Improving Ki67 assessment concordance by the use of an artificial intelligence-empowered microscope: a multi-institutional ring study.

AIMS: The nuclear proliferation biomarker Ki67 plays potential prognostic and predictive roles in breast cancer treatment. However, the lack of interpathologist consistency in Ki67 assessment limits the clinical use of Ki67. The aim of this article was to report a solution utilising an artificial intelligence (AI)-empowered microscope to improve Ki67 scoring concordance. METHODS AND RESULTS: We developed an AI-empowered microscope in which the conventional microscope was equipped with AI algorithms, and AI results were provided to pathologists in real time through augmented reality. We recruited 30 pathologists with various experience levels from five institutes to assess the Ki67 labelling index on 100 Ki67-stained slides from invasive breast cancer patients. In the first round, pathologists conducted visual assessment on a conventional microscope; in the second round, they were assisted with reference cards; and in the third round, they were assisted with an AI-empowered microscope. Experienced pathologists had better reproducibility and accuracy [intraclass correlation coefficient (ICC) = 0.864, mean error = 8.25%] than inexperienced pathologists (ICC = 0.807, mean error = 11.0%) in visual assessment. Moreover, with reference cards, inexperienced pathologists (ICC = 0.836, mean error = 10.7%) and experienced pathologists (ICC = 0.875, mean error = 7.56%) improved their reproducibility and accuracy. Finally, both experienced pathologists (ICC = 0.937, mean error = 4.36%) and inexperienced pathologists (ICC = 0.923, mean error = 4.71%) improved the reproducibility and accuracy significantly with the AI-empowered microscope. CONCLUSION: The AI-empowered microscope allows seamless integration of the AI solution into the clinical workflow, and helps pathologists to obtain higher consistency and accuracy for Ki67 assessment.

Outcome Assessment for a Telemedicine-Based Second Opinion Program for Midwest China.

Through an examination of the records of a telemedicine-based second opinion program in county-level hospitals in central and western China, the impact of this service on the diagnosis and treatment of cancer-related diseases was analyzed and evaluated. In this study, all 135 cancer-related cases were included in the analysis. The basic characteristics of the patients were described, the opinions of the original and second diagnosis and treatment were compared, the rate of consistency between them was calculated, the therapeutic regimens were analyzed and the differences between groups were tested. In 94.07% of the cases, the reason for the doctor's request for second opinion service was to assist in the formulation of therapeutic regimen. 64.44% of cases were confirmed with the diagnosis and 17.78% therapeutic regimen by the second opinion service. 126 cases obtained improved therapeutic regimens, and there were statistically significant differences in treatment methods in the diagnosis changed group. Comparing with other international SO studies, the diagnostic consistency rate obtained in this study was lower but not the lowest. The therapeutic consistency rate was quite low, due to the high proportion of original therapeutic regimens missing. This telemedicine-based second opinion program has brought beneficial improvements to the diagnosis and treatment of cancer-related diseases in county-level hospitals in central and western China.

A Cost-Effectiveness Analysis: First-Line Avelumab Plus Axitinib Versus Sunitinib for Advanced Renal-Cell Carcinoma.

BACKGROUND: Compared with the standard of care with sunitinib, avelumab plus axitinib can increase progression-free survival in the first-line of advanced renal cell carcinoma (RCC), but the economic effect of the treatment is unknown. The purpose of the research was to evaluate the cost-effectiveness of the avelumab plus axitinib versus sunitinib in first-line treatment for advanced RCC from the US payer perspective. METHODS: A Markov model was developed to evaluate the economic and health outcomes of avelumab plus axitinib vs sunitinib in the first-line setting for advanced RCC. The clinical data were obtained from the JAVELIN Renal 101 Clinical Trials. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainty in the model. Health outcomes were measured in quality-adjusted life-years (QALYs). RESULTS: The incremental cost-effectiveness ratio (ICER) of avelumab plus axitinib compared with sunitinib was $565,232 per QALY, the costs were $884,626 and $669,838, QALYs were 3.67 and 3.29, respectively. Sensitivity analysis demonstrated that differences in utilities in PFS and after progression were the most influential factors within the model. When avelumab was at 30% of the full price or axitinib was at 40% of the full price, avelumab and axitinib were approved to be cost-effective if the WTP threshold was $150,000 per QALY. The subgroup analysis showed the ICER of avelumab plus axitinib compared with sunitinib for the patients with PD-L1-positive tumors was $588,105. CONCLUSION: Avelumab plus axitinib in the first-line treatment was not cost-effective in comparison with sunitinib when the threshold of willingness to pay (WTP) was $150,000 per QALY.

Cost-utility analysis of screening for colorectal precancerous lesions and cancer in Beijing: A case-control study.

OBJECTIVE: To provide an objective cost-utility evaluation of a colorectal cancer screening program in a hypothetical general population. MATERIALS AND METHODS: A cost-utility analysis was conducted comparing screened individuals with the general population. Patients were evaluated as part of the screening program which conducted colorectal cancer risk assessments and performed colonoscopies from October 2012 to May 2013. Data were compared to a hypothetical group of the same size, consisting of the general population in which no cancer screening had been conducted. The cost and utility data have been published previously. RESULTS: The average cost per quality-adjusted life year (QALY) of colorectal cancer screening population was 84,092 CNY, while the average cost per QALY of the general population was 122,530 CNY. The colorectal cancer screening program saved 43,530 CNY per additional QALY. CONCLUSION: The colorectal cancer screening program could improve health-related quality of life and reduce medical expenditure.

Medical expenditure for liver cancer in urban China: A 10-year multicenter retrospective survey (2002-2011).

OBJECTIVE: This study aims to understand the medical expenditure for liver cancer during 2002-2011 in urban areas of China. MATERIALS AND METHODS: This is a retrospective study. Based on a stratified cluster sampling method, a medical expenditure survey collected basic personal information from related medical records. Two-tailed independent sample t-test, variance analysis, and Student-Newman-Keuls Tests were used in cost analysis for the corresponding data types. RESULTS: A total of 12,342 liver cancer patients were included in the analysis. Overall average medical expenditure per case for liver cancer diagnosis and treatment in China has increased from ¥21, 950 to ¥40, 386 over the study period. For each liver cancer patient diagnosed between 2009 and 2011, the average expenditures were 29,332 CNY for stage I, 35,754 CNY for stage II, 34,288 CNY for stage III, and 30,275 CNY for stage IV diseases (P < 0.001). Pharmaceuticals accounted for the biggest part of the medical expenditure and it rose from 48.01% to 52.96% during these ten years, and the share of nursing fee expenses was the lowest (around 1%). Over the entire 10-year data period, the per capita expenditure of the east region (32,983 CNY) was higher than that of the west region (26,219 CNY) and slightly higher than the central region (31,018 CNY, P < 0.001). DISCUSSION: As a major cancer in China, liver cancer accounts for a large portion of health economic burden and its medical expenditure is heavy for families. Early diagnosis and treatment for liver cancer will save medical expenditure. CONCLUSION: The economic burden of liver cancer is high in China and related medical expenditure has increased.

[Cost analysis of the colorectal neoplasm screen program in Beijing].

OBJECTIVE: To conduct with a cost analysis of the colorectal neoplasm screening program in Beijing, and provide data evidence for decision making. METHODS: Based on stratified cluster sampling method, we carried out a 2-stage colorectal neoplasm screening program within 6 districts, Dongcheng, Xicheng, Chaoyang, Haidian, Fengtai and Shijingshan, of Beijing city between October, 2012 to May. 2013. The first stage of the program was to conducting a cancer risk level evaluation for community residents who were forty years older and the second stage's task was to providing clinical exam for those high risk people who were selected from the first stage. There were about 12 953 residents were involved in this program. We calculated the main cost of the colorectal neoplasm screen program in Beijing. Then estimate the cost of detecting one Colorectal Neoplasm patient of this program and compare it with the total treatment cost for a patient. RESULT: 2 487 high risk residents were selected by the first stage and 1 055 of them made appointment for the colonoscopy exam but only 375 accepted the exam, participate rate was 35.5%. 9 neoplasm cancer patients and 71 pre-cancer patient were found at the second stage, the detection rate were 69.2/100 000 and 546/100 000, respectively. The direct input for this neoplasm screening program was 227 100 CNY and the transport expense was 4 200 CNY in the calculations. The cost for detecting one cancer patient was about 19 900 CNY. Comparing with the total medical care cost of a cancer patient (1 282 800 CNY), especially for those have been diagnosed as middle to end stage cancer, the screening program (cost 842 800 CNY) might help to reduce the total health expenditure about 128 700 CNY, based on 12 953 local residents age above 40 years old. CONCLUSION: An colonoscopy based colorectal neoplasm screening program showed its function on medical expenditure saving and might have advantage on health social labor creating.

Assessment of dynamic cerebral autoregulation in patients with basilar artery stenosis.

BACKGROUND AND AIMS: Previous studies have shown impaired cerebral autoregulation (CA) in carotid and middle cerebral artery (MCA) stenosis/occlusion. Little is known about CA in patients with basilar artery (BA) stenosis. We therefore investigated dynamic CA patterns in BA stenosis using transfer function analysis (TFA). METHODS: We measured spontaneous oscillations of blood flow velocity (CBFV) in the right posterior cerebral artery (PCA), and left MCA and mean arterial pressure (ABP) continuously in 25 patients with BA stenosis (moderate n=16 with 50-69% occlusion and severe n=9 with ≥ 70% occlusion) and 22 healthy volunteers in supine position during 6 circles per minute deep breath. Analysis was based on the 'black-box' model of transfer function deriving phase and gain in both PCA and MCA. RESULTS: Though changes of phase shift and gain between the patients and healthy controls were observed in MCA, the differences are however not significant. Phase shift in PCA was significantly decreased in severe stenosis when comparing with healthy controls and moderate stenosis (4.2 ± 34.2° VS 41.1 ± 40.4°, 4.2 ± 34.2° VS 34.2 ± 27.2°, both p<0.05), whilst the gain in PCA is increased for moderate BA stenosis and decreased for severe BA stenosis. Furthermore, we found that phase shift were almost abolished in patients with ischemic stroke who developed unfavorable clinical outcome (mRs>2) on the 90 days after stroke onset. CONCLUSION: Dynamic CA in PCA reduces in patients with severe BA stenosis and those with ischemic stroke who present poor outcome in 90 days after stroke onset. Phase shift might be a sensitive index prompting impaired CA in posterior circulation.

Vertically aligned single-walled carbon nanotubes as low-cost and high electrocatalytic counter electrode for dye-sensitized solar cells.

A novel dye-sensitized solar cell (DSSC) structure using vertically aligned single-walled carbon nanotubes (VASWCNTs) as the counter electrode has been developed. In this design, the VASWCNTs serve as a stable high surface area and highly active electrocatalytic counter-electrode that could be a promising alternative to the conventional Pt analogue. Utilizing a scalable dry transfer approach to form a VASWCNTs conductive electrode, the DSSCs with various lengths of VASWCNTs were studied. VASWCNTs-DSSC with 34 µm original length was found to be the optimal choice in the present study. The highest conversion efficiencies of VASWCNTs-DSSC achieved 5.5%, which rivals that of the reference Pt DSSC. From the electrochemical impedance spectroscopy analysis, it shows that the new DSSC offers lower interface resistance between the electrolyte and the counter electrode. This reproducible work emphasizes the promise of VASWCNTs as efficient and stable counter electrode materials in DSSC device design, especially taking into account the low-cost merit of this promising material.

Identification of cytochrome P450 (CYP) isoforms involved in the metabolism of corynoline, and assessment of its herb-drug interactions.

Corynoline, an isoquinoline alkaloid isolated from the genus Corydalis, has been demonstrated to show multiple pharmacological effects including inhibition of acetylcholinesterase, inhibition of cell adhesion, fungitoxic and cytotoxic activity. The present study focused on its metabolism and metabolism-based herb-drug interactions. After corynoline was incubated with human liver microsomes (HLMs) in the presence of NADPH, two metabolites (M-1 and M-2) were formed. Chemical inhibition experiments and assays with recombinant CYP isoforms showed that CYP2C9 was mainly involved in the formation of M-1 and CYP3A4 mainly catalysed the production of M-2. Among seven major CYP isoforms tested, corynoline showed strong inhibitory effects on the activities of CYP3A4 and CYP2C9, with an IC(50) of 3.3 ± 0.9 µm and 31.5 ± 0.5 µm, respectively. Kinetic analysis showed that inhibition of CYP3A4 by corynoline was best fit to a noncompetitive manner with K(i) of 3.2 µm, while inhibition of CYP2C9 by corynoline was best fit to a competitive manner with K(i) of 6.3 µm. Additionally, corynoline exhibited time-dependent inhibition (TDI) toward CYP3A4. The inactivation kinetic parameters (K(I) and k(inact) ) were calculated to be 6.8 µm and 0.07 min(-1) , respectively. These data are of significance for the application of corynoline and corynoline-containing herbs.

Quantitative structure-retention relationship studies for taxanes including epimers and isomeric metabolites in ultra fast liquid chromatography.

Seven pairs of epimers and one pair of isomeric metabolites of taxanes, each pair of which have similar structures but different retention behaviors, together with additional 13 taxanes with different substitutions were chosen to investigate the quantitative structure-retention relationship (QSRR) of taxanes in ultra fast liquid chromatography (UFLC). Monte Carlo variable selection (MCVS) method was adopted to choose descriptors. The selected four descriptors were used to build QSRR model with multi-linear regression (MLR) and artificial neural network (ANN) modeling techniques. Both linear and nonlinear models show good predictive ability, of which ANN model was better with the determination coefficient R(2) for training, validation and test set being 0.9892, 0.9747 and 0.9840, respectively. The results of 100 times' leave-12-out cross validation showed the robustness of this model. All the isomers can be correctly differentiated by this model. According to the selected descriptors, the three dimensional structural information was critical for recognition of epimers. Hydrophobic interaction was the uppermost factor for retention in UFLC. Molecules' polarizability and polarity properties were also closely correlated with retention behaviors. This QSRR model will be useful for separation and identification of taxanes including epimers and metabolites from botanical or biological samples.

Resting energy expenditure and glucose, protein and fat oxidation in severe chronic virus hepatitis B patients.

AIM: To study and determine the resting energy expenditure (REE) and oxidation rates of glucose, fat and protein in severe chronic hepatitis B patients. METHODS: A total of 100 patients with liver diseases were categorized into three groups: 16 in the acute hepatitis group, 56 in the severe chronic hepatitis group, and 28 in the cirrhosis group. The REE and the oxidation rates of glucose, fat and protein were assessed by indirect heat measurement using the CCM-D nutritive metabolic investigation system. RESULTS: The REE of the severe chronic hepatitis group (20.7 +/- 6.1 kcal/d per kg) was significantly lower than that of the acute hepatitis group (P = 0.014). The respiratory quotient (RQ) of the severe chronic hepatitis group (0.84 +/- 0.06) was significantly lower than that of the acute hepatitis and cirrhosis groups (P = 0.001). The glucose oxidation rate of the severe hepatitis group (39.2%) was significantly lower than that of the acute hepatitis group and the cirrhosis group (P < 0.05), while the fat oxidation rate (39.8%) in the severe hepatitis group was markedly higher than that of the other two groups (P < 0.05). With improvement of liver function, the glucose oxidation rate increased from 41.7% to 60.1%, while the fat oxidation rate decreased from 26.3% to 7.6%. CONCLUSION: The glucose oxidation rate is significantly decreased, and a high proportion of energy is provided by fat in severe chronic hepatitis. These results warrant a large clinical trail to assess the optimal nutritive support therapy for patients with severe liver disease.