Carrying on with life as a lung cancer survivor: a qualitative study of Australian survivors' employment, finances, relationships, and healthcare experiences.

Background: With novel therapies, more individuals are living longer with lung cancer (LC). This study aimed to understand the impacts of LC on life domains such as employment, finances, relationships, and healthcare needs. Methods: Individuals 18+, diagnosed with LC, 6-24 months post-treatment were recruited through an Australian LC cohort study (Embedding Research and Evidence in Cancer Healthcare-EnRICH). Demographic, clinical, quality-of-life and distress data were obtained through the EnRICH study database. Participants completed telephone interviews. Qualitative data were analysed via Framework methods. Results: Twenty interviews (10 females) were conducted. Most participants were diagnosed with advanced LC (Stage III =8, Stage IV =6), and were on average 17 (range, 10-24) months post-diagnosis. Four themes related to "carrying on with life" as a LC survivor were identified: (I) the winding path back to work: those working pre-diagnosis discussed challenges of maintaining/returning to employment, and the meaning and satisfaction derived from work. (II) Vulnerability versus protection: managing the financial impacts of LC: wide variations in financial impacts, some described lost income and high healthcare expenses, others felt financially protected. (III) Connection and loneliness: navigating relationships as a survivor: some experienced lost friendships due to their diagnosis, others noted more meaningful connections. (IV) Still under the umbrella: healthcare during survivorship: participants noted the importance of ongoing oncology team connection and the vital role of cancer care coordinators. Conclusions: Many individuals living with LC want to "carry on" with life. Participants spoke of challenges and opportunities across life domains of relationships, work, and finances, and noted the importance of continued specialist healthcare throughout survivorship.

Application of a revised model for coping with advanced cancer to qualitatively explore lung cancer survivors' experiences of ongoing physical effects, novel treatments, uncertainty, and coping.

PURPOSE: Lung cancer remains underrepresented in cancer survivorship research. This study aimed to understand survivors' physical/psychological challenges, experiences of immunotherapy (IO) and targeted therapy (TT), and psychological adjustment through application of the Roberts et al. (2017) advanced cancer adaptation of Folkman and Greer's appraisal and coping model. METHODS: Adults 6-24 months post-initial treatment completion were recruited via an Australian cohort study. Participant demographic, clinical, quality of life, and distress data were obtained through the cohort database. Qualitative interviews were conducted and analyzed using Framework methods. Roberts et al. (2017)'s model informed data interpretation and presentation. RESULTS: Twenty interviews were conducted (10 females; average age 69 years). Participants' diagnostic stages varied (stage I = 2, stage II = 4, stage III = 8, stage IV = 6); most had received IO/TT (n = 14) and were on average 17 months (range 10-24) post-diagnosis. Three themes were identified and mapped to the Roberts' framework: (1) Ongoing illness events: most participants reported functioning well despite ongoing physical effects. Those on IO/TT reported side effects; some were unexpected/serious. (2) Adjusting to life with lung cancer: most expressed hope for the future while simultaneously preparing for disease progression. Those receiving IO/TT experienced uncertainty given limited survival information. (3) Learning to live with lung cancer: participants described emotion, problem, and meaning based on coping strategies. CONCLUSIONS: Findings may guide development of supportive care resources/interventions focused on uncertainty, IO/TT communication and decision-making, and coping. IMPLICATIONS FOR CANCER SURVIVORS: Many people with lung cancer are living well with their ongoing illness. Despite challenges, many survivors are adapting to issues as they arise and are maintaining a sense of hope and optimism.

Clostridium perfringens type D epsilon toxin produces a rapid and dose-dependent cytotoxic effect on cerebral microvascular endothelial cells in vitro.

Clostridium perfringens type D epsilon toxin (ETX) is responsible for a severe and frequently fatal neurologic disorder in ruminant livestock. Light microscopic, immunohistochemical, and ultrastructural studies have suggested that ETX injury to the cerebral microvasculature, with subsequent severe, generalized vasogenic edema and increased intracranial pressure, is critically important in producing neurologic dysfunction. However, the effect of ETX on brain capillary endothelial cells in vitro has not been examined previously, to our knowledge. We exposed a well-characterized human blood-brain barrier cell line to increasing concentrations of ETX, and demonstrated a direct and dose-dependent endotheliotoxic effect. Our findings are concordant with the primacy of vasculocentric brain lesions in the diagnosis of acute epsilon toxin enterotoxemia in ruminant livestock.

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation.

BACKGROUND: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. MAIN BODY: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. CONCLUSIONS: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.

Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction.

Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity.

Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity.

Regimen-related toxicities remain a priority concern within the field of supportive care in cancer. Despite this, many forms of toxicity are under reported and consequently poorly characterised. Although there have been significant improvements in our understanding of regimen-related toxicities, symptom management continues to occur independently raising concerns such as drug interactions and the tendency to emphasise management of a single symptom at the expense of others. This review focuses on two important toxicities induced by chemotherapy; neuropathy/pain and gastrointestinal toxicity, introducing the Toll-like receptor (TLR) 4 pathway as a common component of their pathobiology. Given the global observation of toxicity clusters, identification of a common initiating factor provides an excellent opportunity to simultaneously target multiple side effects of anticancer treatment. Furthermore, identification of common biological underpinnings could perhaps reduce polypharmacy and have pharmacoeconomic benefits.

Advancing drug therapy for brain tumours: a current review of the pro-inflammatory peptide Substance P and its antagonists as anti-cancer agents.

Evidence for the involvement of the Substance P (SP)/NK1 receptor system in the development and progression of cancer strongly supports its potential as a therapeutic target in malignancies. Novel strategies for approaching cancer treatment are urgently required particularly with regard to tumours of the central nervous system (CNS), which are notoriously difficult to effectively treat and associated with extremely poor prognosis for many patients. This is due, in part, to the presence of the highly specialised blood-brain barrier, which is known to restrict common treatments such as chemotherapy and hinder early tumour diagnosis. Additionally, tumours of the CNS are difficult to surgically resect completely, often contributing to the resurgence of the disease many years later. Interestingly, despite the presence of the blood-brain barrier, circulating tumour cells are able to gain entry to the brain and form secondary brain tumours; however, the underlying mechanisms of this process remain unclear. Tachykinins, in particular Substance P, have been implicated in early blood-brain barrier disruption via neurogenic inflammation in a number of other CNS pathologies. Recent evidence also suggests that Substance P may play a central role in the development of CNS tumours. It has been well established that a number of tumour cells express Substance P, NK1 receptors and mRNA for the tachykinin NK1 receptor. This increase in the Substance P/NK1 receptor system is known to induce proliferation and migration of tumour cells as well as stimulate angiogenesis, thus contributing to tumour progression. Accordingly, the NK1 receptor antagonist presents a novel target for anti-cancer therapy for which a number of patents have been filed. This review will examine the role of Substance P in the development of CNS tumours and its potential application as an anti-cancer agent.