The TLR-NF-kB axis contributes to the monocytic inflammatory response against a virulent strain of Lichtheimia corymbifera , a causative agent of invasive mucormycosis

Invasive mucormycosis (IM) is a life-threatening infection caused by the fungal order Mucorales, its diagnosis is often delayed, and mortality rates range from 40-80% due to its rapid progression. Individuals suffering from hematological malignancies, diabetes mellitus, organ transplantations, and most recently COVID-19 are particularly susceptible to infection by Mucorales. Given the increase in the occurrence of these diseases, mucormycosis has emerged as one of the most common fungal infections in the last years. However, little is known about the host immune response to Mucorales. Therefore, we characterized the interaction among L. corymbifera— one of the most common causative agents of IM—and human monocytes, which are specialized phagocytes that play an instrumental role in the modulation of the inflammatory response against several pathogenic fungi. This study covered four relevant aspects of the host-pathogen interaction: i) The recognition of L. corymbifera by human monocytes. ii) The intracellular fate of L. corymbifera. iii) The inflammatory response by human monocytes against the most common causative agents of mucormycosis. iv) The main activated Pattern-Recognition Receptors (PRRs) inflammatory signaling cascades in response to L. corymbifera . Here, we demonstrate that L. corymbifera exhibits resistance to intracellular killing over 24 hours, does not germinate, and inflicts minimal damage to the host cell. Nonetheless, viable fungal spores of L. corymbifera induced early production of the pro-inflammatory cytokine IL-1β, and late release of TNF-α and IL-6 by human monocytes. Moreover, we revealed that IL-1β production predominantly depends on Toll-like receptors (TLRs) priming, especially via TLR4, while TNF-α is secreted via C-type lectin receptors (CTLs), and IL-6 is produced by synergistic activation of TLRs and CTLs. All these signaling pathways lead to the activation of NF-kB, a transcription factor that not only regulates the inflammatory response but also the apoptotic fate of monocytes during infection with L. corymbifera. Collectively, our findings provide new insights into the host-pathogen interactions, which may serve for future therapies to enhance the host inflammatory response to L. corymbifera

COVID-19 vaccines in patients with cancer:immunogenicity, efficacy and safety

Patients with cancer have a higher risk of severe coronavirus disease (COVID-19) and associated mortality than the general population. Owing to this increased risk, patients with cancer have been prioritized for COVID-19 vaccination globally, for both primary and booster vaccinations. However, given that these patients were not included in the pivotal clinical trials, considerable uncertainty remains regarding vaccine efficacy, and the extent of humoral and cellular immune responses in these patients, as well as the risks of vaccine-related adverse events. In this Review, we summarize the current knowledge generated in studies conducted since COVID-19 vaccines first became available. We also highlight critical points that might affect vaccine efficacy in patients with cancer in the future

Frequently asked questions regarding SARS-CoV-2 in cancer patients—recommendations for clinicians caring for patients with malignant diseases

Since early 2020, the SARS-CoV-2 pandemic has a massive impact on health care systems worldwide. Patients with malignant diseases are assumed to be at increased risk for a worse outcome of SARS-CoV-2 infection, and therefore, guidance regarding prevention and management of the infection as well as safe administration of cancer-therapy is required. Here, we provide recommendations for the management of patients with malignant disease in the times of COVID-19. These recommendations were prepared by an international panel of experts and then consented by the EHA Scientific Working Group on Infection in Hematology. The primary aim is to enable clinicians to provide optimal cancer care as safely as possible, since the most important protection for patients with malignant disease is the best-possible control of the underlying disease.Open access funding provided by Projekt DEA

Practical recommendations on the use of lenalidomide in the management of myelodysplastic syndromes

Lenalidomide, an oral immunomodulatory agent, has received approval in the USA from the Food and Drug Administration (FDA) for the management of myelodysplastic syndromes (MDS) classified by the International Prognostic Scoring System (IPSS) as low risk or intermediate-1 risk and with a deletion 5q (del(5q)) cytogenetic abnormality. Although some patients with del(5q) have a relatively good prognosis, all del(5q) patients will become transfusion-dependent at some point during the course of their disease. The results of two clinical trials in more than 160 patients with MDS have demonstrated clear therapeutic benefits of lenalidomide, with >60% of patients achieving independence from transfusion during therapy, irrespective of age, prior therapy, sex, or disease-risk assessment. The recommendations presented in this review will aid the safe administration of lenalidomide for the treatment of patients with low-risk or intermediate-1-risk MDS and a del(5q) cytogenetic abnormality, and they will help physicians avoid unnecessary dose reduction or interruption, thus assuring the best efficacy for patients

Screening and contact precautions - A survey on infection control measures for multidrug-resistant bacteria in German university hospitals

To assess the scope of infection control measures for multidrug-resistant bacteria in high-risk settings, a survey among university hospitals was conducted. Fourteen professionals from 8 sites participated. Reported policies varied largely with respect to the types of wards conducting screening, sample types used for screening and implementation of contact precautions. This variability among sites highlights the need for an evidence-based consensus of current infection control policies

Mixed Response to Ipilimumab in a Melanoma Patient with Brain Metastases: Case Report and Review of the Literature

Management of patients suffering from metastatic malignant melanoma and brain metastasis remains challenging in routine clinical practice. The inhibitory anti-CTLA-4 antibody ipilimumab has recently been approved as second-line therapeutic option for melanoma patients. Increasing evidence suggests distinct therapeutic activity on central nervous system metastases, although this continues to be actively debated. Here, we present the case of a patient suffering from metastatic melanoma, including symptomatic brain metastasis, who showed a partial response to ipilimumab in extracranial tumor manifestations, while the disease was progressing intracranially. Subsequently, intracranial disease progression could be managed by local irradiation. An overview of currently available literature on the efficacy of ipilimumab in melanoma patients with central nervous system metastases is provided

Management of infections in patients with cancer Responsible use of anti-infectives

Patients with cancer are at increased risk of infection due to disease-associated or therapy-induced immunosuppression. Taking into account globally increasing antimicrobial resistance rates and negative effects associated with antibiotic treatments, the effective, appropriate and guideline-conform use of anti-infectives must be promoted in this clinical setting. The application of antibacterial prophylaxis should be limited to high-risk patients. Infection diagnostics and therapeutic strategies differ depending on the extent of expected immunosuppression and the patient's individual risk factors

Invasive Fungal Infection New Treatments to Meet New Challenges

Background: The incidence of invasive fungal infection is approximately 6 cases per 100 000 persons per year. It is estimated that only half of such infections are detected during the patient's lifetime, making this one of the more common overlooked causes of death in intensive-care patients. The low detection rate is due in part to the complexity of the diagnostic work-up, in which the clinical, radiological, and microbiological findings must be considered. Fungi with resistance to antimycotic drugs have been found to be on the rise around the world. Methods: This review is based on pertinent publications retrieved from a selective search in PubMed, with special attention to guidelines on the diagnosis and treatment of invasive fungal infections caused by Candida spp., Aspergillus spp., Mucorales, and Fusarium spp. Resufts: The clinical risk factors for invasive fungal infection include, among others, congenital immune deficiency, protracted (>10 days) marked granulocytopenia (<0.5 x 10(9)/L), allogeneic stem-cell transplantation, and treatment with immunosuppressive drugs or corticosteroids. High-risk groups include patients in intensive care and those with structural pulmonary disease and/or complicated influenza. The first line of treatment, supported by the findings of random ed clinical trials. consists of echinocandins for infections with Candida spp. (candidemia response rates: 75.6% for anidulafungin vs. 60.2% for fluconazole) and azole antimycotic drugs for infections with Aspergillus spp. (response rates: 52.8% for voriconazole vs. 31.6% for conventional amphotericin B). The recommended first-line treatment also depends on the local epidemiology. This challenge should be met by interdisciplinary collaboration. Therapeutic decision-making should also take account of the often severe undesired effects of antimycotic drugs (including impairment of hepatic and/or renal function) and the numerous interactions that some of them have with other drugs. Conclusion: Invasive fungal infections are often overlooked in routine hospital care. They should be incorporated into antimicrobial stewardship programs as an essential component. There is also a pressing need for the development of new classes of antimycotic drug