Neratinib and Ado-Trastuzumab-Emtansine for Pre-treated and Untreated HER2-positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium Trial 022.

PURPOSE: Treatment options for HER2-positive breast cancer brain metastases (BCBM) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab-emtansine (T-DM1) when given in combination. In TBCRC 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts (cohort 4A-previously untreated BCBM, cohorts 4B and 4C- BCBM progressing after local CNS-directed therapy without [4B] and with [4C] prior exposure to T-DM1). Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. Overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018-2021, 6, 17, and 21 patients enrolled to cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% (95% confidence interval [CI]: 4.3-77.7%), 35.3% (95% CI: 14.2-61.7%), and 28.6% (95% CI: 11.3-52.2%), respectively; 38.1-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). Median OS was 30.2 months (cohort 4A; 95% CI: 21.9, not reached [NR]), 23.3 months (cohort 4B; 95% CI: 17.6, NR), and 20.9 months (cohort 4C; 95% CI: 14.9, NR). CONCLUSION: We observed Intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pre-treated.

In-depth characterization of a new patient-derived xenograft model for metaplastic breast carcinoma to identify viable biologic targets and patterns of matrix evolution within rare tumor types.

Metaplastic breast carcinoma (MBC) is a rare breast cancer subtype with rapid growth, high rates of metastasis, recurrence and drug resistance, and diverse molecular and histological heterogeneity. Patient-derived xenografts (PDXs) provide a translational tool and physiologically relevant system to evaluate tumor biology of rare subtypes. Here, we provide an in-depth comprehensive characterization of a new PDX model for MBC, TU-BcX-4IC. TU-BcX-4IC is a clinically aggressive tumor exhibiting rapid growth in vivo, spontaneous metastases, and elevated levels of cell-free DNA and circulating tumor cell DNA. Relative chemosensitivity of primary cells derived from TU-BcX-4IC was performed using the National Cancer Institute (NCI) oncology drug set, crystal violet staining, and cytotoxic live/dead immunofluorescence stains in adherent and organoid culture conditions. We employed novel spheroid/organoid incubation methods (Pu·MA system) to demonstrate that TU-BcX-4IC is resistant to paclitaxel. An innovative physiologically relevant system using human adipose tissue was used to evaluate presence of cancer stem cell-like populations ex vivo. Tissue decellularization, cryogenic-scanning electron microscopy imaging and rheometry revealed consistent matrix architecture and stiffness were consistent despite serial transplantation. Matrix-associated gene pathways were essentially unchanged with serial passages, as determined by qPCR and RNA sequencing, suggesting utility of decellularized PDXs for in vitro screens. We determined type V collagen to be present throughout all serial passage of TU-BcX-4IC tumor, suggesting it is required for tumor maintenance and is a potential viable target for MBC. In this study we introduce an innovative and translational model system to study cell-matrix interactions in rare cancer types using higher passage PDX tissue.

Steroidome and metabolome analysis in gilt saliva to identify potential biomarkers of boar effect receptivity.

Optimal management of gilt reproduction requires oestrus synchronization. Hormonal treatments are used for this purpose, but there is a growing demand for non-hormonal alternatives, especially in organic farms. The boar effect is an important alternative opportunity to induce and synchronize oestrus without hormones. Before puberty, gilts exhibit a 'waiting period' during which boar exposure could induce and synchronize the first ovulation. We searched for salivary biomarkers of this period of boar effect receptivity to improve detection of the gilts to stimulate with the perspective of enhancing the efficacy of the boar effect. Saliva samples were collected from 30 Large-White×Landrace crossbred gilts between 140 and 175 days of age. Gilts were exposed twice a day to a boar and subjected to oestrus detection from 150 to 175 days of age. Among the 30 gilts, 10 were detected in oestrus 4 to 7 days after the first introduction of the boar and were considered receptive to the boar effect, 14 were detected in oestrus more than 8 days after first boar contact, and six did not show oestrus and were considered non-receptive. Saliva samples from six receptive and six non-receptive gilts were analyzed for steroidome and for metabolome using gas chromatography coupled to tandem mass spectrometry and 1H nuclear magnetic resonance spectroscopy, respectively. Four saliva samples per gilt were analyzed: 25 days and 11 days before boar introduction, the day of boar introduction, 3 days later for receptive gilts or 7 days later for non-receptive gilts. Twenty-nine steroids and 31 metabolites were detected in gilt saliva. Salivary concentrations of six steroids and three metabolites were significantly different between receptive and non-receptive gilts: progesterone and glycolate 25 days before boar introduction, 3α5ß20α- and 3ß5α20ß-hexahydroprogesterone, dehydroepiandrosterone, androstenediol, succinate, and butyrate 11 days before boar introduction, and 3ß5α-tetrahydroprogesterone on the day of boar introduction. Thus, nine potential salivary biomarkers of boar effect receptivity were identified in our experimental conditions. Further studies with higher numbers of gilts and salivary sampling points are necessary to ascertain their reliability.

Medicare for All: Considerations for Neuroradiologists.

The year 2019 featured extensive debates on transforming the United States multipayer health care system into a single-payer system. At a time when reimbursement structures are in flux and potential changes in government may affect health care, it is important for neuroradiologists to remain informed on how emerging policies may impact their practices. The purpose of this article is to examine potential ramifications for neuroradiologist reimbursement with the Medicare for All legislative proposals. An institution-specific analysis is presented to illustrate general Medicare for All principles in discussing issues applicable to practices nationwide.

Salivary and urinary metabolome analysis for pre-puberty-related biomarkers identification in porcine.

Estrus synchronization is important for optimal management of gilt reproduction in pig farms. Hormonal treatments, such as synthetic progestogens, are used on a routine basis, but there is a growing demand for non-hormonal alternative breeding tools. Before puberty, gilts exhibit a 'waiting period,' related to the ovarian development and gonadotrophin secretions, during which external stimulations, such as boar exposure, could induce and synchronize first ovulation. Practical non-invasive tools for identification of this period in farms are lacking. During this period, urinary oestrone levels are high, but urine sampling is difficult in group-housed females. The aim of this work was to search for specific biomarkers of the 'waiting period' in saliva and urine. In total, nine 144- to 147-day-old Large White gilts were subjected to trans-abdominal ultrasonography three times a week for 5 weeks until puberty detection (week -5 to week -1 before puberty). Urine and saliva samples were collected for oestrone assay to detect the 'waiting period' and for metabolome analysis using 1H-nuclear magnetic resonance spectroscopy to detect potential biomarkers of the 'waiting period.' Gilts were slaughtered 7 days after puberty detection for puberty confirmation. Results were consistent with ultrasonography data for six gilts. Urine and saliva samples from these six gilts were analyzed. Urinary estrone concentration significantly increased 2 weeks before puberty detection. Metabolome analysis of urine samples allowed the identification of 78 spectral bins, among them, 42 low-molecular-weight metabolites were identified. Metabolome analysis of salivary samples allowed the identification of 59 spectral bins, among them, 23 low-molecular-weight metabolites were detected and 17 were identified. No potential biomarker was identified in urinary samples. In saliva, butyrate and 2HOvalerate, 5.79 ppm (putatively uridine), formate, malonate and propionate could be biomarker candidates to ascertain the pre-puberty period in gilt reproduction. These results confirm that non-invasive salivary samples could allow the identification of the physiological status of the gilts and presumably the optimal time for application of the boar effect. This could contribute to synchronize puberty onset and hence to develop non-hormonal breeding tools.

Prediction of Burst Pressure in Multistage Tube Hydroforming of Aerospace Alloys.

Bursting, an irreversible failure in tube hydroforming (THF), results mainly from the local plastic instabilities that occur when the biaxial stresses imparted during the process exceed the forming limit strains of the material. To predict the burst pressure, Oyan's and Brozzo's decoupled ductile fracture criteria (DFC) were implemented as user material models in a dynamic nonlinear commercial 3D finite-element (FE) software, ls-dyna. THF of a round to V-shape was selected as a generic representative of an aerospace component for the FE simulations and experimental trials. To validate the simulation results, THF experiments up to bursting were carried out using Inconel 718 (IN 718) tubes with a thickness of 0.9 mm to measure the internal pressures during the process. When comparing the experimental and simulation results, the burst pressure predicated based on Oyane's decoupled damage criterion was found to agree better with the measured data for IN 718 than Brozzo's fracture criterion.

A phase II study of ixabepilone and trastuzumab for metastatic HER2-positive breast cancer.

BACKGROUND: A multicenter NCI-sponsored phase II study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer. PATIENTS AND METHODS: Two cohorts were enrolled: cohort 1 had received no prior chemotherapy or trastuzumab for metastatic disease and cohort 2 had received 1-2 prior trastuzumab-containing regimens for metastatic disease. Patients in both cohorts received ixabepilone 40 mg/m(2) as a 3-h infusion and trastuzumab on day 1 of a 21-day cycle. Tumor biomarkers that may predict response to trastuzumab were explored. RESULTS: Thirty-nine women entered the study with 15 patients in cohort 1 and 24 patients in cohort 2. Across both cohorts, the overall RR was 44%, with a clinical benefit rate (CR + PR + SD for at least 24 weeks) of 56%. Treatment-related toxic effects included neuropathy (grade ≥2, 56%), leukopenia (grade ≥2, 26%), myalgias (grade ≥2, 21%), neutropenia (grade ≥2, 23%), and anemia (grade ≥2, 18%). CONCLUSIONS: This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has encouraging activity as first and subsequent line therapy for metastatic breast cancer.

A randomized controlled trial of oral melatonin supplementation and breast cancer biomarkers.

We examined compliance with and the effects of melatonin supplementation on breast cancer biomarkers (estradiol, insulin-like growth factor I (IGF-1), insulin-like growth factor-binding protein 3 (IGFBP-3), and the IGF-1/IGFBP-3 ratio) in postmenopausal breast cancer survivors. In a double-blind, placebo-controlled study, postmenopausal women with a prior history of stages 0-III breast cancer who had completed active cancer treatment (including hormonal therapy) were randomly assigned to either 3 mg oral melatonin (n = 48) or placebo daily for 4 months. Plasma samples were collected at baseline and after the completion of the intervention. The primary endpoints were compliance and change in estradiol and IGF-1/IGFBP-3 levels. Ninety-five women were randomized (48 to melatonin and 47 to placebo). Eighty-six women (91%) completed the study and provided pre- and postintervention bloods. Melatonin was well tolerated without any grade 3/4 toxicity and compliance was high (89.5%). Overall, among postmenopausal women with a prior history of breast cancer, a 4-month course of 3 mg melatonin daily did not influence circulating estradiol, IGF-1, or IGFBP-3 levels. Compliance was comparable between the two groups. Short-term melatonin treatment did not influence the estradiol and IGF-1/IGBBP-3 levels. Effects of longer courses of melatonin among premenopausal women are unknown. Low baseline estradiol levels in our study population may have hindered the ability to detect any further estradiol-lowering effects of melatonin.

Variations of lignocellulosic activities in dual cultures of Pleurotus ostreatus and Trichoderma longibrachiatum on unsterilized wheat straw.

Trichoderma spp., soil filamentous fungi, are antagonists that can cause great losses in mushroom production. We have investigated the influence of T. longibrachiatum on the production of lignocellulolytic enzymes by Pleurotus ostreatus during its vegetative growth on a straw-based cultivation substrate that either had been sterilized, pasteurized or not heat treated. The variations in the lignocellulolytic activities and the electrophoretic patterns in single and dual cultures were used as a tool for perturbation assessment. The various heat treatments of the wheat straw before inoculation affected both the bacterial populations and the abilities of T. longibrachiatum and P. ostreatus to colonize the substrate and to produce extracellar lignocellulolytic enzymes. Interactions between T. longibrachiatum and the microflora of the substrate led to a great decrease of hydrolytic activities due to reduced colonization of the substrate. Pleurotus ostreatus also was affected but it was less sensitive than T. longibrachiatum. As a consequence, in dual cultures with P. ostreatus, the competitive ability of T. longibrachiatum was reduced by bacteria in the substrates. The presence of total microflora or thermotolerant microflora increased the production of phenoloxidase activities by P. ostreatus, despite reduced colonization of the substrate. This contributed to the improvement of the competitive ability of P. ostreatus in the pasteurized substrate. Furthermore, a direct effect of bacteria on T. longibrachiatum also was observed. In sterilized substrate, both laccase and Mn-peroxydase activities were increased dramatically in dual cultures due to a faster production of a laccase isoform, which was stimulated by T. longibrachiatum.

Selection of strains of Lentinula edodes and Lentinula boryana adapted for efficient mycelial growth on wheat straw.

Mycelial growth rates are presented for 11 strains of Lentinula edodes and six strains of Lentinula boryana cultivated on solid media: derived from malt extract (MEA); malt yeast extract (YMEA); and, YMEA plus soluble lignin derivatives (YMEA+WSLD). The results were compared with data for mycelial growth rates, of the same strains cultivated on substrates derived from wheat straw treated at different temperatures (50, 65, 75 and autoclaving at 121 degrees C). In general, the addition of WSLD significantly reduced mycelial growth rates in both species. The greatest mycelial growth rate was obtained on sterilized straw at 121 degrees C for the majority of strains. However, this growth was not significantly different from that obtained at 75 degrees C. L. edodes showed greater growth rates than L. boryana. The feasibility of using estimates of mycelial growth rate on YMEA and YMEA+WSLD are discussed as possible indicators of a strain's potential for mycelial growth on substrates derived from wheat straw.

Agaricus bisporus susceptibility to bacterial blotch in relation to environment: biochemical studies.

Variation of Agaricus bisporus susceptibility to bacterial blotch in relation to environment was studied at the biochemical level. Significant differences were observed between A. bisporus strains for tyrosinase and gamma-glutamyl transferase (GGT) activities and for gamma-L(+)glutaminyl-4-hydroxybenzene (GHB) content. A lower effect was detected for compost quality. GGT activity and GHB content were related to strain susceptibility to bacterial blotch by a linear model depending on strain type, commercial or wild.

The healthy start renal clinic: benefits of tracking and early intervention in pre-end stage renal disease patients.

Several studies have demonstrated a strong association between the benefits of pre-end stage renal disease (ESRD) education and decreased length of hospital stay (LOS) and hospital charges, delay of renal replacement therapy (RRT), and a smooth transition to RRT. The Ochsner Healthy Start Renal Clinic (HSRC) is a multidisciplinary early education and tracking program for pre-ESRD patients and their families. We identified and educated pre-ESRD patients about kidney disease, allowing them to discuss and make informed decisions about their treatment and be better prepared to cope with the transition to RRT and the changes in their lives resulting from kidney failure. HSRC patients demonstrated a significant decrease in length of hospital stay (p = 0.05), a trend towards decreased hospital episodes and charges, decreased use of temporary venous access, and a smooth transition to RRT. The control group was made up of patients who had either refused the structured education or had been referred to HSRC late and received only conventional instruction by a social worker at the point where dialysis was imminent. We compared the number of episodes of hospitalization, LOS, and overall hospital charges for the period immediately surrounding initiation of chronic dialysis (2 months before and 1 month following onset) of all 36 patients who began chronic hemodialysis in our facility between November 1997 and November 1998. HSRC patients had LOS half as long (p=0.05), fewer hospital episodes, and hospital charges of $5,000 less per patient than the non-HSRC group. Initial data strongly suggest that early education and intervention through the coordination of a multidisciplinary team maximize the continuity of patient care.

Changes in nitrogen resources with increases in temperature during production of mushroom compost.

The rise in temperature is an important event during the composting of lignocellulosic materials and has to be controlled and regulated to improve the biodegradation. Phase I mushroom composts were incubated under environmentally controlled conditions. When the temperature was pre-set at 65°C and then later at around 80°C, the microbial respiration and the biodegradations were hardly affected. However residual activities due to thermoresistant bacteria were still measured after 68 h at a constant temperature of 80°C. Significant changes in nitrogen resources were observed: loss of nitrogen from microbial products, an increase in the proportion of nitrogen in non-hydrolysable and stable forms, and an increase in volatilisation of ammonia. These changes were mainly due to physico-chemical mechanisms associated with disturbances in the structure of the microbial community.

Stimulation of environmentally controlled mushroom composting by polysaccharidases.

Polysaccharidases adsorbed on commercial amylodextrins were added to environmentally controlled composts of straw plus poultry manure. After 5 days of composting at 48°C, microbial enzyme activities and numbers of bacteria were higher in the treated compost than in the control. During the next phase at 80°C, between days 5 and 6, more C and N were solubilized in the treated compost. After introducing a microbial inoculum on day 6, and maintaining the substrate at 48°C, colonization by bacteria was faster in the treated compost and consequently, more fibre was degraded. Differences between composts in yields of Agaricus bisporus after 5 weeks of cropping were not significant (P=0.05).

Rates of drug detection in urine samples from various populations.

About 14% of all substance abuse urine tests are positive for 1.2 substances. Cannabinoid and cocaine metabolites are most frequently the cause of positivity. Individuals in probation or parole programs have the highest numbers of positive urine substance abuse tests. Our data suggest that a consistency of positivity exists for substance abuse urine tests and that this positivity, once developed by testing laboratories, can be used for purposes of contractual relations and cost predictions. Valuable educational information that may assist the population serviced by the laboratory in regard to substance abuse can also be obtained.

Complete iodide trapping defect in two cases with congenital hypothyroidism: adaptation of thyroid to huge iodide supplementation.

Two cases of congenital defect in iodide trapping mechanism are related. The absence of thyroid and gastric concentration of 99mTcO4 led to the diagnosis. The study of saliva and gastric:serum concentration ratios confirmed the complete defect. The kinetics of radioiodine studied by external detection showed an early simultaneous decay in the thyroid, the stomach and the left ventricle. Thyroid accumulation of 131I, demonstrated by camera imaging, was estimated to be 0.1% at 48 h. It probably originated from simple diffusion. Iodide supplementation was progressively increased to 4.5 g and 10 g day-1 respectively. It resulted in a normalization of all parameters. Huge doses of iodide did not result in any evidence of hyperthyroidism as TSH rose normally after TRH. Intermittent iodide supplementation in one case could not maintain euthyroidism longer than a few weeks. Daily treatment, therefore, seems necessary.

Multifactorial study of prognostic factors in differentiated thyroid carcinoma and a re-evaluation of the importance of age.

A multivariate analysis of prognostic factors has been carried out with 375 cases of differentiated thyroid cancer (DTC) treated in the same centre by total thyroidectomy and 131I therapy. The patients have been followed for 5 to 23 years. The isolated prognostic roles of age, sex, clinical stage and histology were confirmed, but these factors were found to be strongly interrelated. Multifactorial analysis was conducted following Cox's model. It demonstrated that the prevalent role of clinical staging (nodular versus lobar or massive form) is as important as the initial presence of metastases (P = 0.0001). Histological assessment of differentiation, age and sex were of lesser importance. Thus, the most significant prognostic variable is clinical stage. These data must be taken into account when formulating management protocols for DTC.

Lumbo-peritoneal shunt malfunction. A new, simple and reliable CT sign.

Sixty CT scans in 31 patients who underwent lumboperitoneal shunting for communicating hydrocephalus showed that the size of the ventricles did not represent a good indicator of shunt malfunction. Instead, we discovered that the size of the basal cisterns around the brain stem enabled us to predict blockage earlier and more reliably. In a well functioning shunt, the basal cisterns are usually not visualized. In children with clinical shunt malfunction the cisterns dilate and become visible again. This occurs earlier and more frequently than ventricular enlargement. We therefore conclude that visible cisterns in association with persistent symptoms of malfunction are more reliable predictors of a true blockage that requires shunt revision than serial studies of ventricular size.