Fractionated stereotactic radiotherapy of intracranial postoperative cavities after resection of brain metastases - Clinical outcome and prognostic factors.

Background and Purpose: After surgical resection of brain metastases (BM), radiotherapy (RT) is indicated. Postoperative stereotactic radiosurgery (SRS) reduces the risk of local progression and neurocognitive decline compared to whole brain radiotherapy (WBRT). Aside from the optimal dose and fractionation, little is known about the combination of systemic therapy and postoperative fractionated stereotactic radiotherapy (fSRT), especially regarding tumour control and toxicity. Methods: In this study, 105 patients receiving postoperative fSRT with 35 Gy in 7 fractions performed with Cyberknife were retrospectively reviewed. Overall survival (OS), local control (LC) and total intracranial brain control (TIBC) were analysed via Kaplan-Meier method. Cox proportional hazards models were used to identify prognostic factors. Results: Median follow-up was 20.8 months. One-year TIBC was 61.6% and one-year LC was 98.6%. Median OS was 28.7 (95%-CI: 16.9-40.5) months. In total, local progression (median time not reached) occurred in 2.0% and in 20.4% radiation-induced contrast enhancements (RICE) of the cavity (after median of 14.3 months) were diagnosed. Absence of extracranial metastases was identified as an independent prognostic factor for superior OS (p = <0.001) in multivariate analyses, while a higher Karnofsky performance score (KPS) was predictive for longer OS in univariate analysis (p = 0.041). Leptomeningeal disease (LMD) developed in 13% of patients. Conclusion: FSRT after surgical resection of BM is an effective and safe treatment approach with excellent local control and acceptable toxicity. Further prospective randomized trials are needed to establish standardized therapeutic guidelines.

Stereotactic ultrahypofractionated MR-guided radiotherapy for localized prostate cancer - Acute toxicity and patient-reported outcomes in the prospective, multicenter SMILE phase II trial.

Background: Due to superior image quality and daily adaptive planning, MR-guided stereotactic body radiation therapy (MRgSBRT) has the potential to further widen the therapeutic window in radiotherapy of localized prostate cancer. This study reports on acute toxicity rates and patient-reported outcomes after MR-guided adaptive ultrahypofractionated radiotherapy for localized prostate cancer within the prospective, multicenter phase II SMILE trial. Materials and methods: A total of 69 patients with localized prostate cancer underwent MRgSBRT with daily online plan adaptation. Inclusion criteria comprised a tumor stage ≤ T3a, serum PSA value ≤ 20 ng/ml, ISUP Grade group ≤ 4. A dose of 37.5 Gy was prescribed to the PTV in five fractions on alternating days with an optional simultaneous boost of 40 Gy to the dominant intraprostatic lesion defined by multiparametric MRI. Acute genitourinary (GU-) and gastrointestinal (GI-) toxicity, as defined by CTCAE v. 5.0 and RTOG as well as patient-reported outcomes according to EORTC QLQ-C30 and -PR25 scores were analyzed at completion of radiotherapy, 6 and 12 weeks after radiotherapy and compared to baseline symptoms. Results: There were no toxicity-related treatment discontinuations. At the 12-week follow-up visit, no grade 3 + toxicities were reported according to CTCAE. Up until the 12-week visit, in total 16 patients (23 %) experienced a grade 2 GU or GI toxicity. Toxicity rates peaked at the end of radiation therapy and subsided within the 12-week follow-up period. At the 12-week follow-up visit, no residual grade 2 GU toxicities were reported and 1 patient (1 %) had residual grade 2 enteritic symptoms. With exception to a significant improvement in the emotional functioning score following MRgSBRT, no clinically meaningful changes in the global health status nor in relevant subscores were reported. Conclusion: Daily online-adaptive MRgSBRT for localized prostate cancer resulted in an excellent overall toxicity profile without any major negative impact on quality of life.

Whole-pelvic irradiation with boost to involved nodes and prostate in node-positive prostate cancer-long-term data from the prospective PLATIN-2 trial.

PURPOSE: Node-positive prostate cancer is a potentially curable disease. Definitive radiotherapy to the prostate and lymphatic drainage is an effective treatment option but prospective long-term outcome data are scarce. Thus, the current study aimed to evaluate the toxicity and efficacy of definitive radiation therapy for men with prostate cancer and nodal metastases using modern irradiation techniques. METHODS: A total of 40 treatment-naïve men with node-positive prostate cancer were allocated to the trial. All patients received definitive radiation therapy at two German university hospitals between 2009 and 2018. Radiation was delivered as intensity-modulated radiation therapy (IMRT) with 51 Gy to the lymphatic drainage with simultaneous integrated boost (SIB) up to 61.2 Gy to involved nodes and 76.5 Gy to the prostate in 34 fractions. Feasibility and safety, overall and progression-free survival, toxicity, and quality of life measurements were analyzed. RESULTS: During a median follow-up of 79 months, median overall survival was 107 months and progression-free survival was 78 months. Based on imaging follow-up, no infield relapse was reported during the first 24 months of follow-up. There were 3 (8%) potentially treatment-related grade 3 toxicities. Common iliac node involvement was associated with a higher risk of progression (HR 15.8; 95% CI 2.1-119.8; p = 0.007). CONCLUSION: Definitive radiation to the lymphatic drainage with SIB to the involved nodes and prostate is a safe and effective treatment approach for patients with treatment-naïve, node-positive prostate cancer with excellent infield tumor control rates and tolerable toxicity. Location rather than number of involved nodes is a major risk factor for progression.

First Measurement of the Nuclear-Recoil Ionization Yield in Silicon at 100 eV.

We measured the nuclear-recoil ionization yield in silicon with a cryogenic phonon-sensitive gram-scale detector. Neutrons from a monoenergetic beam scatter off of the silicon nuclei at angles corresponding to energy depositions from 4 keV down to 100 eV, the lowest energy probed so far. The results show no sign of an ionization production threshold above 100 eV. These results call for further investigation of the ionization yield theory and a comprehensive determination of the detector response function at energies below the keV scale.

Detecting and Locating the Site of Local Relapse Using 18F-PSMA-1007 Imaging After Primary Treatment of 135 Prostate Cancer Patients-Potential Impact on PSMA-Guided Radiation Therapy.

PURPOSE: Due to limited imaging options, the visualization of a local relapse of prostate cancer used to pose a considerable challenge. However, since the integration of 18F-PSMA-1007-PET/CT into the clinic, a relapsed tumor can now easily be detected by hybrid imaging. The present study aimed to evaluate and map the allocate relapse in a large cohort of prostate cancer patients focusing on individual patient management conclusions for radiation therapy. PROCEDURES: The current study included 135 men with prostate cancer after primary treatment who underwent 18F-PSMA-1007-PET/CT due to biochemical relapse detecting a local relapse. Imaging data were reassessed and analyzed with regard to relapse locations. For the correlation of tumor foci with clinical data, we used binary logistic regression models as well as the Kruskal-Wallis test and Mann-Whitney test. RESULTS: In total, 69.6% of all patients (mean age: 65 years) underwent prostatectomy while 30.4% underwent radiation therapy. PET imaging detected most frequently a unifocal relapse (72.6%). There was a statistically significantly higher rate of ipsilateral cases among the relapsed tumors. Comparing both treatment approaches, tumors relapsed most commonly within the posterior region after surgery and transition/peripheral zone after radiation therapy, respectively. CONCLUSIONS: The present study confirms that 18F-PSMA-1007-PET/CT is highly suitable for the localization and allocation of a local relapse in patients with prostate cancer. The data enable further optimizing dose prescriptions and target volume delineations of radiation therapy in the future.

[Imaging of oligometastatic disease in selected urologic cancers]. / Bildgebung oligometastasierter Tumoren des Harntraktes.

BACKGROUND: Local treatment of the primary or metastatic sites in urologic malignancies is promising when compared to systemic therapy alone, leading to the definition of a potentially curative oligometastatic state. OBJECTIVES: Comparison of imaging modalities regarding local and metastatic tumor sites in urologic cancers. METHODS: Review of comparative trials addressing quality criteria of imaging modalities. RESULTS: Depending on primary tumor and metastatic site, conventional imaging modalities such as computer tomography (CT) and bone scintigraphy still represent the standard of care in Germany. Due to superior quality criteria, hybrid-imaging techniques were widely adopted for oncological staging and particular due to the new PSMA-ligand (PSMA-PET/CT) in prostate cancer imaging. The development of new radioisotopes as well as their clinical application remains a focus of current research. CONCLUSIONS: High-quality diagnostic imaging modalities lay the groundwork for a precise definition of an oligometastatic state. By enabling treatment of the entire tumor burden, a delay of systemic therapy, longer progression-free survival, or even curative treatment may become achievable.

Constraints on Lightly Ionizing Particles from CDMSlite.

The Cryogenic Dark Matter Search low ionization threshold experiment (CDMSlite) achieved efficient detection of very small recoil energies in its germanium target, resulting in sensitivity to lightly ionizing particles (LIPs) in a previously unexplored region of charge, mass, and velocity parameter space. We report first direct-detection limits calculated using the optimum interval method on the vertical intensity of cosmogenically produced LIPs with an electric charge smaller than e/(3×10^{5}), as well as the strongest limits for charge ≤e/160, with a minimum vertical intensity of 1.36×10^{-7} cm^{-2} s^{-1} sr^{-1} at charge e/160. These results apply over a wide range of LIP masses (5 MeV/c^{2} to 100 TeV/c^{2}) and cover a wide range of ßγ values (0.1-10^{6}), thus excluding nonrelativistic LIPs with ßγ as small as 0.1 for the first time.

Light Dark Matter Search with a High-Resolution Athermal Phonon Detector Operated above Ground.

We present limits on spin-independent dark matter-nucleon interactions using a 10.6 g Si athermal phonon detector with a baseline energy resolution of σ_{E}=3.86±0.04(stat)_{-0.00}^{+0.19}(syst) eV. This exclusion analysis sets the most stringent dark matter-nucleon scattering cross-section limits achieved by a cryogenic detector for dark matter particle masses from 93 to 140 MeV/c^{2}, with a raw exposure of 9.9 g d acquired at an above-ground facility. This work illustrates the scientific potential of detectors with athermal phonon sensors with eV-scale energy resolution for future dark matter searches.

Kids N Fitness: A Group-based Pediatric Weight Management Curriculum Adapted for a Clinical Care Model.

BACKGROUND: The current AAP clinical practice guidelines for the management of pediatric obesity recommend a structured, comprehensive, multi-disciplinary clinical intervention. However, there is a gap in the current literature on standardized curriculums for implementation of such programs. The objective of the present study is to adapt an evidenced-based, family- centered, weekly, weight management curriculum that addresses nutritional, physical activity and behavioral topics for a clinical care model at a tertiary care children's hospital. METHODS: The curriculum was adapted for use in six individual sessions offered monthly by a multidisciplinary team, including a health educator, physician, dietitian, physical therapist and psychologist. Each provider offered specific feedback and curriculum adaptation based on their specialty. All team members completed training with scheduled treatment fidelity monitoring during implementation. To evaluate the effectiveness of the adapted curriculum, 60 adolescents, ages 14-18 years, with overweight or obesity, and at least one family member, will complete the six month intervention. The primary outcome is mean change in zBMI and %BMIp95 at six month and 18 months. Secondary outcomes include retention, satisfaction, effect on metabolic factors and activity level. CONCLUSION: There is a paucity of literature on utilizing a standard curriculum in clinical weight management programs. Drawing from evidenced-based curriculum to strengthen clinical care creates an opportunity to improve existing clinical programs and potentially increase access and implementation of the current treatment recommendations for this high risk population.

[Artificial intelligence and smartphone program applications (Apps) : Relevance for dermatological practice]. / Künstliche Intelligenz und Smartphone-Programm-Applikationen (Apps) : Bedeutung für die dermatologische Praxis.

ADVANTAGES OF ARTIFICIAL INTELLIGENCE (AI): With responsible, safe and successful use of artificial intelligence (AI), possible advantages in the field of dermato-oncology include the following: (1) medical work can focus on skin cancer patients, (2) patients can be more quickly and effectively treated despite the increasing incidence of skin cancer and the decreasing number of actively working dermatologists and (3) users can learn from the AI results. POTENTIAL DISADVANTAGES AND RISKS OF AI USE: (1) Lack of mutual trust can develop due to the decreased patient-physician contact, (2) additional time effort will be necessary to promptly evaluate the AI-classified benign lesions, (3) lack of adequate medical experience to recognize misclassified AI decisions and (4) recontacting a patient in due time in the case of incorrect AI classifications. Still problematic in the use of AI are the medicolegal situation and remuneration. Apps using AI currently cannot provide sufficient assistance based on clinical images of skin cancer. REQUIREMENTS AND POSSIBLE USE OF SMARTPHONE PROGRAM APPLICATIONS: Smartphone program applications (apps) can be implemented responsibly when the image quality is good, the patient's history can be entered easily, transmission of the image and results are assured and medicolegal aspects as well as remuneration are clarified. Apps can be used for disease-specific information material and can optimize patient care by using teledermatology.

Quantification and characterization of granulocyte macrophage colony-stimulating factor activated human peripheral blood mononuclear cells by fluorine-19 cellular MRI in an immunocompromised mouse model.

PURPOSE: The purpose of this study was to test fluorine-19 (19F) cellular magnetic resonance (MRI) as a non-invasive imaging modality to track therapeutic cell migration as a surrogate marker of immunotherapeutic effectiveness. MATERIALS AND METHODS: Human peripheral blood mononuclear cell- (PBMC)-derived antigen presenting cell (APC) were labeled with a 19F-perfluorocarbon (PFC) and/or activated with granulocyte macrophage colony-stimulating factor (GM-CSF). Viability, phenotype and cell lineage characterization preceded 19F cellular MRI of PFC+ PBMC under both pre-clinical 9.4 Tesla (T) and clinical 3T conditions in a mouse model. RESULTS: A high proportion of PBMC incorporated PFC without affecting viability, phenotype or cell lineage composition. PFC+ PBMC were in vivo migration-competent to draining and downstream lymph nodes. GM-CSF addition to culture increased PBMC migration to, and persistence within, secondary lymphoid organs. CONCLUSION: 19F cellular MRI is a non-invasive imaging technique capable of detecting and quantifying in vivo cell migration in conjunction with an established APC-based immunotherapy model. 19F cellular MRI can function as a surrogate marker for assessing and improving upon the therapeutic benefit that this immunotherapy provides.

Man against machine reloaded: performance of a market-approved convolutional neural network in classifying a broad spectrum of skin lesions in comparison with 96 dermatologists working under less artificial conditions.

BACKGROUND: Convolutional neural networks (CNNs) efficiently differentiate skin lesions by image analysis. Studies comparing a market-approved CNN in a broad range of diagnoses to dermatologists working under less artificial conditions are lacking. MATERIALS AND METHODS: One hundred cases of pigmented/non-pigmented skin cancers and benign lesions were used for a two-level reader study in 96 dermatologists (level I: dermoscopy only; level II: clinical close-up images, dermoscopy, and textual information). Additionally, dermoscopic images were classified by a CNN approved for the European market as a medical device (Moleanalyzer Pro, FotoFinder Systems, Bad Birnbach, Germany). Primary endpoints were the sensitivity and specificity of the CNN's dichotomous classification in comparison with the dermatologists' management decisions. Secondary endpoints included the dermatologists' diagnostic decisions, their performance according to their level of experience, and the CNN's area under the curve (AUC) of receiver operating characteristics (ROC). RESULTS: The CNN revealed a sensitivity, specificity, and ROC AUC with corresponding 95% confidence intervals (CI) of 95.0% (95% CI 83.5% to 98.6%), 76.7% (95% CI 64.6% to 85.6%), and 0.918 (95% CI 0.866-0.970), respectively. In level I, the dermatologists' management decisions showed a mean sensitivity and specificity of 89.0% (95% CI 87.4% to 90.6%) and 80.7% (95% CI 78.8% to 82.6%). With level II information, the sensitivity significantly improved to 94.1% (95% CI 93.1% to 95.1%; P < 0.001), while the specificity remained unchanged at 80.4% (95% CI 78.4% to 82.4%; P = 0.97). When fixing the CNN's specificity at the mean specificity of the dermatologists' management decision in level II (80.4%), the CNN's sensitivity was almost equal to that of human raters, at 95% (95% CI 83.5% to 98.6%) versus 94.1% (95% CI 93.1% to 95.1%); P = 0.1. In contrast, dermatologists were outperformed by the CNN in their level I management decisions and level I and II diagnostic decisions. More experienced dermatologists frequently surpassed the CNN's performance. CONCLUSIONS: Under less artificial conditions and in a broader spectrum of diagnoses, the CNN and most dermatologists performed on the same level. Dermatologists are trained to integrate information from a range of sources rendering comparative studies that are solely based on one single case image inadequate.

Diagnostic performance of a deep learning convolutional neural network in the differentiation of combined naevi and melanomas.

BACKGROUND: Deep learning convolutional neural networks (CNN) may assist physicians in the diagnosis of melanoma. The capacity of a CNN to differentiate melanomas from combined naevi, the latter representing well-known melanoma simulators, has not been investigated. OBJECTIVE: To assess the diagnostic performance of a CNN when used to differentiate melanomas from combined naevi in comparison with dermatologists. METHODS: In this study, a CNN with regulatory approval for the European market (Moleanalyzer-Pro, FotoFinder Systems GmbH, Bad Birnbach, Germany) was used. We attained a dichotomous classification (benign, malignant) in dermoscopic images of 36 combined naevi and 36 melanomas with a mean Breslow thickness of 1.3 mm. Primary outcome measures were the CNN's sensitivity, specificity and the diagnostic odds ratio (DOR) in comparison with 11 dermatologists with different levels of experience. RESULTS: The CNN revealed a sensitivity, specificity and DOR of 97.1% (95% CI [82.7-99.6]), 78.8% (95% CI [62.8-89.1.3]) and 34 (95% CI [4.8-239]), respectively. Dermatologists showed a lower mean sensitivity, specificity and DOR of 90.6% (95% CI [84.1-94.7]; P = 0.092), 71.0% (95% CI [62.6-78.1]; P = 0.256) and 24 (95% CI [11.6-48.4]; P = 0.1114). Under the assumption that dermatologists use the CNN to verify their (initial) melanoma diagnosis, dermatologists achieve an increased specificity of 90.3% (95% CI [79.8-95.6]) at an almost unchanged sensitivity. The largest benefit was observed in 'beginners', who performed worst without CNN verification (DOR = 12) but best with CNN verification (DOR = 98). CONCLUSION: The tested CNN more accurately classified combined naevi and melanomas in comparison with trained dermatologists. Their diagnostic performance could be improved if the CNN was used to confirm/overrule an initial melanoma diagnosis. Application of a CNN may therefore be of benefit to clinicians.

[Dermoscopy in special locations : Nails, acral skin, face, and mucosa]. / Dermatoskopie in Sonderlokalisationen : Nägel, akrale Haut, Gesicht und Mukosa.

The use of dermoscopy by dermatologists across Europe has become a standard examination for benign and malignant skin lesions and increasingly also for inflammatory skin diseases. However, based on the experience of the authors from numerous dermoscopy courses, knowledge about important dermoscopic features in special locations such as mucosa or nails is often limited. This may be explained by (1) a different anatomy of the skin and its adnexa in special locations in comparison to the remaining integument, (2) difficult technical access to special locations with a dermatoscope, and (3) a rather low incidence of malignant skin neoplasms in areas of special locations (with the exception of facial skin/scalp). This article aims at explaining dermoscopic characteristics and features of important benign and malignant lesions of nails, acral skin, face, and mucosa.

Erratum: First Dark Matter Constraints from a SuperCDMS Single-Charge Sensitive Detector [Phys. Rev. Lett. 121, 051301 (2018)].

This corrects the article DOI: 10.1103/PhysRevLett.121.051301.

An addiction model-based mobile health weight loss intervention in adolescents with obesity.

BACKGROUND: Clinical approaches to treating childhood obesity can be expensive and poorly reimbursed, and often produce suboptimal results. It has been theorized that overeating may have addictive qualities, and a sizable number of adolescents with obesity endorse addictive habits. Interestingly, few weight management interventions have tested techniques founded in addiction medicine principles. We therefore performed a pilot study of an addiction model based mHealth weight loss intervention in adolescents. METHODS: Adolescents with obesity were recruited from an multidisciplinary weight management clinic (EMPOWER). Adolescents without significant obesity comorbidities, who exhibited signs of addictive eating, based on the Yale Food Addiction Scale, were enrolled in a pilot study of an interactive, addiction-based, weight loss smartphone app with coaching (http://clinicaltrials.gov: NCT02689154). The app was designed to help subjects omit problem foods, avoid snacking and reduce meal size. A contemporary cohort of adolescents who completed the EMPOWER program were evaluated. Feasibility of recruitment, adherence, retention rates, BMI change and cost of intervention were examined. RESULTS: Eighteen participants were recruited to app intervention. App participants had higher retention (100% vs. 37%) and lower total cost per patient ($855.15 vs. $1428.00) than the EMPOWER clinic participants. App participants exhibited a significant decrease in zBMI and %BMIp95 over the 6 months (p < 0.001 and p = 0.001), which was comparable to the age-matched EMPOWER program completers (p = 0.31 and p = 0.06). CONCLUSIONS: An addiction medicine-based mHealth intervention targeted for adolescents was feasible to implement, resulted in high retention and adherence rates, and reduced zBMI and %BMIp95 in a more cost-effective manner than an in-clinic intervention.

Precision and reproducibility of automated computer-guided Psoriasis Area and Severity Index measurements in comparison with trained physicians.

BACKGROUND: The Psoriasis Area and Severity Index (PASI) represents the gold standard for psoriasis severity assessments but is limited by its subjectivity and low intra- and inter-rater consistency. OBJECTIVES: To investigate the precision and reproducibility of automated, computer-guided PASI measurements (ACPMs) in comparison with three trained physicians. METHODS: This was a comparative observational study assessing ACPMs attained by automated total-body imaging and computerized digital image analysis in a cohort of 120 patients affected by plaque psoriasis of various severities. The level of agreement between ACPMs and physicians' PASI measurements was calculated by the intraclass correlation coefficient (ICC). The reproducibility of ACPMs in comparison with physicians' PASI measurements was investigated by performing two successive 'repeat PASI calculations' in the same patients. RESULTS: The agreement between ACPMs and physicians' PASI calculations in 120 fully evaluable patients was high (ICC 0·86, 95% confidence interval 0·80-0·90, mean absolute difference 2·5 PASI points). Repeat ACPMs to measure the reproducibility showed an excellent ICC of 0·99 (95% confidence interval 0·98-0·99) with a mean absolute difference of 0·5 PASI points. The ACPMs thus outperformed the three physicians for intrarater reliability (mean ICC 0·86). CONCLUSIONS: The results of this first clinical study investigating ACPMs in 120 patients with psoriasis indicate a similar precision and higher reproducibility in comparison with trained physicians. Limitations arise from poorly observable body sites and from patients unable to attain predefined postures during automated image acquisition.

Energy Management for Personalized Weight Reduction (EMPOWER) Program: Three-Year Outcome Data.

BACKGROUND: The current consensus guidelines for management of pediatric obesity recommend clinic-based, family-centered, multi-disciplinary interventions. It is well reported that these programs often only lead to modest improvements in BMI status. The individual factors that differentiate which patient's BMI status will improve vs. worsen remains understudied. A retrospective cohort study was conducted to evaluate the outcomes of EMPOWER clinic and identify the participant specific characteristics that predicted BMI status improvement in this population. METHODS: Youth who completed at least 6 visits in EMPOWER were included. Paired t-test was utilized to evaluate the mean change in zBMI, modified BMIz and %BMIp95 from baseline to 6th visit, and multivariate mixed effect models were utilized to analyze effect of baseline characteristics on change in BMI status. RESULTS: 92 participants were included in the analysis, 87% with severe obesity and 66% Hispanic. At the 6th visit, there was a significant reduction in zBMI (-0.09 SD, p <0.001) and modified BMIz (-0.0003 SD, p = 0.04) with a small reduction in %BMIp95 (-1.15 %, p = 0.20). Lower BMI status (p < 0.001) and absence of a comorbidity (p < 0.05) at baseline were predictors of BMI status improvement whereas age, gender, ethnicity, family history of obesity and insurance status were not significant predictors. CONCLUSIONS: Given that implementation of the current guidelines for management of obesity in pediatrics only results in modest BMI status reduction, further investigation is required to understand how the determinants of obesity-related health outcomes can guide development of more innovative, effective interventions for this high risk population.