Epidermal growth factor receptor (EGFR) inhibitors are approved for treating metastatic colorectal cancer (CRC); KRAS mutation testing is recommended prior to treatment. We conducted a ...non-inferiority analysis to examine whether KRAS testing has impacted survival in CRC patients.
We included 1186 metastatic CRC cases from seven health plans. A cutpoint of July, 2008, was used to define two KRAS testing time period groups: "pre-testing" (n = 760 cases) and "post-testing" (n = 426 cases). Overall survival (OS) was estimated, and the difference in median OS between the groups was calculated. The lower bound of the one-sided 95% confidence interval (CI) for the difference in survival was used to test the null hypothesis of post-testing inferiority. Multivariable Cox regression models were constructed to adjust for covariates.
The median unadjusted OS was 15.4 months (95% CI: 14.0-17.5) and 12.8 months (95% CI: 10.0-15.2) in the pre- and post-testing groups, respectively. The OS difference was -2.6 months with one-sided 95% lower confidence bound of -5.13 months, which was less than the non-inferiority margin (-5.0 months, unadjusted p = 0.06), leading to a failure to reject inferiority of OS in the post-testing period. In contrast, in the adjusted analysis, OS non-inferiority was identified in the post-testing period (p = 0.001). Sensitivity analyses using cutpoints before and after July, 2008, also met the criteria for non-inferiority.
Implementation of KRAS testing did not influence CRC OS. Our data support the use of KRAS testing to guide administration of EGFR inhibitors for treatment of metastatic CRC without diminished OS.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prenatal hyperglycaemia may increase metabolic syndrome susceptibility of the offspring. An underlying component of the development of these morbidities is hepatic gluconeogenic molecular ...dysfunction. We hypothesized that maternal hyperglycaemia will influence her offsprings hepatic peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) expression, a key regulator of glucose production in hepatocytes.
We established maternal hyperglycaemia by streptozotocin injection to induce the maternal hyperglycaemic Wistar rat model. Offspring from the severe hyperglycemia group (SDO) and control group (CO) were monitored until 180 days after birth. Blood pressure, lipid metabolism indicators and insulin resistance (IR) were measured. Hepatic PGC-1α expression was analyzed by reverse transcription polymerase chain reaction and Western blotting. mRNA expression of two key enzymes in gluconeogenesis, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK), were analyzed and compared.
In the SDO group, PGC-1α expression at protein and mRNA levels were increased, so were expression of G-6-Pase and PEPCK (P < 0.05). The above effects were seen prior to the onset of IR.
The hepatic gluconeogenic molecular dysfunction may contribute to the metabolic morbidities experienced by this population.
The etiology of recurrent miscarriage (RM) is extremely heterogeneous, including genetic, immunologic, anatomic, endocrinological, and infectious anomalies. About 50% of RM is unexplained or poorly ...understood, which is called idiopathic recurrent miscarriage (IRM). The primary aim of this study was to identify the genetic loci that might be susceptible to IRM. Forty-four Han Chinese patients with IRM during the first trimester of their pregnancies and 44 healthy sex- and ethnic-matched controls were enrolled in this study. A case-control and genome-wide study was performed and 430 polymorphic microsatellite markers were analyzed. Three loci, 6q27 (D6S446, P = .028), 9q33.1 (D9S1776, P = .037), and Xp22.11 (DXS1226, P = .008), significantly associated with IRM were found. This work identified 3 genetic regions that might harbor genes predisposed to IRM and provided new insights for future genetic and etiological study of IRM. Further study is required to confirm it.
To determine the relapse-free survival, overall survival, and response rate of patients with stage III melanoma treated with neoadjuvant biochemotherapy in a multicenter setting.
Patients with ...pathologically proven stage III melanoma, either via clinical detection or sentinel lymph node positivity, were eligible for enrollment. Patients received two cycles of preoperative biochemotherapy followed by complete regional lymphadenectomy and two postoperative courses of biochemotherapy. The biochemotherapy regimen consisted of the following: cisplatin 20 mg/m2 on days 1 to 4, dacarbazine 800 mg/m2 on day 1 only, vinblastine 1.6 mg/m2 on days 1 to 4, interleukin-2 total dose of 36 MU/m2 during 4 days, and interferon alfa 5 MU/m2 on days 1 to 5. Growth factor support was administered with each cycle.
Ninety-two patients were eligible for the study. At a median follow-up of 40.4 months, relapse-free survival and overall survival are 64% and 78%, respectively. There was a lower relapse rate and improved survival for patients with a positive sentinel lymph node compared with patients with clinically detected lymph nodes, although this difference did not reach statistical significance. Of the 50 patients with measurable disease, the overall response rate was 26%. Toxicity of the biochemotherapy was high but generally manageable.
The current study has expanded the preliminary evidence on neoadjuvant biochemotherapy for stage III melanoma.
Individuals with cytological atypia in sputum may be at increased risk for lung cancer. We conducted a longitudinal analysis
of the association between lung cancer incidence and cytological atypia in ...sputum samples collected prospectively from an
ongoing cohort of adults at high risk for lung cancer. Cohort members had a smoking history of ≥30 pack-years and chronic
obstructive pulmonary disease documented by pulmonary airflow testing. Sputum samples collected at baseline and periodically
thereafter were examined by standard cytological methods. From the cohort of 2006 people, there were 83 incident lung cancers
over 4469 person-years of observation. At baseline, the association between personal and behavioral characteristics, and sputum
cytological atypia was assessed by multiple logistic regression. The association between sputum cytological atypia and incident
lung cancer was then assessed by hazard ratios using proportional hazards regression analysis, adjusting for potential confounding
factors. Cytological atypia graded as moderate or worse was associated with continuing cigarette smoking (adjusted odds ratio,
2.5; 95% confidence interval, 1.5–4.1), and with lower levels of intake of fruits and vegetables ( P for trend = 0.04). Atypia was not associated with several other factors, including the degree of airflow obstruction, the
use of vitamin supplements, nonsteroidal anti-inflammatory drugs, or metered-dose steroid inhalers. Incident lung cancer was
increased among those with moderate or worse cytological atypia (adjusted hazards ratio, 2.8; 95% confidence interval, 1.4–5.5).
This association was not confounded by other risk factors. We conclude that in this high-risk cohort, cytological atypia is
associated with continuing smoking and low intake of fruits and vegetables, but that independent of these and other factors,
the risk of incident lung cancer is increased among those with moderate or worse grades of cytological atypia in their sputum.
•A total of 374 multi-detector CT scans are made available to the research community, the biggest such dataset on spine until date (VerSe’19: https://osf.io/nqjyw/; VerSe’20: ...https://osf.io/t98fz/).•The VerSe benchmark includes annotations for two fundamental processing tasks, namely vertebrae labelling and segmentation.•Twenty-six fully-automated algorithms (eleven for VerSe’19, thirteen for VerSe’20, and one baseline) are benchmarked on this dataset, with the top performing algorithm achieving a mean vertebrae identification rate of 96.6% and a Dice coefficient of 91.7% in VerSe’20.•Further insights into these algorithms are provided by examining them at various levels of granularity ranging from dataset-level experiments to vertebrae-level performances to a field-of-view-related analysis.
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Vertebral labelling and segmentation are two fundamental tasks in an automated spine processing pipeline. Reliable and accurate processing of spine images is expected to benefit clinical decision support systems for diagnosis, surgery planning, and population-based analysis of spine and bone health. However, designing automated algorithms for spine processing is challenging predominantly due to considerable variations in anatomy and acquisition protocols and due to a severe shortage of publicly available data. Addressing these limitations, the Large Scale Vertebrae Segmentation Challenge (VerSe) was organised in conjunction with the International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) in 2019 and 2020, with a call for algorithms tackling the labelling and segmentation of vertebrae. Two datasets containing a total of 374 multi-detector CT scans from 355 patients were prepared and 4505 vertebrae have individually been annotated at voxel level by a human-machine hybrid algorithm (https://osf.io/nqjyw/, https://osf.io/t98fz/). A total of 25 algorithms were benchmarked on these datasets. In this work, we present the results of this evaluation and further investigate the performance variation at the vertebra level, scan level, and different fields of view. We also evaluate the generalisability of the approaches to an implicit domain shift in data by evaluating the top-performing algorithms of one challenge iteration on data from the other iteration. The principal takeaway from VerSe: the performance of an algorithm in labelling and segmenting a spine scan hinges on its ability to correctly identify vertebrae in cases of rare anatomical variations. The VerSe content and code can be accessed at: https://github.com/anjany/verse.
Docetaxel, a semisynthetic taxane, improves the survival of stage IIIB and IV non-small cell lung cancer patients. However,
the 5-year survival remains poor, and few patients experience a complete ...remission. In this report, we evaluated the effects
of exisulind, a novel proapoptotic agent that is a sulfone metabolite of sulindac, in combination with docetaxel on the growth
of the human non-small cell lung cancer cell line A549 in vitro and in vivo . Exisulind is a novel sulindac metabolite in that it does not inhibit cyclooxygenase enzymes and has been shown to induce
apoptosis in a variety of human cancers by inhibiting cyclic GMP-dependent phosphodiesterase. Exisulind alone increased the
fraction of cells in the G 1 phase of the cell cycle from 46% to 65%, whereas it decreased the fraction of cells in the S phase from 38% to 14%. Docetaxel
increased the fraction of cells in the S phase from 17% to 19%, and 10 n m docetaxel increased the G2-M phase by 23%. Docetaxel alone induced apoptosis from 11% to 64% at 12–24 h after incubation.
The combination of exisulind with concentrations of docetaxel (in concentrations that alone did not alter cell cycle distribution)
reduced the G 1 accumulation induced by exisulind, increased the fraction of cells in G 2 -M (9–17%), and increased apoptosis (5–62%). The IC 50 for in vitro growth inhibition by exisulind alone was ∼200 μ m and 2.5 n m for docetaxel. The in vitro combination of exisulind and docetaxel produced an additive to synergistic growth inhibition. In athymic nude rats with A549
orthotopic lung cancers, both exisulind and docetaxel alone moderately prolonged survival, inhibited tumor growth and metastases,
and increased apoptosis compared with control animals treated with a carrier. However, the combination of exisulind with docetaxel
significantly prolonged survival ( P = < 0.0004), inhibited tumor growth and metastases ( P = < 0.0001), and increased apoptosis ( P = < 0.001) when compared with control animals. These results provide rationale for conducting clinical trials using the combination
of exisulind and docetaxel in patients with advanced lung cancer.
Study the effects of early overfeeding in the adult offspring of mother with severely hyperglycaemia in pregnancy to islet development and insulin resistance.
Thirty healthy female Wistar rats were ...mated with 10 male Wistar rats and the morning on which sperm were found in three different visual fields of the vaginal smear was designated pregnancy day 1. The pregnant rats were intraperitoneally administered with Streptozotocin (STZ, 50 mg/L) on 5th day of pregnancy, and blood glucose exceeded 20 mmol/L to induce severely gestational diabetes mellitus (SDM) model. The pregnant Wistar rats were assigned to two experimental groups: SDM (n = 16) and control (n = 8). Litter size reduction in the lactation period induced early postnatal overfeeding model. Offspring were divided into three groups according to the level of blood glucose in pregnancy and feeding patterns in lactation: (1) control group (CG): euglycemia in pregnancy, eight pups in lactation; (2) severely gestational diabetes mellitus-normal feeding (SD
Background: There is a need for early detection methods for lung cancer. Radiologic imaging may be more sensitive for peripheral
cancers than for cancers arising in the central airways, from which ...bronchial epithelial cells are exfoliated into the sputum.
Methods: Sputum samples were collected at baseline and periodically thereafter in a cohort of smokers and former smokers with
chronic obstructive lung disease. The association between cytologic atypia and incident lung cancer was assessed by hazard
ratios (HR; 95% confidence intervals) using Cox regression and by odds ratios (95% confidence intervals) using logistic regression,
adjusting for potential confounding factors.
Results: We observed 174 incident lung cancers in a cohort of 2,521 people over 9,869 person-years of observation. Risk for
incident lung cancer was increased among those with cytologic atypia graded as moderate or worse (adjusted HR, 2.37; 1.68-3.34).
The association between sputum atypia and lung cancer incidence was greatest for those sputum samples collected 5 months or
less before the diagnosis of lung cancer (odds ratio, 10.32; 5.34-19.97). The association was substantially stronger for squamous
cell lung cancers (HR, 5.13; 2.89-9.10) than for adenocarcinomas (HR, 1.85; 0.94-3.65).
Conclusion: Cytologic atypia is a marker for increased lung cancer risk. These cytologic changes seem to arise from late events
that are most apparent for cancers arising in the central respiratory airways. Whether cytologic atypia might complement radiologic
imaging in a combined approach to lung cancer, early detection requires additional evaluation of those two methods used together.
(Cancer Epidemiol Biomarkers Prev 2008;17(1):158–63)
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