Gastric cancer and the epoch of immunotherapy approaches

The incidence of gastric cancer(GC) fell dramatically over the last 50 years, but according to IARC-Globocan 2008, it is the third most frequent cause of cancerrelated deaths with a case fatality GC ratio higher than other common malignancies. Surgical resection is the primary curative treatment for GC though the overall 5-year survival rate remains poor(approximately 20%-25%). To improve the outcome of resectable gastric cancer, different treatment strategies have been evaluated such as adjuvant or perioperative chemotherapy. In resected gastric cancer, the addition of radiotherapy to chemotherapy does not appear to provide any additional benefit. Moreover, in metastatic patients, chemotherapy is the mainstay of palliative therapy with a median overall survival of 8-10 mo and objective response rates of merely 20%-40%. Therefore, the potential for making key beneficial progress is to investigate the GC molecular biology to realize innovative therapeutic strategies, such as specific immunotherapy. In this review, we provide a panoramic view of the different immune-based strategies used for gastric cancer treatment and the results obtained in the most significant clinical trials. In detail, firstly we describe the therapeutic approaches that utilize the monoclonal antibodies while in the second part we analyze the cell-based immunotherapies.

Evaluation and comparison of short chain fatty acids composition in gut diseases

BACKGROUND An altered (dysbiosis) and unhealthy status of the gut microbiota is usually responsible for a reduction of short chain fatty acids (SCFAs) concentration. SCFAs obtained from the carbohydrate fermentation processes are crucial in maintaining gut homeostasis and their determination in stool samples could provide a faster, reliable and cheaper method to highlight the presence of an intestinal dysbiosis and a biomarker for various gut diseases. We hypothesize that different intestinal diseases, such as celiac disease (CD), adenomatous polyposis (AP) and colorectal cancer (CRC) could display a particular fecal SCFAs’ signature. AIM To compare the fecal SCFAs’ profiles of CD, AP, CRC patients and healthy controls, using the same analytical method. METHODS In this cross-sectional study, we defined and compared the SCFAs’ concentration in fecal samples of 9 AP, 16 CD, 19 CRC patients and 16 healthy controls (HC). The SCFAs’ analysis were performed using a gas-chromatography coupled with mass spectrometry method. Data analysis was carried out using Wilcoxon ranksum test to assess pairwise differences of SCFAs’ profiles, partial least squaresdiscriminate analysis (PLS-DA) to determine the status membership based on distinct SCFAs’ profiles, and Dirichlet regression to determine factors influencing concentration levels of SCFAs. RESULTS We have not observed any difference in the SCFAs’ amount and composition between CD and healthy control. On the contrary, the total amount of SCFAs was significantly lower in CRC patients compared to HC (P = 0.044) and CD (P = 0.005). Moreover, the SCFAs’ percentage composition was different in CRC and AP compared to HC. In detail, HC displayed higher percentage of acetic acid (P value = 1.3 × 10-6) and a lower amount of butyric (P value = 0.02192), isobutyric (P value = 7.4 × 10-5), isovaleric (P value = 0.00012) and valeric (P value = 0.00014) acids compared to CRC patients. AP showed a lower abundance of acetic acid (P value = 0.00062) and higher percentages of propionic (P value = 0.00433) and isovaleric (P value = 0.00433) acids compared to HC. Moreover, AP showed higher levels of propionic acid (P value = 0.03251) and a lower level of isobutyric acid (P value = 0.00427) in comparison to CRC. The PLS-DA model demonstrated a significant separation of CRC and AP groups from HC, although some degree of overlap was observed between CRC and AP. CONCLUSION Analysis of fecal SCFAs shows the potential to provide a non-invasive means of diagnosis to detect patients with CRC and AP, while CD patients cannot be discriminated from healthy subjects.

Role of preoperative CT colonography in patients with colorectal cancer

In patients with colorectal cancer(CRC),accurate preoperative evaluation is essential for a correct therapeutic plan.Colonoscopy and intravenous contrastenhanced computed tomography(CT)are currently recommended in the preoperative work-up for CRC.Preoperative colonoscopy has some limitations such as misdiagnosis of synchronous cancers in cases of incomplete exploration of the colon and inaccurate tumor localization.Intravenous contrast-enhanced CT successfully documents distant metastases although it sometimes enables unsatisfactory locoregional staging.Computed tomography colonography(CTC)is obtained after gas insufflation of the colon and offers a comprehensive preoperative evaluation in patients with CRC,including a definition of the segmental location of the tumor,presence of synchronous lesions or lack thereof,and fairly accurate locoregional staging.CTC has some limitations,including a lack of biopsy capability,suboptimal sensitivity for synchronous small polyps,and unsatisfactory nodal staging.Bearing in mind these limitations,CTC could be employed as a"one-stop-shop"examination for preoperative assessment in patients with CRC.

Role of gut microbiota-immunity axis in patients undergoing surgery for colorectal cancer:Focus on short and long-term outcomes

Human body is colonized by a huge amount of microorganisms mostly located in the gastrointestinal tract.These dynamic communities,the environment and their metabolites constitute the microbiota.Growing data suggests a causal role of a dysbiotic microbiota in several pathologies,such as metabolic and neurological disorders,immunity dysregulations and cancer,especially the well-studied colorectal cancer development.However,many were preclinical studies and a complete knowledge of the pathogenetic mechanisms in humans is still absent.The gut microbiota can exert direct or indirect effects in different phases of colorectal cancer genesis.For example,Fusobacterium nucleatum promotes cancer through cellular proliferation and some strains of Escherichia coli and Bacteroides fragilis produce genotoxins.However,dysbiosis may also cause a proinflammatory state and the stimulation of a Th17 response with IL-17 and IL-22 secretion that have a pro-oncogenic activity,as demonstrated for Fusobacterium nucleatum.Microbiota has a crucial role in several stages of postoperative course;dysbiosis in fact seems related with surgical site infections and Enterococcus faecalis(and other collagenase-producers microbes)are suggested as a cause of anastomotic leak.Consequently,unbalanced presence of some species,together with altered immune response may also have a prognostic role.Microbiota has also a substantial role in effectiveness of chemotherapy,chemoresistance and in the related side effects.In other words,a complete knowledge of the fine pathological mechanisms of gut microbiota may provide a wide range of new diagnostic tools other than therapeutic targets in the light of tailored medicine.

Gut microbiota and immune system in liver cancer:Promising therapeutic implication from development to treatment

Liver cancer is a leading cause of death worldwide,and hepatocellular carcinoma(HCC)is the most frequent primary liver tumour,followed by cholangiocarcinoma.Notably,secondary tumours represent up to 90% of liver tumours.Chronic liver disease is a recognised risk factor for liver cancer development.Up to 90% of the patients with HCC and about 20% of those with cholangiocarcinoma have an underlying liver alteration.The gut microbiota-liver axis represents the bidirectional relationship between gut microbiota,its metabolites and the liver through the portal flow.The interplay between the immune system and gut microbiota is also well-known.Although primarily resulting from experiments in animal models and on HCC,growing evidence suggests a causal role for the gut microbiota in the development and progression of chronic liver pathologies and liver tumours.Despite the curative intent of“traditional”treatments,tumour recurrence remains high.Therefore,microbiota modulation is an appealing therapeutic target for liver cancer prevention and treatment.Furthermore,microbiota could represent a non-invasive biomarker for early liver cancer diagnosis.This review summarises the potential role of the microbiota and immune system in primary and secondary liver cancer development,focusing on the potential therapeutic implications.

Evaluation of prognostic factors and clinicopathological patterns of recurrence after curative surgery for colorectal cancer

BACKGROUND Colorectal cancer is a common tumor with a quite high-related mortality.Despite the used curative treatments,patients will develop cancer recurrence in up to 50%of the cases and/or other primary neoplasms.Although most of the recurrences are discovered within 3 years from the first treatment,a small percentage is found after 5 years.The early detection of recurrence is crucial to allow further therapies improving patients’survival.Several follow-up programs have been developed but the optimal one is far from being established.AIM To evaluation of potential prognostic factors for timing and patterns of recurrence in order to plan tailored follow-up programs.METHODS Perioperative and long-term data of all consecutive patients surgically treated with curative intent,from January 2006 to June 2009,for colorectal adenocarcinoma,were retrospectively reviewed to find potential prognostic factors associated with:(1)Recurrence incidence;(2)Incidence of an early(within 3 years from surgery)or late recurrence;and(3)Different sites of recurrence.In addition,the incidence of other primary neoplasms has been evaluated in a cohort of patients with a minimum potential follow-up of 10 years.RESULTS Our study included 234 patients.The median follow-up period has been 119±46.2 mo.The recurrence rate has been 25.6%.Patients with a higher chance to develop recurrence had also the following characteristics:Higher levels of preoperative glycemia and carcinoembryonic antigen,highest anaesthesiologists Score score,occlusion,received a complex operation performed with an open technique,after a longer hospital stay,and showed advanced tumors.The independent prognostic factors for recurrence were the hospital stay,N stage 2,and M stage 1(multivariate analysis).Younger ages were significantly associated with an early recurrence onset.Patients that received intermediate colectomies or segmental resections,having an N stage 2 or American Joint Committee on Cancer stage 3 tumors were also associated with a higher risk of liver recurrence,while metastatic diseases at diagnosis were linked with local recurrence.Neoadjuvant treatments showed lung recurrence.Finally,bigger tumors and higher lymph node ratio were associated with peritoneal recurrence(marginally significant).Thirty patients developed a second malignancy during the follow-up time.CONCLUSION Several prognostic factors should be considered for tailored follow-up programs,eventually,beyond 5 years from the first treatment.

Complications Following Surgery for Gastric Cancer: Analysis of Prospectively Collected Data

Background and Aims: The complication rate after surgery for gastric cancer varies according to the particular definition of morbidity, so it’s necessary to report them using a standardized method, the Clavien-Dindo system. The purpose of this study was to prospectively analyze all post-gastrectomy complications in patients with gastric adenocarcinoma according to the severity grade using Clavien-Dindo system, in order to identify risk factors for postoperative complications and their prognostic significance on survival. Methods: This study is based on data from 90 consecutive patients who underwent gastrectomy for gastric neoplasia between January 2010 and February 2014 at the same unit. 15 patients were excluded (benign tumors, GISTs, missing data). Complications were categorized according to the Clavien-Dindo classification (uncomplicated patients vs patients classified ≥Grade I). The following risk factors were studied: age, BMI, sex, operation method, extent of resection, duration of surgery, transfusions, TNM staging, and lymph node ratio. Multivariate logistic regression was used to evaluate the association between risk factors and presence of complications. To assess the effect on overall survival, after selection of covariates using backward elimination, the Cox proportional hazard model was applied. Results: Among these patients, 49 (65.3%) developed complications, stratified as follows: Grade I, 6 (8%);Grade II, 24 (32%);Grade III, 6 (8%);Grade IV, 13 (17.3%). The laparoscopic technique (OR = 0.050;95% CI = 0.005 - 0.550, p = 0.0143) and no transfusions (OR = 0.219;95% CI = 0.058 - 0.827, p = 0.0251) were found to reduce the incidence of postoperative complications in the multivariate analysis. With regard to the survival analysis, lymph node ratio, malnutrition, extended resection and presence of complications were significant predictors of reduced survival in the multivariate analysis. Conclusions: Some variables can predict the risk of postoperative complications, the occurrence of which is a predictor of reduced probability of survival. In this respect it’s essential to reduce complications.

Impact of microbiota-immunity axis in pancreatic cancer management

The microbiota impact on human diseases is well-known,and a growing body of literature is providing evidence about the complex interplay between microbiotaimmune system-human physiology/pathology,including cancers.Together with the defined risk factors(e.g.,smoke habits,diet,diabetes,and obesity),the oral,gut,biliary,and intrapancreatic microbiota contribute to pancreatic cancer development through different pathways including the interaction with the immune system.Unfortunately,a great majority of the pancreatic cancer patients received a diagnosis in advanced stages not amenable to be radically treated and potentially cured.Given the poor pancreatic cancer prognosis,complete knowledge of these complicated relationships could help researchers better understand the disease pathogenesis and thus provide early potential noninvasive biomarkers,new therapeutic targets,and tools for risk stratification that might result in greater therapeutic possibilities and eventually in a better and longer patient survival.

Evaluating the best treatment for multifocal hepatocellular carcinoma:A propensity score-matched analysis

BACKGROUND Hepatocellular carcinoma(HCC)is a common tumour often diagnosed with a multifocal presentation.Patients with multifocal HCC represent a heterogeneous group.Although Trans-Arterial ChemoEmbolization(TACE)is the most frequently employed treatment for these patients,previous data suggested that liver resection(LR)could be a safe and effective procedure.AIM To compare LR and TACE in patients with multifocal HCC in terms of procedurerelated morbidity and oncologic outcomes.METHODS All patients with multifocal HCC who underwent LR or TACE as the first procedure between May 2011 and March 2021 were enrolled.The decision to perform surgery or TACE was made after a multidisciplinary team evaluation.Only patients in Child-Pugh class A or B7 and stage B(according to the Barcelona Clinic Liver Cancer staging system,without severe portal hypertension,vascular invasion,or extrahepatic spread)were included in the final analysis.Propensity score matching was used to adjust the baseline differences between patients undergoing LR and the TACE group[number and diameter of lesions,presence of cirrhosis,alpha-fetoprotein(AFP)levels,and Model for End-Stage Liver Disease score].The Kaplan-Meier method was used to estimate overall survival(OS)and disease-free survival(DFS).The outcomes of LR and TACE were compared using the log-rank test.RESULTS After matching,30 patients were eligible for the final analysis,15 in each group.Morbidity rates were 42.9% and 40% for LR and TACE,respectively(P=0.876).Median OS was not different in the LR and TACE groups(53 mo vs 18 mo,P=0.312),while DFS was significantly longer with LR(19 mo vs 0 mo,P=0.0001).Subgroup analysis showed that patients in the Italian Liver Cancer(ITA.LI.CA)B2 stage,with AFP levels lower than 400 ng/mL,less than 3 lesions,and lesions bigger than 41 mm,benefited more from LR in terms of DFS.Patients classified as ITA.LI.CA B3,with AFP levels higher than 400 ng/mL and with more than 3 lesions,appeared to receive more benefit from TACE in terms of OS.CONCLUSION In a small cohort of patients with multifocal HCC,LR confers longer DFS compared with TACE,with similar OS and post-procedural morbidity.

Fecal metabolomic profiles: A comparative study of patients with colorectal cancer vs adenomatous polyps

BACKGROUND Colorectal cancer(CRC),the third most common cause of death in both males and females worldwide,shows a positive response to therapy and usually a better prognosis when detected at an early stage.However,the survival rate declines when the diagnosis is late and the tumor spreads to other organs.Currently,the measures widely used in the clinic are fecal occult blood test and evaluation of serum tumor markers,but the lack of sensitivity and specificity of these markers restricts their use for CRC diagnosis.Due to its high sensitivity and precision,colonoscopy is currently the gold-standard screening technique for CRC,but it is a costly and invasive procedure.Therefore,the implementation of custom-made methodologies including those with minimal invasiveness,protection,and reproducibility is highly desirable.With regard to other screening methods,the screening of fecal samples has several benefits,and metabolomics is a successful method to classify the metabolite shift in living systems as a reaction to pathophysiological influences,genetic modifications,and environmental factors.AIM To characterize the variation groups and potentially recognize some diagnostic markers,we compared with healthy controls(HCs)the fecal nuclear magnetic resonance(NMR)metabolomic profiles of patients with CRC or adenomatous polyposis(AP).METHODS Proton nuclear magnetic resonance spectroscopy was used in combination with multivariate and univariate statistical approaches,to define the fecal metabolic profiles of 32 CRC patients,16 AP patients,and 38 HCs well matched in age,sex,and body mass index.RESULTS NMR metabolomic analyses revealed that fecal sample profiles differed among CRC patients,AP patients,and HCs,and some discriminatory metabolites including acetate,butyrate,propionate,3-hydroxyphenylacetic acid,valine,tyrosine and leucine were identified.CONCLUSION In conclusion,we are confident that our data can be a forerunner for future studies on CRC management,especially the diagnosis and evaluation of the effectiveness of treatments.

A New Early Gastric Cancer after Subtotal Gastric Resection for Early Cancer: Case Report and Review of the Literature

Although the prognosis of early gastric cancer (EGC) is considered to be satisfactory, some patients experience tumor relapse after curative surgery. Both pathogenesis and risk factors of recurrence remain unclear. We describe a case report of a 49-year-old male who underwent subtotal gastric resection D2A for angular gastric cancer. Histological examination revealed gastric adenocarcinoma with low grade of differentiation and colloid areas, intramucosal, and absence of neoplastic proliferation in the surgical margins, in omental stroma and in the six examined lymph nodes (pT1, pN0). 11 years later, the same patient underwent D2 total gastrectomy for gastric cancer in the remnant stomach. New histological examination revealed again gastric adenocarcinoma, intramucosal, medium degree of differentiation, no documentable neoplastic proliferation within the limits of surgical resection, in the thirty-three examined lymph nodes and in the omentum (pT1, pN0).

Unexpected Hypertensive Pneumothorax after Digestive Upper Endoscopy: A Case Report

We report an unexpected massive left pneumothorax at the end of a digestive upper endoscopy without evidences of perforation or airway over-pressure. The possible air passage through a diaphragmatic failing is discussed.