The stress-activated protein kinases (SAPKs), which are distantly related to the MAP kinases, are the dominant c-Jun amino-terminal protein kinases activated in response to a variety of cellular stresses, including treatment with tumour-necrosis factor-alpha and interleukin-beta (refs 1, 2). SAPK phosphorylation of c-Jun probably activates the c-Jun transactivation function. SAPKs are part of a signal transduction cascade related to, but distinct from, the MAPK pathway. We have now identified a novel protein kinase, called SAPK/ERK kinase-1 (SEK1), which is structurally related to the MAP kinase kinases (MEKs). SEK1 is a potent activator of the SAPKs in vitro and in vivo. An inactive SEK1 mutant blocks SAPK activation by extracellular stimuli without interfering with the MAPK pathway. Although alternative mechanisms of SAPK activation may exist, as an immediate upstream activator of the SAPKs, SEK1 further defines a signalling cascade that couples cellular stress agonists to the c-Jun transcription factor.

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For patients with oligometastatic NSCLC, chemotherapy followed by consolidative radiation therapy without maintenance chemotherapy was associated with encouraging long-term outcomes.

BackgroundTo determine the clinical benefits of systemic targeted agents across multiple histologies after stereotactic radiosurgery (SRS) for brain metastases.MethodsBetween 2000 and 2013, 737 patients underwent upfront SRS for brain metastases. Patients were stratified by whether or not they received targeted agents with SRS. 167 (23%) received targeted agents compared to 570 (77%) that received other available treatment options. Time to event data were summarized using Kaplan-Meier plots, and the log rank test was used to determine statistical differences between groups.ResultsPatients who received SRS with targeted agents vs those that did not had improved overall survival (65% vs. 30% at 12 months, p < 0.0001), improved freedom from local failure (94% vs 90% at 12 months, p = 0.06), improved distant failure-free survival (32% vs. 18% at 12 months, p = 0.0001) and improved freedom from whole brain radiation (88% vs. 77% at 12 months, p = 0.03). Improvement in freedom from local failure was driven by improvements seen in breast cancer (100% vs 92% at 12 months, p < 0.01), and renal cell cancer (100% vs 88%, p = 0.04). Multivariate analysis revealed that use of targeted agents improved all cause mortality (HR = 0.6, p < 0.0001).ConclusionsTargeted agent use with SRS appears to improve survival and intracranial outcomes.

Aims-To investigate and characterise the appearance of non-transferrin bound iron (NTBI) in the serum ofpatients after cytotoxic chemotherapy and to compare this with the onset and duration of neutropenia. Method-Non-transferrin bound iron was measured by a bleomycin assay in patients undergoing intensive chemotherapy for treatment of acute leukaemia or lymphoma. Results-NTBI was detected after 26 of 27 courses of chemotherapy and lasted for a mean of 14-5 days. The presence of NTBI correlated with the serum iron binding saturation, but not with serum ferritin. Neutropenia occurred after all courses of chemotherapy and lasted for a mean of 20-0 days. NTBI and neutropenia occurred concurrently after 23 courses of chemotherapy, and had a mean joint duration of 9'5 days. Conclusions-NTBI is consistently present in the serum of patients after cytotoxic chemotherapy, often at the same time as the patient is neutropenic. This may be an additional risk factor for the development of infective episodes after chemotherapy.

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Background The effect of immunotherapy on brain metastasis patients remains incompletely understood. Our goal was to evaluate its effect on survival, neurologic death, and patterns of failure after stereotactic radiosurgery (SRS) without prior whole-brain radiation therapy (WBRT) in patients with lung and melanoma primaries metastatic to the brain. Methods We performed a retrospective analysis of 271 consecutive lung or melanoma patients treated with upfront SRS for brain metastases between 2013 and 2018. Of these patients, 101 (37%) received immunotherapy and 170 (63%) did not. Forty-three percent were treated with nivolumab. Thirty-seven percent were treated with pembrolizumab. Fifteen percent were treated with ipilimumab. One percent were treated with a combination of nivolumab and ipilimumab. One percent were treated with atezolizumab. Three percent were treated with another immunotherapy regimen. Survival was estimated by the Kaplan–Meier method and cumulative incidences of neurologic death, and local and distant brain failure were estimated using death as a competing risk. Results The median overall survival (OS) of patients treated with immunotherapy vs without was 15.9 (95% CI: 13.3 to 24.8) vs 6.1 (95% CI: 5.1 to 8.8) months (P < .01). The 1-year cumulative incidence of neurologic death was 9% in patients treated with immunotherapy vs 23% in those treated without (P = .01), while nonneurologic death was not significantly different (29% vs 41%, P = .51). Median brain metastasis velocity (BMV) did not differ between groups, and rates of salvage SRS and WBRT were similar. Conclusions The use of immunotherapy in patients with lung cancer or melanoma metastatic to the brain treated with SRS is associated with improved OS and decreased incidence of neurologic death.