Hyperthermia and Tumor Immunity

Thermal ablation is a cornerstone in the management of cancer patients. Typically, ablation procedures are performed for patients with a solitary or oligometastatic disease with the intention of eradicating all sites of the disease. Ablation has traditionally played a less prominent role for patients with a widely metastatic disease. For such patients, attempting to treat numerous sites of disease compounds potential risks without a clear clinical benefit and, as such, a compelling justification for performing an intervention that is unlikely to alter a patient’s clinical trajectory is uncommon. However, the discovery of immune checkpoints and the development of immune checkpoint inhibitors have brought a new perspective to the relevance of local cancer therapies such as ablation for patients with a metastatic disease. It is becoming increasingly apparent that local cancer therapies can have systemic immune effects. Thus, in the new perspective of cancer care centered upon immunologic principles, there is a strong interest in exploring the utility of ablation for patients with a metastatic disease for its immunologic implications. In this review, we summarize the unmet clinical need for adjuvant interventions such as ablation to broaden the impact of systemic immunotherapies. We additionally highlight the extant preclinical and clinical data for the immunogenicity of common thermal ablation modalities.

The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy–VISTA-Endovascular

Background The smoking-paradox of a better outcome in ischemic stroke patients who smoke may be due to increased efficacy of thrombolysis. We investigated the effect of smoking on outcome following endovascular therapy (EVT) with mechanical thrombectomy alone versus in combination with intra-arterial (IA-) thrombolysis. Methods The primary endpoint was defined by three-month modified Rankin Scale (mRS). We performed a generalized linear model and reported relative risks (RR) for smoking (adjustment for age, sex, hypertension, atrial fibrillation, stroke severity, time to EVT) in patient data stemming from the Virtual International Stroke Trials Archive—Endovascular database. Results Among 1,497 patients, 740(49.4%) were randomized to EVT; among EVT patients, 524(35.0%) received mechanical thrombectomy alone and 216(14.4%) received it in combination with IA-thrombolysis. Smokers (N = 396) had lower mRS scores (mean 2.9 vs. 3.2; p = 0.02) and mortality rates (10% vs. 17.3%; p<0.001) in univariate analysis. In all patients and in patients treated with mechanical thrombectomy alone, smoking had no effect on outcome in regression analyses. In patients who received IA-thrombolysis (N = 216;14%), smoking had an adjusted RR of 1.65 for an mRS≤1 (95%CI 0.77–3.55). Treatment with IA-thrombolysis itself led to reduced RR for favorable outcome (adjusted RR 0.30); interaction analysis of IA-thrombolysis and smoking revealed that non-smokers with IA-thrombolysis had mRS≤2 in 47 cases (30%, adjusted RR 0.53 [0.41–0.69]) while smokers with IA-thrombolysis had mRS≤2 in 23 cases (38%, adjusted RR 0.61 [0.42–0.87]). Conclusions Smokers had no clear clinical benefit from EVT that incorporates IA-thrombolysis.

Updated Insights on EGFR Signaling Pathways in Glioma

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood–brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.

Unexpected Response to Nivolumab in a “Fast Progressor” Head and Neck Cancer Patient

Prior to the advent of immune checkpoint inhibitors targeting PD-1/PD-L1 axis no drug demonstrated to improve survival or quality of life in the second-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC). Nivolumab appear to have a clear clinical benefit for R/M-HNSCC, based on improved survival, good toxicity profile, reduction in symptoms and improvement in overall quality of life. This benefit seems to be greater for PD-L1 positive patients and independent of previous treatment, even being observed among heavily pre-treated patients. However, even in responding tumors acquired resistance to nivolumab usually occurred, limiting the drug’s activity. We report a case of unexpected prolonged stable disease in second-line treatment with nivolumab after a rapid progression disease under first-line chemotherapy in biomarker-positive R/M-HNSCC.

Sleep, inflammation, and disease

Sleep is a fundamental requirement for living individuals. Sleep disturbances and sleep disorders have extensive effects on the immune system, affecting one’s susceptibility to, and ability to fight off, infections—both bacterial and viral—and the subsequent development of different diseases. This is mediated by the increase in pro-inflammatory cytokines associated with sleep loss and disruption. A number of common conditions, such as obesity, cardiovascular disease, metabolic syndrome, obstructive sleep apnoea syndrome, rheumatoid arthritis, and systemic lupus erythematosus, all share pro-inflammatory mechanisms and the presence of sleep disturbances. Early identification of sleep disorders, and the associated adverse inflammatory and metabolic risk factors, in affected individuals would have a clear clinical benefit.

Unnecessary Transfers for Acute Surgical Care: Who and Why?

Interhospital transfers for acute surgical care occur commonly, but without clear guidelines or protocols. Transfers may subject patients and delivery systems to significant burdens without clear clinical benefit. The incidence and factors associated with unnecessary transfers are not well described. We conducted a retrospective cohort study of patient transfers within a regional referral network to a tertiary center for nontrauma acute surgical care from 2009 to 2013. Clinically unnecessary transfers were defined as transfers that resulted in no intervention (operation, endoscopy, or interventional radiology procedure) and discharge to home within 72 hours. We performed bivariate and multivariate logistic regression analyses. The study population included 2177 patient transfers, 19 per cent of which were determined to be clinically unnecessary. After adjustment, clinically unnecessary transfers were more commonly performed for patient request (odds ratio = 2.52, 95% confidence interval = 1.60–3.99), continuity of care (1.87, 1.44–2.42), and care by urologic (1.50, 1.06–2.13) and vascular services (1.44, 1.03–2.01). Patients with higher comorbidity and severity of illness scores were less likely to have unnecessary transfers. The burden of unnecessary transfers could be mitigated by identifying appropriate transfer candidates through mutually developed guidelines, interfacility collaboration, and increased use of remote care to provide surgical subspecialty consultation and maintain continuity.

What makes a good biomarker?

The last decade has seen an extraordinary amount of effort devoted in biomedical research to the field of biomarkers. There have been some notable successes with novel markers being adopted into clinical practice bringing clear clinical benefit to some patients — particularly with the increasing numbers of medicines being approved with companion diagnostics. However, it is fair to say that there has not yet been the numbers of clinically valuable biomarkers brought to medical practice that the research effort would seem to warrant. This paper evaluates examples of successful biomarkers, markers which might be considered partial successes and a few problematic examples and ar-gues that more effort spent in the validation phase of marker development, and less in the discovery phase might be a more efficient way to allocate research resources.