Implementation of perioperative FLOT compared to ECX/EOX chemotherapy regimens in resectable esophagogastric adenocarcinomas: an analysis of real-world data.

BACKGROUND AND PURPOSE: Perioperative 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) is recommended in resectable esophagogastric adenocarcinoma based on randomised trials. However, the effectiveness of FLOT in routine clinical practice remains unknown as randomised trials are subject to selection bias limiting their generalisability. The aim of this study was to evaluate the implementation of FLOT in real-world patients. METHODS: Retrospectively collected data were analysed in consecutive patients treated before or after the implementation of FLOT. The primary endpoint was complete pathological response (pCR) and secondary endpoints were margin-free resection (R0), overall survival (OS), relapse-free survival (RFS) tolerability of chemotherapy and surgical complications. RESULTS: Mean follow-up time for patients treated with FLOT (n = 205) was 37.7 versus 47.0 months for epirubicin, cis- or oxaliplatin, and capecitabine (ECX/EOX, n = 186). Surgical resection was performed in 88.0% versus 92.0%; pCR were observed in 3.8% versus 2.4%; and R0 resections were achieved in 78.0% versus 86.0% (p = 0.03) in the ECX/EOX and FLOT cohorts, respectively. Survival analysis indicated no significant difference in RFS (p = 0.17) or OS (p = 0.37) between the cohorts with a trend towards increased OS in performance status 0 (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.50-1.04). More patients treated with ECX/EOX completed chemotherapy (39% vs. 28%, p = 0.02). Febrile neutropenia was more common in the FLOT cohort (3.8% vs. 11%, p = 0.0086). 90-days mortality (1.2% vs. 0%) and frequency of anastomotic leakage (8% vs. 6%) were equal and low. INTERPRETATION: Patients receiving FLOT did not demonstrate improved pCR, RFS or OS. However, R0 rate was improved and patients in good PS trended towards improved OS.

Innate immune function during antineoplastic treatment is associated with 12-months survival in non-small cell lung cancer.

Introduction: The immune system has proven to be a key player in the progression as well as containment of cancer with new treatment strategies based on immunotherapy targeting this interaction. Assessing immune function could reveal critical information about the immune response to therapeutic interventions, revealing predictive biomarkers for tailored care and precision medicine. Methods: We investigated immune function in 37 patients with inoperable non-small cell lung cancer (NSCLC) undergoing treatment with PD-L1 immune checkpoint inhibitor (ICI), chemotherapy (CT) or chemo-radiotherapy (CT/RT). Blood samples before (day 0) and during therapy (day 7, 21 and 80) were investigated by a standardized immunoassay, TruCulture®. Results: Outcomes revealed a developing innate immune response induced by both immunotherapy and chemotherapy. NSCLC-patients displayed evidence of chronic innate immune activation and exhaustion prior to treatment. This pattern was particularly pronounced during treatment in patients dying within 12-months follow-up. Compared to treatment with CT, ICI demonstrated a higher ex vivo-stimulated release of proinflammatory cytokines. Discussion: These preliminary findings may pave the way for tailored treatment and immune-monitoring.

[Circulating tumour DNA in the treatment of cancer].

Circulating tumour DNA analysis has a potential to improve multiple aspects of cancer management. This includes: a) early cancer detection in asymptomatic individuals, b) identification of patients with residual disease after curative intended treatment, c) patient stratification in relation to treatment decisions like adjuvant therapy and intensity of radiological surveillance, d) monitoring treatment effect for optimised adaptive therapy, e) identification of actionable targets, and f) early recurrence detection. These points are summarised in this review.

HER2 Positivity in Histological Subtypes of Salivary Gland Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: HER2 aberrations in salivary gland carcinomas (SGC) as well as benefit of HER2 directed therapy have been reported in small studies. However, reliable estimates of the prevalence of HER2 positivity in SGC and its various histological subtypes are lacking. OBJECTIVE: To assess the prevalence of HER2 positivity in histological subtypes of salivary gland carcinomas (SGC). METHODS: Studies were identified by a systematic review of the literature. Data on in situ hybridization (ISH) and immunohistochemistry (IHC) were extracted to derive pooled prevalence estimates calculated by a random effects model. Characteristics of the studies were extracted for subgroup analysis. RESULTS: Fifty studies including 3372 patients were identified, providing data on sixteen histological subtypes. Based on the meta-analysis, the estimated prevalence of HER2 positivity were 43% (95% CI: 36% - 51%) in salivary duct carcinoma (SDC), 39% (95% CI: 32% - 45%) in carcinoma ex pleomorphic adenoma (CEP), 17% (95% CI: 7.5% - 33%) in squamous cell carcinoma (SCC), 13% (95% CI: 7.6% - 21%) in adenocarcinoma NOS (ADC), 6.7% (95% CI: 0.17%-32%) in poorly differentiated carcinoma, 5.5% (95% CI: 2.9% - 9.6%) in mucoepidermoid carcinoma, 4.3% (95% CI: 1.4% - 13%) in myoepithelial carcinoma, 1.8% (95% CI: 0.04%-9.6%) in epithelial-myoepithelial carcinoma, 0.45% (95% CI: 0.0097% - 18%) in acinic cell carcinoma and 0.15% (0.037% - 5.4%) in adenoid cystic carcinoma. Estimates for five additional subtypes were assessed. CONCLUSION: Prevalence of HER 2 positivity in SGC varies greatly based on histological subtype, with SDC, CEP, SCC, and ADC displaying the highest rates.

Prevalence of HER2 overexpression and amplification in squamous cell carcinoma of the esophagus: A systematic review and meta-analysis.

Accurate data on HER2 positivity in esophageal squamous cell carcinoma patients (ESCC) is lacking. We conducted a systematic review and meta-analysis (Single Incidence Rates; metarate package, R) to examine the prevalence of HER2 in ESCC. Data on in situ hybridization (ISH) and immunohistochemistry (IHC) were extracted to derive pooled prevalence estimates, characteristics of the studies were extracted for subgroup analysis. Eighteen studies with 1505 patients were identified. HER2 gene amplification by ISH were prevalent in 10 % (95 % CI 6.9 %-15 %). Prevalence of HER2 overexpression (IHC3+) and borderline HER2 expression (IHC2+) were 6 % (95 % CI: 3.5 %-8.7 %) and 10 % (95 % CI: 6.0 %-17 %), respectively. An estimated 8.6 % (95 % CI: 5.5 %-13 %) of ESCC were HER2 positive using initial IHC followed by reflex ISH confirmation of borderline HER2 expression. In conclusion: Estimated prevalence of HER 2 positivity in ESCC were 10 % assessed by ISH and 8.6 % assessed by initial IHC followed by ISH.

Mortality and cardiovascular morbidity among patients diagnosed with Takayasu's arteritis: a Danish nationwide cohort study.

OBJECTIVES: To assess the long-term mortality and risk of cardiovascular events (CVE) among Danish patients with Takayasu's arteritis (TAK). METHODS: Administrative registers with nationwide coverage were used to identify patients diagnosed with TAK in Denmark during 1994-2014 and construct an age- and gender-matched cohort of population-controls. CVE were identified by means of hospital discharge diagnoses and categorised as major or minor, based on severity. Cox regression analyses were used to calculate hazard ratios (HRs) for death and first-time hospitalisations for CVE as a measure of relative risk. RESULTS: 79 patients with TAK were identified, corresponding to an incidence rate of 0.7 (95% confidence interval (CI): 0.6-0.9)/million/year. Median duration of follow-up in the TAK cohort was 6.4 (IQR: 3.7-11) years. Mortality was significantly higher among the TAK patients than among the population controls during the first 3 years of follow-up [HR for death: 8.0 (95% CI: 3.0-21)], but not after >3 years [HR for death: 0.5 (95% CI: 0.1-3.5)]. Risk of CVE was significantly increased among TAK patients after ≤3 years [HR for major CVE: 12 (95% CI: 3.8-37), HR for minor CVE: 19 (95% CI: 7.5-50)] as well as after >3 years [HR for major CVE: 7.6 (95% CI: 2.8-21), HR for minor CVE: 3.0 (95% CI: 1.01-9.0)]. CONCLUSIONS: Compared to the general population, patients with TAK experience markedly increased mortality during early follow-up periods. The long-term risk of CVE is high among patients affected by the disease.

Role of age, Rho-kinase 2 expression, and G protein-mediated signaling in the myogenic response in mouse small mesenteric arteries.

The myogenic response (MR) and myogenic tone (MT) in resistance vessels is crucial for maintaining peripheral vascular resistance and blood flow autoregulation. Development of MT involves G protein-coupled receptors, and may be affected by aging. AIMS: (1) to estimate the mesenteric blood flow in myogenically active small mesenteric arteries; (2) to investigate the signaling from Gαq/11 and/or Gα12 activation to MT development; (3) to investigate the role of Rho-kinase 2 and aging on MT in mesenteric resistance arteries. METHODS: we used pressure myography, quantitative real-time PCR, and immunolocalization to study small (<200 µm) mesenteric arteries (SMA) from young, mature adult, and middle aged mice. RESULTS: Poiseuille flow calculations indicated autoregulation of blood flow at 60-120 mm Hg arterial pressure. Gαq/11 and Gα12 were abundantly expressed at the mRNA and protein levels in SMA. The Gαq/11 inhibitor YM-254890 suppressed MT development, and the Phosholipase C inhibitors U73122 and ET-18-OCH3 robustly inhibited it. We found an age-dependent increase in ROCK2 mRNA expression, and in basal MT. The specific ROCK2 inhibitor KD025 robustly inhibited MT in SMAs in all mice with an age-dependent variation in KD025 sensitivity. The inhibitory effect of KD025 was not prevented by the L-type Ca2+ channel activator BayK 8644. KD025 reversibly inhibited MT and endothelin-1 vasoconstriction in small pial arteries from Göttingen minipigs. CONCLUSIONS: MT development in SMAs occurs through a Gαq/11 /PLC/Ca2+ -dependent pathway, and is maintained via ROCK2-mediated Ca2+ sensitization. Increased MT at mature adulthood can be explained by increased ROCK2 expression/activity.