Abstract To evaluate, from a US payer perspective, the cost-effectiveness of treatment strategies for metastatic colorectal cancer (mCRC), we performed a systematic review of published ...cost-effectiveness analyses. We identified 14 papers that fulfilled our search criteria and revealed varying levels of value among current treatment strategies. Older agents such as 5-fluorouracil, irinotecan, and oxaliplatin provide high-value treatments. More modern agents targeting the EGFR or VEGF pathways, such as bevacizumab, cetuximab, and panitumumab, do not appear to be cost-effective treatments at their current costs. The analytical methods used within the papers varied widely, and this variation likely plays a significant role in the heterogeneity in incremental cost-effectiveness ratios. The cost-effectiveness of current treatment strategies for mCRC is highly variable. Drugs recently approved by the US Food and Drug Administration for mCRC are not cost-effective, and this is primarily driven by high drug costs.
Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in ...the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R² = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs.
ABSTRACT
Classical novae are shock-powered multiwavelength transients triggered by a thermonuclear runaway on an accreting white dwarf. V1674 Her is the fastest nova ever recorded (time to declined ...by two magnitudes is t2 = 1.1 d) that challenges our understanding of shock formation in novae. We investigate the physical mechanisms behind nova emission from GeV γ-rays to cm-band radio using coordinated Fermi-LAT, NuSTAR, Swift, and VLA observations supported by optical photometry. Fermi-LAT detected short-lived (18 h) 0.1–100 GeV emission from V1674 Her that appeared 6 h after the eruption began; this was at a level of (1.6 ± 0.4) × 10−6 photons cm−2 s−1. Eleven days later, simultaneous NuSTAR and Swift X-ray observations revealed optically thin thermal plasma shock-heated to kTshock = 4 keV. The lack of a detectable 6.7 keV Fe Kα emission suggests super-solar CNO abundances. The radio emission from V1674 Her was consistent with thermal emission at early times and synchrotron at late times. The radio spectrum steeply rising with frequency may be a result of either free-free absorption of synchrotron and thermal emission by unshocked outer regions of the nova shell or the Razin–Tsytovich effect attenuating synchrotron emission in dense plasma. The development of the shock inside the ejecta is unaffected by the extraordinarily rapid evolution and the intermediate polar host of this nova.
Aims Recent data revealed that patients with myocardial infarction (MI) have a high prevalence of previously unknown diabetes mellitus (DM) and impaired glucose tolerance (IGT). The added prognostic ...importance of this finding has not been prospectively explored. To investigate whether a newly detected abnormal glucose tolerance (IGT or DM) assessed early after an MI, is related to long-term prognosis. Methods and results Patients (n=168; age 63.5±9.3 years) with MI, no previous DM and admission blood glucose <11.0 mmol/l were followed for major cardiovascular events defined as the composite of cardiovascular death, non-fatal MI, non-fatal stroke or severe heart failure (HF). According to an oral glucose tolerance test (OGTT) before hospital discharge, 55 patients had normal and 113 abnormal glucose tolerance (GT). During the follow-up of median 34 months there were eight cardiovascular deaths, 15 patients had a recurrent MI, six had a stroke and ten severe HF. All patients who died from cardiovascular causes had abnormal GT. The composite cardiovascular event occurred in 31 (18%) patients. The probability of remaining free from cardiovascular events was significantly higher in patients with normal than abnormal GT (p=0.002). Together with previous MI, abnormal GT was the strongest predictor of future cardiovascular events (hazard ratio 4.18; CI 1.26-13.84; p=0.019). Conclusions Abnormal glucose tolerance is a strong risk factor for future cardiovascular events after myocardial infarction. Since it is common and possible to detect even during the hospital phase it may be a target for novel secondary preventive efforts.
Clostridium difficile
infection (CDI) is one of the most common causes of nosocomial infectious diarrhea in children during anticancer therapy or undergoing hematopoietic stem cell transplantation ...(HSCT) in Europe. Immunosuppression in these patients is a risk factor for CDI. Malignant diseases, age, acute graft-versus-host disease (aGVHD), HLA mismatch, or use of total body irradiation may play an important role in CDI course. The aim of this study was to evaluate the incidence, course, and outcome of CDI in children treated for malignancy or undergoing HSCT. Between 2012 and 2015, a total number of 1846 patients were treated for malignancy in Polish pediatric oncological centers (PHO group) and 342 underwent transplantation (HSCT group). In PHO group, episodes of CDI occurred in 210 patients (14%). The incidence of CDI was higher in patients with hematological malignancies in comparison to that with solid tumors. Patients with acute myeloblastic leukemia had shorter time to episode of CDI than those with acute lymphoblastic leukemia. Patients over 5 years and treated for acute leukemia had more severe clinical course of disease in PHO group. In HSCT group, CDI occurred in 29 (8%) patients. The incidence of CDI was higher in patients transplanted for acute leukemia. The recurrence rate was 14.7% in PHO and 20.7% in HSCT patients. CDI incidence was highest in patients with hematological malignancies. Most of patients experienced mild CDI. Age < 5 years and diagnosis other than acute leukemia were the positive prognostic factors influencing clinical CDI course.
Hyperglycaemia and cardiovascular disease Bartnik, M.; Norhammar, A.; Rydén, L.
Journal of internal medicine,
August 2007, Letnik:
262, Številka:
2
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
.
Coronary artery disease and type 2 diabetes are chronic diseases of substantial and growing prevalence. Their coincidence is common, markedly enhancing mortality and morbidity. The risk for ...cardiovascular disease increases along a spectrum of blood glucose concentrations already apparent at levels regarded as normal. Accordingly, strategies for the early detection of glucometabolic disturbances are needed to find ways to prevent the occurrence of cardiovascular complications or to treat them already at an early stage. More specifically, abnormal glucose tolerance is almost twice as common amongst patients with a myocardial infarction as in population‐based controls and a normal glucose regulation is indeed less common than abnormal glucose metabolism also amongst patients with stable coronary artery disease. Already an abnormal glucose tolerance is a strong risk factor for future cardiovascular events after an acute myocardial infarction. An oral glucose tolerance test should, therefore, be a part of the evaluation of total risk in all patients with coronary artery disease. As glucose disturbances are common and easy to detect, they may be suitable targets for novel secondary preventive efforts.
Background: Patients with coronary artery disease (CAD) and abnormal glucose regulation (AGR) are at high risk for subsequent cardiovascular events, underlining the importance of accurate ...glucometabolic assessment in clinical practice. Objective: To investigate different methods to identify glucose disturbances among patients with acute and stable coronary heart disease. Methods: Consecutive patients referred to cardiologists were prospectively enrolled at 110 centres in 25 countries (n = 4961). Fasting plasma glucose (FPG) and glycaemia 2 h after a 75-g glucose load were requested in patients without known glucose abnormalities (n = 3362). Glucose metabolism was classified according to the World Health Organization and American Diabetes Association (ADA; 1997, 2004) criteria as normal, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. Results: Data on FPG and 2-h post-load glycaemia were available for 1867 patients, of whom 870 (47%) had normal glucose regulation, 87 (5%) had IFG, 591 (32%) had IGT and 319 (17%) had diabetes. If classification had been based on the ADA criterion from 1997, the proportion of misclassified (underdiagnosed) patients would have been 39%. The ADA 2004 criterion would have overdiagnosed 8% and underdiagnosed 33% of the patients, resulting in a total misclassification rate of 41%. For ethical concerns and practical reasons, oral glucose tolerance test (OGTT) was not conducted in 1495 of eligible patients. These patients were more often women, had higher age and waist circumference, and were therefore more likely to have AGR than those who were included. A model based on easily available clinical and laboratory variables, including FPG, high-density lipoprotein cholesterol, age and the logarithm of glycated haemoglobin A1c, misclassified 44% of the patients, of whom 18% were overdiagnosed and 26% were underdiagnosed. Conclusion: An OGTT is still the most appropriate method for the clinical assessment of glucometabolic status in patients with coronary heart disease.
Research Abstract
This study investigated the forces required while performing the common patient handling task of moving a patient up in bed using traditional cotton sheets or friction-reducing ...slide sheets. Twenty-nine healthy adult participants 18 to 36 years of age were recruited as “patients.” Hand forces and lumbar compression and shear forces were calculated on the “caregiver” when performing the repositioning task. Significant differences in lumbar compression and lumbar sagittal shear forces at L4–L5 and at L5-S1 were found among the three sheet types. No difference in peak sum hand force was found between the slide sheets; however, the traditional cotton sheet created the greatest force at the hands and every sheet exceeded the recommended summative hand force of 35 pounds. As such, sliding patients up in bed may contribute to increased risk of musculoskeletal injuries in caregivers. This study investigated the forces required while performing the common patient handling task of moving a patient up in bed using traditional cotton sheets or friction-reducing slide sheets. Twenty-nine healthy adult participants 18 to 36 years of age were recruited as “patients.” Hand forces and lumbar compression and shear forces were calculated on the “caregiver” when performing the repositioning task. Significant differences in lumbar compression and lumbar sagittal shear forces at L4–L5 and at L5-S1 were found among the three sheet types. No difference in peak sum hand force was found between the slide sheets; however, the traditional cotton sheet created the greatest force at the hands and every sheet exceeded the recommended summative hand force of 35 pounds. As such, sliding patients up in bed may contribute to increased risk of musculoskeletal injuries in caregivers.
Workplace Health Saf
2013;61(9):393–400.
Carvalho CMB, Bartnik M, Pehlivan D, Fang P, Shen J, Lupski JR. Evidence for disease penetrance relating to CNV size: Pelizaeus–Merzbacher disease and manifesting carriers with a familial 11 Mb ...duplication at Xq22.
The potential causes for the incomplete penetrance of Pelizaeus–Merzbacher disease (PMD) in female carriers of PLP1 mutations are not well understood. We present a family with a boy having PMD in association with PLP1 duplication and three females who are apparent manifesting carriers. Custom high‐resolution oligonucleotide array comparative genomic hybridization (aCGH) and breakpoint junction sequencing were performed and revealed a familial complex duplication consisting of a small duplicated genomic interval (∼56 kb) and a large segmental duplication (∼11 Mb) that resulted in a PLP1 copy number variation gain. Breakpoint junction analysis implicates a replication‐based mechanism underlying the rearrangement formation. X‐inactivation studies (XCI) showed a random to moderate advantageous skewing pattern in peripheral blood cells but a moderate to extremely skewed (≥90%) pattern in buccal cells. In conclusion, our data show that complex duplications involving PLP1 are not uncommon, can be detected at the level of genome resolution afforded by clinical aCGH and duplication and inversion can be produced in the same event. Furthermore, the observation of three manifesting carriers with a large genomic rearrangement supports the contention that duplication size along with genomic content can be an important factor for penetrance of the PMD phenotype in females.
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