Determining the value of the abdominal core health quality collaborative to support regulatory decisions.

PURPOSE: The study objective is to document value created by real-world evidence from the Abdominal Core Health Quality Collaborative (ACHQC) for regulatory decisions. The ACHQC is a national effort that generates data on hernia repair techniques and devices. METHODS: Two retrospective cohort evaluations compared cost and time of ACHQC analyses to traditional postmarket studies. The first analysis was based on 25 reports submitted to the European Medicines Agency of 20 mesh products for post-market surveillance. A second analysis supported label expansion submitted to the Food and Drug Administration, Center for Devices and Radiological Health for a robotic-assisted surgery device to include ventral hernia repair. Estimated costs of counterfactual studies, defined as studies that might have been done if the registry had not been available, were derived from a model described in the literature. Return on investment, percentage of cost savings, and time savings were calculated. RESULTS: 45,010 patients contributed to the two analyses. The cost and time differences between individual 25 ACHQC analyses (41,112 patients) and traditional studies ranged from $1.3 to $2.2 million and from 3 to 4.8 years, both favoring use of the ACHQC. In the second label expansion analysis (3,898 patients), the estimated return on investment ranged from 11 to 461% with time savings of 5.1 years favoring use of the ACHQC. CONCLUSIONS: Compared to traditional postmarket studies, use of ACHQC data can result in cost and time savings when used for appropriate regulatory decisions in light of key assumptions.

Changes over time in the course of advanced pancreatic cancer treatment with systemic chemotherapy: a pooled analysis of five clinical trials from two decades of the German AIO study group.

BACKGROUND: Over the past two decades, our group has conducted five multicenter trials focusing on first-line systemic therapy for patients with advanced pancreatic cancer. The current pooled analysis was designed to evaluate prognosis over time and the impact of clinical characteristics on survival. PATIENTS AND METHODS: Individual patient data were derived from five prospective, controlled, multicenter trials conducted by the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO): 'Gem/Cis', 'Ro96', 'RC57', 'ACCEPT' and 'RASH', which recruited patients between December 1997 and January 2017. RESULTS: Overall, 912 patients were included. The median overall survival (OS) for all assessable patients was 7.1 months. OS significantly improved over time, with a median OS of 8.6 months for patients treated from 2012 to 2017 compared with 7.0 months from 1997 to 2006 [hazard ratio (HR) 1.06; P < 0.004]. Eastern Cooperative Oncology Group performance status (HR 1.48; P < 0.001), use of second-line treatment (HR 1.51; P < 0.001), and Union for International Cancer Control (UICC) stage (III versus IV) (HR 1.34, P = 0.002) had a significant impact on OS. By contrast, no influence of age and gender on OS was detectable. Comparing combination therapy with single-agent chemotherapy did not demonstrate a survival benefit, nor did regimens containing epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as afatinib or erlotinib, compared with chemotherapy-only arms. Patients with early-onset pancreatic cancer (age at study entry of ≤50 years, n = 102) had a similar OS compared with those >50 years (7.1 versus 7.0 months; HR 1.13; P = 0.273). The use of a platinum-containing regimen was not associated with better outcomes in patients with early-onset pancreatic cancer. CONCLUSIONS: Within this selected group of patients treated within prospective clinical trials, survival has shown improvement over two decades. This effect is likely attributable to the availability of more effective combination therapies and treatment lines, rather than to any specific regimen, such as those containing EGFR-TKIs. In addition, concerning age and sex subgroups, the dataset did not provide evidence for distinct clinical behavior.

Geriatric assessment and the variance of treatment recommendations in geriatric patients with gastrointestinal cancer-a study in AIO oncologists.

BACKGROUND: Geriatric assessment (GA) is recommended to detect vulnerabilities for elderly cancer patients. To assess whether results of GA actually influence the treatment recommendations, we conducted a case vignette-based study in medical oncologists. MATERIALS AND METHODS: Seventy oncologists gave their medical treatment recommendations for a maximum of 4 out of 10 gastrointestinal cancer patients in three steps: (i) based on tumor findings alone to simulate the guideline recommendation for a '50-year-old standard patient without comorbidities'; (ii) for the same situation in elderly patients (median age 77.5 years) according to the comorbidities, laboratory values and a short video simulating the clinical consultation; and (iii) after the results of a full GA including interpretation aid [Barthel Index, Cumulative Illness Rating Scale (CIRS), Geriatric 8 (G8), Geriatric Depression Scale (GDS), Mini Mental Status Examination (MMSE), Mini-Nutritional Assessment (MNA), Timed Get Up and Go (TGUG), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 (EORTC QLQ-C30), stair climb test]. RESULTS: Data on 164 treatment recommendations were analyzed. The recommendations had a significantly higher variance for elderly patients than for 'standard' patients (944 versus 602, P < 0.0001) indicating a lower agreement between oncologists. Knowledge on GA had marginal influence on the treatment recommendation or its variance (944 versus 940, P = 0.92). There was no statistically significant influence of the working place or the years of experience in oncology on the variance of recommendations. The geriatric tools were rated approximately two times higher as being 'meaningful' (53%) and 'useful for the presented cases' (49%) than they were 'used in clinical practice' (19%). The most commonly used geriatric tool in patient care was the MNA (30%). CONCLUSIONS: The higher variance of treatment recommendations indicates that it is less likely for elderly patients to get the optimal recommendation. Although the proposed therapeutic regimen varied higher in elderly patients and the oncologists rated the GA results as 'useful', the GA results did not influence the individual recommendations or its variance. Continuing education on GA and research on implementation into clinical practice are needed.

Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

The PerPAIN trial: a pilot randomized controlled trial of personalized treatment allocation for chronic musculoskeletal pain-a protocol.

BACKGROUND: The therapy of chronic musculoskeletal pain (CMSP) is complex and the treatment results are often insufficient despite numerous therapeutic options. While individual patients respond very well to specific interventions, other patients show no improvement. Personalized treatment assignment offers a promising approach to improve response rates; however, there are no validated cross-disease allocation algorithms available for the treatment of chronic pain in validated personalized pain interventions. This trial aims to test the feasibility and safety of a personalized pain psychotherapy allocation with three different treatment modules and estimate initial signals of efficacy and utility of such an approach compared to non-personalized allocation. METHODS: This is a randomized, controlled assessor-blinded pilot trial with a multifactorial parallel arm design. CMSP patients (n = 105) will be randomly assigned 1:1 to personalized or non-personalized treatment based on a cluster assignment of the West Haven-Yale Multidimensional Pain Inventory (MPI). In the personalized assignment condition, patients with high levels of distress receive an emotional distress-tailored intervention, patients with pain-related interference receive an exposure/extinction-tailored treatment intervention and patients who adapt relatively well to the pain receive a low-level smartphone-based activity diary intervention. In the control arm, patients receive one of the two non-matching interventions. Effect sizes will be calculated for change in core pain outcome domains (pain intensity, physical and emotional functioning, stress experience, participant ratings of improvement and satisfaction) after intervention and at follow-up. Feasibility and safety outcomes will assess rates of recruitment, retention, adherence and adverse events. Additional data on neurobiological and psychological characteristics of the patients are collected to improve treatment allocation in future studies. CONCLUSION: Although the call for personalized treatment approaches is widely discussed, randomized controlled trials are lacking. As the personalization of treatment approaches is challenging, both allocation and intervention need to be dynamically coordinated. This study will test the feasibility and safety of a novel study design in order to provide a methodological framework for future multicentre RCTs for personalized pain psychotherapy. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00022792 ( https://www.drks.de ). Prospectively registered on 04/06/2021.

Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer.

BACKGROUND: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. METHODS: FIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. DISCUSSION: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy. TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.

Stress reactivity as a putative mechanism linking childhood trauma with clinical outcomes in individuals at ultra-high-risk for psychosis: Findings from the EU-GEI High Risk Study.

AIMS: Childhood trauma is associated with an elevated risk for psychosis, but the psychological mechanisms involved remain largely unclear. This study aimed to investigate emotional and psychotic stress reactivity in daily life as a putative mechanism linking childhood trauma and clinical outcomes in individuals at ultra-high-risk (UHR) for psychosis. METHODS: Experience sampling methodology was used to measure momentary stress, affect and psychotic experiences in the daily life of N = 79 UHR individuals in the EU-GEI High Risk Study. The Childhood Trauma Questionnaire was used to assess self-reported childhood trauma. Clinical outcomes were assessed at baseline, 1- and 2-year follow-up. RESULTS: The association of stress with positive (ß = -0.14, p = 0.010) and negative affect (ß = 0.11, p = 0.020) was modified by transition status such that stress reactivity was greater in individuals who transitioned to psychosis. Moreover, the association of stress with negative affect (ß = 0.06, p = 0.019) and psychotic experiences (ß = 0.05, p = 0.037) was greater in individuals exposed to high v. low levels of childhood trauma. We also found evidence that decreased positive affect in response to stress was associated with reduced functioning at 1-year follow-up (B = 6.29, p = 0.034). In addition, there was evidence that the association of childhood trauma with poor functional outcomes was mediated by stress reactivity (e.g. indirect effect: B = -2.13, p = 0.026), but no evidence that stress reactivity mediated the association between childhood trauma and transition (e.g. indirect effect: B = 0.14, p = 0.506). CONCLUSIONS: Emotional and psychotic stress reactivity may be potential mechanisms linking childhood trauma with clinical outcomes in UHR individuals.

Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the 'burden of therapy' method.

BACKGROUND: Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non-small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the 'Burden of Therapy/Toxicity' (BOTh) for each patient on every day during the clinical study. RESULTS: One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). CONCLUSION: The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).

R0 resection following chemo (radio)therapy improves survival of primary inoperable pancreatic cancer patients. Interim results of the German randomized CONKO-007± trial.

PURPOSE: Chemotherapy with or without radiotherapy is the standard in patients with initially nonmetastatic unresectable pancreatic cancer. Additional surgery is in discussion. The CONKO-007 multicenter randomized trial examines the value of radiotherapy. Our interim analysis showed a significant effect of surgery, which may be relevant to clinical practice. METHODS: One hundred eighty patients received induction chemotherapy (gemcitabine or FOLFIRINOX). Patients without tumor progression were randomized to either chemotherapy alone or to concurrent chemoradiotherapy. At the end of therapy, a panel of five independent pancreatic surgeons judged the resectability of the tumor. RESULTS: Following induction chemotherapy, 126/180 patients (70.0%) were randomized to further treatment. Following study treatment, 36/126 patients (28.5%) underwent surgery; (R0: 25/126 [19.8%]; R1/R2/Rx [n = 11/126; 6.1%]). Disease-free survival (DFS) and overall survival (OS) were significantly better for patients with R0 resected tumors (median DFS and OS: 16.6 months and 26.5 months, respectively) than for nonoperated patients (median DFS and OS: 11.9 months and 16.5 months, respectively; p = 0.003). In the 25 patients with R0 resected tumors before treatment, only 6/113 (5.3%) of the recommendations of the panel surgeons recommended R0 resectability, compared with 17/48 (35.4%) after treatment (p < 0.001). CONCLUSION: Tumor resectability of pancreatic cancer staged as unresectable at primary diagnosis should be reassessed after neoadjuvant treatment. The patient should undergo surgery if a resectability is reached, as this significantly improves their prognosis.

Longitudinal determination of resilience in humans to identify mechanisms of resilience to modern-life stressors: the longitudinal resilience assessment (LORA) study.

Resilience is the maintenance and/or quick recovery of mental health during and after periods of adversity. It is conceptualized to result from a dynamic process of successful adaptation to stressors. Up to now, a large number of resilience factors have been proposed, but the mechanisms underlying resilience are not yet understood. To shed light on the complex and time-varying processes of resilience that lead to a positive long-term outcome in the face of adversity, the Longitudinal Resilience Assessment (LORA) study has been established. In this study, 1191 healthy participants are followed up at 3- and 18-month intervals over a course of 4.5 years at two study centers in Germany. Baseline and 18-month visits entail multimodal phenotyping, including the assessment of mental health status, sociodemographic and lifestyle variables, resilience factors, life history, neuropsychological assessments (of proposed resilience mechanisms), and biomaterials (blood for genetic and epigenetic, stool for microbiome, and hair for cortisol analysis). At 3-monthly online assessments, subjects are monitored for subsequent exposure to stressors as well as mental health measures, which allows for a quantitative assessment of stressor-dependent changes in mental health as the main outcome. Descriptive analyses of mental health, number of stressors including major life events, daily hassles, perceived stress, and the ability to recover from stress are here presented for the baseline sample. The LORA study is unique in its design and will pave the way for a better understanding of resilience mechanisms in humans and for further development of interventions to successfully prevent stress-related disorder.

Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status and primary tumor location: analysis of untreated RAS-wild-type mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109).

PURPOSE: In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. METHODS: We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. RESULTS: BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (- 57.6% vs. - 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1-4.4) vs. 3.9 (95% CI 2.5-5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9-8.0) versus 2.6 (95% CI 1.2-4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11-0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0-41.3) vs. 5.4 (95% CI 5.0-5.9) months; HR 0.27 (95% CI 0.13-0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site. CONCLUSIONS: BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.

Consensus in determining the resectability of locally progressed pancreatic ductal adenocarcinoma - results of the Conko-007 multicenter trial.

BACKGROUND: One critical step in the therapy of patients with localized pancreatic cancer is the determination of local resectability. The decision between primary surgery versus upfront local or systemic cancer therapy seems especially to differ between pancreatic cancer centers. In our cohort study, we analyzed the independent judgement of resectability of five experienced high volume pancreatic surgeons in 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer. METHODS: Pretherapeutic CT or MRI scans of 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer were evaluated by 5 independent pancreatic surgeons. Resectability and the degree of abutment of the tumor to the venous and arterial structures adjacent to the pancreas were reported. Interrater reliability and dispersion indices were compared. RESULTS: One hundred ninety-four CT scans and 6 MRI scans were evaluated and all parameters were evaluated by all surgeons in 133 (66.5%) cases. Low agreement was observed for tumor infiltration of venous structures (κ = 0.265 and κ = 0.285) while good agreement was achieved for the abutment of the tumor to arterial structures (interrater reliability celiac trunk κ = 0.708 P < 0.001). In patients with vascular tumor contact indicating locally advanced disease, surgeons highly agreed on unresectability, but in patients with vascular tumor abutment consistent with borderline resectable disease, the judgement of resectability was less uniform (dispersion index locally advanced vs. borderline resectable p < 0.05). CONCLUSION: Excellent agreement between surgeons exists in determining the presence of arterial abutment and locally advanced pancreatic cancer. The determination of resectability in borderline resectable patients is influenced by additional subjective factors. TRIAL REGISTRATION: EudraCT:2009-014476-21 (2013-02-22) and NCT01827553 (2013-04-09).

Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib.

BACKGROUND: Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS: Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63). CONCLUSIONS: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. CLINCALTRIALS.GOV NUMBER: NCT02184195.

Hair and saliva test fails to identify allergies in dogs.

OBJECTIVES: Several companies offer saliva and/or hair tests for food and environmental allergies in companion animals, but provide no validation of test accuracy. We examined one such hair and saliva allergy test to determine whether it could reliably differentiate between a normal dog and an allergic dog, and to examine test repeatability. MATERIALS AND METHODS: Ten fur and saliva samples were submitted from a known allergic dog and a normal, non-allergic dog. Five fake fur samples and water were also submitted to determine whether the test could differentiate between a real dog and toy animal. The company performed testing for 128 food and environmental allergens. Statistical analyses were performed to determine whether the response distribution differed significantly between dogs, using the Pearson chi-square coefficient, as well as to determine test-retest reliability by calculating Cohen's kappa for each allergen. RESULTS: The distribution of test results from samples obtained from allergic, non-allergic or fake dogs was not different from that expected due to random chance. Test-retest reproducibility was poor to slight. CLINICAL SIGNIFICANCE: Hair and saliva testing should not be used to diagnose allergies and is not a substitute for veterinary-directed allergy evaluation and diagnostics.

[Resilience trajectories-examples from longitudinal studies]. / Verläufe von Resilienz ­ Beispiele aus Längsschnittstudien.

BACKGROUND: According to current research concepts resilience can be defined as adaptation to past and ongoing exposure. Accordingly, adaptation to exposure is a dynamic process, which can be different in different population groups. Prospective longitudinal studies provide unique opportunities to investigate resilience processes. OBJECTIVES: The aim of this article is to define the concept of resilience, describe examples of longitudinal studies investigating resilience in children, adults and older individuals, exemplary describe four ongoing longitudinal resilience studies in which the authors of the article are participating and identify and analyze methodological challenges in empirical resilience research. MATERIAL AND METHODS: This study was based on a qualitative literature review of published prospective studies investigating resilience listed in PubMed and study protocols of the four longitudinal studies. RESULTS: The exemplarily described studies have shown that resilience processes are changeable in all age groups and subject to a variety of influencing factors. The specific and potentially age-associated types of alterations have so far been difficult to determine and need further clarification. DISCUSSION: In view of the dynamic course of resilience, prospective longitudinal studies are urgently needed. Prospective longitudinal studies have the potential to identify resilience mechanisms and predictors of the course of resilience in different population groups, such as children, adolescents, adults and older individuals. Furthermore, resilience research needs to develop an improved and precise assessment of exposure to stressors.

Efficacy of gemcitabine plus erlotinib in rash-positive patients with metastatic pancreatic cancer selected according to eligibility for FOLFIRINOX: A prospective phase II study of the 'Arbeitsgemeinschaft Internistische Onkologie'.

INTRODUCTION: In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. PATIENTS AND METHODS: For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1-4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%. RESULTS: Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8-50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7-68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. CONCLUSIONS: First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).

Treatment recommendations within the leeway of clinical guidelines: A qualitative interview study on oncologists' clinical deliberation.

BACKGROUND: Recommending the optimal treatment for an individual patient requires a well-balanced consideration of various medical, social and ethical factors. The interplay of these factors, interpretation of the patient's situation and understanding of the existing clinical guidelines can lead to divergent therapy recommendations, depending on the attending physician. Gaining a better understanding of the individual process of medical decision-making and the differences occurring will support the delivery of optimal individualized care within the clinical setting. METHODS: A case vignette of a 64-year-old patient with locally advanced pancreatic adenocarcinoma was discussed with oncologists in 14 qualitative, semi-structured interviews at two academic institutions. Relevant factors that emerged were ranked by the participants using the Q card sorting method. Qualitative data analysis and descriptive statistics were performed. RESULTS: Oncologists recommend different therapeutic approaches within the leeway of the relevant clinical guidelines. One group of participants endorses a rather aggressive and potentially curative approach with a combination chemotherapy following the FOLFIRINOX protocol to provide the patient with the best chances of resectability. The second group suggests a milder chemotherapy approach with gemcitabine, highlighting the palliative approach and the patient's quality of life. Clinical guidelines are generally seen as an important point of reference, but are complicated to apply in highly individual cases. CONCLUSION: The physician's individual assessment of factors, such as biological age, general condition or prognosis, plays a decisive role in treatment recommendations, particularly in those cases which are not fully covered by guidelines. Judgment and discretion remain crucial in clinical decision-making and cannot and should not be fully ruled out by evidence-based guidelines. Therefore, a more comprehensive reflection on the interaction between evidence-based medicine and the physician's estimation of each individual case is desirable. Knowledge of existing barriers can enhance the implementation of guidelines, for example, through medical education.

Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group.

BACKGROUND: To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy. PATIENTS AND METHODS: A total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan-Meier method, log-rank tests and Cox models. RESULTS: In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) [multivariate hazard ratio (HR) for PFS: 1.20 (1.02-1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17-1.70), P < 0.001]. BRAF mutation was also associated with inferior PFS [multivariate HR: 2.19 (1.59-3.02), P < 0.001] and OS [multivariate HR: 2.99 (2.10-4.25), P < 0.001]. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors [multivariate HR 2.26 (1.25-4.1), P = 0.001]. A similar trend for OS was seen in the KRAS G13D-variant [n = 71, multivariate HR 1.46 (0.96-2.22), P = 0.10]. More frequent KRAS exon 2 variants like G12D [n = 152, multivariate HR 1.17 (0.86-1.6), P = 0.81] and G12V [n = 92, multivariate HR 1.27 (0.87-1.86), P = 0.57] did not have significant impact on OS. CONCLUSION: Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival.

[ASCO-update 2015 - highlights of the 51. meeting of the american society of clinical oncology/ASCO 2015]. / ASCO-Update 2015 - Neuigkeiten vom 51. Meeting der American Society of Clinical Oncology/ASCO 2015.

The field of gastrointestinal oncology is rapidly developing, on the one hand through the identification of novel molecular targets and therapeutic principles, on the other hand through the establishment and improvement of multidisciplinary treatment strategies. The following manuscript summarizes the most important trial results of the ASCO Meeting 2015 for gastrointestinal cancers. Besides trials on perioperative treatment of esophageal-, pancreatic- and colon cancer, we will present impressive data on new therapeutic strategies such as immunotherapy in gastric-, liver and microsatellite instable colorectal cancer. The trials will be put into context by the authors.

Apical filling characteristics of carrier-based techniques vs. single cone technique in curved root canals.

OBJECTIVES: In this in vitro study, we assessed filling characteristics (adaptation, homogeneity, sealer percentage, position of the carrier) of warm and cold obturation methods in curved root canals. MATERIALS AND METHODS: A reciprocating method was used to prepare 90 curved roots (25 ° average curvature) to an apical size of 25.08. They were then obturated with either (A) Guttafusion (VDW, Munich, Germany), (B) Thermafil (Maillefer, Ballaigues, Switzerland) or (C) single cone technique using 25.08 gutta-percha (VDW) and sealer (2Seal easymix) (n = 30 each group). Five sections in 1-mm steps were obtained from each root, beginning 1 mm short of the apex. The percentage of voids in contact with root canal walls (PVO), the proportion of voids per area (PVA) and the percentage of sealer per area (PSA) were measured. RESULTS: Little to no differences between Guttafusion and Thermafil were seen in curved root canals with respect to adaptation and homogeneity in the apical region. Both methods showed significantly better adaptation and homogeneity than the single cone technique. The proportion of sealer was significantly greater when roots were obturated with Guttafusion than with Thermafil, but both warm obturation techniques had significantly smaller sealer areas than the single cone technique. CONCLUSIONS: Compared to the single cone technique, a more favourable root canal filling with less sealer could be expected from both warm obturation techniques in curved root canals. CLINICAL RELEVANCE: The easier-to-handle Guttafusion leads to comparable results as Thermafil in curved root canals.