Fluorescence Enhancement of Single V2 Centers in a 4H-SiC Cavity Antenna.

Solid state quantum emitters are a prime candidate in distributed quantum technologies since they inherently provide a spin-photon interface. An ongoing challenge in the field, however, is the low photon extraction due to the high refractive index of typical host materials. This challenge can be overcome using photonic structures. Here, we report the integration of V2 centers in a cavity-based optical antenna. The structure consists of a silver-coated, 135 nm-thin 4H-SiC membrane functioning as a planar cavity with a broadband resonance yielding a theoretical photon collection enhancement factor of ∼34. The planar geometry allows us to identify over 20 single V2 centers at room temperature with a mean (maximum) count rate enhancement factor of 9 (15). Moreover, we observe 10 V2 centers with a mean absorption line width below 80 MHz at cryogenic temperatures. These results demonstrate a photon collection enhancement that is robust to the lateral emitter position.

Precise Characterization of a Waveguide Fiber Interface in Silicon Carbide.

Spin-active optical emitters in silicon carbide are excellent candidates toward the development of scalable quantum technologies. However, efficient photon collection is challenged by undirected emission patterns from optical dipoles, as well as low total internal reflection angles due to the high refractive index of silicon carbide. Based on recent advances with emitters in silicon carbide waveguides, we now demonstrate a comprehensive study of nanophotonic waveguide-to-fiber interfaces in silicon carbide. We find that across a large range of fabrication parameters, our experimental collection efficiencies remain above 90%. Further, by integrating silicon vacancy color centers into these waveguides, we demonstrate an overall photon count rate of 181 kilo-counts per second, which is an order of magnitude higher compared to standard setups. We also quantify the shift of the ground state spin states due to strain fields, which can be introduced by waveguide fabrication techniques. Finally, we show coherent electron spin manipulation with waveguide-integrated emitters with state-of-the-art coherence times of T 2 ∼ 42 µs. The robustness of our methods is very promising for quantum networks based on multiple orchestrated emitters.

High-Fidelity Optical Readout of a Nuclear-Spin Qubit in Silicon Carbide.

Quantum state readout is a key requirement for a successful qubit platform. In this work, we demonstrate a high-fidelity quantum state readout of a V2 center nuclear spin based on a repetitive readout technique. We demonstrate up to 99.5% readout fidelity and 99% for state preparation. Using this efficient readout, we initialize the nuclear spin by measurement and demonstrate its Rabi and Ramsey nutation. Finally, we use the nuclear spin as a long-lived memory for quantum sensing application of a weakly coupled diatomic nuclear-spin bath.

Qudit-Based Spectroscopy for Measurement and Control of Nuclear-Spin Qubits in Silicon Carbide.

Nuclear spins with hyperfine coupling to single electron spins are highly valuable quantum bits. Here we probe and characterize the particularly rich nuclear-spin environment around single silicon vacancy color centers (V2) in 4H-SiC. By using the electron spin-3/2 qudit as a four level sensor, we identify several sets of ^{29}Si and ^{13}C nuclear spins through their hyperfine interaction. We extract the major components of their hyperfine coupling via optical detected nuclear magnetic resonance, and assign them to shells in the crystal via the density function theory simulations. We utilize the ground-state level anticrossing of the electron spin for dynamic nuclear polarization and achieve a nuclear-spin polarization of up to 98±6%. We show that this scheme can be used to detect the nuclear magnetic resonance signal of individual spins and demonstrate their coherent control. Our work provides a detailed set of parameters and first steps for future use of SiC as a multiqubit memory and quantum computing platform.

The complex intervention day hospice - a quality-assured study on the implementation, realization, and benefits with model character for Germany (IMPULS) using the example of "Day hospice Adiuvantes".

BACKGROUND: Currently, a conclusive experience on the uniform implementation and benefits of day hospice structures and interventions is lacking in Germany. The following questions should be clarified: (1) Which structural conditions and interventional measures should be established in day hospices from the point of view of patients, relatives, and specialist staff?; (2) Are the planned structures or interventions feasible and implementable under real conditions and accepted by patients, relatives, and staff?; (3) How can a final implementation and intervention catalog for day hospices be designed?; (4) Is this final catalog of services feasible, reasonable, economical, and effective under everyday conditions in day hospices? METHODS: We planned to perform a multistage investigation, guided by the Medical Research Council Framework for the development and evaluation of complex interventions. In Stage 1, an initial theoretical construct on structures and interventions will be established through an extensive literature and guideline review on day hospices and through qualitative interviews. In a nominal group process, we will create a catalog of offers. In Stage 2, feasibility testing is conducted in a single-day hospice under real-life conditions using quantitative quality indicators and qualitative interviews. Structures and interventions can be adapted here if necessary. In a second nominal group process, a final structure and offer catalog is created, which is then implemented in Stage 3 in the day hospice under investigation and evaluated under real daily conditions through a process and effectiveness test. For this purpose, qualitative and quantitative quality indicators will be used and a comparative cohort of patients who are not cared for in the day hospice - but in the same network structure (oncology-palliative care network Lower Bavaria) - is examined. DISCUSSION: Finally, the initial statements on the reasonable and realizable structures or interventions in day hospices and their benefits in daily real-life conditions as well as possible optimization processes shall be made. TRIAL REGISTRATION: The study was retrospectively registered in the German Clinical Trials Register (DRKS-ID DRKS00031613, registration date April 04, 2023) and the display portal of the Center for Clinical Trials of the University Hospital Regensburg (Z-2022-1734-6, registration date July 01, 2023).

AI-Powered Virtual Screening of Large Compound Libraries Leads to the Discovery of Novel Inhibitors of Sirtuin-1.

The discovery of new scaffolds and chemotypes via high-throughput screening is tedious and resource intensive. Yet, there are millions of small molecules commercially available, rendering comprehensive in vitro tests intractable. We show how smart algorithms reduce large screening collections to target-specific sets of just a few hundred small molecules, allowing for a much faster and more cost-effective hit discovery process. We showcase the application of this virtual screening strategy by preselecting 434 compounds for Sirtuin-1 inhibition from a library of 2.6 million compounds, corresponding to 0.02% of the original library. Multistage in vitro validation ultimately confirmed nine chemically novel inhibitors. When compared to a competitive benchmark study for Sirtuin-1, our method shows a 12-fold higher hit rate. The results demonstrate how AI-driven preselection from large screening libraries allows for a massive reduction in the number of small molecules to be tested in vitro while still retaining a large number of hits.

An interaction-based drug discovery screen explains known SARS-CoV-2 inhibitors and predicts new compound scaffolds.

The recent outbreak of the COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has shown the necessity for fast and broad drug discovery methods to enable us to react quickly to novel and highly infectious diseases. A well-known SARS-CoV-2 target is the viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication, which is essential for the viral life cycle. Here, we applied an interaction-based drug repositioning algorithm on all protein-compound complexes available in the protein database (PDB) to identify Mpro inhibitors and potential novel compound scaffolds against SARS-CoV-2. The screen revealed a heterogeneous set of 692 potential Mpro inhibitors containing known ones such as Dasatinib, Amodiaquine, and Flavin mononucleotide, as well as so far untested chemical scaffolds. In a follow-up evaluation, we used publicly available data published almost two years after the screen to validate our results. In total, we are able to validate 17% of the top 100 predictions with publicly available data and can furthermore show that predicted compounds do cover scaffolds that are yet not associated with Mpro. Finally, we detected a potentially important binding pattern consisting of 3 hydrogen bonds with hydrogen donors of an oxyanion hole within the active side of Mpro. Overall, these results give hope that we will be better prepared for future pandemics and that drug development will become more efficient in the upcoming years.

FOLFOXIRI Plus Cetuximab or Bevacizumab as First-Line Treatment of BRAFV600E-Mutant Metastatic Colorectal Cancer: The Randomized Phase II FIRE-4.5 (AIO KRK0116) Study.

PURPOSE: BRAFV600E mutation is associated with a poor outcome in metastatic colorectal cancer (mCRC). This clinical trial investigated the efficacy of triplet chemotherapy (fluorouracil, folinic acid, oxaliplatin, and irinotecan) combined with either cetuximab or bevacizumab in patients with previously untreated BRAFV600E-mutant mCRC. PATIENTS AND METHODS: In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points. RESULTS: Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52; P = .92 [one-sided]). In the full analysis set, median PFS was significantly inferior in the experimental arm (6.7 months v 10.7 months; hazard ratio [HR], 1.89; P = .006). Median OS analyzed at an event rate of 64.5% showed a trend toward shorter survival in cetuximab-treated patients (12.9 months v 17.1 months; HR, 1.4; P = .20). CONCLUSION: To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAFV600E-mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAFV600E-mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAFV600E-mutant mCRC.

The Contribution of Intersectoral Healthcare Centres with an Extended Outpatient Care Model to Improve Regional Care-Structures-A Qualitative Study.

Many smaller hospitals in Germany are currently threatened with closure due to economic reasons and politically derived centralization. In some-especially rural areas-this may result in a lack of accessible local care structures. At the same time, patients are unnecessarily admitted to hospitals due to insufficient primary care structures and healthcare coordination. Intersectoral health centers (IHC), as new intermediary structures, may offer round-the-clock monitoring (Extended Outpatient Care, EOC), with fewer infrastructure needs than hospitals and, thus, could offer a sustainable solution. In an iterative process, 30 expert interviews (with physicians, nurses and other healthcare experts) formed the basis for the derivation of diagnostic groups, relevant related patient characteristics and scenarios, as well as structural preconditions necessary for safe care in the setting of the new model of IHC/EOC. Additionally, three workshops within the multidisciplinary research team (including healthcare services researchers, GPs, and health economists) were performed. Inductive categories on disease-, case-, sociodemographic- and infrastructure-related criteria were derived following thematic analysis. Due to the expert interviews, general practice equipment plus continuous monitoring beds should form the basic infrastructure for EOCs, which should be adjusted to local needs and infrastructure demands. GPs could be aided through (electronic) support by other specialists. IHC, as a physician-led facility, should rely on experienced nurses to allow for 24-h services and to support integrated team-based primary care with GPs. Alongside nurses, case managers, therapists and social workers can be included in the structure, allowing for improved integration of (primary) care services. In order to sustain low-threshold, local access to care, especially in rural areas, IHC with extended monitoring and integration of coordinative support, emerged as a promising solution that could solve many common patient needs without the need for hospital-based inpatient care.

Standard diametric versus volumetric early tumor shrinkage as a predictor of survival in metastatic colorectal cancer: subgroup findings of the randomized, open-label phase III trial FIRE-3 / AIO KRK-0306.

OBJECTIVES: Early tumor shrinkage (ETS) quantifies the objective response at the first assessment during systemic treatment. In metastatic colorectal cancer (mCRC), ETS gains relevance as an early available surrogate for patient survival. The aim of this study was to increase the predictive accuracy of ETS by using semi-automated volumetry instead of standard diametric measurements. METHODS: Diametric and volumetric ETS were retrospectively calculated in 253 mCRC patients who received 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) combined with either cetuximab or bevacizumab. The association of diametric and volumetric ETS with overall survival (OS) and progression-free survival (PFS) was compared. RESULTS: Continuous diametric and volumetric ETS predicted survival similarly regarding concordance indices (p > .05). In receiver operating characteristics, a volumetric threshold of 45% optimally identified short-term survivors. For patients with volumetric ETS ≥ 45% (vs < 45%), median OS was longer (32.5 vs 19.0 months, p < .001) and the risk of death reduced for the first and second year (hazard ratio [HR] = 0.25, p < .001, and HR = 0.39, p < .001). Patients with ETS ≥ 45% had a reduced risk of progressive disease only for the first 6 months (HR = 0.26, p < .001). These survival times and risks were comparable to those of diametric ETS ≥ 20% (vs < 20%). CONCLUSIONS: The accuracy of ETS in predicting survival was not increased by volumetric instead of diametric measurements. Continuous diametric and volumetric ETS similarly predicted survival, regardless of whether patients received cetuximab or bevacizumab. A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors. KEY POINTS: • ETS based on volumetric measurements did not predict survival more accurately than ETS based on standard diametric measurements. • Continuous diametric and volumetric ETS predicted survival similarly in patients receiving FOLFIRI with cetuximab or bevacizumab. • A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors.

Consequences of the Corona crisis on outpatient oncological care - a qualitative study among nurses and medical assistants.

INTRODUCTION: The Covid-19 pandemic has caused great personal stress for medical staff. To ensure adequate outpatient care for cancer patients, extensive safety and hygiene measures must be taken. This interview-based study examines the effects-both personal and professional-of the pandemic on the work routine of outpatient hematology/oncology nurses and medical assistants. PATIENTS, MATERIALS AND METHODS: Half a year after the outbreak of Covid-19 and the introduction of infection control regulations in three outpatient hematological/oncological centers, the affected medical staff (n = 15) were surveyed about the consequences for patient care and clinical work using audio-recorded telephone interviews. The interviews were transcribed and analyzed using a qualitative content analysis. RESULTS: The Covid-19 pandemic has complicated the medical care of cancer patients, but only a slight deterioration of medical and psycho-oncological care was observed. The level of stress experienced by medical staff is moderate, with hygiene and safety measures at the workplace helping to reduce stress. CONCLUSION: From the point of view of medical staff, the Covid-19 pandemic has had a moderate impact on the outpatient care of cancer patients. Safety measures against Covid-19 are decisive for ensuring the continuation of therapy and for motivating employees.

Inpatient Hospices in Germany: Medical Care Situation and Use of Supportive Oncological Therapies for Symptom Control in Tumor Patients.

Background: More than 80% of the residents in German hospices suffer from tumor disease. But the administration of supportive-oncological therapies in hospices for symptom control is controversially discussed. Objectives: This study aims to investigate the care situation of tumor patients in German hospices with regard to medical care and the use of supportive-oncological therapies. Methods: In February 2019, all hospices in Germany were offered the opportunity to participate in an anonymous online survey on medical and drug care for their tumor patients. The survey was conducted using the online platform SoSci Survey and ended in April 2019. The analysis was descriptive. Results: Of 202 hospices, 112 responded to the questionnaire. The hospices were distributed nationwide. Most have 8 to 10 places. More than 80% of hospice residents are tumor patients, and the length of stay is usually three to four weeks. Medical care is primarily provided by primary care physicians. While specialized outpatient palliative care is increasingly involved in care, hematologists/oncologists are rarely represented. Supportive-oncological therapies are rarely prescribed, whereas medication for other chronic conditions is often continued. The percentage of supportive-oncological therapies prescribed is higher in hospices with oncology co-care. Conclusions: Although most hospice residents suffer from malignant disease, co-care by a hematologist/oncologist is rare. Supportive-oncology therapies, particularly for symptom relief, may therefore be rarely used. However, since a small select group of hospice residents may benefit from these therapies, further investigation in this direction should be undertaken.

FOLFOX plus panitumumab or FOLFOX alone as additive therapy following R0/1 resection of RAS wild-type colorectal cancer liver metastases - The PARLIM trial (AIO KRK 0314).

PURPOSE: This trial investigates the addition of panitumumab to chemotherapy with fluorouracil/folinic acid and oxaliplatin (FOLFOX) in a 2:1 randomised, controlled, open-label, phase II trial in RAS wild-type colorectal cancer patients with R0/1-resected liver metastases. EXPERIMENTAL DESIGN: The primary endpoint was progression-free survival (PFS) two years after randomisation. The experimental arm (12 weeks of biweekly mFOLFOX6 plus panitumumab followed by 12 weeks of panitumumab alone) was considered active if the two-year PFS rate was ≥65%. Based on historical data, a two-year PFS rate of 50% was estimated in the control arm (12 weeks of biweekly FOLFOX). The trial was performed with a power of 80% and an alpha of 0.05. Secondary endpoints included overall survival (OS) and toxicity. The trial is registered with ClinicalTrials.gov, NCT01384994. RESULTS: The full analysis set consists of 70 patients (pts) in the experimental arm and 36 pts in the control arm. The primary endpoint was missed with a two-year PFS of 35.7% with FOLFOX plus panitumumab and 30.6% in the control arm. In comparative analyses, trends towards improved PFS (HR 0.83; 95%CI, 0.52-1.33; P = 0.44) and OS (HR 0.70; 95% CI, 0.34-1.46; P = 0.34) were observed in favour of the panitumumab-based study arm. No new or unexpected safety signals were observed with FOLFOX plus panitumumab following liver resection. CONCLUSION: The PARLIM trial failed to demonstrate a two-year PFS rate of 65% after resection of colorectal liver metastases. The positive trends in survival endpoints may support future trials evaluating treatment with anti-EGFR agents after resection of liver metastases.

First-line fluoropyrimidine plus bevacizumab followed by irinotecan-escalation versus initial fluoropyrimidine, irinotecan and bevacizumab in patients with metastatic colorectal cancer - Final survival and per-protocol analysis of the randomised XELAVIRI trial (AIO KRK 0110).

BACKGROUND: The randomised open-label phase III XELAVIRI trial failed to demonstrate non-inferiority of the sequential application of fluoropyrimidine plus bevacizumab followed by additional irinotecan at first progression (Arm A) versus initial combination of all agents (Arm B) for untreated metastatic colorectal cancer in the initial analysis of time-to-failure-of-strategy (TFS, 90% confidence boundary of 0.8). Here, we evaluate efficacy in the full analysis set (FAS), the per-protocol set, in addition to age-related and molecular subgroups. METHODS: Median TFS, overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method and log-rank test. Cox regression models assessed hazard ratios (HRs) and confidence intervals (CIs) (TFS: 90%; OS, PFS: 95%). RESULTS: Of 421 patients, 390 (92.6%), 391 (92.9%) and 357 (84.8%) events for TFS, OS and PFS were observed in the FAS with a median follow-up of 54.2 months (Arm A) versus 52.9 months (Arm B). Non-inferiority of sequential treatment for TFS was missed in the FAS (HR 0.93; 90% CI, 0.79-1.10; P = 0.482) and not shown in the per-protocol set (HR 0.93; 90% CI, 0.75-1.13, P = 0.433). Formal non-inferiority for TFS was observed for patients older than 70 years (HR 1.06; 90% CI, 0.80-1.41; P = 0.670) and patients with RAS mutant tumours (HR 1.12; 90% CI, 0.87-1.43; P = 0.465). In RAS/BRAF wild-type tumours, combination treatment was significantly superior to sequential therapy in all end-points. CONCLUSIONS: In the overall population, XELAVIRI just missed to demonstrate the non-inferiority of sequential compared to combination therapy for TFS. However, the non-inferiority of sequential treatment was observed in elderly patients and RAS mutant tumours. TRIAL REGISTRATION: Trial registration ID (clinicaltrials.gov) NCT01249638.

Serial Analysis of Gene Mutations and Gene Expression during First-Line Chemotherapy against Metastatic Colorectal Cancer: Identification of Potentially Actionable Targets within the Multicenter Prospective Biomarker Study REVEAL.

Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected DNA from primary tumor specimens (P), hepatic metastasis specimens after treatment (M), and liquid biopsies (L) taken prior to (pre), during (intra), and after (post) treatment to next generation sequencing. We performed Nanostring expression analysis in P and M specimens. Comparative bioinformatics and statistical analysis revealed typical mutational patterns with frequent alterations in TP53, APC, and KRAS in P specimens (n = 48). P and pre-L (n = 42), as well as matched P and M (n = 30), displayed a similar mutation spectrum. In contrast, gene expression profiles classified P (n = 31) and M (n = 23), distinguishable by up-regulation of immune/cytokine receptor and autophagy programs. Switching of consensus molecular subtypes from P to M occurred in 58.3% of cases. M signature genes SFRP2 and SPP1 associated with inferior survival, as validated in an independent cohort. Molecular changes during first-line treatment were detectable by expression profiling rather than by mutational tumor and liquid biopsy analyses. SFRP2 and SPP1 may serve as biomarkers and/or actionable targets.

Environmental Attitudes in 28 European Countries Derived From Atheoretically Compiled Opinions and Self-Reports of Behavior.

People differ in their personal commitment to fighting climate change and protecting the environment. The question is, can we validly measure people's commitment by what they say and what they claim they do in opinion polls? In our research, we demonstrate that opinions and reports of past behavior can be aggregated into comparable depictions of people's personal commitment to fighting climate change and protecting the environment (i.e., their environmental attitudes). In contrast to the commonly used operational scaling approaches, we ground our measure of people's environmental attitudes in a mathematically formalized psychological theory of the response process-the Campbell paradigm. This theory of the response process has already been extensively validated, and its relevance for manifest behavior has repeatedly been shown as well. In our secondary analysis of Eurobarometer data (N = 27,998) from 28 European countries, we apply the Campbell paradigm to a set of indicators that was not originally collected to be aggregated into a single scale. With our research, we propose a distinct way to measure behavior-relevant environmental attitudes that can be used even with a set of indicators that was originally atheoretically compiled. Overall, our study suggests that the Campbell paradigm provides a sound psychological measurement theory that can be applied to cross-cultural comparisons in the environmental protection domain.

Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3.

BACKGROUND: The evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients' age and sidedness of primary tumour. METHODS: The study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS. RESULTS: Overall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31). CONCLUSIONS: In FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC. CLINICAL TRIAL: FIRE-3 (NCT00433927).

Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy-Analysis of the Phase 3 XELAVIRI Trial.

INTRODUCTION: Early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial. METHODS: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex. RESULTS: In 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in RAS/BRAF wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: p < 0.001, HR 0.532; OS: p < 0.001, HR 0.574 vs. PFS: p = 0.107; OS: p = 0.965). CONCLUSIONS: Initial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

Oral and Subcutaneous Anticancer Therapy Training Course for Non-physician Healthcare Professionals: a Survey Evaluating the Relevance of its Content and its Implications in the Practice of Cancer Care.

The creation of antitumor agents with an oral or subcutaneous route of administration has had important positive implications in the development of drugs to treat cancers, but issues such as false drug intake, uncontrolled side effects, and limited supervision may jeopardize the ability of these agents to improve treatment. A potential solution is the recruitment of non-physician healthcare professionals (i.e., nurses and physician assistants) and a special training course for them that focuses on the improvement of patient compliance. We developed and implemented three special professional training modules for non-physician healthcare professionals, which focus on the pharmacological aspects and side effects of oral and subcutaneous antitumor medications in regard to management strategies and communication issues that these non-physician healthcare professionals should address. Subsequently, we administered a questionnaire survey evaluating the course content and the implementation of the course in practice to the training participants to collect data for its implementation. Of 165 questionnaires that were administered, 44 (27%) were answered. The participants rated the course as being highly useful for their daily work. The participants reported a significant improvement in their professional expertise from the course. They emphasized the importance of medical topics and practical content to be included in the course delivery. The course encouraged 75% of the responders to start independent consultations with cancer patients that focused on questions of medication adherence for oral and subcutaneous antitumor medications, as well as the management of their side effects. Based on our results, at least a portion of the non-physician healthcare workforce is highly interested in engaging in active and autonomous co-supervision of patients who are treated with oral and subcutaneous antitumor medications. In addition to the theoretical basics of the treatment modalities, educational courses on oral and subcutaneous antitumor medications for non-physician healthcare professionals should focus on practical training and topics relevant to patient care.