Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent ...poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer.
Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1:1:1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR).
Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively hazard ratio (HR) 0.789; 95% CI 0.536–1.162; P = 0.227, interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503–1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278–2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032–2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP.
Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population.
NCT01506609
In women with HER2-positive metastatic breast cancer who had previously received HER2-targeted therapy, tucatinib, a new selective inhibitor of the HER2 tyrosine kinase, was added to trastuzumab and ...capecitabine and compared with trastuzumab and capecitabine plus placebo. Progression-free survival at 1 year was 33% with tucatinib and 12% with placebo.
Veterinarians working with dairy cows are suggested to refocus their efforts from being task-oriented providers of single-cow therapy and develop themselves into advice-oriented herd health ...management advisors. The practising cattle veterinarian's ability to translate knowledge into on-farm application requires a profound understanding of the dairy farm as an integrated system. Consequently, educating and motivating farmers are key issues. To achieve such insight the veterinarian needs to work with several scientific disciplines, especially epidemiology and (behavioural) economics. This trans-disciplinary approach offers new methodological possibilities and challenges to students of dairy herd health management.
Advisors working with dairy herd health management may sometimes experience that farmers do not follow their advice. Potentially, this could lead to the interpretation that such farmers are behaving irrationally. However, farmers who are confronted with advice suggesting a change of behaviour are placed in a state of cognitive dissonance. To solve such dissonance they may either comply with the advice or reduce the dissonance by convincing themselves that the suggested change in management is impossible to implement. Consequently, herd health management advisors must understand the fundamental and instrumental relationships between individual farmers' values, behaviour and perception of risk, to stimulate and qualify the farmer's decision-making in a way that will increase the farmer's satisfaction and subjective well-being.
Traditionally, studies on herd health economics have focussed on financial methods to measure the value of technical outcomes from suggested changes in management, following the basic assumption that farmers strive to maximise profit. Farmers, however, may be motivated by very different activities, e.g. animal health and welfare or other farmers' recognition, making it impossible to provide 'one-size-fts-all' consultancy because the best decision depends heavily on the internal logic and context-bound reality on each dairy farm. Relevant information may be available, but to be implemented at farm level it has to be communicated effectively. This requires a trustworthy communicator. Consequently, veterinarians are recommended to receive training in communication; keywords in this process are dialogue and refection. An educational framework based on science and the authors' experience is presented. The aim is to guide practising cattle veterinarians into a personal learning process considered necessary for them to be recognised by farmers as trustworthy dairy herd health advisors.
Transgenic porcine cancer models bring novel possibilities for research. Their physical similarities with humans enable the use of surgical procedures and treatment approaches used for patients, ...which facilitates clinical translation. Here, we aimed to develop an inducible oncopig model of intestinal cancer. Transgenic (TG) minipigs were generated using somatic cell nuclear transfer by handmade cloning. The pigs encode two TG cassettes: (a) an Flp recombinase‐inducible oncogene cassette containing KRAS‐G12D, cMYC, SV40LT – which inhibits p53 – and pRB and (b) a 4‐hydroxytamoxifen (4‐OHT)‐inducible Flp recombinase activator cassette controlled by the intestinal epithelium‐specific villin promoter. Thirteen viable transgenic minipigs were born. The ability of 4‐OHT to activate the oncogene cassette was confirmed in vitro in TG colonic organoids and ex vivo in tissue biopsies obtained by colonoscopy. In order to provide proof of principle that the oncogene cassette could also successfully be activated in vivo, three pigs were perorally treated with 400 mg tamoxifen for 2 × 5 days. After two months, one pig developed a duodenal neuroendocrine carcinoma with a lymph node metastasis. Molecular analysis of the carcinoma and metastasis confirmed activation of the oncogene cassette. No tumor formation was observed in untreated TG pigs or in the remaining two treated pigs. The latter indicates that tamoxifen delivery can probably be improved. In summary, we have generated a novel inducible oncopig model of intestinal cancer, which has the ability to form metastatic disease already two months after induction. The model may be helpful in bridging the gap between basic research and clinical usage. It opens new venues for longitudinal studies of tumor development and evolution, for preclinical assessment of new anticancer regimens, for pharmacology and toxicology assessments, as well as for studies into biological mechanisms of tumor formation and metastasis.
Here, we have constructed an inducible transgenic intestinal cancer pig model. Induction with tamoxifen initiates carcinogenesis, specifically in the intestinal cells, through deactivation of p53 and pRB signaling and activation of KRAS and cMYC signaling. The model opens new venues for longitudinal studies of tumor development and evolution, for preclinical studies of novel anticancer regimens, and for pharmacology and toxicology assessments.
Background: Post‐thoracotomy pain syndrome (PTPS) and its social consequences have been inconsistently investigated as most studies were either small sized, focused on a limited number of risk ...factors or included heterogeneous surgical procedures. The current objectives were to obtain detailed information on the consequences of PTPS after thoracotomy and video‐assisted thoracic surgery (VATS) from homogenous unselected nationwide data, and to suggest mechanisms for the development of PTPS.
Methods: Data from 1327 patients were collected using a prospective national database and combined with a detailed questionnaire.
Results: The response rate was 81.5%, resulting in 546 patients without prior thoracic surgery for the final analysis. Follow‐up was 22 months (range 12–36). PTPS occurred in 33% thoracotomy patients and 25% VATS patients. Clinically relevant pain was present in 11–18% of the patients and severe pain in 4–12% depending on the level of physical activity. In PTPS patients, 64% also had pain from other locations on the body. Perceived sensory changes in the thoracic area were present in 63% of PTPS patients vs. 25% in pain‐free patients (P<0.001). When comparing VATS with thoracotomy, no consistent differences in the prevalence, distribution of pain, sensory changes or effect of pain on daily activities were observed although clinically relevant and severe pain was reduced after VATS.
Conclusions: This nationwide study corroborates that PTPS is a clinically relevant problem influencing daily activities a long time after thoracotomy and VATS. Nerve injury and increased pain responsiveness may explain the majority of symptoms, the prevalence and distribution of pain including perceived sensory sensations.
Lung cancer is the leading cause of cancer-related death in all Nordic countries which, though similar in demographics and healthcare systems, have noticeable differences in lung cancer survival. ...Historically, Denmark and Finland have had higher lung cancer incidences and lower survival than Norway and Sweden. All four countries have national cancer registries. Data in these registries are often compared, but their full potential as a source of learning across the Nordic countries is impeded by differences between the registries. In this paper, we describe and compare the Nordic registries on lung cancer-specific data and discuss how a more harmonized registration practice could increase their usefulness as a source for mutual learning and quality improvements.
We describe and compare the characteristics of data on lung cancer cases from registries in Denmark, Finland, Norway and Sweden. Moreover, we compare the results from the latest annual reports and specify how data may be acquired from the registries for research.
Denmark has a separate clinical lung cancer registry with more detailed data than the other Nordic countries. Finland and Norway report lung cancer survival as relative survival, whereas Denmark and Sweden report overall survival. The Danish Lung Cancer Registry and the Swedish Cancer Registry do not receive data from the Cause of Death registries in contrast to the Finnish Cancer Registry and the Cancer Registry of Norway.
The lung cancer registries in Denmark, Finland, Norway and Sweden have high level of completeness. However, several important differences between the registries may bias comparative analyses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•Healthcare is organized in a different way in Denmark and the Netherlands.•Mortality of NSCLC surgery is low in both countries in the period 2013–2016.•In the Netherlands there were more patients ...with a complicated course after surgery.•Accuracy between clinical and pathological stage was around 53% in both countries.•We should pursue uniform definitions of endpoints in national datasets.
Organization and governance of national healthcare might play an important role in decision-making and outcomes in patients with lung cancer. Both Denmark and the Netherlands have a high level of healthcare but a different financial coverage, governance and level of centralization. By using both national databases we analyzed the consequences of these differences on patterns of care and outcomes with a focus on morbidity, mortality and clinical staging.
General numbers on both healthcare systems were requested. All patients who had surgery for lung cancer from 2013 to 2016 were included. Mortality, morbidity and clinical staging were analyzed for patients with NSCLC without metastases, only one operation and no neo-adjuvant therapy.
In 2016 annual budget as share of gross national product was 10.4% for both countries. In Denmark 4 hospitals performed lung surgery in 2016, compared to 43 hospitals in the Netherlands. We included 4030 Danish and 8286 Dutch patients. In the subgroup 30-day mortality was 1.5% in Denmark compared to 1.9% in the Netherlands. The percentage of patients with a complicated course was 24.4% and 34.8% respectively (p < 0.05). Accuracy between cTNM and pTNM was 53.0% in Denmark and 52.9% in the Netherlands.
Surgery for lung cancer is at a high level in both countries, reflected by low mortality-rates. Centralization has been implemented successfully in Denmark, which might explain the lower rate of patients with a complicated post-operative course, although different definitions preclude firm conclusions. In both countries correct clinical staging of lung cancer remains a challenge.
Body condition scores (BCS) are very useful for dairy herd management and breeding programs, but the consistency and quality of recordings made by consultants in the field are unknown. The objectives ...of this study were 1) to estimate the agreement in BCS within and among practicing dairy veterinarians and 2) to provide an indication of the effects of training and the value of calibration, and of what efforts need to be made to obtain a validity and precision in BCS adequate for management purposes. A total of 2,230 scores were recorded by 51 practicing dairy veterinarians and 6 highly trained instructors. The 6 instructors were cross-trained to validate calibration consistency in assigning BCS. Each individual scored approximately 20 cows twice, with the second scoring occurring approximately 2.5h after the first. Between the 2 recordings, the respective instructors conducted a training session for the practicing veterinarians using other cows. A weighted kappa coefficient was used to assess agreement among and within classifiers. Excellent agreement (kappa ≥0.86) was documented between repeated BCS recorded for the same cows by the highly trained instructors. In addition, the BCS provided by multiple classifiers from the instructor team appeared to be comparable across herds and classifiers. This legitimizes the use of BCS for benchmarking at both the cow and the herd level. The within-classifier and between-classifier kappa values were in the ranges of 0.22 to 0.75 and 0.17 to 0.78, respectively, in the group of practicing dairy veterinarians. Many of the veterinarians provided estimates of average BCS that differed considerably from the BCS recorded by the instructors. Between-classifier comparisons of herd BCS are not warranted unless a validation has been performed. If scores are collected by multiple classifiers with varying experience, a valid but imprecise estimate of the true population mean of BCS may be obtained if classifiers are inexperienced. The limited training effort used in this study seemed to have brought about substantial improvement in the validity and precision of the BCS determined by practicing veterinarians, compared with the BCS recorded on the same cows by highly trained classifiers.
The generation of large transgenic animals is impeded by complex cloning, long maturation and gastrulation times. An introduction of multiple gene alterations increases the complexity. We have cloned ...a transgenic Cas9 minipig to introduce multiple mutations by CRISPR in somatic cells. Transgenic Cas9 pigs were generated by somatic cell nuclear transfer and were backcrossed to Göttingen Minipigs for two generations. Cas9 expression was controlled by FlpO-mediated recombination and was visualized by translation from red to yellow fluorescent protein. In vitro analyses in primary fibroblasts, keratinocytes and lung epithelial cells confirmed the genetic alterations executed by the viral delivery of single guide RNAs (sgRNA) to the target cells. Moreover, multiple gene alterations could be introduced simultaneously in a cell by viral delivery of sgRNAs. Cells with loss of TP53, PTEN and gain-of-function mutation in KRASG12D showed increased proliferation, confirming a transformation of the primary cells. An in vivo activation of Cas9 expression could be induced by viral delivery to the skin. Overall, we have generated a minipig with conditional expression of Cas9, where multiple gene alterations can be introduced to somatic cells by viral delivery of sgRNA. The development of a transgenic Cas9 minipig facilitates the creation of complex pre-clinical models for cancer research.
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