The objective of this research focuses on the development of a statistical methodology able to answer the question of whether variation in the intake of sulfur amino acids (SAA) affects the metabolic ...process. Traditional approaches, which evaluate specific biomarkers after a series of preprocessing procedures, have been criticized as not being fully informative, as well as inappropriate for translation of methodology. Rather than focusing on particular biomarkers, our proposed methodology involves the multifractal analysis that measures the inhomogeneity of regularity of the proton nuclear magnetic resonance (1H-NMR) spectrum by wavelet-based multifractal spectrum. With two different statistical models (Model-I and Model-II), three different geometric features of the multifractal spectrum of each 1H-NMR spectrum (spectral mode, left slope, and broadness) are employed to evaluate the effect of SAA and discriminate 1H-NMR spectra associated with different treatments. The investigated effects of SAA include group effect (high and low doses of SAA), depletion/repletion effect, and time over data effect. The 1H-NMR spectra analysis outcomes show that group effect is significant for both models. The hourly variation in time and depletion/repletion effects does not show noticeable differences for the three features in Model-I. However, these two effects are significant for the spectral mode feature in Model-II. The 1H-NMR spectra of the SAA low groups exhibit highly regular patterns with more variability than that of the SAA high groups for both models. Moreover, the discriminatory analysis conducted using the support vector machine and the principal components analysis shows that the 1H-NMR spectra of SAA high and low groups can be easily discriminatory for both models, while the spectra of depletion and repletion within these groups are discriminatory for Model-I and Model-II. Therefore, the study outcomes imply that the amount of SAA is important and that SAA intake affects mostly the hourly variation of the metabolic process and the difference between depletion and repletion each day. In conclusion, the proposed multifractal analysis of 1H-NMR spectra provides a novel tool to investigate metabolic processes.
CD19 CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and ...infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with >= grade 3 neutropenia seen in 21/70 (30-0%) patients at day 30 and persisting in 3/31 (9-7%) patients at 1 year. B cells were undetectable in 30/34 (88-2%) patients at day 30, but were detected in 11/19 (57-9%) at 1 year. Median IgG levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/μl at 1 year after axi-cel (n=19, range 33 - 269). In total, 23/85 (27-1%) patients received IVIG after axi-cel, and 34/85 (40-0%) received G-CSF. Infections in the first 30 days occurred in 31/85 (36-5%) patients, of which 11/85 (12-9%) required intravenous antibiotics or hospitalization ("severe") and were associated with cytokine release syndrome (CRS), neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, 7 severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T cell immunosuppression without severe infection.
The Bland-Altman plot with the limits of agreement has been widely used as an absolute index for assessing test-retest reliability or reproducibility between two measurements. We have observed that ...in the settings where the relative index such as concordance correlation coefficient (CCC) or intraclass correlation coefficient is employed, the limits of agreement approach may be inconsistent with the scaled index. Particularly, the broad width of the limits of agreement may indicate a lack of agreement when the two measurements are highly concordant but an acceptable difference is not known and the common variance of the data is large. This research aims to create a novel, CCC-based guidance for graphical evaluation of reproducibility or reliability.
The concordance correlation coefficient is used to create a 100(1-α)% reference band from two measurements. Simulation studies and real examples, including the peak expiratory flow rate data in Bland and Altman's paper and the test-retest reproducibility data of the Radiomics study, are implemented to assess the use of the reference band.
In the absence of an acceptable difference between measurements, we found that the limits of agreement may not be consistent with the concordance correlation coefficient. Our simulation study results and real data application show that the proposed method can provide practitioners with a novel graphical evaluation that is consistent with results from the concordance correlation coefficient.
Our proposed novel scaled index-based guidance can be used for the graphical evaluation of reproducibility or reliability and may have advantages over the limits of agreement in settings where the concordance correlation coefficient is employed.
The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression ...of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state.
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•Characterization of a histone H4-Y88 phosphorylation in CRPCs•Androgen receptor is a key epigenetic target of the H4-Y88 phosphorylation in CRPCs•Targeting H4-Y88 phosphorylation subdues the expression of AR and AR splice variant•The epigenetic inhibitor (R)-9bMS mitigates enzalutamide resistance
Mahajan et al. report that ACK1 phosphorylates histone H4 at Y88 upstream of the AR transcription start site, leading to the WDR5/MLL2 complex-mediated increase of AR transcription. Inhibition of ACK1 reverses the pY88-H4 marks and reduces AR and AR-V7 levels to mitigate castration-resistant prostate tumor growth.
Background
Regorafenib is an oral multikinase inhibitor targeting angiogenesis, oncogenesis, and cancer proliferation/metastasis. This study evaluated the efficacy of regorafenib in refractory ...biliary tract cancer (BTC) in a multi‐institutional phase 2 study.
Methods
Patients with BTC who progressed on at least 1 line of systemic therapy received regorafenib at 160 mg daily for 21 days on and 7 days off. The primary endpoint was 6‐month overall survival (OS), and the secondary endpoints were median OS, progression‐free survival (PFS), and objective response rates. Pretreatment plasma was collected for cytokine evaluation.
Results
A total of 39 patients were enrolled, and 33 were evaluable for efficacy. The median PFS and OS were 3.7 and 5.4 months, respectively, with survival rates of 46.2% at 6 months, 35.9% at 12 months, and 25.6% at 18 months for the intention‐to‐treat population. For the 33 evaluable patients who received regorafenib for at least 3 weeks, the median PFS and OS were 3.9 and 6.7 months, respectively, with survival rates of 51.5% at 6 months, 39.4% at 12 months, and 27.3% at 18 months. The objective response rate was 9.1%, and the disease control rate was 63.6%. Twenty‐eight patients (71.8%) experienced grade 3/4 adverse events. Among the 23 cytokines analyzed, elevated baseline vascular endothelial growth factor D (VEGF‐D) was associated with shorter PFS, whereas elevated baseline interleukin 6 (IL‐6) and glycoprotein 130 (GP130) were associated with shorter OS.
Conclusions
Regorafenib demonstrated modest clinical efficacy in heavily pretreated patients with BTC. Further exploration of biomarkers is warranted to identify a group of patients with BTC who may benefit from regorafenib.
Regorafenib can provide modest clinical efficacy and a manageable safety profile in heavily pretreated patients with advanced biliary tract cancer.
Abstract We study the reproducibility of quantitative imaging features that are used to describe tumor shape, size, texture from computed tomography (CT) scans of non-small cell lung cancer (NSCLC). ...CT images are dependent on various scanning factors. We focus on characterizing image features that are reproducible in the presence of variations due to patient factors and segmentation methods. Thirty-two NSCLC nonenhanced lung CT scans were obtained from the Reference Image Database to Evaluate Response data set. The tumors were segmented using both manual (radiologist expert) and ensemble (software-automated) methods. A set of features (219 threedimensional and 110 two-dimensional) was computed, quantitative image features were statistically filtered to identify a subset of reproducible and nonredundant features. The variability in the repeated experiment was measured by the test-retest concordance correlation coefficient (CCCTreT ). The natural range in the features, normalized to variance, was measured by the dynamic range (DR). In this study, there were 29 features across segmentation methods found with CCCTreT and DR ≥ 0.9 and R2Bet ≥ 0.95. These reproducible features were tested for predicting radiologist prognostic score; some texture features (run-length and Laws kernels) had an area under the curve of 0.9. The representative features were tested for their prognostic capabilities using an independent NSCLC data set (59 lung adenocarcinomas), where one of the texture features, run-length gray-level nonuniformity, was statistically significant in separating the samples into survival groups ( P ≤ .046).
Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive pancreatic precursor lesions that can potentially develop into invasive pancreatic ductal adenocarcinoma. Currently, the ...International Consensus Guidelines (ICG) for IPMNs provides the basis for evaluating suspected IPMNs on computed tomography (CT) imaging. Despite using the ICG, it remains challenging to accurately predict whether IPMNs harbor high grade or invasive disease which would warrant surgical resection. A supplementary quantitative radiological tool, radiomics, may improve diagnostic accuracy of radiological evaluation of IPMNs. We hypothesized that using CT whole lesion radiomics features in conjunction with the ICG could improve the diagnostic accuracy of predicting IPMN histology.
To evaluate whole lesion CT radiomic analysis of IPMNs for predicting malignant histology compared to International Consensus Guidelines.
Fifty-one subjects who had pancreatic surgical resection at our institution with histology demonstrating IPMN and available preoperative CT imaging were included in this retrospective cohort. Whole lesion semi-automated segmentation was performed on each preoperative CT using Healthmyne software (Healthmyne, Madison, WI). Thirty-nine relevant radiomic features were extracted from each lesion on each available contrast phase. Univariate analysis of the 39 radiomics features was performed for each contrast phase and values were compared between malignant and benign IPMN groups using logistic regression. Conventional quantitative and qualitative CT measurements were also compared between groups,
(categorical) and Mann Whitney
(continuous) variables.
Twenty-nine subjects (15 males, age 71 ± 9 years) with high grade or invasive tumor histology comprised the "malignant" cohort, while 22 subjects (11 males, age 70 ± 7 years) with low grade tumor histology were included in the "benign" cohort. Radiomic analysis showed 18/39 precontrast, 19/39 arterial phase, and 21/39 venous phase features differentiated malignant from benign IPMNs (
< 0.05). Multivariate analysis including only ICG criteria yielded two significant variables: thickened and enhancing cyst wall and enhancing mural nodule < 5 mm with an AUC (95%CI) of 0.817 (0.709-0.926). Multivariable post contrast radiomics achieved an AUC (95%CI) of 0.87 (0.767-0.974) for a model including arterial phase radiomics features and 0.834 (0.716-0.953) for a model including venous phase radiomics features. Combined multivariable model including conventional variables and arterial phase radiomics features achieved an AUC (95%CI) of 0.93 (0.85-1.0) with a 5-fold cross validation AUC of 0.90.
Multi-phase CT radiomics evaluation could play a role in improving predictive capability in diagnosing malignancy in IPMNs. Future larger studies may help determine the clinical significance of our findings.
In older patients with acute myeloid leukemia, the more frequent presence of biologically inherent therapy-resistant disease and increased comorbidities translate to poor overall survival and ...therapeutic challenges. Optimal front-line therapies for older patients with acute myeloid leukemia remain controversial. We retrospectively evaluated survival outcomes in 980 elderly (≥70 years) acute myeloid leukemia patients from a single institution between 1995 and 2016. Four treatment categories were compared: high-intensity (daunorubicin/cytarabine or equivalent), hypomethylating agent, low-intensity (low-dose cytarabine or similar without hypomethylating agents), and supportive care therapy (including hydroxyurea). At a median follow up of 20.5 months, the median overall survival for the entire cohort was 7.1 months. Multivariate analysis identified secondary acute myeloid leukemia, poor-risk cytogenetics, performance status, front-line therapy, age, white blood cell count, platelet count, and hemoglobin level at diagnosis as having an impact on survival. High-intensity therapy was used in 360 patients (36.7%), hypomethylating agent in 255 (26.0%), low-intensity therapy in 91 (9.3%), and supportive care in 274 (28.0%). Pairwise comparisons between hypomethylating agent therapy and the three other treatment groups demonstrated statistically significant superior median overall survival with hypomethylating agent 14.4 months)
high-intensity therapy 10.8 months, hazard ratio 1.35, 95% confidence interval (CI): 1.10-1.65;
=0.004, low-intensity therapy (5.9 months, hazard ratio 2.01, 95%CI: 1.53-2.62;
<0.0001), and supportive care (2.1 months, hazard ratio 2.94, 95%CI: 2.39-3.61;
<0.0001). Our results indicate a significant survival benefit with hypomethylating agents compared to high-intensity, low-intensity, or supportive care. Additionally, high-intensity chemotherapy resulted in superior overall outcomes compared to low-intensity therapy and supportive care. Results from this study highlight the need for novel therapeutic approaches besides utilization of intensive chemotherapy in this specific aged population.
Pencil beam (PB) and collapsed cone convolution (CCC) dose calculation algorithms differ significantly when used in the thorax. However, such differences have seldom been previously directly ...correlated with outcomes of lung stereotactic ablative body radiation (SABR).
Data for 201 non-small cell lung cancer patients treated with SABR were analyzed retrospectively. All patients were treated with 50 Gy in 5 fractions of 10 Gy each. The radiation prescription mandated that 95% of the planning target volume (PTV) receive the prescribed dose. One hundred sixteen patients were planned with BrainLab treatment planning software (TPS) with the PB algorithm and treated on a Novalis unit. The other 85 were planned on the Pinnacle TPS with the CCC algorithm and treated on a Varian linac. Treatment planning objectives were numerically identical for both groups. The median follow-up times were 24 and 17 months for the PB and CCC groups, respectively. The primary endpoint was local/marginal control of the irradiated lesion. Gray's competing risk method was used to determine the statistical differences in local/marginal control rates between the PB and CCC groups.
Twenty-five patients planned with PB and 4 patients planned with the CCC algorithms to the same nominal doses experienced local recurrence. There was a statistically significant difference in recurrence rates between the PB and CCC groups (hazard ratio 3.4 95% confidence interval: 1.18-9.83, Gray's test P=.019). The differences (Δ) between the 2 algorithms for target coverage were as follows: ΔD99GITV = 7.4 Gy, ΔD99PTV = 10.4 Gy, ΔV90GITV = 13.7%, ΔV90PTV = 37.6%, ΔD95PTV = 9.8 Gy, and ΔDISO = 3.4 Gy. GITV = gross internal tumor volume.
Local control in patients receiving who were planned to the same nominal dose with PB and CCC algorithms were statistically significantly different. Possible alternative explanations are described in the report, although they are not thought likely to explain the difference. We conclude that the difference is due to relative dosimetric underdosing of tumors with the PB algorithm.
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