Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.

BACKGROUND: Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers. METHODS: We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients. RESULTS: Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. CONCLUSIONS: In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).

Fluid-attenuated inversion-recovery sequence with fat suppression as an alternative to contrast-enhanced MRI in pediatric synovitis.

BACKGROUND: Non-contrast magnetic resonance imaging (MRI) fluid-attenuated inversion-recovery sequence (FLAIR) with fat suppression (FS) has not been validated in children. OBJECTIVE: Compare FLAIR to T1-weighted post contrast (T1CE) in the detection of knee synovitis. METHODS AND MATERIALS: Institutional review board (IRB) waived consent. Children who underwent T1CE and FLAIR sequences of the knee on a 3-T magnet from April 2021 to December 2021 were included. Two pediatric radiologists assessed axial FLAIR and T1CE images for synovitis and synovial thickness. Reliability and agreement were assessed. Sensitivities, specificities, and accuracy were calculated for FLAIR using T1CE as reference standard. RESULTS: In total, 42 knees (39 patients) were assessed (median age 12.9 years (2.3-17.8 years); 62% male, 38% female). Readers judged 20/42 (48%) knees to have synovitis. Sensitivity of FLAIR for reader 1 was 79% (19/24; 95% CI 0.58, 0.93) and 84% (16/19; 95% CI 0.60, 0.97) for reader 2. Specificity of FLAIR for reader 1 was 94% (17/18; 95% CI 0.73, 1) and 83% (19/23; 95% CI 0.61, 0.95) for reader 2. Accuracy for readers 1 and 2 was 86% (36/42; 95% CI 0.71, 0.95) and 83% (35/42; 95% CI 0.69, 0.93), respectively. Inter-reader reliability was good (0.75-0.90) for synovial measurements for FLAIR (ICC = 0.80; 95% CI 0.71, 0.86) and moderate for T1 CE (ICC = 0.62 (95% CI 0.48, 0.73)). CONCLUSION: FLAIR FS depicts synovium in the pediatric knee with similar reliability to T1 CE and may be an acceptable alternative to contrast in the initial diagnosis of synovitis.

Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study.

BACKGROUND: Approximately 15-20% of advanced gastric and gastro-oesophageal junction cancers overexpress HER2. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan improved response and overall survival versus chemotherapy in patients from Japan and South Korea with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal junction cancer whose disease progressed after two lines of previous therapy including trastuzumab. Here, we report primary and updated analyses of the single-arm, phase 2 DESTINY-Gastric02 trial, which aimed to examine trastuzumab deruxtecan in patients living in the USA and Europe. METHODS: DESTINY-Gastric02 is a single-arm, phase 2 study in adult patients from 24 study sites in the USA and Europe (Belgium, Spain, Italy, and the UK). Eligible patients were aged at least 18 years and had an Eastern Cooperative Oncology Group performance status of 0 or 1, pathologically documented unresectable or metastatic gastric or gastro-oesophageal junction cancer, progressive disease on or after first-line therapy with a trastuzumab-containing regimen, with at least one measurable lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and centrally confirmed HER2-positive disease on a postprogression biopsy. Patients were given 6·4 mg/kg of trastuzumab deruxtecan intravenously every 3 weeks until disease progression, withdrawal by patient, physician decision, or death. The primary endpoint was confirmed objective response rate by independent central review. The primary endpoint and safety were assessed in the full analysis set (ie, participants who received at least one dose of study drug). Here, we report the primary analysis of this study, with a data cutoff of April 9, 2021, and an updated analysis, with a data cutoff of Nov 8, 2021. This trial is registered with ClinicalTrials.gov, NCT04014075, and is ongoing. FINDINGS: Between Nov 26, 2019, and Dec 2, 2020, 89 patients were screened and 79 were enrolled and subsequently treated with trastuzumab deruxtecan (median age 60·7 years [IQR 52·0-68·3], 57 [72%] of 79 were male, 22 [28%] were female, 69 [87%] were White, four [5%] were Asian, one [1%] was Black or African American, one [1%] was Native Hawaiian or Pacific Islander, one had missing race, and three [4%] were other races). At the primary analysis (median follow-up 5·9 months [IQR 4·6-8·6 months]), confirmed objective response was reported in 30 (38% [95% CI 27·3-49·6]) of 79 patients, including three (4%) complete responses and 27 (34%) partial responses, as assessed by independent central review. As of data cutoff for the updated analysis (median follow-up 10·2 months [IQR 5·6-12·9]), a confirmed objective response was reported in 33 (42% [95% CI 30·8-53·4]) of 79 patients, including four (5%) complete responses and 29 (37%) partial responses, as assessed by independent central review. The most common grade 3 or worse treatment-emergent adverse events were anaemia (11 [14%]), nausea (six [8%]), decreased neutrophil count (six [8%]), and decreased white blood cell count (five [6%]). Drug-related serious treatment-emergent adverse events occurred in ten patients (13%). Deaths determined to be associated with study treatment occurred in two patients (3%) and were due to interstitial lung disease or pneumonitis. INTERPRETATION: These clinically meaningful results support the use of trastuzumab deruxtecan as second-line therapy in patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. FUNDING: Daiichi Sankyo and AstraZeneca.

Doctors' perceived working conditions, psychological health and patient care: a meta-analysis of longitudinal studies.

OBJECTIVES: Studies have demonstrated an association between doctors' perceived working conditions, and their psychological well-being and patient care. However, few have examined inter-relationships among these three domains, and even fewer using longitudinal designs. Using meta-analytical structural equation modelling, we tested longitudinal relationships among doctors' perceived working conditions, their psychological well-being and patient care. We further tested if doctors' psychological well-being mediates the relationship between perceived working conditions and patient care. METHODS: We carried out a systematic review using Academic Search Premier, Business Source Premier, PsycInfo, PsycArticles and Medline for the 20-year period between January 2000 and the start of the pandemic (January 2020). We included studies with practising doctors as participants, and that reported a quantifiable bivariate effect size between at least two of the three constructs of interest-perceived working conditions (ie, job demands, job resource), psychological well-being (ie, emotional exhaustion, work engagement) and patient care (ie, clinical care, patient safety). We pooled relationship effect sizes using random-effects meta-analysis, before testing for indirect effects using two-stage structural equation modelling. RESULTS: Twenty-three samples from 11 countries representing 7275 doctors were meta-analysed. The results indicated that job resources predicted work engagement (ρ=0.18; 95% CI 0.11 to 0.24) and emotional exhaustion (ρ=-0.21; 95% CI -0.31 to -0.11), while job demands predicted emotional exhaustion (ρ=0.27; 95% CI 0.17 to 0.36). Better clinical care was also associated with higher levels of job resources (ρ=0.16; 95% CI 0.04 to 0.29), and lower levels of emotional exhaustion (ρ=-0.21; 95% CI -0.37 to -0.12) and job demands (ρ=-0.27; 95% CI -0.43 to -0.10). Both factors of the work environment were associated with clinical care through doctors' emotional exhaustion, but there were insufficient studies to test the indirect effects for work engagement or patient safety. CONCLUSION: Our results demonstrate the need for a systems perspective to address working conditions to support both doctors' psychological well-being and patient care. Interventions should target doctors' job resources as they are more strongly associated with psychological well-being. However, given that job demands were strongly associated with emotional exhaustion, and in turn, clinical care, there is a need to better manage doctors' workload, conflict and pressure to support the current psychological well-being crises among this occupational group. PROSPERO REGISTRATION NUMBER: CRD42020189070.

Exploring three-body fragmentation of acetylene trication.

The three-body breakup of [C2H2]3+ formed in collision with Xe9+ moving at 0.5 atomic units of velocity is studied by using recoil ion momentum spectroscopy. Three-body breakup channels leading to (H+, C+, CH+) and (H+, H+, C2 +) fragments are observed in the experiment and their kinetic energy release is measured. The breakup into (H+, C+, CH+) occurs via concerted and sequential modes, whereas the breakup into (H+, H+, C2 +) shows only the concerted mode. By collecting events coming exclusively from the sequential breakup leading to (H+, C+, CH+), we have determined the kinetic energy release for the unimolecular fragmentation of the molecular intermediate, [C2H]2+. By using ab initio calculations, the potential energy surface for the lowest electronic state of [C2H]2+ is generated, which shows the existence of a metastable state with two possible dissociation pathways. A discussion on the agreement between our experimental results and these ab initio calculations is presented.

Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review.

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-targeted therapies improve survival for patients with HER2-positive breast cancer but carry risks of hematologic, cardiopulmonary, gastro-hepatobiliary, and other adverse events (AEs). In this review, we describe published AE incidences for HER2-targeted therapies for metastatic breast cancer (mBC). METHODS: We searched PubMed and Embase to identify studies on HER2-targeted therapies in HER2-positive mBC, reporting on AEs of special interest, and published between January 1, 2009, and February 6, 2020. Treatment regimens were categorized into mutually exclusive therapy-based categories, with primary therapy determined by worldwide approval date. RESULTS: One hundred and fifty-three included articles assessed a combined 29,238 patients treated with the following therapy-based regimens: trastuzumab or biosimilars (78 studies), lapatinib (40), T-DM1 (ado-trastuzumab emtansine) (20), pertuzumab (14), neratinib (8), MM-302 (1), T-DXd (2), tucatinib (3), and pyrotinib (3). While direct comparisons of AE incidence are not warranted owing to study heterogeneity, proportions of patients experiencing any Grade 3 + AE ranged across therapy-based regimens from 39.4% (lapatinib) to 66.3% (neratinib). The most common hematologic AE of special interest, of any grade and regardless of causality, was leukopenia/white blood cells decreased [21.4% (T-DXd)-46.2% (pyrotinib)]. Cardiopulmonary AEs of special interest included interstitial lung disease [2.7% (trastuzumab)-5.2% (T-DXd)], pneumonitis [0.2% (lapatinib)-7.4% (trastuzumab)], and decreased ejection fraction [1% (T-DXd)-13.6% (trastuzumab)]. Gastro-hepatobiliary AEs of special interest included nausea [33.9% (trastuzumab)-78.3% (T-DXd)], vomiting [19.2% (T-DM1)-48.2% (T-DXd)], diarrhea [19.6% (T-DM1)-96.9% (pyrotinib)], and hepatotoxicity [5.9% (lapatinib)-53.6% (T-DM1)]. CONCLUSION: Differing AE profiles for anti-HER2 therapies should be considered when assessing benefit-risk profile for treatment options.

Deterrents in recruitment of COVID-19 convalescent plasma donors: Experience from a hospital-based blood centre in India.

INTRODUCTION: Recruitment of Covid-19 convalescent plasma (CCP) donors may present as a challenge due to inexperience and differences in donor profile as compared to whole blood donation. Present study highlights the deterrents to recruiting CCP donors at a hospital based blood centre. MATERIALS AND METHODS: Potential CCP donors were contacted individually by telephone and a group approach through camp organisers from May to July 2020. Recruitment challenges were noted and deferrals of these recruited donors during screening and medical examination was obtained and analysed. RESULTS: Total 1165 potential CCP donors were contacted. Around 47% donors were lost due to challenges related to information storage and retrieval. Fear of health, family pressure, and fear of a new procedure were major reason (27.2%) for unwillingness to donate. The main reasons for deferral among potential donors were multiparity (38%) and being overage/underage (31.6%). Finally, 468 donors were recruited including 408 by individual approach and 60 by a group approach. From these absence of detectable COVID-19 antibodies were found in 15.4%. Few donors (9.0%) were deferred as they had not completed 28 days post recovery. CONCLUSION: The process of CCP donor recruitment differs from that of whole blood donation and requires an individualised approach with involvement of clinicians in the initial phases of the pandemic. A group approach targeting specific organisations could be adopted for a successful CCP collection program. There is a need to relook into some aspects of donor selection such as consideration of multiparous female donors and overage/underage donors after reviewing scientific evidence.

A Retrospective Evaluation of Airway Anatomy in Young Children and Implications for One-Lung Ventilation.

OBJECTIVE: One-lung ventilation (OLV) in children remains a niche practice with few studies to guide best practices. The objective of this study was to describe lower airway anatomy relevant to establishment of OLV in young children. DESIGN: Retrospective, observational study using pre-existing studies in the electronic health record. SETTING: Single institution, academic medical center, tertiary-care hospital. PARTICIPANTS: Pediatric patients <8 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Chest computed tomographic scans of 111 children 4 days to 8 years of age were reviewed. Measurements were taken from the thyroid isthmus to the carina, carina to first lobar branch on the left and right, diameter of the trachea at the carina, and diameter of the left and right mainstem bronchi. Dimensions were correlated with the outer diameter of endotracheal tubes and bronchial blockers. The left mainstem bronchus is consistently smaller than the right. Lung isolation using a mainstem technique on the left should use an endotracheal tube a half size smaller than would be used for tracheal intubation. The length from the carina to the first lobar branch on the left is consistently 3 times longer than on the right. Further, age-delineated bronchial diameters suggest that the clinician should transition from a 5F to a 7F Arndt bronchial blocker at 3-to-4 years of age. CONCLUSION: A more detailed and accurate understanding of pediatric lower airway anatomy may assist the clinician in successfully performing OLV in young children.

Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer.

PURPOSE: Anti-human epidermal growth factor receptor 2 (HER2) therapies are associated with interstitial lung disease (ILD), also referred to as pneumonitis. In this literature review, we describe the incidence of ILD among patients with HER2-positive metastatic breast cancer (MBC) receiving anti-HER2 therapies, and we describe existing recommendations for monitoring and managing drug-induced ILD among these patients. METHODS: We searched PubMed and Embase to identify clinical trials and postmarket observational studies that investigated anti-HER2 therapies for HER2-positive MBC, reported on ILD, and were published during January 1, 2009 to July 15, 2019. Articles were screened by two researchers; data were extracted from the full-text articles. RESULTS: The 18 articles selected for this review assessed 9,886 patients who received trastuzumab (8 articles), lapatinib (4 articles), trastuzumab emtansine (3 articles), trastuzumab deruxtecan (2 articles), or trastuzumab duocarmazine (1 article). The overall incidence of all-grade ILD was 2.4% (n = 234), with 66.7% (n = 156) occurring as grade 1-2 events, 0.5% grade 3-4 (n = 54; incidence), and 0.2% grade 5 (n = 16; incidence). The highest ILD incidence (21.4%) was among patients receiving trastuzumab combined with everolimus and paclitaxel. Ten studies indicated that ILD events were managed via dose interruption, dose reduction, or treatment discontinuation; two studies included detailed guidelines on managing drug-induced ILD. CONCLUSIONS: ILD is a well-described adverse drug reaction associated with several anti-HER2 drugs. Published ILD management guidelines are available for few anti-HER2 treatment regimens; however, guidance for monitoring for anti-HER2 drug-induced ILD is lacking.

Blood Pressure and Outcome After Mechanical Thrombectomy With Successful Revascularization.

Background and Purpose- Successful reperfusion can be achieved in more than two-thirds of patients treated with mechanical thrombectomy. Therefore, it is important to understand the effect of blood pressure (BP) on clinical outcomes after successful reperfusion. In this study, we investigated the relationship between BP on admission and during the first 24 hours after successful reperfusion with clinical outcomes. Methods- This was a multicenter study from 10 comprehensive stroke centers. To ensure homogeneity of the studied cohort, we included only patients with anterior circulation who achieved successful recanalization at the end of procedure. Clinical outcomes included 90-day modified Rankin Scale, symptomatic intracerebral hemorrhage (sICH), mortality, and hemicraniectomy. Results- A total of 1245 patients were included in the study. Mean age was 69±14 years, and 51% of patients were female. Forty-nine percent of patients had good functional outcome at 90-days, and 4.7% suffered sICH. Admission systolic BP (SBP), mean SBP, maximum SBP, SBP SD, and SBP range were associated with higher risk of sICH. In addition, patients in the higher mean SBP groups had higher rates of sICH. Similar results were found for hemicraniectomy. With respect to functional outcome, mean SBP, maximum SBP, and SBP range were inversely associated with the good outcome (modified Rankin Scale score, 0-2). However, the difference in SBP parameters between the poor and good outcome groups was modest. Conclusions- Higher BP within the first 24 hours after successful mechanical thrombectomy was associated with a higher likelihood of sICH, mortality, and requiring hemicraniectomy.

Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer.

BACKGROUND: Trastuzumab and pertuzumab are approved for the neoadjuvant treatment of human epidermal growth receptor 2 (HER2)-positive breast cancer, but cardiac safety data is limited. We report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. METHODS: Fifty-seven patients treated with neoadjuvant dose-dense AC-THP followed by adjuvant trastuzumab-based therapy between September 1, 2013, and March 1, 2015, were identified. The primary outcome was cardiac event rate, defined by heart failure (New York Heart Association [NYHA] class III/IV) or cardiac death. Patients underwent left ventricular ejection fraction (LVEF) monitoring at baseline, after AC, and serially during 1 year of anti-HER2 therapy. RESULTS: The median age was 46 years (range 26-68). Two (3.5%) patients developed NYHA class III/IV heart failure 5 and 9 months after initiation of trastuzumab-based therapy, leading to permanent discontinuation of anti-HER2 treatment. Seven (12.3%) patients developed a significant LVEF decline (without NYHA class III/IV symptoms). The median LVEF was 65% (range 55%-75%) at baseline and 64% (range 53%-72%) after AC, and decreased to 60% (range 35%-70%), 60% (range 23%-73%), 61% (range 25%-73%), and 58% (range 28%-66%) after 3, 6, 9, and 12 months (± 6 weeks) of trastuzumab-based therapy. CONCLUSION: The incidence of NYHA class III/IV heart failure after neoadjuvant AC-THP (followed by adjuvant trastuzumab-based therapy) is comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity from trastuzumab plus pertuzumab following a doxorubicin-based regimen. IMPLICATIONS FOR PRACTICE: Dual anti-human epidermal growth receptor 2 (HER2) therapy with trastuzumab and pertuzumab combined with standard chemotherapy has received accelerated approval for the neoadjuvant treatment of stage II-III HER2-positive breast cancer. Cardiac safety data for trastuzumab and pertuzumab in this setting are limited to clinical trials that utilized epirubicin-based chemotherapy. Formalized investigations into the cardiac safety of trastuzumab and pertuzumab with doxorubicin- (rather than epirubicin) based regimens are important because these regimens are widely used for the adjuvant and neoadjuvant treatment of breast cancer. The known role of HER2 signaling in the physiological adaptive responses of the heart provides further rationale for study on the potential cardiotoxicity of dual anti-HER2 blockade. Findings from this retrospective study provide favorable preliminary data on the cardiac safety of trastuzumab and pertuzumab in combination with a regimen of neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel, one of the preferred breast cancer treatment regimens, according to the National Comprehensive Cancer Network.

Pathologic Complete Response with Neoadjuvant Doxorubicin and Cyclophosphamide Followed by Paclitaxel with Trastuzumab and Pertuzumab in Patients with HER2-Positive Early Stage Breast Cancer: A Single Center Experience.

OBJECTIVES: Trastuzumab (H) and pertuzumab (P) with standard chemotherapy is approved for use in the neoadjuvant setting for human epidermal growth receptor 2 -positive patients. A retrospective analysis was performed of patients treated with dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), trastuzumab, and pertuzumab (THP) in the neoadjuvant setting. Here, the pathologic complete response (pCR) rates are reported. METHODS: An electronic medical record review was conducted of patients treated with HP-based therapy in the neoadjuvant setting from September 1, 2013, to March 1, 2015. Data on patient demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy were collected. The pCR was defined as total (tpCR, ypT0/is ypN0), German Breast Group (GBG) pCR (ypT0 ypN0), breast pCR (bpCR) with in situ disease (ypT0/is) and without in situ disease (ypT0), and explored axillary pCR (ypN0). RESULTS: Charts from 66 patients were reviewed, and 57 patients were evaluable for pCR. Median age was 46 years (range 26-68 years). Median tumor size was 4 cm. Of 57 patients, 53 (93%) had operable breast cancer (T1-3, N0-1, M0). Three patients (5.3%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (1.7%) had inflammatory breast cancer (T4d, any N, M0). Overall, 44 (77%) and 13 (23%) had hormone receptor (HR)-positive and negative diseases, respectively. Median numbers of cycles of neoadjuvant treatment were as follows: AC (4, range 1-4), T (4, range 1-4), trastuzumab (6, range 3-8), and pertuzumab (6, range 2-8). In these 57 patients, the rates of tpCR and bpCR with in situ disease were demonstrated in 41/57 (72%) patients, and the rates of GBG pCR and bpCR without in situ disease were found in 30/57 (53%) patients. Of 26 patients with biopsy-proven lymph nodal involvement, axillary pCR occurred in 22 (85%) patients. CONCLUSION: At a single center, the tpCR and GBG pCR rates of dd AC followed by THP are high at 72% and 53%, respectively. The Oncologist 2017;22:139-143Implications for Practice: This is the first study describing the role of doxorubicin and cyclophosphamide followed by paclitaxel and dual anti-HER2 therapy with trastuzumab and pertuzumab (ACTHP) in patients with early stage HER2-positive breast cancer. Total (breast + lymph node) pathological complete remission (pCR) remission (ypT0/is ypN0) and German Breast Group pCR rates (ypT0/ ypN0) were high at 72% and 53%, respectively, with the ACTHP regimen. Rate of axillary clearance in patients with known axillary involvement was high at 85%, which may translate into less extensive axillary surgeries in this subset in the future.

Boronic acid recognition of non-interacting carbohydrates for biomedical applications: increasing fluorescence signals of minimally interacting aldoses and sucralose.

To address carbohydrates that are commonly used in biomedical applications with low binding affinities for boronic acid based detection systems, two chemical modification methods were utilized to increase sensitivity. Modified carbohydrates were analyzed using a two component fluorescent probe based on boronic acid-appended viologen-HPTS (4,4'-o-BBV). Carbohydrates normally giving poor signals (fucose, l-rhamnose, xylose) were subjected to sodium borohydride (NaBH4) reduction in ambient conditions for 1 h yielding the corresponding sugar alcohols from fucose, l-rhamnose and xylose in essentially quantitative yields. Compared to original aldoses, apparent binding affinities were increased 4-25-fold. The chlorinated sweetener and colon permeability marker sucralose (Splenda), otherwise undetectable by boronic acids, was dechlorinated to a detectable derivative by reactive oxygen and hydroxide intermediates by the Fenton reaction or by H2O2 and UV light. This method is specific to sucralose as other common sugars, such as sucrose, do not contain any carbon-chlorine bonds. Significant fluorescence response was obtained for chemically modified sucralose with the 4,4'-o-BBV-HPTS probe system. This proof of principle can be applied to biomedical applications, such as gut permeability, malabsorption, etc.

Recalcitrant hypertrophic herpes genitalis in HIV-infected patient successfully treated with topical imiquimod.

Herpes Simplex Virus type 2 is the primary cause of genital ulceration worldwide. The presence of atypical features like deep ulcerations, hypertrophic, or pseudotumoural lesions or unusual location can be a marker for co-infection with HIV. These immunocompromised patients are usually resistant to the conventional antiviral treatment. We present a case of an HIV-infected patient with hypertrophic herpes genitalis, refractory to conventional oral antiviral therapy, who was successfully treated with a combination of oral valcyclovir and topical application of 5% imiquimod.

Network structure of turbulent premixed flames.

In this paper, a generalized description of the complex topology of turbulent premixed flames stabilized in a model gas turbine combustor is obtained using network analysis. Networks are created using the visibility algorithm applied to points on the flame edge obtained from Hydroxyl radical (OH)-Planar Laser Induced Fluorescence images of turbulent premixed flames. The network structure thus obtained showed the emergence of a few massively connected nodes which were found to represent the folded regions of the flame front. These nodes, which are called the hubs of the network, are vital for determining the overall structure of the flame front. Degree distribution of the formulated networks is used to characterize the flame-turbulence interaction inherent in the system. Turbulent flame front networks were found to be rigid enough to be unaffected by random perturbations but highly vulnerable towards coordinated removal of hubs or folds. These findings could serve as the first network-analytic approach to characterize turbulence-flame interaction dynamics with the use of a flourishing network theory, which enhances ongoing works based on vortex dynamics, hydrodynamic stability, and thermo-acoustic instability.

Mixing of oxidized and bilayer phospholipids.

Composition and phase dependence of the mixing of 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), with the oxidized phospholipid, 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC) were investigated by characterizing the aggregation states of DPPC/PGPC and DOPC/PGPC using a fluorescence quenching assay, dynamic light scattering, and time-resolved fluorescence quenching in the temperature range 5-60°C. PGPC forms 3.5nm radii micelles of aggregation number 33. In the gel phase, DPPC and PGPC fuse to form mixed vesicles for PGPC molar fraction, XPGPC≤0.3 and coexisting vesicles and micelles at higher XPGPC. Data suggest that liquid phase DPPC at 50°C forms mixed vesicles with segregated or hemi fused DPPC and PGPC for XPGPC≤0.3. At 60°C, DPPC and PGPC do not mix, but form coexisting vesicles and micelles. DOPC and PGPC do not mix in any proportion in the liquid phase. Two dissimilar aggregates of the sizes of vesicles and PGPC micelles were observed for all XPGPC for T≥22°C. DOPC-PGPC and DPPC-PGPC mixing is non-ideal for XPGPC>0.3 in both gel and fluid phases resulting in exclusion of PGPC from the bilayer. Formation of mixed vesicles is favored in the gel phase but not in the liquid phase for XPGPC≤0.3. For XPGPC≤0.3, aggregation states change progressively from mixed vesicles in the gel phase to component segregated mixed vesicles in the liquid phase close to the chain melting transition temperature to separated coexisting vesicles and micelles at higher temperatures.

Transfer of HMW glutenin subunits from Aegilops kotschyi to wheat through radiation hybridization.

High molecular weight glutenin subunits (HMWGS) are responsible for dough elasticity and bread making quality of bread wheat. Related wild non-progenitor species, Aegilops kotschyi possesses higher molecular weight x and y glutenin subunits than the bread wheat cultivars. A wheat-Aegilops substitution line with 1U chromosome was used for the transfer of (HMWGS) of 1U to wheat by using pollen radiation hybridization approach. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiling showed different patterns of allelic variations with either the presence or absence of HMWGS, Glu-1A (1, null), Glu-1B (7, 7 + 8, 17 + 18) and Glu-1D (5 + 10, 2 + 12, null). The pollen irradiated wheat-Aegilops derivatives, B-56-1-4-2, B-56-1-4-3, B-14-1 and B-14-2 with Glu1Ux and 1Uy and absence or presence of some Glu-1A and Glu-1B HMWGS showed high micro SDS sedimentation test (MST) values while B-16-1 and B-16-2 had moderate MST values and high protein content. However, B-58-3 with transfer of Glu-1Ux + 1Uy for Glu-1D showed very low MST values indicating that Glu-1Ux + 1Uy enhance MST value only in the presence of Glu1D HMWGS. The transfer/substitution of alien HMW-GS for Glu-1A and or Glu-1B loci only can lead to improved bread making quality of wheat.