Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE.

BACKGROUND: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. PATIENTS AND METHODS: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. CONCLUSIONS: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Pre-hospital stroke screening and notification of patients with reperfusion-eligible acute ischaemic stroke using modified Face Arm Speech Time test.

OBJECTIVES: To investigate the effects of pre-hospital stroke screening and notification on reperfusion therapy for patients with acute ischaemic stroke. METHODS: Pre-hospital stroke screening criteria were established based on a modified version of the Face Arm Speech Time (FAST) test. Screening was performed during ambulance transport by emergency medical service (EMS) personnel who completed a 2-hour training session on stroke screening. Temporal trends affecting acute ischaemic stroke investigation and intervention were compared before and after implementation of the pre-hospital screening. RESULTS: From July 2018 to October 2019, 298 patients with suspected stroke were screened by EMS personnel during ambulance transport prior to hospital arrival. Of these 298 patients, 213 fulfilled the screening criteria, 166 were diagnosed with acute stroke, and 32 received reperfusion therapy. The onset-to-door time was shortened by more than 1.5 hours (100.6 min vs 197.6 min, P<0.001). The door-to-computed tomography time (25.6 min vs 32.0 min, P=0.021), door-to-needle time (49.2 min vs 70.1 min, P=0.003), and door-to-groin puncture time for intra-arterial mechanical thrombectomy (126.7 min vs 168.6 min, P=0.04) were significantly shortened after implementation of the pre-hospital screening and notification, compared with historical control data of patients admitted from January 2018 to June 2018, before implementation of the screening system. CONCLUSION: Implementation of pre-hospital stroke screening using criteria based on a modified version of the FAST test, together with pre-arrival notification, significantly shortened the door-to-reperfusion therapy time for patients with ischaemic stroke. Pre-hospital stroke screening during ambulance transport by EMS personnel who complete a 2-hour focused training session is effective for identifying reperfusion-eligible patients with stroke.

Extract of white button mushroom affects skin healing and angiogenesis.

White button mushroom extract was examined in this study on (1) its potential effect on angiogenesis in chorioallantoic culture and (2) its recovering effect on the skin after injury in the ICR mice. Methods used included TUNEL assay on apoptosis, immunohistochemistry for vascular endothelial growth factor (VEGF), proliferative cell nuclear antigen (PCNA), epidermal growth factor (EGF), transforming growth factor ß (TGF-ß), and immune factor CD4 and western blotting. The results of chorioallantoic culture showed that the mushroom treatment led to significant increase in densities of VEGF sites. In the skin injury, ICR mice model increased EGF, PCNA, and collagen fibers, along with decrease of TUNEL positive apoptotic cells and limited reaction of TGF-ß and CD4 indicated that white button mushroom extract appeared to have beneficial effects on skin in regeneration and after injury.

Intestinal and liver changes after chronic ketamine and ketamine plus alcohol treatment.

The effects of long-term chronic ketamine treatment on the intestine and the liver were studied in the ICR mice which had daily intraperitoneal injection of ketamine at 30 mg/kg per day for 7 months. The intestine showed no significant pathology after treatment but had a decrease of the positive sites of proliferative cell nuclear antigen in the mucosae of the intestines after ketamine and ketamine plus alcohol (added in the last month) treatment. No significant apoptosis (via TUNEL) nor necrosis (via lactic acid dehydrogenase) was detected in the intestines of all control and ketamine-treated groups, with the exception of an increase of lactic acid dehydrogenase in the mucosae of the intestines of the ketamine plus alcohol group. In the liver, loss of glycogen was observed in animals after ketamine and ketamine plus alcohol treatment, in addition to the pathology reported in a previous work. The decrease in quantity of glycogen in the liver reflected either a failure of glycogen synthesis from glucose or an increase of glycogenolysis in the liver.

How would composite traditional Chinese medicine protect the brain--an example of the composite formula "Pien Tze Huang".

Chinese medicine has a long history of several thousand years. The main form of Traditional Chinese Medicine (TCM) is composite, i.e. a mixture of up to 10 medicinal products. Thus a composite prescription of 4-5 kinds of Chinese medicinal products may contain several hundred kinds of chemical composition. The active ingredients and clinical efficacy of which are difficult to characterize. We aim to review the Chinese literature of TCMs with neuroprotective effects. We illustrate with our study on Pien Tze Huang (PZH) the use of in vivo tests in the study of composite TCM. Our results show evidence that PZH might have neuropreventive effects in rats.

Permanent deficits in brain functions caused by long-term ketamine treatment in mice.

Ketamine, an injectable anesthetic, is also a popular recreational drug used by young adults worldwide. Ketamine is a non-competitive antagonist of N-methyl-d-aspartate receptor, which plays important roles in synaptic plasticity and neuronal learning. Most previous studies have examined the immediate and short-term effects of ketamine, which include learning and cognitive deficits plus impairment of working memory, whereas little is known about the long-term effects of repeated ketamine injections of common or usual recreational doses. Therefore, we aimed to evaluate the deficits in brain functions with behavioral tests, including wire hang, hot plate and water maze tests, plus examine prefrontal cortex apoptotic markers, including Bax, Bcl-2 and caspase-3, in mice treated with 6 months of daily ketamine administration. In our study, following 6 months of ketamine injection, mice showed significant deterioration in neuromuscular strength and nociception 4 hours post-dose, but learning and working memory were not affected nor was there significant apoptosis in the prefrontal cortex. Our research revealed the important clinical finding that long-term ketamine abuse with usual recreational doses can detrimentally affect neuromuscular strength and nociception as part of measurable, stable and persistent deficits in brain function.

Enterococcus species distribution among human and animal hosts using multiplex PCR.

AIMS: This study evaluated the use of Enterococcus species differentiation as a tool for microbial source tracking (MST) in recreational waters. METHODS AND RESULTS: Avian, mammalian and human faecal samples were screened for the occurrence of Enterococcus avium, Enterococcus casseliflavus, Enterococcus durans, Enterococcus gallinarum, Enterococcus faecium, Enterococcus faecalis, Enterococcus hirae and Enterococcus saccharolyticus using multiplex PCR. Host-specific patterns of Enterococcus species presence were observed only when data for multiple Enterococcus species were considered in aggregate. CONCLUSIONS: The results suggest that no single Enterococcus species is a reliable indicator of the host faecal source. However, Enterococcus species composite 'fingerprints' may offer auxiliary evidence for bacterial source identification. SIGNIFICANCE AND IMPACT OF STUDY: This study presents novel information on the enterococci species assemblages present in avian and mammalian hosts proximate to the nearshore ocean. These data will aid the development of appropriate MST strategies, and the approach used in this study could potentially assist in the identification of faecal pollution sources.

Structure and biological activities of a heparin-derived hexasaccharide with high affinity for basic fibroblast growth factor.

We demonstrated previously that heparin-derived hexasaccharides are the smallest fragments of the polysaccharide with comparable basic fibroblast growth factor (bFGF)-modulating activity in vitro (Ishihara, M., Tyrrell, D.J., Stauber, G.B., Brown, S., Cousens, L., and Stack, R.J. (1993) J. Biol. Chem. 268, 4675-4683. In this report, a specific hexasaccharide having high affinity for recombinant human bFGF was isolated and its structure deduced by analysis of its reduced disaccharide products after treatment with nitrous acid at pH 1.5, and by 1H NMR spectroscopy. The hexasaccharide has the structure [IdoA(2-OSO3)alpha 1-4GlcNSO3(6-OSO3)alpha 1-4]2IdoA(2-OSO3)alpha 1-4 AManR(6-OSO3). The hexasaccharide effectively inhibits the binding of syndecan-transfected RO-12 UC cells to bFGF-coated wells (Ishihara, M., Tyrrell, D.J., Kiefer, M.C., Barr, P.J., and Swiedler, S.J. (1992) Anal. Biochem. 202, 310-315), prevents the binding of 125I-bFGF to confluent monolayers of adrenocortical endothelial (ACE) cells, and inhibits the bFGF-dependent proliferation of ACE cells. Unlike the heparin from which it was derived, however, the hexasaccharide cannot promote the binding of 125I-bFGF to a recombinant high affinity bFGF receptor (flg) or restore the bFGF-dependent proliferative response to ACE cells grown in the presence of 5 mM sodium chlorate. Collectively, these data indicate that a hexasaccharide can be as effective as heparin as an antagonist of bFGF-mediated cell mitogenesis.

DNA sequence dependence of closely opposed cyclobutyl pyrimidine dimers induced by UV radiation.

Treatment of UV-irradiated DNAs with Micrococcus luteus pyrimidine dimer-DNA glycosylase results in the formation of double-strand breaks due to cleavage at closely opposed pyrimidine dimers. To determine if the induction of closely opposed dimers is significantly affected by DNA nucleotide sequence, end-labeled DNA fragments of known nucleotide sequence were UV irradiated, incubated with pyrimidine dimer-DNA glycosylase, and analyzed by electrophoresis through nondenaturing polyacrylamide gels. Distinct bands of increased electrophoretic mobility were observed, indicating that bifilar cleavage had occurred with greater probability at specific sites in each DNA sequence. In vitro enzymatic photoreactivation of dimers prior to treatment with pyrimidine dimer-DNA glycosylase prevented the appearance of bands. DNA sequence analysis revealed the presence of closely opposed runs of pyrimidines at sites of more frequent bifilar cleavage. Our results indicate that the induction of closely opposed dimers occurs with greater probability at specific sites in DNA sequences and that such sites are characterized by the presence of closely opposed pyrimidine runs.

A sensitive, enzymatic assay for the detection of closely opposed cyclobutyl pyrimidine dimers induced in human diploid fibroblasts.

A sensitive, enzymatic assay has been developed for the detection of closely opposed cyclobutyl pyrimidine dimers induced in UV-irradiated human diploid fibroblasts. In this assay closely opposed dimers are detected as bifilar enzyme-sensitive sites. Single-strand incisions are made at the positions of individual pyrimidine dimers through the action of M. luteus pyrimidine dimer-DNA glycosylase. Incisions at closely opposed dimers, effectively expressed as double-strand breaks, are quantified from the resulting reduction in DNA double-strand molecular weight as determined by velocity sedimentation through neutral sucrose density gradients. The stability of the bacteriophage lambda cos site under our reaction conditions indicates that opposed incisions must be relatively close to be expressed as a double-strand break. The dose response for the induction of bifilar enzyme-sensitive sites in mammalian cells was found to be complex but can be approximated by a function that increases as the 1.2-1.4 power of UV dose. The frequency of bifilar enzyme-sensitive sites observed decreased during postirradiation incubation of excision-repair-proficient human diploid fibroblasts with less than 20% still detectable at 24 h after irradiation with 5 J/m2 (254 nm). By comparison, over 80% of the bifilar enzyme-sensitive sites induced in fibroblasts assigned to xeroderma pigmentosum complementation group A remained detectable 24 h after irradiation. The implications of these results for models addressing the induction and repair of closely opposed pyrimidine dimers are discussed.

Repair of closely opposed cyclobutyl pyrimidine dimers in UV-sensitive human diploid fibroblasts.

An enzyme-sensitive site assay has been used to examine the fate of closely opposed pyrimidine dimers (bifilar enzyme-sensitive sites) in fibroblasts from individuals afflicted with various genetic disorders that confer increased cellular sensitivity to UV radiation. The disappearance of bifilar enzyme-sensitive sites was found to be normal in cells from individuals with Fanconi's anemia, Cockayne's syndrome, dyskeratosis congenita and the variant form of xeroderma pigmentosum. The rate of bifilar enzyme-sensitive site removal in XP cells assigned to complementation group C was reduced by an amount similar to that observed for the repair of isolated dimers. Our results indicate that the initiation of repair at closely opposed dimers is slow in XP-C cells but normal in all other cells examined.

Bifilar enzyme-sensitive sites in ultraviolet-irradiated DNA are indicative of closely opposed cyclobutyl pyrimidine dimers.

Incubation of UV-irradiated DNA with pyrimidine dimer-DNA glycosylase in cell-free lysates prepared from Micrococcus luteus results in the appearance of double-strand breaks. It has previously been assumed that such double-strand breaks result from cleavage at closely opposed dimers. We have used hybrid molecules of bacteriophage T7 DNA comprised of two unirradiated strands, two UV-irradiated strands, or one unirradiated and one UV-irradiated strand to test this hypothesis. Bifilar cleavage was observed only with molecules consisting of two irradiated strands and no bifilar cleavage was observed after the monomerization of pyrimidine dimers by enzymatic photoreactivation. Our results indicate that at least 80% of the double-strand breaks result from cleavage at closely opposed dimers and that the induction of dimers in one strand does not influence the induction of dimers at closely opposed positions in the complementary strand of a DNA double helix.