Increased PD-L1 expression in high-grade bladder cancer with squamous cell differentiation in Bulgarian and French patients' samples.

Urothelial carcinomas (UC) of the bladder are biologically and clinically heterogeneous and the most common malignancy of the urinary tract in developed countries worldwide, where several checkpoint targets as programmed death ligand-1 (PD-L1) and programmed cell death protein (PD-1) have received the most attention in the treatment of bladder cancer. However, the clinicopathological impact of this biomarker has not yet been established enough. OBJECTIVE: To evaluate programmed death ligand-1 (PD-L1) expression in UCs of the bladder in Bulgarian and French patients' samples. MATERIALS AND METHODS: Urothelial bladder carcinomas cases from 2016-2020 were retrospectively were analyzed. The cohort included 105 cases: 42 (40%) low grade and 63 (60%) high grade. Immunohistochemical (IHC) staining for PD-L1 expression was performed using an anti-PD-L1 primary antibody clone 22C3pharmDx only to 73/105 cases. RESULTS: Approximately 21/73 cases (28.8%) of urothelial bladder carcinomas demonstrated positive PD-L1 expression, and in 52/73 cases (71.2%) were negative. Positive PD-L1 expression was associated with high grade and high pathologic stage (p < 0.001). We found that PD-L1 was expressed in a significant percentage in UC with squamous differentiation (40%), followed by classic UC (30%). An association between histological grading systems of bladder UC (WHO1973 and WHO 2016) and the TNM-staging system, estimated by Pearson correlation coefficients (r = 0.590 and r = 0.583, respectively, p < 0.001) was observed. CONCLUSIONS: We found that PD-L1 expression is increased in patients with muscle-invasive UC, and PD-L1 might be a new biomarker that correlates with the pathological stage of urothelial bladder cancer and might predict recurrence-free survival.

Bilateral pheochromocytoma/intra-adrenal paraganglioma in von Hippel-Lindau patient causing acute myocardial infarction.

A 26-year-old male presented to the emergency department complaining of obstipation, severe headache and abdominal pain. An autopsy revealed bilateral pheochromocytoma and acute myocardial infarction. The tumor cells showed positive immunoreactivity of both chromogranin A and synaptophysin and were negative for adrenocortical markers such as SF-1, c17, scc, 3-HSD as well as SDHB, suggesting a germline mutation of the gene SDHB or SDHD. Molecular genetic analyses did not show a mutation in these two genes, but a mutation in the VHL gene, in exon 3: VHL c.499C>T. This is a missense mutation and causes an amino acid change (Arg167Trp).

New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis.

Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.

Autoantibodies related to ataxia and other central nervous system manifestations of gluten enteropathy.

Gluten ataxia and other central nervous system disorders could be linked to gluten enteropathy and related autoantibodies. In this narrative review, we focus on the various neuro-logical manifestations in patients with gluten sensitivity/celiac disease, immunological and autoimmune mechanisms of ataxia in connection to gluten sensitivity and the autoantibodies that could be used as a biomarker for diagnosing and following. We focused on the anti-gliadin antibodies, antibodies to different isoforms of tissue transglutaminase (TG) (anti-TG2, 3, and 6 antibodies), anti-glycine receptor antibodies, anti-glutamine acid decarboxylase antibodies, anti-deamidated gliadin peptides antibodies, etc. Most studies found a higher prevalence of these antibodies in patients with gluten sensitivity and neurological dysfunction, presented as different neurological disorders. We also discuss the role of a gluten-free diet on the clinical improvement of patients and also on imaging of these disorders.

Multinucleated giant cells of bladder mucosa are modified telocytes: Diagnostic and immunohistochemistry algorithm and relation to PD-L1 expression score.

BACKGROUND: Multinucleated giant cells (MGCs) in bladder carcinomas are poorly studied. AIM: To describe the function, morphogenesis, and origin of mononuclear and MGCs in urothelial carcinoma (UC) of the bladder in Bulgarian and French patients. METHODS: Urothelial bladder carcinomas (n = 104) from 2016-2020 were analyzed retrospectively using immunohistochemical (IHC) and histochemical stain examination. Giant cells in the bladder stroma were found in 35.6% of cases, more often in high-grades. RESULTS: We confirm that MGCs in the mucosa in UC of the bladder were positive for both mesenchymal and myofibroblast markers (vimentin, smooth muscle actin, Desmin, and CD34) and the macrophage marker CD68. Furthermore, IHC studies revealed the following profile of these cells: Positive for p16; negative for epithelial (CK AE1/AE3 and GATA-3), vascular (CD31), neural (PS100 and C-KIT), cambial, blastic (CD34-blasts and C-KIT), and immune markers (IG G, immunoglobulin G4, and PD-L1); no proliferative activity, possess no specific immune function, and cannot be used to calculate the Combined Positive Score scale. CONCLUSION: In conclusion, the giant stromal cells in non-tumor and tumor bladder can be used as a characteristic and relatively constant, although nonspecific, histological marker for chronic bladder damage, reflecting the chronic irritation or inflammation. Likewise, according to the morphological and IHC of the mono- and multinucleated giant cells in the bladder, they are most likely represent telocytes capable of adapting their morphology to the pathology of the organ.

Retroperitoneal and abdominal bleeding in anticoagulated COVID-19 hospitalized patients: Case series and brief literature review.

BACKGROUND: Hospitalized and severely ill coronavirus disease 2019 (COVID-19) patients necessitate prophylactic or therapeutic anticoagulation to minimize the risk of thrombosis at different sites. Life-threatening bleeding complications include spontaneous iliopsoas hematoma, peritoneal bleeding, and extra-abdominal manifestations such as intracranial hemorrhage. CASE SUMMARY: Bleeding in the abdominal wall results in less severe complications than seen with iliopsoas hematoma or peritoneal bleeding. In our case series of 9 patients, we present retroperitoneal and abdominal bleeding complications following anticoagulation in hospitalized COVID-19 patients with severe acute respiratory syndrome coronavirus 2 pneumonia. Contrast-enhanced computed tomography (CE-CT) is the best imaging modality for assessing hematoma secondary to anticoagulation and determines the therapeutic approach, whether interventional, surgical, or conservative management. CONCLUSION: We present the role of CE-CT for rapid and precise localization of the bleeding site and prognostic counseling. Finally, we provide a brief review of the literature.

Abdominal Apoplexy: Sudden Death Due to Massive, Nontraumatic Intra-abdominal Hemorrhage.

Abdominal apoplexy or idiopathic spontaneous intraperitoneal hemorrhage (ISIH), the modern way to describe this condition, is a rare phenomenon representing intra-abdominal bleeding with no traumatic origin. The condition is severe and potentially life-threatening. A man in his 70s was found dead at his home. The autopsy revealed a massive hemoperitoneum with no visible traumatic injuries externally or internally. The source of the bleeding was unknown despite the careful examination of the internal organs and splanchnic vessels. The cause of death was attributed to massive exsanguination due to the rupture of a small blood vessel as a complication of generalized arteriosclerosis and hypertensive disease. Despite its rare occurrence, the forensic pathologist should always consider this pathological condition when, during the autopsy, a massive intraabdominal hemorrhage with or without a visible source of the bleeding is discovered in the absence of any visible traumas.

Navigating the Challenges of Gluten Enteropathy and Infertility: The Role of Celiac-Related Antibodies and Dietary Changes.

Celiac disease (CD) is an autoimmune condition that is initiated in genetically susceptible individuals by the exposure of the intestines to gluten, and the early start of symptoms is related to malabsorption. Atypical variants of the illness are often identified in adulthood and are frequently associated with manifestations outside of the intestines, including metabolic osteopathy, anemia, and dermatitis herpetiformis. But also, empirical data suggest a correlation between CD and reproductive abnormalities, including repeated abortions. Infertility and repeated miscarriages frequently manifest in women diagnosed with CD and may serve as the initial clinical indication of a subclinical form. Furthermore, the condition may manifest as amenorrhea, infertility, and the delivery of infants with a low birth weight. Regarding the mechanisms of CD in infertility, along with the anti-tTG action to hinder the invasiveness of trophoblast, these antibodies could damage endometrial angiogenesis, which has been shown in in vitro models with human endometrial cells and in vivo in murine models. Another important aspect is the role of nutrient deficiencies, such as zinc deficiency (connected to impaired hormone production, secondary amenorrhea, and pre-eclampsia) and folic acid, etc. Therefore, our objective was to conduct a comprehensive review of the existing literature pertaining to this specific topic and to elucidate the role of the autoantibodies in its pathogenesis.

The End or a New Era of Development of SARS-CoV-2 Virus: Genetic Variants Responsible for Severe COVID-19 and Clinical Efficacy of the Most Commonly Used Vaccines in Clinical Practice.

Although the chief of the World Health Organization (WHO) has declared the end of the coronavirus disease 2019 (COVID-19) as a global health emergency, the disease is still a global threat. To be able to manage such pandemics in the future, it is necessary to develop proper strategies and opportunities to protect human life. The data on the SARS-CoV-2 virus must be continuously analyzed, and the possibilities of mutation and the emergence of new, more infectious variants must be anticipated, as well as the options of using different preventive and therapeutic techniques. This is because the fast development of severe acute coronavirus 2 syndrome (SARS-CoV-2) variants of concern have posed a significant problem for COVID-19 pandemic control using the presently available vaccinations. This review summarizes data on the SARS-CoV-2 variants that are responsible for severe COVID-19 and the clinical efficacy of the most commonly used vaccines in clinical practice. The consequences after the disease (long COVID or post-COVID conditions) continue to be the subject of studies and research, and affect social and economic life worldwide.

Islet transplantation-immunological challenges and current perspectives.

Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes (T1D) by transplanting pancreatic beta cells. Overall, pancreatic islet transplantation has improved to a great extent, and cellular replacement will likely become the mainstay treatment. We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced. Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h. Approximately 54% of the patients gained insulin independence at the end of the first year, while only 20% remained insulin-free at the end of the second year. Eventually, most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation, which imposed the need to improve immunological factors before transplantation. We also discuss the immunosuppressive regimens, apoptotic donor lymphocytes, anti-TIM-1 antibodies, mixed chimerism-based tolerance induction, induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes, pretransplant infusions of donor apoptotic cells, B cell depletion, preconditioning of isolated islets, inducing local immunotolerance, cell encapsulation and immunoisolation, using of biomaterials, immunomodulatory cells, etc.

High Concordance of CT Colonography and Colonoscopy Allows for the Distinguishing and Diagnosing of Intestinal Diseases.

(1) Although new imaging methods for examining the GIT with high diagnostic capabilities were introduced, the improvement and implementation of safe, efficient, and cost-effective approaches continue, and GIT diseases are still challenging to diagnose; (2) Methods: We aim to show the possibilities of computed tomography (CT) colonography for early diagnosis of colon diseases using a multidetector 32-channel CT scanner after appropriate preparation; (3) Results: After a colonoscopy was performed earlier, 140 patients were examined with CT colonography. Complete colonoscopy was performed in 80 patients (57.1%) out of 140 who underwent CT colonography. Incomplete colonoscopy was observed in 52 patients (37.2%); in 5 patients (3.6%), it was contraindicated, and in 3 patients (2.1%), it was not performed because of patients' refusal. We determined that in cases of complete FCS in 95% of patients, CT colonography established the same clinical diagnosis as FCS. In cases of incomplete, refused, or contraindicated FCS in 32.7% (17 patients), FCS failed to diagnose correctly. The main reasons for incomplete colonoscopy were: intraluminal obturation of tumor nature-17 patients (33%), extraluminal obturation (compression) from a tumor formation-4 patients (8%), stenotic changes of non-tumor nature-11 patients (21%), congenital diseases with changes in the length of the lumen of the intestinal loops-7 patients (13%), and subjective factors (pain, poor preparation, contraindications) in 13 patients (25%); (4) Conclusions: Our results confirmed that CT colonography is a method of choice in cases of negative FCS results accompanied by clinical data for the neoplastic process and in cases of incomplete and contraindicated FCS. Also, the insufflation system we developed optimizes the method by improving the quality of the obtained images and ensuring good patient tolerance.

Long-term effectiveness, outcomes and complications of bariatric surgery.

Dietary imbalance and overeating can lead to an increasingly widespread disease - obesity. Aesthetic considerations aside, obesity is defined as an excess of adipose tissue that can lead to serious health problems and can predispose to a number of pathological changes and clinical diseases, including diabetes; hypertension; atherosclerosis; coronary artery disease and stroke; obstructive sleep apnea; depression; weight-related arthropathies and endometrial and breast cancer. A body weight 20% above ideal for age, gender and height is a severe health risk. Bariatric surgery is a set of surgical methods to treat morbid obesity when other treatments such as diet, increased physical activity, behavioral changes and drugs have failed. The two most common procedures currently used are sleeve gastrectomy and gastric bypass. This procedure has gained popularity recently and is generally considered safe and effective. Although current data show that perioperative mortality is low and better control of comorbidities and short-term complications is achieved, more randomized trials are needed to evaluate the long-term outcomes of bariatric procedures. This review aims to synthesize and summarize the growing evidence on the long-term effectiveness, outcomes and complications of bariatric surgery.

Endothelial Dysfunction and Pregnant COVID-19 Patients with Thrombophilia: A Narrative Review.

Pregnancy with SARS-CoV-2 infection can raise the risk of many complications, including severe COVID-19 and maternal-fetal adverse outcomes. Additionally, endothelial damage occurs as a result of direct SARS-CoV-2 infection, as well as immune system, cardiovascular, and thrombo-inflammatory reactions. In this narrative review, we focus on endothelial dysfunction (ED) in pregnancy, associated with obstetric complications, such as preeclampsia, fetal growth retardation, gestational diabetes, etc., and SARS-CoV-2 infection in pregnant women that can cause ED itself and overlap with other pregnancy complications. We also discuss some shared mechanisms of SARS-CoV-2 pathophysiology and ED.

Blood Coagulation and Thrombotic Disorders following SARS-CoV-2 Infection and COVID-19 Vaccination.

Although abundant data confirm the efficacy and safety profile of the developed vaccines against COVID-19, there are still some concerns regarding vaccination in high-risk populations. This is especially valid for patients susceptible to thrombotic or bleeding events and hesitant people due to the fear of thrombotic incidents following vaccination. This narrative review focuses on various inherited and acquired thrombotic and coagulation disorders and the possible pathophysiologic mechanisms interacting with the coagulation system during immunization in view of the currently available safety data regarding COVID-19 vaccines. Inherited blood coagulation disorders and inherited thrombotic disorders in the light of COVID-19, as well as blood coagulation and thrombotic disorders and bleeding complications following COVID-19 vaccines, along with the possible pathogenesis hypotheses, therapeutic interventions, and imaging for diagnosing are discussed in detail. Lastly, the lack of causality between the bleeding and thrombotic events and COVID-19 vaccines is debated, but still emphasizes the importance of vaccination against COVID-19, outweighing the minimal risk of potential rare adverse events associated with coagulation.

Child abuse syndrome - a forensic case of fatal impulsive act of violence.

Child abuse syndrome is a medico-social problem widely spread around the world, which includes a complex of clinically manifested forms of violence against children. This syndrome includes different forms of physical violence, sexual violence, neglect, and emotional violence against children. The main problem with this type of violence continues to be the large number of unregistered "hidden" cases. The consequences of violence against children are serious and have a lasting negative effect on the physical and mental health of the victims. Child abuse is often a result of impulsive violent behavior with minimal provocation and may have a fatal outcome.

COVID-19 in patients with gastrointestinal stromal tumors: Recommendations for management and vaccination.

The coronavirus disease 2019 (COVID-19) pandemic profoundly affected the management and treatment of patients with malignancies. Based on the progress reported in the literature, we reviewed the recommendations for treatment and vaccination in patients with gastrointestinal stromal tumor (GIST) during COVID-19. We focus on whether there is a risk and what could be the possible effects of vaccinating patients with GIST/cancer. Since the situation is quickly changing, and the health services have been severely disrupted, the diagnosis, treatment and recommendations for vaccination of these patients against COVID-19 are still not updated. The approval of vaccines in the pandemic gave hope that we would soon be able to return to a more normal life. However, the oncology community needs to adapt and provide the most effective treatment and care models for patients with rare cancer, such as GIST. Collecting data on the impact of vaccination in patients with GIST/cancer also will be beneficial in expanding knowledge about the future planning of treatment strategies and optimizing care in the event of a subsequent pandemic.

Surgical complications in COVID-19 patients in the setting of moderate to severe disease.

The coronavirus disease 2019 (COVID-19) pandemic has had a considerable impact on the work of physicians and surgeons. The connection between the patient and the surgeon cannot be replaced by telemedicine. For example, the surgical staff faces more serious difficulties compared to non-surgical specialists during the COVID-19 pandemic. The primary concerns include the safest solutions for protecting healthcare staff and patients and the ability to provide adequate surgical care. Additionally, the adverse effects of any surgery delays and the financial consequences complicate the picture. Therefore, patients' admission during the COVID-19 pandemic should be taken into consideration, as well as preoperative measures. The COVID-19 situation brings particular risk to patients during surgery, where preoperative morbidity and mortality rise in either asymptomatic or symptomatic COVID-19 patients. This review discusses the recent factors associated with surgical complications, mortality rates, outcomes, and experience in COVID-19 surgical patients.

Current concept for tertiary lymphoid structures in urothelial carcinoma of the bladder: a literature review and our experience.

Bladder carcinoma (BC) is one of the most common malignancies of the urinary system in developed countries, with a high number of recurrences. The secondary lymphoid organs (SLO) are crucial for initiating the adaptive immune response. They are developed as a part of a genetically preprogrammed process during embryogenesis. However, SLO's organogenesis can be reduplicated de novo in other tissues by a process termed lymphoid neo-genesis, giving rise to tertiary lymphoid structures (TLS). These well-organized lymphoid structures in cancer are essential modulators of cancer immunologic response, and the histological examination of TLS gave a new strategy for cancer immunotherapy. This review explores the biological and histological characteristics of TLS in muscle non-invasive and invasive BC.