoform 2 (CLDN18.2)-positive, human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJ) is not yet fully elucidated. METHODS: We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) that investigated Zolbetuximab plus chemotherapy versus chemotherapy alone for GC or GEJ adenocarcinoma. We computed hazard-ratios (HRs) or odds-ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). RESULTS: Three studies and 1,233 patients were included. Comparing with Zolbetuximab plus chemotherapy versus chemotherapy alone, progression-free survival (PFS) rate (HR 0.64; 95% CI 0.49-0.84; p < 0.01) and overall survival (OS) rate (HR 0.72; 95% CI 0.62-0.83; p < 0.01) were significant in favor of the Zolbetuximab group. Regarding effectiveness, the Objective Response Rate (ORR) was (OR 1.15; 95% CI 0.87-1.53; p = 0.34). CONCLUSIONS: In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of Zolbetuximab alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with advanced CLDN18.2-positive GC/GEJ cancer.

Prognostic Impact of Primary Tumor Sidedness in Stage III Colorectal Cancer: Real-World Evidence from a Brazilian Cohort.

BACKGROUND: Primary tumor sidedness (PTS) is an independent prognostic factor in patients with metastatic colorectal cancer (CRC), with a worse prognosis for right-sided tumors. There are limited data on the prognostic impact of PTS in stage III CRC. The main objective of this study was to analyze the prognostic impact of PTS in stage III CRC. PATIENTS AND METHODS: A retrospective and uni-institutional cohort study was performed in an oncology reference center. Patients with stage III CRC treated with a 5-fluorouracil and oxaliplatin-based chemotherapy regimen (mFLOX regimen) from October 2007 to February 2013 were included. The primary outcome was the probability of overall survival (OS) at 5 years stratified by PTS. Secondary outcomes were the probability of disease-free survival (DFS) at 5 years and an analysis of the prognostic impact of clinical and molecular biomarkers. Kaplan‒Meier curves were used, and Cox models were used to evaluate prognostic factors associated with OS and DFS. RESULTS: Overall, 265 patients were evaluated. Transverse colon tumors, multicentric tumors, and undetermined primary subsites were excluded, resulting in 234 patients classified according to PTS: 95 with right sidedness (40.6%) and 139 with left sidedness (59.4%). The median follow-up time was 66 months [interquartile range (IQR): 39-81]. The 5-year OS probabilities for right-sided and left-sided tumors were 67% (95% CI: 58%-77%) and 82% (75%-89%), respectively [hazard ratio (HR): 2.02, 95% CI: 1.18-3.46; P = .010]. The 5-year probabilities of DFS for right-sided and left-sided tumors were 58% (49%-69%) and 65% (58%-74%), respectively (HR: 1.29, 0.84-1.97; P = 0.248). CONCLUSION: These data suggest that there may be a worse prognosis (inferior OS at 5 years) for resected right-sided stage III CRC patients treated in the real world. However, these data need to be confirmed by prospective studies with a larger number of participants.

A multi-center retrospective study on the efficacy and safety of regorafenib vs. regorafenib combined with PD-1 inhibitors as a second-line therapy in patients with advanced hepatocellular carcinoma.

Background: At present, there are no definitive optimal treatment options for patients with hepatocellular carcinoma (HCC) following first-line treatment failure. To maximize the survival benefit of patients, we compared the combination therapy of regorafenib and programmed death-1 (PD-1) inhibitors with regorafenib monotherapy as a second-line treatment for patients with advanced HCC. Methods: Our multicenter retrospective study evaluated consecutive patients with advanced HCC who received regorafenib plus PD-1 inhibitors or regorafenib alone as a later-line therapy from May 2019 to January 2022. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, and safety was assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: A total of 133 patients were included in the study (regardless of first-line treatment), including 94 who received regorafenib plus PD-1 inhibitors and 39 who received regorafenib. The regorafenib plus PD-1 inhibitors group had a significantly higher ORR (25.53% vs. 10.26%, P=0.015), higher DCR (87.23% vs. 66.67%, P=0.006), and longer PFS (median 9.0 vs. 4.0 months, P<0.0001) than the regorafenib group. Meanwhile, the median OS (mOS) did not differ between the regorafenib plus PD-1 and regorafenib monotherapy groups {mOS, 14.0 months [95% confidence interval (CI), 14.0-16.0 months] vs. 12.0 months (95% CI, 10.0-22.0 months)}. There was no notable difference in the total incidence of treatment-related adverse effects (TRAEs) (71.79% vs. 78.72%, P=0.39) and the incidence of grade 3/4 serious adverse effects (5.13% vs. 18.09%, P=0.19) between the regorafenib monotherapy group and PD-1 inhibitors combination group. Conclusions: Compared with regorafenib alone, regorafenib combined with PD-1 inhibitors therapy increased PFS, ORR but did not improve OS, and can be used an option in second-line HCC therapy, regardless of first-line treatments. Regorafenib combined with PD-1 inhibitors is recommended as early as a second-line therapy to benefit patients. The combination regimen was as safe as regorafenib monotherapy for treatment of HCC in patients with compensated liver disease [Child-Turcotte-Pugh (CTP) A/B].

Advances in MRI-Based Assessment of Rectal Cancer Post-Neoadjuvant Therapy: A Comprehensive Review.

Rectal cancer presents significant diagnostic and therapeutic challenges, with neoadjuvant therapy playing a pivotal role in improving resectability and patient outcomes. MRI serves as a critical tool in assessing treatment response. However, differentiating viable tumor tissue from therapy-induced changes on MRI remains a complex task. In this comprehensive review, we explore treatment options for rectal cancer based on resectability status, focusing on the role of MRI in guiding therapeutic decisions. We delve into the nuances of MRI-based evaluation of treatment response following neoadjuvant therapy, paying particular attention to emerging techniques like radiomics. Drawing from our insights based on the literature, we provide essential recommendations for post-neoadjuvant therapy management of rectal cancer, all within the context of MRI-based findings.

Tremelimumab and durvalumab in the treatment of unresectable, advanced hepatocellular carcinoma.

Liver cancer is the third most common cause of cancer-related mortality worldwide, with over 780,000 deaths in 2018. About 90% of liver cancer cases are hepatocellular carcinoma (HCC), a prototype of inflammation-driven cancer, leading to a robust rationale for the exploration of immune therapy. Previously approved agents for first-line therapy, such as sorafenib, lenvatinib and bevacizumab combined with atezolizumab, have focused on angiogenesis. HIMALAYA was the first trial to demonstrate the benefit of dual immune checkpoint inhibitors, representing a new treatment option in this scenario.

Liver cancer is the third most common cause of cancer-related mortality worldwide, with over 780,000 deaths in 2018. About 90% of liver cancer cases originate in liver cells and are referred to as hepatocellular carcinoma (HCC). Systemic treatment (medications) is the mainstay for patients with advanced disease who are not suitable for resection or liver transplant and aims to improve survival and quality of life. HIMALAYA was the first study to demonstrate the benefit of using a combination of two immunotherapy medications for initial treatment.

The development and validation of a novel senescence-related long-chain non-coding RNA (lncRNA) signature that predicts prognosis and the tumor microenvironment of patients with hepatocellular carcinoma.

Background: The epigenetic regulators of cellular senescence, especially long non-coding RNAs (lncRNAs), remain unclear. The expression levels of lncRNA were previously known to be prognostic indicators for tumors. We hypothesized that lncRNAs regulating cellular senescence could also predict prognosis in patients with hepatocellular carcinoma (HCC) and developed a novel lncRNA predictive signature. Methods: Using RNA sequencing data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) database, a co-expression network of senescence-related messenger RNAs (mRNAs) and lncRNAs was constructed. Using univariate Cox regression analysis and a stepwise multiple Cox regression analysis, we constructed a prognostic HCC senescence-related lncRNA signature (HCCSenLncSig). Kaplan-Meier analysis was used to compare the overall survival (OS) of high- and low-risk groups stratified by the HCCSenLncSig. Furthermore, the HCCSenLncSig risk score and other clinical characteristics were included to develop an HCC prognostic nomogram. The accuracy of the model was evaluated by the time dependent receiver operating characteristic (ROC) and calibration curves, respectively. Results: We obtained a prognostic risk model consisting of 8 senescence-related lncRNAs: AL117336.3, AC103760.1, FOXD2-AS1, AC009283.1, AC026401.3, AC021491.4, AC124067.4, and RHPN1-AS1. The HCCSenLncSig high-risk group was associated with poor OS [hazard ratio (HR) =1.125, 95% confidence interval (CI): 1.082-1.169; P<0.001]. The accuracy of the model was further supported by ROC curves (the area under the curve is 0.783, sensitivity of 0.600, and specificity of 0.896 at the cut-off value of 1.447). The HCCSenLncSig was found to be an independent prognostic factor from other clinical factors in both univariate and multivariate Cox regression analyses. The prognostic nomogram shows HCCSenLncSig has a good prognostic effect for survival risk stratification. Finally, we found that a higher number of immunosuppressed Treg cells infiltrate in high-risk patients (P<0.001 compared to low-risk patients), possibly explaining why these patients have a poor prognosis. On the other hand, the expression of immunotherapy markers, such as CD276, PDCD1, and CTLA4, was also up-regulated in the high-risk patients, indicating potential immunotherapy response in these patients. Conclusions: The development of HCCSenLncSig allows us to better predict HCC patients' survival outcomes and disease risk, as well as contribute to the development of novel HCC anti-cancer therapeutic strategies.

SURGICAL TREATMENT IN CLINICAL STAGE IV GASTRIC CANCER: A COMPARISON OF DIFFERENT PROCEDURES AND SURVIVAL OUTCOMES.

AIM: Even in clinical stage IV gastric cancer (GC), surgical procedures may be required to palliate symptoms or in an attempt to improve survival. However, the limited survival of these patients raises doubts about who really had benefits from it. This study aimed to analyze the surgical outcomes in stage IV GC treated with surgical procedures without curative intent. METHODS: Retrospective analyses of patients with stage IV GC submitted to surgical procedures including tumor resection, bypass, jejunostomy, and diagnostic laparoscopy were performed. Patients with GC undergoing curative gastrectomy served as the comparison group. RESULTS: Surgical procedures in clinical stage IV were performed in 363 patients. Compared to curative surgery (680 patients), stage IV patients had a higher rate of comorbidities and ASA III/IV classification. The surgical procedures that were performed included 107 (29.4%) bypass procedures (partitioning/gastrojejunal anastomosis), 85 (23.4%) jejunostomies, 76 (20.9%) resections, and 76 (20.9%) diagnostic laparoscopies. Regarding patients' characteristics, resected patients had more distant metastasis (p=0.011), bypass patients were associated with disease in more than one site (p<0.001), and laparoscopy patients had more peritoneal metastasis (p<0.001). According to the type of surgery, the median overall survival was as follows: resection (13.6 months), bypass (7.8 months), jejunostomy (2.7 months), and diagnostic (7.8 months, p<0.001). On multivariate analysis, low albumin levels, in case of more than one site of disease, jejunostomy, and laparoscopy, were associated with worse survival. CONCLUSION: Stage IV resected cases have better survival, while patients submitted to jejunostomy and diagnostic laparoscopy had the worst results. The proper identification of patients who would benefit from surgical resection may improve survival and avoid futile procedures.

GASTRIC CANCER WITH POSITIVE EXPRESSION OF ESTROGEN RECEPTOR ALPHA: A CASE SERIES FROM A SINGLE WESTERN CENTER. / CÂNCER GÁSTRICO COM EXPRESSÃO POSITIVA DO RECEPTOR DE ESTROGÊNIO ALFA: UMA SÉRIE DE CASOS DE UM ÚNICO CENTRO OCIDENTAL.

AIM: Despite advances in therapies, the prognosis of patients with advanced gastric cancer (GC) remains poor. Several studies have demonstrated the expression of estrogen receptor alpha (ERa); however, its significance in GC remains controversial. The present study aims to report a case series of GC with ERa-positive expression and describe their clinicopathological characteristics and prognosis. METHODS: We retrospectively evaluated patients with GC who underwent gastrectomy with curative intent between 2009 and 2019. ERa expression was assessed by immunohistochemistry through tissue microarray construction. Patients with ERa-negative gastric adenocarcinoma served as a comparison group. RESULTS: During the selected period, 6 (1.8%) ERa-positive GC were identified among the 345 GC patients analyzed. All ERa-positive patients were men, aged 34-78 years, and had Lauren diffuse GC and pN+ status. Compared with ERa-negative patients, ERa-positive patients had larger tumor size (p=0.031), total gastrectomy (p=0.012), diffuse/mixed Lauren type (p=0.012), presence of perineural invasion (p=0.030), and lymph node metastasis (p=0.215). The final stage was IIA in one case, IIIA in three cases, and IIIB in two cases. Among the six ERa-positive patients, three had disease recurrence (peritoneal) and died. There was no significant difference in survival between ERa-positive and ERa-negative groups. CONCLUSIONS: ERa expression is less common in GC, is associated with diffuse histology and presence of lymph node metastasis, and may be a marker related to tumor progression and worse prognosis. Also, a high rate of peritoneal recurrence was observed in ERa-positive patients.

OBJETIVO: Apesar do avanço nas terapias, o prognóstico de pacientes com câncer gástrico (CG) avançado permanece ruim. Vários estudos demonstraram a expressão do receptor de estrogênio alfa (REa), porém seu significado no CG permanece controverso. relatar uma série de casos de CG com expressão de REa-positivo, e descrever suas características clínicopatológicas e prognóstico. MÉTODOS: Avaliamos retrospectivamente os pacientes com CG submetidos à gastrectomia com intenção curativa entre 2009 e 2019. A expressão do REa foi avaliada por imuno-histoquímica por meio da construção de microarranjos de tecido (TMA). Pacientes com adenocarcinoma gástrico ERa-negativos serviram como grupo comparação. RESULTADOS: No período selecionado, foram identificados 6 (1,8%) CG REa-positivos entre os 345 CG analisados. Todos os ERa-positivos eram homens, com idades entre 34-78 anos, tinham CG do tipo difuso de Lauren e pN+. Comparado aos REa-negativos, os CG REa-positivos associaram-se a maior diâmetro (p=0,031), gastrectomia total (p=0,012), tipo de Lauren difuso/misto (p=0,012), presença de invasão perineural (p=0,030) e metástase linfonodal (p=0,215). O estágio final foi o IIA em um caso; IIIA em três e IIIB em dois casos. Entre os 6 pacientes REa -positivos, 3 tiveram recorrência da doença (peritoneal) e morreram. Não houve diferença significativa na sobrevida entre os grupos REa-positivo e negativo. CONCLUSÃO: A expressão do REa é menos comum no CG, estando associada à histologia difusa e presença de metástases linfonodal, podendo servir como um marcador relacionado à progressão tumoral e pior prognóstico. Além disso, uma alta taxa de recorrência peritoneal foi observada em pacientes ERa-positivos.

Surgical treatment in clinical stage iv gastric cancer: a comparison of different procedures and survival outcomes / Tratamento cirúrgico no câncer gástrico estágio clínico iv: uma comparação de diferentes procedimentos e resultados de sobrevida

ABSTRACT - BACKGROUND: Even in clinical stage IV gastric cancer (GC), surgical procedures may be required to palliate symptoms or in an attempt to improve survival. However, the limited survival of these patients raises doubts about who really had benefits from it. AIM: This study aimed to analyze the surgical outcomes in stage IV GC treated with surgical procedures without curative intent. METHODS: Retrospective analyses of patients with stage IV GC submitted to surgical procedures including tumor resection, bypass, jejunostomy, and diagnostic laparoscopy were performed. Patients with GC undergoing curative gastrectomy served as the comparison group. RESULTS: Surgical procedures in clinical stage IV were performed in 363 patients. Compared to curative surgery (680 patients), stage IV patients had a higher rate of comorbidities and ASA III/IV classification. The surgical procedures that were performed included 107 (29.4%) bypass procedures (partitioning/gastrojejunal anastomosis), 85 (23.4%) jejunostomies, 76 (20.9%) resections, and 76 (20.9%) diagnostic laparoscopies. Regarding patients' characteristics, resected patients had more distant metastasis (p=0.011), bypass patients were associated with disease in more than one site (p<0.001), and laparoscopy patients had more peritoneal metastasis (p<0.001). According to the type of surgery, the median overall survival was as follows: resection (13.6 months), bypass (7.8 months), jejunostomy (2.7 months), and diagnostic (7.8 months, p<0.001). On multivariate analysis, low albumin levels, in case of more than one site of disease, jejunostomy, and laparoscopy, were associated with worse survival. CONCLUSION: Stage IV resected cases have better survival, while patients submitted to jejunostomy and diagnostic laparoscopy had the worst results. The proper identification of patients who would benefit from surgical resection may improve survival and avoid futile procedures.

RESUMO - RACIONAL: Mesmo no câncer gástrico (CG) em estágio clínico IV (ECIV), procedimentos cirúrgicos podem ser necessários para aliviar sintomas ou na tentativa de melhorar a sobrevida. No entanto, a sobrevida limitada desses pacientes levanta dúvidas sobre quem realmente se beneficiaria. OBJETIVO: Analisar os resultados cirúrgicos do CG ECIV tratado com procedimentos cirúrgicos sem intenção curativa. MÉTODOS: Análise retrospectiva dos pacientes com CG ECIV submetido a procedimentos cirúrgicos, incluindo: ressecção tumoral, bypass, jejunostomia e laparoscopia diagnóstica. Pacientes submetidos à gastrectomia curativa serviram como grupo de comparação. RESULTADOS: Os procedimentos cirúrgicos em ECIV foram realizados em 363 pacientes. Comparado à cirurgia curativa (680 pacientes), os pacientes em ECIV apresentaram maior taxa de comorbidades e classificação ASA III/IV. Os procedimentos cirúrgicos realizados foram: 107 (29,4%) bypass (partição/anastomose gastrojejunal), 85 (23,4%) jejunostomias, 76 (20,9%) ressecções e 76 (20,9%) laparoscopias diagnósticas. Em relação às características dos pacientes, os ressecados apresentaram predomínio de metástases distantes (p=0,011); os de bypass associaram-se a doença em mais de um sítio (p<0,001); e os laparoscópicos, metástases peritoneais (p<0,001). A sobrevida global mediana de acordo com o tipo de cirurgia foi: ressecção (13,6 meses), bypass (7,8 meses), jejunostomia (2,7 meses) e diagnóstica (7,8 meses) (p<0,001). Na análise multivariada, níveis baixos de albumina, mais de um sítio de doença, jejunostomia e laparoscopia associaram-se a pior sobrevida. CONCLUSÃO: Pacientes em ECIV ressecados apresentam melhor sobrevida, enquanto aqueles submetidos à jejunostomia e laparoscopia diagnóstica tiveram piores resultados. A identificação adequada dos pacientes que se beneficiariam com a ressecção cirúrgica pode melhorar a sobrevida e evitar procedimentos pouco eficazes.

Cytotoxic T-lymphocyte-associated protein 4 in gastric cancer: Prognosis and association with PD-L1 expression.

BACKGROUND: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is one of the most studied immune checkpoint in gastric cancer (GC). However, the prognostic role of CTLA-4 expression in GC is poorly described. This study aimed to evaluate CTLA-4 expression in GC and its impact on survival, including patients treated with standard platinum-based chemotherapy (CMT), and association with PD-L1 expression. METHODS: All GC patients who underwent D2-gastrectomy were investigated retrospectively. Tumor samples were examined for CTLA-4 and PD-L1 by immunohistochemistry. Tumor-infiltrating inflammatory cells, including CD4 + and CD8 + , were also examined. RESULTS: Among the 284 GC patients included, 159 (56%) were CTLA-4 positive and the remaining 125 (44%) were classified as negative. CTLA-4 positive GC was associated with increased inflammatory cell infiltration (p < 0.001), high CD8 + T cells (p = 0.016) and PD-L1 expression (p = 0.026). Considering GC referred for treatment, CTLA-4 negative patients who received CMT had a significant improvement in disease-free survival compared to untreated CLTA-4 negative (p = 0.028). In multivariate analysis, GC positive for both CTLA-4 and PD-L1 had a prognostic impact on survival. CONCLUSION: CTLA-4 positive was associated with PD-L1 expression and a high tumor-infiltrating CD8 + T cells. Accordingly, positivity for both CTLA-4 and PD-L1 was an independent factor associated to better survival in GC patients.

Epidemiology and Outcomes of Patients With Brain Metastases From Colorectal Cancer-Who Are These Patients?

BACKGROUND: Brain metastases (BMs) from colorectal cancer (CRC) are unusual; however, an increase in incidence has been reported. The evidence available on the subject is scarce, and a better understanding is warranted. We aimed to characterize the epidemiology and the outcomes of patients with BMs from CRC. PATIENTS AND METHODS: A cohort of patients with BMs from CRC was retrospectively evaluated. Patients were treated in a single center between May 2008 and April 2019. BMs were confirmed by brain computed tomography or magnetic resonance imaging. RESULTS: A total of 247 consecutive patients were evaluated. Most patients had a left-sided primary tumor (193, 78%) and at least two extra-cranial metastatic sites (194, 78%). Ninety-six patients (39%) were RAS wild-type; 68 patients (27%) were RAS mutated; and 83 patients (34%) were not characterized. Median time from the initial diagnosis to BMs was 27.6 months (interquartile range, 13.1-46.9). Regarding local therapy, 43 patients (17.4%) were treated with BM surgery alone, 76 patients (30.8%) with radiotherapy (RT) alone, and 58 patients (23.5%) with both surgery and RT. Median overall survival (OS) was 2.9 months (95% confidence interval [CI], 2.2-3.5). Six-month and 1-year OS rates were 29% (95% CI, 23-25) and 13.5% (95% CI, 9.2-18.6), respectively. In a multivariable analysis, BM surgery alone (hazard ratio [HR], 0.56; P = .018), RT alone (HR, 0.51; P = .001), and surgery plus RT (HR, 0.27; P < .001) were associated with superior OS, whereas Eastern Cooperative Oncology Group Performance Status 3 or 4 (HR, 2.01; P = .009) and male gender (HR, 1.46; P = .012) were negative prognostic factors. RAS status was not associated with OS. CONCLUSION: BMs occur late during the course of colorectal cancer and are more common in patients with a left-sided primary tumor and a high volume of metastatic disease. BMs from colorectal cancer are still associated with an extremely poor prognosis; however, selected patients may benefit from treatment with surgical resection and radiotherapy.

Hepatoid esophagogastric adenocarcinoma and tumoral heterogeneity: a case report.

Hepatoid adenocarcinoma of the stomach is an uncommon subtype of gastric cancer remarkably similar to hepatocellular carcinoma in histopathological analysis. It is also commonly associated with high serum alfa-fetoprotein and a poorer prognosis, despite the emergence of new therapeutic options. In recent years, next generation sequencing (NGS) technology has made it possible to identify and describe the genes and molecular alterations common to gastric cancer thereby contributing to the advancement of targeted therapies. A 62-year-old patient, with no prior risk factor for hepatocellular carcinoma (HCC), presented to the emergency room with dysphagia for solids, abdominal pain and weight loss of about 3 kilograms over 3 months. Histopathological analysis presented with disparities regarding HER2 and programmed death-ligand 1 (PD-L1) status in the primary and metastatic sites. We describe a case of a de novo metastatic, human epidermal growth factor receptor 2 (HER2) positive esophagogastric junction hepatoid adenocarcinoma. Although this is a rare subgroup of gastric cancer, treatment strategies were based in recent studies in immunotherapy and guided therapy, taking into consideration the molecular findings from the patient's tumor NGS analysis. Data about HER2 and PDL1 heterogeneity were also reviewed. Despite the aggressiveness and rarity of this histology, the patient had a good response to treatment.

RhoA, Claudin 18, and c-MET in Gastric Cancer: Clinicopathological Characteristics and Prognostic Significance in Curative Resected Patients.

Background: Recently, markers related to molecular classification were suggested as promising therapeutic targets for treatment and prediction of prognosis in gastric cancer (GC), including c-MET, RhoA, and Claudin-18 (CLDN18). This study aimed to investigate their expression in GC and its correlation with clinicopathological characteristics and survival. Methods: We retrospectively evaluated GC patients who underwent curative gastrectomy. c-MET, RhoA, and CLDN18 were analyzed through immunohistochemistry (IHC), and groups for analysis were determined according to the median values obtained for each marker. Results: Among the 349 GC evaluated, 180 (51.6%), 59 (16.9%), and 61 (17.5%) patients were completely negative for c-MET, RhoA, and CLDN18, respectively. Total gastrectomy, D1 lymphadenectomy, poorly differentiated histology, and greater inflammatory infiltrate were more frequent in the c-MET-negative group. Diffuse type, greater inflammatory infiltrate, and advanced pT and pTNM stage were associated with low-RhoA GC. The venous invasion was more frequent in the low-CLDN18 group. Furthermore, c-MET was positively correlated with RhoA and negatively with CLDN18. HER2 expression was associated with c-MET-positive and high-CLDN18 GC; and loss of E-cadherin expression in c-MET-negative and low-RhoA GC. c-MET-negative and Low-RhoA were significantly associated with worse disease-free survival. Conclusions: c-MET, RhoA, and CLD18 expression occurred frequently in GC. RhoA GC had distinct clinicopathological characteristics related to prognosis. c-MET and RhoA were associated with survival but were not independent predictors of prognosis.

Scoring systems for PD-L1 expression and their prognostic impact in patients with resectable gastric cancer.

The combined positive score (CPS) and tumor proportion score (TPS) have been developed to evaluate programmed death ligand-1 (PD-L1) expression, especially due to the potential benefit of the targeted therapy. However, the prognostic value of PD-L1 scoring systems in gastric cancer (GC) remains unclear. This study aimed to evaluate PD-L1 expression according to CPS and TPS in curative resected GC patients and its correlation with prognosis. We retrospectively evaluated 284 GC patients who underwent D2-gastrectomy by tissue microarray. PD-L1 expression was analyzed by immunohistochemistry. PD-L1 positivity by CPS and TPS was observed in 45 (15.8%) and 34 (12%) patients, respectively. Larger tumor size (p = 0.028), undetermined Lauren type (p < 0.001), and heavy inflammatory infiltrate (p = 0.009) were associated with CPS-positive GC. TPS-positive were more frequent in patients with larger tumor size (p = 0.004), undetermined type (p < 0.001), moderate/severe inflammatory infiltrate (p = 0.001), total gastrectomy (p = 0.036), and poorly differentiated histology (p = 0.025). No differences were observed in the pT, pN, and pTNM status according to the PD-L1 scores. Both scores were associated with Epstein-Barr virus positivity, microsatellite instability and p53-normal expression. The disease-free survival (DFS) was worse for CPS-negative compared to CPS-positive group (p = 0.052). No difference was observed between TPS-positive and negative groups (p = 0.436). Total gastrectomy, advanced pT status, and CPS-negative were independent factor for worse survival in GC. CPS was an independent prognostic factor for survival and could be used as a prognostic biomarker in patients with resectable GC.

Câncer gástrico com expressão positiva do receptor de estrogênio alfa: uma série de casos de um único centro ocidental / Gastric cancer with positive expression of estrogen receptor alpha: a case series from a single western center

RESUMO - RACIONAL: Apesar do avanço nas terapias, o prognóstico de pacientes com câncer gástrico (CG) avançado permanece ruim. Vários estudos demonstraram a expressão do receptor de estrogênio alfa (REa), porém seu significado no CG permanece controverso. OBJETIVO: relatar uma série de casos de CG com expressão de REa-positivo, e descrever suas características clínicopatológicas e prognóstico. MÉTODOS: Avaliamos retrospectivamente os pacientes com CG submetidos à gastrectomia com intenção curativa entre 2009 e 2019. A expressão do REa foi avaliada por imuno-histoquímica por meio da construção de microarranjos de tecido (TMA). Pacientes com adenocarcinoma gástrico ERa-negativos serviram como grupo comparação. RESULTADOS: No período selecionado, foram identificados 6 (1,8%) CG REa-positivos entre os 345 CG analisados. Todos os ERa-positivos eram homens, com idades entre 34-78 anos, tinham CG do tipo difuso de Lauren e pN+. Comparado aos REa-negativos, os CG REa-positivos associaram-se a maior diâmetro (p=0,031), gastrectomia total (p=0,012), tipo de Lauren difuso/misto (p=0,012), presença de invasão perineural (p=0,030) e metástase linfonodal (p=0,215). O estágio final foi o IIA em um caso; IIIA em três e IIIB em dois casos. Entre os 6 pacientes REa -positivos, 3 tiveram recorrência da doença (peritoneal) e morreram. Não houve diferença significativa na sobrevida entre os grupos REa-positivo e negativo. CONCLUSÃO: A expressão do REa é menos comum no CG, estando associada à histologia difusa e presença de metástases linfonodal, podendo servir como um marcador relacionado à progressão tumoral e pior prognóstico. Além disso, uma alta taxa de recorrência peritoneal foi observada em pacientes ERa-positivos.

ABSTRACT - BACKGROUND: Despite advances in therapies, the prognosis of patients with advanced gastric cancer (GC) remains poor. Several studies have demonstrated the expression of estrogen receptor alpha (ERa); however, its significance in GC remains controversial. AIM: The present study aims to report a case series of GC with ERa-positive expression and describe their clinicopathological characteristics and prognosis. METHODS: We retrospectively evaluated patients with GC who underwent gastrectomy with curative intent between 2009 and 2019. ERa expression was assessed by immunohistochemistry through tissue microarray construction. Patients with ERa-negative gastric adenocarcinoma served as a comparison group. RESULTS: During the selected period, 6 (1.8%) ERa-positive GC were identified among the 345 GC patients analyzed. All ERa-positive patients were men, aged 34-78 years, and had Lauren diffuse GC and pN+ status. Compared with ERa-negative patients, ERa-positive patients had larger tumor size (p=0.031), total gastrectomy (p=0.012), diffuse/mixed Lauren type (p=0.012), presence of perineural invasion (p=0.030), and lymph node metastasis (p=0.215). The final stage was IIA in one case, IIIA in three cases, and IIIB in two cases. Among the six ERa-positive patients, three had disease recurrence (peritoneal) and died. There was no significant difference in survival between ERa-positive and ERa-negative groups. CONCLUSIONS: ERa expression is less common in GC, is associated with diffuse histology and presence of lymph node metastasis, and may be a marker related to tumor progression and worse prognosis. Also, a high rate of peritoneal recurrence was observed in ERa-positive patients.

Brazilian gastric cancer association guidelines (part 2): update on treatment / Diretrizes da associação brasileira de câncer gástrico (parte 2): atualização sobre o tratamento

ABSTRACT Background : The II Brazilian Consensus on Gastric Cancer of the Brazilian Gastric Cancer Association BGCA (Part 1) was recently published. On this occasion, countless specialists working in the treatment of this disease expressed their opinion in the face of the statements presented. Aim : To present the BGCA Guidelines (Part 2) regarding indications for surgical treatment, operative techniques, extension of resection and multimodal treatment. Methods: To formulate these guidelines, the authors carried out an extensive and current review regarding each declaration present in the II Consensus, using the Medline/PubMed, Cochrane Library and SciELO databases initially with the following descriptors: gastric cancer, gastrectomy, lymphadenectomy, multimodal treatment. In addition, each statement was classified according to the level of evidence and degree of recommendation. Results : Of the 43 statements present in this study, 11 (25,6%) were classified with level of evidence A, 20 (46,5%) B and 12 (27,9%) C. Regarding the degree of recommendation, 18 (41,9%) statements obtained grade of recommendation 1, 14 (32,6%) 2a, 10 (23,3%) 2b e one (2,3%) 3. Conclusion : The guidelines complement of the guidelines presented here allows surgeons and oncologists who work to combat gastric cancer to offer the best possible treatment, according to the local conditions available.

RESUMO Racional: O II Consenso Brasileiro de Câncer Gástrico da Associação Brasileira de Câncer Gástrico ABCG (Parte 1) foi recentemente publicado. Nesta ocasião inúmeros especialistas que atuam no tratamento desta doença expressaram suas opiniões diante declarações apresentadas. Objetivo: Apresentar as Diretrizes da ABCG (Parte 2) quanto às indicações de tratamento cirúrgico, técnicas operatórias, extensão de ressecção e terapia combinada. Métodos: Para formulação destas diretrizes os autores realizaram extensa e atual revisão referente a cada declaração presente no II Consenso, utilizando as bases Medline/PubMed, Cochrane Library e SciELO, inicialmente com os seguintes descritores: câncer gástrico, gastrectomia, linfadenectomia, terapia combinada. Ainda, cada declaração foi classificada de acordo com o nível de evidência e grau de recomendação. Resultados: Das 43 declarações presentes neste estudo, 11 (25,6%) foram classificadas com nível de evidência A, 20 (46,5%) B e 12 (27,9%) C. Quanto ao grau de recomendação, 18 (41,9%) declarações obtiveram grau de recomendação 1, 14 (32,6%) 2a, 10 (23,3%) 2b e um (2,3%) 3. Conclusão: O complemento das diretrizes aqui presentes possibilita que cirurgiões e oncologistas que atuam no combate ao câncer gástrico possam oferecer o melhor tratamento possível, de acordo com as condições locais disponíveis.

Remnant gastric cancer: a neglected group with high potential for immunotherapy.

PURPOSE: The importance of targeted therapy and interest in the study of predictive markers in gastric cancer (GC) have increased in recent years with the use of anti-HER2 therapy and immunotherapy with anti-PD1/PD-L1 for microsatellite instability (MSI) and PD-L1 + tumors. However, the behavior of remnant GC (RGC) in this scenario is poorly reported. Thus, this study aims to evaluate the clinicopathological characteristics and prognosis of RGC and its association with the expression of current markers for targeted therapy. METHODS: All RGC resections performed in a single center from 2009 to 2019 were retrospectively reviewed. As a comparison group, 53 primary proximal GC (PGC) who underwent total D2-gastrectomy were selected. HER2, MSI status and PD-L1 expression were analyzed by immunohistochemistry. Combined Positive Score (CPS) was used to determine PD-L1 positivity. RESULTS: A total of 40 RGC were included. RGC patients were older (p = 0.001), had lower BMI (p = 0.001) and number of resected lymph nodes (p < 0.001) compared to the PGC. Regarding markers expression, MSI was higher in RGC than PGC (27.5% vs 9.4%, p = 0.022). The frequency of CPS-positive was 32.5% and 26.4% in RGC and PGC, respectively (p = 0.522). HER2 positivity was 17.5% and 22.6% for RGC and PGC, respectively (p = 0.543). In survival analysis, DFS was better for RGC CPS-positive than RGC CPS-negative (p = 0.039) patients. There was no difference in survival considering MSI status. CONCLUSION: RGC had higher incidence of MSI than PGC, and CPS-positive RGC was associated with better survival. The immunological profile of RGC patients suggests that they would be good candidates for immunotherapy.