Patients with Biallelic BRCA1/2 Inactivation respond to Olaparib treatment across Histologic tumor types

Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with offlabel olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive offlabel drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non-BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay

Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer

Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement

The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Göttingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitroso-redox balance

Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach

Despite the apparent appropriateness of left ventricular (LV) remodeling following myocardial infarction (MI), it poses an independent risk factor for development of heart failure. There is a paucity of studies into the molecular mechanisms of LV remodeling in large animal species. We took an unbiased molecular approach to identify candidate transcription factors (TFs) mediating the genetic reprogramming involved in post-MI LV remodeling in swine. Left ventricular tissue was collected from remote, non-infarcted myocardium, 3 weeks after MI-induction or sham-surgery. Microarray analysis identified 285 upregulated and 278 downregulated genes (FDR < 0.05). Of these differentially expressed genes, the promoter regions of the human homologs were searched for common TF binding sites (TFBS). Eighteen TFBS were overrepresented >two-fold (p < 0.01) in upregulated and 13 in downregulated genes. Left ventricular nuclear protein extracts were assayed for DNA-binding activity by protein/DNA array. Out of 345 DNA probes, 30 showed signal intensity changes >two-fold. Five TFs were identified in both TFBS and protein/DNA array analyses, which showed matching changes for COUP-TFII and glucocorticoid receptor (GR) only. Treatment of swine with the GR antagonist mifepristone after MI reduced the post-MI increase in LV mass, but LV dilation remained unaffected. Thus, using an unbiased approach to study post-MI LV remodeling in a physiologically relevant large animal model, we identified COUP-TFII and GR as potential key mediators of post-MI remodeling

Objective cognitive performance and subjective complaints in patients with chronic Q fever or Q fever fatigue syndrome.

Primary aim of this study was to compare cognitive performance of patients with chronic Q fever or Q fever fatigue syndrome (QFS) to matched controls from the general population, while taking performance validity into account. Second, we investigated whether objective cognitive performance was related to subjective cognitive complaints or psychological wellbeing. Cognitive functioning was assessed with a neuropsychological test battery measuring the domains of processing speed, episodic memory, working memory and executive functioning. Tests for performance validity and premorbid intelligence were also included. Validated questionnaires were administered to assess self-reported fatigue, depressive symptoms and cognitive complaints. In total, 30 patients with chronic Q fever, 32 with QFS and 35 controls were included. A high percentage of chronic Q fever patients showed poor performance validity (38%) compared to controls (14%, p = 0.066). After exclusion of participants showing poor performance validity, no significant differences between patients and controls were found in the cognitive domains. QFS patients reported a high level of cognitive complaints compared to controls (41.2 vs 30.4, p = 0.023). Cognitive complaints were not significantly related to cognitive performance in any of the domains for this patient group. The high level of self-reported cognitive complaints in QFS patients does not indicate cognitive impairment. A large proportion of the chronic Q fever patients showed suboptimal mental effort during neuropsychological assessment. More research into the underlying explanations is needed. Our findings stress the importance of assessing cognitive functioning by neuropsychological examination including performance validity, rather than only measuring subjective cognitive complaints

Impact of hyperglycemia on the efficacy of chemotherapy-A systematic review of preclinical studies

Antineoplastic agents can provoke hyperglycemia in cancer patients with and without diabetes mellitus. We systematically reviewed the impact of hyperglycemia on the efficacy of chemotherapy. MEDLINE was searched for preclinical intervention studies which compared chemotherapy response in hyperglycemic and euglycemic conditions. Thirteen preclinical studies, including 23 cell lines and 2 animal experiments were identified. In 14 cell lines and 2 animal studies, chemotherapy response was lower in a hyperglycemic (>15mmol/L) compared to a euglycemic environment (5mmol/L). The response was similar in 4 cell lines. In the remaining 5 cell lines, the hyperglycemic environment potentiated chemotherapy efficacy. Hyperglycemia attenuated the antiproliferative effect of chemotherapy in preclinical experiments, but the results are inconsistent. Whether hyperglycemia influences efficacy of chemotherapy in patients needs to be explore

Impact of Q-fever fatigue syndrome on patients' work status.

BACKGROUND: Chronic illnesses can increase the risk of unemployment, but evidence on the specific impact of Q-fever fatigue syndrome (QFS) on work is lacking. AIMS: The aim of this study was to describe and quantify the impact of QFS on work. METHODS: Changes in work status from 1 year prior to 4 years after acute Q-fever infection of QFS patients were retrospectively collected with a self-report questionnaire measuring employment status and hours of paid work per week. In addition, information on work ability, job satisfaction and need for recovery after work was collected in 2016. Data were compared to participants from the general population. RESULTS: The proportion of employed QFS patients from 1 year prior to 4 years after acute infection decreased from 78 to 41%, while remaining relatively constant in the general population (82 to 78%). Working QFS patients showed a decrease in mean hours of paid work from 35 to 22 h per week, which is significantly steeper compared to the general population (31-28 h per week) (P < 0.001). QFS patients showed a significantly lower work ability (P < 0.001), lower job satisfaction (P = 0.006) and greater need for recovery (P < 0.001) compared to the general population. CONCLUSIONS: The number of QFS patients with paid work decreased over the years, while patients who continue to work experience lower work ability, job satisfaction and increased need for recovery. Occupational physicians should be aware of the occurrence and severity of the impact of QFS on work, even after many years

Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases

Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo tumor. In this study tumor biopsies were obtained from 14 patients with metastatic colorectal cancer (i) to test the feasibility of organoid culture from metastatic biopsy specimens and (ii) to compare the genetic diversity of patient-derived tumor organoids and the original tumor biopsy. Genetic analysis was performed using SOLiD sequencing for 1,977 cancer-relevant genes. Copy number profiles were generated from sequencing data using CopywriteR. Here we demonstrate that organoid cultures can be established from tumor biopsies of patients with metastatic colorectal cancer with a success rate of 71%. Genetic analysis showed that organoids reflect the metastasis from which they were derived. Ninety percent of somatic mutations were shared between organoids and biopsies from the same patient, and the DNA copy number profiles of organoids and the corresponding original tumor show a correlation of 0.89. Most importantly, none of the mutations that were found exclusively in either the tumor or organoid culture are in driver genes or genes amenable for drug targeting. These findings support further exploration of patient-derived organoids as an ex vivo platform to personalize anticancer treatment

Impact of Q-fever on physical and psychosocial functioning until 8 years after Coxiella burnetii infection: An integrative data analysis.

BACKGROUND: This study aimed to determine short- and long-term physical and psychosocial impact of Coxiella burnetii infection in three distinct entities: Q-fever fatigue syndrome (QFS), chronic Q-fever, and patients with past acute Q-fever without QFS or chronic Q-fever. METHODS: Integrative data analysis was performed, combining original data from eight studies measuring quality of life (QoL), fatigue, physical and social functioning with identical validated questionnaires, from three months to eight years after onset infection. Linear trends in each outcome were compared between Q-fever groups using multilevel linear regression analyses to account for repeated measures within patients. RESULTS: Data included 3947 observations of 2313 individual patients (228 QFS, 135 chronic Q-fever and 1950 patients with past acute Q-fever). In the first years following infection, physical and psychosocial impact was highest among QFS patients, and remained high without significant improvements over time. In chronic Q-fever patients, QoL and physical functioning worsened significantly over time. Levels of fatigue and social participation in patients with past acute Q-fever improved significantly over time. CONCLUSION: The impact differs greatly between the three Q-fever groups. It is important that physicians are aware of these differences, in order to provide relevant care for each patient group