Search

Metastatic pulmonary calcification is an underdiagnosed metabolic lung disease characterized by diffuse calcium deposition in the lungs, often associated with secondary hyperparathyroidism due to chronic renal failure. A 31-year-old man with chronic renal failure initially presented with diffuse pain symptoms, deterioration of general condition, and respiratory insufficiency. Noncontrast-enhanced computed tomography of the chest was performed using a spectral-detector-based dual-energy CT. It showed multiple, centrilobular, ground-glass opacities, and nodules, ultimately leading to the diagnosis. Calcium suppression proved to be highly useful to classify the pulmonary alterations.

Summary Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding Sanofi and Regeneron Pharmaceuticals.

Background Invasive fungal diseases remain a major cause of morbidity and mortality in cancer patients undergoing intensive cytotoxic therapy. The choice of the most appropriate antifungal treatment (AFT) depends on the fungal species suspected or identified, the patient's risk factors (eg length and depth of granulocytopenia) and the expected side effects. Objectives Since the last edition of recommendations for 'Treatment of invasive fungal infections in cancer patients' of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) in 2013, treatment strategies were gradually moving away from solely empirical therapy of presumed or possible invasive fungal diseases (IFDs) towards pre-emptive therapy of probable IFD. Methods The guideline was prepared by German clinical experts for infections in cancer patients in a stepwise consensus process. MEDLINE was systematically searched for English-language publications from January 1975 up to September 2019 using the key terms such as 'invasive fungal infection' and/or 'invasive fungal disease' and at least one of the following: antifungal agents, cancer, haematological malignancy, antifungal therapy, neutropenia, granulocytopenia, mycoses, aspergillosis, candidosis and mucormycosis. Results AFT of IFDs in cancer patients may include not only antifungal agents but also non-pharmacologic treatment. In addition, the armamentarium of antifungals for treatment of IFDs has been broadened (eg licensing of isavuconazole). Additional antifungals are currently under investigation or in clinical trials. Conclusions Here, updated recommendations for the treatment of proven or probable IFDs are given. All recommendations including the levels of evidence are summarised in tables to give the reader rapid access to key information.

Background: About 20% of patients diagnosed with classical Hodgkin lymphoma (cHL) are 60 years or older. They have a comparatively poor prognosis, particularly when presenting in advanced stages. In previous trials, older patients did not benefit from intensified regimens in terms of overall survival due to a high toxicity-related death rate. In order to improve tolerability, we developed the B-CAP regimen (brentuximab vedotin, cyclophosphamide, doxorubicin and predniso(lo)ne), incorporating the antibody-drug conjugate brentuximab vedotin into a CHOP-based chemotherapy backbone. We report the first results of our multicenter phase II study evaluating B-CAP in older cHL patients. Methods: We recruited patients with newly diagnosed advanced-stage cHL aged 60 years or older and eligible for polychemotherapy (Cumulative Illness Rating Scale for Geriatrics ≤6 in total and ≤3 per organ system) in five European countries. Treatment consisted of six cycles B-CAP; radiotherapy to Positron Emission Tomography (PET) positive residuals was applied. The primary endpoint was the CT-based objective response rate (ORR; complete [CR] or partial remission (PR]) after six cycles of B-CAP, aiming at excluding an ORR of 60% or less via a one-sided 95% confidence interval. All patients completing interim staging after two cycles were considered eligible. Results: Between November 2015 and September 2017, 50 patients were recruited, of whom one withdrew consent before start of treatment. Of the remaining 49, 26 patients (53%) were male, 47 (96%) had stage III-IV disease, and the median age was 66 years (range 60-84). One patient died from infection before interim staging, and 48 patients were eligible for the primary endpoint. There were no further treatment-related deaths. The CT-based ORR was 98% (one-sided 95% CI 90.5%-100%) with 21 patients having CR, 26 patients having PR, and one patient having progressive disease in the restaging after completion of B-CAP therapy. All patients with CT-based CR and 10/26 patients with PR had a negative PET (Deauville < 4), resulting in a complete metabolic response rate of 65%. Dose delivery was high with only two patients stopping treatment after four and five cycles, respectively, due to toxicity. Progression-free and overall survival as well as safety data will be presented. Conclusion: B-CAP is feasible and effective in patients older than 60 years with advanced-stage cHL and should be subject of further research. Disclosures Boell: honoraria and research funding from Celgene, MSD, Mundipharma, Johnson & Johnson and Takeda: Consultancy, Honoraria, Research Funding. Fosså:Janssen Pharmaceuticals, Inc.: Honoraria. Leppa:Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Bayer: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Molin:Bristol-Myers Squibb: Honoraria; Roche Holding AG: Honoraria; Merck & Co., Inc: Honoraria; Takeda Pharmaceuticals: Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

Cetuximab is an anti-epidermal growth factor receptor (EGFR) antibody approved for the treatment of colorectal and head and neck cancer [1]. EGFR is also expressed on multiple myeloma (MM) plasma cells and bone marrow stromal cells (BMSCs) [2,3]. Th e inhibition of EGFR has been shown to induce apoptosis in myeloma cells revealing a synergistic eff ect with dexamethasone [2]. Th us, the anti-EGFR antibody cetuximab might be of clinical benefi t in the treatment of MM, especially in combination with dexamethasone. Here, we report the fi nal results of the fi rst clinical trial with an anti-EGFR antibody in MM, the EMMA1 trial. Eligible patients were adults with recurrent or refractory Durie – Salmon stage II or III MM who were not candidates for or had already undergone high-dose chemotherapy and autologous stem cell transplant (ASCT). Review boards at participating institutions approved the study, which was conducted according to the International Conference on Harmonization and the Guidelines for Good Clinical Practice. Written informed consent was obtained from all patients in accordance with the Declaration of Helsinki 1995. EMMA1 was an open-label, non-randomized phase II study (ClinicalTrials.gov Identifi er: NCT00368121). Th e primary endpoint was overall response rate (ORR) after 16 weeks of treatment. Secondary endpoints included adverse events during treatment, freedom from treatment failure (FFTF), progression-free survival (PFS) and overall survival (OS). Clinical benefi t rate (CB, defi nition: at least stable disease [SD]) was calculated in post hoc analyses. Patients received a cetuximab loading dose of 400 mg/m 2 intravenously on day 1 followed by weekly administrations of 250 mg/m 2 intravenously. Patients achieving at least SD after 4 weeks or responding to treatment within 8 weeks received cetuximab for a total of 16 weeks. Patients not achieving stable disease after 4 weeks or a response after 8 weeks of cetuximab treatment additionally received 20 mg oral dexamethasone on days 1 – 3 of each 7-day cycle. Patients achieving a response or stable disease after 16 weeks of treatment could continue study medication for an additional 6 months (patients receiving cetuximab alone) or for an additional 3 months (patients receiving cetuximab plus dexamethasone; dexamethasone was tapered down according to local guidelines). Responding patients who relapsed during the follow-up period of 2 years were off ered a second treatment with cetuximab following initial study guidelines. Tumor response was monitored by quantitative serum

Purpose: We recently developed a fully human monoclonal antibody (5F11) directed against the CD30 receptor, which is an excellent target for antibody based immunotherapy of malignant lymphoma cells. The antibody is cytotoxic for lymphoma cells in vitro and in vivo, however a partial or even complete resistance of several Hodgkin cell lines has been observed. In this study we analysed, whether the efficacy of 5F11 can be improved by combination with bortezomib. Methods and Results: Bortezomib is an inhibitor of the ubiquitin-proteasomes pathway that is toxic to multiple solid and hemotologic tumor cells. Using XTT viability assays, TUNEL assays and Facs analysis we demonstrate a synergistic toxic effect of 5F11 and bortezomib on the Hodgkin cell lines tested (L540, L1236, L428) and the CD30 expressing ALCL Karpas299. Moreover the growth of subcutaneous L540 derived tumors in SCID mice is inhibited by 5F11 in combination with bortezomib. The synergy depends on the regime of the drugs and is only seen when a pre-incubation with the antibody is followed by exposure to bortezomib. Immunofluorescence analysis demonstrates that the sensitization of the tumor cells correlates with a 5F11 dependent localisation of the survival factor NF-kB into the cell nuclei. A transfected NF-kB responsive reporter gene is 2–3 fold activated in 5F11 treated L428 cells and enhanced NF-kB binding is detected performing EMSA.. We furthermore measured an increased expression of the NF-kB target gene c-flip, that is down regulated after additional incubation of the tumor cells with bortezomib. Conclusion: Our data indicate that initial activation of NF-kB and downstream anti-apoptotic proteins in response to 5F11 via CD30 sensitizes the tumor cells to bortezomib induced cell death. The in vitro and in vivo activity of the combination of 5F11 and bortezomib suggests a therapeutic value for the treatment of HD patients.