Early administration of remdesivir plus convalescent plasma therapy is effective to treat COVID-19 pneumonia in B-cell depleted patients with hematological malignancies.

Patients with hematological malignancies (HMs) are at a higher risk of developing severe form and protracted course of COVID-19 disease. We investigated whether the combination of viral replication inhibition with remdesivir and administration of anti-SARS-CoV-2 immunoglobulins with convalescent plasma (CP) therapy might be sufficient to treat B-cell-depleted patients with COVID-19. We enrolled 20 consecutive patients with various HMs with profound B-cell lymphopenia and COVID-19 pneumonia between December 2020 and May 2021. All patients demonstrated undetectable baseline anti-SARS-CoV-2 immunoglobulin levels before CP. Each patient received at least a complete course of remdesivir and at least one unit of CP. Previous anti-CD20 therapy resulted in a more prolonged SARS-CoV-2 PCR positivity compared to other causes of B-cell lymphopenia (p = 0.004). Timing of CP therapy showed a significant impact on the clinical outcome. Simultaneous use of remdesivir and CP reduced time period for oxygen weaning after diagnosis (p = 0.017), length of hospital stay (p = 0.007), and PCR positivity (p = 0.012) compared to patients who received remdesivir and CP consecutively. In addition, time from the diagnosis to CP therapy affected the length of oxygen dependency (p < 0.001) and hospital stay (p < 0.0001). In those cases where there were at least 10 days from the diagnosis to plasma administration, oxygen dependency was prolonged vs. patients with shorter interval (p = 0.006). In conclusion, the combination of inhibition of viral replication with passive immunization was proved to be efficient and safe. Our results suggest the clear benefit of early, combined administration of remdesivir and CP to avoid protracted COVID-19 disease among patients with HMs and B-cell lymphopenia.

Beyond the physico-chemical barrier: Glycerol and xylitol markedly yet differentially alter gene expression profiles and modify signalling pathways in human epidermal keratinocytes.

Polyols (e.g. glycerol, xylitol) are implicated as moisturizers of the skin and other epithelial tissues. However, we lack information about their exact cellular mechanisms and their effects on the gene expression profiles. Therefore, in this study, we aimed at investigating the effects of glycerol and xylitol on human epidermal keratinocytes. The polyols (identical osmolarities; xylitol: 0.0045%-0.45%; glycerol: 0.0027%-0.27%) did not alter cellular viability or intracellular calcium concentration. However, they exerted differential effects on the expression of certain genes and signalling pathways. Indeed, both polyols up-regulated the expression of filaggrin, loricrin, involucrin and occludin; yet, xylitol exerted somewhat more profound effects. Moreover, while both polyols stimulated the MAPK pathway, only xylitol induced the activation-dependent translocation of protein kinase Cδ, a key promoter of epidermal differentiation. Finally, in various keratinocyte inflammation models, both polyols (albeit with different efficacies) exerted anti-inflammatory effects. Taken together, these data strongly suggest that glycerol and xylitol differentially modulate expressions of multiple genes and activities of signalling pathways in epidermal keratinocytes. Thus, our findings invite clinical trials to explore the applicability and the impact of a combined glycerol-xylitol therapy in the management of various skin conditions.

[Diagnostic difficulties caused by a pulmonary infiltrate]. / Diagnosztikai nehézséget okozó pulmonalis infiltrátum.

UNLABELLED: Lung infiltration still causes differential diagnostic difficulties, which may delay the start of definitive treatment. CASE REPORT: The examination of a 30-year-old man began due intermittent, remittent and permanent fever. Chest X-ray confirmed infiltration in the right upper lobe, which was accompanied by elevated CRP and physiological levels of procalcitonin. Most likely atypical pneumonia, tuberculosis, Wegener's granulomatosis or a malignant process was suspected. Throughout his examination infection could not be verified, repeated CT guided transthoracic needle biopsy suggested the possibility of a malignant process. Through surgical exploration the intraoperative histology was not informative; thus, the pneumonitis-remodelled right lung was removed due to the possibility of malignant transformation. Histological examination revealed lymphocyte rich classical Hodgkin lymphoma, which was found to be stage IV/B based on the 18FDG-PET/CT scan; therefore, eight cycles of ABVD (adriablastin, bleomycin, vinblastine, and dacarbazine) therapy was administered successfully. The patient is currently (for 30 months) in a complete metabolic remission. CONCLUSION: Primary pulmonary Hodgkin lymphoma is a rare disease entity (in this case it might be the original process), in which the diagnosis is often difficult. 18FDG-PET/CT may be a useful early diagnostic tool investigating fever of unknown origin.

Myeloid growth factor therapy in malignant lymphomas--a 5-year retrospective study from Hungary.

Myeloid growth factors help to prevent and cure neutropenic events in malignant lymphoma patients treated by chemotherapeutical regimens. Administering either filgrastim or pegfilgrastim, treatment schedule can be kept well and less dose reductions are needed, which results in better survival rates. The aim of this study was to examine the indications and the outcome of myeloid precursor therapy among our malignant lymphoma patients. Between 2003 and 2007, 249 malignant lymphoma patients received 1,655 cycles of different polychemotherapies. Myeloid growth factor therapy was administered in 138 cases by 65 patients, which meant 8.33% of all treatment cycles and 26.1% of all patients, respectively. As for the indications, prevention was more common than intervention (71.7% vs. 28.3%). By preventive usage of growths factors, two-thirds of threatening neutropenic events could be avoided. Side effects were uncommon and mild: grades I-II toxicity was observed in 31% of all treatments. Analyzing the risk factors for febrile neutropenia among patients who received myeloid growth factor therapy compared to those who did not, we found the incidence of comorbidities, hypoalbuminemia, advanced stage disease, and aggressive chemotherapies significantly different in the two groups. Interestingly, there was no significant difference regarding the median age and the incidence of low body surface area. Our observations support that myeloid precursor therapy is an effective and safe implement to prevent or treat neutropenia in high-risk malignant lymphoma patients.

[Changing patterns in the clinical, pathological features of Hodgkin lymphoma]. / Változnak-e a Hodgkin-lymphoma klinikopatológiai jellemzoi?

UNLABELLED: Hodgkin lymphoma shows a well-known geographic pattern, but temporal changes have been found recently as well. PATIENTS AND METHODS: The Authors analyzed 439 Hodgkin lymphoma patients' clinicopathological and treatment data. Patients were treated at our department from 1980 until the end of 2008. RESULTS: The first period contained 117 patients, the second 147 and third 115 Hodgkin lymphoma patients. The mean age of the patients was 40.1, 35.9 and 36.8 years in order. The male/female ratio: 1.42, 1.45, 1.04 in order. The incidence of mixed cellularity histological subtype is decreasing; nodular sclerosis shows an increasing tendency. The number of early stage patients (59.12%) is beyond the advanced stage (40%) in the last decade. The 10-year overall survival data were progressing 44.1%, 70.6% and 90.5% (survival prognosis) in the last decade. CONCLUSIONS: Changes can be explained by the altered nature of Hodgkin lymphoma, the changes in socioeconomic status and the development of diagnostic and therapy methods.

[Therapy for patients with primary refractory and relapsed Hodgkin-lymphoma--our experience]. / Refrakter és relabált Hodgkin-lymphomás betegeink kezelésével szerzett tapasztalataink.

UNLABELLED: Recovery have been achieved in the majority of Hodgkin-lymphoma patients. Unfortunately some of the patients refracter and about third of the patients relapsed after the first-line treatment. AIM AND METHODS: We investigated the frequency and treatment of refracter or relapsed Hodgkin lymphoma patients between 1996 and 2006. RESULTS: We examined 76 women and 71 men, who had HL in this period. 141 patients (95,9%) had remission after first-line therapy. 6 women were primary refracter, 4 of them had high-dose therapy and autolog stem cell transplantation. They died in spite of the multiple treatment. 31 patients - 13 men and 18 women - had relapse (16 cases were in one year). 14 patients had high-dose therapy and autolog stem cell transplantation, 11 patients had only chemotherapy, 3 had only radiotherapy and 3 patients were treated by combined modality treatment. 6 of the relapsed patients were died, 5 because of the progression of lymphoma and one because of secunder myelodysplasia. CONCLUSIONS: Relapsed patients have a good prognosis, but refracter patients have long chance despite autolog or allogen hemopoietic stem cell transplantation. Searching for new therapeutical modalities for these patients is extremely important.

Protein kinase C isoenzymes differentially regulate the differentiation-dependent expression of adhesion molecules in human epidermal keratinocytes.

Epidermal expression of adhesion molecules such as desmogleins (Dsg) and cadherins is strongly affected by the differentiation status of keratinocytes. We have previously shown that certain protein kinase C (PKC) isoforms differentially alter the growth and differentiation of human epidermal HaCaT keratinocytes. In this paper, using recombinant overexpression and RNA interference, we define the specific roles of the different PKC isoenzymes in modulation of expression of adhesion molecules in HaCaT keratinocytes. The level of Dsg1, a marker of differentiating keratinocytes, was antagonistically regulated by two Ca-independent 'novel' nPKC isoforms; i.e. it increased by the differentiation-promoting nPKCdelta and decreased by the growth-promoting nPKCepsilon. The expression of Dsg3 (highly expressed in proliferating epidermal layers) was conversely regulated by these isoenzymes, and was also inhibited by the differentiation inducer Ca-dependent 'conventional' cPKCalpha. Finally, the expression of P-cadherin (a marker of proliferating keratinocytes) was regulated by all of the examined PKCs, also in an antagonistic manner (inhibited by cPKCalpha/nPKCdelta and stimulated by cPKCbeta/nPKCepsilon). Collectively, the presented results strongly argue for the marked, differential, and in some instances antagonistic roles of individual Ca-dependent and Ca-independent PKC isoforms in the regulation of expression of adhesion molecules of desmosomes and adherent junctions in human epidermal keratinocytes.

Protein kinase C-beta and -delta isoenzymes promote arachidonic acid production and proliferation of MonoMac-6 cells.

In this study, we investigated the putative roles of certain protein kinase C (PKC) isoenzymes in the regulation of proliferation and arachidonic acid (AA) release in the human monocytoid MonoMac-6 cell line. Experiments employing specific PKC inhibitors and molecular biological methods (RNA-interference, recombinant overexpression) revealed that the two dominantly expressed isozymes, i.e., the "conventional" cPKCbeta and the "novel" nPKCdelta, promote AA production and cellular proliferation. In addition, using different phospholipase A(2) (PLA(2)) inhibitors, we were able to show that the calcium-independent iPLA(2) as well as diacylglycerol lipase (but not the cytosolic PLA(2)) function as "downstream" targets of cPKCbeta and nPKCdelta. In addition, we have also found that, among the other existing PKC isoforms, cPKCalpha plays a minor inhibitory role, whereas nPKCvarepsilon and aPKCzeta apparently do not regulate these cellular processes. In conclusion, in this paper we provide the first evidence that certain PKC isoforms play pivotal, specific, and (at least partly) antagonistic roles in the regulation of AA production and cellular proliferation of human monocytoid MonoMac-6 cells.

Malignant lymphomas and autoimmunity-a single center experience from Hungary.

Autoimmune diseases and malignant lymphomas have numerous similarities in their etiology and pathogenesis. Patients with autoimmune disorders have increased risk to develop non-Hodgkin's lymphomas, yet little is known about the occurrence of autoimmune features within lymphoma patients. Our aim was to examine the prevalence of autoimmune diseases among patients with non-Hodgkin's (NHL) and Hodgkin's lymphoma (HL). We reviewed 352 patients' charts with malignant lymphomas to assess the rate of associated autoimmune diseases. Of 231 NHL patients, 30 (12.9%) had autoimmune disorders, while there were 11 patients who suffered from more than one disease entity. It was Sjögren's syndrome that occurred in the largest number (eight cases), other frequent entities were undifferentiated connective tissue disease (seven), thyroiditis (six), rheumatoid arthritis (four), and systemic vasculitis (four). The female/male ratio was significantly different between patients with or without autoimmune diseases, while no other clinical features differed significantly between the two groups. Ten patients (33.3%) were initially diagnosed with lymphoma, 13 (43.3%) of them had already been diagnosed with autoimmune disease at the time of lymphoma occurrence. Six patients (20%) with previously diagnosed immunological disorder developed new autoimmune condition after the treatment of lymphoma. Lymphoma and autoimmune disease occurred simultaneously in one patient. Among the 121 HL patients, 14 (11.5%) had associated autoimmune disease. Ten patients developed thyroiditis after the lymphoma treatment, two had immune thrombocytopenia, and one had autoimmune hemolytic anemia. One female patient was diagnosed with systemic sclerosis 10 years before the onset of HL. Our results highlight that an increased risk for the development of autoimmune diseases should be considered in patients both with NHL and HL.

Changing patterns in the clinical pathological features of hodgkin lymphoma: a report from debrecen, hungary.

Introduction. Hodgkin lymphoma shows a well-known geographic pattern, but temporal changes have been found recently as well. Patients and Methods. 439 Hodgkin lymphoma patients' clinicopathological and treatment data were processed in calendar periods of approximately ten years. The patients were treated at our department from 1980 until the end of 2008. Results. The first period (1980-89) contained 177 patients, the second (1990-99) 147, and the third (2000-08) 115 Hodgkin lymphoma patients. The mean age of the patients was 40.1, 35.9, and 36.8 years in order. The male/female ratio: 1.42, 1.45, 1.05 in order. Contrary-wise a unimodal age group pattern could have been seen with an incidence peak between 30 and 39 in the past decades. The incidence of classical mixed cellularity histological subtype is decreasing (43.7%, 58.23%, 42.6%, P = 0.0098 (it is only significant in the second period)); classical nodular sclerosis shows an increasing tendency (25%, 27.32%, 34.78%, P = 0.1734). The first incidence peak is predominantly created by classical nodular sclerosis, meanwhile the second peak by classical mixed cellularity. The number of early-stage patients (59.12%) is beyond the advanced stage (40%) in the last decade. Meanwhile, the number of second-stage patients was increasing (25.8%, 26.35%, 49.56% P < 0.0001) and of patients in third stage was decreasing (53.4 %, 50.67%, 20% P < 0.0001). The 5- and 10-year overall survival data were progressing: 59.7 %, 77.4 %, and 90.5 % and 44.1 %, 70.6 % and 90.5 % (expected survival) in the last decade. Conclusions. Changes can be explained by the altered nature of Hodgkin lymphoma, the changes in socioeconomic status and the development of diagnostic and therapy methods.