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A machine learning algorithm predicts molecular subtypes in pancreatic ductal adenocarcinoma with differential response to gemcitabine-based versus FOLFIRINOX chemotherapy.
Kaissis, G, Ziegelmayer, S, Lohöfer, F, Steiger, K, Algül, H, Muckenhuber, A, Yen, HY, Rummeny, E, Friess, H, Schmid, R, et al
PloS one. 2019;(10):e0218642
Abstract
PURPOSE Development of a supervised machine-learning model capable of predicting clinically relevant molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) from diffusion-weighted-imaging-derived radiomic features. METHODS The retrospective observational study assessed 55 surgical PDAC patients. Molecular subtypes were defined by immunohistochemical staining of KRT81. Tumors were manually segmented and 1606 radiomic features were extracted with PyRadiomics. A gradient-boosted-tree algorithm was trained on 70% of the patients (N = 28) and tested on 30% (N = 17) to predict KRT81+ vs. KRT81- tumor subtypes. A gradient-boosted survival regression model was fit to the disease-free and overall survival data. Chemotherapy response and survival were assessed stratified by subtype and radiomic signature. Radiomic feature importance was ranked. RESULTS The mean±STDEV sensitivity, specificity and ROC-AUC were 0.90±0.07, 0.92±0.11, and 0.93±0.07, respectively. The mean±STDEV concordance indices between the disease-free and overall survival predicted by the model based on the radiomic parameters and actual patient survival were 0.76±0.05 and 0.71±0.06, respectively. Patients with a KRT81+ subtype experienced significantly diminished median overall survival compared to KRT81- patients (7.0 vs. 22.6 months, HR 4.03, log-rank-test P = <0.001) and a significantly improved response to gemcitabine-based chemotherapy over FOLFIRINOX (10.14 vs. 3.8 months median overall survival, HR 2.33, P = 0.037) compared to KRT81- patients, who responded significantly better to FOLFIRINOX over gemcitabine-based treatment (30.8 vs. 13.4 months median overall survival, HR 2.41, P = 0.027). Entropy was ranked as the most important radiomic feature. CONCLUSIONS The machine-learning based analysis of radiomic features enables the prediction of subtypes of PDAC, which are highly relevant for disease-free and overall patient survival and response to chemotherapy.
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Associations of Serum S100B and S100P With the Presence and Classification of Diabetic Peripheral Neuropathy in Adults With Type 2 Diabetes: A Case-Cohort Study.
Afarideh, M, Zaker Esteghamati, V, Ganji, M, Heidari, B, Esteghamati, S, Lavasani, S, Ahmadi, M, Tafakhori, A, Nakhjavani, M, Esteghamati, A
Canadian journal of diabetes. 2019;(5):336-344.e2
Abstract
OBJECTIVES Novel biomarkers of diabetic peripheral neuropathy provide potentially useful information for early identification and treatment of diabetic neuropathy, ultimately serving to reduce the burden of disease. This study was designed to investigate the potential associations of serum S100B and S100P (calcium-modulated proteins) with the presence and classification of diabetic peripheral neuropathy in adults with type 2 diabetes. METHODS In a case-cohort setting, the data of 44 participants diagnosed with diabetic peripheral neuropathy, 44 control participants with type 2 diabetes but free of peripheral neuropathy and 87 healthy control individuals were collected and analyzed. RESULTS Serum S100P concentrations were elevated in participants with diabetic peripheral neuropathy compared with their controls with type 2 diabetes (median [IQR]: 2,235 pg/mL [1,497.5 to 2,680] vs. 1,200 pg/mL [975 to 1,350)], respectively; p<0.001). Conversely, serum S100B values were comparable in these 2 groups (p=0.570). Those with the typical diabetic peripheral neuropathy had significantly higher serum S100P levels compared to their counterparts with the atypical group of diabetic peripheral neuropathies (p=0.048). The independent significant association between serum S100P and diabetic peripheral neuropathy persisted into the multivariable adjusted logistic regression model (OR for S100P: 1.004 [95% CI 1.002 to 1.006]; p<0.001). CONCLUSIONS The present study's findings demonstrated that serum S100P is a more significant indicator of peripheral neuropathy in type 2 diabetes than is serum S100B. Prospective longitudinal studies are required to confirm the prognostic value of baseline serum S100P to predict incident peripheral neuropathy in people with diabetes.
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Vitrectomy and Vitrector Port Needle Biopsy of Choroidal Melanoma for Gene Expression Profile Testing Immediately before Brachytherapy.
Reddy, DM, Mason, LB, Mason, JO, Crosson, JN, Yunker, JJ
Ophthalmology. 2017;(9):1377-1382
Abstract
PURPOSE Transvitreal and transscleral needle biopsy can result in complications including vitreous hemorrhage and retinal detachment. This study evaluated a technique using 25-gauge vitrectomy as an adjunct to needle biopsy immediately before brachytherapy to minimize these complications and preserve good visual acuity. DESIGN Retrospective, observational case series. PARTICIPANTS Fifty-seven consecutive eyes of 57 patients with treatment-naïve medium choroidal melanomas without extraocular extension from July 2012 through September 2015. METHODS Fifty-seven consecutive eyes of 57 patients with a clinically diagnosed choroidal melanoma underwent complete 25-gauge posterior vitrectomy followed by transvitrector port fine-needle aspiration biopsy of the tumor immediately before implantation of a radioactive iodine 125 plaque as treatment for the tumor. Cytopathologic analysis was not performed on the tumor aspirates in this study. MAIN OUTCOME MEASURES Best-corrected postoperative visual acuity, postoperative complications of the reported technique, implantation tumor development, local tumor recurrence, presence of metastatic disease after surgery, and sufficiency of the tumor aspirates obtained by the reported technique for successful gene expression profile testing and prognostic classification. RESULTS Mean preoperative and postoperative visual acuities were similar (20/60 vs. 20/80, respectively). Mean tumor thickness was 5.0 mm (range, 2.5-10 mm) and mean tumor basal diameter was 13.1 mm (range, 7-22 mm). Only 1 of 57 eyes (1.8%) showed a transient vitreous hemorrhage, biopsy yield was 100% for genetic analysis, and no patients showed recurrence or implantation tumor at the vitrector site. CONCLUSIONS Combined 25-gauge posterior vitrectomy and 25-gauge trans-vitrector port needle aspiration biopsy immediately before brachytherapy is excellent for obtaining tumor aspirate for gene expression profiling while controlling for hemostasis, resulting in few complications.
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Endocan and albuminuria in type 2 diabetes mellitus.
Cikrikcioglu, MA, Erturk, Z, Kilic, E, Celik, K, Ekinci, I, Yasin Cetin, AI, Ozkan, T, Cetin, G, Dae, SA, Kazancioglu, R, et al
Renal failure. 2016;(10):1647-1653
Abstract
BACKGROUND Endocan is a newly identified proteoglycan released from endothelium, stimulating angiogenesis and when increased, indicates endothelial activation (inflammation). Our aim was to examine the association between serum endocan levels and urine albumin-creatinine ratio (UACR). METHOD One hundred and thirty-seven patients with type 2 diabetes mellitus and normal serum creatinine who had no co-morbidities other than hypertension, diabetic nephropathy, retinopathy, or neuropathy were divided into normoalbuminuria (G1), microalbuminuria (G2), and macroalbuminuria (G3) groups and compared cross-sectionally regarding serum endocan levels. RESULT There were 55, 47, and 35 patients in G1, G2, and G3, respectively. The groups were comparable in terms of gender, age, duration of diabetes, diabetic neuropathy/retinopathy, fasting glucose, HbA1c, serum creatinine level, and eGFR. Patients in G3 had significantly higher blood pressure but lower serum albumin and endocan levels. UACR showed a negative bivariate correlation with serum endocan levels (r = -.282, p = .001). There was bivariate positive correlation between endocan and systolic blood pressure (r=.185, p = .030). In linear regression analysis, UACR was negatively correlated with endocan while positively correlated with systolic blood pressure, duration of diabetes, and platelet distribution width. CONCLUSION Patients with macroalbuminuria had lower endocan levels, and increasing UACR was associated with decreasing serum endocan levels. Despite the occurrence of angiogenesis and glomerular hypertrophy in the early phase of diabetic nephropathy, ensuing significant renal injury over time may reduce the expression of endocan. Serum endocan levels may represent a novel marker for nephropathy progression.
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Intrinsic subtypes and genomic signatures of primary breast cancer and prognosis after systemic relapse.
Falato, C, Tobin, NP, Lorent, J, Lindström, LS, Bergh, J, Foukakis, T
Molecular oncology. 2016;(4):517-25
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Abstract
Molecular subtypes and gene expression signatures are widely used in early breast cancer but their role in metastatic disease is less explored. Two hundred-twenty patients diagnosed with primary breast cancer and subsequent relapse in Stockholm, Sweden between 1997 and 2006 were identified and their primary tumor was assessed for immunohistochemistry (IHC)- and PAM50-based subtypes, risk of recurrence (ROR-S) score, 21-gene and 70-gene signatures using research-based microarray expression profiles. Clinical and pathological data were retrospectively collected. Post-relapse survival within intrinsic subtypes and genomic signatures was investigated by Kaplan-Meier and Cox regression methods. ROR weighted for proliferation index (ROR-P) was explored and the prognostic contribution provided when combined to a clinical model estimated as change in LR- χ(2). IHC classified 27%, 24%, 36% and 13% of the tumors as luminal A, luminal B, HER2+ and triple negative, respectively. PAM50 categorized 22%, 24%, 26%, 22%, 6% of the tumors as luminal A, luminal B, HER2-enriched, basal-like and normal-like. Triple negative and basal tumors had a significantly shorter median post-relapse survival in comparison with luminal. Overall, neither IHC nor PAM50 subtypes, 21- and 70- gene profiles were prognostic in multivariable models. Low and medium ROR-S had a longer survival compared with the high-risk group (23 vs 10 months; p = 0.04). ROR-P independently correlated with post-relapse survival (p = 0.002) and provided the most significant prognostic information when added to a clinical model. ROR score from primary tumor represents an independent prognostic factor of post-relapse survival beyond classical clinical and pathological variables.
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CARD8 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease.
Germain, A, Guéant, RM, Chamaillard, M, Bresler, L, Guéant, JL, Peyrin-Biroulet, L
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2015;(11):938-42
Abstract
BACKGROUND AND AIMS Post-operative recurrence is frequent in Crohn's disease. Genetic factors associated with post-operative recurrence remain poorly understood. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. METHODS Crohn's disease patients who had at least one bowel resection were retrospectively identified from the "Nancy IBD cohort". Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for 200 genetic variants and analyzed with the log-rank test. RESULTS 137 patients had at least 1 resection in our cohort: 38 had a surgical recurrence (28%). In multivariate analysis, current smoker status (OR 6.97, 95% CI 1.85-26.22, p=0.004), post-operative complications after prior surgery (OR 2.72, 95% CI 1.02-7.22, p=0.044), and Caspase recruitment domain-containing protein 8 (CARD8) homozygosity for the risk allele (OR 7.56, 95% CI 1.13-50.37, p=0.036) remained significantly and independently associated with surgical recurrence. CONCLUSION Current smoker status was associated with increased risk of surgical recurrence. A novel association between CARD8 and increased risk of surgical recurrence in Crohn's disease was observed. CARD8 could be a new marker for risk stratification and prevention of recurrent surgery.