Impact of Age at Diagnosis on Clinicopathological Features, Prognosis, and Management of Gastric Cancer: A Retrospective Single-Center Experience from Spain.

The impact of age on various aspects of gastric cancer (GC) remains controversial. Clarifying this issue can improve our understanding of the disease, refine risk stratification models, and aid in personalized therapeutic approaches. This study aimed to evaluate the influence of age at diagnosis on the clinicopathological features, prognosis, and management of a specific cohort of Spanish patients with resected GC. The study encompassed 315 patients treated at a single tertiary hospital in Spain, divided into two age-based subgroups: ≤65 years and >65 years. The mean and median ages at diagnosis were 72 and 76 years. Most tumors were diagnosed at pT3 stage (49.2%), and 59.6% of patients had lymph node metastases. 21.3% of cases were diagnosed with GC at age ≤ 65 years. Younger patients showed a significantly higher prevalence of flat, diffuse, high-grade tumors, signet-ring cells, perineural infiltration, D2 lymphadenectomies, and adjuvant therapy. They also exhibited a higher rate of recurrences, but had a significantly longer follow-up. Kaplan-Meier curves indicated no significant prognostic differences based on age. Finally, age did not independently predict overall survival or disease-free survival. Our results suggest that younger patients may require more aggressive treatment due to adverse clinicopathologic features, but the lack of prognostic differences among age groups in our cohort indicates the need for further investigation into the complex interplay between age, clinicopathologic factors, and long-term outcomes in GC.

Prognostic role of the number of resected and negative lymph nodes in Spanish patients with gastric cancer.

INTRODUCTION: Lymph node (LN) involvement is one of the most critical prognostic factors in resected gastric cancer (GC). Some analyses, mainly conducted in Asian populations, have found that patients with a higher number of total lymph nodes (NTLN) and/or negative lymph nodes (NNLN) have a better prognosis, although other authors have failed to confirm these results. MATERIALS AND METHODS: Retrospective study including all patients with GC resected in a tertiary hospital in Spain between 2001 and 2019 (n = 315). Clinicopathological features were collected and patients were categorized according to the NTLN and the NNLN. Statistical analyses were performed. RESULTS: Mean NNLN was 17. The NNLN was significantly related to multiple clinicopathological variables, including recurrence and tumor-related death. The classification based on the NNLN (N1: ≥16, N2: 8-15, N3: ≤7) effectively stratified the entire cohort into three distinct prognostic groups and maintained its prognostic value within both the pN0 and pN+ patient subsets. Furthermore, it was an independent prognostic indicator for both overall and disease-free survival. Conversely, the mean NTLN was 21.9. Patients with ≤16 LN retrieved exhibited distinct clinicopathological features compared to those with >16 LN, but no significant differences were observed in terms of recurrence or disease-associated death. The application of alternative cut-off points for NTLN (10, 20, 25, 30, and 40) showed no prognostic significance. CONCLUSIONS: In Spanish patients with resected GC the NNLN hold prognostic significance, while the NTLN does not appear to be prognostically significant. Incorporating the NNLN into GC staging may enhance the accuracy of the TNM system.

Clinicopathological differences, risk factors and prognostic scores for western patients with intestinal and diffuse-type gastric cancer.

BACKGROUND: In the molecular era, the Laurén system is still a cost-effective and widely implemented classification for gastric cancer (GC) and it has been recently associated with clinical, histological and molecular features of these tumors. Despite recent advances in the understanding of the molecular biology of GC, there is a need to develop new prognostic tools for patient stratification in clinical practice. Thus, the identification of easily available prognostic factors in patients with intestinal and diffuse-type tumors can significantly improve risk assessment and patient stratification in GC. AIM: To identify clinicopathological differences, risk factors, and to develop cost-effective prognostic scores for patients with intestinal and diffuse-type GC. METHODS: Retrospective study of all patients undergoing surgery for GC at a tertiary referral center from 2001 to 2019. 286 cases met inclusion criteria (intestinal: 190, diffuse: 96). Clinical data and gross findings were collected. All specimens were reviewed by two independent pathologists and a detailed protocol for histologic evaluation was followed. Five tissue microarrays (TMAs) were constructed and sections of the TMA block were immunostained for HERCEPTEST, MSH2, MSH6, MLH1 and PMS2. Statistical analyses were performed and prognostic scores were developed based on hazard ratios. RESULTS: Intestinal and diffuse-type GC showed different epidemiological, clinicopathological and prognostic features. Diffuse tumors were significantly associated with younger age, less symptomatology, flat morphology, deeper invasion, perineural infiltration, advanced stage at diagnosis, administration of adjuvant therapy and poorer prognosis. Intestinal lesions were fungoid or polypoid, showed necrosis, desmoplasia, microsatellite instability and HERCEPTEST positivity and were diagnosed at earlier stages. Tumor depth, desmoplasia, macroscopic type and lymph node involvement were independently related to the Laurén subtype. Furthermore, intestinal and diffuse GC were associated with different risk factors for progression and death. Vascular invasion, perineural infiltration and growth pattern were important prognostic factors in intestinal-type GC. On the contrary, tumor size and necrosis were significant prognosticators in diffuse-type GC. Our recurrence and cancer-specific death scores for patients with intestinal and diffuse-type GC showed an excellent patient stratification into three (diffuse GC) or four (intestinal) prognostic groups. CONCLUSION: Our findings support that Laurén subtypes represent different clinicopathological and biological entities. The development of specific prognostic scores is a useful and cost-effective strategy to improve risk assessment in GC.

Are Borrmann's Types of Advanced Gastric Cancer Distinct Clinicopathological and Molecular Entities? A Western Study.

Most studies on the clinicopathological impact of Borrmann classification for gastric cancer (GC) have been performed in Asian patients with type IV tumors, and immunohistochemical features of Borrmann types have scarcely been analyzed. We assessed the clinicopathological, molecular features and prognostic value of Borrmann types in all patients with advanced GC resected in a Western institution (n = 260). We observed a significant relationship between Borrmann types and age, systemic symptoms, tumor size, Laurén subtype, presence of signet-ring cells, infiltrative growth, high grade, tumor necrosis, HERCEPTEST positivity, microsatellite instability (MSI) and molecular subtypes. Polypoid GC showed systemic symptoms, intestinal-type histology, low grade, expansive growth and HERCEPTEST positivity. Fungating GC occurred in symptomatic older patients. It presented intestinal-type histology, infiltrative growth and necrosis. Ulcerated GC showed smaller size, intestinal-type histology, high grade and infiltrative growth. Most polypoid and ulcerated tumors were stable-p53-not overexpressed or microsatellite unstable. Flat lesions were high-grade diffuse tumors with no MSI, and occurred in younger and less symptomatic patients. No association was found between Borrmann classification and prognosis. According to our results, Borrmann types may represent distinct clinicopathological and biological entities. Further research should be conducted to confirm the role of Borrmann classification in the stratification of patients with advanced GC.

Targeting Galectin-1 by Aflibercept Strongly Enhances Its Antitumor Effect in Neuroendocrine Carcinomas.

BACKGROUND: Galectin-1 (Gal-1) plays major roles in cancer by modulating different processes leading to tumor development and progression. In the last years, it has been suggested as a promising target for anticancer therapy. Recently, aflibercept has shown high affinity for Gal-1. Here, we investigated how aflibercept could exert its antitumor activity via Gal-1-driven pathways in neuroendocrine carcinomas (NECs). METHODS AND RESULTS: NEC tumor xenografts were used to assess the effect of aflibercept on Gal-1 functions. Aflibercept induced a significant reduction of Gal-1 at epithelial, stromal, and extracellular localizations in lung NEC, whereas this was not observed in colon NECs, which displayed low expression of Gal-1. Additionally, aflibercept significantly reduced p-VEGFR2 protein, extracellular matrix remodeling, epithelial-mesenchymal transition, and activation of cancer-associated fibroblast hampering cell invasion in lung NEC but not in colon NEC. Gal-1 screening in human NECs confirmed that pulmonary and pancreatic tumors displayed higher levels of Gal-1 than colon NECs, becoming good candidates to benefit from aflibercept treatment. CONCLUSIONS: The lack of validated predictive markers of aflibercept is a weakness for guaranteeing the best treatment management with this drug. This work provides new mechanistic insight of aflibercept depending on Gal-1. Thus, in tumors overexpressing Gal-1, aflibercept has not only an antiangiogenic effect but also prevents Gal-1-mediated tumor-stroma cross talk. The stronger aflibercept effect in tumors with high levels of Gal-1 points out this protein as a molecular marker to predict the efficacy of this agent not only for NECs but also for other tumors with high levels of this protein.

Proposal for a clinicopathological prognostic score for resected gastric cancer patients.

BACKGROUND: Factors other than pTNM stage have been associated with gastric cancer (GC) prognosis, and several alternative prognostic scores have been constructed. Our aims are to identify prognostic factors in western GC patients and to build clinicopathological prognostic models for overall survival (OS) and disease-free survival (DFS). METHODS: A Retrospective study of 204 cases of GC resected during the years 2000 to 2014 was conducted in our hospital. Clinicopathological features were assessed, univariate and multivariate analysis were performed and prognostic scores were constructed. RESULTS: Most patients were diagnosed at pTNM stages II and III (36.9% and 48.1%, respectively). According to Laurén classification, tumors were intestinal (55.8%), diffuse (35.2%) and mixed (9%). During follow-up, 43.5% of patients had tumor recurrence, and 28.6% died due to tumor. Univariate analysis showed that patient age, Laurén subtype, signet-ring cell morphology, pTNM stage, tumor grade, perineural invasion, growth pattern, intratumoral inflammation, adjuvant therapy, and desmoplasia were significantly related to tumor progression or death. Multivariate analysis showed that Laurén subtype, pT stage, and lymph node ratio (LNR) were significantly and independently associated with GC recurrence. Laurén subtype and LNR were significantly related to patient survival. Prognostic scores for tumor progression and death were developed and patients were classified into four prognostic groups which showed good prognostic performance. CONCLUSION: A prognostic model comprising histological features such as Laurén subtype can be easily applied in clinical practice, and provides more prognostic information than pTNM stage alone. These models can further stratify resected GC patients and have the potential to aid in the individualization of patient management.

Prognostic Role of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Immunohistochemical Expression in Patients with Resected Gastric Carcinomas.

Aryl hydrocarbon receptor (AHR) interacting protein (AIP) is a chaperone which binds to inactive AHR in the cell cytoplasm. AHR is best known for mediating the toxicity of halogenated aromatics, but it has also been linked to carcinogenesis and tumor progression in several tumor types. Our aims are to assess the features of AIP immunohistochemical (IHC) staining and to evaluate its possible role as a prognostic marker in gastric cancer (GC). Retrospective study of 147 cases of resected GC. Clinicopathological features were collected, tissue microarrays were constructed for AIP IHC and statistical analysis were performed. AIP staining was observed in 50.3% of tumors. All AIP-positive cases exhibited cytoplasmic or membranous staining, variably associated with nuclear co-staining. 93.2% of AIP-positive tumors showed AIP immunoreactivity in 100% of cells. Staining intensity was mild, moderate and intense in 33.8%, 13.5% and 52.7% of cases. Tumors were stratified according to AIP staining intensity into low expression (no or mild AIP immunoreactivity) and high expression (moderate or intense AIP immunoreactivity). 36.6% of our cases showed high AIP expression. High AIP expression was significantly and independently correlated to tumor progression and cancer death. Tumors with high AIP expression showed lower survival and higher progression rates. AIP expression might be useful for determining GC prognosis. More studies are needed to clarify the role of AHR pathway in GC, AIP expression and its potential use as a surrogate marker for selecting patients for AHR modulation therapy.

Strong Antitumor Activity of Bevacizumab and Aflibercept in Neuroendocrine Carcinomas: In-Depth Preclinical Study.

BACKGROUND: Neuroendocrine carcinoma (NEC) is a rare and very aggressive tumor. It has been greatly understudied, and very little is known about optimal treatment strategy for patients with this disease. The purpose of this study was to evaluate in vivo whether anti-vascular endothelial growth factor (VEGF) drugs could be a therapeutic alternative for these tumors with a poor prognosis. METHODS: We have developed 2 xenograft models using either human cell line derived from lung (H460) or from colon (COLO320) NEC to assess the effect of 2 antiangiogenic drugs, aflibercept and bevacizumab, on tumor growth and their pathological characteristics. Additionally, tumors were subjected to immunohistochemistry staining and proteins were measured with Western blot and ELISA. RESULTS: Both aflibercept and bevacizumab showed significant antitumor activity (p < 0.001). In the H460 model, aflibercept resulted in 94% tumor growth inhibition (TGI) and bevacizumab treatment resulted in 72.2% TGI. Similarly, in the COLO320 model, aflibercept and bevacizumab resulted in 89.3 and 84% TGI, respectively. Moreover, antitumor activity occurs early after treatment initiation. Using Tumor Control Index score, which address the kinetics of tumor growth in a way comparable to the methods used in human clinical studies, we confirmed that both drugs inhibit significantly tumor growth. When tumor stabilization was evaluated, aflibercept shows higher ability to stabilize NEC tumors than bevacizumab. CONCLUSION: Results derived from this study strongly support anti-VEGF therapies, especially aflibercept, as a novel therapeutic option in NECs. Further studies are necessary, but our observations encourage the evaluation of antiangiogenics in clinical trials combined with standard chemotherapy.

MUC1 expression in colorectal carcinoma: Clinicopathological correlation and prognostic significance / Expresión de MUC1 en el carcinoma colorectal: correlación clinicopatológica y valor pronóstico

Introduction: MUC1 overexpression has been linked to cancer development and has been associated with a higher stage at diagnosis and presence of lymph node or distant metastases. However, its prognostic significance is still unclear. We aimed to evaluate the relationship between MUC1 expression and prognosis of colorectal carcinoma. Materials and methods: Immunohistochemical expression of MUC1 in 96 colorectal carcinomas with analysis of potential prognostic influence. Results: 55.2% of patients were women and the mean age was 65.9 years. Tumors were more frequently located in rectum or sigmoid colon (60.4% and 21.9%). Most tumors were T3 (60.3%). 36.9% of patients showed lymph node metastases and 30.2% showed distant metastasis at the time of diagnosis. MUC1 was intensely positive in 46% and negative in 37.9% of tumors. Overall, 61% of patients recurred and 40.4% died during follow-up. 58.5% of tumors of surviving patients were intensely positive for MUC1 and 29.5% were negative, as compared with 28.5% (intense positivity) and 51.4% (negativity) in the group of patients who died (p=0.022). 65% of tumors of patients without recurrences showed intense positivity for MUC1 and 23% of them were negative as compared with 33.9% (intense positivity) and 47% (negativity) in the group of patients who recurred (p=0.019). Conclusions: Loss of MUC1 expression was more frequent in cases with disease recurrence or death, as compared with patients with stable disease, in whom intense positivity was more frequently seen. These findings disagree with the majority of previous studies, indicating the need for further investigation

Introducción: La sobreexpresión de MUC1 se ha asociado al desarrollo de cáncer, mayor estadio al diagnóstico y la presencia de metástasis ganglionares o a distancia. Sin embargo, su valor pronóstico es dudoso. Nuestro objetivo es evaluar la relación entre la expresión inmunohistoquímica de MUC1 y el pronóstico del carcinoma colorrectal (CRC). Material y métodos: Expresión inmunohistoquímica de MUC1 en 96 CRC y análisis de su influencia pronóstica. Resultados: El 55,2% de los pacientes eran mujeres, con edad media de 65,9 años. Los tumores se localizaban principalmente en recto o sigma (60,4 y 21,9%). El 60,3% de los CRC fueron estadio T3. El 36,9% de pacientes mostraron metástasis ganglionares y el 30,2% a distancia. MUC1 fue intensamente positivo en el 46% y negativo en el 37,9% de los casos. En el 61% de los pacientes se observaron recurrencias y el 40,4% falleció. Un 58,5% de tumores de pacientes vivos mostró positividad intensa y un 29,5% negatividad para MUC1, en comparación con un 28,5 y 51,4% de positividad intensa y negatividad en los pacientes que murieron (p=0,022). El 65% de los tumores de pacientes sin recurrencias fueron intensamente positivos para MUC1 y el 23% fue negativo, en comparación con un 33,9 y 47% de positividad intensa y negatividad en pacientes con recurrencias (p=0,019). Conclusiones: La pérdida de expresión de MUC1 fue más frecuente en pacientes con recurrencias o fallecidos que en pacientes estables. Estos resultados son contrarios a la mayoría de estudios previos y subrayan la necesidad de realización de más estudios

MUC1 expression in colorectal carcinoma: Clinicopathological correlation and prognostic significance.

INTRODUCTION: MUC1 overexpression has been linked to cancer development and has been associated with a higher stage at diagnosis and presence of lymph node or distant metastases. However, its prognostic significance is still unclear. We aimed to evaluate the relationship between MUC1 expression and prognosis of colorectal carcinoma. MATERIALS AND METHODS: Immunohistochemical expression of MUC1 in 96 colorectal carcinomas with analysis of potential prognostic influence. RESULTS: 55.2% of patients were women and the mean age was 65.9 years. Tumors were more frequently located in rectum or sigmoid colon (60.4% and 21.9%). Most tumors were T3 (60.3%). 36.9% of patients showed lymph node metastases and 30.2% showed distant metastasis at the time of diagnosis. MUC1 was intensely positive in 46% and negative in 37.9% of tumors. Overall, 61% of patients recurred and 40.4% died during follow-up. 58.5% of tumors of surviving patients were intensely positive for MUC1 and 29.5% were negative, as compared with 28.5% (intense positivity) and 51.4% (negativity) in the group of patients who died (p=0.022). 65% of tumors of patients without recurrences showed intense positivity for MUC1 and 23% of them were negative as compared with 33.9% (intense positivity) and 47% (negativity) in the group of patients who recurred (p=0.019). CONCLUSIONS: Loss of MUC1 expression was more frequent in cases with disease recurrence or death, as compared with patients with stable disease, in whom intense positivity was more frequently seen. These findings disagree with the majority of previous studies, indicating the need for further investigation.

Immunohistochemical classification of gastric cancer based on new molecular biomarkers: a potential predictor of survival.

Several classification systems have been described for stratifying patients with gastric carcinoma (GC). However, their prognostic value is low, and there is an urgent need for identification of molecular markers and development of new classifications. Retrospective study of 206 cases of GC diagnosed and surgically resected in our hospital between 2000 and 2017. Clinicopathological features of all cases were assessed and tissue microarrays were constructed for immunohistochemical (IHC) study. Patients were stratified based on IHC results. Mean patient age was 71 years and most patients were male (54.6%). Most tumors were located in the gastric antrum and body, and they were mostly fungoid or ulcerative lesions. GC were mainly intestinal-type tumors and 60.3% were diagnosed at pT3. 56.2% of patients showed recurrences and 29.4% died due to GC. According to our IHC classification, 23.5% of tumors showed microsatellite instability, 6% were E-cadherin negative, 53.5% were stable-p53 not overexpressed, and 17% were stable with p53 overexpression. IHC classification was significantly correlated with patient gender, gross morphology, Laurén classification, tumor necrosis, perineural infiltration, type of leading edge, and patient outcome. Multivariate analysis showed that IHC subtype was significantly and independently associated with overall survival, together with clinical symptoms, signet cell phenotype, tumor grade and vessel invasion. The application of IHC classifications based on molecular biomarkers in clinical practice can aid in the stratification of GC patients. More studies are needed to evaluate the reproducibility and clinical significance of these classifications.

Luminal oxidants selectively modulate electrogenic ion transport in rat colon.

AIM: To investigate the effects of luminal exposure to H2O(2) and two related thiol oxidizing agents on basal and stimulated chloride secretion in native colon using electrophysiological and pharmacological approaches. METHODS: Unstripped rat distal colon segments were mounted in Ussing chambers. Potential difference, calculated resistance and short-circuit current across unstripped colon segments were monitored with a dual voltage/current clamp. Paracellular permeability was assessed by measuring the mucosa-to-serosa flux of a fluorescent probe (FITC). RESULTS: Luminal exposure to hydrogen peroxide transitorily stimulated chloride secretion without altering barrier function. This stimulatory effect could be blocked by basolateral atropine but not indomethacin. The cysteine and methionine oxidizing compounds, phenylarsine oxide and chloramine T respectively, mimicked the effect of H2O(2), except for a drop in transcolonic resistance after 30 min. In contrast to the observed stimulatory effect on basal secretion, cAMP-stimulated electrogenic ion transport was blunted by luminal H2O(2). However, the Ca(2+)-activated response remained unchanged. CONCLUSION: H2O(2) may be an important selective modulator of intestinal ion and water secretion in certain pathologic conditions such as inflammation or ischemia-reperfusion by multiple mechanisms.