Lung ultrasound predicts clinical course but not outcome in COVID-19 ICU patients: a retrospective single-center analysis.

BACKGROUND: Point-of-care lung ultrasound (LU) is an established tool in the first assessment of patients with coronavirus disease (COVID-19). Purpose of this study was to evaluate the value of lung ultrasound in COVID-19 intensive care unit (ICU) patients in predicting clinical course and outcome. METHODS: We analyzed lung ultrasound score (LUS) of all COVID-19 patients admitted from March 2020 to December 2020 to the Internal Intensive Care Unit, Ludwig-Maximilians-University (LMU) of Munich. LU was performed according to a standardized protocol at ICU admission and in case of clinical deterioration with the need for intubation. A normal lung scores 0 points, the worst LUS has 24 points. Patients were stratified in a low (0-12 points) and a high (13-24 points) lung ultrasound score group. RESULTS: The study included 42 patients, 69% of them male. The most common comorbidities were hypertension (81%) and obesity (57%). The values of pH (7.42 ± 0.09 vs 7.35 ± 0.1; p = 0.047) and paO2 (107 [80-130] vs 80 [66-93] mmHg; p = 0.034) were significantly reduced in patients of the high LUS group. Furthermore, the duration of ventilation (12.5 [8.3-25] vs 36.5 [9.8-70] days; p = 0.029) was significantly prolonged in this group. Patchy subpleural thickening (n = 38; 90.5%) and subpleural consolidations (n = 23; 54.8%) were present in most patients. Pleural effusion was rare (n = 4; 9.5%). The median total LUS was 11.9 ± 3.9 points. In case of clinical deterioration with the need for intubation, LUS worsened significantly compared to baseline LU. Twelve patients died during the ICU stay (29%). There was no difference in survival in both LUS groups (75% vs 66.7%, p = 0.559). CONCLUSIONS: LU can be a useful monitoring tool to predict clinical course but not outcome of COVID-19 ICU patients and can early recognize possible deteriorations.

Sequential HLA-haploidentical transplantation utilizing post-transplantation cyclophosphamide for GvHD prophylaxis in high-risk and relapsed/refractory AML/MDS.

This study evaluates the role of sequential therapy in HLA-haploidentical transplantation (haplo-HSCT) of high-risk, relapsed/refractory AML/MDS. We analyzed the course of 33 adults with active disease at time of transplantation (AML n = 30; MDS n = 3; median age 58 years, range: 32-71). Sequential therapy consisted of cytoreductive chemotherapy (FLAMSA n = 21; clofarabine n = 12) applied shortly prior to reduced intensity conditioning for T-cell-replete haplo-HSCT using post-transplantation cyclophosphamide as GvHD prophylaxis. No graft rejection was observed. Complete remission at day +30 was achieved in 97% of patients. CI of acute GvHD grade II-IV and chronic GvHD was 24% (no grade IV) and 23%, respectively. NRM at 1 and 3 years was 15%, each. Severe regimen-related toxicities (grade III-IV) were observed in 58%, predominantly involving the gastrointestinal tract (diarrhea 48%, mucositis 15%, transient elevation of transaminases 18%). Probability of relapse at 1 and 3 years was 28% and 35%. At a median follow-up of 36 months, the estimated 1- and 3-year overall survival was 56% and 48%. Disease-free survival was 49% and 40%, respectively. At 3 years, GvHD and relapse-free survival (GRFS) was 24% while chronic GvHD and relapse-free survival (CRFS) was 29%. Thus, our results indicate that sequential haplo-HSCT is an effective salvage treatment providing high anti-leukemic activity, favorable tolerance, and acceptable toxicity in patients suffering from advanced AML/MDS.

Characteristics and Outcome of Patients After Allogeneic Hematopoietic Stem Cell Transplantation Treated With Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome.

OBJECTIVES: The acute respiratory distress syndrome is a frequent condition following allogeneic hematopoietic stem cell transplantation. Extracorporeal membrane oxygenation may serve as rescue therapy in refractory acute respiratory distress syndrome but has not been assessed in allogeneic hematopoietic stem cell transplantation recipients. DESIGN: Multicenter, retrospective, observational study. SETTING: ICUs in 12 European tertiary care centers (Austria, Germany, France, and Belgium). PATIENTS: All allogeneic hematopoietic stem cell transplantation recipients treated with venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome between 2010 and 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-seven patients, nine of whom underwent noninvasive ventilation at the time of extracorporeal membrane oxygenation initiation, were analyzed. ICU admission occurred at a median of 146 (interquartile range, 27-321) days after allogeneic hematopoietic stem cell transplantation. The main reason for acute respiratory distress syndrome was pneumonia in 81% of patients. All but one patient undergoing noninvasive ventilation at extracorporeal membrane oxygenation initiation had to be intubated thereafter. Overall, seven patients (19%) survived to hospital discharge and were alive and in remission of their hematologic disease after a follow-up of 18 (range, 5-30) months. Only one of 24 patients (4%) initiated on extracorporeal membrane oxygenation within 240 days after allogeneic hematopoietic stem cell transplantation survived compared to six of 13 (46%) of those treated thereafter (p < 0.01). Fourteen patients (38%) experienced bleeding events, of which six (16%) were associated with fatal outcomes. CONCLUSIONS: Discouraging survival rates in patients treated early after allogeneic hematopoietic stem cell transplantation do not support the use of extracorporeal membrane oxygenation for acute respiratory distress syndrome in this group. On the contrary, long-term allogeneic hematopoietic stem cell transplantation recipients otherwise eligible for full-code ICU management may be potential candidates for extracorporeal membrane oxygenation therapy in case of severe acute respiratory distress syndrome failing conventional measures.

Virus infection in HLA-haploidentical hematopoietic stem cell transplantation: incidence in the context of immune recovery in two different transplantation settings.

We retrospectively compared the incidence of virus infections and outcome in the context of immune reconstitution in two different HLA-haploidentical transplantation (haplo-HSCT) settings. The first was a combined T-cell-replete and T-cell-deplete approach using antithymocyte globulin (ATG) prior to transplantation in patients with hematological diseases (cTCR/TCD group, 28 patients; median age 31 years). The second was a T-cell-replete (TCR) approach using high-dose posttransplantation cyclophosphamide (TCR/PTCY group, 27 patients; median age 43 years). The incidence of herpesvirus infection was markedly lower in the TCR/PTCY (22 %) than in the cTCR/TCD group (93 %). Recovery of CD4+ T cells on day +100 was faster in the TCR/PTCY group. CMV reactivation was 30 % in the TCR/PTCY compared to 57 % in the cTCR/TCD group, and control with antiviral treatment was superior after TCR/PTCY transplantation (100 vs 50 % cTCR/TCD). Twenty-five percent of the patients in the cTCR/TCD group but no patient in the TCR/PTCY group developed PTLD. While 1-year OS was not different (TCR/PTCY 59 % vs cTCR/TCD 39 %; p = 0.28), virus infection-related mortality (VIRM) was significantly lower after TCR/PTCY transplantation (1-year VIRM, 0 % TCR/PTCY vs 29 % cTCR/TCD; p = 0.009). On day +100, predictors of better OS were lymphocytes >300/µl, CD3+ T cells >200/µl, and CD4+ T cells >150/µl, whereas the application of steroids >1 mg/kg was correlated with worse outcome. Our results suggest that by presumably preserving antiviral immunity and allowing fast immune recovery of CD4+ T cells, the TCR approach using posttransplantation cyclophosphamide is well suited to handle the important issue of herpesvirus infection after haplo-HSCT.

Complete pathological response to neoadjuvant pemetrexed/cisplatin in combination with regional hyperthermia in a patient with sarcomatoid peritoneal mesothelioma.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare disease. Although most patients eligible for surgery undergo cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy, the role of perioperative systemic chemotherapy still remains undefined. Here we report the case of a 52-year-old female patient with advanced sarcomatoid DMPM. After five cycles of systemic pemetrexed and cisplatin, along with two cycles of regional hyperthermia, tumor resection with histomorphological examination showed a complete pathological response. We therefore conclude that there is a subgroup of DMPM patients that might benefit from systemic neoadjuvant chemotherapy with pemetrexed and cisplatin.

Feasibility of clofarabine cytoreduction followed by haploidentical hematopoietic stem cell transplantation in patients with relapsed or refractory advanced acute leukemia.

Clofarabine is a novel purine nucleoside analogue with immunosuppressive and anti-leukemic activity in acute lymphoblastic and myeloid leukemia (AML, ALL). This retrospective study was performed to evaluate the feasibility and anti-leukemic activity of a sequential therapy using clofarabine for cytoreduction followed by conditioning for haploidentical hematopoietic stem cell transplantation (HSCT) in patients with non-remission acute leukemia. Patients received clofarabine (5 × 30 mg/m² IV) followed by a T cell replete haploidentical transplantation for AML (n = 15) or ALL (n = 3). Conditioning consisted of fludarabine, cyclophosphamide plus either melphalan, total body irradiation or treosulfan/etoposide. High-dose cyclophosphamide was administered for post-grafting immunosuppression. Neutrophil engraftment was achieved in 83 % and complete remission in 78% at day +30. The rate of acute graft versus host disease (GvHD) grade II-IV was 22%, while chronic GvHD occured in five patients (28%). Non-relapse mortality (NRM) after 1 year was 23%. At a median follow-up of 19 months, estimated overall survival and relapse-free survival at 1 year from haploidentical HSCT were 56 and 39%, respectively. Non-hematological regimen-related grade III-IV toxicity was observed in ten patients (56%) and included most commonly transient elevation of liver enzymes (44%), mucositis (40%), and skin reactions including hand-foot syndrome (17%), creatinine elevation (17%), and nausea/vomiting (17%). The concept of a sequential therapy using clofarabine for cytoreduction followed by haploidentical HSCT proved to be feasible and allows successful engraftment, while providing an acceptable toxicity profile and anti-leukemic efficacy in patients with advanced acute leukemia. NRM and rate of GvHD were comparable to results after HSCT from HLA-matched donors.

PTCY-Based Haploidentical Donor Transplantation versus HLA-Matched Related and Unrelated Donor Transplantations in Patients with Refractory or Relapsed Lymphoma-A Matched-Pair Analysis.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has demonstrated its potential as a curative option for patients with r/r lymphoma. With the introduction of post-transplant cyclophosphamide-based (PTCY) graft-versus-host disease (GvHD) prophylaxis, allo-HCT using haploidentical related donors (Haplo-HSCT) has emerged as a valuable alternative for patients without an available HLA-matched donor. In this study, we compared intermediate and long-term outcomes between Haplo-HSCT and HLA-matched related donor (MRD) and unrelated donor (URD) transplantations in 16 matched pairs using age, disease status, lymphoma classification and performance status as matching criteria. Of note, 88% of patients in each group presented with active disease at the time of conditioning. After a median follow-up of >10 years, 10-year overall and progression-free survival and non-relapse mortality incidence after Haplo-HSCT were 31%, 25% and 38%, respectively, and did not differ compared to the values observed in MRD-HSCT and URD-HSCT. A remarkable lower incidence of acute GvHD ≥ II and moderate and severe chronic GvHD was observed after Haplo-HSCT compared to MRD-HSCT (50%/50%, p = 0.03/0.03) and URD-HSCT (44%/38%, p = 0.04/0.08), resulting in slightly higher 10-year GvHD-free and relapse-free survival (25%) and chronic GvHD-free and relapse-free survival (25%) in the Haplo-HSCT group. In conclusion, Haplo-HSCT is an effective treatment in patients with non-remission NHL. Given its advantage of immediate availability, haploidentical donors should be preferably used in patients with progressive disease lacking an HLA-matched related donor.

sCD25 as an independent adverse prognostic factor in adult patients with HLH: results of a multicenter retrospective study.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but often fatal hyperinflammatory syndrome caused by an inborn or acquired error of immunity. In adults, the underlying immunodeficiency generally arises alongside severe infections, malignancies, autoimmune diseases, and immunosuppressive treatment. To analyze risk factors and outcome in adults, we conducted a multicenter retrospective study. A total of 62 adult (age ≥18 years) patients met at least one of the following inclusion criteria: (1) ≥5 of 8 HLH-2004 criteria, (2) HScore ≥ 200 plus 4 HLH-2004 criteria, or (3) mutation compatible with an HLH diagnosis. Most patients (65%) were male, and the median age at diagnosis was 53.5 years (range, 19-81 years). All patients were assigned to 4 etiologic subgroups based on their most likely HLH trigger. The survival probability of the 4 etiologic subgroups differed significantly (P = .004, log-rank test), with patients with an underlying malignancy having the worst clinical outcome (1-year survival probability of 21%). The parameters older age, malignant trigger, elevated serum levels of aspartate transferase, creatinine, international normalized ratio, lactate dehydrogenase, sCD25, and a low albumin level and platelet count at treatment initiation were significantly (P < .1) associated with worse overall survival in the univariate Cox regression model. In multivariate analysis, sCD25 remained the only significant prognostic factor (P = .005). Our results suggest that sCD25 could be a useful marker for the prognosis of patients with HLH that might help to stratify therapeutic interventions.

Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases.

BACKGROUND: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM. METHODS: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint. RESULTS: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine. CONCLUSIONS: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.

Anthracycline-induced cardiotoxicity: cardiac monitoring by continuous wave-Doppler ultrasound cardiac output monitoring and correlation to echocardiography.

BACKGROUND: Anthracyclines are agents with a wellknown cardiotoxicity. The study sought to evaluate the hemodynamic response to an anthracycline using realtime continuous-wave (CW)-Doppler ultrasound cardiac output monitoring (USCOM) and echocardiography in combination with serum biomarkers. METHODS: 50 patients (26 male, 24 female, median age 59 years) suffering from various types of cancer received an anthracycline-based regimen. Patients' responses were measured at different time points (T0 prior to infusion, T1 6 h post infusion, T2 after 1 day, T3 after 7 days, and T4 after 3 months) with CW-Doppler ultrasound (T0-T4) and echocardiography (T1, T4) for hemodynamic parameters such as stroke volume (SV; SVUSCOM ml) and ejection fraction (EF; EFechocardiography%) and with NT-pro-BNP and hs-Troponin T (T0-T4). RESULTS: During the 3-month observation period, the relative decrease in the EF determined by echocardiography was -2.1% (▵T0-T4, T0 71 ± 7.8%, T4 69.5 ± 7%, p = 0.04), whereas the decrease in SV observed using CW-Doppler was -6.5% (▵T0-T4, T0 54 ± 19.2 ml, T4 50.5 ± 20.6 ml, p = 0.14). The kinetics for serum biomarkers were inversely correlated. CONCLUSIONS: Combining real-time CW-Doppler USCOM and serum biomarkers is feasible for monitoring the immediate and chronic hemodynamic changes during an anthracycline-based regimen; the results obtained were comparable to those from echocardiography.

Mechanical ventilation with positive end-expiratory pressure in critically ill patients: comparison of CW-Doppler ultrasound cardiac output monitoring (USCOM) and thermodilution (PiCCO).

BACKGROUND: Aggressive mechanical ventilation can markedly and unpredictably affect cardiac function. The fall in cardiac output (CO) is due to a reduction in left ventricular stroke volume (SV). The aim of the present pilot study was to assess the effects of different positive end-expiratory pressure (PEEP) levels on circulatory function and to compare them with continuous wave (CW)-Doppler ultrasound cardiac output monitoring (USCOM) and a thermodilution-based haemodynamic monitoring system (PiCCO). METHODS: Twenty mechanically ventilated (PEEP < or = 10 mbar) adult patients (female n = 6, male n = 14, mean age 62 years, mean SAPS II-score 48.5), the majority with pneumonia and septic shock) were followed with USCOM and PiCCO at stepwise increased PEEP-levels from 0-10 mbar (1 mbar steps). The changes in CO/SV were recorded. RESULTS: With both methods, an increase of PEEP resulted in a decrease of SV and CO. Although the absolute decrease was consistently higher by USCOM, the changes of the parameters were qualitatively comparable. CO fell from 8.83 L/min (+/- 2.39) by 0.4 L/min to 8.49 L/min (+/- 2.48) with PiCCO and from 9.3 L/min (+/- 3.43) by 1.0 L/min to 8.3 L/min (+/- 3.2) with USCOM. The median CO/SV fell by 4.5%/5.2% with PiCCO and 10.8%/9% with USCOM, respectively. Correlation of CO values with the two methods by Bland-Altman yielded comparable results (mean percentage error at PEEP 0 mbar 13%, PEEP 10 mbar 18%). An adequate flow signal with USCOM was achieved in all patients. CONCLUSIONS: A significant influence of mechanical ventilation with PEEP on haemodynamic parameters was evident both with USCOM and PiCCO. While thermodilution methods like PiCCO are well established but time-consuming and invasive, CW-Doppler based USCOM constitutes an important tool for easy, rapid and reliable diagnosis and haemodynamic monitoring of critically ill patients.

The Feasibility of Percutaneous Dilatational Tracheostomy in Immunosuppressed ICU Patients with or without Thrombocytopenia.

Background: Percutaneous dilatational tracheostomy (PDT) has become the preferred method in several intensive care units (ICUs), but data on PDT performed in immunosuppressed and thrombocytopenic patients are scarce. This study aimed to analyze the feasibility of PDT in immunosuppressed and thrombocytopenic patients compared to conventional open surgical tracheostomy (OST). Methods: We retrospectively analyzed the charts of patients who underwent PDT or OST between May 2017 and November 2020. Our outcomes were stoma site infections and bleeding complications. Results: 63 patients underwent PDT, and 21 patients underwent OST. Distribution of gender ratio, age, SAPS II, time of ventilation before tracheostomy, and preexisting hematooncological diseases was comparable between the two groups. After allogeneic stem cell transplantation (alloSCT), patients were more likely to undergo PDT than OST (p=0.033). The PDT cohort suffered from mucositis more frequently (p=0.043). There were no significant differences in leucocyte or platelet count on the tracheostomy day. Patients with coagulation disorders and patients under immunosuppression were distributed equally among both groups. Stoma site infection was documented in five cases in PDT and eight cases in the OST group. Moderate infections were remarkably increased in the OST group. Smears were positive in six cases in the PDT group; none of these patients had local infection signs. In the OST group, smears were positive in four cases; all had signs of a stroma site infection. Postprocedural bleedings occurred in eight cases (9.5%) and were observed significantly more often in the OST group (p=0.001), leading to emergency surgery in one case of the OST group. Conclusion: PDT is a feasible and safe procedure in a predominantly immunosuppressed and thrombocytopenic patient cohort without an increased risk for stoma site infections or bleeding complications.

The feasibility of electromagnetic sensing aided post pyloric feeding tube placement (CORTRAK) in patients with thrombocytopenia with or without anticoagulation on the intensive care unit.

BACKGROUND: The successful initiation of enteral nutrition is frequently hampered by various complications occurring in patients treated in the intensive care unit (ICU). Successful placement of a nasojejunal tube by CORTRAK enteral access system (CEAS) has been reported to be a simple bedside tool for placing the postpyloric (PP) feeding tube. METHODS: We evaluated the efficacy and side effects using CEAS to establish EN in patients with critical illness, thrombocytopenia, and/or anticoagulation. RESULTS: Fifty-six mechanically ventilated patients were analyzed. Twenty-four of them underwent prior hematopoietic stem cell transplantation (SCT). Sixteen patients received extracorporeal membrane oxygenation treatment because of acute respiratory distress syndrome. The median platelet count at PP placement was 26 g/L (range, 4-106 g/L); 16 patients received therapeutic anticoagulation (activated partial thromboplastin time, 50-70 s). CEAS-assisted placement of a PP nasojejunal tube was performed successfully in all patients. The most frequent adverse event was epistaxis in 27 patients (48.2%), which was mostly mild (Common Terminology Criteria for Adverse Events grade 1, n = 21 [77.8%], and grade 2, n = 6). A significant association between a low platelet count and bleeding complications was observed (P < 0.001). CONCLUSION: Performed by an experienced operator, CEAS is a simple, rapidly available, and effective bedside tool for safely placing PP feeding tubes for EN in patients with thrombocytopenia, even when showing an otherwise-caused coagulopathy in the ICU. Higher-grade bleeding complications were not observed despite their obvious correlation to thrombocytopenia. A prospective study is in preparation.

Follow-up lung ultrasound to monitor lung failure in COVID-19 ICU patients.

OBJECTIVES: Point-of-care lung ultrasound (LU) is an established tool in the first assessment of patients with coronavirus disease (COVID-19). To assess the progression or regression of respiratory failure in critically ill patients with COVID-19 on Intensive Care Unit (ICU) by using LU. MATERIALS AND METHODS: We analyzed all patients admitted to Internal Intensive Care Unit, Ludwig-Maximilians-University (LMU) of Munich, from March 2020 to December 2020 suffering lung failure caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). LU was performed according to a standardized protocol at baseline and at follow up every other day for the first 15 days using a lung ultrasound score (LUSS). Ventilation data were collected simultaneously. RESULTS: Our study included 42 patients. At admission to ICU, 19 of them (45%) were mechanically ventilated. Of the non-invasive ventilated ones (n = 23, 55%), eleven patients required invasive ventilation over the course. While LUS did not differ at admission to ICU between the invasive ventilated ones (at baseline or during ICU stay) compared to the non-invasive ventilated ones (12±4 vs 11±2 points, p = 0.2497), LUS was significantly lower at d7 for those, who had no need for invasive ventilation over the course (13±5 vs 7±4 points, p = 0.0046). Median time of invasive ventilation counted 18 days; the 90-day mortality was 24% (n = 10) in our cohort. In case of increasing LUS between day 1 (d1) and day 7 (d7), 92% (n = 12/13) required invasive ventilation, while it was 57% (n = 10/17) in case of decreasing LUS. At d7 we found significant correlation between LU and FiO2 (Pearson 0.591; p = 0.033), p/F ratio (Pearson -0.723; p = 0.005), PEEP (Pearson 0.495; p = 0.043), pplat (Pearson 0.617; p = 0.008) and compliance (Pearson -0.572; p = 0.016). CONCLUSION: LUS can be a useful tool in monitoring of progression and regression of respiratory failure and in indicating intubation in patients with COVID-19 in the ICU.

Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection.

Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design.

Long-term follow-up of patients with metastatic breast cancer: results of a retrospective, single-center analysis from 2000 to 2005.

Recent epidemiological studies suggest that chemotherapy for metastatic breast cancer (MBC) has not contributed to a marked improvement in the patient outcome during the last decades. Randomized trials that investigated the efficacy of a first-line schedule for MBC, observed a median survival of 18-24 months. This study aimed to analyze patients with MBC who have been treated in a single university outpatient clinic for survival. Patients with MBC who had received their complete anticancer treatment in our outpatient clinic between 2000 and 2005 were analyzed for treatment schedules and survival. A total of 232 patients [median age, 53 years; range, 27-87 years; estrogen receptor and/or progesterone-positive hormone receptor, n=174 (75%); human epidermal growth factor receptor 2 overexpression (human epidermal growth factor receptor 2 positive), n=79 (34%)] were included in this analysis, of which 43.7% of hormone receptor-positive patients received 1-2, 28.3% received 3-4, and 1.7% received more than four hormonal regimens. In addition, 53.4% of all patients received up to three chemotherapeutic agents in palliative intent, whereas four to six regimens were applied in 22.1, and 12.9% received more than six subsequent regimens. An increased number of regimens were associated with an improvement in survival. The median overall survival was 44 months (95% confidence interval: 39-49). HR positivity, bone only, or single-site metastases were associated with an improved survival. An improved survival was also shown in patients who underwent locoregional procedures for oligometastatic disease (n=31; median overall survival >50 months), whereas triple-negative breast cancer was related to worse outcome (16 months; 95% confidence interval: 7-25). These data collected from a selective patient population of a single center support the hypothesis that the sequential use of all treatment modalities for MBC to its full potential may result in an increased survival. Whether innovative medicine, a step-by-step escalation of all treatment modalities according to standard guidelines and individualized clinical requirements, and a multidisciplinary treatment approach contribute to these good outcomes is debatable.

Clinical characterization of patients with metastatic colorectal cancer depending on the KRAS status.

This retrospective study investigated the clinical characteristics of patients with metastatic colorectal cancer (mCRC) depending on the KRAS status, thereby differentiating KRAS exon 2 mutations in codon 12 versus codon 13. In total, 273 patients with mCRC receiving first-line therapy were analyzed. One hundred patients were treated within the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab), 147 patients within the AIO KRK-0104 trial (cetuximab plus CAPIRI or CAPOX), and further 26 patients received therapy outside the study. Thirty-eight tumors with KRAS mutation in codon 13, 140 tumors with mutation in codon 12, and 95 tumors with KRAS wild type as a comparison were included in this analysis. Bivariate analyses demonstrated significant differences between KRAS wild-type, codon 12-mutated, and codon 13-mutated tumors with regard to synchronous lymph node metastasis (P=0.018), organ metastasis (76.8% vs. 65.9% vs. 89.5%, P=0.009), liver metastasis (89.5% vs. 78.2% vs. 92.1%, P=0.025), lung metastasis (29.5% vs. 42.9% vs. 50%, P=0.041), liver-only metastasis (48.4% vs. 28.8% vs. 28.9%, P=0.006), and metastases in two or more organs (49.5, 61.4, 71.1, P=0.047). Regression models indicated a significant impact of KRAS mutations in codon 12 versus codon 13 for synchronous organ and nodal metastasis (P=0.01, 0.03). This pooled analysis indicates that mCRC is a heterogeneous disease, which seems to be defined by KRAS mutations of the tumor. Compared with KRAS codon 12 mutations, codon 13-mutated mCRC presents as a more aggressive disease frequently associated with local and distant metastases at first diagnosis.

[Update 2021: COVID-19 from the perspective of intensive care]. / Update 2021: COVID-19 aus Sicht der Intensivmedizin.

COVID-19 continues to challenge health-care systems and ICUs around the globe more than one year into the pandemic and in spite of all advances in diagnosis and treatment of the disease caused by the novel SARS-CoV-2. Many open questions remain concerning optimal medical therapy, respiratory management and resource allocation, particuly in times of limited available health care personell. In the following short article, we summarized current knowlegde on management of COVID-19 in the ICU.

Anthropometric analysis of body habitus and outcomes in critically ill COVID-19 patients.

AIMS: This study aimed to determine whether anthropometric markers of thoracic skeletal muscle and abdominal visceral fat tissue correlate with outcome parameters in critically ill COVID-19 patients. METHODS: We retrospectively analysed thoracic CT-scans of 67 patients in four ICUs at a university hospital. Thoracic skeletal muscle (total cross-sectional area (CSA); pectoralis muscle area (PMA)) and abdominal visceral fat tissue (VAT) were quantified using a semi-automated method. Point-biserial-correlation-coefficient, Spearman-correlation-coefficient, Wilcoxon rank-sum test and logistic regression were used to assess the correlation and test for differences between anthropometric parameters and death, ventilator- and ICU-free days and initial inflammatory laboratory values. RESULTS: Deceased patients had lower CSA and PMA values, but higher VAT values (p < 0.001). Male patients with higher CSA values had more ventilator-free days (p = 0.047) and ICU-free days (p = 0.017). Higher VAT/CSA and VAT/PMA values were associated with higher mortality (p < 0.001), but were negatively correlated with ICU length of stay in female patients only (p < 0.016). There was no association between anthropometric parameters and initial inflammatory biomarker levels. Logistic regression revealed no significant independent predictor for death. CONCLUSION: Our study suggests that pathologic body composition assessed by planimetric measurements using thoracic CT-scans is associated with worse outcome in critically ill COVID-19 patients.

Outcome Prediction in Patients with Severe COVID-19 Requiring Extracorporeal Membrane Oxygenation-A Retrospective International Multicenter Study.

The role of veno-venous extracorporeal membrane oxygenation therapy (V-V ECMO) in severe COVID-19 acute respiratory distress syndrome (ARDS) is still under debate and conclusive data from large cohorts are scarce. Furthermore, criteria for the selection of patients that benefit most from this highly invasive and resource-demanding therapy are yet to be defined. In this study, we assess survival in an international multicenter cohort of COVID-19 patients treated with V-V ECMO and evaluate the performance of several clinical scores to predict 30-day survival. METHODS: This is an investigator-initiated retrospective non-interventional international multicenter registry study (NCT04405973, first registered 28 May 2020). In 127 patients treated with V-V ECMO at 15 centers in Germany, Switzerland, Italy, Belgium, and the United States, we calculated the Sequential Organ Failure Assessment (SOFA) Score, Simplified Acute Physiology Score II (SAPS II), Acute Physiology And Chronic Health Evaluation II (APACHE II) Score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) Score, Predicting Death for Severe ARDS on V­V ECMO (PRESERVE) Score, and 30-day survival. RESULTS: In our study cohort which enrolled 127 patients, overall 30-day survival was 54%. Median SOFA, SAPS II, APACHE II, RESP, and PRESERVE were 9, 36, 17, 1, and 4, respectively. The prognostic accuracy for all these scores (area under the receiver operating characteristic-AUROC) ranged between 0.548 and 0.605. CONCLUSIONS: The use of scores for the prediction of mortality cannot be recommended for treatment decisions in severe COVID-19 ARDS undergoing V-V ECMO; nevertheless, scoring results below or above a specific cut-off value may be considered as an additional tool in the evaluation of prognosis. Survival rates in this cohort of COVID-19 patients treated with V­V ECMO were slightly lower than those reported in non-COVID-19 ARDS patients treated with V-V ECMO.