Incidence of Barotrauma in Patients With COVID-19 Pneumonia During Prolonged Invasive Mechanical Ventilation - A Case-Control Study.

BACKGROUND: SARS-CoV2 can cause pulmonary failure requiring prolonged invasive mechanical ventilation (MV). Lung protective ventilation strategies are recommended in order to minimize ventilator induced lung injury. Whether patients with COVID-19 have the same risk for complications including barotrauma is still unknown. Therefore, we investigated barotrauma in patients with COVID-19 pneumonia requiring prolonged MV. METHODS: All patients meeting diagnosis criteria for ARDS according to the Berlin Definition, with PCR positive SARS-CoV2 infection and prolonged mechanical ventilation, defined as ≥2 days, treated at our ARDS referral center between March and April 2020 were included in a retrospective registry analysis. Complications were detected by manual review of all patient data including respiratory data, imaging studies, and patient files. RESULTS: A total of 20 patients with severe COVID-19 pulmonary failure (Overall characteristics: median age: 61 years, female gender 6, median duration of MV 22 days) were analyzed. Eight patients (40%) developed severe barotrauma during MV (after median 18 days, range: 1-32) including pneumothorax (5/20), pneumomediastinum (5/20), pneumopericard (1/20), and extended subcutaneous emphysema (5/20). Median respirator settings 24 hours before barotrauma were: Peak inspiratory pressure (Ppeak) 29 cm H2O (range: 27-35), positive end-expiratory pressure (PEEP) 14 cm H2O (range: 5-24), tidal volume (VT) 5.4ml/kg predicted body weight (range 0.4-8.6), plateau pressure (Pplateau) 27 cm H2O (range: 19-30). Mechanical ventilation was significantly more invasive on several occasions in patients without barotrauma. CONCLUSION: Barotrauma in COVID-19 induced respiratory failure requiring mechanical ventilation was found in 40% of patients included in this registry. Our data suggest that barotrauma in COVID-19 may occur even when following recommendations for lung protective MV.

Resolving a sticky situation: A case report of mechanical thrombectomy of Histoacryl emboli in the right atrium and inferior vena cava.

A 68-year-old male with liver cirrhosis presented with dizziness and dyspnea two days after endoscopic Histoacryl occlusion of gastric varicses. Imaging revealed a large endovascular embolization of Histoacryl glue, spanning from porto-caval collaterals via the inferior vena cava to the right atrium, partially occluding right atrial inflow. This case report describes the successful removal of this large net-like mass of Histoacryl glue using thrombectomy devices from the inferior vena cava and the right atrium. Postprocedure imaging showed near-complete clearance with residual fragments in the superior mesenteric vein and small emboli in the pulmonary arteries. The patient was discharged in stable condition. Histoacryl glue can cause severe complications if embolized. This case highlights the potential of advanced thrombectomy devices for managing embolic complications from endovascular treatments.

Potent in vitro and in vivo activity of sorafenib in multiple myeloma: induction of cell death, CD138-downregulation and inhibition of migration through actin depolymerization.

Despite considerable advances, multiple myeloma (MM) remains incurable and the development of novel therapies targeting the interplay between plasma cells (PCs) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363-bearing non-obese diabetic severe combined immunodeficient mice with a deficient interleukin-2 receptor gamma chain (NSG). In vitro, we observed a dose-dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co-expressing histone 2B-mCherry and cytochrome c-GFP, bortezomib- and sorafenib-induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138-downregulation and abolished CXCL12-induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho-ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363-bearing NSG. Correspondingly, sorafenib induced clinical responses in MM-/AL-amyloidosis patients. We conclude that, in addition to the cytotoxic and anti-angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PCs and their supportive microenvironment.

BubR1 is frequently repressed in acute myeloid leukemia and its re-expression sensitizes cells to antimitotic therapy.

Spindle poison-based therapy is of only limited benefit in acute myeloid leukemia while lymphoblastic leukemia/lymphoma responds well. In this study, we demonstrated that the spindle assembly checkpoint protein BubR1 was down-regulated in the vast majority of cases of acute myeloid leukemia whereas its expression was high in lymphoblastic cells. Correct function of the spindle assembly checkpoint is pivotal in mediating mitotic delay in response to spindle poisons. Mitotic delay by the spindle assembly checkpoint is achieved by inhibition of anaphase-promoting complex-dependent proteolysis of cyclin B and securin. We demonstrated a link between the repression of the spindle assembly checkpoint protein BubR1 in acute myeloid leukemia and the limited response to spindle poison. In accordance with its established role as an anaphase-promoting complex-inhibitor, we found that repression of BubR1 was associated with enhanced anaphase-promoting complex activity and cyclin B and securin degradation, which leads to premature sister-chromatid separation and failure to sustain a mitotic arrest. This suggests that repression of BubR1 in acute myeloid leukemia renders the spindle assembly checkpoint-mediated inhibition of the anaphase-promoting complex insufficient, which facilitates completion of mitosis in the presence of spindle poison. As both direct and BubR1-mediated restoration of cyclin B expression enhanced response to spindle poison, we propose that the downstream axis of the spindle assembly checkpoint is a promising target for tailored therapies for acute myeloid leukemia.

Does colorectal cancer in ulcerative colitis patients constitute a risk for chemotherapy refractoriness?:a systemic approach by detailed analysis via the electronic tumor base documentation system.

BACKGROUND: Ulcerative colitis (UC) patients may develop colorectal cancer (CRC), especially with pancolitis and longer UC duration. The question whether CRC with underlying UC has a dismal prognosis remains unsettled. PATIENTS AND METHODS: We performed an electronic tumor base documentation (eTBD) search of CRC and UC patients at our department to address whether (1) CRC prognosis is impaired and (2) defined risks can be determined. RESULTS: With the inclusion of an index patient with UC and unresponsive CRC, 20 additional patients were identified via eTBD. Chemotherapy response was less substantial, with complete response or stable disease in 3 patients each, but rapidly progressing or refractory disease in 15/21 patients. 12 out of the 21 patients died. Our hazard ratio analysis revealed International Union against Cancer (UICC) stage IV and III disease, grade 3 tumors, longer latency from UC to CRC and age >60 years as potential risks. Median progression-free survival and overall survival were 48 and 82 months, respectively. Time from tumor dissemination to death was 10 months. CONCLUSIONS: The prognosis of CRC in UC patients is not necessarily impaired, albeit chemotherapy response with disseminated disease may be unfavorable. Our data should be enlarged by subsequent analyses to better elucidate whether response in UC and CRC is more challenging and defined risks can be confirmed.

Coronary angiography following out-of-hospital cardiac arrest (OHCA): a review of outcomes and clinical considerations.

INTRODUCTION: In patients suffering a sudden out-of-hospital cardiac arrest (OHCA), the prevalence of a coronary artery lesion as the underlying cause is relatively high, but many other causes have been described. For this reason, identifying patients who would benefit from an emergency coronary angiography is important. AREAS COVERED: In the present manuscript, we reviewed the literature covering some relevant studies regarding the role of coronary angiography in patients with OHCA, including our local algorithm for the management of patients with OHCA. We particularly focused on the selection of patients who would benefit from an emergency coronary angiography, the time period until the performance of the angiography, the role of extracorporeal cardiopulmonary resuscitation (ECPR), the identification of a coronary artery lesion as the underlying cause of cardiac arrest and clinical outcomes. EXPERT OPINION: In summary, a local standard algorithm for the management of patients with OHCA appears favorable. An emergency coronary angiography should be advised in patients with a presumed cardiac cause and without obvious non-cardiac cause. A shockable initial rhythm, ST elevation in the post-resuscitation ECG, a previously known coronary artery disease, and ECPR are important predictors of cardiac cause of OHCA.

Extracorporeal Membrane Oxygenation Support as a Bridge to Recovery during Chemotherapy in a Young Patient with Metastatic Choriocarcinoma and Severe Acute Respiratory Distress Syndrome.

INTRODUCTION: A young woman presented at a local hospital with severe dyspnea directly after childbirth. She was di-agnosed with choriocarcinoma and massive pulmonary metastases. Shortly after administration of polychemotherapy she developed severe acute respiratory distress syndrome (ARDS). CASE PRESENTATION: The patient was transferred to the intensive care unit (ICU) and extracorporeal membrane oxygenation (ECMO) center of the university hospital. Venovenous ECMO support was implemented for 28 days while enabling continuous chemotherapy. After 49 days in the ICU, she was transferred to the oncology ward in a stable respiratory state. DISCUSSION/CONCLUSION: Although the survival rates of ARDS in the general ICU population have improved lately due to improved management of ARDS and ECMO support, the data on adult cancer patients receiving ECMO support are very limited. Only few small retrospective studies on ECMO support in adult cancer patients have been conducted. Unfortunately the survival rates of patients after allogenic hematopoietic stem cell transplantation and ECMO support were discouraging. Nevertheless, cancer patients with at least stable disease who are eligible for full-code ICU management may be potential candidates for ECMO in case of severe ARDS. Our case report not only shows that patients suffering from choriocarcinoma with pulmonary metastases may develop severe ARDS in the context of polychemotherapy, but also demonstrates that ECMO support enables chemotherapy continuation and complete remission of the underlying choriocarcinoma.

Prognostic risk factor evaluation in patients with relapsed or refractory multiple myeloma receiving lenalidomide treatment: analysis of renal function by eGFR and of additional comorbidities by comorbidity appraisal.

INTRODUCTION: Renal impairment (RI) is a dreaded complication in multiple myeloma (MM) and has been associated with decreased progression-free survival (PFS) and overall survival (OS). METHODS: Forty-five consecutive patients with MM received lenalidomide therapy combined with either dexamethasone or standard chemotherapy, with dose modification according to current guidelines. Comorbidity indices (hematopoietic cell transplantation-specific comorbidity index [HCT-CI], Kaplan Feinstein [KF], and the Freiburg comorbidity index [FCI]) were analyzed and renal function was determined by estimated glomerular filtration rate (eGFR) before lenalidomide treatment and 1, 3, and 6 months after treatment. RESULTS: The median patient age was 66 years. Pretreatment was substantial with ≥ 2 treatment lines in 71% of patients. Lenalidomide induced median PFS and OS of 13 and 25 months, respectively. The analysis of comorbidity scores identified only the FCI as significant, with different PFS for low-risk vs. high-risk patients of 20 vs. 9 months (p = .0036) and OS of not reached vs. 12.8 months (p < .0001), respectively. Although baseline renal function by serum creatinine evaluation appeared normal (median 1.0 mg/dL), mild RI was readily detectable by eGFR (median 83 mL/min/1.73 m(2)). When patients without RI were compared with those with mild, moderate, and severe RI, 1- and 2-year PFS rates were similar (hazard ratio [HR] with decreasing eGFR, 1.028; p = .6927). For OS, the HR of 1.192 indicated decreased survival probabilities with deteriorating eGFR (p = .0411), which was perceived by eGFR but not serum creatinine assessment (p = .2253). CONCLUSIONS: Lenalidomide was well tolerated in intensively pretreated and elderly MM patients, including those with RI. PFS was not significantly different in patients with decreasing eGFRs, albeit RI and other comorbidities remained significant for OS.

Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy.

An international myeloma meeting entitled "Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy" was held in Freiburg, Germany in July 2011 to discuss novel insights into and approaches to myeloma bone disease and other bone-seeking tumors. This review briefly summarizes the most prominent data of the meeting and current literature on our understanding of bone disease, the role of imaging techniques, operative interventions and systemic bone-seeking treatment, all of which should further improve our future therapeutic choices.

Early and mature endothelial progenitors and VEGFR2+-cells in multiple myeloma: association with disease characteristics and variation in different cell compartments.

We analyzed (1) early endothelial progenitors (EPCs; CD34(+)/AC133(+)/VEGFR2(+)), mature EPCs (CD34(+)/VEGFR2(+)) and VEGFR2(+)-cells in bone marrow (BM)-specimens of multiple myeloma (MM)- vs. monoclonal gammopathy (MGUS)-patients and healthy controls; (2) differences of BM-, peripheral blood (PB)- and leukapheresis (LP)-samples; and (3) the association of EPCs and VEGFR2(+)-cells with MM-parameters. MM patients demonstrated highest early and mature EPCs and VEGFR2(+)-cells in the BM, particularly with advanced and active disease. Endothelial cells differed in BM-, PB- and LP-specimens, albeit seemed less associated with unfavorable prognostic MM-parameters. Our data suggest that especially VEGFR2(+)-cells and mature EPCs in MM are of value to explore further.

Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches.

Treatment for multiple myeloma (MM) has changed beyond recognition over the past two decades. During the early 1980s, MM inevitably resulted in a slow progressive decline in quality of life until death after about 2 years, while today patients can expect a 50% chance of achieving a complete remission, median survival of 5 years, and a 20% chance of surviving longer than 10 years. An international expert opinion meeting (including members of the GIMEMA and DSMM study groups) was held in 2009. One of the outcomes of the meeting was the development of a consensus statement outlining contemporary optimal clinical practice for the treatment of MM. The international panel recommended that the state of the art therapy for MM should comprise: (a) evidence-based supportive care, (b) effective and well-tolerated chemotherapeutic regimens, (c) autologous hematopoietic stem cell transplant (ASCT) for patients suitable for intensive conditioning therapy, and (d) evidence-based incorporation of novel anti-MM agents. Maintenance strategies have also become increasingly important for the prolongation of remission after front-line therapies. In addition, improved understanding of the biology of MM has led to the development of novel biological therapeutic agents such as thalidomide, lenalidomide, bortezomib, and others. These agents specifically target intracellular mechanisms and interactions, such as those within the bone marrow microenvironment, and have been integrated into MM treatment. This report reviews recent clinical advances in the treatment strategies available for MM and provides an overview of the state of the art management of patients with MM.

European Myeloma Network: the 3rd Trialist Forum Consensus Statement from the European experts meeting on multiple myeloma.

Over the past two decades, not only treatment options, but also the diagnosis, staging, and risk assessment of multiple myeloma (MM), have undergone significant development, partially due to a deeper understanding of MM pathogenesis. Conventional cytogenetics and fluorescence in situ hybridization are routinely assessed in MM, and when combined with ISS stage may attain an even better predictive potential. In order to achieve even more effective and individualized therapies, one crucial goal is the identification of genes and gene combinations that predict for response or resistance to chemotherapy. High-dose chemotherapy with autologous stem cell transplant (SCT) still remains the standard therapy for younger patients, with novel agents now being included in both pre-transplant regimens and post-transplant consolidation/maintenance approaches. Similarly, novel agents are also being incorporated into allogeneic SCT for selected patients. In the treatment of elderly patients with MM, novel agents have been successfully incorporated into less intensive regimens, including melphalan/prednisone, low-dose dexamethasone, and cyclophosphamide/dexamethasone. While second-generation proteasome inhibitors are currently being intensively investigated, the subcutaneous administration of bortezomib, being equivalent to the established i.v. route, is now entering clinical practice. Supportive care remains a crucial aspect in the management of MM. The European Myeloma Network Trialist Group aims to address these contemporary aspects in MM.