Vol 53, No 4 (2025)

Background: The transcription factor Oct4 plays an important role in tumor progression; however, it has not been adequately studied in neuroendocrine neoplasms. Its impact on the differentiation, functional activity of neuroendocrine cells and mechanisms of neurosecretory granule formation remains unclear.

Aim: To evaluate the diagnostic value of the qualitative and quantitative determination of the transcription factor Oct4 cytoplasmic expression in neuroendocrine tumors (NETs) of various localizations, hormonal activity, and grade.

Methods: In this single-center observational cross-sectional comparative two-sample study we analyzed the Oct4 expression in primary and metastatic NETs in tumor samples from 257 patients (243 with NETs and 14 with other tumor types) who were followed up or consulted at Moscow Regional Research and Clinical Institute (MONIKI) from 2000 to 2025. Tissue samples of tumors obtained during surgery or biopsy, as well as samples of unaffected NET-adjacent mucosa of the small intestine, colon and rectum, stomach, pancreatic islets and adrenal medullaries were examined. The Oct4 expression was assessed by immunohistochemistry with anti-Oct4 monoclonal antibodies (MRQ-10, RTU). A positive result was an intensive and even cytoplasmatic reaction in most tumor cells scored as 3+ if 90 to 100% cells were stained and 2+ if 50 to 89% cells were stained. A negative result for the expression looked as mild cytoplasmatic staining or focal reaction in cytoplasm of some tumor cells (1+) or complete absence of staining (0).

Results: Oct4 expression was present in 181 epithelial NETs of various locations and functional activities (56 bronchopulmonary, 7 thymus / mediastinum, 33 pancreas, 45 stomach, 32 intestine, 4 kidneys and 4 Merkel cell carcinomas), in 62 non-epithelial NETs (54 adrenal pheochromocytomas and 8 extra-adrenal paragangliomas), and in 14 non-neuroendocrine tumors. There were 135 low-grade (LG) NETs and 44 high-grade (HG) neuroendocrine carcinomas (22 small cell and 22 large cell). Positive (2+/3+) Oct4 cytoplasmatic staining was found in 100% of LG ECL- and EC-cell NETs of the stomach, small intestine, and appendix + colon (32/32, 20/20, and 4/4, respectively), 98.1% (53/54) of adrenal pheochromocytomas, 51.4% (18/35) of lung carcinoids, 40% (2/5) of thymus/mediastinum, and 24.5% (8/33) of pancreatic NETs. The highest Oct4 expression (3+) was detected in total (100%) of LG NETs of the small intestine (20/20) and appendix + colon (4/4), 90.6% (29/32) of the stomach, 75.4% (41/54) of adrenal pheochromocytomas (41/54), 22.8% (8/35) of lung carcinoids, 20% (1/5) of thymus / mediastinum, 62.5% (3/8) of extra-adrenal paragangliomas, and in none of pancreatic NETs. The highest Oct4 expression (3+) was found in 2 of 11 pheochromocytomas with increased metastatic potential, compared to 41 of 42 those with low metastatic potential. All NETs of the kidneys (4/4) and rectum (5/5), gastrinomas and somatostatinomas of the pancreas (3/3 and 2/2, respectively), 1 oncocytic pheochromocytoma (1.8%), 62.5% (5/8) of extra-adrenal paragangliomas and all tumors without neuroendocrine differentiation (100%, 14/14) were negative for Oct4. Positive Oct4 expression was observed significantly more frequent in functionally active NETs than in functionally inactive ones (67.4% vs 40.6%, respectively, odds ratio (OR) 3.03, 95% confidence interval (CI) 1.47 to 6.25, p = 0.003), and in well-differentiated NETs compared with neuroendocrine carcinomas (60.6% vs 6.8%, OR 21.01, 95% CI 6.19 to 71.25; p < 0.001). Positive cytoplasmic expression of Oct4 with a high specificity of 94.83% and sensitivity of 60.58% is a marker of well-differentiated NETs. The predictive value of positive cytoplasmic expression of Oct4 in the diagnosis of well-differentiated NETs is 96.51%.

Conclusion: The maximal Oct4 expression was found in the cytoplasm of EC- and ECL-cell of well-differentiated NETs of the gastrointestinal tract, as well as in adrenal pheochromocytomas and their normal cell counterparts. Positive cytoplasmic expression of Oct4 was a highly specific marker of well-differentiated NETs with possible hormonal activity. The specificity of Oct4 expression in various NETs could be used for the development of new individuated approaches to their diagnosis and therapy.

Introduction: Severe forms of ulcerative colitis (UC), pseudomembranous colitis (PMC), and ischemic colitis (IC) often exhibit clinical and morphological mimicry, complicating the differential diagnosis. In severe and fulminant cases, pathological changes in the colonic wall become increasingly uniform, thereby diminishing the impact of initial etiological factors on therapeutic decision-making. Currently, there are no clear clinical and laboratory criteria for predicting failure of conservative treatment in severe colitis.

Aim: To identify factors associated with unfavorable outcomes of conservative therapy in patients with severe and fulminant UC, PMC, and IC.

Methods: This was a single-center retrospective comparative cohort study in patients with severe and fulminant UC, PMC, and IC undergoing conservative treatment at the Loginov Moscow Clinical Scientific Center from 2015 to 2024. Based on a multidisciplinary team consensus on the presence of relative indications for surgery, two groups matched by sex, age (± 5 years), and diagnosis were formed: the main group (n = 36) included patients who declined surgery and continued their conservative management; the control group (n = 36) was selected via 1:1 propensity matching from the cohort without any surgical indications.

Results: The cohort’s diagnostic distribution was as follows: UC (n = 42), PMC (n = 22), and IC (n = 8). Fulminant disease was significantly more frequent in the main group (15/36) than in the control group (2/36; p < 0.001). The patients with relative surgical indications more often exhibited a systemic inflammatory response syndrome (12 vs 2 cases; p = 0.003) and in-hospital deaths (6 vs 0; p = 0.011). We were able to identify key predictors of mortality, such as PMC (odds ratio [OR] 8.0; 95% confidence interval [CI] 1.17–54.50), severe multiorgan dysfunction defined by a SOFA score ≥ 4 (OR 22.0; 95% CI 1.54–314.29), history of prior colonic resection (OR 20.0; 95% CI 1.95–204.73), the requirement for high-volume albumin infusion (≥ 1350 mL), being a marker of systemic decompensation and therapeutic intensity (OR 10.5; 95% CI 1.41–78.06), elevated serum creatinine (≥ 102.0 µmol/L; OR 28.8; 95% CI 2.62–315.30), and elevated serum urea (≥ 7.9 mmol/L; OR 40.0; 95% CI 3.42–468.07).

Conclusion: Thus, in the patients with severe and fulminant colitis under conservative treatment, the risk stratification based on the predictors identified, reflecting the severity of systemic decompensation and multiorgan failure enables timely surgical decision-making when there is no clinical improvement during medical therapy.

According to the provisions of Maastricht VI Consensus, the “test and treat” strategy is preferable and eradication therapy for Helicobacter pylori is recommended to patients with dyspepsia syndrome. However, some genotype specifics of the pathogen related to its ability to impact the development of H. pylori-associated disorders, increased resistance to antibiotics, and negative consequences of the multicomponent treatment of patients with helicobacteriosis make it necessary to review the unequivocal benefits of mandatory eradication strategy. The aim of this review is to analyze the diagnostic potential of identification of pathogenic H. рylori strains for well-grounded personalized eradication treatment. Taking into account the H. pylori genotype, it is plausible to differentiate the pathogen depending on the presence of VacA and CagA positive strains in infected individuals. Patients with precancerous conditions and/or a family history of gastric cancer living in regions endemic for helicobacteriosis have a high risk of contamination with pathogenic strains and the development of gastric cancer. A comparative analysis of H. pylori identification methods has revealed a problem in the helicobacteriosis diagnosis consisting in the absence of test systems designed to identify pathogenic strains of the microorganism capable of synthesizing oncogenic proteins. Administration of eradication therapy to all those infected without consideration of H. рylori pathogenicity is associated with an increase of antibiotic resistance to the drugs recommended for treatment, the development of dysbiosis and other side effects. According to the results of an experimental study, the use of antimicrobial therapy is justified only 13–20% of the patients. The development of enzyme-linked immune assays, immunochromatographic and other tests system for detection of H. pylori pathogenic proteins, seems promising.

The use of whole genome sequencing (WGS) of the pathogens to identify the risk groups with potentially ineffective eradication should be considered as progress. Assessment of H. pylori‘s sensitivity to antimicrobials before the administration of the first line eradication therapy makes it possible to timely correct the treatment and increase its efficacy.

A rare co-occurrence of Crohn’s disease (CD) and familial Mediterranean fever (FMF) is a complex comorbidity with similarities in their immune pathophysiology and clinical manifestations. This case highlights the challenges in differential diagnosis and therapeutic dilemmas arising from the need to simultaneously manage two immune-mediated diseases.

We report a clinical case of an Armenian man with recurrent abdominal pain, chronic diarrhea, episodes of dynamic intestinal obstruction and weight loss. His examination at the age of 39 years revealed signs of systemic inflammation, such as increased erythrocyte sedimentation rate to 62 mm/h, C-reactive protein level to 63 mg/l, and fecal calprotectin to 1039 micrograms/g. Endoscopic examination showed gastric ulcers (0.7 × 0.5 cm), an ileum stricture impenetrable with an endoscope, as well as multiple ulcers of the terminal ileum (SES-CD 9 points). The histological report concluded on chronic ulcerative ileitis with high activity. After one year, the results of molecular genetic testing showed a homozygous pathogenic variant of the MEFV c.2177T>C gene (p.Val726Ala) was identified, confirming FMF with persistent activity (serum amyloid A was increased to 32.3 micrograms/ml). The patient was diagnosed with stricturing CD with severe progressive course (A2L1L4B2p) and colchicine-resistant FMF. For CD, the patient consecutively treated with adalimumab, upadacitinib, and ustekinumab with partial response and subsequent ileocecal resection. For FMF, he received colchicine without an effect and canakinumab with complete cessation of attacks. Administration of two targeted agents for two diseases was discussed, but no final decision was taken. By the time of writing this manuscript (January 2025), the patient retained the endoscopic activity of CD with no attacks FMF under treatment with ustekinumab and colchicine.

In patients with Crohn’s disease, particularly those of Armenian descent, presenting with atypical abdominal pain and treatment resistance, FMF should be excluded. Molecular genetic testing for MEFV mutations should be included into the diagnostic workup, as their presence should be regarded as a CD modifying factor associated with the disease severity and complication risks. FMF-effective drugs (e. g., canakinumab) may not control CD progression, while CD-targeted therapies (adalimumab, ustekinumab) may not fully resolve FMF manifestations. The safety and efficacy of combining biologics remain unresolved. This case underscores the need for a multidisciplinary approach, development of clear criteria to assessing the activity of combined disease, and further research to optimize treatment strategies.