Przemyslaw Zdziarski

Objectives: Endocrine neoplasms, as a general rule, show systemic, neuro-inflammatory and metabolic consequences, known as paraneoplastic syndrome. The comorbidity of thyroid tumors with neurological and autoimmune diseases prompt looking for common neuro-immuno-endocrine mechanisms of these disorders. While most TCs are well described, there is a gap in the literature after the isolation of oncocytic/Hürthle cell carcinoma (HCC), as a unique type due to immunoendocrine and metabolic features (low TSH-receptor expression and radioiodine avidity). The aim of this study was to collect clearly defined reports of HCC (as a separate entity) and to attempt determining common clinical symptoms and the usefulness of various diagnostic techniques (comprehensive critical review). This may be an introduction to modern treatment (patient-centered care) since the main cause of mortality is not local progression or metastases. Results: Until now, due to misnomenclature and data misinterpretation, HCC has been treated according to general standards (with overuse of TSH-ST and RIA). High thyroglobulin level, decreased total thyroxin (with normal FT3 and spontaneous decrease in TSH), hypercalcemia, as well as the “reverse flip-flop” phenomenon, as common symptoms, indicate the neuroendocrine origin of HCC. Sparse, well-documented lymph node metastases are another feature, although from few studies. Most studies omit the N stage. Whole-body ¹³¹iodine and ¹⁸F-fluorodeoxyglucose scintigraphy may be useful before FNAB. Fine-needle aspiration biopsy (FNAB), as a “gold standard” in early diagnosis of thyroid nodules, delays HCC diagnosis because of the inability to determine a benign/malignant nature. Conclusions: Final HCC outcome may be affected by various overlapping immunoendocrine factors (paraneoplastic effects). Due to very few thyroid function tests performed in HCC, we have proposed a set of basic laboratory analyses, core biopsy in HCC differentiation, and diagnostic chain for standardization. According to the review, adaptation and treatment of HCC based on existing standards for other thyroid cancers seem to be insufficient, and the risks outweigh the benefits. The key recommendations resulting from the 5th edition of the WHO Classification of Endocrine Neoplasms are only the beginning of refuting many myths and biases.

Background. Critical and progressive cachexia may be observed in numerous medical disciplines, but in patients with various diseases, several pathways overlap (endocrine, inflammatory and kidney diseases, heart failure, cancer). Methods. Unlike numerous cohort studies that examine thyroid cancer and risk factors, a different method was used to avoid bias and analyze the sequence of events, i.e., the pathway. A case-control analysis is presented on patients with initial immune-mediated thyroiditis complicated by cachexia, presenting pulmonary pathology coexisting with opportunistic infection, and ultimately diagnosed with cancer (TC—thyroid cancer, misdiagnosed as lung cancer). Results. Contrary to other patients with lung cancer, the presented patients were not active smokers and exclusively women who developed cachexia with existing autoimmune processes in the first phase. Furthermore, the coexistence of short overall survival without cancer progression in the most seriously ill patients, as well as correlation with sex (contrary to history of smoking) and predisposition to mycobacterial disease, are very suggestive. Although we describe three different autoimmune conditions (de Quervain’s, Graves’, and atrophic thyroiditis), disturbances in calcium and metabolic homeostasis, under the influence of hormonal and inflammatory changes, are crucial factors of cachexia and prognosis. Conclusions. The unique sequence sheds light on immune-mediated thyroid disease as a subclinical paraneoplastic process modified by various therapeutic regimens. However, it is also associated with cachexia, systemic consequences, and atypical sequelae, which require a holistic approach. The differential diagnosis of severe cachexia, adenocarcinoma with pulmonary localization, and tuberculosis reactivation requires an analysis of immunological and genetic backgrounds. Contrary to highly specialized teams (e.g., lung cancer units), immunotherapy and general medicine in aging populations require a multidisciplinary, holistic, and inquiring approach. The lack of differentiation, confusing biases, and discrepancies in the literature are the main obstacles to statistical research, limiting findings to correlations of common factors only. Time-lapse case studies such as this one may be among the first to build evidence of a pathway and an association between inflammatory and endocrine imbalances in cancer cachexia.

Critical and progressive cachexia may be observed in numerous medical disciplines, but in patients with various diseases several pathways overlap (endocrine, inflammatory and kidney diseases, heart failure, cancer). A case-control analysis is presented of patients with initial immune-mediated thyroiditis complicated with cachexia, pulmonary pa-thology coexisting with opportunistic infection, finally diagnosed cancer (thyroid cancer, misdiagnosed as NSCLC). Contrary to other patients with lung cancer the presented pa-tients were not active smokers, exclusively women who developed cachexia with existing autoimmune process in the first phase. Furthermore, coexistence of short overall survival without cancer progression in the most seriously ill patients, correlation with sex (con-trary to history of smoking) and predisposition to mycobacterial disease are very sug-gestive. The unique sequence shed light on immune-mediated thyroid disease as a sub-clinical paraneoplastic process modified by various therapeutic regimens, however, with systemic consequences and a sequel, requiring holistic approach. Differential diagnosis of severe cachexia, adenocarcinoma with pulmonary localization and tuberculosis reac-tivation require analysis of immunological and genetic background. Contrary to highly specialized teams (e.g. lung cancer units) the immunotherapy and general medicine in aging populations require multidisciplinary observation, holistic and inquiring approach. Lack of differentiation, confusing bias as well as discrepancy in literature are the main obstacles in statistical research, that indicate correlation of common factors only. Such time-lapse case studies may be first to build evidence of a pathway and association be-tween immune parameters, comorbidity and cancer.

Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted a previously introduced clinical model of host–virus interaction (i.e., infectious process in immunodeficiency) for analysis of B cells and the specific IgG role (an observational study of a CVID patient who received intravenous immunoglobulin (IVIG). Suddenly, the patient deteriorated and a positive results of for HBs and HBV-DNA (369 × 10⁶ copies) were detected. Despite lamivudine therapy and IVIG escalation (from 0.3 to 0.4 g/kg), CT showed an 11 cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs were positive in time-lapse analysis (range 111–220 IU/mL). Replacement therapy intensification was complicated by an immune complex disease with renal failure. Fulminant HCC in CVID and the development of a tumor as the first sign is of interest. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HB substitution has not been proven to be effective, oncoprotective, nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, and patient selection more precise with the exclusion of HBV-positive donors. Our clinical model showed an HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g., chronic hepatitis). The lack of cell cooperation as well as B cell deficiency observed in CVID play a crucial role in high HBV replication, especially in carcinogenesis.

Background: Humoral memory and specific antibody levels depend on the kind of antigen and individual immunofactors. The presence of IgM antibodies or a fourfold rise in specific IgG levels are generally accepted as diagnostic factors in the serology of acute viral infections. This basic model is not adequate for the herpes virome, especially after hematopoietic stem cell transplantation (HSCT), due to continuous, usually multifocal antigenic stimulation, various donor serostatuses, immunosuppression, and individual immunoreconstitution. Methods: A case–control study was conducted to identify active infection cases of human herpesvirus (HHV) (from 300 diagnosed immunocompromised patients) and to evaluate historically associated humoral factors to look at outcomes. We considered only the data of patients with meticulous differential diagnosis to exclude other causes, and thereby to observe pathways and temporal relationships, not the statistical ones usually collected in cohorts. Despite the small number, such data collection and analysis methods avoid a number of biases and indicate cause and effect. Results: In this observational study, a retrospective analysis of data from 300 patients with clinical diagnosis of herpes simplex virus (HSV) and varicella zoster virus (VZV) reactivation showed a number of biases. Two well-differentiated cases (confirmed by a Tzanck test) with various diseases and conditioning evolutions of immune parameters showed an interesting pathway. Exponential decreases in specific IgGs after HSCT preceded virus replication were observed, with a cytopathic effect (shingles, VZV encephalitis and HSV-induced mucositis). The minima (lowest IgG levels) before herpesvirus reactivation were 234.23 mIU/mL and 94 RU/mL for VZV and HSV, respectively. This coincided with a low CD4 titer, but without other infectious processes. Other immune response parameters such as Treg, cytotoxic T cells, and complement and total IgG level were the same as they were before the transplant procedure. Interestingly, a second wave of immunoreconstitution with an anamnestic antibody response was not always observed. It coincided with prolonged herpes viral infection. A patient with lymphocyte depletion in conditioning showed an earlier second wave of immunoreconstitution (6th vs. 14th month). Conclusions: As is typical for infancy, the kinetics of the IgG level is unique after HSCT (the decline phase is first). Host microbiome factors (e.g., HHV1–3-serostatus) should be taken into account to predict risk of non-relapse mortality and survival after HSCT. The levels of specific antibodies help in predicting prognoses and improve disease management. A lack of differentiation and the confusing bias of the assessor (i.e., observer selection bias) are the main obstacles in statistical HHV1–3 research. Such time-lapse case studies may be the first to build evidence of a pathway and an association between immune parameters and HHV disease.

Background: Humoral memory and specific antibodies levels depend on kind of the antigen and individual immunofactors., The presence of IgM antibodies or fourfold rise in specific IgG level, are generally accepted as diagnostic in serology of acute viral infection. This basic model is not adequate for herpesvirome especially after hematopoietic stem cell transplantation (HSCT) due to continuous, usually multifocal antigenic stimulation, various donor serostatus, immunosuppresion and individual immunoreconstitution. Methods: A case-control study was conducted for identifying cases of Human herpesviruses (HHV) active infection (from 300 diagnosed immunocompromised patients) and evaluating historically associated humoral factors to look at outcomes. We enrolled only patients’ data with meticulous differential diagnosis to exclude other causes, thereby observe pathways and temporal relationships, not statistical ones, usually collected in cohorts. Despite the small number such data collection and analysis avoids a number of biases and indicates cause and effect.Results. In the observational study retrospective analysis of data from 300 patients with clinical diagnosis of herpes simplex (HSV) and varicella zoster virus(VZV) reactivation showed a number of biases. In two well differentiated cases (confirmed by Tzanck test) with various disease and conditioning evolution of immunoparameters showed interesting pathway. Exponential decrease of specific IgG after HSCT precedes virus replication with cytopathic effect (shingles, VZV-encephalitis and HSV-induced mucositis). Minima (smallest IgG levels) before herpes virus reactivation were 234,23 mIU/ml and 94 RU/ml for VZV and HSV, respectively. This coincides with low CD4 titer, but without other infectious process. Other immune response parameters such as Treg, cytotoxic T cells, complement and total IgG level were quite the same as before the transplant procedure. Interestingly, the second wave of immunoreconstitution with anamnestic antibody response was not always observed. It coincided with prolonged herpes viral infection. Patient with lymphocyte depletion in conditioning showed earlier second wave of immunoreconstitution (6th vs 14th month) Conclusions: Typical for infancy kinetics of IgG level is unique after HSCT (the decline phase is first). Host-microbiome factors (i.e. HHV1-3 -serostatus) should be taken into account to predict risk of non-relapse mortality and survival after HSCT. The levels of specific antibodies help to predict the prognosis and improve the management. The lack of differentiation, assessor and confusing bias are the main obstacles in statistical HHV1-3 research. Such time-lapse case studies may be first to build evidence of a pathway and association between immunoparameters and HHV disease.

Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially under influence of oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted previously introduced clinical model of host-virus interaction (i.e. infectious process in immunodeficiency) for analysis of B cells and specific IgG role (observational study of a CVID patient who received intravenous immunoglobulin (IVIG)) Suddenly, the patient deteriorated with positive result of HBs, HBV-DNA (369x106copies). In spite of lamivudine therapy and IVIG escalation (from 0.3 to 0.4g/kg), CT showed 11cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs had been positive in time-lapse analysis (range 111-220 IU/ml). Replacement therapy intensification was complicated by immune complex disease with renal failure. The fulminant HCC in CVID and the development of the tumor as the first sign is interesting. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HBs substitution has not been proven to be effective, oncoprotective nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, patient selection more precise with the exclusion of HBV-positive donors. Our clinical model show HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g. chronic hepatitis). Lack of cell cooperation, B cell deficiency observed in CVID plays a crucial role in high HBV replication, especially in carcinogenesis.

Background: Cutaneous tuberculosis (CTB) and its paucibacillary forms are rare and difficult to diagnose, especially in immunocompromised patients with significant comorbidity. The aim of the study was to introduce the modern concept of the microbiome and diagnostic chain into clinical practice (patient-centered care) with the presentation of an atypical form of cutaneous tuberculosis with necrotizing non-healing ulcers leading to polymicrobial infection.Methods: The study material included samples from sputum, broncho-alveolar lavage and skin ulcer, taken from a patient developing cutaneous tuberculosis. The microbiological investigation was performed, and identification of the isolates was carried out using genotyping and the matrix-assisted laser desorption ionization-time of flight mass spectrometry.Results: The immunocompromised patient with humoral abnormality (plasma cell dyscrasia) and severe paraproteinemia developed multiorgan tuberculosis. Although cutaneous manifestation preceded systemic and pulmonary symptoms (approximately half a year), the mycobacterial genotyping confirmed the same MTB strain existence in skin ulcers and the respiratory system. Therefore, the infectious chain: transmission, the portal of entry, and bacterial spreading in vivo, were unclear. Microbial diversity found in wound microbiota (among others Gordonia bronchialis, Corynebacterium tuberculostearicum, Staphylococcus haemolyticus, and Pseudomonas oryzihabitans) was associated with the spread of a skin lesion. The in vitro biofilm-forming capacity of strains isolated from the wound may represent the potential virulence of these strains. Thus, the role of polymicrobial biofilm may be crucial in ulcer formation and CTB manifestation.Conclusions: Severe wound healing as a unique biofilm-forming niche should be tested for Mycobacterium (on species and strain levels) and coexisting microorganisms using a wide range of microbiological techniques. In immunodeficient patients with non-typical CTB presentation, the chain of transmission and MTB spread is still an open issue for further research.

Cutaneous tuberculosis (CTB) is a very rare disease and accounts for only 1–2% of cases of extrapulmonary tuberculosis (EPTB). Due to the variety of its clinical manifestations, the uncharacteristic appearance of its lesions, resembling other dermatoses in the early stages, and the limited experience of clinicians due to the rarity of CTB, diagnosis is very difficult. Particularly noteworthy is the fact that most cases of EPTB, including skin tuberculosis (TB), can be a manifestation of systemic involvement. In this paper, we present a case of an immunocompromised patient who was diagnosed with CTB almost a year after the first dermatological lesions were located on the lower extremities. At the same time, due to respiratory symptoms, a diagnosis of pulmonary TB (PTB) was made, and radiological and microbiological confirmations were obtained.

Cytomegalovirus (CMV) syndrome and infectious disease are defined as pathogen detection with appropriate clinical symptoms, but there are not pathognomonic signs of CMV disease. Although the prodrome of acute minor viral infections leukopenia (lymphopenia and neutropenia) is noted with onset of fever, followed by monocytosis, the role of monocytosis in CMV disease has not been described. Furthermore, under influence of corticosteroid therapy, CMV reactivation and monocytosis are described, but without a strict relationship with steroids dose. In the study, the monocyte level was investigated during the CMV infectious process. Regrettably, a non-selected group of 160 patients with high CMV viremia showed high dispersion of monocyte level and comparable with the median value for healthy subjects. Therefore, we investigated monocyte level in CMV-infected patients in relation to the logarithmic phase of the infectious process. Samples from patients with active CMV replication (exponential growth of CMV viremia) were tested. Significant monocytosis (above 1200/µL) during the logarithmic phase of CMV infection (with exponent between 3.23 and 5.77) was observed. Increased count and percentage of monocytes correlated with viral replication in several clinical situations except when there was a rapid recovery without relapse. Furthermore, glucocorticoids equivalent to 10 and 20 mg of dexamethasone during a 2–3-week period caused monocytosis—significant increase (to 1604 and 2214/µL, respectively). Conclusion: In light of the logarithmic increase of viral load, high monocytosis is a hallmark of CMV replication. In the COVID-19 era, presence of high virus level, especially part of virome (CMV) in the molecular technique, is not sufficient for the definition of either proven or probable CMV replication at any site. These preliminary observations merit additional studies to establish whether this clinical response is mediated by monocyte production or by decrease of differentiation to macrophages.