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Stereotactic body radiotherapy (SBRT) has firmly established its role in stage I NSCLC. Clinical trial results may not fully apply to real-world scenarios. This study aimed to uncover the real-world incidence of acute toxicity and 90-day mortality in patients with SBRT-treated stage I NSCLC and develop prediction models for these outcomes.

•Contour adaptation conformity analyzed for LN-metastases, rectal- + prostate cancer.•Contour adaptation conformity among RTTs and radiation oncologists is comparable.•Role expansion of RTTs with daily contour adaptation impacts workflow efficiency.

Background: For localised prostate cancer, focal therapy offers an organ-sparing alternative to radical treatments (radiotherapy or prostatectomy). Currently, there is no randomised comparative effectiveness data evaluating cancer control of both strategies. Methods: Following the eligibility criteria PSA < 20 ng/mL, Gleason score ≤ 7 and T-stage ≤ T2c, we included 830 radical (440 radiotherapy, 390 prostatectomy) and 530 focal therapy (cryotherapy, high-intensity focused ultrasound or high-dose-rate brachytherapy) patients treated between 2005 and 2018 from multicentre registries in the Netherlands and the UK. A propensity score weighted (PSW) analysis was performed to compare failure-free survival (FFS), with failure defined as salvage treatment, metastatic disease, systemic treatment (androgen deprivation therapy or chemotherapy), or progression to watchful waiting. The secondary outcome was overall survival (OS). Median (IQR) follow-up in each cohort was 55 (28–83) and 62 (42–83) months, respectively. Results: At baseline, radical patients had higher PSA (10.3 versus 7.9) and higher-grade disease (31% ISUP 3 versus 11%) compared to focal patients. After PSW, all covariates were balanced (SMD < 0.1). 6-year weighted FFS was higher after radical therapy (80.3%, 95% CI 73.9–87.3) than after focal therapy (72.8%, 95% CI 66.8–79.8) although not statistically significant (p= 0.1). 6-year weighted OS was significantly lower after radical therapy (93.4%, 95% CI 90.1–95.2 versus 97.5%, 95% CI 94–99.9; p= 0.02). When compared in a three-way analysis, focal and LRP patients had a higher risk of treatment failure than EBRT patients (p< 0.001), but EBRT patients had a higher risk of mortality than focal patients (p= 0.008). Conclusions: Within the limitations of a cohort-based analysis in which residual confounders are likely to exist, we found no clinically relevant difference in cancer control conferred by focal therapy compared to radical therapy at 6 years.

Introduction: Focal therapy (FT) ablates areas of prostate cancer rather than treating the whole gland. We compared oncological outcomes of FT to radical prostatectomy (RP). Methods: Using prospective multicentre databases of 761 FT and 572 RP cases (November/2005-September/2018), patients with PSA < 20 ng/ml, Gleason </= 4 + 3 and stage </= T2c were 1–1 propensity score-matched for treatment year, age, PSA, Gleason, T-stage, cancer core length and use of neoadjuvant hormones. FT included 1–2 sessions. Primary outcome was failure-free survival (FFS) defined by need for salvage local or systemic therapy or metastases. Differences in FFS were determined using Kaplan–Meier analysis with log-rank test. Results: 335 radical prostatectomy and 501 focal therapy patients were eligible for matching. For focal therapy, 420 had HIFU and 81 cryotherapy. Cryotherapy was used predominantly for anterior cancer. After matching, 246 RP and 246 FT cases were identified. For radical prostatectomy, mean (SD) age was 63.4 (5.6) years, median (IQR) PSA 7.9 g/ml (6–10) and median (IQR) follow-up 64 (30–89) months. For focal therapy, these were 63.3 (6.9) years, 7.9 ng/ml (5.5–10.6) and 49 [34–67] months, respectively. At 3, 5 and 8 years, FFS (95%CI) was 86% (81–91%), 82% (77–88%) and 79% (73–86%) for radical prostatectomy compared to 91% (87–95%), 86% (81–92%) and 83% (76–90%) following focal therapy (p= 0.12). Conclusions: In patients with non-metastatic low- intermediate prostate cancer, oncological outcomes over 8 years were similar between focal therapy and radical prostatectomy.

Background: In men with recurrence of prostate cancer post radiation therapy, further treatment remains a challenge. The default salvage option of androgen-deprivation therapy (ADT) has adverse effects. Alternatively, selected men may be offered salvage therapy to the prostate. Herein, we present long-term oncological outcomes of two whole-gland ablation techniques, cryotherapy (sCT) and high-intensity-focused ultrasound (sHIFU). Methods: Men undergoing sCT (1995–2004) and sHIFU (2006–2018) at Western University were identified. Oncological endpoints included biochemical recurrence (BCR), ADT initiation, metastases, castration resistance (CRPC), and prostate cancer-specific mortality (PCSM). Survival analysis with competing risks of mortality was performed. Multivariable analysis was performed using Fine and Gray regression. Results: A total of 187 men underwent sCT and 113 sHIFU. Mean (SD) age of the entire cohort was 69.9 (5.9 years), median pre-radiation PSA 9.6 ng/ml (IQR 6.1–15.2), and pre-salvage PSA 4.5 ng/ml (IQR 2.8–7.0). Median total follow-up was 116 months (IQR 67.5–173.8). A total of 170 (57.6%) developed BCR, 68 (23.4%) metastases, 143 (49.3%) were started on ADT, 58 (20.1%) developed CRPC, and 162 (56%) patients died of which 59 (36.4%) were of prostate cancer. On multivariable analysis, sHIFU (HR 1.65, 95% CI 1.15–2.36, p= 0.006) and pre-salvage PSA (HR 1.09, 95% CI 1.06–1.13, p< 0.0001) were associated with a higher risk of BCR. Similarly, sHIFU patients had a higher risk of CRPC (HR 2.31, 95% CI 1.23–4.35, p= 0.009). The cumulative incidence (for both treatments) of PCSM was 16.5% (95% CI 12.2–21.4%) at 10 years and 28.4% (95% CI 22.1–34.9%) at 20 years, with no difference between treatment modalities. Pre-salvage PSA was a common predictor for the measured oncological outcomes. Conclusions: Although sHIFU had higher BCR and CRPC rates, there were no differences in PCSM when compared with sCT. The long-term oncological data on two ablation techniques highlighted that only 50% of patients started ADT after 10-year follow-up.

Het doel van deze studie was de oncologische en functionele uitkomsten van salvage cryochirurgie (sCC) te beoordelen bij lokaal recidief prostaatcarcinoom na radiotherapie (rrPCA). De studie werd uitgevoerd bij 169 patiënten. Er vond retrospectieve analyse plaats van recidiefvrije overleving (BRFS), algehele overleving, metastasevrije overleving, androgeendeprivatietherapie (ADT)-vrije overleving, functionele uitkomsten en complicaties. De mediane follow-up was 36 maanden (IQR = 18–66). BRFS na vijf en acht jaar was 52% (95%-BI = 43–62) en 45% (95%-BI = 35–57), respectievelijk. PSA bij initiële diagnose, de initiële behandeling, het interval tussen de primaire behandeling en SCS, leeftijd bij SCS en post-SCS PSA-nadir waren significante voorspellers van BRFS. De vijf-jaars ADT-vrije overleving was 70% (95%-BI = 62–79). Complicaties van graad III of hoger traden op bij 1,2% van de patiënten. Bij 19% en 92% van de patiënten trad new onset urine-incontinentie respectievelijk erectiele disfunctie op, bij 6,5% persisterende urinaire fistels en bij 12% desobstructie. SCS heeft aanvaardbare oncologische resultaten, maar kan gepaard gaan met ernstige complicaties (urine-incontinentie, stenose en fistels).

Flexible synthetic access to a novel biarylic GC binding motif is presented, consisting of a pyridone connected to a fused pyrrolo[2,3-b]pyridone. Extensive molecular modeling led to an optimized design with perfect complementarity to the Hoogsteen site inside DNA’s major groove. A wide range of functional elements can be introduced by minor modifications of the synthetic strategy. Our approach relies on mild Pd-catalyzed coupling reactions, featuring a triple heterohalogenated orthogonally addressable pyridine as a key intermediate.

Introduction: Whole-gland salvage treatment of radiorecurrent prostate cancer has a high rate of severe toxicity. The standard of care in case of a biochemical recurrence is androgen deprivation treatment, which is associated with morbidity and negative effects on quality of life. A salvage treatment with acceptable toxicity might postpone the start of androgen deprivation treatment, might have a positive influence on the patients’ quality of life, and might even be curative. Here, toxicity and biochemical outcome are described after magnetic resonance imaging–guided focal salvage high-dose-rate brachytherapy in patients with radiorecurrent prostate cancer.Materials and Methods: Seventeen patients with pathologically proven locally recurrent prostate cancer were treated with focal high-dose-rate brachytherapy in a single 19-Gy fraction using magnetic resonance imaging for treatment guidance. Primary radiotherapy consisted of external beam radiotherapy or low-dose-rate brachytherapy. Tumors were delineated with Ga-68–prostate-specific membrane antigen or F18-choline positron emission tomography in combination with multiparametric magnetic resonance imaging. All patients had a prostate-specific antigen level of less than 10 ng/mL at the time of recurrence and a prostate-specific antigen doubling time of ≥12 months. Toxicity was measured by using the Common Terminology Criteria for Adverse Events version 4.Results: Eight of 17 patients had follow-up interval of at least 1 year. At a median follow-up interval of 10 months (range 3-40 months), 1 patient experienced a biochemical recurrence according to the Phoenix criteria, and prostate-specific membrane antigen testing revealed that this was due to a distant nodal metastasis. One patient had a grade 3 urethral stricture at 2 years after treatment.Conclusion: Focal salvage high-dose-rate brachytherapy in patients with radiorecurrent prostate cancer showed grade 3 toxicity in 1 of 17 patients and a distant nodal metastasis in another patient. Whether this treatment option leads to cure in a subset of patients or whether it can successfully postpone androgen deprivation treatment needs further investigation.

As estimated by the International Energy Agency, geothermal power can contribute to 3.5 % of worldwide power and 3.9 % to heat production by 2050. This includes the development of enhanced geothermal systems (EGSs) in low‐enthalpy systems. EGS technology is still in an early stage of development. Pushing EGS technologies towards market maturity requires a long‐term strategic approach and massive investments in research and development. Comprehensive multidisciplinary research programs that combine fundamental and applied concepts to tackle technological, economic, ecological, and safety challenges along the EGS process chain are needed. The Karlsruhe Institute of Technology (KIT) has defined a broad research program on EGS technology development following the necessity of a transdisciplinary approach. The research concept is embedded in the national research program of the Helmholtz Association and is structured in four clusters: reservoir characterization and engineering, thermal water circuit, materials and geoprocesses, and power plant operation. The proximity to industry, closely interlinked with fundamental research, forms the basis of a target‐orientated concept. The present paper aims to give an overview of geothermal research at KIT and emphasizes the need for concerted research efforts at the international level to accelerate technological breakthrough of EGS as an essential part of a future sustainable energy system. Harnessing underground power: The Karlsruhe Institute of Technology (KIT), located within the Upper Rhine Graben, takes advantage of favorable geothermal conditions and has defined a comprehensive research program on enhanced geothermal systems technology development following the necessity of a transdisciplinary approach. Research activities cover the whole process chain, including system integration, and span from fundamental to applied research across scales.

Bedside teaching is seen as one of the most important modalities in teaching a variety of skills important for the medical profession, but its use is declining. A literature review was conducted to reveal its strengths, the causes of its decline and future perspectives, the evidence with regard to learning clinical skills and patient/student/teacher satisfaction. PubMed, Embase and the Cochrane library were systematically searched with regard to terms related to bedside teaching. Articles regarding the above-mentioned subjects were included. Bedside teaching has shown to improve certain clinical diagnostic skills in medical students and residents. Patients, students/residents and teachers all seem to favour bedside teaching, for varying reasons. Despite this, the practice of bedside teaching is declining. Reasons to explain this decline include the increased patient turnover in hospitals, the assumed violation of patients’ privacy and an increased reliance on technology in the diagnostic process. Solutions vary from increasingly using residents and interns as bedside teachers to actively educating staff members regarding the importance of bedside teaching and providing them with practical essentials. Impediments to bedside teaching need to be overcome if this teaching modality is to remain a valuable educational method for durable clinical skills.

DNA interaction with artificial binders is of great interest, especially in light of the broad range of possible biomedical applications. The growing understanding of replication, transcription and translation opened the path for new approaches to target pathological effects at a very early stage. Meanwhile, the competitive binding to nucleic acids by designed molecules, which, for example, block certain sequences for natural binders, such as transcription factors, has become a promising concept in the context of gene therapy. On the other extreme, the transport of nucleic acids over the cell membrane into the nucleus by transfection agents opens the possibility to reprogram protein biosynthesis within host cells.In the past decades several substance classes have been developed for a noncovalent specific DNA binding with predictable biological effects, such as peptide nucleic acids or polyamide ligands. Calixarenes have not received so much attention, although they consist of a compact aromatic core tuneable in size, and allow the introduction of cationic functionalities at their upper and lower rims. Formerly being utilized as receptor moieties due to the possibility of complexating guests in their cavities, calixarenes are now also used as molecular scaffolds for multivalent ligands and are, therefore, suitable tools for cooperative DNA complexation.This review surveys specific supramolecular interactions between calixarene derivatives and nucleic acids, with an emphasis on structural elements in the calixarenes and the biological consequences of their complex formation with DNA strands.