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Individuals with severe mental illness usually require informal care, which is frequently underestimated. There is much data on medical costs and outcomes of psychiatric care but less research on informal caregiving and its role in measuring recovery. This paper presents the results of an observational, crosssectional study that follows up on individuals with schizophrenia and affective disorders and their caregivers in an outpatient setting one year after hospital discharge. The burden of informal care is evaluated with the Burden Assessment Scale (BAS) as a primary outcome measure and hours spent in care and financial aspects of informal caregiving. One hundred and five individuals with mental illness (50 with schizophrenia and 55 with affective disorder) and 105 carers are followed up one year after hospital discharge. The time spent in informal care has decreased (p < .001) with 1.4 hours per day for both diagnostic groups and is 4.4 hours per day for schizophrenia and 2.5 hours per day for affective disorders (p = .005). The monthly financial support is 203 Euro and 192 Euro, respectively (p = .373). The mean BAS score has decreased by 8.1 points for schizophrenia and 8.6 points for affective disorders (p = .412). While showing a statistically significant decrease in outpatient setting compared to inpatient setting, the burden of care at follow-up is still substantial. Statistically significant predictors of a high burden of care (measured by total BAS score) are patient’s severity of illness (p = .019), history of threats (p = .004), time spent in informal care (p < .001), the stigma of mental illness (p < .001), and younger caregiver (p = .030)

Aim This report aims to illustrate the possibility of an acute onset of psychosis after COVID‐19 infection in a patient without previous history of psychiatric disorders and to highlight the need for early screening and intervention in such cases. Methods Clinical presentation of a case, followed by clinical discussion and literature review of the effect of the new coronavirus SARS‐CoV‐2 and its impact on mental health in terms of neuropsychiatric conditions. Results We present a case of acute and transient psychotic disorder following complete recovery of COVID‐19 bilateral pneumonia. The patient has no prior psychiatric history and presents with acute onset, disorganized behaviour, Cotard's delusion and a potentially high risk of psychotic homicide and suicide. Conclusion Early intervention and treatment with antipsychotic medication are of crucial importance for the effective treatment and complete recovery of these patients.

Depression leads to a significant economic and financial burden, which determines the need for implementation of screening programs involving community pharmacists. The aim of this study was to screen patients with chronic conditions for depressive symptoms and to assess their current quality of life at community pharmacies in Sofia Province, Bulgaria. A pilot prospective anonymous survey among patients with chronic diseases was conducted. Questionnaires were used: Patient Health Questionnaire-9 (PHQ-9), EQ-5D-5L and a specially designed questions list. The data were analyzed statistically using MedCalc software version 16.4.1. A total of 119 chronically ill patients were screened for depression by community pharmacists for the period March 2020–August 2020 during and after the first wave of the COVID-19 pandemic. Women (59.7%) and patients over 60 years of age (> 50%) predominated. Most patients had only one disease (47.2%), with the most common diseases being cardiovascular, followed by other endocrine and metabolic diseases. Of the respondents, 64.9% showed depressive symptoms, of which 50.9% were mild and 14% severe. The median pharmacotherapy cost was higher for patients with depression compared to patients who do not show depressive symptoms: BGN 28.50 compared to BGN 14.77. The obtained results suggest that the implementation of an early depression screening service in the community pharmacy settings would provide easy and timely access of patients to adequate mental care. The service would lead to improved quality of pharmaceutical care in Bulgaria and increased range of services that pharmacists offer in community pharmacy practice.

Background and objectives Major psychiatric disorders require prolonged use of psychotropic medications and pose a significant economic burden. The purpose of the study is to examine the trend in outpatient utilization and public expenditures for reimbursed psychotropic medicines for major psychiatric disorders in Bulgaria from 2013 to 2017. Methods Data on the cost and utilization of reimbursed psychotropic medications for schizophrenia and affective disorders are collected retrospectively from the National Health Insurance Fund (NHIF) for the period 2013–2017. The diagnostic groups included in the analysis are based on ICD codes from F20.0 to F33.4. Psychotropic drugs are systematized according to ATC code and INN. Reimbursed pharmacotherapy costs are analyzed per year and diagnosis. Drug utilization is calculated for each year in defined daily doses per 1000 inhabitants per day (DDD/1000inh/day). Results The number of patients decreased from 62 500 to 54 000, or from 834 per 1 00 000 in 2013 to 733 per 1 00 000 in 2017, or with a 3.5% decrease per year. The highest number (28,674 in 2013; 26,235 in 2017) and with the highest relative share (46%–49%) were patients with paranoid schizophrenia. The reimbursed pharmacotherapy cost showed a decreasing tendency from 35 to 31 million BGN in 2013 and 2017, respectively. In total 31 INN of medicines for psychotic disorders therapy were reimbursed. The utilization of all ATC groups is decreasing from 28.04 to 17.38 DDD/1000inh/day. Conclusions The number of reimbursed patients with major psychiatric disorders, as well as the cost of pharmacotherapy and utilization of psychotropic medicines decreased in the period 2013–2017.

Histone deacetylase (HDAC) inhibitors, approved for the treatment of cutaneous T-cell lymphoma (CTCL), are non-selective agents associated with an unsatisfactory response and considerable side-effects. Targeting single HDAC isoforms is considered to provide novel therapeutic options. HDAC6 is overexpressed in primary samples from patients with CTCL and preclinical studies using transgenic mice that spontaneously develop a CTCL-like disease, have suggested that combinations including HDAC6 inhibitors may be successful in the treatment of CTCL. PI3K inhibition is currently being tested in clinical trials for CTCL with promising results. Since HDAC6 is known to diminish the activity of Akt via its deacetylation, the aim of the present study was to evaluate the therapeutic potential of selective HDAC6 inhibitors in combination with PI3K inhibitors in CTCL. Through the genetic and pharmacological inhibition of HDAC6, it was demonstrated that combining HDAC6 with PI3K inhibition may be an attractive therapeutic option for patients with CTCL.

Objective The current article is aimed at identifying the best practice for counseling around depression in community and outpatient pharmacies, resulting in a draft guideline, proposing key steps and an algorithm for integration of community pharmacists into care for patients with depression. Methods A literature review was performed followed by a detailed analysis, for the purpose of creation a short draft document used as a basis for creation of a guideline for pharmaceutical care for patients with depression. The technological scheme PRISMA flow diagram was applied. The paper is based on current knowledge, taking into consideration already published articles, guidelines, and recommendations about pharmaceutical care for patients with depression, giving a basis for further studies. Results This paper includes two main sections: 1) depression - a short description of the main symptoms, risk factors and pharmacotherapy guidelines available in Bulgaria important for the purposes of ensuring qualitative community-based pharmaceutical care; and 2) the pharmacists' role in providing high-quality care - the main aspects of pharmaceutical care for patients with depression with specific examples. Conclusion The involvement of pharmacists in supporting depressive patients is crucial taking into account the specific characteristics of the pharmacological treatment: delayed onset of clinical results, risks in case of sudden pharmacotherapy abruption without physician consultation, multiple adverse drug reactions and drug-drug, drug-food and drug-alcohol interactions, etc. The current article could also be used as an initial document for creating a methodological guideline for providing pharmaceutical care services for patients with depression.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous disease group of unknown etiology with a complex immunological background. As CTCL arises from T cells that have a vital role in the antitumor response, their therapy is largely aimed at reversing the immunological mechanisms leading to or manifesting during this malignancy. Early disease stages can be controlled with skin-directed therapy in most CTCL cases. Still, advanced CTCL has a dismal prognosis and warrants systemic therapy. Despite considerable progress in understanding the pathophysiology of the disease and the numerous systemic treatment options available, long-term remission rates with conventional treatments alone are still low. Allogeneic hematopoietic stem cell transplantation is currently the only curative option for advanced CTCL, including mycosis fungoides and Sézary syndrome. The aims of this review is to summarize the recent findings on the immunology of this heterogeneous disease and to present the advances in its clinical management.

Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma. Chlormethine (CL) is recommended as first-line therapy for MF, with a major purpose to kill tumor cells through DNA alkylation. To study the extent of treatment susceptibility and tumor specificity, we investigated the gene expression of different DNA repair pathways, DNA double-stranded breaks, and tumor cell proliferation of clonal TCR Vβ+ tumor cell populations in cutaneous T-cell lymphoma skin cells on direct exposure to CL. Healthy human T cells were less susceptible to CL exposure than two T-lymphoma cell lines, resulting in higher proportions of viable cells. Interestingly, in T cells from MF lesions, we observed a downregulation of several important DNA repair pathways, even complete silencing of RAD51AP1, FANC1, and BRCA2 involved in homologous recombination repair. In the presence of CL, the double-stranded DNA breaks in malignant MF skin T cells increased significantly as well as the expression of the apoptotic gene CASP3. These data point toward an important effect of targeting CL on MF skin tumor T cells, which support CL use as an early cutaneous lymphoma treatment and can be of synergistic use, especially beneficial in the setting of combination skin-directed therapies for cutaneous T-cell lymphoma., Graphical abstract

Background and objectives Severe mental disorders require informal care, usually provided by family members of the affected. The aim of the study is to examine the burden of informal caregiving for individuals with schizophrenia and affective disorders prior to hospital admission in Bulgaria. Methods The study has an observational, cross-sectional, retrospective design. Individuals with schizophrenia and affective disorders and their caregivers are evaluated upon the patients’ admission for inpatient treatment. The objective and subjective consequences of providing informal care are evaluated with the Burden Assessment Scale (BAS) as a primary outcome measure. Its factor structure and determinants of high burden of care are examined. Results 117 individuals with mental disorder and 117 caregivers are evaluated, dichotomized in two groups according to the patient's diagnosis. The time spent in informal care is 5.7 hours per day (SD = 2.9) for schizophrenia and 3.9 hours per day (SD = 3.0) for affective disorders, p = .002. The mean score on the BAS is 44.7 (SD = 11.0) and 42.0 (SD = 12.8) respectively, p = .221. A common pattern of the burden with a 5-factor solution explaining 66% of the variance is presented, including the factors Limitations, Conflicts, Guilt, Trap, and Stigma. Contributors for the increase in the BAS are stigma (p Conclusions The caregivers of individuals with schizophrenia and affective disorders experience considerable objective and subjective burden.

Schizophrenia is a serious mental disorder which requires complex treatment and care. Although proof for effective, cost-effective and affordable treatment is available, health economic research is lacking in many low and middle-income countries. The aim of this study was to evaluate the costs and outcomes for individuals with acute exacerbations of schizophrenia before and after inpatient admission and to evaluate the cost-effectiveness of the current treatment in the clinical practice. We used an ambispective comparative observational health economic study design. The participants were individuals with schizophrenia and their primary caregivers. Costs at baseline and follow-up were evaluated from a healthcare perspective. The primary outcomes were psychopathology, social functioning and quality of life for the patients and burden of informal care for the caregivers. Cost-effectiveness planes and cost-effectiveness acceptability curves were generated to illustrate the cost-effectiveness of treating schizophrenia in the real clinical practice, compared to a do-nothing alternative. The main finding is that treatment of individuals with schizophrenia results in improved outcomes for both patients and caregivers, while it is associated with increased healthcare costs from 135.75 Euro (SD = 193.36) per patient before hospital treatment to 189.00 Euro (SD = 126.98) per patient in the follow-up (95% CI: −112.48; −2.31). After application of sensitivity analysis at a particular level of willingness to pay, the treatment remains cost-effective for all 4 outcomes. In conclusion, the treatment of patients with schizophrenia in Bulgaria is cost-effective at acceptable levels of willingness to pay for a unit of improvement on four different outcomes.

Background: In cancer, the lack of early diagnostic biomarkers is a challenge, results in delayed diagnosis, and can seriously affect treatment and prognosis. Therefore, defining accurate methods for early identification of rare malignant cells is of pivotal importance. We explore the potential of artificial intelligence (AI) to uncover tumor-defining cells in Sezary syndrome (SS), a rare type of skin lymphoma. Methods: We established a 37-antibody mass cytometry panel to generate single-cell data from peripheral blood and trained an AI model, called CellCNN, on the datasets. CellCNN is a supervised machine learning algorithm that trains a convolutional neural network with a single layer using labelled single-cell data as inputs. Our study included a discovery cohort of 60 individuals (20 Sezary syndrome patients and as comparators 20 healthy donors and 20 atopic dermatitis patients) and a validation cohort of 33 individuals, containing 11 individuals of each group. Algorithm performance was assessed with area under the curve (AUC), specificity, sensitivity, and F1 score (weighted average of sensitivity and specificity). Findings: We discovered a combination of cell surface markers by mass cytometry to sensitively and specifically identify tumor-defining SS cells in blood and validated our results in a blinded setting with zero false positives and only one false negative prediction (AUC of 0.98, sensitivity of 0.91, specificity of 1.0, F1 score of 0.95). To allow easy implementation into routine diagnostics, we further reduced the number of markers to 15 to be used in standard FACS assays. Diagnostic predictions with those FACS settings still achieved very high sensitivity of 1.0 and specificity of 0.91 (AUC of 0.94, F1 score of 0.95). Furthermore, we could show that our model can even classify blood samples from SS patients at an early stage of initial clinical manifestation, which is currently a grand challenge, with a high accuracy (AUC of 0.93, sensitivity of 1.0, specificity of 0.91, F1 score of 0.95). Interpretation: This study reports the successful validation and performance of an AI-based algorithm to detect rare tumor-defining cells in lymphoma blood samples. Furthermore, our model allows to accurately distinguish tumor samples at initial clinical suspicion and in advanced disease from its benign mimicker. Our findings pave the way for an easy-to-implement and sensitive diagnostic approach to facilitate early diagnosis of Sezary syndrome, and other tumors with blood involvement as well.

Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex 1 virus (HSV-1) approved for cancer therapy. We investigate its effect on the clinical, histological, single-cell transcriptomic, and immune repertoire level using repeated fine-needle aspirates (FNAs) of injected and noninjected lesions in primary cutaneous B cell lymphoma (pCBCL). Thirteen patients received intralesional T-VEC, 11 of which demonstrate tumor response in the injected lesions. Using single-cell sequencing of the FNAs, we identify the malignant population and separate three pCBCL subtypes. Twenty-four hours after the injection, we detect HSV-1T-VEC transcripts in malignant and nonmalignant cells of the injected lesion but not of the noninjected lesion. Oncolytic virotherapy results in a rapid eradication of malignant cells. It also leads to interferon pathway activation and early influx of natural killer cells, monocytes, and dendritic cells. These events are followed by enrichment in cytotoxic T cells and a decrease of regulatory T cells in injected and noninjected lesions.

A novel B cell subset that produces proangiogenic cytokines is increased in pathologies associated with angiogenesis., B cells contribute to immune responses through the production of immunoglobulins, antigen presentation, and cytokine production. Several B cell subsets with distinct functions and polarized cytokine profiles have been reported. In this study, we used transcriptomics analysis of immortalized B cell clones to identify an IgG4+ B cell subset with a unique function. These B cells are characterized by simultaneous expression of proangiogenic cytokines including VEGF, CYR61, ADM, FGF2, PDGFA, and MDK. Consequently, supernatants from these clones efficiently promote endothelial cell tube formation. We identified CD49b and CD73 as surface markers identifying proangiogenic B cells. Circulating CD49b+CD73+ B cells showed significantly increased frequency in patients with melanoma and eosinophilic esophagitis (EoE), two diseases associated with angiogenesis. In addition, tissue-infiltrating IgG4+CD49b+CD73+ B cells expressing proangiogenic cytokines were detected in patients with EoE and melanoma. Our results demonstrate a previously unidentified proangiogenic B cell subset characterized by expression of CD49b, CD73, and proangiogenic cytokines.

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Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (L-CTCL) that arises from malignant clonally derived skin-homing CD4 + T cells. Based on advancements in our understanding of the mechanisms underlying L-CTCL, boosting the suppressed immune response emerges as a promising strategy in SS management. Immune checkpoint inhibitory molecules have already demonstrated efficacy in a wide spectrum of malignancies. Currently, agents targeting the programmed death-1 (PD-1) axis are under evaluation in L-CTCL. Here we investigated the expression of PD-1 and its ligands, PD-L1 and PD-L2 in blood and skin from patients with L-CTCL. We demonstrate that PD-1 expression is markedly increased on tumor T cells compared to non-tumor CD4 + T cells from SS patients and to CD4 + cells from healthy individuals. In contrast, PD-L1 shows decreased expression on tumor T cells, while PD-L2 expression is low without significant differences between these groups. Functional PD-1 blockade in vitro resulted in reduced Th2 phenotype of non-tumor T lymphocytes, but enhanced the proliferation of tumor T cells from SS patients. Our study sheds some light on the PD-1 axis in both peripheral blood and skin compartments in SS patients, which may be relevant for the treatment of L-CTCL with immune checkpoint inhibitor.

Background: Parkinson’s disease (PD), which occurs in 1% of the population, is the second most common neurodegenerative disorder. Despite the broad spectrum of PD manifestations and high disease prevalence, there are insufficient data on medicine utilization and prescription strategies. The purpose of the current study was to analyze published data concerning treatment approaches and to compare them with Bulgarian therapeutic practice. Design and methods: We conducted a systematic review of the PubMed and Google Scholar databases, and we calculated medicine utilization in Bulgaria during 2018 and 2019 using the WHO methodology. Results: The literature search identified a total of 311 publications, but only 12 met the inclusion criteria. Eleven studies pointed out that levodopa-containing medicine are the most frequently used, followed by dopamine agonists. The highest rate was found for levodopa-containing products and decarboxylase inhibitor (1.06 and 1.33 DDD/1000 inh/day), followed by anticholinergic Biperiden (0.494 and 0.455 DDD/1000 inh/day) during 2018 and 2019 in Bulgaria. Conclusion: Overall, the treatment approaches used in the last decade comply with guideline recommendations, despite variations in levodopa and dopamine agonist utilization. Even though new medicines have been approved for PD management, levodopa- containing products are still most often prescribed and used worldwide. Significance for public health Parkinson’s disease is the second most common neurodegenerative disorder affecting high number of the population. The achieved clinical results and disease control depending on early patients’ diagnostic and treatment. This study emphasizes on medicines utilization and most often used treatment approaches on Parkinson’s disease management. In addition, this is the first study exploring medicines utilization in Bulgaria. The findings reveal real medicines utilization in Bulgaria during 2018-2019 and its comparison with those found in the other countries. Regardless development of new therapies, levodopa-containing products reveals the highest rate of utilization as in most of the compared countries as in Bulgaria

In Sézary syndrome (SS) impaired T-cell function and cytokine profile lead to immune evasion. Immune checkpoints non-redundantly regulate immune responses and targeting them is promising. We evaluated the expression of BTLA, CTLA-4, FCRL3, LAG-3, and TIGIT in tumor and non-tumor SS T-cells.Compared to CD4+ T helper cells from ten healthy individuals, tumor cells of eight SS patients had a significant upregulation of BTLA (1.5-fold

Sézary syndrome is a primary cutaneous T-cell lymphoma characterized by pruritic erythroderma, peripheral lymphadenopathy and the presence of malignant T cells in the blood. Unequivocal detection of malignant cells in patients with Sézary syndrome is of important diagnostic, prognostic and therapeutic value. However, no single Sézary syndrome specific cell surface marker has been identified. In a cohort of patients with Sézary syndrome, CD164 expression on total CD4+ lymphocytes was significantly upregulated compared with healthy controls. CD164 expression was in most cases limited to CD4+CD26- malignant T lymphocytes, unequivocally identified using flow-cytometry by the expression of a specific Vβ clone for each patient. Increased expression of CD164 may be a promising diagnostic parameter and a potential target for a CD164-linked therapeutic approach in Sézary syndrome.

Activated leukocyte cell adhesion molecule (ALCAM, CD166) is a cell adhesion molecule of the immunoglobulin superfamily and has been implicated in diverse pathophysiological processes including T cell activation, leukocyte trafficking, and (lymph)angiogenesis. However, exploring the therapeutic potential of ALCAM blockade in immune-mediated inflammatory disorders has been difficult due to the lack of antibodies with blocking activity toward murine ALCAM. In this study, we identified and characterized a monoclonal antibody with high affinity and specificity for murine ALCAM. This antibody reduced in vitro T cell activation induced by antigen-presenting dendritic cells (DCs) as well as (trans)migration of murine DCs across lymphatic endothelial monolayers. Moreover, it reduced emigration of DCs from in vitro-cultured human skin biopsies. Similarly, antibody-based blockade of ALCAM reduced (lymph)angiogenic processes in vitro and decreased developmental lymphangiogenesis in vivo to levels observed in ALCAM-deficient mice. Since corneal allograft rejection is an important medical condition that also involves (lymph)angiogenesis, DC migration and T cell activation, we investigated the therapeutic potential of ALCAM blockade in murine corneal disease. Blocking ALCAM lead to DC retention in corneas and effectively prevented corneal allograft rejection. Considering that we also detected ALCAM expression in human corneal DCs and lymphatics, our findings identify ALCAM as a potential novel therapeutic target in human corneal allograft rejection.

To examine the cost of psychotic disorders in Bulgaria prior to hospital admission and following discharge from two perspectives: healthcare and societal; and to evaluate the association between the costs and the patient’s characteristics. 96 individuals with psychosis experiencing psychotic exacerbation and their primary caregivers were evaluated upon the patients’ hospital admission. The participants were followed up after 12 months. The costs were evaluated from healthcare and societal perspective using the Client’s Sociodemographic and Service Receipt Inventory (CSSRI-EU). The psychopathology, functioning, quality of life and caregiver’s burden were measured using standardized instruments. The mean differences in the costs and the associations with the clinical and socio-demographic characteristics of the patients were evaluated. The healthcare costs increase from EUR 120.66 (SD = 163.85) at baseline to EUR 177.54 (SD = 136.98) at follow-up. The total cost from societal perspective are up to sixfold higher than the healthcare costs at both assessments [EUR 717.41 (SD = 402.33) and 880.40 (SD = 1592.00), respectively] and do not change significantly. A major shift in the subtypes of costs, and significant associations of the costs with the socio-demographic and clinical characteristics, were found. Psychotic disorders and psychotic exacerbations have high societal costs. The underfunding of mental healthcare in Bulgaria is at the expense of high caregivers’ and societal cost. The treatment of psychotic exacerbation is effective and investment in mental healthcare for the improvement of the psychopathology, social functioning, quality of life and the burden of informal care should be viewed as a sustainable investment.

Background. The outcome of patients with adenocarcinoma of the esophagogastric junction (AEG) remains poor. The programmed cell-death-protein-1 (PD-1), a co-inhibitory receptor primarily expressed by T-cells, represents a potential new therapeutic target. PD-1, PD-1 ligand 1 (PD-L1), and PD-L2 expression have all been described as prognostic factors in a variety of cancers. Their expression patterns in AEG, however, are poorly understood. We analyzed PD-L1, PD-L2 and PD-1 expression by tumor-infiltrating lymphocytes (TILs) and cancer-cells in tumor-biospecimens in AEG-patients. Methods. 168 patients who underwent esophagectomy because of AEG between 1992–2011 were included in this study. PD-L1, PD-L2 and PD-1 expression were evaluated by immunohistochemistry and correlated with various clinicopathological parameters, disease-free survival (DFS) and long-term overall survival (OS). Results. PD-L1 expression by cancer-cells (cancer-cell-PD-L1(+)) was found in 43.5% of patients whereas PD-L1 expression by TILs (TILs-PD-L1(+)) was observed in 69%. PD-L2 expression by cancer-cells and TILs was only found in 3.5% and 1.8%, respectively. Additionally, 77.4% of tumors contained PD-1(+)-cancer-cells and 81% PD-1(+)-TILs. Patients with increased expression of PD-1 by cancer-cells and TILs showed significantly reduced OS and DFS, as determined by univariate, but not multivariate analysis. Expression of PD-L1 by cancer-cells was found to be an independent predictor for improved DFS (p = 0.038) and OS (p = 0.042) in multivariate analysis. Conclusions. Cancer cells and TILs displayed PD-L1 expression in around 50% and PD-1 expression in around 80% of tumor-biospecimens obtained from AEG patients. Expression of PD-L1 is an independent predictor of favorable outcome in AEG, whereas PD-1 expression is associated with worse outcome and advanced tumor stage.

Pulmonary metastasectomy (PM) is routinely performed in colorectal cancer (CRC) patients with oligometastatic spreading to the lungs. Patients with an aggressive tumor phenotype should be excluded from PM, since its benefit is outweighed by early tumor recurrence and impaired prognosis. Expression of PD-1 and its ligands are prognostic factors in a variety of primary tumors. However, their impact on patients' outcome in the setting of PM for CRC has not been evaluated before. 53 CRC patients with pulmonary metastases receiving PM with curative intent were included in this study. Tissue samples of resected pulmonary metastases and available corresponding primary tumors were collected and assessed for PD-1, PD-L1 and PD-L2 expression by tumor-infiltrating lymphocytes (TILs) and tumor cells. Expression patterns were correlated with clinical outcome parameters. PD-1 and PD-L1 expression was commonly found in TILs and tumor cells. Expression levels significantly differed between metastases and primary tumors. High PD-1 expression by TILs was associated with impaired overall survival (low vs high expression (mean, 95% CI): 78 mo (60–96) vs 35 mo (25–44); p = 0.011). Additionally, the subgroup of patients, who experienced an upgrading in their TILs/PD1 status between primary and metastasis had a worse survival outcome compared with patients with the same grade or a downgrading (34 mo (26–42) vs 96 mo (72–120); p = 0.004). Thus, PD-1 expression by TILs is a strong prognostic marker in CRC patients with pulmonary spreading treated by PM. Moreover, this study provides a rationale for a therapeutic PD-1 pathway blockade in the treatment of CRC lung metastases. Future, large-scale studies are warranted to validate the findings of this single-center, retrospective analysis.

Background Despite recent advances in the therapy for adenocarcinoma of the esophagogastric junction (AEG), overall prognosis remains poor. Programmed cell death protein 1 (PD1) is a co-inhibitory receptor primarily expressed by T-cells. Tumor cells can escape anticancer immune responses by triggering the PD1 pathway. Moreover, PD1 receptor engagement on cancer cells may trigger tumor-intrinsic growth signals. This study aimed to evaluate the potential clinical relevance of PD1 expression by tumor-infiltrating lymphocytes (TILs) and cancer cells in the AEG. Methods Patients with AEG who underwent esophagectomy from 1992 to 2011 were included in the study. Expression of PD1was evaluated by immunohistochemistry and correlated with long-term overall survival (OS), disease-free survival (DFS), and various clinicopathologic parameters. Results Tumor biospecimens from 168 patients were analyzed. In the analysis, 81% of the patients showed high tumoral frequencies (>5%) of PD1-expressing TILs (TIL-PD1+), and 77% of patient tumors harbored high levels (>5%) of PD1+ cancer cells (cancer-PD1+). Expression of PD1 by TILs and cancer cells correlated significantly (p

Rare T- or NK-cell lymphomas with cutaneous manifestation may display a highly aggressive clinical course and major diagnostic/therapeutic challenges. This report describes our experiences with different lymphomas of this rare category and the therapeutic options used. This retrospective, descriptive, monocentric, cross-sectional case study, identified 4 rare aggressive T-/NK-cell lymphomas with manifestation in the skin, which were diagnosed in a tertiary care centre over a period of 4 years. Two patients had an Epstein-Barr virus-associated extranodal NK/T-cell lymphoma and 2 patients had a primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. Concomitant extracutaneous involvement was observed in 2 of all 4 patients. Two patients had fulminant disease progression and resistance to chemotherapy. Two patients underwent allogeneic haematopoietic stem cell transplantation, which resulted in one complete remission and one partial remission. This report emphasizes the importance of an early diagnostic work-up and a prompt aggressive therapeutic approach.