Gastroenterology and Hepatology from Bed to Bench

Anti-tumoral immune therapy consists of monoclonal antibodies that target intra-cellular immune checkpoints—which under normal circumstances, act as regulators of T-cell immunity. By serving as inhibitors of cellular checkpoints, monoclonal antibodies stimulate the immune system thus augmenting the body’s response against cancer. These immune-enhancers or stimulators have revolutionized the treatment of malignancy as they continue to show improvement in the overall survival of cancer patients. Currently, in the United States, six immune checkpoint inhibitors are approved for the treatment of a variety of solid tumors (1). As these checkpoint inhibitors are relatively new, only a scant amount of literature is available regarding both their adverse effects and management thereof. In addition, as newer antibodies are being developed, and expected to be enlisted among the armamentarium of cancer chemotherapeutic agents—the need to understand their toxicity and adverse effects is of paramount importance. Herein, we review some of the gastrointestinal and liver sequelea secondary to the usage of immunotherapeutic checkpoint inhibitor agents in cancer chemotherapy, as well as present the diagnosis and recommended treatment strategies for their adverse effects.   

Keywords: Anti-tumoral immune therapy, Treatment, Gastrointestinal and liver diseases.

(Please cite as: Weissman S, Saleem S, Al-Dulaimi D. Gastrointestinal and Liver adverse effects of anti-tumoral immune therapy: from recognition to treatment. Gastroenterol Hepatol Bed Bench 2021;14(3):195-199).

Aim: This study aims to identify the risk factors of disease-related death in patients with colon cancer in the presence of competing risks.

Background: Competing risk analysis is an effective method for identifying risk factors of death from disease, and the evidence related to the prognosis of death in patients with colon cancer in the country is rare.

Methods: In this historical cohort study, the information of 196 patients with colon cancer who were referred to Imam Khomeini Clinic in Hamadan during the years 2003 to 2017 were examined. Death due to the progression of cancer was considered an interesting cause, and death related to other causes was considered a competing event. Predictors of death due to the progression of cancer were determined in the presence of competing risks. The cause-specific hazard regression model was used to determine the effects of covariates. Data was analyzed using R software vol. 3.4.3 and survival packages.

Results: The mean (SD) age of patients was 57.1 (12.9) years, and 52.6% were male. The results of the multivariate cause-specific hazard regression model showed that the patient's age at the time of cancer diagnosis, T stage, stage of the disease and N stage had significant effects on the hazard of death due to cancer progression (p<0.05).

Conclusion: In the presence of various causes of death, using the cause-specific hazard model to identify the risk factors of each cause separately can better support clinical decisions compared to other models.

Keywords: Competing risk, Colon cancer, Cause-specific risk, Death due to cancer progression.

(Please cite as: Roshanaei GH, Safari M, Faradmal J, Abbasi M, Khazaei S. Factors related to mortality due to progression of disease in patients with colon cancer in the presence of competing risks: a retrospective cohort study in the west of Iran. Gastroenterol Hepatol Bed Bench 2021;14(3):200-205).

Aim: In this study, these methods were used to estimate the treatment effect in patients with gastric cancer in the presence of noncompliance.

Background: In medical sciences, simple and advanced methods are used to estimate treatment effects in the presence of noncompliance.

Methods: This historical cohort study surveyed 178 patients with gastric cancer underwent chemotherapy alone (chemotherapy alone group) and 193 patients underwent surgery and chemotherapy (surgery plus chemotherapy group) from 2003 to 2007 at the Cancer Institute of Imam Khomeini Hospital (Tehran). Demographic and clinical characteristics were extracted from patients' hospital records. The survival of patients was calculated as being from diagnosis to death or to the end of the study. The treatment effect was estimated using three methods: treatment as a time-dependent covariate, IPCW, and Structural Nested Models using STATA and R software.  

Results: Fifty-six patients (31.5%) who underwent chemotherapy and 69 patients (35.8%) who underwent surgery and chemotherapy died by the end of the study. The hazard ratio in group I compared to group II was estimated between 1.5 to 2.07 times based on the simple analysis method. The modified hazard ratio was estimated to be 1.21 (95% CI: 1.11-1.32) based on the SNM method. Surgery plus chemotherapy is superior to chemotherapy alone, and it improves the overall survival (OS) rate of gastric cancer patients.

Conclusion: Survival was improved in patients undergoing chemotherapy and surgery together compared to those undergoing chemotherapy alone. The results of the current study suggest that treatment effect can be estimated unbiasedly using the appropriate method.  

Keywords: Treatment effect, Noncompliance, Time-dependent covariate, Inverse probability of censoring weights, Structural nested model.

(Please cite as: Safari M, Mahjub H, Esmaeili H, Sadighi S, Roshanaei Gh. Estimating the treatment effect in patients with gastric cancer in the presence of noncompliance. Gastroenterol Hepatol Bed Bench 2021;14(3):206-214).

Aim: The current study was designed to evaluate the role of semi-quantitative EUS- elastography (strain ratio) in staging malignant pancreatic lesions.

Background: Pancreatic cancer is considered one of the most lethal malignancies with a survival rate of only 5% worldwide. Pancreatic lesions include a wide range of diagnoses from benign to malignant forms. Biopsy and pathological study are the gold standard for the differentiation of malignant lesions and staging of tumors. Recently, endoscopic ultrasound sonography (EUS) elastography has been noticed as a non-invasive diagnosis modality. Nevertheless, no evidence of its potential to determine different stages of malignant tumors is available.

Methods: This prospective study included 81 adult patients with a confirmed diagnosis of malignant pancreatic lesion in different clarified stages. All diagnoses were confirmed after endoscopic ultrasound sonography via pathological investigation of surgical specimens or needle biopsies. The results of EUS-elastography based on tumor size (T staging), involved lymph nodes (N staging), and metastasis (M staging) were compared with the gold standard.

Results: The mean age of patients was 60.11±13.57 years. The mean SR elastography value was 52.78±48.97. Elastography could not significantly discriminate T stage, N stage, or M stage of tumors (p=0.57, p=0.92, p=0.11, respectively). Moreover, the Spearman rank correlation coefficients for the correlation between T staging, N staging,  M staging and SR elastography were not significant (p=0.40, p=0.94, p=0.39, respectively).

Conclusion: The non-invasive modality EUS-elastography cannot replace the gold standard in staging tumors; however, EUS-elastography seemed to differentiate benign lesions from malignant ones.  

Keywords: Pancreatic neoplasms, Elasticity imaging techniques, Neoplasm staging.

(Please cite as: Saffarian A, Eslami P, Dooghaie Moghadam A, Almasi F, Pourhoseingholi MA, Asadzadeh Aghdaei H, et al. The potential of endoscopic ultrasound sonography (EUS)-elastography in determining the stage of pancreatic tumor. Gastroenterol Hepatol Bed Bench 2021;14(3):215-220).

Aim: This research aimed to study the association of food insulin index and biochemical parameters with the odds of developing NAFLD in adult Iranians.

Background: Hyperinsulinemia may play an important role in the development of non-alcoholic fatty liver disease (NAFLD) because of the relationship between insulin response and body fat accumulation.

Methods: A case-control study of 169 NAFLD patients and 200 healthy adults aged 18-55 years was conducted. Dietary data was collected using a validated 168-item quantitative food frequency questionnaire (FFQ). Food insulin index (FII) was calculated by dividing the total insulin load by total energy intake (kcal/day). Total insulin load (ILoverall) was also calculated using a standard formula.  

Results: Mean participant age was 43.9 ± 5.9 years. Patients with NAFLD were significantly associated with higher body mass index, levels of liver enzymes, triglyceride, low density lipoprotein-cholesterol (LDL), total cholesterol, and fasting blood sugar (FBS) compared to the healthy subjects (p < 0.05). The highest tertiles of FII were associated with higher odds of NAFLD (OR=1.4, 95% CI: 0.88-2.48, p for trend <0.001) and obesity (OR=2.33, 95% CI: 0.97-5.75) compared to the lowest tertiles. Potential confounders for the association were controlled.

Conclusion: This study found that adherence to a diet with high FII was associated with greater odds of NAFLD and overweight or obesity. Additional studies are required to better understand this association.

Keywords: Insulin, Biochemical processes, Obesity, Chronic diseases, Non-alcoholic fatty liver disease.

(Please cite as: Fatahi S, Sohouli MH, Rayi A, Teymoori F, Shidfar F. The association between food insulin index and odds of non-alcoholic fatty liver disease (NAFLD) in adults: a case-control study. Gastroenterol Hepatol Bed Bench 2021;14(3):221-228).

Aim: The associations between serum levels of melatonin and concentrations of tumor necrosis factor (TNF)-a and interleukin (IL)-6 were assessed among patients with different degrees of non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) has become a very common worldwide disease.

Methods: In this cross-sectional study, adult patients diagnosed with fatty liver disease by Fibroscan evaluation were included if they met the inclusion/exclusion criteria for NAFLD. The participants were categorized into the three following groups: 1) fibrosis> 9.1KP and steatosis >290 dbm; 2) fibrosis: 6-9.0 KP and steatosis 240-285; and 3) fibrosis < 5.8 KP and steatosis<240 dbm. Post-fasting, 5 ml of venous blood was collected for laboratory assessment, and a questionnaire including demographic, anthropometric, laboratories and clinical data was completed.

Results: A total of 97 participants were included. The mean age was 42.21±11 years, and 59 patients (60.0%) were female. Melatonin levels as well as pro-inflammatory cytokines levels were correlated with advancing fibrosis and steatosis in univariate analysis. A significant association was observed between these cytokines and advancing fibrosis, severe steatosis levels, and melatonin concentrations. Furthermore, in the multiple linear regression model, melatonin levels showed a significant association with these cytokines.  

Conclusion: Melatonin may have protective effects on tissue injury during advancing liver fibrosis via cytokines modulation. Therefore, it can be considered as a potential therapeutic management strategy for NAFLD.

Keywords: Fatty liver, Cytokine, Melatonin, Inflammation.

(Please cite as: Sohrabi M, Gholami A, Amirkalali B, Taherizadeh M, Kolahdoz M, SafarnezhadTameshkel F, et al. Is melatonin associated with pro-inflammatory cytokine activity and liver fibrosis in non-alcoholic fatty liver disease (NAFLD) patients? Gastroenterol Hepatol Bed Bench 2021;14(3):229-236).

Abstract

Background: due to the problem of organ shortage and high demand of liver transplantation among patients, this problem has been exacerbated, thus providing more information on the causes of liver re-transplantation and its prognosis and other related issues to this procedure is of great importance. The aim of this study was to investigate the causes of liver re-transplantation in patients referred to Imam Khomeini Hospital Liver Transplantation Center and also the prognosis of this re-transplantation.

Methods: This study was conducted in 2018 as a historical cohort. In this study, the records of liver transplantation patients at Imam Khomeini Hospital Liver Transplantation Center between 2000 to 2016 and were studied. Required data were extracted from the records of patients undergoing liver transplantation. Patients' data were entered SPSS 20 software and analyzed.

Results: In this study 1030 patients with mean age of 43.15 ± 14.57 years were studied. There were 426 women (41.4%) and 604 men (58.6%). The number of primary transplants was 966 with a mean age of 43.19 ± 14.72 and the number of re-transplants 64 with a mean age of 42.56 ± 12.82. Significant differences were found between the two groups in terms of MELD and CHILD scores, cold ischemic time, total and direct bilirubin levels, liver function factors (ALT, AST, and alkaline phosphatase), hemoglobin, and WBC. There was no significant difference between the two groups in terms of age, sex and platelets (> 0.05). The mortality rate was 241 (23.39%) in all patients and the mortality rate was 206 (21.32%) and in liver transplant patients was 35 (54.68%). The mortality rate in the transplant group was statistically higher (> 0.001). Secondary is primary non-functional graft (PNF) (37.5%) with 1, 3- and 5-years survival rates of 82%, 81% and 70% in primary group and 59%, 43% and 32% in re-transplantation. There was a significant difference in survival between the two groups (P <0.05). Hemoglobin and alkaline phosphatase were predictors of survival rates in transplant patients.

Conclusion: The results of this study showed that survival rate in re-transplant patients was significantly lower than primary transplant and mortality rate in re-transplant patients was significantly higher.

Key words: liver re-transplant; prognosis; Survival

Aim: The present study aimed to cross-culturally adapt and assess the validity and reliability of the English version of the Wexner questionnaire translated into the Persian language in Iranian patients.

Background: Constipation is one of the most common gastrointestinal disorders; therefore, it is necessary to utilize an index for both the clinic and research studies.

Methods: In the first phase, the English version of the Wexner questionnaire was translated into the Persian language. In the second phase, the Persian version was assessed to evaluate the psychometric properties in 136 patients with functional constipation who referred to gastrointestinal and physical medicine clinics. Content validity was assessed by face validity. Construct validity was tested based on hypothesis testing and structural validity. The correlation of the total scores of the Wexner questionnaire and the Patient Assessment Constipation Quality Of Life (PAC-QOL) questionnaire was used for concurrent criterion validity. Internal consistency and test-retest reliability were calculated using Cronbach's α and intraclass correlation coefficient (ICC).The floor/ceiling effect of the questionnaire was also evaluated.

Results: The content validity of the Persian version of Wexner’s questionnaire was acceptable. The construct and concurrent criteria validity showed moderate correlation. The internal consistency and intrarater reliability were moderate (0.51) and excellent (r_p = 0.97, p-value <0.001), respectively. No floor/ceiling effect was seen.

Conclusion: The Persian version of the Wexner questionnaire showed good validity and reliability in Iranian patients and can therefore be applied in clinics as well as in research for Persian-speaking countries.

Keywords: Constipation, Validity, Reliability, Persian version, Questionnaire

(Please cite as: Majidirad F, Hadian MR, Asl Soleimani H, Jalaie SH,  T, Bazaz Bebahani R, et al. Cross-cultural adaptation, validity, and reliability of the Wexner questionnaire in patients with functional constipation in an Iranian population. Gastroenterol Hepatol Bed Bench 2021;14(3):243-249).

Aim: This study aimed to analyze the cost-effectiveness of two routine therapeutic methods for H. pylori eradication in Iran

Background: Because of the importance of Helicobacter pylori (H. pylori) eradication on gastric cancer prevalence and costs, an economic analysis of the eradication methods is essential for health systems.

Methods: This cross-sectional study was conducted on 7,496 participants with positive Hepadnaviridae (HPsAg) test results for H. pylori; 6,163 of them were treated with furazolidone (group A), and 1,333 participants were treated with clarithromycin (group B). Data on GP visits, medications, and HPsAg costs as direct costs and absence from work and transportation as indirect costs was collected by researcher-made questionnaire. Indirect costs were calculated based on face-to-face interviews with 365 patients of the Persian Cohort Center. Successful eradication of H. pylori infection (negative HPsAg) was defined as the effectiveness of the interventions. Incremental cost-effectiveness ratio (ICER) was used to compare the overall results.

Results: The total direct cost of H. pylori for groups A and B were estimated at 13.7 and 5.83 billion IRR, respectively. The highest and lowest percentages of total costs were the cost of diagnostic services and the time cost, respectively. There was a significant difference between the two groups in drug costs (p<0.001). The effect ratio for groups A and B was 85.93% and 96.54%, respectively. Cost per effectiveness was higher for clarithromycin (CE=3,250,170 IRR) than for furazolidone (CE=2,988,488 IRR), and ICER showed that 5.1 Million IRR per participant is needed to eradicate H. pylori.

Conclusion: Based on the results, furazolidone was more cost-effective than clarithromycin for H. pylori treatment. Therefore, due to the high prevalence of H. pylori and the economic conditions of the health system in Iran, furazolidone can be a cost-effective choice between the two conventional treatment methods considering the results of further research and possible side effects.

Keywords: Cost-effectiveness, Helicobacter pylori, Eradication, Furazolidone, Clarithromycin.

(Please cite as: Pourfarzi F, Zahirian Moghadam T, Zandian H, Malekzadeh R, Yazdanbod A. Cost-effectiveness analysis of two routine therapeutic methods for Helicobacter pylori eradication: a Persian cohort-based study. Gastroenterol Hepatol Bed Bench 2021;14(3):250-259).

Aim: The current study aimed to determine the antifungal susceptibility profile of Candida species isolated from gastroesophageal lesions

Background: Gastroesophageal candidiasis is a common infection among HIV/AIDS patients and those who are taking PPI and H2RAs drugs. More than 20 Candida spp. can cause different types of mucocutaneous infections in humans. The present study was conducted to assess the antifungal susceptibility testing of clinical Candida spp. isolated from gastroesophageal lesions.

Methods: Forty-eight clinical samples were collected from 60 patients undergoing endoscopy. All isolates were identified by molecular techniques (PCR-RFLP). The profiles of the susceptibility of Candida spp. to seven antifungal agents, i.e. amphotericin B, fluconazole, itraconazole, luliconazole, voriconazole, posaconazole, and caspofungin, were evaluated using broth microdilution.

Results: The susceptibility profile of Candida isolates revealed 100% sensitivity to amphotericin B, caspofungin, and voriconazole. Moreover, fluconazole- (6.5%) and itraconazole-resistant (2.1%) isolates were observed.

Conclusion: With regard to the increase in fluconazole-resistant Candida species, it is necessary to determine the in vitro antifungal susceptibility pattern of clinical isolates for the best management of infection and to prevent the emergence of drug resistant isolates.

Keywords: antifungal susceptibility testing, Candida spp., gastroesophageal.

(Please cite as: Mirshekar M, Emami MH, Mohammadi R. In vitro antifungal susceptibility pattern of Candida species isolated from gastroesophageal candidiasis. Gastroenterol Hepatol Bed Bench 2021;14(3):260-266).

Aim: This research examined silibinin's anti-inflammatory outcomes on the NOD-like receptor protein-3 (NLRP3) and NF-κB gene expression, which plays a notable role in inciting inflammatory pathways.

Background: Hepatic ischemia-reperfusion (I/R) is a common phenomenon in many clinical cases, including liver surgery and transplantation. Inflammatory mediators are vital contributors to the expansion of hepatic damage after I/R injury (I/RI), and therefore, targeting inflammation is a considerable candidate for the management of hepatic I/RI and its complications.

Methods: Thirty-two male Wistar rats were divided equally into four groups: 1) Control (Vehicle) group, in which rats underwent laparotomy and received normal saline; 2) SILI group, in which rats underwent laparotomy, and 30 mg/kg silibinin was injected intraperitoneal (IP); 3) I/R group, in which rats underwent I/R and received normal saline; and 4) I/R + SILI group, who encountered I/R after laparotomy and received silibinin. After one hour of ischemia and three hours of reperfusion, blood and liver tissue samples were assembled for future biochemical, histological, and gene expression studies.

Results: In vivo analysis attested that serum AST and ALT activities were significantly lessened by silibinin in the SILI + I/R group (p <0.001). Silibinin ameliorated inflammatory liver tissue injuries, including neutrophil and macrophage infiltration, hepatocyte degeneration, cytoplasmic vacuolation, vascular endothelial damages, and sinusoid dilation observed in the I/R group. During I/R, NLRP3 and NF-κB gene expression showed a significant increment compared to the control group (p <0.001), which could be alleviated by silibinin (p <0.01).  

Conclusion: The results evidence that adjusting the expression of NLRP3 and NF-κB genes during I/R is probably one of the mechanisms of the anti-inflammatory effects of silibinin.   

Keywords: Ischemia, NF-Κb, NLRP3, Reperfusion, Silibinin.

(Please cite as: Zarpou S, Mosavi H, Bagheri A, Malekzadeh Shafaroudi M, Khonakdar-Tarsi A. NF-κB and NLRP3 gene expression changes during warm hepatic ischemia-reperfusion in rats with and without silibinin. Gastroenterol Hepatol Bed Bench 2021;14(3):267-275).

This study aimed to report an unusual presentation of an advanced gastric adenocarcinoma. Leptomeningeal carcinomatosis is a rare event in gastric adenocarcinoma. It is much more uncommon as the primary manifestation in post-mortem evaluation of the cause of death in a patient presenting with headache and neurological signs and symptoms. Herein, we discuss our experience with a case of gastric adenocarcinoma, who was diagnosed after death, presenting with neurological signs and symptoms of leptomeningeal carcinomatosis. A 52-year-old gentleman presented with intractable headache and neck pain as well as vertigo. His physical examination showed only decreased deep tendon reflexes. He died after a short period of coma. Post-mortem evaluation showed numerous signet ring cells in the subarachnoid space as well as gastric malignant ulcer. In patients with intractable headache with no identifiable cause, meningeal involvement and infiltration should be considered as the probable underlying cause. Radiologic findings are not significant; however, lumbar puncture can be diagnostic.

Keywords: leptomeningeal carcinomatosis, gastric adenocarcinoma, autopsy.

(Please cite as: Geramizadeh B, Fereidooni M, Dehghan AR, Bagheri-Lankarani K. Autopsy diagnosis of leptomeningeal carcinomatosis, the first manifestation of gastric adenocarcinoma: a rare case report and review of the literature. Gastroenterol Hepatol Bed Bench 2021;14(3):276-280).

Hepatoid adenocarcinoma is a poorly differentiated alpha-fetoprotein-producing (AFP) tumor frequently located in the stomach, ovary, and pancreas. Presentation in the stomach has a high mortality rate due to late diagnosis, which offers the patient few therapeutic alternatives. On February 22, 2019, a 44-year-old woman from Lima entered the emergency department for pain in the right hypochondrium for 4 months, weight loss, nausea, and asthenia. On physical examination, hepatomegaly presented with a liver spam of 17 cm. Serology showed severe anemia and AFP of 49,800. The tomography showed multiple hypodense lesions in the liver and the presence of nodes. Endoscopy showed Bormann III gastric malignancy. Gastric biopsy determined undifferentiated epithelial malignancy; the immunohistochemical mark (+) for AFP and PAS Diastase confirmed a hepatoid gastric adenocarcinoma. A rare variant of gastric adenocarcinoma was evident, which often mimics an HCC. In this case, multiple liver metastases were observed that differed from the diagnosis of HCC, so this variant must always be taken into account when a primary gastric tumor presents with hepatic metastases.

Keywords: Hepatoid adenocarcinoma, Metastases, Liver.

(Please cite as: Quino-Florentini M,  Garcia-Rojas F, Guerra-Canchari P, Cerrillo-Sanchez G. Gastric hepatoid adenocarcinoma with multiple liver metastasis: a case report. Gastroenterol Hepatol Bed Bench 2021;14(3):281-285).

Acute appendicitis is one of the most common causes of abdominal emergent surgical disease worldwide. Enterobius vermicularis, a human intestinal parasite, is reported to be associated with acute appendicitis.

We report a case of an 8-year-old girl who was admitted to the emergency unit with complaints of severe abdominal pain and was diagnosed with acute appendicitis. Microscopic pathological examination showed lymphoid follicles with prominent germinal centers and mantle zones within the appendix wall. Cross-sections of multiple female and male Enterobius vermicularis worms and a few longitudinal sections of E.vermicularis were seen.

1. vermicularis is one of the most common human parasitic infections, so the possibility of infection of the appendix with E. vermicularis should be considered in the differential diagnosis of agents of appendicitis.

Keywords: Appendicitis, Parasite, Enterobius, Khoy.

(Please cite as: Hooshyar H, Jannati Dastgerdi M, Kazemi E. Acute appendicitis: a case report of hyperinfection with Enterobius vermicularis. Gastroenterol Hepatol Bed Bench 2021;14(3):286-289).