Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

Purpose The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). Methods In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). Results Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. Conclusions No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation

Intracavitary brachytherapy with additional Heyman capsules in the treatment of cervical cancer.

PURPOSE: Brachytherapy is a mandatory component of primary radiochemotherapy in cervical cancer. The dose can be applied with a traditional intracavitary approach (IC alone) or with multiple catheter brachytherapy to optimize dose distribution in an individual concept. We therefore evaluated whether the utilization of a tandem-ring applicator plus additional intracavitary applicators (add IC) provides an advantage over the traditional IC alone approach, as this method is less time consuming and less invasive compared to a combined intracavitary/interstitial brachytherapy. METHODS: Twenty three procedures of intracavitary brachytherapy for cervical cancer with additional intracavitary applicators performed in seven patients treated between 2016 and 2018 in our institution were included in this study. Plans were optimized for D90 HR-CTV with and without the utilization of the additional applicators and compared by statistical analysis. RESULTS: D90 for HR-CTV was 5.71 Gy (±1.17 Gy) for fractions optimized with add IC approach and 5.29 Gy (±1.24 Gy) for fractions without additional applicators (p < 0.01). This translates to a calculated mean EQD2 HR-CTV D90 of 80.72 Gy (±8.34 Gy) compared to 77.84 Gy (±8.49 Gy) after external beam therapy and four fractions of brachytherapy for add IC and IC alone, respectively (p < 0.01). The predictive value of improved coverage of HR-CTV in the first fraction was high. CONCLUSION: In a subgroup of cases, the addition of intracavitary Heyman capsules can be an alternative to interstitial brachytherapy to improve the plan quality compared to standard IC alone brachytherapy. The benefit from the addition of applicators in the first fraction is predictive for the following fractions

Circulating microRNAs as prognostic therapy biomarkers in head and neck cancer patients.

BACKGROUND: The prediction of therapy response in head and neck squamous cell cancer (HNSCC) requires biomarkers, which are also a prerequisite for personalised therapy concepts. The current study aimed to identify therapy-responsive microRNAs (miRNAs) in the circulation that can serve as minimally invasive prognostic markers for HNSCC patients undergoing radiotherapy. METHODS: We screened plasma miRNAs in a discovery cohort of HNSCC patients before therapy and after treatment. We further compared the plasma miRNAs of the patients to age- and sex-matched healthy controls. All miRNAs identified as biomarker candidates were then confirmed in an independent validation cohort of HNSCC patients and tested for correlation with the clinical outcome. RESULTS: We identified a signature of eight plasma miRNAs that differentiated significantly (P=0.003) between HNSCC patients and healthy donors. MiR-186-5p demonstrated the highest sensitivity and specificity to classify HNSCC patients and healthy individuals. All therapy-responsive and patient-specific miRNAs in plasma were also detectable in tumour tissues derived from the same patients. High expression of miR-142-3p, miR-186-5p, miR-195-5p, miR-374b-5p and miR-574-3p in the plasma correlated with worse prognosis. CONCLUSIONS: Circulating miR-142-3p, miR-186-5p, miR-195-5p, miR-374b-5p and miR-574-3p represent the most promising markers for prognosis and therapy monitoring in the plasma of HNSCC patients. We found strong evidence that the circulating therapy-responsive miRNAs are tumour related and were able to validate them in an independent cohort of HNSCC patients

Fanconi anemia, complementation group A (FancA) overexpression confers radioresistance to oral keratinocytes.

Head and neck squamous cell carcinoma (HNSCC) is worldwide the 6th most frequent cancer and affects more than 550,000 individuals per year. Standard treatments include surgery, chemotherapy, radiotherapy, and molecular target regimes addressing the EGF receptor. Despite current developments, the radioresistance of tumours remains a main issue that causes therapy failure. Therefore, the identification of molecular markers that predict the radiation response of HNSCC could improve therapy by the enforcement of personalized therapy approaches. DNA gains on chromosome 16q23-24 have been shown to correlate with reduced progression-free survival after radiotherapy in HNSCC (Bauer et al., 2008). Located on chromosome 16q24.3, FancA has been proposed as a potential biomarker for the radiation response. To clarify the effect of FancA overexpression in vitro, FancA overexpressing keratinocytes were generated and characterized for their radiation response. FancA overexpressing cells demonstrated an enhanced clonogenic survival compared to the vector control (OKF6/vec) and the parental cell line (OKF6/TERT1) in response to gamma-irradiation, proving a radioprotective mechanism of FancA.   To identify key players and pathways involved in FancA mediated radioresistance, microarray based global transcriptome analysis was performed on OKF6/FancA and OKF6/vec cells at 15 min, 2 h and 4 h after treatment with 4 Gy of gamma-irradiation or sham-irradiation (0 Gy). To analyse the effects of the FancA overexpression alone, OKF6/TERT1 cells were also subjected to transcriptome analyses. Differentially expressed genes were mapped to the global human interaction network from the Reactome database to reconstruct interaction networks and perform pathway enrichment analyses.   FancA overexpression alone induced altered expression of 1129 genes (FDR<0.05). Interestingly, 37 of the top 50 genes are known to belong to the IFN signature. Pathway enrichment analysis identified 32 significantly overrepresented pathways including IFN signalling, mTOR, EGF receptor, ERBB1 and FGF signalling pathways. Gamma-irradiation led to the differential expression of 205 and 371 genes in OKF6/FancA and OKF6/vec cells, respectively. Pathway enrichment analysis showed the involvement of DNA damage response pathways in both cell lines. However, FOXM1 TF network, ECM, WNT, ERBB4, Aurora, c-Myc signalling pathways and the senescence-associated secretory phenotype (SASP) were involved exclusively in the radiation response of FancA overexpressing cells. Therefore, these pathways will be subjected to further in-depth analyses, in order to identify candidate targets for an improved personalized radiotherapy. Moreover, correlation of the 16q24.3 marker with overall survival was validated in the TCGA HNSCC cohort (n=113) supporting our findings. This collaborative project is funded by the BMBF (ZISS 02NUK024)