Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01).

BACKGROUND: Primary analysis of the multicenter, open-label, single-arm, phase II DESTINY-Breast01 trial (median follow-up 11.1 months) demonstrated durable antitumor activity with trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). We report updated cumulative survival outcomes with a median follow-up of 26.5 months (data cut-off 26 March 2021). PATIENTS AND METHODS: Patients with HER2-positive mBC resistant or refractory to T-DM1 received T-DXd 5.4 mg/kg intravenously every 3 weeks until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included overall survival (OS), duration of response (DoR), progression-free survival (PFS), and safety. RESULTS: The ORR by ICR was 62.0% [95% confidence interval (CI) 54.5% to 69.0%] in patients who received T-DXd 5.4 mg/kg every 3 weeks (n = 184). Median OS was 29.1 months (95% CI 24.6-36.1 months). Median PFS and DoR were 19.4 months (95% CI 14.1-25.0 months) and 18.2 months (95% CI 15.0 months-not evaluable), respectively. Drug-related treatment-emergent adverse events (TEAEs) were observed in 183 patients (99.5%), and 99 patients (53.8%) had one or more grade ≥3 TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 15.8% of patients (n = 29), of which 2.7% (n = 5) were grade 5. CONCLUSIONS: These updated results provide further evidence of sustained antitumor activity of T-DXd with a consistent safety profile in heavily pretreated patients with HER2-positive mBC.

Event-free survival by residual cancer burden with pembrolizumab in early-stage TNBC: exploratory analysis from KEYNOTE-522.

BACKGROUND: KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. PATIENTS AND METHODS: A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. RESULTS: Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. CONCLUSIONS: Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR.

IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study.

BACKGROUND: The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A-F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). RESULTS: Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%-71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). CONCLUSION: Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02622074.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with early breast cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.

In view of the planned new edition of the most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of primary breast cancer published in 2015, it was decided at the ESMO Asia Meeting in November 2018, by both the ESMO and the Korean Society of Medical Oncology (KSMO), to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the latest ESMO 2019 guidelines to take into account the ethnic and geographical differences associated with the treatment of early breast cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with early breast cancer representing the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO) Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices, and the drug availability and reimbursement situations, in the individual participating Asian countries.

Efficacy and safety of PAC-14028 cream - a novel, topical, nonsteroidal, selective TRPV1 antagonist in patients with mild-to-moderate atopic dermatitis: a phase IIb randomized trial.

BACKGROUND: Transient receptor potential vanilloid subfamily, member 1 (TRPV1) may play an important role in pruritus and inflammation induction in atopic dermatitis (AD). The treatment effect of TRPV1 antagonist via topical application in patients with AD remains unknown. OBJECTIVES: To assess the clinical efficacy and safety of PAC-14028, a TRPV1 antagonist, via topical application in patients with AD. METHODS: In this 8-week, phase IIb, randomized, double-blind, multicentre, vehicle-controlled study, patients with mild-to-moderate AD were randomized to receive PAC-14028 cream 0·1%, 0·3%, 1·0% or vehicle cream twice daily. The primary efficacy end point was the Investigator's Global Assessment (IGA) success rate defined as the percentage of patients with an IGA score of 0 or 1 at week 8. The secondary efficacy end points included the severity Scoring of Atopic Dermatitis (SCORAD) index and Eczema Area and Severity Index (EASI) 75/90. RESULTS: A total of 194 patients were enrolled. IGA success rates at week 8 were 14·58% for vehicle cream, 42·55% for PAC-14028 cream 0·1% (P = 0·0025 vs. vehicle), 38·30% for PAC-14028 cream 0·3% (P = 0·0087 vs. vehicle) and 57·45% for PAC-14028 cream 1·0% (P < 0·001 vs. vehicle). In particular, statistically significant differences were found between the vehicle and treatment groups in the IGA success rates with two-grade improvement. The SCORAD index, EASI 75/90, sleep disturbance score and pruritus visual analogue scale showed a trend towards improvement. No significant safety issues were reported. CONCLUSIONS: PAC-14028 cream may be an effective and safe treatment modality for the treatment of patients with mild-to-moderate AD.

Clinical relevance of amnestic versus non-amnestic mild cognitive impairment subtyping in Parkinson's disease.

BACKGROUND AND PURPOSE: To clarify whether subtyping of amnestic and non-amnestic mild cognitive impairment (MCI) is clinically relevant in Parkinson's disease (PD) by analyzing patterns of neuroimaging and longitudinal cognitive changes. METHODS: We performed comparative analyses of cortical thickness, hippocampal volume, white matter integrity and resting-state functional connectivity between the patients with de-novo PD with amnestic MCI (PD-aMCI) (n = 50) and non-amnestic MCI (PD-naMCI) (n = 50) subtypes. Additionally, we assessed the longitudinal rate of cognitive decline in each cognitive domain over time and the rate of dementia conversion in patients with de-novo PD-aMCI (n = 125) and PD-naMCI (n = 61). RESULTS: The demographic data showed that scores in memory domains were lower in the PD-aMCI group compared with the PD-naMCI group. There were no significant differences in cortical thickness, hippocampal volume and white matter integrity between the two groups, although the PD-aMCI group exhibited more cortical thinning and hippocampal atrophy relative to the control group. The PD-aMCI group exhibited increased functional connectivity in the left posterior parietal region with the salience network relative to the PD-naMCI group. The longitudinal cognitive assessment demonstrated that patients with PD-aMCI exhibited a more rapid cognitive decline in frontal/executive function than those with PD-naMCI (P = 0.022). In addition, the PD-aMCI group had a higher risk of dementia conversion than the PD-naMCI group. CONCLUSIONS: This study suggests that the designation of PD-MCI subtypes based on memory function would highlight the heterogeneity of functional correlates as well as the longitudinal cognitive prognosis.

A randomized, multi-center, open-label, phase III study of once-per-cycle DA-3031, a pegylated G-CSF, in comparison with daily filgrastim in patients receiving TAC chemotherapy for breast cancer.

PURPOSE: This multi-center, randomized, phase III study was conducted to demonstrate the non-inferiority of DA-3031 compared with daily filgrastim in patients during the first cycle of chemotherapy for breast cancer in terms of the duration of severe neutropenia (DSN). METHODS: Seventy-four patients with breast cancer who were receiving combination chemotherapy with docetaxel, doxorubicin, and cyclophosphamide (TAC) were enrolled. All participants were randomized to receive either daily subcutaneous injections of filgrastim 100 µg/m2/day for up to 10 days or a single subcutaneous injection of DA-3031 at fixed doses of 6 mg on day 2 of each chemotherapy cycle. RESULTS: The mean duration of grade 4 (G4) neutropenia in cycle 1 was 2.08 ± 0.85 days for the filgrastim group and 2.28 ± 1.14 days for the DA-3031 group. The difference between groups was 0.2 ± 1.10 days (95 % confidence interval (CI) = -0.26, 0.66), which supported non-inferiority. No statistically significant differences were observed in nadir absolute neutrophil count (ANC) (154.34/mm3 and 161.75/mm3 for the filgrastim and DA-3031 groups, respectively; P = 0.8414) or in time to ANC recovery (10.03 ± 0.75 and 9.83 ± 1.56 days in the filgrastim and DA-3031 groups, respectively; P = 0.0611) during cycle 1. Serious AEs occurred in six (15.8 %) patients receiving filgrastim and in ten (27.8 %) patients receiving DA-3031; however, none was determined to be related to the study drug. CONCLUSIONS: DA-3031 and daily filgrastim are similar in regard to DSN and safety in breast cancer patients receiving TAC chemotherapy.

Effects of sugammadex vs. pyridostigmine-glycopyrrolate on post-operative nausea and vomiting: propensity score matching.

BACKGROUND: Sugammadex is a new agent that reverses neuromuscular blockade by aminosteroid neuromuscular blocker. This retrospective study compared the effects of sugammadex on post-operative nausea and vomiting (PONV) with those of a pyridostigmine-glycopyrrolate mixture. METHODS: We reviewed the electronic medical records of 7179 patients who had received fentanyl-based, intravenous, patient-controlled analgesia (IV-PCA) at Chung-Ang University Hospital between January 1, 2010 and December 31, 2015. We categorized the patients into two groups on the basis of the type of reversal agent to neuromuscular blockade that was used: a traditional reversal agent (pyridostigmine-glycopyrrolate mixture; Group R; n = 7059) and sugammadex (Group S; n = 120). The propensity score matching method was then used to select 408 subjects in Group R and 115 subjects in Group S; on the basis of their covariates, these subjects were then matched with a counterpart in the other group. RESULTS: After propensity score matching, the two groups were well balanced with respect to all baseline covariates. In Group S, the numeric rating scale of nausea on day 0, as well as the number of patients who vomited on day 0, was lower than that in group R. Furthermore, Group S used fewer rescue antiemetics on day 0 and had a higher complete response on day 0. CONCLUSION: Sugammadex might be more beneficial for PONV compared to pyridostigmine-glycopyrrolate mixture for patients who have received opioid-based IV-PCA.

Testosterone effects on pain and brain activation patterns.

BACKGROUND: This study investigated whether pain and pain-related unpleasantness ratings were altered by blood testosterone levels. We also investigated whether activation of brain regions that represent pain intensity [primary somatosensory cortex (S1)] and pain-related unpleasantness [perigenual ACC (pACC) and orbitofrontal cortex (OFC)] were affected by blood testosterone levels. METHODS: Twenty-six healthy men were recruited. Blood testosterone levels were measured before fMRI scanning. The participants were classified into two groups (high vs. low testosterone) according to their blood testosterone level (each group n = 13). The middle finger was immersed in a 50°C water bath (50°C, 30 s, five times) to induce identical noxious stimulation in all participants. RESULTS: The low testosterone group showed statistically significantly higher pain (P = 0.047), unpleasantness (P = 0.047), anxiety (P = 0.015), and fear ratings (P = 0.01) than the high testosterone group. Fear rating increased as pain rating rose and as testosterone level decreased (P < 0.001). When participants received noxious stimulation, the pACC and OFC were more highly activated in the low testosterone group compared to the high testosterone group. Activation of S1, a region related to pain intensity, did not differ between both groups. CONCLUSION: Compared to the high testosterone group, the low testosterone group had significant activation in the pACC and OFC, regions that represent pain-related unpleasantness, but not in S1 that represents pain intensity, leading to higher pain ratings. These findings emphasize the importance of considering the effects of testosterone levels when treating patients.

Sevoflurane post-conditioning increases nuclear factor erythroid 2-related factor and haemoxygenase-1 expression via protein kinase C pathway in a rat model of transient global cerebral ischaemia.

BACKGROUND: The antioxidant mechanism of sevoflurane post-conditioning-induced neuroprotection remains unclear. We determined whether sevoflurane post-conditioning induces nuclear factor erythroid 2-related factor (Nrf2, a master transcription factor regulating antioxidant defence genes) and haemoxygenase-1 (HO-1, an antioxidant enzyme) expression, and whether protein kinase C (PKC) is involved in Nrf2 activation, in a rat model of transient global cerebral ischaemia/reperfusion (I/R) injury. METHODS: Eighty-six rats were assigned to five groups: sham (n=6), control (n=20), sevoflurane post-conditioning (two cycles with 2 vol% sevoflurane inhalation for 10 min, n=20), chelerythrine (a PKC inhibitor; 5 mg kg(-1) i.v. administration, n=20), and sevoflurane post-conditioning plus chelerythrine (n=20). The levels of nuclear Nrf2 and cytoplasmic HO-1 were assessed 1 or 7 days after ischaemia (n=10 each, apart from the sham group, n=3). RESULTS: On day 1 but not day 7 post-ischaemia, Nrf2 and HO-1 expression were significantly higher in the sevoflurane post-conditioning group than in the control group. Chelerythrine administration reduced the elevated Nrf2 and HO-1 expression induced by sevoflurane post-conditioning. CONCLUSIONS: Sevoflurane post-conditioning increased Nrf2/HO-1 expression via PKC signalling in the early phase after transient global cerebral I/R injury, suggesting that activation of antioxidant enzymes may be responsible for sevoflurane post-conditioning-induced neuroprotection in the early phase after cerebral I/R injury.

Emergence agitation after orthognathic surgery: a randomised controlled comparison between sevoflurane and desflurane.

BACKGROUND: This study aimed to compare emergence agitation following sevoflurane and desflurane anaesthesia in adults undergoing orthognathic surgery. The hypothesis was that there might be a difference in the incidence of emergence agitation following sevoflurane and desflurane anaesthesia considering the difference in blood solubility and speed of recovery between the two. METHODS: In this prospective randomised double-blind study, 144 adults undergoing orthognathic surgery were randomly allocated to either sevoflurane or desflurane anaesthesia. The incidence of emergence agitation and possible causative factors were then compared between the groups. RESULTS: The incidence of emergence agitation was lower in the desflurane group than in the sevoflurane group (24% vs. 71%, P < 0.001). In addition, the time intervals between the discontinuation of anaesthetics and the first response, extubation, and discharge from post-anaesthesia care unit were significantly shorter in the desflurane group (P = 0.002, P < 0.001 and P = 0.003, respectively). The other variables were similar in the two groups. CONCLUSIONS: In adults undergoing orthognathic surgery, desflurane anaesthesia was associated with less emergence agitation than was sevoflurane anaesthesia.

Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) who received taxane plus trastuzumab treatment.

BACKGROUND: The aim of this study was to investigate the role of human epidermal growth factor receptor (HER3) and PTEN expression in patients with HER2-overexpressing metastatic breast cancer (MBC). METHODS: One hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as first-line therapy were included in this analysis. Immunohistochemical (IHC) staining with HER3 and PTEN antibodies were conducted retrospectively. RESULTS: Patients who had negative HER3 staining (62.4%) had a better progression-free survival (PFS) than did those who had positive HER3 staining (P=0.001; median PFS, 21 vs 11 months). Patients who had a PTEN score >20 (78.1%) showed longer PFS than did those with a PTEN score ≤20 (P=0.006; median PFS, 13 vs 9 months). Patients who had a PTEN score >20 exhibited a longer overall survival (OS) than did those with a PTEN score ≤20 (P=0.005; median OS, 48 vs 25 months). HER3 negativity and PTEN loss were identified as independent risk factors for PFS. PTEN loss was identified as an independent risk factor for OS. CONCLUSION: HER3 and PTEN expressions may be predictive markers, and PTEN expression may be a predictive and prognostic biomarker for trastuzumab treatment in HER2-positive MBCs.

Development and validation of Chemotherapy-induced Alopecia Distress Scale (CADS) for breast cancer patients.

BACKGROUND: A psychometric scale for assessing the distress that breast cancer patients experience due to the chemotherapy-induced alopecia was developed and validated. PATIENTS AND METHODS: Twenty-five items for chemotherapy-induced alopecia distress were developed based on a qualitative study, and a cross-sectional survey was conducted with 305 Korean women with breast cancer. To extract factor structure and evaluate construct validity, exploratory and confirmatory factor analysis (CFA) was carried out. Concurrent and discriminant validity were tested by correlations with the psychosocial factors. In addition, external validity analysis was conducted using data from another prospective study of 428 breast cancer patients. RESULTS: Exploratory factor analysis and CFA yielded 17 items in four domains and the model fit was good (CFI=0.925). Coefficient alphas ranged from 0.77 to 0.95 for subdomains and 0.95 for total, and it was similar with the validation dataset confirming its external validity. The total Chemotherapy-Induced Alopecia Distress Scale (CADS) was moderately correlated with the body image (r=-0.47, P<0.001), more weakly correlated with the patients' overall quality of life (QOL, r=-0.28, P<0.001), but did not correlate with self-esteem (r=-0.07, P=0.23). CONCLUSIONS: Our study confirmed that the CADS is a reliable and valid tool for measuring distress of chemotherapy-induced alopecia.

Peripheral artery questionnaire improves ankle brachial index screening in symptomatic patients with peripheral artery disease.

AIM: The peripheral artery questionnaire (PAQ) is a disease-specific health status measure of patients with peripheral artery disease (PAD). Whether the PAQ scores are associated with a PAD diagnosis among patients with symptoms suspicious for PAD is unknown and could help increase the pretest probability of ankle brachial index (ABI) screening among patients with suspicious symptoms. METHODS: The PAQ was completed by 567 patients evaluated for potential intermittent claudication at six tertiary centres. Demographics, medical history, physical examination findings and the PAQ domain scores were compared with ABI. A diagnostic threshold < 0.90 for a PAD diagnosis was assessed with a ROC of PAQ scores. The correlation between the PAQ Summary Score and ABI was also calculated. RESULTS: The PAQ Summary Score was significantly lower in patients with low ABI as compared with those having a normal ABI (37.6 ± 19.0 vs. 70.1 ± 22.7, p < 0.001). The PAQ Summary Score and ABI were highly correlated (r = 0.56, p < 0.001) and the optimal PAQ Summary Score for predicting low ABI was 50.3 (AUC = 0.86, sensitivity 80.3%, specificity 78.3%). CONCLUSIONS: The PAQ Summary Score was associated with an increased likelihood of PAD in patients with suspected PAD symptoms, and a low summary score (≤ 50.3) was an optimal threshold for predicting PAD among patients referred for ABI.

Determination of feeder cell-based cellular niches supporting the colonization and maintenance of spermatogonial stem cells from prepubertal domestic cat testes.

Recently, isolation and in vitro culture of putative spermatogonial stem cells (SSCs) in the domestic cat have been conducted. However, the cellular niche conditions that facilitate the establishment and long-term maintenance of feline SSCs (FSSCs) have not been described. Therefore, we investigated the type of feeder cells used to stimulate colony formation and growth of FSSCs among the various factors in the FSSC niche. Spermatogonial stem cells isolated from feline testes were cultured on mitotically inactivated testicular stromal cells (TSCs) derived from cats, dogs and mice, and mouse embryonic fibroblasts (MEFs). The formation and growth of colonies derived from SSCs cultured on each type of feeder cell were identified at passage 0, and the morphology, alkaline phosphatase (AP) activity and expression of SSC-specific genes in surviving colonies were investigated at passage 4. Among these diverse feeder cells, TSCs from cat showed the greatest colony formation, growth and maintenance of FSSCs, and SSC colonies cultured by passage 4 showed a typical dome-shaped morphology, AP activity and expression of SSC-specific genes (NANOG, OCT4, SOX2 and CD9). Accordingly, these results demonstrate that feline TSCs could be used as feeder cells to support the establishment and maintenance of SSCs from domestic cats.

First Report of White Blister Rust Caused by Albugo candida on Wasabi in Korea.

Wasabi (Wasabia japonica (Miq.) Matsum.), a member of the Brassicaceae family, is a commercially important crop in East Asian countries such as China, Japan, Korea, and Taiwan. In Korea, wasabi is under commercial development since it has become popular as a condiment due to its strong pungent constituents. In May 2013, wasabi plants showing typical symptoms of white blister rust disease were first observed in plastic greenhouses in Taebaek City, Korea. Leaves of infected plants had whitish sori on the lower surfaces and chlorotic blotches on the corresponding upper leaf surfaces. Later, sori changed to creamy to light tan with necrosis of leaf lesion. New infections might occur anytime during the growing season. A representative sample was deposited in the Korea University Herbarium (KUS-F27596). Microscopic examination of fresh materials was performed under a light microscope. The grouped sporangiophores were hyaline, clavate or cylindric, and measured 20 to 35 × 10 to 14 µm. The sporangia were arranged in basipetal chains, hyaline, globose to subglobose, with uniform wall thickness and measured 16 to 21 × 13 to 18 µm. The primary sporangia were morphologically similar to the secondary sporangia, although the former exhibited a slightly thicker wall than the latter. No resting organs were observed. Previously, the white blister rust pathogen on wasabi has been considered either Albugo candida or A. wasabiae, although the latter name is often considered a synonym of A. candida. Based on the morphological characteristics and the specific host plant, the causal agent of this disease was identified as A. candida (2). To confirm this morphological identification, genomic DNA was extracted from infected plant tissue, and the amplification and sequencing of the internal transcribed spacer (ITS) region of rDNA of the Korean specimen were performed using procedures outlined by Choi et al. (1), with oomycete-specific primer set, DC6 and LR0. The resulting 835-bp sequence of the region was deposited in GenBank (Accession No. KF887494). Since this was the first ITS sequence submitted for A. candida on wasabi, comparable data were not available. A comparison with the ITS sequences available in the GenBank database revealed that it is identical to A. candida found on Capsella bursa-pastoris (AF271231), and shows a high similarity of 99% with many A. candida sequences originating from other brassicaceous plants. Therefore, the pathogen found in Korea was confirmed to be A. candida. In Korea, it has been reported that A. candida attacks Brassica juncea, B. campestris subsp. penikensis, and B. napus (3), but to our knowledge this is the first record of A. candida on wasabi (4). The white blister rust caused by A. candida is one of the most devastating diseases of wasabi in Japan and Taiwan where the crop is widely cultivated. On the other hand, in the United States, Canada, and New Zealand, where wasabi is a new crop on a commercial scale, there is no record of this disease. These facts taken together suggest that wasabi white blister rust be not only currently spreading in East Asia, but it also poses a new and serious threat to production of this crop in countries in which it is currently absent. References: (1) Y. J. Choi et al. Mol. Phylogenet. Evol. 40:400, 2006. (2) Y. J. Choi et al. Fungal Divers. 27:11, 2007. (3) Y. J. Choi et al. Plant Pathol. J. 27: 192, 2011. (4) D. F. Farr and A. Y. Rossman. Fungal Databases. Syst. Mycol. Microbiol. Lab., Online publication, ARS, USDA, Retrieved November 15, 2013.

Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-ß42 over Amyloid Positron Emission Tomography.

BACKGROUND: Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. METHODS: We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-ß42 (Aß42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. RESULTS: NP with CAA had significantly lower CSF Aß42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aß42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CONCLUSIONS: CSF Aß42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial.

BACKGROUND: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR. RESULTS: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1. CONCLUSIONS: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.