Encephalitis is a severe immune-related adverse event secondary to treatment with immune checkpoint inhibitors (ICIs). The spectrum of ICI-induced encephalitis (ICI-iE) ranges from disease that ...resolves fully to lethal forms. Moreover, ICIs may unmask a paraneoplastic encephalitis. To our knowledge, the factors associated with ICI-iE prognosis are unknown.
To evaluate the presentation of ICI-iE and to identify features helpful in assessing outcomes.
This systematic review pooled case series from the published literature (n = 77) and medical records from 1 center (n = 5) to assess the association between the form of ICI-iE presentation and its prognosis. Eligibility criteria included references identified by searches of PubMed and Web of Knowledge databases in the English literature from June 2000 (first patient dose of ipilimumab) to April 17, 2020, that examined patients with encephalitis with presumed autoimmune etiologic features induced by ICIs. Information regarding clinical, cerebrospinal fluid, and neuroimaging (magnetic resonance imaging) features, as well as treatment given, were extracted.
A total of 82 patients (52 men 63%; median age, 61.0 years interquartile range, 52.5-70.0 years) were included. Most patients presented with focal syndromes (39 48%) or meningoencephalitis (36 44%). Seven patients (9%) had nonclassifiable ICI-iE. Neuronal autoantibodies were detected in 23 patients with focal syndromes and 1 patient with nonclassifiable ICI-iE. Most autoantibodies were onconeuronal (17 of 24 71%), targeting intracellular antigens. Patients without a focal syndrome or with a negative-antibody focal syndrome had a good prognosis (49 of 55 89%). Among patients with autoantibodies, those with anti-glutamic acid decarboxylase or anticell surface responded to treatment and had a favorable prognosis (100%). However, patients with other autoantibodies had poor outcomes (17 of 24 71%). Antineuronal autoantibodies (13 of 24 54% vs 5 of 41 12%; P < .001), focal syndrome (16 of 39 41% vs 4 of 43 9%; P = .001), and abnormal magnetic resonance imaging findings (14 of 39 36% vs 4 of 32 13%; P = .02) were associated with poor outcomes. Conversely, fever (21 of 23 91% vs 41 of 59 70%; P = .04) and more inflammatory changes in cerebrospinal fluid (30 of 31 97% vs 21 of 33 64%; P = .001) were associated with a better prognosis.
Immune checkpoint inhibitors may induce mainly 2 different encephalitic syndromes: a focal limbic or extralimbic encephalitis and a meningoencephalitis. Immune checkpoint inhibitor-induced encephalitis is associated with an overall favorable outcome, with a low rate of fatal events. An undetected preexisting paraneoplastic encephalitic syndrome may be triggered by ICIs, and this type of syndrome has the worst outcome among all the different types of ICI-induced encephalitis syndromes. Clinical presentation and systematic measurement of autoantibodies will be a helpful guide for the therapeutic strategy and for counseling regarding prognosis.
Highlights • In the era of targeted treatments, chemotherapy remains the backbone for treatment of breast cancer being an option for all molecular subtypes of the disease. This review is intended to: ...• Give a practical guideline for treating women with metastatic breast cancer (MBC) helping clinicians to make evidence based decisions following treatment with an anthracycline and a taxane. • Provide an update on cytotoxic drugs recently evaluated in late line MBC. • Identify priorities in the development of new cytotoxics for women with MBC.
•Interstitial lung disease (ILD) is potentially life-threatening event related with crizotinib.•Incidence of crizotinib-related ILD was 1.2% and predisposing factors are unknown.•Crizotinib ...rechallenge should be considered only in mild cases of ILD.•Switching treatment to other ALK inhibitors was reported without ILD recurrence.
We present a 45-year-old patient diagnosed with anaplastic lymphoma kinase (ALK)-rearranged metastatic lung cancer who developed grade 4 interstitial lung disease (ILD) while on crizotinib treatment and was lately treated with brigatinib with no reappearance of ILD. To our knowledge, this is the first case report of successful treatment with brigatinib after crizotinib-induced ILD. Even though ILD secondary to brigatinib has been reported in clinical trials, no pulmonary toxicity has been seen in our patient, suggesting no crosslink lung toxicity between crizotinib and brigatinib.
Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its ...somatic molecular profile is unknown.
Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants.
Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation.
Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.
•Pharmacokinetic resistance is a consequence of a drug not being delivered at sufficient concentration to, or with adequate distribution in, a tumour.•Drug distribution and penetration through ...tumours and normal tissues may influence selection of the optimal candidate(s) during drug development as well as affecting the preferred dose and schedule of drug administration in clinical practice.•MALDI-MSI is a technique for imaging the distribution of anti-cancer drugs and their metabolites within tumours that can be used in drug development to: characterize drug distribution within the body to identify anticipated toxicities or target organs; define drug distribution within the tumour and its relationship with the tumour microenvironment and drug targets; select the best drug candidate, dose, schedule or combinations based on tumour pharmacokinetic profile; facilitate proof-of-concept studies for new drug delivery systems.
Failure of systemic cancer treatment can be, at least in part, due to the drug not being delivered to the tumour at sufficiently high concentration and/or sufficiently homogeneous distribution; this is termed as “pharmacokinetic drug resistance”. To understand whether a drug is being adequately delivered to the tumour, “precision pharmacology” techniques are needed. Mass spectrometry imaging (MSI) is a relatively new and complex technique that allows imaging of drug distribution within tissues. In this review we address the applicability of MSI to the study of cancer drug distribution from the bench to the bedside. We address: (i) the role of MSI in pre-clinical studies to characterize anti-cancer drug distribution within the body and the tumour, (ii) the application of MSI in pre-clinical studies to define optimal drug dose or schedule, combinations or new drug delivery systems, and finally (iii) the emerging role of MSI in clinical research.
Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense ...temozolomide (DIT) was evaluated in patients with first recurrence of GBM.
Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored.
The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK.
With personalised dosing, nabiximols had acceptable safety and tolerability with no drug-drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial.
ClinicalTrials.gov: Part 1- NCT01812603; Part 2- NCT01812616.
Abstract
Background and Aims
Acute tubulointerstitial nephritis (ATIN) diagnostic lays on the kidney biopsy given the absence of non-invasive biomarkers for disease demonstration and follow-up. The ...aim of this study was to evaluate the accuracy of ten urinary inflammatory-related cytokines in the diagnostic of ATIN and its clinical distinction from acute tubular necrosis (ATN).
Method
Observational prospective study including 21 ATIN and 12 ATN patients, and 6 healthy controls. We determined the urinary levels of 10 inflammation-related cytokines using a multiplex bead-based Luminex assay. We registered clinical, analytical and histological data from the medical records.
Results
Urinary levels of I-TAC/CXCL11, CXCL10, IL-6, TNFα and MCP-1 were higher in ATIN compared to healthy controls. In contrast, healthy controls exhibited higher EGF urinary levels compared to ATIN patients. Follow-up samples available from 11/21 ATIN patients showed a significant decrease in I-TAC/CXCL11, MIG/CXCL9 and CXCL10 levels. Urinary levels of I-TAC/CXCL11, IL-6 and MCP-1 were significantly higher in ATIN compared to ATN patients, with I-TAC/CXCL11 as the best discriminatory biomarker based on its higher AUC in the ROC curve and likelihood ratio. The combinatory model of the three cytokines increased the sensitivity of the individual biomarkers in the distinction of ATIN/ATN but the best results were obtained when blood eosinophil count and leukocyturia were added to the model. We found a positive correlation of the extent of the tubulointerstitial infiltrate in kidney biopsies with the urinary concentration of I-TAC/CXCL11, MIG/CXCL9, CXCL10, IL17, IFNα, MCP1 and EGF, indicating the potential renal source of the cytokines
Conclusion
the higher cytokine levels in ATIN compared to ATN patients and healthy controls, the significant decline after treatment and the positive correlation of the cytokines with the grade of the inflammatory infiltrate allows us to propose I-TAC/CXCL11, CXCL10, IL6 and MCP-1 as candidate biomarkers in this disease.
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