Exosomal Functional Cargoes from Liquid Biopsy of Gastric Cancer: A Systematic Review of Studies With Potential Clinical Relevance.

BACKGROUND/AIM: Liquid biopsy (LB) is a promising non-invasive tool to detect cancer. Over the last few years, exosomes recruited from LB have attracted the attention of researchers for their involvement in cancer. We focused on the role of LB exosomes in gastric cancer (GC). MATERIALS AND METHODS: We investigated the world literature on exosome-encapsulated functional biomarkers (non-coding RNAs and DNAs) taken from GC patients' LBs. Only the studies exploring serum, intraperitoneal fluid or gastric lavage were included. RESULTS: As of 2022, fifty articles with an overall count of 3552 GC patients were investigated. Given the statistically significant associations with the clinicopathological categories of tumor depth, lymph node metastasis, staging class and tumor size, most exosome-mediated microRNAs, long non-coding RNAs and circular RNAs proved to exert a potentially important bioclinical role in terms of diagnosis, screening, prognosis and therapeutic targets. CONCLUSION: In the future, resorting to exosomal biomarkers taken from LB of affected patients could revolutionize the non-invasive fight against GC.

Combined Analysis of Intragastric Malignant Exfoliation and Ca 72.4 Concentration in Stomach Adenocarcinoma: The "GL1 Ca 72.4" Parameter.

INTRODUCTION/OBJECTIVE: Differently from other digestive malignancies, gastric cancer (GC) pathobiology is still little known and understood. Recently, cytopathology and molecular biology on gastric juice/gastric lavage (GJ/GL) of GC patients have provided novel and interesting results in terms of screening, diagnosis, prognosis, and therapy. However, entertaining cytologic examination and molecular test as a unified solo-run test is previously unreported. Our aim was to assess the new parameter "GL Ca 72.4" for GC patients. METHODS: Between April 2012 and July 2013, GJ/GL obtained from 37 surgical GC patients were tested for the presence/absence (GL1/GL0) of exfoliated malignant cells along with the intragastric concentration of Ca 72.4 (normal value <6.49 ng/mL: Ca 72.4n; elevated level ≥6.49 ng/mL: Ca 72.4+). RESULTS: At a median follow-up of 79.3 months, all the GC alive patients were "GL0 Ca 72.4n." The "GL1 Ca 72.4+" parameter, in comparison with GL0 Ca 72.4n, strongly correlated with deeper tumor invasion (p = 0.027), severe nodal metastasis (p = 0.012), worst metastatic node ratio (p = 0.041), higher number of metastatic lymph nodes (30 vs. 20 nodes, p = 0.014), angiolymphatic invasion (p = 0.044), advanced stage (p = 0.034), and adjuvant therapy (p = 0.044). The Kaplan-Meier model showed that GL1 Ca 72.4+ subjects had shorter overall survival (OS) than GL0 Ca 72.4n cases (9.7 vs. 43.2 months, respectively, p = 0.042). At univariate analysis, the GL1 Ca 72.4+ parameter resulted a significant prognostic factor for OS (p = 0.023). CONCLUSIONS: The combined cyto-molecular parameter "GL1 Ca 72.4+" appears to be a strong indicator of aggressive tumor behavior and a significant prognostic factor of poor survival for GC patients.

Elevated Gastric Juice Carbohydrate Antigen 72.4 (Ca 72.4) Is an Independent Prognostic Factor of Poor Survival for Gastric Cancer Patients.

BACKGROUND/AIM: As of 2020, carbohydrate antigen 72.4 (Ca 72.4) has been rarely investigated in the gastric juice (GJ) of patients with gastric cancer (GC). Our aim was to analyze the significance and role of this tumor antigen in the GJ of our GC population. PATIENTS AND METHODS: Between April 2012 and July 2013, 37 patients with operable GC were prospectively investigated to determine the GJ Ca 72.4 levels before surgical manipulation. RESULTS: GJ Ca 72.4 ≥6.49 ng/ml strongly correlated with the traditional categories of aggressive cancer (advanced tumor depth and stage, lymph node invasion and metastatic lymphatic ratio, indication to adjuvant treatment). It also associated with shorter survival (p=0.049) and is, thus, suggested as an independent factor of poor prognosis in GC patients (p=0.047). CONCLUSION: The GJ Ca 72.4 parameter should be considered an indicator of an aggressive tumor phenotype and should be used in the prognostic assessment of GC patients.

Gastric Lavage Malignant Cells (yGL) and Hypohemoglobinemia (yAnemia) as New Systems of Tumor Regression Grading and Prognostic Prediction for Gastric Cancer After Neoadjuvant Treatment.

BACKGROUND/AIM: Although reckoned necessary for survival benefit, neoadjuvant chemotherapy (NAC) of gastric cancer (GC) patients has so far provided questionable results. Consequently, searching for new and clearer systems of response to NAC, post-NAC re-evaluation and prognostic prediction appears essential. The purpose of this study was to examine endogastric cytopathology and hemoglobin level count as new features, potentially useful for GC patients after NAC. PATIENTS AND METHODS: Between April 2012 and October 2018, 21 of 116 patients with resectable GC received NAC and were investigated for the presence of free-floating malignant cells in their gastric lavage (yGL1) and the development of hypohemoglobinia (yAnemia). RESULTS: yGL1 and yAnemia were found in 11 and 12 patients, respectively. yGL1 correlated with the traditional parameters of tumor regression (p=0.0424). Both yGL1 and yAnemia were found to be independent predictive factors of overall and progression-free survival (p≤0.0364). CONCLUSION: In the light of our results, the yGL1 and yAnemia appear two promising, simple and interesting clinicopathological features which should always be examined for better clarifying GC patients' response to NAC.

Long non-coding RNAs in the gastric juice of gastric cancer patients.

Differently from other digestive malignancies, gastric cancer (GC) carcinogenesis seems more heterogeneous and unclear. This entails failing in identification of reliable serum tumor markers for screening early GC (EGC) as well as persisting ominous prognosis of this disease. Recently, investigation of human noncoding genome, especially long noncoding molecules (lncRNAs), has provided promising data. As for GC, however, since the current information on GC-specific lncRNAs is still scarce and comes largely from analyses performed on tissue or serum of affected patients, we decided to review the current literature dealing with expression of such molecules in the gastric juice (GJ) of GC patients. In the case of GC, in fact, several cytological and molecular works have already demonstrated GJ to be an interesting biological material for improving clinicopathologic and prognostic knowledge of this cancer. For this review, we burrowed into the literature on lncRNAs expressed in GJ of GC patients. PubMed, Science Direct, Scopus, Web of Science, Google Scholar and ResearchGate were the search engines entertained. As of 2018, only seven studies have been reported. LINC00152, AA174084, UCA1, RMRP, ABHD11-AS1, LINC00982 and H19 were the GJ lncRNAs examined. Following our review, we can conclude that, due to their high specificity and reliability, GJ lncRNAs should deserve a prominent role in the field of GC research: importantly, they could be used for screening EGC, ameliorating the existing methods of staging (which are still far from being completely accurate), improving the prognostic capacity of the current diagnostic armamentarium and, finally, providing new and valuable therapeutic targets.

Preoperative gastric lavage in gastric cancer patients undergoing surgical, endoscopic or minimally invasive treatment: An oncological measure preventing peritoneal spillage of intragastric cancer cells and development of related metastases.

In addition to classical metastatic pathways, recently gastric cancer was described having an alternative route called "endoluminal exfoliation". Provisional analyses demonstrated, in fact, this kind of shedding is associated with several clinico-pathological features indicative of aggressive behavior and resulted to be an independent prognostic factor entailing poor prognosis. Compared with non-sowing counterparts, in fact, patients affected with exfoliating early and advanced gastric carcinomas met with shorter overall survival, disease free survival, progression free survival and time to tumor progression. In spite of these interesting results, however, the clinico-pathological and oncological significance of this unconventional metastatic route is still to be clarified. Such an investigation is further urged by the increasing widespread employment of minimally invasive treatments for gastric cancer which include a wide spectrum of intragastric interventions and maneuvers. Indeed, endoscopic mucosal resection, endoscopic submucosal dissection, endoscopic full-thickness resection, intragastric laparoscopic surgery and hybrid procedures all take place inside of the stomach. However, iatrogenic perforations can occur during execution of these treatments leading to spillage of malignant cells from gastric to the peritoneal cavity or trocar insertion sites. Furthermore, many other gastric conditions and interventions can collide with endogastric presence of floating cancer cells: spontaneous ulceration or perforation, laparotomy surgery, gastrointestinal occlusion, diverticula. Viability, migration and intraluminal transportability of the intragastric floating cancer cells represents another original and intriguing topic. All these considerations led us to entertain the hypothesis that removing the exfoliated cancer cells from the gastric lumen could save patients from the dreaded potential risk of spillage. Performing gastric lavage before starting any kind of tumor intervention could be the most appropriate procedure to adopt with prophylactic intent. Should our speculation prove to be clinically significant, preoperative gastric lavage should be pointed out as a simple but cogent method useful for preventing oncological mishaps such as spillage of gastric cancer cells and development of related recurrences or metastases.

Gastric Cancer Cells in Peritoneal Lavage Fluid: A Systematic Review Comparing Cytological with Molecular Detection for Diagnosis of Peritoneal Metastases and Prediction of Peritoneal Recurrences.

BACKGROUND/AIM: Detecting free tumor cells in the peritoneal lavage fluid of gastric cancer patients permits to assess a more accurate prognosis, predict peritoneal recurrence and select cases for a more aggressive treatment. Currently, cytology and molecular biology comprise the two most popular methods of detection that are under constant study by researchers. MATERIALS AND METHODS: We burrowed into the available literature comparing cytological with molecular detection of free intraperitoneal gastric cancer cells. PubMed, Science Direct, Scopus and Google Scholar were the search engines investigated. RESULTS: As of 2017, 51 dedicated studies have been published. Messenger RNA of carcinoembryonic antigen was the genetic target most frequently described. The genetic technique is usually superior to cytology in sensitivity (38-100% vs. 12.3-67% respectively), whereas cytological examination tends to show a slight pre-eminence in specificity (approximately 100%). CONCLUSION: So far, given the imperfection of each method, employment of both cytology and molecular examination seem to be mandatory.

Laparoscopic Intragastric Surgery for Treating Early Gastric Cancer.

BACKGROUND/AIM: Although there is an increasing number of studies on laparoscopic resection of early gastric cancer (EGC), as of 2018 no standardized strategy exists. We reviewed available literature dealing with laparoscopic intragastric (intraluminal) surgery (LIGS) conducted for patients with EGC to better define indications, benefits and limitations of this particular minimally invasive technique. MATERIALS AND METHODS: PubMed, MEDLINE, Science Direct, Scopus, Web of Science, Google Scholar and ResearchGate were the search engines investigated. Only LIGS for EGC was entertained; studies conducted for other gastric diseases were excluded. Suitable articles written in all languages were included in the review. RESULTS: As of 2018, we found 19 studies dealing with LIGS for EGC: studies on 72 humans and four pigs were identified. Among 72 human participants, there were 59 mucosal, five submucosal and one subserosal cancer. CONCLUSION: Based on our review, LIGS appears as a cogent option to endoscopic resection for treating superficial EGC.

Gastric Juice MicroRNAs as Potential Biomarkers for Screening Gastric Cancer: A Systematic Review.

BACKGROUND/AIM: To date, the combination of gastroscopy with biopsy remains the only test validated for screening gastric cancer (GC). Currently, analysis of circulating microRNAs (miRNAs or miRs) is providing interesting information on GC prognosis, but since these molecules are shared by several types of cancer, its clinical use could be questionable and difficult. MicroRNAs in gastric juice (GJ) could represent a cogent alternative to screening GC by biopsy. MATERIALS AND METHODS: We investigated the pertinent literature dealing with GC GJ microRNAs through four popular search engines (PubMed, Science Direct, Scopus and Google Scholar). RESULTS: As of 2017, only four studies had been published and were all from Chinese experience. MiR-421, miR-129, miR-21, miR-106a and miR-133a were the five molecules studied in the GJ of the enrolled patients. CONCLUSION: The GJ miRNA test is reliable and reproducible. The discussed GJ miRNAs appear to be new potential biomarkers for the screening of GC.

Utility of Nasogastric Tube for Medical and Surgical Oncology of Gastric Cancer: A Prospective Institutional Study on a New and Precious Application of an Old and Economic Device.

BACKGROUND/AIM: Concerning gastric cancer (GC), nasogastric tube (NGT) is routinely employed for peri-operative decompression and palliative enteral nutrition. Additionally, we believe to have found a further application. PATIENTS AND METHODS: Between April 2012 and April 2017, 96 GC patients received preoperative nasogastric lavage (GL). All samples were cytologically examined to detect the presence (GL1) or absence (GL0) of malignant cells. Data were analyzed with classificatory, staging and prognostic purpose. RESULTS: GL1 was detected in 46 GC patients: association with tumor depth, lymph node and distant metastasis, lymphovascular and peri-neural invasion, diffuse type and signet-ring cells was significant (respectively p=0.0274, 0.0324, 0.0446, 0.0287, <0.0001, 0.0413, <0.0001). GL1 entailed significantly poorer overall (OS), progression-free, disease-free survival and tumor progression (18 vs. 32 months). At multivariate analysis, GL1 was an independent prognostic factor for worse OS (p=0.0287). CONCLUSION: NGT seems an economic oncologic measure useful for obtaining information on GC staging and prognosis.

Early Gastric Cancer Exfoliating into Gastric Lavage (GL1 EGC) Shows a More Aggressive Behavior and Poorer Survival Compared to the Non-Exfoliative Counterpart (GL0 EGC).

BACKGROUND/AIM: Early gastric cancer (EGC) is usually associated with excellent prognosis. Some cases, however, entail a poorer survival. Our aim was to assess if EGC exfoliating into gastric lavage (GL) has a more aggressive behavior than the non-exfoliative counterpart. PATIENTS AND METHODS: Between April 2012 and April 2017, 96 gastric cancer patients were prospectively submitted to preoperative GL to detect the presence (GL1) or absence (GL0) of exfoliated malignant cells. RESULTS: A total of 16 patients had EGC. T1b cases had significantly poorer overall (OS), progression-free (PFS) and disease-free survival (DFS) than their GL0 counterpart (16.3 vs. 61 months, p=0.0032). Similarly, the entire T1 class (T1a plus T1b EGCs) showed worse OS, PFS, DFS (15.5 vs. 61 months, p=0.0008) and time-to-tumor progression (17 vs. 61 months, p=0.0103). CONCLUSION: In the case of EGC, the GL0-GL1 classification should become a routine clinical practice to identify the aggressive tumor phenotypes requiring for closer follow-up or additional treatment.

Measuring Intragastric Tumor Markers in Gastric Cancer Patients: a Systematic Literature Review on Significance and Reliability.

As of 2017, no serum tumor marker has shown high levels of sensitivity or specificity for early detection, classification, staging, prediction and prognosis of patients affected by gastric cancer. In this regard, since 1975 several authors have investigated the gastric juice or gastric lavage of patients with gastric adenocarcinoma in order to determine the concentrations of intragastric tumor markers and discover the perfect antigen for this cancer. To date, however, a systematic review of the literature on intragastric tumor markers is still unreported. After a thorough search, we found important as well as unimportant findings and have come to clearly defined conclusions. We believe that describing the current state of knowledge achieved by the scientific community in this particular field of research could augment information on the complex pathobiology of gastric cancer and entail a deeper understanding of its unpredictable malignant behavior.

Detection of cancer cells and tumor markers in gastric lavage of patients with gastric cancer: Do these findings have a clinicopathological significance and oncological implication?

Although decreasing in the incidence over the last years, currently gastric adenocarcinoma represents the second cause of cancer related-death worldwide. Further knowledge and novel therapies are desperately needed in order to make the prognosis of these patients more acceptable. Infact, even though in recent years numerous staging parameters have been largely studied and unanimously recognized for their clinical and prognostic value, today too many shadows still exist around the capacity to predict exactly the natural history or post-treatment behavior of this cancer even among patients of the same stage. This study has identified the presence of isolated cancer cells as well as tumor markers (CEA, Ca 19.9, Ca 72.4 and Ca 50) from the gastric lavage of patients affected by gastric adenocarcinoma. Such findings led to the hypothesis that endoluminal exfoliation of neoplastic cells and the release of their products (tumor markers) into the gastric juice might be an expression of neoplastic behavior as well as aggressive malignancy. Should this hypothesis become a reality, some important progress could be made in the knowledge, staging, prediction as well as management and follow-up of this inauspicious type of cancer.

Analyzing Gastric Lavage of Gastric Cancer Patients: A Prospective Observational Study on Cytopathology and Determination of Intragastric CEA, CA 19.9, CA 72.4, and CA 50.

OBJECTIVES: To investigate gastric lavage (GL) cytopathology and immunometric analysis as novel clinicopathologic and prognostic parameters for gastric cancer (GC). STUDY DESIGN: In 38 patients with gastric adenocarcinoma, we performed a cytopathologic analysis and an immunometric assay of GL using four tumor markers (CEA, CA 19.9, CA 72.4, and CA 50). The intragastric tumor marker levels were compared with a control group consisting of 41 non-GC patients to determine a statistically significant cutoff value. RESULTS: GL cytopathology demonstrated the presence of cancer cells in 13 (34.2%) of the 38 GC patients: such a finding correlated to the parameters pT and pN with a statistically significant validity (p < 0.0267 and p < 0.0306, respectively). Measurement of intragastric CA 19.9 and CA 50 attained a statistically significant cutoff value (p < 0.002 and p < 0.0096, respectively), which was invalidated by the low sensitivity of the ROC curve analysis. CONCLUSIONS: In contrast to determination of its tumor markers, GL cytopathology correlated well with pT and pN staging parameters. Should this and other features be corroborated by future studies, the GL cytology test could be routinely used to detect aggressive types of GC even at early stages and result in important progress in the knowledge, staging, prediction, as well as management and follow-up of this inauspicious type of cancer.

The burden of comorbidity and the C-reactive protein levels in nonthyroidal illness syndrome with metabolic syndrome and atherosclerosis-related cardiovascular complications.

Thyroid hormones undergo significant modifications during severe illnesses, and the low T3 levels are the hallmark of nonthyoidal illness syndrome (NTIS), due to a reduced extrathyroidal conversion from T4. We examined 41 patients with NTIS by a modified cumulative illness rating scale (CIRS) and the measurement of FT3, FT4, TSH, and C-reactive protein (CRP) levels. Fifty-seven control subjects were enrolled. We observed reduced FT3 and increased FT4 levels in NTIS patients (P < 0.05). The CIRS scores (severity and comordity index) were inversely related to FT3 and positively related to FT4 levels (P < 0.05). The CRP and the FT4 concentrations were positively associated (P < 0.01). Our study showed that the reduced FT3 and increased FT4 levels were significantly related to the comorbidity and severity of systemic illnesses, probably as a result of impairment in the peripheral hormonal conversion. The CIRS scale and the CRP are useful tools for a better evaluation of these patients.

[Gastric pacing to treat morbid obesity: two years experience in four patients]. / Il gastric pacing per il trattamento dell'obesità patologica. Esperienza a due anni in 4 pazienti.

BACKGROUND: Gastric pacing to treat morbid obesity has been found to be safe and the implant technique simple to perform. Appetite is reduced and satiety is increased after the implant. There are two components in the Implantable Gastric Stimulation (IGS): (a) an electrical stimulator connected to a (b) bipolar lead that is positioned in the muscle wall of the stomach. We describe the optimal procedure to safely place the components. We present our results after preliminary experiences. METHODS: From August 2005 to January 2006, 4 patients (F) mean age 44 (33-63) underwent to IGS implant. The mean BMI was 41.8 (378-47), mean weight 117.2 Kg (107-133) . The IGS was activated 30 days after implant. Fasting and postprandial plasma ghrelin concentrations after a test meal were measured before and 1, 2, 3 and 6 months after implanting operation. RESULTS: All procedures were successfully completed laparoscopically. There were no major operative complications. Postoperative course was uneventful in all cases. One patient was lost to follow up after six months. Postoperative lead dislodgement and cutaneous decubitus occurred in another patient, making necessary the removing of the device. For the other two patient only in one there was a significant weight loss (49 Kg), in the second weight was unchanged. Plasma ghrelin concentrations were no correlated among patients, and results were not in line with what waited by the producer. CONCLUSION: Morbid obese patients can undergo IGS implantation by laparoscopy with minimal perioperative complications. Attention to technical details is essential. In accordance with the producer (Medtronic) our data demonstrate that gastric pacing is a safe procedure for selected patients supported by adequate psychological treatment, but outcome about weight loss should be evaluated among bigger trial, as our experience didn't give satisfactory results, and therefore discouraged us to carry on with the study.

The hypothalamic-pituitary-thyroid axis in subjects with subclinical thyroid diseases: the impact of the negative feedback mechanism.

OBJECTIVE: To evaluate the hypothalamus-pituitary-thyroid (HPT) axis in patients with subclinical thyroid dysfunction recently reported to have either symptoms or organ involvements with potential morbidity, in order to better differentiate these patients with respect to controls. PATIENTS: Sixtythree patients with subclinical hyperthyroidism (HyperT), 178 normal subjects (EuT) and 106 patients with subclinical hypothyroidism (HypoT) were enrolled; the groups presented normal thyroid hormone (FT4, FT3) levels and, respectively, reduced (HyperT), normal (EuT) and increased (HypoT) TSH levels. The negative feedback was simultaneously evaluated by multiple linear regression. RESULTS: The mean TSH, FT4 and FT3 levels were significantly different in the three groups. The negative correlation between thyroid hormones (FT4 and FT3) and TSH secretion was significant (p<0.001 in HyperT; p<0.01 in EuT; p<0.000001 in HypoT group). FT4 mostly contributed to the negative correlation with TSH. The normal ranges of TSH values was accurately defined on the basis of the regression equation in the EuT group, due to the combining influence of both thyroid hormones (FT3 and FT4). No patient of the HyperT or HypoT group fell inside the range of estimated values of the normal group. CONCLUSIONS: The HPT axis in patients with subclinical hyper- and hypo-thyroidism is significantly modified with respect to normal subjects. The status of the axis, as evaluated by the relationship between the three hormones (FT4, FT3, TSH) together considered, is characteristic of the normal or pathologic condition. A reliable method based on the regression analysis is proposed to correctly evaluate the status of the HPT axis.

Effects of mental stress on cardiovascular and endocrine response in Air Force Academy cadets.

OBJECTIVES: Pilots are exposed to the "stress of flight" and the chronically activated stress response may play an important role in circulatory system disease progression. We studied the effect of an experimental mental stress on cardiovascular and neuroendocrine activity, in Air Force Academy cadets, before and after one month intensive course. DESIGN: Nine cadets were submitted to a psychometric evaluation before Stroop test (ST), including Minnesota Multiphasic Personality Inventory, State and Trait Anxiety Inventory (STAI X1 and X2 form) and Reaction Scheme Test. After ST, subjects completed a STAI X1 form. Heart rate (HR), systolic and diastolic blood pressure (SBP and DBP) were monitored and serum prolactin (PRL), growth hormone (GH), adrenocorticotropin (ACTH) and cortisol levels were determined, during ST. The protocol was repeated at the end of the course. RESULTS: No significant differences were evident in PRL, GH and ACTH levels. Cortisol concentrations were significantly higher before the course. ST did not modify hormone secretion. ST induced a significant and reproducible elevation of HR and SBP. Basal HR, SBP and DBP values were significantly elevated after the course. Two subjects presented a particular psychometric profile, a different cardiovascular response to ST and did not pass the course. CONCLUSIONS: acute mental stress significantly activated cardiovascular response without modifying endocrine responses, in relation to the psychological profiles. A significant increase of cardiovascular parameters was present after the course, with enhanced dichotomy between the endocrine and sympathetic system, suggesting a careful evaluation and follow-up for circulatory system diseases in cadets.