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Objectives An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the “real-world” setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany. Patients and methods This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1. Results In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4–10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9–9.2) with druggable ALK alterations. Conclusion Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.

ZusammenfassungÜber Register können Fragestellungen zur Gesundheitsversorgung im Alltag untersucht werden. Sie sind daher eine wesentliche Methode der Versorgungsforschung. Das Deutsche Netzwerk Versorgungsforschung (DNVF) fördert die Qualität von Registern durch einen wissenschaftlichen Austausch, durch Fortbildungsangebote sowie durch Empfehlungen in Form eines Memorandums „Register für die Versorgungsforschung“. Die vorliegenden Empfehlungen stellen ein Update zur ersten Fassung des Memorandums von 2010 dar. Das Update beschreibt die Einsatzmöglichkeiten und Zielsetzungen von Registern in der Versorgungsforschung und stellt den aktuellen Stand zu allen Aspekten eines guten Designs und eines sachgerechten Betriebs von Registern dar. Das Memorandum kann Verantwortlichen für die Entwicklung eines Registers als Leitfaden zur Erreichung einer hohen Qualität dienen; potentiellen Nutzern von Daten und Ergebnissen aus Registern ermöglicht es, die Qualität eines Registers zu bewerten. Projektförderer und Gesundheitspolitik können sich bei der Rahmensetzung für Finanzierung und gesetzliche Anforderungen an den Qualitätskriterien orientieren. Neben einer Definition werden im Memorandum verschiedene für die Konzeption eines Registers relevante Bereiche vorgestellt. Dies umfasst die Phasen der Entwicklung eines Registers von der Planung über den Entwurf bis zur Umsetzung, die technische Organisation und den Betrieb eines Registers, die Auswertung von Registerdaten, die Berichterstattung über die Ergebnisse sowie den Datenschutz. Aus diesen Bereichen abgeleitete Kriterien zur Beurteilung der Qualität eines Registers werden beschrieben. Hierfür wird abschließend eine Checkliste präsentiert.

Non‐clear cell renal cell carcinoma is a very rare malignancy that includes several histological subtypes. Each subtype may need to be addressed separately regarding prognosis and treatment; however, no Phase III clinical trial data exist. Thus, treatment recommendations for patients with non‐clear cell metastatic RCC (mRCC) remain unclear. We present first prospective data on choice of first‐ and second‐line treatment in routine practice and outcome of patients with papillary mRCC. From the prospective German clinical cohort study (RCC‐Registry), 99 patients with papillary mRCC treated with systemic first‐line therapy between December 2007 and May 2017 were included. Prospectively enrolled patients who had started first‐line treatment until May 15, 2016, were included into the outcome analyses (n = 82). Treatment was similar to therapies used for clear cell mRCC and consisted of tyrosine kinase inhibitors, mechanistic target of rapamycin inhibitors and recently checkpoint inhibitors. Median progression‐free survival from start of first‐line treatment was 5.4 months (95% confidence interval [CI], 4.1–9.2) and median overall survival was 12.0 months (95% CI, 8.1–20.0). At data cutoff, 73% of the patients died, 6% were still observed, 12% were lost to follow‐up, and 9% were alive at the end of the individual 3‐year observation period. Despite the lack of prospective Phase III evidence in patients with papillary mRCC, our real‐world data reveal effectiveness of systemic clear cell mRCC therapy in papillary mRCC. The prognosis seems to be inferior for papillary compared to clear cell mRCC. Further studies are needed to identify drivers of effectiveness of systemic therapy for papillary mRCC., What's new? Over the past decade, the treatment landscape for locally advanced or metastatic renal cell carcinoma (mRCC) has dramatically changed. To date, however, guideline recommendations mainly address patients with clear cell mRCC, due to a lack of prospective Phase III evidence for the rarer, non‐clear cell mRCC subtypes. This is the first longitudinal, prospective cohort study evaluating treatment and survival of patients with papillary mRCC outside a prospective clinical trial setting. The presented real‐world data help bridge the evidence gap by revealing the frequent use and effectiveness of systemic clear cell mRCC therapy in papillary mRCC, with a seemingly inferior prognosis.

Objectives Despite intensive research, the therapeutic options in extensive-stage small cell lung cancer (SCLC) are still limited. Data from routine clinical practice, so-called “real-world data”, are centrally important to assess and improve the standard of care. We present prospectively documented data on systemic first-, second- and third-line treatment, number of treatment lines and outcome parameters of patients treated by medical oncologists in Germany. Materials and methods This is a descriptive analysis on 432 patients with extensive-stage SCLC enrolled at start of first-line therapy into the prospective German clinical cohort study TLK (Tumour Registry Lung Cancer). Patients were recruited by 87 sites between February 2010 and December 2013 and followed-up individually for 3 years. Results The majority of patients (93%) received a first-line platinum-based combination therapy. Carboplatin plus etoposide was documented more frequently than cisplatin plus etoposide (46 vs. 35%); patients receiving carboplatin were older (68 vs. 63 years) and more often presented with poorer performance status (17 vs. 11% ECOG ≥ 2). Both regimens yielded similar response and survival rates. Median first-line overall survival (OS) was 10.2 months (95% confidence interval [CI] 8.6–12.3) for carboplatin plus etoposide and 12.2 months (95% CI 10.1–14.7) for cisplatin plus etoposide. Most patients (77%) would have been eligible for participation in a clinical trial. 50% of the patients received a second and 22% a third line of treatment. Median second-line OS was 5.8 months (95% CI 4.8–7.5), median third-line OS 5.7 months (95% CI 3.8–7.0). Conclusion To our knowledge, this is the first study of prospectively documented patients with extensive-stage SCLC in routine clinical practice. We present treatment algorithms as well as outcome parameters for a large cohort in first-, second- and third-line treatment. The survival times and response rates reported in this routine setting correspond to the respective measures from large prospective trials.

Purpose Quality of life (QoL) plays an important role in recovery—especially after an incisive diagnosis such as breast cancer. Here, we present a comprehensive assessment of QoL for pre- and postmenopausal patients, starting from initial systemic treatment of early breast cancer until 3 years later, in patients from a so-called “real-world” setting. Methods 251 premenopausal and 478 postmenopausal patients with early breast cancer have been recruited into the longitudinal MaLife project within the prospective, multicentre, German Tumour Registry Breast Cancer between 2011 and 2015. The questionnaires FACT-G, FACT-Taxane, FACT-ES, EORTC QLQ-BR23, BFI and HADS were filled in at start of treatment (T0), 6, 12, 24 and 36 months later. The proportion of patients with clinically meaningful changes at 36 months was determined. Results This first interim analysis shows that the FACT-G global QoL improved over time regardless of the menopausal status. However, clinically meaningful decrease of social/family well-being (48–51%), arm symptoms (44–49%) and symptoms of neurotoxicity (55–56%) was frequently reported 3 years after start of treatment. Many premenopausal patients also reported a clinically meaningful worsening of endocrine symptoms (64%), emotional well-being (36%) and fatigue intensity (37%). Additionally, 3 years after start of treatment, 15% of the patients were classified as doubtful cases and 18% as definite cases of anxiety. Conclusions Despite improvements in global QoL, breast cancer survivors report worsened ailments 3 years after start of therapy. Follow-up care should distinguish between premenopausal patients needing special attention for emotional/menopausal issues, and postmenopausal patients needing particular care regarding physical concerns. Electronic supplementary material The online version of this article (10.1007/s10549-019-05197-whttps://doi.org/10.1007/s10549-019-05197-w) contains supplementary material, which is available to authorized users.

Pancreatic cancer is a highly lethal malignancy. Developments in recent years have broadened our therapeutic armamentarium. Novel drugs such as nab-paclitaxel, liposomal irinotecan and chemotherapy regimens such as FOLFIRINOX have been successfully tested in clinical trials. Data on patients outside of clinical trials are scarce but necessary to assess and improve the standard of care. We present data on treatment and survival of 1,174 patients with locally advanced, inoperable, or metastatic pancreatic ductal adenocarcinoma. Between February 2014 and June 2017, patients were recruited by 104 sites at start of first-line therapy into the ongoing, prospective clinical cohort study TPK (Tumour Registry Pancreatic Cancer). As first-line therapy, 89% of patients received one of the three treatment regimens: gemcitabine monotherapy (23%), nab-paclitaxel plus gemcitabine (42%), or FOLFIRINOX (24%). The corresponding subgroups differed: Patients receiving gemcitabine monotherapy were older and more comorbid (median age 78 years, 73% ECOG ≥ 1) than patients receiving nab-paclitaxel plus gemcitabine (median age 71, 64% ECOG ≥ 1) or patients receiving FOLFIRINOX (median age 60, 52% ECOG ≥ 1). At least 40% of patients died before receiving second-line treatment. First-line progression-free survival was 4.6 months (95% CI: 3.7-5.2) for gemcitabine, 5.6 months (95% CI: 5.0-6.2) for nab-paclitaxel plus gemcitabine, and 6.3 months (95% CI: 5.5-6.9) for FOLFIRINOX. Our data represent the treatment reality in a German community setting. Although there are no stringent inclusion criteria for our cohort study, overall survival is comparable to that reported by randomised clinical trials.

Despite increasing treatment options, multiple myeloma (MM) remains incurable for most patients. Data on improvement of outcomes are derived from selected patient populations enrolled in clinical trials and might not be conferrable to all patients. Therefore, we assessed the trial eligibility, sequential treatment, and survival of non-transplant patients with MM treated in German routine care. The prospective clinical cohort study TLN (Tumour Registry Lymphatic Neoplasms) recruited 285 non-transplant patients with symptomatic MM at start of first-line treatment in 84 centres from 2009 to 2011. Demographic and clinical data were collected until August 2016. Trial-ineligibility was determined by presence of at least one of the common exclusion criteria: heart/renal failure, liver/renal diseases, polyneuropathy, HIV positivity. All other patients were considered potentially trial-eligible. Thirty percent of the patients in our study were classified as trial-ineligible. Median first-line progression-free survival (PFS) and overall survival (OS) of trial-ineligible patients were inferior to that of potentially trial-eligible patients: PFS 16.2 months (95% CI (confidence interval) 11.1–20.4) vs. 27.3 months (95% CI 23.3–33.0); OS 34.2 months (95% CI 21.6–48.1) vs. 58.6 months (95% CI 48.6–64.4). A high percentage of non-transplant patients with MM in German routine care would be ineligible for participation in clinical trials. Despite similar treatment algorithms, their first-line PFS and OS were shorter than those of potentially trial-eligible patients; the survival data of the latter were similar to results from clinical trials. Physicians should be aware of the fact that results from clinical trials may not mirror “real world” patient outcomes when discussing outcome expectations with patients. Trial registration: Clinicaltrials.gov identifier: NCT00889798.

Purpose Although treatment for early breast cancer improved prognosis greatly, it can have significant long-term consequences, which must be considered during treatment decision. Methods 453 patients with neoadjuvant or adjuvant treatment intention were recruited into the MaTox project within the prospective, multicentre, population-based German TMK cohort study (Tumour Registry Breast Cancer) between 2008 and 2009. Patient-reported outcomes (PROs) on 26 treatment-related symptoms were assessed via a specifically designed questionnaire at 4 weeks, 6 months, 18 months and 3 years after start of systemic treatment. Results The results show that alterations in smell, taste and appetite were clearly improved 3 years after treatment. In contrast, post-surgical symptoms, restrictions in memory/attention, musculoskeletal system and polyneuropathy worsened substantially over time and were persistent after 3 years: 78% of the patients recorded impairment in memory, 73% muscle pain, 67% pain at the operated site and 57% paraesthesia in fingers or toes. A logistic regression model showed that risk factors for developing persistent paraesthesia symptoms were age, early paraesthesia symptoms and taxane-based therapy. Conclusions Our data show that most patients with breast cancer have persistent impairments negatively influencing their daily life even 3 years after treatment. Furthermore, we highlight areas requiring special attention in follow-up care. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4365-7) contains supplementary material, which is available to authorized users.

Korrektur zu 10.1016/j.lungcan.2020.10.012

Importance: Mortality, morbidity, and health-related quality of life (HRQoL) are patient-relevant end points generally considered in the early benefit assessments of new cancer treatments. Progression-related end points, such as time to progression or progression-free survival, are not included, although patients and physicians testify to the detrimental association of disease progression with HRQoL. Objective: To examine the association of disease progression and HRQoL in 4 prevalent solid-cancer entities in routine clinical practice. Design, Setting, and Participants: This cohort study evaluated data from 4 prospective, nonintervention, multicenter registries collected between 2011 and 2018 in 203 centers in Germany. Patients' HRQoL was assessed regularly for up to 5 years. The change in HRQoL scores after disease progression was examined with linear mixed models, adjusting for demographic and clinical covariates. Patients with metastatic breast, pancreatic, lung, and colorectal cancer were recruited at the start of systemic first-line treatment. Data analysis was performed from February 2019 to April 2019. Exposures: All patients received systemic, palliative first-line treatment according to their physician's choice. Main Outcomes and Measures: The primary outcome was deterioration of HRQoL associated with disease progression, as measured by 4 validated questionnaires: Functional Assessment of Cancer Therapy-General version 4, European Organization for Research and Treatment of Cancer QLQ-C30 version 3.0, European Organization for Research and Treatment of Cancer QLQ-C15-PAL version 1, and Hospital Anxiety and Depression Scale. Results: More than 8000 questionnaires from 2314 patients with 2562 documented disease progressions were analyzed. In total, 464 patients had breast cancer (464 [100.0%] female; median [range] age, 61.6 [26.4-90.1] years), 807 patients had pancreatic cancer (352 [43.6%] female; median [range] age, 70.0 [39.0-93.0] years), 341 patients had lung cancer (118 [34.6%] female; median [range] age, 65.9 [28.4-88.2] years), and 702 patients had colorectal cancer (248 [35.3%] female; median [range] age, 66.9 [26.9-92.1] years). The first disease progression was associated with a statistically significant worsening of 37 of 45 HRQoL scales; for 17 of these scales, the worsening was clinically meaningful. Scale scores for appetite loss (pancreatic cancer, 10.2 points [95% CI, 6.8-13.5 points]; lung cancer, 10.8 points [95% CI, 5.4-16.2 points]; colorectal cancer, 8.8 points [95% CI, 5.5-12.2]; all P

Grainyhead/CP2 transcription factor family members are widely conserved among the animal kingdom and have been implicated in different developmental processes. Thus far, nothing has been known about their roles in zebrafish. Here we identify seven zebrafish grainyhead-like (grhl) / cp2 genes, with focus on grhl1, which is expressed in the periderm and in epidermal ionocyte progenitors, but downregulated when ionocytes differentiate. In addition, expression was detected in other "non-keratinocyte" cell types of the epidermis, such as pvalb8-expressing cells, which according to our lineage tracing experiments are derived from the same pool of progenitor cells like keratinocytes and ionocytes. Antisense morpholino oligonucleotide-based loss-of-function analysis revealed that grhl1 is dispensable for the development and function of all investigated epidermal cell types, but required as a negative regulator of its own transcription during ionocyte differentiation. Knockdown of the transcription factor Foxi3a, which is expressed in a subset of the grhl1 population, caused a loss of ionocytes and a corresponding increase in the number of pvalb8-expressing cells, while leaving the number of grhl1-positive cells unaltered. We propose that grhl1 is a novel common marker of all or most "non-keratinocyte" epidermal progenitors, and that the sub-functionalisation of these cells is regulated by differential positive and negative effects of Foxi3 factors.

Ionocytes are specialized epithelial cell types involved in the maintenance of osmotic homeostasis. In amniotes, they are present in the renal system, while in water-living embryos of lower vertebrates additional ionocytes are found in the skin. Thus far, relatively little has been known about the mechanisms of ionocyte development. Here we demonstrate that skin ionocytes of zebrafish embryos derive from the same precursor cells as keratinocytes. Carrying out various combinations of gain- and loss-of-function studies, we show that the segregation of ionocytes from the epidermal epithelium is governed by an interplay between Notch signaling and two Forkhead-box transcription factors, Foxi3a and Foxi3b. The two foxi3 genes are expressed in ionocyte precursors and are required both for ionocyte-specific expression of the Notch ligand Jagged2a, and for ionocyte differentiation, characterized by the production of particular ATPases. Ionocytic Notch ligands, in turn, signal to neighboring cells, where activated Notch1 leads to a repression of foxi3 expression, allowing those cells to become keratinocytes. A model for ionocyte versus keratinocyte development will be presented, postulating additional thus far unidentified pro-ionocyte factors.

s / The Breast 24 S3 (2015) S21–S75 S39 Aim: The idea is to overcome such mental and familial stress utilizing the services of volunteers and survivors as doctors are too busy to be able to spend quality time with the patients. Method: We have a substantial flow of cancer patient as oncology unit of MAS Clinic, India. The idea is to train volunteers to do this communicating under the guidance of doctors. Through regular orientation get together of new patient and their relatives with survivors and volunteers. Result: Till the end of 2014 we have been able to successfully do this kind of job in a substantial number of patients where come to our notice. Conclusion: Psychological support is an essential element of holistic patient care in diagnosis of cancer. And this can be effectively done through the help of volunteers and survivors also. Clinical Issues: Medical Oncology