Method For Evaluation Of Response Research Articles

Study on response evaluation method for low-seismic-class piping with U-bolts

Simple support structures such as U-bolts and clamps are used for the low-seismic-class piping designed using the constant pitch span method. Recently, the safety of the piping is required during the earthquake, and the demand for safety in nuclear power plants has increased. As a result, the high seismic resistance has also been required for the low-seismic-class piping. In the response analysis, the support structure constrains the displacement in two translational directions, but not the axial displacement of the pipe. Depending on the routing of the piping, a large axial response displacement may occur, and the structural integrity of the piping and the support structure may not be ensured. Therefore, measures have been taken to add or reinforce support structures. In practice, pipes are subjected to the axial friction resistance by the support structure, which reduces the response displacement. A static element test was conducted to understand this axial resistance. In this test, the friction resistance force was measured with no tightening force. Specimens were G28 (about 3 kg) and G54 (about 6.5 kg) pipe elements. The resistance force about 3.5 to 7 N for G28 and about 7 to 15 N for G54, and the friction coefficient about 0.18 were observed. By taking this into consideration, it is expected that the response displacement during the earthquake will decrease. The development of a rational seismic evaluation method considering the frictional resistance in the axial direction will be continued.

Evaluation of response in patients with hepatocellular carcinoma treated with intratumoral dendritic cell vaccination using intravoxel incoherent motion (IVIM) MRI and histogram analysis.

Immunotherapy of hepatocellular carcinoma (HCC) is an emerging method with promising results. Immunotherapy can have an antitumor effect without affecting tumor size, calling for functional imaging methods for response evaluation. To evaluate the response to intratumoral injections with the immune primer ilixadencel in HCCs with diffusion-weighted magnetic resonance imaging (DW-MRI) using intravoxel incoherent motion (IVIM) and histogram analysis. A total of 17 patients with advanced HCC were treated with intratumoral injections with ilixadencel on three occasions 2-5 weeks apart. The patients were examined with IVIM before each injection as well as approximately three months after the first injection. The 10th percentile of perfusion-related parameter D* decreased significantly after the first and second intratumoral injections of ilixadencel compared to baseline (P < 0.05). There was a non-significant trend of lower median region of interest f (perfusion fraction) before injection 2 compared to baseline (P = 0.07). There were significant correlations between the 10th percentile and median of D at baseline and change in tumor size after three months (r = 0.79, P < 0.01 and r = 0.72, P < 0.05, respectively). DW-MRI with IVIM and histogram analysis revealed significant reductions of D* early after treatment as well as an association between D at baseline and smaller tumor growth at three months. The lower percentiles (10th and 50th) were found more important. Further research is needed to confirm our preliminary findings of reduced perfusion after ilixadencel vaccinations, suggesting a treatment effect on HCC.

Comparison of mRECIST versus densitometric method for radioembolization treatment response evaluation in hepatocellular carcinoma patients

Comparison of mRECIST versus densitometric method for radioembolization treatment response evaluation in hepatocellular carcinoma patients

Iterative Methods for the Biomechanical Evaluation of Corneal Response. A Case Study in the Measurement Phase

The number of corneal surgeries steadily grew in recent years and boosted the development of corneal biomechanical models. These models can contribute to simulating surgery by reducing associated risks and the need for secondary interventions due to ectasias or other problems related to correcting other diseases. Biomechanical models are based on the geometry obtained with corneal topography, which is affected by intraocular pressure and material properties. Knowledge of stress distribution in the measurement phase is a key factor for improving the accuracy of in silico mechanical models. In this work, the results obtained by two different methods: prestress method and displacements method were compared to evaluate the stress and strain distribution in a general geometric model based on the Navarro eye geometry and two real corneal geometries. The results show that both methods are equivalent for the achievement of the stress distribution in the measurement phase. Stress distribution over the corneal geometry in the measurement phase is a key factor for accurate biomechanical simulations, and these simulations could help to develop patient-specific models and reduce the number of secondary interventions in clinical practice.

A fast and accurate method for the seismic response analysis of reinforced concrete frame structures considering Beam-Column joint deformation

Many previous investigations of reinforced concrete (RC) frame structures have demonstrated that beam-column joints may experience significant nonlinearities under earthquake excitations. However, most available analysis methods assume that the joint region remains rigid. Because joint failure may result in strength and stiffness losses and even induce structural collapse, it is difficult for an analytical model with a rigid joint assumption to obtain an accurate prediction of the structural nonlinear response. The behavior of a joint is mainly affected by the shear deformation of the joint core and bond-slip of beam longitudinal reinforcements in the joint. Although many different types of modeling approaches have been presented to effectively represent the behavior mechanism of beam-column joints, the introduction of joint models inevitably increases the complexity of the analytical model of the global structure and the effort of the solution process. Therefore, achieving highly efficient analysis on the premise of accurately predicting the seismic response of RC frame structures is still a topic that deserves investigation. This study presents an efficient analysis method for the accurate evaluation of the nonlinear response of RC frames considering the effect of beam-column joint deformation based on the concept of local inelasticity separation. The proposed method captures the bond-slip behavior at beam ends by adding inelastic rotation hinge mechanisms to the ends of the existing inelasticity-separated fiber beam-column model and uses a sliding hinge mechanism to simulate the inelastic shear response of the joint core. A small number of additional inelastic degrees of freedom that are separated from the global displacement degrees of freedom of the structure is introduced to describe both the inelastic rotation behavior and the inelastic deformation of the proposed bond-slip hinge mechanism and the sliding hinge mechanism. Consequently, the Woodbury formula can be utilized for nonlinear iterative solutions to avoid updating the global stiffness matrix, thus significantly improving the computational efficiency. The exactness of the proposed method is verified against experimental data, and its application is illustrated through a seismic response analysis example.

A Simple Critical Response Evaluation Method for Base-Isolation Building-Connection Hybrid System Under Double Impulse as Representative of Near-Fault Ground Motion

We revisit a unique building system including a base-isolation, building-connection hybrid control system. The base-isolation system withstands pulse-type earthquake ground motions effectively and the building-connection system resists long-duration earthquake ground motions efficiently. A simple smart critical response evaluation method without nonlinear time-history response analysis is proposed for this hybrid building system under near-fault ground motions. An analytical expression of the maximum elastic-plastic deformation of a damped bilinear hysteretic single-degree-of-freedom (SDOF) model under critical double impulse as a representative of pulse-type ground motions derived in our previous paper plays an important role in the development of the simple critical response evaluation method. A two-step transformation procedure into an SDOF model is proposed. The first step is the transformation of the main base-isolated building into an SDOF system and the second step is the reduction of the connecting dampers supported on a sub building to a damper with a sophisticated compensation factor on an assumed rigid wall. The evaluation of damping coefficients with the consideration of yielding of the base-isolation story is a key step in this paper. Different from the previous work, the equivalent damping coefficient is derived depending on the response range before and after yielding of the base-isolation story. This treatment enhances the accuracy of the proposed method. The accuracy and reliability of the proposed response evaluation method is demonstrated by the time-history response analysis of the multi-degree-of-freedom (MDOF) model.

The role of adaptation measures in contrasting heat-related health effects among vulnerable groups: a review from the EXHAUSTION European project

BACKGROUND AND AIM: The health burden associated with extreme heat depends on population vulnerability, intensity of the exposure and the population’s adaptation capacity. A systematic literature review was conducted in Pubmed and Web of Science, between 1990- 2020, to provide evidence on how adaptation interventions may affect heat-related health effects. METHODS: Both MeSH and free-text terms were included in the search. Studies were categorized based on the type of intervention: (1)public health response plans; (2)indoor and outdoor thermal environmental interventions (air conditioning and passive cooling, green spaces); (3)behavioral change interventions. Studies were evaluated considering whether they provided direct or indirect evidence of the intervention in terms of changing health-effect estimates. RESULTS:Of the 58 studies retained, 75% were based in north America and Europe, and the remaining studies were located in Asia or Australia. Only 5 studies (9%) directly assessed the effect of a specific intervention, through an experimental or a quasi-experimental design, while the remaining 53 studies (91%) were indirect evaluations (21 studies compared effect-estimates before-after the evaluation, 25 studies analyzed the effect modification due to presence/absence of the intervention, and 7 with a cross-sectional approach). 24 studies assessed heat plans, 29 evaluated thermal environment interventions and 5 considered behavioral measures. Although heterogenous, several studies reported a reduction in heat-related mortality\morbidity over time indirectly related to the introduction of heat plans and warning systems especially among the elderly. Studies also assessed differences by socio-economic status and people with chronic disease most at risk during heat waves. Evidence of beneficial effects of green areas and indoor cooling was promising, but inconsistent. Among workers, changes in work clothing such as cooling vests and working in cooled environments improved productivity and reduced health effects. CONCLUSIONS:The review provides updated evidence on heat response measures and evaluation methods necessary to enhance public health response and drive policy. KEYWORDS: Temperature extremes and variability, climate, review

Effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma under real-world conditions in Germany - The non-interventional study NIELS.

Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small-molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC. The aim of this non-interventional study was to assess effectiveness with a special focus on duration of response (DOR), safety and utilization of vismodegib for treatment of laBCC in daily practice in Germany. This non-interventional study (NIS) observed treatment of laBCC with vismodegib according to the German label in clinical practice. All available patients who had received at least one dose of vismodegib between commercial availability of vismodegib in Germany (02 August 2013) and 3 years before end of study (31 March 2016) could be included and were documented retrospectively and/or prospectively for up to 3 years. Primary effectiveness variable was DOR. Assessment of tumour response was carried out by the treating physicians. Exploratory variables included utilization of vismodegib, decision makers for therapy and method of tumour response evaluation. All statistical analyses were descriptive. Between September 2015 and March 2019, 66 patients were observed at 26 German centres. The objective response rate (ORR) was 74.2% and the disease control rate (DCR) was 90.9%. The median DOR was 15.9 months (95% CI: 9.2; 25.7; n=49 patients with response). The median progression-free survival (PFS) was 19.1 months and the median time to response (TTR) 2.7 months. A total of 340 adverse events were reported in 63 (95.5%) patients; no new safety signals were identified. The NIS NIELS shows effectiveness and safety of vismodegib in patients with laBCC. It confirms the transferability of the results of the pivotal trial into routine clinical practice.

Vibration measurement of a steel building with viscoelastic dampers using acceleration sensors

With the rapid development of sensor technology, wireless measurement systems are applied to various fields, such as safety monitoring and health evaluation of existing buildings. This study aims to develop a vibration measurement based on wireless acceleration sensors. This paper presents a simple response evaluation method of a steel structure with a stud-type damper composed of viscoelastic material and two steel columns. The series of measurements consists of micro-tremor measurements and seismic motion monitoring before and after seismic retrofitting. The changes in vibrational properties indicate the damping effect. To obtain the vibrational properties of the structure correctly, we investigated the natural frequency, deformation mode, and restoring force characteristics. The effectiveness of using a wireless system in the evaluation of existing buildings and the feasibility of the evaluation method can be obtained using the results of this experiment. Despite being the result of only one structure, this simple vibration measurement method's effectiveness is demonstrated.

Guidance for footbridge design: a new simplified method for the accurate evaluation of the structural response in serviceability conditions

This paper proposes a simplified hand-calculation methodology that permits a fast response assessment (both in vertical and lateral direction) under different pedestrian scenarios. This simplified method has the same accuracy than that of very sophisticated numerical nonlinear finite element models including pedestrian inter-variability, interaction among pedestrians in flows, and pedestrian-structure interaction. The method can capture the effects of pedestrian loads in and out of resonance. This methodology is based on a new, and experimentally contrasted, stochastic pedestrian load model derived by the authors implementing a multi-disciplinary state-of-the-art research, and on a large set of sophisticated finite element analyses.There is a significant gap in the literature available for bridge designers. Some current codes do not indicate how the performance for serviceability limit-states should be assessed, in particular for lateral direction. Others define methods that are not based on the latest research in this field and that require the use of dynamic structural analysis software. A very sophisticated load model, such as that described above, and recently proposed by the authors, may not be accessible for most of the design offices, due to time and software constraints. However, an accurate assessment of the serviceability limit state of vibrations during the design stages is paramount. This paper aims to provide designers with an additional simple tool for both preliminary and detailed design for the most typical structural configurations.First, the paper presents the methodology, followed by an evaluation of the impact of its simplifications on the response appraisal. Second, the paper evaluates the validity of the methodology by comparing responses predicted by the method to those experimentally measured at real footbridges. Finally, the paper includes a parametric analysis defining the maximum accelerations expected from pedestrian streams crossing multiple footbridges. This parametric analysis considers different variables such as section type, structural material, span length and traffic-flow characteristics, and shows the sensitivity of the serviceability response to traffic-flow characteristics and span length in particular.

The value of dynamic contrast enhanced ultrasound (DCE-US) in monitoring treatment effect of high-intensity focused ultrasound (HIFU) in locally advanced pancreatic cancer (LAPC).

To evaluate the feasibility of dynamic contrast enhanced ultrasound (DCE-US) in predicting treatment response of high-intensity focused ultrasound (HIFU) in patients with locally advanced pancreatic cancer (LAPC) lesions. In this prospective study, 10 patients with pathologically confirmed LAPC lesions (7 men, 3 women; average age, 61.13±5.80 years) were prospectively enrolled. All patients received HIFU treatment with peak intensity at 12000 W/cm2. Contrast enhanced ultrasound (CEUS) was performed with an ACUSON Oxana 2 ultrasound equipment and a 6 C-1 transducer (1-6 Hz). A dose of 2.4 ml SonoVue was injected for each examination. Time intensity curves (TICs) were generated and quantitative analyses were performed by SonoLiver software. B mode ultrasound (BMUS) features, CEUS enhancement patterns, TICs, CEUS quantitative parameters and serum carcinoma antigen 19-9 (CA19-9) levels were compared before and 4 weeks after HIFU treatment. Statistical analyses were performed with SPSS Version 20.0 and GraphPad Prism 5. While comparing before and after HIFU, no significant difference was obtained on mean size of lesion, BMUS or CEUS features. After HIFU treatment, TICs showed decreased and delayed enhancement. Among all CEUS quantitative parameters, significant decrease could be found in maximum intensity (MI) (60.66±23.95% vs 41.31±26.74%) and mean transit time (mTT) (76.66±47.61 s vs 38.42±28.35 s). CA19-9 level decreased significantly after HIFU (2747.92±4237.41 U/ml vs 715.08±1773.90 U/ml) (P = 0.05). DCE-US combining with quantitative analysis might be a useful imaging method for early treatment response evaluation of HIFU in LAPC lesions.

Why the natural frequency and the damping coefficient do not evaluate the dynamic response of clinically used pressure monitoring circuits correctly.

The dynamic response of pressure monitoring circuits must be evaluated to obtain true invasive blood pressure values. Since Gardner's recommendations in 1981, the natural frequency and the damping coefficient have become standard parameters for anesthesiologists. In 2006, we published a new dynamic response evaluation method (step response analysis) that can plot frequency spectrum curves instantly in clinical situations. We also described the possibility of the defect of the standard parameters. However, the natural frequency and the damping coefficient are considered the gold standard and are even included in a major anesthesiology textbook. Therefore, we attempted to clarify the issues of these parameters with easy-to-understand pressure waves and basic numerical formulae. A blood pressure wave calibrator, a single two-channel pressure amplifier, and personal computer were used to analyze blood pressure monitoring circuits. All data collection and analytical processes were performed using our step response analysis program. We compared two different circuits with almost the same natural frequency and damping coefficients. However, their amplitude spectrum curves and input/output pressure values were significantly different. The natural frequency and the damping coefficient are inadequate for the dynamic response evaluation. These parameters are primarily obtained from the phase spectrum curve and not from the amplitude spectrum curve. We strongly recommend an evaluation using the amplitude spectrum curve with our step response analysis method. It is crucial to maintain an amplitude gain of 1 (input amplitude = output amplitude) in the pressure wave frequency range of 0-20Hz.

Early response assessment and prediction of overall survival after peptide receptor radionuclide therapy

BackgroundResponse after peptide receptor radionuclide therapy (PRRT) can be evaluated using anatomical imaging (CT/MRI), somatostatin receptor imaging ([68Ga]Ga-DOTA-TATE PET/CT), and serum Chromogranin-A (CgA). The aim of this retrospective study is to assess the role of these response evaluation methods and their predictive value for overall survival (OS).MethodsImaging and CgA levels were acquired prior to start of PRRT, and 3 and 9 months after completion. Tumour size was measured on anatomical imaging and response was categorized according to RECIST 1.1 and Choi criteria. [68Ga]Ga-DOTA-TATE uptake was quantified in both target lesions depicted on anatomical imaging and separately identified PET target lesions, which were either followed over time or newly identified on each scan with PERCIST-based criteria. Response evaluation methods were compared with Cox regression analyses and Log Rank tests for association with OS.ResultsA total of 44 patients were included, with median follow-up of 31 months (IQR 26–36 months) and median OS of 39 months (IQR 32mo-not reached)d. Progressive disease after 9 months (according to RECIST 1.1) was significantly associated with worse OS compared to stable disease [HR 9.04 (95% CI 2.10–38.85)], however not compared to patients with partial response. According to Choi criteria, progressive disease was also significantly associated with worse OS compared to stable disease [HR 6.10 (95% CI 1.38–27.05)] and compared to patients with partial response [HR 22.66 (95% CI 2.33–219.99)]. In some patients, new lesions were detected earlier with [68Ga]Ga-DOTA-TATE PET/CT than with anatomical imaging. After 3 months, new lesions on [68Ga]Ga-DOTA-TATE PET/CT which were not visible on anatomical imaging, were detected in 4/41 (10%) patients and in another 3/27 (11%) patients after 9 months. However, no associations between change in uptake on 68Ga-DOTA-TATE PET/CT or serum CgA measurements and OS was observed.ConclusionsProgression on anatomical imaging performed 9 months after PRRT is associated with worse OS compared to stable disease or partial response. Although new lesions were detected earlier with [68Ga]Ga-DOTA-TATE PET/CT than with anatomical imaging, [68Ga]Ga-DOTA-TATE uptake, and serum CgA after PRRT were not predictive for OS in this cohort with limited number of patients and follow-up time.

Seismic Response of Long-Span Domes Supported by Multi-Storey Substructures

This paper investigates the seismic response characteristics of long-span domes. The natural periods of the prominent modes are longer than medium-span domes, which leads to a greater contribution from the higher modes to the response of the long-span dome. The acceleration distributions, particularly the vertical acceleration distributions are sensitive to the dominant mode shapes of these higher modes. This leads to inaccuracies when applying the previously proposed response evaluation methods. The vibration modes of multi-storey supporting substructures also affect the excited vibration modes of the roof. In this paper, the dynamic characteristics and seismic response of 150m-span domes supported by multi-storey substructures are studied. The effects of the post- yield stiffness of multi-storey substructures are also analysed by considering two structural systems, buckling- restrained braced frames (BRBF) and damped spine frames. A simple design procedure to evaluate the equivalent static loads using amplification factors and incorporating the effects of higher modes is proposed based on response spectrum analysis and equivalent linearisation procedures. The accuracy of the proposed method is evaluated by comparing the responses with those obtained from non-linear response history analysis.

Multi-institutional comparative effectiveness of advanced cancer longitudinal imaging response evaluation methods: Current practice versus artificial intelligence-assisted.

2010 Background: Current-practice methods to evaluate advanced cancer longitudinal tumor response include manual measurements on digital medical images and dictation of text-based reports that are prone to errors, inefficient, and associated with low inter-observer agreement. The purpose of this study is to compare the effectiveness of advanced cancer longitudinal imaging response evaluation using current practice versus artificial intelligence (AI)-assisted methods. Methods: For this multi-institutional longitudinal retrospective study, body CT images from 120 consecutive patients with multiple serial imaging exams and advanced cancer treated with systemic therapy were independently evaluated by 24 radiologists using current-practice versus AI-assisted methods. For the current practice method, radiologists dictated text-based reports and separately categorized response (CR, PR, SD, and PD). For the AI-assisted method, custom software included AI algorithms for tumor measurement, target and non-target location labelling, and tumor localization at follow up. The AI-assisted software automatically categorized tumor response per RECIST 1.1 calculations and displayed longitudinal data in the form of a graph, table, and key images. All studies were read independently in triplicate for assessment of inter-observer agreement. Comparative effectiveness metrics included: major errors, time of image interpretation, and inter-observer agreement for final response category. Results: Major errors were found in 27.5% (99/360) for current-practice versus 0.3% (1/360) for AI-assisted methods (p &lt; 0.001), corresponding to a 99% reduction in major errors. Average time of interpretation by radiologists was 18.7 min for current-practice versus 9.8 min for AI-assisted method (p &lt; 0.001), with the AI-assisted method being nearly twice as fast. Total inter-observer agreement on final response categorization for radiologists was 52% (62/120) for current-practice versus 75% (90/120) for AI-assisted method (p &lt; 0.001), corresponding to a 45% increase in total inter-observer agreement. Conclusion: In a large multi-institutional study, AI-assisted advanced cancer longitudinal imaging response evaluation significantly reduced major errors, was nearly twice as fast, and increased inter-observer agreement relative to the current-practice method, thereby establishing a new and improved standard of care.

Study on vibration suppression method of vehicle with engine start-stop and automatic start-stop

On the basis of previous research, this paper takes a more comprehensive study on the vibration of a vehicle with automatic transmission when engine start-stop and automatic start-stop. A 13 degrees of freedom (DOFs) vehicle dynamic model is established, and the dynamic response evaluation method is put forward. Three methods to reduce the vibration of powertrain and vehicle are analyzed, and the results show that increasing the damping of the mounting system can effectively reduce the vibration in these three methods. A novel semi-active hydraulic damping strut (HDS) as the fourth mount is designed and developed, the installation position and its outer channel size are optimized and calculated respectively based on its damping force calculation method and the design method of the powertrain mounting system (PMS). The calculation results of evaluation indexes with engine start-stop are analyzed in-depth. The optimized parameters of the semi-active HDS are taken into the 13 DOFs dynamic model to analyze the dynamic response of the engine automatic start-stop process, and the values of the evaluation indexes are decreased. To validate the effectiveness of the design method of the semi-active HDS, the experiment of the vehicle with and without the semi-active HDS are carried out, and the test results show that the seat rail acceleration are reduced with semi-active HDS introduced. The active side acceleration of the torque strut calculated by the 13 DOFs model is consistent well with the measured value with and without the semi-active HDS, which proves that the model is reasonable.

The Adequacy of Evaluation by Rheumatologists before Undergoing Arthroscopic Synovectomy in Rheumatoid Arthritis Patients

Purpose: The purpose of this study was to evaluate the relationship between the progression of arthritis and the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) through the treatment-resistant mono joint rheumatoid arthritis treated with arthroscopic synovectomy.Methods: We retrospectively reviewed 65 patients who underwent arthroscopic synovectomy for rheumatoid wrist or elbow which had not responded to systemic treatment for at least 6 months. The main treatment response evaluation methods of rheumatologists were the American College of Rheumatology (ACR) response criteria, and the ACR/EULAR (European League Against Rheumatism) remission criteria. The medical records, results of laboratory tests and radiographs of wrist or elbow that had been performed by rheumatologists before arthroscopic synovectomy were investigated. We examined whether the results of laboratory tests and arthritic change of radiograph had statistically significant correlation. Results: The mean duration of joint symptom until referral to orthopedic department was 23 months (range, 1 month to 9.2 years). During this period, rheumatologists had took average one X-ray (range, 0–3). Forty-seven patients (72.3%) had CRP of 1 mg/dL or less as included in the ACR/EULAR remission criteria. Seventeen out of 65 patients who had two or more X-ray were able to evaluate the progression of arthritis. The change of arthritis and mean ESR (p=0.787) or CRP (p=0.303) the same period didn’t have statistically significant relationship (Spearman correlation analysis).Conclusion: Since the method of evaluating the treatment response of rheumatologists is to assess the systemic condition, arthritis of one joint that is resistant to treatment is considered to require periodic radiographs as method to assess itself.

PS1179 TREATMENT FREE REMISSION IN CHRONIC MYELOID LEUKEMIA PATIENTS HARBORING ATYPICAL BCR‐ABL1 TRANSCRIPTS

Background:The majority of chronic myeloid leukemia (CML) patients carry a t(9;22) translocation characterized by chromosomal breakpoints located on exon 13 or 14 of the BCR gene and on exon 2 of the ABL1 gene. This translocation generates a fusion gene e13a2 or e14a2. In rare cases of CML, breakpoints on chromosome 9 and 22 are located in unusual regions, giving rise to atypical rare transcript which are carried by 1.9% of the patients (Baccarani, Leukemia 2019). These transcripts, including e13a3, e14a3, e1a2, e19a2, e8a2, are not amplified by RT‐qPCR which is the standardized method of molecular response evaluation. In patients with atypical fusion genes, two‐step qualitative (nested) RT‐PCR can represent an alternative method of MRD with a sensitivity of 10–4, 10–5 at the second step (Van Dongen, Leukemia 1997). It is nowadays judged safe to discontinue treatment TKI for CML both in experimental trials on treatment free remission (TFR) and in clinical practice. Nonetheless, clinical trials and current guidelines exclude patients with atypical transcripts (Hochhaus, Ann Oncol 2017)Aims:To evaluate safety issue and duration of TFR in patients with atypical transcripts who discontinue TKI treatment.Methods:We retrospectively identified patients with chronic phase CML and rare atypical transcripts who stopped treatment with TKIs. Identification of transcript was done by RT‐PCR followed by sequencing. Molecular follow‐up was performed by qualitative two‐step nested RT‐PCR. For the purpose of this study, we defined Deep Molecular Response (DMR) as undetectable transcript at nested RT‐PCR.Results:Seven patients carrying atypical transcripts with a stable DMR discontinued TKIs for various reasons such as severe comorbidities, toxicity or patient request. Median duration of treatment with the tyrosine kinase inhibitors was 71 months (range: 34–195), median duration of DMR at nested PCR before discontinuation was 43 months (30–93). Only one patient resumed TKI therapy two months after stop due to RT‐PCR positivity in two consecutive controls. The other six patients remained off‐treatment at last observation after a median follow‐up of 25 months (5 ‐ 77). Five patients remained negative (undetectable transcript) in all samples after discontinuation. In patient 3, who stopped 2ndline Nilotinib for intolerance, fluctuation after stopping TKI was observed between negative RT‐PCR and low‐level positivity at the second step of nested PCR (2 out of 13 samples). No progressions occurred. All patients, including the one that resumed therapy, are in DMR at the last follow‐up.Summary/Conclusion:To our knowledge there are no reports in the literature about patients with atypical transcript who discontinued therapy. Although current guidelines do not recommend discontinuation for patients lacking a standardized method for response monitoring, we observed that in clinical practice patients with atypical transcript stopped the treatment successfully. Further clinical observations as well as the application of new technologies such as digital PCR in these rare cases are both required.image

Nailfold capillaroscopy in systemic sclerosis - state of the art: The evolving knowledge about capillaroscopic abnormalities in systemic sclerosis.

Capillaroscopy is a unique method for morphological evaluation of the nailfold capillaries that plays a crucial role for early diagnosis of systemic sclerosis. The first description of the pathological capillaroscopic changes in systemic sclerosis was made by Brown and O'Leary in 1925. Several decades later they have been validated and accepted as a diagnostic criterion in the current 2013 EULAR/ACR classification criteria. This article summarizes the evolving knowledge about the use of nailfold capillaroscopy in systemic sclerosis. Initially, Maricq et al. suggested two major categories of capillaroscopic findings in systemic sclerosis - an 'active'and 'slow' capillaroscopic pattern. Their description and terminology suggested a correlation between capillaroscopic changes and disease activity and progression. In the later classification of Cutolo et al., three phases were defined, i.e. 'early', 'active' and 'late' that reflect the time-related evolution of the capillaroscopic changes suggesting their association with disease duration. Current knowledge about the microvascular changes in systemic sclerosis supports both associations with disease activity and disease duration. The general opinion about the association of capillaroscopic findings with clinical involvement and disease activity in systemic sclerosis is not uniform. This is supposedly because the phase changes of systemic sclerosis-related microangiopathy are almost a universal feature in scleroderma and are not specific for a certain type of an accompaning clinical manifestation. Thus, the speed of progression of microvascular alterations might be a decisive criterion, and in cases of rapid dynamics of capillaroscopic findings, it could be considered as an indicator of disease activity. Interestingly, vascular 'recovery' has been observed after treatment with immunosuppressive drugs, haematopoietic stem cell transplantation, and the endothelin receptor antagonist - bosentan. The evolving knowledge about nailfold capillaroscopy in systemic sclerosis will further spread its application from a mainly diagnostic tool to an established, reliable method for evaluation of disease activity, prognosis and therapeutic response.

A novel biomarker, active whole skeletal total lesion glycolysis (WS-TLG), as a quantitative method to measure bone metastatic activity in breast cancer patients

ObjectiveThere is no good response evaluation method for skeletal metastasis. We aimed to develop a novel quantitative method to evaluate the response of skeletal metastasis, especially lytic lesions, for treatment.MethodsA method to measure active bone metastatic burden quantitatively using F-18 fluorodeoxyglucose positron emission tomography with computed tomography (FDG–PET/CT) in breast cancer patients, whole skeletal total lesion glycolysis (WS-TLG), a summation of each skeletal lesion’s TLG, was developed. To identify active bone lesions, a tentative cutoff value was decided using FDG–PET/CT in 85 breast cancer patients without skeletal metastasis and 35 with skeletal metastasis by changing the cutoff value. Then, the WS-TLG method was evaluated by comparing to PET Response Criteria in Solid Tumor (PERCIST) or European Organization for Research and Treatment of Cancer (EORTC) criteria for only bone in 15 breast cancer patients with skeletal metastasis who were treated.ResultsA cutoff value of the standardized uptake value (SUV) = 4.0 gave 91% (77/85) specificity and 97% (34/35) sensitivity. We decided on SUV = 4.0 as a tentative cutoff value. Skeletal metastases of lytic and mixed types showed higher WS-TLG values than those of blastic or intertrabecular types, although statistical significance was not tested. All 15 patients showed agreement with PERCIST or EORTC in the therapeutic bone response.ConclusionThis quantitative WS-TLG method appears to be a good biomarker to evaluate skeletal metastasis in breast cancer patients, especially lytic or mixed types. Further clinical studies are warranted to assess the clinical values of this new WS-TLG method.