Diagnostic, Clinical and Post-SARS-CoV-2 Scenarios in Cancer Patients with SARS-CoV-2: Retrospective Analysis in Three German Cancer Centers.

Oncologists face challenges in the management of SARS-CoV-2 infections and post-SARS-CoV-2 cancer treatment. We analyzed diagnostic, clinical and post-SARS-CoV-2 scenarios in patients from three German cancer centers with RT-PCR confirmed SARS-CoV-2 infection. Sixty-three patients with SARS-CoV-2 and hematologic or solid neoplasms were included. Thirty patients were initially asymptomatic, 10 of whom developed COVID-19 symptoms subsequently. Altogether 20 (32%) patients were asymptomatic, 18 (29%) had mild, 12 (19%) severe and 13 (20%) critical courses. Lymphocytopenia increased risk of severe/critical COVID-19 three-fold (p = 0.015). Asymptomatic course was not associated with age, remission status, therapies or co-morbidities. Secondary bacterial infection accompanied more than one third of critical COVID-19 cases. Treatment was delayed post-SARS-CoV-2 in 46 patients, 9 of whom developed progressive disease (PD). Cancer therapy was modified in 8 SARS-CoV-2 survivors because of deteriorating performance or PD. At the last follow-up, 17 patients had died from COVID-19 (n = 8) or PD (n = 9) giving an estimated 73% four-month overall survival rate. SARS-CoV-2 infection has a heterogenous course in cancer patients. Lymphocytopenia carries a significant risk of severe/critical COVID-19. SARS-CoV-2 disruption of therapy is as serious as SARS-CoV-2 infection itself. Careful surveillance will allow early restart of the anti-cancer treatment.

Impact of pre-OP independence in patients with limited brain metastases on long-term survival.

BACKGROUND: Brain metastasis represents a major complication with a significantly shorter overall survival of many oncological diseases, in particular of lung cancer, breast cancer and malignant melanoma patients. However, despite the poor prognosis, sometimes clinical decision-making, between on the one hand not to harm the patient and on the other hand not withholding a potential therapeutic option, is very challenging. Thus the aim of this retrospective study was to compare various scores, including scores for activities of daily living (ADL) before resection of brain metastases and to analyse their impact on survival. METHODS: Our single institution retrospective patient cohort (N = 100) with a median age of 63.6 years, which had all undergone resection of one or more brain metastases, was categorized using the original patient files. The cohort includes 52 patients with lung cancer, 27 patients with breast cancer, 8 patients with colorectal carcinoma and 13 patients with kidney cancer. To categorize, we used different score systems which were capable to evaluate the patient in relation to self-sufficiency, activity and self-determination as part of ADL. The retrospective analysis includes the ECOG-Status, Karnofsky-Index, Barthel-Index, ASA-Classification and Katz-Index. Pre-processing and the analysis of the data was implemented using KNIME, where we used the R-plugin nodes to perform the final statistical tests with R. RESULTS: Our analysis reveals that most of the ADL scores we tested are able to give a reliable prediction on overall survival after brain metastasis surgery. The survival rates decrease significantly with a lower score in all tested score systems, with the exception of the ASA-Risk score. In particular, the Katz Index < 6 was identified to have a significant correlation with a lower cancer specific survival (CSS) (HR 3.33, 95%-CI [2.17-5.00]; p-Value = 9.6*10- 9), which is easy to use and has reproducible measurements. CONCLUSIONS: Pre-operative independence assessment by indices of ADL represents a predictor for overall survival after resection of brain metastases. Especially the easily, objectively and rapidly applicable Katz-Score is a very helpful tool to assess the pre-operative status, which could be additionally included in clinical decision making in daily practice.

Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy.

AIMS: Phosphatase inhibitor-1 (I-1) is a conditional amplifier of beta-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to beta-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response. METHODS AND RESULTS: We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiac function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause-effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to beta-adrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the beta-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute beta-adrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca(2+) release channel and the sarcoplasmic reticulum (SR) Ca(2+)-ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca(2+) release and Ca(2+) uptake and thus stabilize the SR and account for the protection. CONCLUSION: Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment.

Long-term beta-adrenergic stimulation leads to downregulation of protein phosphatase inhibitor-1 in the heart.

Desensitization of the beta-adrenoceptor/cAMP/PKA pathway is a hallmark of heart failure. Inhibitor-1 (I-1) acts as a conditional amplifier of beta-adrenergic signalling downstream of PKA by inhibiting type-1 phosphatases in the PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus presumably contributes to beta-adrenergic desensitization. To test whether I-1 downregulation is a consequence of excessive adrenergic drive in heart failure, rats were treated via minipumps with isoprenaline 2.4 mg/kg/day (ISO) or 0.9% NaCl for 4 days. As expected, chronic ISO increased heart-to-body weight ratio by approximately 40% and abolished the inotropic response to acute ISO in papillary muscles by approximately 50%. In the ISO-treated hearts I-1 mRNA and protein levels were decreased by 30% and 54%, respectively. This was accompanied by decreased phospholamban phosphorylation (-40%), a downstream target of I-1, and a reduction in 45Ca2+ uptake (-54%) in membrane vesicles. Notably, phospholamban phosphorylation correlated significantly with I-1 protein levels indicating a causal relationship. We conclude that I-1 downregulation in heart failure is likely a consequence of the increased sympathetic adrenergic drive and participates in desensitization of the beta-adrenergic signalling cascade.