Evaluation of the Effects of Gastro Protect as an Alternative Medicine on Gastritis and Other Gastrointestinal Symptoms.

INTRODUCTION: The use of herbal medicine as a part of the Complementary and Alternative Medicine is increasing worldwide. Herbal remedies are used to better different conditions including gastritis. MATERIAL AND METHODS: We conducted a prospective randomized control clinical trial on a total sample of 72 patients with gastritis in order to examine the effects of the commercial herbal product Gastro Protect. After 6 weeks of conventional therapy the patients were divided into two groups with 36 patients each. As a continuation of the treatment, Group 1 received conventional therapy + Gastro Protect and Group 2 received conventional therapy + Placebo. We analyzed 14 selected gastrointestinal symptoms, five related to digestive problems, and nine related to stool and bowel problems. For assessing the selected symptoms we used seven point gastrointestinal symptom rating scale (GSRS). RESULTS: The Gastro Protect group had a significantly lower GSRS score (better condition) compared to the Placebo group related to all five selected symptoms of digestive problems as: abdominal pain (p=0.0250), hunger pain (p=0.0276), nausea (p=0.0019), heartburn (p=0.00001), and acid reflux (p=0.0017). The Gastro Protect group, also had a significantly lower GSRS score (better condition) compared to the Placebo group related to three out of nine selected bowel symptoms: rumbling (p=0.0022), abdominal distension (p=0.0029), and gas or flatus (p=0.0039). CONCLUSION: Gastro protect was effective in treating gastritis and other gastrointestinal symptoms. It was safe for usage and showed almost no side effects. In our study, Gastro Protect reduced the examined gastric symptoms and related examined intestinal symptoms.

The Value of Injection Therapy with Botulinum Toxin in Pain Treatment of Primary Chronic Anal Fissures Compared to Anal Dilation, and Local Nifedipine in Combination with Lidocaine.

Introduction: Anal fissure is a longitudinal tear of the mucosa of the anal canal extending from the outer anal orifice in the direction of the dentate line of the inner anal opening. Fissures are divided into primary and secondary, and acute or chronic. Besides minimal rectal bleeding, itching and soiling, primary chronic anal fissures (PCAF) manifest with anal pain as theirs main determinant. It is described as the most troubling symptom. Aim: To compare the effect of injection therapy with botulinum toxin A (ITBT) vs. anal dilation (AD), and local nifedipine with lidocaine (LNL) in pain treatment of PCAF. Materials and Methods: This controlled retrospective prospective longitudinal study covered 94 patients, divided in 3 groups. The first was treated with ITBT, the second with AD and third using LNL (31, 33 and 30 patients respectively). Clostridium botulinum toxin A was used, dissolved with saline to concentration of 200 U/ml. The solution was applied to both sides of PCAF at dose of 40U. Modified technique of AD was done using 3 fingers of a single hand, progressively introduced into the anal canal, followed by gradual lateral distraction during 1 min. LNL therapy was conducted using nifedipine (0.3%) with lidocaine (1.5%) ointment, applied twice daily for 3 weeks. To measure pain, a visual analog scale (VAS) was used. The follow-up period was 12 weeks with checkup at week 4. Results: The median age of participants was 46.6±13.9 years (50 males vs. 44 females). The type of therapy had a significantly different effect on pain at week 4 (p=0.0003). Severe pain was present in only 2 ITBT patients, 16 AD, and 6 LNL patients. Post hoc analyses showed different pain disappearance time by week 12 (p <0.0001). The mean time was shortest in ITBT group (6.1±1.5 weeks). Anal pain intensity significantly differed among the 3 groups (Fisher exact, p=0.002). Namely, 71% in ITBT group rated the pain as weakest (VAS score 1) compared to 18.2% in AD and 30% of patients in LNL group. The overall pain reduction significance was in favor of ITBT, due to the differences between the ITBT and AD groups (p=0.00024) and ITBT compared to LNL group (p=0.018). Conclusion: ITBT is superior to AD and LNL in reducing pain in PCAF.

Biologic Therapy in Inflammatory Bowel Disease - Results from a Single Tertiary Care Center in North Macedonia.

Medical therapies used for Inflammatory Bowel Disease (IBD) include conventional (e.g. 5-aminosalicylates, steroids, immunomodulators) and biologic (e.g. inhibitors of tumor necrosis factor - alpha, integrin inhibitors, interleukin inhibitors) medications. Biologics, due to their high cost, were unfortunately not covered by the public health insurance system in North Macedonia until 2019 and, therefore, not widely utilized for our IBD patients. In 2019, the University Clinic of Gastroenterology and Hepatology in Skopje developed a biologic therapy supply, provided by the National Health Insurance Fund, making this therapy available for a larger number of patients. This report presents the initial results of our prospective, single tertiary-care center study on the effects of biologic therapy in patients with IBD in North Macedonia. The study is focused on the evaluation of clinical outcomes after anti-tumor necrosis factor alpha (anti TNF-alpha) therapy in IBD patients with prior inadequate response to conventional medications.

Testicular Mixed Germ Cell Tumor Presenting with Upper Gastrointestinal Bleeding: A Case Report.

Testicular mixed germ cell tumors (TMGCTs) are aggressive neoplasms that often have metastases at the time of diagnosis, primarily in the lungs, bones, and brain. Gastrointestinal metastases are rare, occurring in less than 5% of cases, while duodenal involvement is extremely rare, with only few reported cases. Furthermore, gastrointestinal bleeding is an atypical initial presentation of metastatic TMGCTs. Herein, we present a very rare case of upper gastrointestinal bleeding caused by a duodenal metastasis of a TMGCT in a 24-year-old man. The patient was admitted to our hospital due to abdominal pain and melena with a hemoglobin level of 52 g/L. He had no history of testicular swelling, or any other symptoms or signs of a testicular tumor. Upper gastrointestinal endoscopy revealed a duodenal tumor mass with irregular bleeding, and abdominal ultrasound and computed tomography showed a duodenal mass that infiltrate retroperitoneum. Emergency surgery was performed, and the histopathological findings of the resected specimen were consistent with TMGCT metastasis. Subsequently, a testicular tumor was confirmed and surgically removed; however, multiple metastatic deposits were observed in the lungs. Due to the patient's poor general condition, chemotherapy was not performed. The patient died 3 months after the initial diagnosis. This case suggests that, although duodenal metastatic TMGCTs are rare, they should be considered in the differential diagnosis of gastrointestinal bleeding in young male patients.

Chronic Abdominal Pain, an Overlooked Diagnosis of Median Arcuate Ligament Syndrome (MALS).

Median arcuate ligament syndrome (MALS) is a rare condition that is often overlooked as a result of its nonspecific symptoms. It is usually presented with nausea, bloating, abdominal postprandial pain, and weight loss. The diagnosis of MALS is usually delayed and made by excluding other causes for the symptoms. The diagnosis of this syndrome is based on clinical presentation and radiological findings on computer tomography angiography (CTA) or magnetic resonance angiography (MRA). Surgery is treatment of choice, with promising results from laparoscopic surgery.

Epidermal Growth Factor Receptor immunohistochemical expression in hepatocellular carcinoma without Epidermal Growth Factor Receptor exons 18-21 mutations.

Introduction: EGFR targeted therapies, have been proved beneficial for patients with HCC, nevertheless additional research on EGFR immunoexpresion and EGFR mutations is still needed, especially in population in which it has not been done yet. The aim of this study is to evaluate EGFR immunoexpression in HCC without EGFR exons 18-21 mutations and to evaluate its influence on survival in HCC patients in North Macedonia. Methods: We studied 31 cases of HCC for EGFR immunohistochemical expression and EGFR exons 18-21 mutations. The following clinical parameters were analyzed: Hepatitis B and C virus infection, presence of cirrhosis, tumor size, enlarged lymph nodes, metastases, alpha fetoprotein level and overall survival. Presence of the EGFR immunosignal (membranous and cytoplasmic) and the percentage of positive tumor cells in the entire tumor tissue specimen were semi-quantitatively determined. Results: Hepatitis B and C virus infection, tumor size, metastatic disease and EGFR immunoexpression have influence on patient's survival. No EGFR exons 18-21 mutations were detected in this group of HCCs. EGFR expression of 61%-80% in tumor tissue significantly influenced survival of the patients (p < 0.01). Multiple Cox regression confirmed tumor size of 5-10 cm (p < 0.05), tumor size > 10 cm (p < 0.01) and EGFR expression in range of 61% to 80% (p < 0.05) as independent survival predictors in patients with HCC. Conclusion: EGFR overexpression in range of 61% to 80% was an independent survival predictor in patients with HCC, implying that these patients could benefit from EGFR inhibition. However, the absence of EGFR mutations in exons 18-21 in any of the cases of this study suggest that single drug EGFR targeted therapy in patients with HCC may be insufficient.

Late Onset of Pancreatic Metastases from Renal Cell Carcinoma. A Case Report.

Metastasis of renal cell carcinoma (RCC) to the pancreas is a rare entity accounting only 0.25-3% of all pancreatic tumors. We present a rare case of isolated three focal pancreatic metastases from RCC, occurring 15 years after the left nephrectomy. The majority of the pancreatic metastases are asymptomatic, as it was in case of our patient excluding the weight loss for the last three months. We demonstrate the importance of the medical history, radiological examinations, histological and immunohistochemical analysis in making a definitive diagnosis.

Hepatocellular carcinoma - clinicopathological characteristics, survival, and expression of various histologic molecular markers.

The aim of this study was to make a clinical characterisation of patients with hepatocellular carcinoma and to investigate the expression of a set of molecular markers in patients from the Republic of North Macedonia. We analysed 60 patients for clinicopathologic factors, and we investigated tumour tissue and surrounding liver tissue for immunoexpression of E-cadherin, ß-catenin, cyclin D1, and p53. Infection with hepatitis virus B and C (p < 0.001), tumour dimension (p < 0.001), vascular invasion (p < 0.002), and tumour differentiation (p < 0.021) significantly influenced the survival of the patients. E-cadherin and ß-catenin expression reduction and cyclin D1 and p53 overexpression were significantly higher in the tumour than in the non-tumour tissue (p < 0.001; p < 0.001; p = 0.001; p < 0.001, respectively). No significant correlation was found between clinicopathological characteristics and the analysed molecules nor between the molecules themselves. The immunoexpression of E-cadherin, ß-catenin, cyclin D1, and p53 was not related to the tumour aggressiveness and prognosis. However, their significantly higher expression in HCC tissue compared to that in non-tumour tissue indicate their important role in hepatocarcinogenesis. The clinicopathological characteristics of the neoplasm remain highly predictive factors for the survival of the patients.

Tertiary Lymphoid Structures in Colorectal Cancers and Their Prognostic Value.

BACKGROUND: Tumor-infiltrating lymphocytes (TIL) in tumour stroma are considered to be involved in the elimination of malignant cells and prevention of metastasis formation. TIL consist of T lymphocytes including cytotoxic lymphocytes that are a constituent part of the effector mechanism of anti-tumour immunity and B lymphocytes that can form tertiary lymphoid structures (TLS). TLS has been described in several solid tumours and colorectal carcinoma (CRC), and the influence on the local and systemic anti-cancer response. AIM: This study aimed to quantify the presence of TLS in CRC patients and to determine their role in tumour progression. PATIENTS AND METHODS: The study included 103 patients with CRC who underwent surgery at the University Clinic of Digestive Surgery in Skopje, whose operative material was analysed at the Institute of Pathology, Medical Faculty in Skopje. The density of TLS was determined and correlated with the neoplasm status of local growth (T), positive lymph nodes, lymphatic invasion, and stage of the disease and tumour grade. RESULTS: The density of TLS was significantly higher in patients with higher stage, lower T status, and negative lymph nodes, in patients with no lymphatic invasion and with better-differentiated tumours. CONCLUSION: The density of TLS plays an important role in controlling the tumour growth, and it can be a parameter for neoplasm progression in CRC patients. The density of TLS influences the control of tumour progression.

TP53 Mutation in Correlation to Immunohistochemical Expression of P53 Protein in Patients with Hepatocellular Carcinoma.

BACKGROUND: Mutations causing p53 inactivation are among the most common genetic alterations in human malignant tumours including hepatocellular carcinoma. Detection of p53 gene mutations in patients with hepatocellular carcinoma (HCC) should provide relevant data for the patients from the Republic of Macedonia and should allow the survivals additional therapeutic option as is gene therapy. AIM: We aimed to detect p53 gene mutations in HCC tissue, and to correlate them with the immunoexpression of p53 protein and multiple clinicopathologic characteristics of a tumour. MATERIAL AND METHODS: We analysed thirty patients with HCC for multiple clinic-pathological characteristics. Tumour tissue samples were immunostained for p53 and detection of p53 gene mutations was performed by polymerase chain reaction followed by Sanger sequencing. RESULTS: Changes in p53 gene sequence were detected in four patients (13.33%), one of them a polymorphism and the other three were missense point mutations with p53 immunoexpression of 50%, 0%, 0% and 90%, respectively. All patients with p53 mutations had cirrhosis. Two of them had Hepatitis B infection, moderately differentiated tumour and T2 status. There was one case with a well-differentiated tumour and one with T4 status. All of them were with vascular invasion. The size of the tumours was in the range of 2.5 cm to 16 cm. All 3 mutations were located in exon 7. CONCLUSION: Mutations in p53 gene are not always associated with obviously altered immunoexpression of p53 protein. Detection of p53 gene mutations is necessary in each case because the new therapeutic modalities offer to apply gene therapy.

HER2 Positive Gastric Carcinomas and Their Clinico-Pathological Characteristics.

BACKGROUND: HER2 protein expression in gastric carcinoma, in correlation with existing, acknowledged prognostic factors which include the parameters that determine the TNM stage of the disease, could become the basis for ongoing research in the field of molecular targeted and personalised therapy. AIM: To determine the expression of the HER2 protein in gastric carcinoma and to correlate the expression of a HER2 protein with clinicopathological characteristics of the disease. MATERIAL AND METHODS: The data of HER2 protein expression and the parameters of the TNM classification were obtained from the histopathological reports of the Institute of Pathology in Skopje, and for the clinical stage we used patient's files from the University Clinic for Abdominal Surgery in Skopje. RESULTS: The analysis of the correlation of HER2 protein expression and TNM classification parameters pointed out a significant correlation between HER2 protein expression and intragastric localisation of gastric carcinoma (P = 0.005), and the tumour grade of differentiation (P = 0.034). There was also a positive correlation between HER2 protein expression pattern and positive lymph nodes in patients with gastric carcinoma (P = 0.03). The expression pattern of HER2 +++ was significantly more common registered in patients with positive lymph nodes (P = 0.03). CONCLUSION: The expression of HER2 protein could represent a biological marker with prognostic and predictive value in patients with gastric carcinoma. Considering the high mortality rate in patients with gastric carcinoma and lack of international standardised therapeutic approach, research of the role and significance of HER2 overexpression and Trastuzumab therapy may prove useful in the development of new therapeutic strategies.

Tumour Lymphocytic Infiltration, Its Structure and Influence in Colorectal Cancer Progression.

BACKGROUND: The role of the immune system in the control of tumour progression has been stressed, recently. Many studies indicate the fact that the immune system can prevent tumour progression in several types of human malignant neoplasms including colorectal cancer. According to some authors, a higher density of "tumour-associated lymphocytes" (TAL), in malignant neoplasms, correlate with prolonged survival of patients. AIM: This study aims to determine the structure and the influence of the immune cells, TAL, in the progression of colorectal cancer (CRC). PATIENTS AND METHODS: The study included 103 patients with CRC operated at the University Clinic of Digestive Surgery in Skopje, whose operative material was analysed at the Institute of Pathology, Medical Faculty in Skopje. The structure of tumor-associated cells and their density were determined and were correlated with neoplasm's grade, local growth (T), positive lymph nodes, lymphatic invasion and stage of the disease. RESULTS: CD4+, CD8+ and CD20+ lymphocytes (Ly) were found in TAL. The density of TAL was significantly different in neoplasms with different T status, lymphatic invasion, patients with and without nodal metastasis and patients with a different stage of the disease. The density of CD4+, CD8+, and CD20+ cells were significantly different in neoplasms with different T. The density of CD8+ and CD20+ lymphocytes was lower in patients with nodal metastasis and higher stage. CONCLUSION: The density of tumor-associated lymphocytes can anticipate the disease progression in patients with colorectal cancer, and the density of TAL influences the control of tumour progression.

Immunohistochemical Expression of Epidermal Growth Factor Receptor in Hepatocellular Carcinoma.

INTRODUCTION: Epidermal growth factor receptor (EGFR) signaling plays an important role in various cancers, including hepatocellular carcinoma (HCC). We aimed to evaluate immunoexpression of EGFR in HCC and surrounding non-tumor liver tissue and to correlate it to multiple clinicopathologic data. MATERIAL AND METHODS: We analyzed 60 patients with HCC for multiple clinicopathologic characteristics and survival. Presence of the immunosignal and the percentage of positive tumor cells at the whole tumor tissue sample and adjacent cirrhotic liver tissue were semi-quantitatively determined. RESULTS: Nineteen patients (31.67%) were female and 41 (68.33%) were male ranging in age from 31 to 85 years, median 61.88±10.51. Mean survival time for female patients was 8.86±1.76 months, for male 13.03±1.50 months and overall survival was 11.6051±1.19 months. The most patients had: T2 status (41.67%), no enlarged lymph nodes (90%), vascular invasion (63.33%) and well differentiated (43.33%) tumors. EGFR immunoexpression was determined in range from 0% to 100% in both tumor and non-tumor tissue with mean value of 39.58% in tumor and 86.86% in cirrhotic tissue (p<0.00). Higher percent of tumor EGFR positive cells were found in cases with higher T status, higher levels of AFP and poorly differentiated carcinoma, but not significantly. Lower percent of tumor EGFR positive cells were found in patients with vascular invasion and enlarged lymph nodes, but also not significantly. EGFR expression in tumor tissue significantly influenced survival of the patients (p<0.05). CONCLUSION: The study showed that expression of EGFR in lower percentage of tumor cells was associated to favorable prognosis, making it a potential prognostic marker and therapeutic target.