Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Prognostic value of deep learning-derived body composition in advanced pancreatic cancer-a retrospective multicenter study.

BACKGROUND: Despite the prognostic relevance of cachexia in pancreatic cancer, individual body composition has not been routinely integrated into treatment planning. In this multicenter study, we investigated the prognostic value of sarcopenia and myosteatosis automatically extracted from routine computed tomography (CT) scans of patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We retrospectively analyzed clinical imaging data of 601 patients from three German cancer centers. We applied a deep learning approach to assess sarcopenia by the abdominal muscle-to-bone ratio (MBR) and myosteatosis by the ratio of abdominal inter- and intramuscular fat to muscle volume. In the pooled cohort, univariable and multivariable analyses were carried out to analyze the association between body composition markers and overall survival (OS). We analyzed the relationship between body composition markers and laboratory values during the first year of therapy in a subgroup using linear regression analysis adjusted for age, sex, and American Joint Committee on Cancer (AJCC) stage. RESULTS: Deep learning-derived MBR [hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.47-0.77, P < 0.005] and myosteatosis (HR 3.73, 95% CI 1.66-8.39, P < 0.005) were significantly associated with OS in univariable analysis. In multivariable analysis, MBR (P = 0.019) and myosteatosis (P = 0.02) were associated with OS independent of age, sex, and AJCC stage. In a subgroup, MBR and myosteatosis were associated with albumin and C-reactive protein levels after initiation of therapy. Additionally, MBR was also associated with hemoglobin and total protein levels. CONCLUSIONS: Our work demonstrates that deep learning can be applied across cancer centers to automatically assess sarcopenia and myosteatosis from routine CT scans. We highlight the prognostic role of our proposed markers and show a strong relationship with protein levels, inflammation, and anemia. In clinical practice, automated body composition analysis holds the potential to further personalize cancer treatment.

Impact of encorafenib on survival of patients with BRAFV600E-mutant metastatic colorectal cancer in a real-world setting.

PURPOSE: Patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) have a dismal prognosis. The best strategies in these patients remain elusive. Against this background, we report the clinical course of patients with BRAFV600E-mutant mCRC to retrieve the best treatment strategy. PATIENTS AND METHODS: Clinico-pathological data were extracted from the electronic health records. Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). Objective response rate (ORR) was assessed according to RECIST 1.1. RESULTS: In total, 51 patients were enrolled. FOLFOXIRI was administered to 12 patients; 29 patients received FOLFOX or FOLFIRI as first-line treatment. Median OS was 17.6 months. Median PFS with FOLFOXIRI (13.0 months) was significantly prolonged (HR 0.325) as compared to FOLFOX/FOLFIRI (4.3 months). However, this failed to translate into an OS benefit (p = 0.433). Interestingly, addition of a monoclonal antibody to chemotherapy associated with superior OS (HR 0.523). A total of 64.7% patients received further-line therapy, which included a BRAF inhibitor in 17 patients. Targeted therapy associated with very favourable OS (25.1 months). CONCLUSION: Patients with BRAFV600E-mutated mCRC benefit from the addition of an antibody to first-line chemotherapy. Further-line treatment including a BRAF inhibitor has a dramatic impact on survival.

Smaller panel, similar results: genomic profiling and molecularly informed therapy in pancreatic cancer.

BACKGROUND: Pancreatic cancer has a dismal prognosis. One reason is resistance to cytotoxic drugs. Molecularly matched therapies might overcome this resistance but the best approach to identify those patients who may benefit is unknown. Therefore, we sought to evaluate a molecularly guided treatment approach. MATERIALS AND METHODS: We retrospectively analyzed the clinical outcome and mutational status of patients with pancreatic cancer who received molecular profiling at the West German Cancer Center Essen from 2016 to 2021. We carried out a 47-gene DNA next-generation sequencing (NGS) panel. Furthermore, we assessed microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status and, sequentially and only in case of KRAS wild-type, gene fusions via RNA-based NGS. Patient data and treatment were retrieved from the electronic medical records. RESULTS: Of 190 included patients, 171 had pancreatic ductal adenocarcinoma (90%). One hundred and three patients had stage IV pancreatic cancer at diagnosis (54%). MMR analysis in 94 patients (94/190, 49.5%) identified 3 patients with dMMR (3/94, 3.2%). Notably, we identified 32 patients with KRAS wild-type status (16.8%). To identify driver alterations in these patients, we conducted an RNA-based fusion assay on 13 assessable samples and identified 5 potentially actionable fusions (5/13, 38.5%). Overall, we identified 34 patients with potentially actionable alterations (34/190, 17.9%). Of these 34 patients, 10 patients (10/34, 29.4%) finally received at least one molecularly targeted treatment and 4 patients had an exceptional response (>9 months on treatment). CONCLUSIONS: Here, we show that a small-sized gene panel can suffice to identify relevant therapeutic options for pancreatic cancer patients. Informally comparing with previous large-scale studies, this approach yields a similar detection rate of actionable targets. We propose molecular sequencing of pancreatic cancer as standard of care to identify KRAS wild-type and rare molecular subsets for targeted treatment strategies.

Build-up and dephasing of Floquet-Bloch bands on subcycle timescales.

Strong light fields have created opportunities to tailor novel functionalities of solids1-5. Floquet-Bloch states can form under periodic driving of electrons and enable exotic quantum phases6-15. On subcycle timescales, lightwaves can simultaneously drive intraband currents16-29 and interband transitions18,19,30,31, which enable high-harmonic generation16,18,19,21,22,25,28-30 and pave the way towards ultrafast electronics. Yet, the interplay of intraband and interband excitations and their relation to Floquet physics have been key open questions as dynamical aspects of Floquet states have remained elusive. Here we provide this link by visualizing the ultrafast build-up of Floquet-Bloch bands with time-resolved and angle-resolved photoemission spectroscopy. We drive surface states on a topological insulator32,33 with mid-infrared fields-strong enough for high-harmonic generation-and directly monitor the transient band structure with subcycle time resolution. Starting with strong intraband currents, we observe how Floquet sidebands emerge within a single optical cycle; intraband acceleration simultaneously proceeds in multiple sidebands until high-energy electrons scatter into bulk states and dissipation destroys the Floquet bands. Quantum non-equilibrium calculations explain the simultaneous occurrence of Floquet states with intraband and interband dynamics. Our joint experiment and theory study provides a direct time-domain view of Floquet physics and explores the fundamental frontiers of ultrafast band-structure engineering.

The OUTREACH study: oncologists of German university hospitals in rotation on a palliative care unit-evaluation of attitude and competence in palliative care and hospice.

PURPOSE: The effect of the duration of an educational rotation presented at a palliative care unit on the palliative care knowledge gain and the increase of palliative care self-efficacy expectations are unclear. METHODS: This national prospective multicenter pre-post survey conducted at twelve German University Comprehensive Cancer Centers prospectively enrolled physicians who were assigned to training rotations in specialized palliative care units for three, six, or twelve months. Palliative care knowledge [in %] and palliative care self-efficacy expectations [max. 57 points] were evaluated before and after the rotation with a validated questionnaire. RESULTS: From March 2018 to October 2020, questionnaires of 43 physicians were analyzed. Physicians participated in a 3- (n = 3), 6- (n = 21), or 12-month (n = 19) palliative care rotation after a median of 8 (0-19) professional years. The training background of rotating physicians covered a diverse spectrum of specialties; most frequently represented were medical oncology (n = 15), and anesthesiology (n = 11). After the rotation, median palliative care knowledge increased from 81.1% to 86.5% (p < .001), and median palliative care self-efficacy expectations scores increased from 38 to 50 points (p < .001). The effect of the 12-month rotation was not significantly greater than that of the 6-month rotation. CONCLUSION: An educational rotation presented in a specialized palliative care unit for at least six months significantly improves palliative care knowledge and palliative care self-efficacy expectations of physicians from various medical backgrounds.

A prognostic systemic inflammation score (SIS) in patients with advanced intrahepatic cholangiocarcinoma.

PURPOSE: Systemic-inflammatory response parameters (SIR) are known prognostic markers in different tumour entities, but have not been evaluated in patients with iCCA treated with systemic chemotherapy. Therefore, we evaluated the impact of different SIR markers on the clinical course of patients with advanced iCCA treated at our center. METHODS: SIR markers were retrospectively evaluated in 219 patients with iCCA at the West-German-Cancer-Center Essen from 2014 to 2019. Markers included neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), CRP, and the modified Glasgow-Prognostic-Score (mGPS), which were correlated with clinico-pathological findings, response to chemotherapy (ORR), progression-free (PFS) and overall survival (OS) using Kaplan-Meier analyses, and Cox proportional models. RESULTS: Median overall survival (OS) of the entire cohort was 14.8 months (95% CI 11.2-24.4). Median disease-free survival (DFS) in 81 patients undergoing resection was 12.3 months (95% CI 9.7-23.1). The median OS from start of palliative CTX (OSpall) was 10.9 months (95% 9.4-14.6). A combined Systemic Inflammatory Score (SIS) comprising all evaluated SIR markers correlated significantly with ORR, PFS, and OSpall. Patients with a high SIS (≥ 2) vs. SIS 0 had a significantly inferior OSpall (HR 8.7 95% CI 3.71-20.38, p < 0.001). Multivariate analysis including known prognostic markers (ECOG, CA19-9, LDH, and N- and M-status) identified the SIS as an independent prognostic factor. CONCLUSIONS: Inflammatory markers associate with inferior survival outcomes in patients with iCCA. A simple SIS may guide treatment decisions in patients treated with systemic chemotherapy.

Palliative care outpatients in a German comprehensive cancer center-identifying indicators for early and late referral.

PURPOSE: Despite that early integration of palliative care is recommended in advanced cancer patients, referrals to outpatient specialised palliative care (SPC) frequently occur late. Well-defined referral criteria are still missing. We analysed indicators associated with early (ER) and late referral (LR) to SPC of an high volume outpatient unit of a comprehensive cancer center. METHODS: Characteristics, laboratory parameters and symptom burden of 281 patients at first SPC referral were analysed. Timing of referral was categorized as early, intermediate and late (> 12, 3-12 and < 3 months before death). Ordinal logistic regression analysis was used to identify factors related to referral timing. Kruskal-Wallis test was used to determine symptom severity and laboratory parameter in each referral category. RESULTS: LRs (50.7%) had worse scores of weakness, loss of appetite, drowsiness, assistance of daily living (all p < 0.001) and organisation of care (p < 0.01) in contrast to ERs. The mean symptom sum score was significantly higher in LRs than ERs (13.03 vs. 16.08; p < 0.01). Parameters indicative of poor prognosis, such as elevated LDH, CRP and neutrophil-to-lymphocyte ratio (NLR) (p < 0.01) as well as the presence of ascites (p < 0.05), were significantly higher (all p < 0.001) in LRs. In univariable analyses, psychological distress (p < 0.05) and female gender (p < 0.05) were independently associated with an ER. CONCLUSION: A symptom sum score and parameters of poor prognosis like NLR or LDH might be useful to integrate into palliative care screening tools.

Multimodal survival prediction in advanced pancreatic cancer using machine learning.

BACKGROUND: Existing risk scores appear insufficient to assess the individual survival risk of patients with advanced pancreatic ductal adenocarcinoma (PDAC) and do not take advantage of the variety of parameters that are collected during clinical care. METHODS: In this retrospective study, we built a random survival forest model from clinical data of 203 patients with advanced PDAC. The parameters were assessed before initiation of systemic treatment and included age, CA19-9, C-reactive protein, metastatic status, neutrophil-to-lymphocyte ratio and total serum protein level. Separate models including imaging and molecular parameters were built for subgroups. RESULTS: Over the entire cohort, a model based on clinical parameters achieved a c-index of 0.71. Our approach outperformed the American Joint Committee on Cancer (AJCC) staging system and the modified Glasgow Prognostic Score (mGPS) in the identification of high- and low-risk subgroups. Inclusion of the KRAS p.G12D mutational status could further improve the prediction, whereas radiomics data of the primary tumor only showed little benefit. In an external validation cohort of PDAC patients with liver metastases, our model achieved a c-index of 0.67 (mGPS: 0.59). CONCLUSIONS: The combination of multimodal data and machine-learning algorithms holds potential for personalized prognostication in advanced PDAC already at diagnosis.

Coherent Modulation of Quasiparticle Scattering Rates in a Photoexcited Charge-Density-Wave System.

We present a complementary experimental and theoretical investigation of relaxation dynamics in the charge-density-wave (CDW) system TbTe_{3} after ultrafast optical excitation. Using time- and angle-resolved photoemission spectroscopy, we observe an unusual transient modulation of the relaxation rates of excited photocarriers. A detailed analysis of the electron self-energy based on a nonequilibrium Green's function formalism reveals that the phase space of electron-electron scattering is critically modulated by the photoinduced collective CDW excitation, providing an intuitive microscopic understanding of the observed dynamics and revealing the impact of the electronic band structure on the self-energy.

[PARPACT: Paramedic Palliative Care Test : Validation of a questionnaire to assess palliative care knowledge and self-efficacy expectations of paramedics]. / PARPACT ­ Paramedic Palliative Care Test : Validierung eines Tests für palliatives Wissen und Selbstwirksamkeitserwartung bei Mitarbeiter*innen im Rettungswesen.

BACKGROUND: Given the large number of palliative patients cared for by the emergency services, education and training in palliative care topics are playing an increasingly important role. To support decision-making in an emergency setting a palliative or emergency card has been introduced in many cities. OBJECTIVES: To assess the success of educational interventions and the effect of the palliative or emergency card, a questionnaire was developed and validated to determine palliative knowledge and palliative self-efficacy expectations in the emergency services. MATERIALS AND METHODS: A Delphi process was applied for development and content validation. Factor analysis was used for construct validation. Criterion validity was assessed with the help of 22 nurses specially trained in palliative care. Reliability was determined using Cronbach's alpha as a measure of internal consistency. RESULTS: In all, 291 of 750 paramedics participated in the voluntary survey. After completion of the Delphi process, there was consensus that the important topics of pain, dyspnea, sedation, end-of-life care, euthanasia, and legal aspects were covered in the questionnaire. Factor analysis was in favor of a six-factor solution. Criterion validation revealed a significant difference in palliative knowledge between palliative care nurses (MRang 289.73) and paramedics (MRang 146.97, U = 281.000, r = 0.40, p < 0.001). Cronbach's alpha was 0.70 for the knowledge questions and 0.82 for the palliative care self-efficacy expectancy subscale. CONCLUSIONS: The Paramedic Palliative Care Test (PARPACT) is a validated measurement tool for testing educational interventions in paramedicine.

Changes in fatigue, barriers, and predictors towards physical activity in advanced cancer patients over a period of 12 months-a comparative study.

PURPOSE: Physical activity (PA) is recommended to improve advanced cancer patients' (ACP) physical functioning, fatigue, and quality of life. Yet, little is known about ACPs' attitude towards PA and its influence on fatigue and depressiveness over a longer period. This prospective, non-interventional cohort study examined ACPs' fatigue, depression, motivation, and barriers towards PA before and after 12 months of treatment among ACP METHODS: Outpatients with incurable cancer receiving treatment at a German Comprehensive Cancer Center reporting moderate/severe weakness/tiredness during self-assessment via MIDOS II were enrolled. Fatigue (FACT-F), depression (PHQ-8), cancer-related parameters, self-assessed PA behavior, motivation for and barriers against PA were evaluated (T0). Follow-up data was acquired after 12 months (T1) using the same questionnaire. RESULTS: At follow-up, fatigue (p=0.017) and depressiveness (p=0.015) had increased in clinical relevant extent. Physically active ACP did not show significant progress of FACT-F (p=0.836) or PHQ-8 (p=0.799). Patient-reported barriers towards PA remained stable. Logistic regression analyses identified motivation as a positive predictor for PA at both time points (T0, ß=2.152, p=0.017; T1, ß =2.264, p=0.009). Clinically relevant depression was a negative predictor for PA at T0 and T1 (T0, ß=-3.187, p=0.044; T1, ß=-3.521, p=0.041). CONCLUSION: Our findings emphasize the importance of psychological conditions in physical activity behavior of ACP. Since psychological conditions seem to worsen over time, early integration of treatment is necessary. By combining therapy approaches of cognitive behavioral therapy and exercise in interdisciplinary care programs, the two treatment options might reinforce each other and sustainably improve ACPs' fatigue, physical functioning, and QoL. TRIAL REGISTRATION: German Register of Clinical Trials, DRKS00012514, registration date: 30.05.2017.

FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma.

BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

Combined systemic inflammation score (SIS) correlates with prognosis in patients with advanced pancreatic cancer receiving palliative chemotherapy.

PURPOSE: The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains dismal. New cytotoxic agents such as nab-paclitaxel and liposomal irinotecan (nal-Iri) have extended the armamentarium of therapeutic options in the last years. Nowadays, sequential therapeutic strategies with moderately toxic chemotherapeutic protocols can be administered to the patients. However, prognostic and predictive biomarkers are still missing to identify those patients, which profit most from a "continuum of care" concept rather than receiving intensive first-line protocols such as FOLFIRINOX. To this end, we retrospectively evaluated the impact of the systemic inflammation as one essential hallmark of cancer in patients with advanced PDAC treated with sequential systemic. METHODS: A cohort of 193 PDAC patients treated at our center from January 2005 to August 2011 were retrospectively evaluated for the following systemic inflammatory response (SIR) markers: neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR) C-reactive protein (CRP), and the modified Glasgow Prognostic Score (mGPS). SIR markers were correlated with clinico-pathological findings, response to chemotherapy and overall survival (OS) using Kaplan-Meier curves and Cox proportional models. RESULTS: All evaluated SIR markers were significantly associated with OS in patients with metastatic disease but not in patients with locally advanced PDAC. Interestingly, all SIR markers were only prognostic in patients not receiving antibiotics as surrogate marker for systemic bacterial infections. Based on the evaluated SIR markers, we propose a new Systemic Inflammation Score (SIS), which significantly correlated with reduced OS (HR: 3.418 (1.802-6.488, p < 0.001)) and the likelihood of receiving further-line systemic therapies (p = 0.028). CONCLUSION: Routinely assessed SIR biomarkers have potential to support therapeutic decision making in patients with metastatic PDAC.

Revealing Hidden Orbital Pseudospin Texture with Time-Reversal Dichroism in Photoelectron Angular Distributions.

We performed angle-resolved photoemission spectroscopy (ARPES) of bulk 2H-WSe_{2} for different crystal orientations linked to each other by time-reversal symmetry. We introduce a new observable called time-reversal dichroism in photoelectron angular distributions (TRDAD), which quantifies the modulation of the photoemission intensity upon effective time-reversal operation. We demonstrate that the hidden orbital pseudospin texture leaves its imprint on TRDAD, due to multiple orbital interference effects in photoemission. Our experimental results are in quantitative agreement with both the tight-binding model and state-of-the-art fully relativistic calculations performed using the one-step model of photoemission. While spin-resolved ARPES probes the spin component of entangled spin-orbital texture in multiorbital systems, we unambiguously demonstrate that TRDAD reveals its orbital pseudospin texture counterpart.

Fatigue, barriers to physical activity and predictors for motivation to exercise in advanced Cancer patients.

BACKGROUND: In order to counteract fatigue, physical activity (PA) is recommended for all stages of cancer. However, only few advanced cancer patients (ACP) are physically active. Quantitative data with high numbers of ACP reporting barriers to PA are missing. This study aimed to identify barriers to PA in ACP with tiredness/weakness and investigate their motivation towards it. METHODS: Outpatients with metastatic cancer receiving cancer care at a German Cancer Center reporting moderate/severe tiredness/weakness during self-assessment (MIDOS II) were enrolled. We assessed Fatigue-(FACF-F) and Depression (PHQ8) Scores, demographics, cancer-specific parameters, motivation for PA, physical, psychological and social barriers. RESULTS: 141 of 440 eligible patients (32.0%) with different diagnoses agreed to participate. Patients frequently reported "I feel weakened due to my tumor therapy" (n = 108; 76.6%), physical symptoms (tiredness, weakness, dyspnea, joint-problems, pain, nausea [n = 107; 75.9%]) and fatigue (n = 99; 70.2%) as barriers to PA. However, no significant group differences regarding these barriers were found between physically active and inactive patients. Social barriers were rarely chosen. Motivated patients were 5.6 times more likely to be physically active (p < 0.001), also motivation turned out to be the strongest predictor for a physically active behavior (ß = 1.044; p = 0.005). Motivated attitude towards PA was predicted by fatigue (ß = - 2.301; p = 0.008), clinically relevant depression (ß = - 1.390, p = 0.039), knowledge about PA and quality of life (QoL) (ß = 0.929; p = 0.002), PA before diagnosis (ß = 0.688; p = 0.005 and Interest in exercise program (ß = 0.635; p = 0.008). CONCLUSION: "I feel weakened due to my tumor therapy" is the most reported barrier to PA among both, physically and inactive patients. Motivation for PA is the strongest predictor of performing PA. Interest in PA, knowledge about PA/QoL and PA before diagnosis are main predictors of a motivated attitude. Absence/presence of social barriers did not associate with motivation, fatigue and depression proved to be a negative predictor. Programs including information, motivational counseling and individualized training should be offered for ACP to overcome barriers and reduce fatigue. TRIAL REGISTRATION: German Register of Clinical Trials DRKS00012514, registration date: 30.5.2017.

Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial.

BACKGROUND: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. PATIENTS AND METHODS: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. RESULTS: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). CONCLUSIONS: MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).

Substrate-specificity of cytochrome P450-mediated detoxification as an evolutionary strategy for specialization on furanocoumarin-containing hostplants: CYP6AE89 in parsnip webworms.

The parsnip webworm, Depressaria pastinacella, is restricted to two hostplant genera containing six structurally diverse furanocoumarins. Of these, imperatorin is detoxified by a specialized cytochrome P450, CYP6AB3. A previous whole-larva transcriptome analysis confirmed the presence of nine transcripts that belong to the CYP6AE subfamily. Here, by examining midgut-specific gene expression patterns we determined that CYP6AE89 transcripts were highly expressed and furanocoumarin-inducible. Computer docking and energy-minimization of a CYP6AE89 model with all six furanocoumarins showed that 5-methoxylated bergapten and 8-methoxylated xanthotoxin had the smallest distances from the heme to the proton-donor residue in the catalytic I-helix, and that the 5,8-dimethoxylated isopimpinellin and bergapten had the smallest energy-minimized distance from the heme oxygen to the furan ring double bond. To evaluate this prediction, we expressed the CYP6AE89 protein in an Escherichia coli system, and used it to detect high catalytic activity against the two mono-methoxylated linear furanocoumarins - bergapten and xanthotoxin - and weak activity against isopimpinellin. Thus, CYP6AE89, like CYP6AB3, is probably specialized for detoxifying only a subset of hostplant furanocoumarins. A maximum-likelihood tree built with six representative lepidopterans with manually annotated cytochrome P450s shows that CYP6AE89 may have evolved much faster than the other CYP6AE proteins, possibly indicative of host selection pressure.