Free-Circulating Methylated DNA in Blood for Diagnosis, Staging, Prognosis, and Monitoring of Head and Neck Squamous Cell Carcinoma Patients: An Observational Prospective Cohort Study

Abstract BACKGROUND Circulating cell-free DNA methylation testing in blood has recently received regulatory approval for screening of colorectal cancer. Its application in other clinical settings, including staging, prognosis, prediction, and recurrence monitoring is highly promising, and of particular interest in head and neck squamous cell carcinomas (HNSCCs) that represent a heterogeneous group of cancers with unsatisfactory treatment guidelines. METHODS Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) DNA methylation in plasma from 649 prospectively enrolled patients (training study: 284 HNSCC/122 control patients; testing study: 141 HNSCC/102 control patients) was quantified before treatment and longitudinally during surveillance. RESULTS In the training study, 59% of HNSCC patients were methylation-positive at 96% specificity. Methylation levels correlated with tumor and nodal category (P &amp;lt; 0.001). Initially increased methylation levels were associated with a higher risk of death [SEPT9: hazard ratio (HR) = 5.27, P = 0.001; SHOX2: HR = 2.32, P = 0.024]. Disease recurrence/metastases were detected in 47% of patients up to 377 days earlier compared to current clinical practice. The onset of second cancers was detected up to 343 days earlier. In the testing study, sensitivity (52%), specificity (95%), prediction of overall survival (SEPT9: HR = 2.78, P = 0.022; SHOX2: HR = 2.50, P = 0.026), and correlation with tumor and nodal category (P &amp;lt;0.001) were successfully validated. CONCLUSIONS Methylation testing in plasma is a powerful diagnostic tool for molecular disease staging, risk stratification, and disease monitoring. Patients with initially high biomarker levels might benefit from intensified treatment and posttherapeutic surveillance. The early detection of a recurrent/metastatic disease or a second malignancy could lead to an earlier consecutive treatment, thereby improving patients' outcomes. </jats:sec

A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma

Purpose: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. Experimental design: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. Results: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. Conclusions: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation

Untersuchung zur analgetischen Wirksamkeit von Delta 9 Tetrahydrocannabinol (Dronabinol) bei Patienten mit chronischen Schmerzen, die mit einem medikamentös-analgetischen Schema der Stufe II oder III nach WHO behandelt werden

Cannabinoide wirken über spezifische Cannabinoidrezeptoren, die im Zentralnervensystem (CB-1) und in peripheren Organen (CB-1 und CB-2) vorkommen und an Neuronen schmerzmodulierender spinaler und supraspinaler Zentren die Neurotransmitterausschüttung regulieren. Von entscheidender Bedeutung ist hierbei die Hemmung der Adenylatzyklase über ein inhibitorisches G-Protein und die Aktivitätsänderung von Kalzium- und Kaliumkanälen. In den letzten Jahren rückte die Interaktion zwischen Cannabinoiden und Opioidanalgetika in das Interesse der Schmerzforschung. Tierexperimentellen Studien zufolge sind Cannabinoide dazu in der Lage, die antinozizeptive Wirkung von Opioiden durch bisher nicht eindeutig geklärte Mechanismen zu potenzieren. Bei diesen Prozessen sind sowohl schmerzmodulatorische spinale als auch supraspinale Zentren involviert. Der Synergismus wurde im Tiermodell einerseits der Aktivierung des spinalen Dynorphinsystems durch das Canabi-noid zugeschrieben, dessen Metabolite (Dynorphin B und Enkephaline) durch Bindung an Delta- und Kappa-Opioidrezeptoren zu einer Potenzierung der antinozizeptiven Wirkung von Opioidanalgetika führen. Andererseits könnten Veränderungen der Genexpression in schmerzmodulatorischen Zentren wie dem periaquäduktalen Grau für diesen Synergismus zuständig sein . Die vorliegende Pilotstudie hat diese These erstmals am Menschen untersucht

Extraretinal induced visual sensations during IMRT of the brain.

We observed visual sensations (VSs) in patients undergoing intensity modulated radiotherapy (IMRT) of the brain without the beam passing through ocular structures. We analyzed this phenomenon especially with regards to reproducibility, and origin.Analyzed were ten consecutive patients (aged 41-71 years) with glioblastoma multiforme who received pulsed IMRT (total dose 60Gy) with helical tomotherapy (TT). A megavolt-CT (MVCT) was performed daily before treatment. VSs were reported and recorded using a triggered event recorder. The frequency of VSs was calculated and VSs were correlated with beam direction and couch position. Subjective patient perception was plotted on an 8x8 visual field (VF) matrix. Distance to the orbital roof (OR) from the first beam causing a VS was calculated from the Dicom radiation therapy data and MVCT data. During 175 treatment sessions (average 17.5 per patient) 5959 VSs were recorded and analyzed. VSs occurred only during the treatment session not during the MVCTs. Plotting events over time revealed patient-specific patterns. The average cranio-caudad extension of VS-inducing area was 63.4mm (range 43.24-92.1mm). The maximum distance between the first VS and the OR was 56.1mm so that direct interaction with the retina is unlikely. Data on subjective visual perception showed that VSs occurred mainly in the upper right and left quadrants of the VF. Within the visual pathways the highest probability for origin of VSs was seen in the optic chiasm and the optic tract (22%).There is clear evidence that interaction of photon irradiation with neuronal structures distant from the eye can lead to VSs

Beam path an occurrence of visual sensations in relation to bony structure.

<p>During 175 treatment fractions 97285 beams were administered. 5959 visual sensations were registered. To exclude direct interaction with the retina all supraorbital VSs caused by beams with central beam axis distance < ½ beam size to the orbital roof were eliminated. From this 2970 (50%) VSs occurred above the orbital roof without direct interaction to the retina.</p><p>Beam path an occurrence of visual sensations in relation to bony structure.</p

Beam path an occurrence of visual sensations in relation to bony structure.

<p>During 175 treatment fractions 97285 beams were administered. 5959 visual sensations were registered. To exclude direct interaction with the retina all supraorbital VSs caused by beams with central beam axis distance < ½ beam size to the orbital roof were eliminated. From this 2970 (50%) VSs occurred above the orbital roof without direct interaction to the retina.</p><p>Beam path an occurrence of visual sensations in relation to bony structure.</p

Diagram of the registered data of all patients 1–10 (a-j) shows patient specific patterns of relative frequency of the visual sensations (1 = light sensation was registered in all fractions) related to cranio-caudal couch travel [mm] (lower horizontal axis) and fraction time [s] (upper horizontal axis).

<p>Position of orbital roof is marked with a red dashed line. Every patient showed a pattern, which indicates that the VSs are induced by specific beam paths.</p

Analysis of the 8x8 visual field matrix of all 10 Patients (100 fractions).

<p>Summation of all perceptions independent from primary tumor site (a). Perception of visual sensations divided in patients with right (b) and left sided tumor location (c). Visual sensations were mainly projected in the upper right or left and the central visual field but not in the lower parts suitable for the majority of the beams. No relationship between primary tumor site and location of light perception can be made. Interestingly most beams were located supraorbital. However the main VSs were registered in the upper visual field and not, as expected in the lower quadrants.</p

Hydrofilm Polyurethane Films Reduce Radiation Dermatitis Severity in Hypofractionated Whole-Breast Irradiation: An Objective, Intra-Patient Randomized Dual-Center Assessment

Radiation-induced skin injury represents the most frequent side effect in breast cancer patients undergoing whole-breast irradiation (WBI). Numerous clinical studies on systemic and topical treatments for radiation dermatitis have failed to provide sustainable treatment strategies. While protective skin products such as dressings are undoubtedly the standard of care in wound care management, their utilization as preventive treatment in radiotherapy has been somewhat neglected in recent years. In this prospective, intra-patient randomized observational study, Hydrofilm polyurethane films were prophylactically applied to either the medial or lateral breast-half of 74 patients with breast cancer undergoing hypofractionated whole-breast irradiation following breast-preserving surgery. Maximum radiation dermatitis severity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.03 toxicity scores, photospectrometric erythema and pigmentation measurements and patient-assessed modified Radiation-Induced Skin Reaction Assessment Scale (RISRAS) scale. Phantom studies revealed a clinically negligible dose build-up of less than 0.1% with Hydrofilm. Compared to the control compartments physician-assessed radiation dermatitis severity was reduced in the hydrofilm compartments (mean 0.54 vs. 1.34; p = &lt; 0.001). Objective photospectrometric skin measurements showed decreased erythema (p = 0.0001) and hyperpigmentation (p = 0.002) underneath Hydrofilm. Hydrofilm also completely prevented moist desquamation, and significantly reduced patients’ treatment-related symptoms of itching, burning, pain, and limitations of day-to-day-activities. Significant beneficial effects were observed in terms of radiation dermatitis severity, erythema, hyperpigmentation as well as subjective treatment-related symptom experiences, while adverse reactions were rare and minor. Therefore, a prophylactic application of Hydrofilm polyurethane films can be suggested in hypofractionated WBI