An exploratory clinical trial of preoperative non-invasive localization before breast-conserving surgery using augmented reality technology.

PURPOSE: This single-center, randomized, prospective, exploratory clinical trial was conducted to assess the clinical efficacy of an augmented reality (AR)-based breast cancer localization imaging solution for patients with breast cancer. METHODS: This clinical trial enrolled 20 women who were diagnosed with invasive breast cancer between the ages of 19 and 80, had a single lesion with a diameter ≥ 5 mm but ≤ 30 mm, had no metastases to other organs, and had not received prior chemotherapy. All patients underwent mammography, ultrasound, computed tomography, and magnetic resonance imaging for preoperative assessment. Patients were randomly assigned to ultrasound-guided skin marking localization (USL) and AR-based localization (ARL) groups (n = 10 in each group). Statistical comparisons between USL and ARL groups were made based on demographics, radiologic features, pathological outcomes, and surgical outcomes using chi-square and Student t-tests. RESULTS: Two surgeons performed breast-conserving surgery on 20 patients. Histopathologic evaluation of all patients confirmed negative margins. Two independent pathologists evaluated the marginal distances, and there were no intergroup differences in the readers' estimates (R1, 6.20 ± 4.37 vs. 5.04 ± 3.47, P = 0.519; R2, 5.10 ± 4.31 vs. 4.10 ± 2.38, P = 0.970) or the readers' average values (5.65 ± 4.19 vs. 4.57 ± 2.84, P = 0.509). In comparing the tumor plane area ratio, there was no statistically significant difference between the two groups in terms of either reader's mean values (R1, 15.90 ± 9.52 vs. 19.38 ± 14.05, P = 0.525; R2, 15.32 ± 9.48 vs. 20.83 ± 12.85, P = 0.290) or the overall mean values of two readers combined (15.56 ± 9.11 vs. 20.09 ± 13.38, P = 0.388). Convenience, safety, satisfaction, and reusability were all superior in the AR localization group (P < 0.001) based on the two surgeons' responses. CONCLUSION: AR localization is an acceptable alternative to ultrasound-guided skin marking with no significant differences in surgical outcomes.

Mitochondrial chaperone HSP-60 regulates anti-bacterial immunity via p38 MAP kinase signaling.

Mitochondria play key roles in cellular immunity. How mitochondria contribute to organismal immunity remains poorly understood. Here, we show that HSP-60/HSPD1, a major mitochondrial chaperone, boosts anti-bacterial immunity through the up-regulation of p38 MAP kinase signaling. We first identify 16 evolutionarily conserved mitochondrial components that affect the immunity of Caenorhabditis elegans against pathogenic Pseudomonas aeruginosa (PA14). Among them, the mitochondrial chaperone HSP-60 is necessary and sufficient to increase resistance to PA14. We show that HSP-60 in the intestine and neurons is crucial for the resistance to PA14. We then find that p38 MAP kinase signaling, an evolutionarily conserved anti-bacterial immune pathway, is down-regulated by genetic inhibition of hsp-60, and up-regulated by increased expression of hsp-60 Overexpression of HSPD1, the mammalian ortholog of hsp-60, increases p38 MAP kinase activity in human cells, suggesting an evolutionarily conserved mechanism. Further, cytosol-localized HSP-60 physically binds and stabilizes SEK-1/MAP kinase kinase 3, which in turn up-regulates p38 MAP kinase and increases immunity. Our study suggests that mitochondrial chaperones protect host eukaryotes from pathogenic bacteria by up-regulating cytosolic p38 MAPK signaling.

FDA Approval Summary: Mylotarg for Treatment of Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia.

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose "fractionated" schedule of 3 mg/m2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%-40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen. IMPLICATIONS FOR PRACTICE: Gemtuzumab ozogamicin (GO) 3 mg/m2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.

Comparison of odor identification among amnestic and non-amnestic mild cognitive impairment, subjective cognitive decline, and early Alzheimer's dementia.

Olfactory impairment might be an important clinical marker and predictor of Alzheimer's disease (AD). In the present study, we aimed to compare the degree of olfactory identification impairment in each mild cognitive impairment (MCI) subtype, subjective memory impairment, and early AD dementia and assessed the relationship between olfactory identification and cognitive performance. We consecutively included 50 patients with amnestic MCI, 28 patients with non-amnestic MCI, 20 patients with mild AD, and 17 patients with subjective memory impairment (SMI). All patients underwent clinical and neuropsychological assessments. A multiple choice olfactory identification cross-cultural smell identification test was also utilized. Controlling for age and gender, olfactory impairment was significantly more severe in patients with AD and amnestic MCI compared with the results from the non-amnestic MCI and SMI groups. Higher scores on MMSE, verbal and non-verbal memory, and frontal executive function tests were significantly related to olfactory identification ability. In conclusion, olfactory identification is impaired in amnestic MCI and AD. These findings are consistent with previous studies. In amnestic MCI patients, this dysfunction is considered to be caused by underlying AD pathology.

Association of arterial stiffness with cognition in patients with Lewy body disorder.

The brachial-ankle pulse wave velocity (baPWV) is a marker for arterial stiffness, which is associated with cardiovascular diseases. Arterial stiffness is associated with cognitive function in the elderly and patients with Alzheimer's disease (AD). We aimed to investigate the association between arterial stiffness and cognitive function in patients with Lewy body disorder (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We consecutively included 123 patients with PD, 10 patients with DLB, and 27 AD controls. Patients with PD were divided into three groups of normal cognition (PD-NC, n = 63), mild cognitive impairment (PD-MCI, n = 43), and dementia (PD-D, n = 17). Arterial stiffness, measured as baPWV, was compared between the PD-NC, PD-MCI, PD-D, DLB, and AD patients. In LBD, we analyzed the association between arterial stiffness and each cognitive domain with adjustment for covariates. Higher baPWV was significantly associated with cognitive decline in patients with LBD (baPWV in PD-D > PD-MCI > PD-NC; DLB > PD-NC). There was no significant difference in baPWV between PD-D, DLB, and AD patients. In LBD patients, higher baPWV was associated with lower mini mental state examination score (ß ± SE = -0.003 ± 0.001, p = 0.007) and more severe dementia. Higher baPWV was also associated with lower performance in attention, language, visuospatial function, memory, and executive function in LBD patients. This suggests that vascular brain injury is associated with cognitive dysfunction in LBD.

Unconventional Role of Caspase-6 in Spinal Microglia Activation and Chronic Pain.

Chronic pain affects ~20% of the worldwide population. The clinical management of chronic pain is mostly palliative and results in limited success. Current treatments mostly target the symptoms or neuronal signaling of chronic pain. It has been increasingly recognized that glial cells, such as microglia, and inflammatory signaling play a major role in the pathogenesis of chronic pain. Caspases (CASPs) are a family of protease enzymes involved in apoptosis and inflammation. They are pivotal components in a variety of neurological diseases. However, little is known about the role of CASPs in microglial modulation as to chronic pain. In particular, our recent studies have shown that CASP6 regulates chronic pain via microglial inflammatory signaling. Inhibition of microglia and CASP signaling might provide a new strategy for the prevention and treatment of chronic pain.

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling.

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

Background 99mTc-methoxyisobutylisonitrile uptake of breast-specific gamma imaging in relation to background parenchymal enhancement in magnetic resonance imaging.

OBJECTIVES: This study investigated factors that could affect background uptake of (99m)Tc- methoxyisobutylisonitrile (MIBI) on normal breast by breast-specific gamma imaging (BSGI). In addition, the impact of background (99m)Tc-MIBI uptake on the diagnostic performance of BSGI was further investigated. METHODS: One hundred forty-five women with unilateral breast cancer who underwent BSGI, MRI, and mammography were retrospectively enrolled. Background uptake on BSGI was evaluated qualitatively and quantitatively. Patients were classified into non-dense and dense breast groups according to mammographic breast density. Background parenchymal enhancement (BPE) was rated according to BI-RADS classification. The relationship of age, menopausal status, mammographic breast density, and BPE with background (99m)Tc-MIBI uptake was analyzed. RESULTS: Heterogeneous texture and high background uptake ratio on BSGI were significantly correlated with younger age (p < 0.001, respectively), premenopausal status (p < 0.001 and p = 0.003), dense breast (p < 0.001, respectively), and marked BPE (p < 0.001, respectively). On multivariate analysis, only BPE remained a significant factor for background MIBI uptake (p < 0.001).There was a significant reduction in positive predictive value (p = 0.024 and p = 0.002) as background MIBI uptake and BPE grade increased. CONCLUSIONS: BPE on MRI was the most important factor for background MIBI uptake on BSGI. High background MIBI uptake or marked BPE can diminish the diagnostic performance of BSGI. KEY POINTS: • Age, menopause, density, and background parenchymal enhancement affect background MIBI uptake. • BPE is an independent factor for background MIBI uptake on BSGI. • Marked BPE may impair BSGI interpretation.

An imaging protocol for dynamic contrast-enhanced breast MRI with 3.0T: using sagittal sequence interleaved between axial sequences.

BACKGROUND: B1 transmission-field inhomogeneity has been reported at 3.0 Tesla (T) breast imaging. Enhancement measurements of breast cancers at 3.0T may be insufficient for some patients and improvements in imaging protocols are needed. PURPOSE: To quantify B1 inhomogeneities in normal tissue and malignant masses at 3.0T breast MR imaging and to evaluate effect of an imaging protocol using an interleaved sagittal sequence in dynamic contrast-enhanced MRI (DCE-MRI). MATERIAL AND METHODS: A total of 76 patients were included who underwent DCE-MRI of the breast at 3.0T with an imaging protocol consisting of 1st, 2nd, and 4-6th bilateral axial sequences, and 3rd and 7th unilateral sagittal sequences. Signal intensity (SI) of normal breast tissue was measured at nipple level in four bilateral locations (anterior, posterior, medial, and lateral). Mean whole breast and location specific SI were calculated and compared between right and left breast using a paired t-test. All malignant masses were classified into three groups according to tumor size on MRI (≤2 cm, 2-4 cm, >4 cm). SI of malignant masses was measured independently on axial and sagittal sequences. The axial-sagittal SI gap in each mass was calculated and difference between right and left breast was compared using the t test. Size of each malignant mass was compared with pathologic findings to assess performance of the imaging protocol. RESULTS: SI of normal breast tissue were lower for the right breast (R-L difference, -91.9; P < 0.0001) and in all four locations (anterior, P < 0.01; posterior, P < 0.01; medial, P < 0.0001; lateral, P < 0.0001). SI of malignant masses were lower for the right breast among same size of the lesions (P < 0.0001), particularly < 4 cm (P < 0.0001). Decreased right to left difference in SI was produced with an interleaved sagittal sequence, as axial-sagittal gap of malignant masses was significant when tumor locates on the right side (P < 0.001). The concordance rate in predicting size of mass in this imaging protocol was 92.2%. CONCLUSION: The interleaved sagittal sequence is helpful to adjust reduced SI of malignant masses on right breast at 3.0T. This imaging protocol is clinically applicable by adding a single sequence during DCE-MRI of the breast.

Frustration and Anger Mitigation After Service Failure: The Effect of Other Consumer's Explanation and Employee's Explanation on Frustration and Anger After the Service Failure.

Purpose: Based on the attribution and appraisal theories of emotion, this study investigates whether a consumer's frustration and anger after a service failure reduces in different ways after hearing explanations from different sources (other customer vs employee vs none) under different blame attribution circumstances (situational vs service provider), and its subsequent influence on complaining intention. Methods: In Study 1, valid data from 239 participants (46.9% female, Mage=35.6 years) were used to test the interaction effect of the explanation source and blame attribution on frustration and anger. In Study 2, using valid answers from 253 students at Korea University (57.9% female, Mage=20.9 years), Study 1 was replicated and, in addition, tested the moderated mediating impact on complaining intention. The overall theoretical model was tested with ANOVA and Hayes process model 8. Results: When blame attribution was situational, the employee's explanation did not mitigate either frustration or anger, whereas the other customer's explanation mitigated frustration but not anger. In contrast, when blame attribution was towards the service provider, the employee's explanation mitigated both frustration and anger, whereas the other customer's explanation mitigated only frustration. In addition, the mitigation of frustration and anger by other customers subsequently led to a decrease in complaining intention, which was stronger and only significant when blame attribution was situational. However, only anger acted as a mediator between the employee's explanation and complaining intention, which did not vary according to blame attribution. Conclusion: The results of the study advance the current knowledge on informational support as a service recovery process by suggesting the crucial role of other consumers in mitigating the target customer's frustration, especially under situational service failure, which successively leads to a decrease in complaining intention, whereas the employee's explanation decreases complaining intention only through the mitigation of anger.

Estimating exposures from spray products using robotic simulations.

There is an increasing need for exposure data to enable more precise information for risk estimates and improved public health protection. While personal monitoring data are preferred, it is often difficult to collect due to the resources needed to complete a human research study. In this study, we successfully programmed a robotic arm to mimic human use (spraying) of a fabric crafts protector (FCP) and human cleaning (spraying and wiping) of a glass pane with glass cleaner (GC). The robot was then used in place of human subjects to assess inhalation exposures to volatile organic compounds (VOCs) during the use of the FCP and GC. Air sampling data were collected while the robot used the products to estimate personal exposures to VOCs. Average VOC concentrations were 1.57 ppm for FCP spraying and 0.17 ppm for GC spraying and wiping. During FCP spraying, average acetone concentrations were 0.88 ppm and average isopropyl alcohol concentrations were 0.26 ppm. During GC spraying and wiping, average 2-butoxyethanol concentrations were 0.15 ppm. Air sampling data were found to be within the range of data reported in the literature during human use of similar glass cleaning products. No data was found in the literature during use of fabric protector spray products. This study contributes exposure measurement data with detailed contextual information to help characterize inhalation exposures during the use of 2 spray products. In addition, the study offers a systematic, efficient method for generating exposure data which can be used to improve health and safety risk assessments used for public health protection.

Intrinsically disordered region-mediated condensation of IFN-inducible SCOTIN/SHISA-5 inhibits ER-to-Golgi vesicle transport.

Newly synthesized proteins in the endoplasmic reticulum (ER) are sorted by coat protein complex II (COPII) at the ER exit site en route to the Golgi. Under cellular stresses, COPII proteins become targets of regulation to control the transport. Here, we show that the COPII outer coat proteins Sec31 and Sec13 are selectively sequestered into the biomolecular condensate of SCOTIN/SHISA-5, which interferes with COPII vesicle formation and inhibits ER-to-Golgi transport. SCOTIN is an ER transmembrane protein with a cytosolic intrinsically disordered region (IDR), which is required and essential for the formation of condensates. Upon IFN-γ stimulation, which is a cellular condition that induces SCOTIN expression and condensation, ER-to-Golgi transport was inhibited in a SCOTIN-dependent manner. Furthermore, cancer-associated mutations of SCOTIN perturb its ability to form condensates and control transport. Together, we propose that SCOTIN impedes the ER-to-Golgi transport through its ability to form biomolecular condensates at the ER membrane.

Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus.

UNLABELLED: The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC(0-∞)) by approximately 4.6-fold and increased tacrolimus DN_AUC(0-∞) by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t(½)) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t(½) of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. CONCLUSION: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life-threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained.

Effectiveness of breast-specific gamma imaging (BSGI) for breast cancer in Korea: a comparative study.

Despite the fact that mammography has been the golden standard in breast cancer detection for several decades, its sensitivity decreases for women with dense breast tissue, which happens to be common in Korea. As an alternative, breast ultrasonography can be effective diagnostic modalities that complement the defect of mammography. Recently, breast-specific gamma imaging (BSGI) has been introduced as a new diagnostic modality for breast cancer. This study was designed to analyze the effectiveness of BSGI in particular. In a retrospective study, 471 patients underwent BSGI, breast ultrasonography, and mammography simultaneously during the period between February 2009 and March 2010. The indications of BSGI were as follows: (a) patient who was diagnosed with malignancy prior to surgery, (b) patient who is under follow up after cancer surgery, (c) patient with lesions which cannot be evaluated by breast ultrasonography or mammography, (d) patient with multiple benign lesions, and (e) patient with suspicious lesion who refuses biopsy. Among these patients, 121 patients underwent biopsy, whereas others were followed up with imaging studies. We compared the BSGI results with those of mammography, breast ultrasonography, and pathology. The mean age of the patients was 49.63 ± 10.43 years. There were 107 patients with 110 malignant lesions and 364 patients with benign lesions. Total 474 lesions were evaluated. The sensitivities of BSGI, mammography, and breast ultrasonography were 94.45%, 93.64%, and 98.18%, respectively, whereas the specificities of BSGI, mammography, and breast ultrasonography were 90.93%, 90.66%, and 87.09%, respectively. The sensitivity and specificity of BSGI for axillary lymph node (LN) status were 44.7 4% and 87.88%, respectively. BSGI is a good complementary imaging modality with high sensitivity and high specificity for breast cancer detection. However, it has low efficacy for the evaluation for axillary LN status.