Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Home healthcare patient, caregiver and provider perspectives on use of unscheduled acute care and the usability and acceptability of on-demand telehealth solutions.

BACKGROUND/OBJECTIVES: Home health care (HHC) agencies provide an important role in helping to transition patients from acute care to independent residential living. Telehealth has the potential to transform care delivery in HHC, however the majority of studies in HHC have focused on the use of telemonitoring for patients with specific chronic conditions. The objective of this study was to examine reasons HHC patients use acute care services and assess the acceptability of on-demand telehealth services among HHC patients, caregivers and personnel to help alleviate the need for seeking in-person acute care. Design/Setting/Participants/Measures: This study was a secondary analysis of qualitative data from in-depth interviews of 30 HHC personnel, patients and caregivers from a Medicare-certified HHC agency affiliated with a large healthcare system from January through May 2020. A conventional content analysis approach was used to identify themes. RESULTS: Themes associated with reasons for seeking acute care included: sense of urgency, behavioral and psychosocial factors, and access to care. Participants described their perceptions of the benefits, usability and acceptability and barriers to using telehealth. Patients and HHC personnel agreed that on-demand telehealth should not replace in-person visits but all identified roles that on-demand telehealth services could play in improving communication and access to care. The biggest barriers to use of telehealth identified by HHC personnel were cost, access and ability to use technology by HHC patients. CONCLUSION: This study identified reasons HHC patients seek unscheduled acute care and the usability and acceptability of on-demand telehealth services to increase access to care among HHC patients. These findings underscore the need to improve communication and coordination between patients, HHC personnel, and primary care providers and the role that on-demand telehealth services can have in transforming HHC.

Characterizing axillary web syndrome: ultrasonographic efficacy.

The aim of this study was to determine if ultrasound could successfully characterize axillary web syndrome (AWS) and clarify the pathophysiologic basis of AWS as a vascular or lymphatic abnormality, or an abnormal tissue structure. This prospective study evaluated women who developed AWS following breast cancer surgery. Using an 18 MHz ultrasound transducer, images were taken of the AWS cord and compared to mirror images on the contralateral side. A blinded radiologist assessed the ultrasound characteristics of and structural changes in the skin and subcutaneous tissue and formulated an opinion as to the side in which AWS was located. Seventeen subjects participated in the study. No structure or abnormality consistent with AWS could be identified by ultrasound. There were no statistical differences between the ipsilateral and contralateral side in skin thickness; subcutaneous reflector thickness, number or disorganization; or subcutaneous tissue echodensity (p>0.05). The radiologist correctly identified the side with AWS in 12 of 17 subjects (=0.41). A distinct ultrasonographic structure or abnormality could not be identified in subjects with AWS using 18 MHz ultrasound. The inability to identify a specific structure excludes the possibility that AWS is associated with vein thrombosis or a fascial abnormality, and supports the theory that AWS may be pathology that is not visible with 18 MHz ultrasound, such as microlymphatic stasis or binding of fibrin or other proteins in the interstitial space.

Characteristics of patients with respiratory allergy in France and factors influencing immunotherapy prescription: a prospective observational study (REALIS).

To describe the sensitization profile of respiratory allergies in France, identifying factors influencing the prescription of allergen immunotherapy (AIT) [Transversal phase (T)], and assess treatment efficacy, tolerability, compliance and satisfaction [Longitudinal phase (L)]. French allergists (600) and pneumo-allergists (600) were offered participation and asked to recruit the first 20 new patients with allergic rhinitis (AR) and/or asthma, consulting for a first time allergy check-up with skin prick-test (T), and 5 patients sensitized to pollens (skin test and/or specific IgE) for whom SLIT with pollens was prescribed (L). In the T phase, 2,714 patients were recruited by 169 specialists, mostly allergists (76.5%). The majority (98%) suffered from AR, alone (57.7%) or with asthma (40.3%) and 80.3% suffered from moderate-to-severe rhinitis, mostly persistent (65.8%). Asthma, when present, was mostly intermittent (63.7%) or mild persistent (20.1%). Sensitization to house dust mites was the most common (64.5%), followed by grass pollens (61.5%), tree pollens (41.6%) and cat danders (30.5%). Poly-sensitization was seen in 73.6% of patients. AIT, mostly sublingual, was recommended in 55.6% of the patients, mostly (78.1%) because of insufficient control with symptomatic treatments. The overall impact of symptoms on QOL, positive skin test to grass pollens, ocular pruritus and/or nasal obstruction and moderate-to-severe rhinitis were significant predictors of SLIT prescription. Poly-sensitization or concomitant asthma were not seen as deterrents. Most patients consulting a specialist for allergy testing suffer from moderate-to-severe rhinitis. Treatment in current practice includes immunotherapy in half of the patients, and follows ARIA recommendations.

Probabilistic prediction of Epileptic Seizures using SVM.

In this paper, an algorithm based on the linear Support Vector Machine (SVM) tool was proposed to classify intracranial electroencephalography (iEEG) signals as ictal or interictal to perform human seizure prediction, efficiently. Various univariate linear measures were extracted, and the developed classifier performed adequately well with numerous performance metrics, especially the dataset was suffering from a significant imbalanced class, with the majority of samples representing non-seizure events. The proposed tool was indeed able to forecast accurately such rare events, seizures, from a large set of EEG dataset. In fact, our model can predict some seizures with up to 0.4 probability and about 30-40 minutes in advance. The proposed work employed intracranial EEG recordings of 6 patients in the Freiburg EEG database, totalling trained and tested on 34 seizures of 140-hour-long. It exhibits a sensitivity of 78% and specificity of 100% employing a 2-second-long window with 10-fold cross-validation.

Axillary web syndrome following breast cancer surgery: symptoms, complications, and management strategies.

Axillary web syndrome (AWS) is a common condition occurring in up to 86% of patients following breast cancer surgery with ipsilateral lymphadenectomy of one or more nodes. AWS presents as a single cord or multiple thin cords in the subcutaneous tissues of the ipsilateral axilla. The cords may extend variable distances "down" the ipsilateral arm and/or chest wall. The cords frequently result in painful shoulder abduction and limited shoulder range of motion. AWS most frequently becomes symptomatic between 2 and 8 weeks postoperatively but can also develop and recur months to years after surgery. Education about and increased awareness of AWS should be promoted for patients and caregivers. Assessments for AWS should be performed on a regular basis following breast cancer surgery especially if there has been associated lymphadenectomy. Physical therapy, which consists of manual therapy, exercise, education, and other rehabilitation modalities to improve range of motion and decrease pain, is recommended in the treatment of AWS.

Active Learning of the Floor of Mouth Anatomy with Ultrasound.

More emphasis is now being placed on active learning in medical education. Ultrasound is an active learning tool that can be used to supplement didactic instruction. This study describes a self-guided activity for learning floor of mouth ultrasound. Thirty-three first year medical students learned floor of mouth scan technique and ultrasound anatomy through a brief PowerPoint module. They subsequently performed the scan on a standardized patient. Each student was asked to label the floor of mouth muscles on the image he or she acquired. After the activity, the students were given a quiz on anatomic relationships of the floor of mouth. Perceptions about the activity were collected through a survey. All 33 students obtained a floor of mouth image within a three minute time limit. Twenty-four (73%) students were able to completely and accurately label the image in time. The mean score on the muscle relationships quiz was 93%. Overall perceptions were very positive with most students expressing a "high" or "very high" level of interest in incorporating similar self-guided activities within the curriculum. This study showed that it is feasible for students to learn scan technique and recognize relevant ultrasound anatomy in an independent fashion through a brief active learning module. Furthermore, the students found the activity enjoyable. The implication is that similar activities could be developed which would provide additional ways to incorporate active learning strategies.

Evaluation of continuous infusion suramin in metastatic breast cancer: impact on plasma levels of insulin-like growth factors (IGFs) and IGF-binding proteins.

Suramin represents a new class of antitumor drugs that targets growth factor networks. In this Phase II trial, suramin was administered by continuous infusion to 10 patients with advanced breast cancer. The target level of 280 microgram/ml suramin was achieved in a median of 10 days; toxicities in this patient group were low. We monitored the insulin-like growth factor (IGF) network in these patients because of the previously defined growth-promoting role of the IGFs in breast cancer. Plasma levels of total IGF-I and total IGF-II showed variable responses to suramin with median decreases of 24 and 23%, respectively, for the 10 patients; for total IGF-I levels, this did not reach statistical significance. On the other hand, free IGF-I plasma levels were consistently and dramatically increased (over 250%) after suramin infusion. IGF-binding proteins (IGFBPs), modulators of IGF bioavailability, were also measured. Levels of IGFBP-3, the major carrier of IGFs in the circulation, were decreased 21% after suramin treatment when measured by immunoradiometric assay. However, the majority of the plasma IGFBP-3 remaining after suramin was not the intact high-affinity IGF-binding form but rather a 30-kDa fragment with markedly reduced affinity for IGF-I. IGFBP-3 protease activity was evident in the plasma of 3 of 10 patients after suramin. Measurements of plasma IGFBP-1, IGFBP-2, and IGFBP-4 revealed no significant changes in response to suramin. The dramatic increase in active free IGF-I seen after suramin raises concern and underscores the importance of measuring relevant biomarkers in clinical trials.

Characterization and partial purification of the insulin-like growth factor (IGF)-dependent IGF binding protein-4-specific protease from human fibroblast conditioned media.

Insulin-like growth factors (IGFs) are one of the most potent stimulators of cell growth. IGFs are modulated by six high affinity binding proteins (IGFBPs) which are, in turn, regulated through post-translational modifications such as proteolysis. In the conditioned media of human fibroblasts, IGFBP-4 is cleaved by an apparently novel IGFBP-4-specific protease that requires IGF for functional activity. We have used several biochemical manipulations, including size exclusion chromatography, native gel electrophoresis, chaotropic salt precipitation, hydrophobic interaction chromatography, ion exchange chromatography, isoelectric focusing, lectin affinity chromatography, and metal chelating affinity chromatography to both characterize and partially purify the IGF-dependent IGFBP-4 protease. Our results indicate that this protease is a highly glycosylated, Zn+2 binding metalloprotease with a native molecular weight greater than 200 kDa.

PP144. Profile of lupus pregnancy in internal medecine practice.

INTRODUCTION: The pregnancies in systemic erythematous lupus (SLE) disease is a situation of high risk and involve both the mother and the fetus. The prematurity and the miscarriage are there more frequent, with increase risks of eclampsia, acute hypertension, HELP syndrome and of worsening renal disease. So the morbimortality is multiplied particularly when a anti-phospholipid syndrome 'APLS' is associated. The pregnancy remains however authorized when the SLE is in remission for more than 6 months with a validated treatment and successful means of monitoring. OBJECTIVES: To review the clinical profile of the pregnancies at the SLE patients with or without APLS in Internal Medicine Practice. METHODS: it's a retrospective study, in an internal medical centre over a period going from January, 2008 till December, 2011. The collection of the data is made from the index cards of clinical observations collecting items to interpret the data. All the patients are diagnosed referring to the criteria ACR (SLE/APLS) and all benefit from a follow-up in a obstetrics monitoring (ultrasounds to monitor growth and placental development). RESULTS: On a cohort of 80 SLE young patients hospitalized we brought together 20 patients answering eligibility criteria. The average age is of 26 years (21-41), SLE evolve with an average of 2.5years, the parity is estimated at 5 on average by patient. The pregnancies are programmed in only in 25% . The others cases of pregnancy remain the consequence of a not adapted contraception (50%). Lupus patients have history of renal damage (8) requiring immunosuppressive therapy (4) but renal function is preserved at all the patient's. The treatment is adapted to the clinical context and prophylactic doses of heparin and a baby aspirin are required in most situations. The cardiovascular and metabolic risk factors show an overweight (12), one dyslipemia (10), type 2 diabetes (2), and hypertension (3). The pregnancy is at the origin of a degradation of the renal function (4) with definitive chronic renal Insufficiency (1). The specific events observed are a HELLP syndrome (1), pre-eclampsia (2), fetal losses (5), ischemic strokes (4) and post-partum cardiomyopathy (1). The pregnancies require caesarians (15) with ligature of trunks (2). We deplore fetal deaths (7) in tripled (1) and in twin (1) during the period of follow-up. We note a small birth weight (7), a preterm birth (5), a foetal distress (5) at the origin of a psychomotor disorders (1) and we observed a case of a transient skin lupus (1). CONCLUSION: The frequency of the maternal and fetal complications is partially understandable by the fact that the majority of the pregnancies neither are programmed, nor authorized by the treating physician. Indeed, between the denial of the disease and the desire of pregnancy in everything taken, the patients often take the risk and put the treating physician in front of pregnancies in top risks.

Strategies to defeat ketamine-induced neonatal brain injury.

Studies using animal models have shown that general anesthetics such as ketamine trigger widespread and robust apoptosis in the infant rodent brain. Recent clinical evidence suggests that the use of general anesthetics on young children (at ages equivalent to those used in rodent studies) can promote learning deficits as they mature. Thus, there is a growing need to develop strategies to prevent this injury. In this study, we describe a number of independent approaches to address therapeutic intervention. Postnatal day 7 (P7) rats were injected with vehicle (sterile PBS) or the NMDAR antagonist ketamine (20 mg/kg). After 8 h, we prepared brains for immunohistochemical detection of the pro-apoptotic enzyme activated caspase-3 (AC3). Focusing on the somatosensory cortex, AC3-positive cells were then counted in a non-biased stereological manner. We found AC3 levels were markedly increased in ketamine-treated animals. In one study, microarray analysis of the somatosensory cortex from ketamine-treated P7 pups revealed that expression of activity dependent neuroprotective protein (ADNP) was enhanced. Thus, we injected P7 animals with the ADNP peptide fragment NAPVSIPQ (NAP) 15 min before ketamine administration and found we could dose-dependently reverse the injury. In separate studies, pretreatment of P6 animals with 20 mg/kg vitamin D(3) or a nontoxic dose of ketamine (5 mg/kg) also prevented ketamine-induced apoptosis at P7. In contrast, pretreatment of P7 animals with aspirin (30 mg/kg) 15 min before ketamine administration actually increased AC3 counts in some regions. These data show that a number of unique approaches can be taken to address anesthesia-induced neurotoxicity in the infant brain, thus providing MDs with a variety of alternative strategies that enhance therapeutic flexibility.

Desensitization protocol using bortezomib for highly sensitized patients awaiting heart or lung transplants.

The use of bortezomib in combination with other desensitization therapies like plasmapheresis, IVIG, and rituximab has allowed the decrease of antibody levels during treatment in some patients. However, all patients described here have experienced rebound effects to the same or higher levels than the ones before therapy was started. Unfortunately, no donors became available to some of these patients when their antibodies were at lower levels. Three out of the four patients presented had adverse reactions to bortezomib which include nausea, vomiting, diarrhea, myalgias and severe neuropathy. In one patient (pre-heart transplant patient #1) we noticed that some clones were selectively more susceptible to the treatment with bortezomib than others. We will continue antibody monitoring in this patient and hopefully the possibility is there, even though the overall PRA is not reduced, that certain clones will be affected and no longer produced antibody allowing these patients a wider selection of acceptable donors.

Insulin and interleukin-4 induce desensitization to the mitogenic effects of insulin-like growth factor-I. Pivotal role for insulin receptor substrate-2.

Insulin-induced desensitization to insulin-like growth factor-I (IGF-I) stimulated mitogenesis in bovine fibroblasts involves steps distal to IGF-I binding to its tyrosine kinase receptor. When quiescent cultures of bovine fibroblasts were stimulated with 10 nM IGF-I and total cell lysates immunoblotted with anti-phosphotyrosine antibody, we observed a band at approximately 97 kDa, representing the beta-subunit of the IGF-I receptor, and a predominant tyrosyl-phosphorylated species migrating as a broad band between 170 and 190 kDa. The majority of proteins in this latter band were immunoprecipitated by antibodies against insulin receptor substrate (IRS)-2 and not by antibodies against IRS-1. Pretreatment of bovine fibroblasts with 10 nM insulin for 48 h blocked subsequent IGF-I-stimulated DNA synthesis and the IGF-I-induced increase in tyrosyl-phosphorylated IRS-2. Insulin pretreatment did not alter IRS-1 or IRS-2 expression by these cells, as assessed by metabolic labeling and direct immunoblotting with IRS antibodies. The interleukin-4 (IL-4) cytokine receptor also has IRS-2 as its major substrate for tyrosine phosphorylation. Although 10 nM IL-4 was as effective as 10 nM IGF-I in stimulating IRS-2 phosphorylation, 10 nM IL-4 did not have comparable mitogenic power in these cells. Nonetheless, pretreatment of bovine fibroblasts with IL-4 inhibited IGF-I-stimulated DNA synthesis by 50-60%, concomitant with a decrease in IGF-I-induced IRS-2 phosphorylation. Insulin-induced desensitization could be prevented if a specific inhibitor of phosphatidylinositol 3-kinase (LY294002), but not an inhibitor of mitogen-activated protein kinase (PD98059), was present during the preincubation period. LY294002 also prevented the shift in IRS-2 molecular mass in response to prolonged incubation of cells with insulin. These data indicate that, in a nontransformed cell system, IRS-2 plays a key role in cellular desensitization to IGF-I-stimulated mitogenesis most likely through a feedback mechanism in the phosphatidylinositol 3-kinase pathway. Furthermore, they suggest that signaling through IRS-2 may provide an important point of integration for hormone, growth factor, and cytokine receptor systems that regulate critical cellular growth responses.

Determination of shelf life of concentrated yogurt (labneh) produced by in-bag straining of set yogurt using hazard analysis.

Strained yogurt, labneh, produced by straining cow's milk set yogurt in cloth bags, was stored at 5, 15, and 25 degrees C, and changes in microbial counts, pH, titratable acidity, percentage of free whey, and sensory attributes were monitored during storage. Counts of total aerobes, psychrotrophic yeasts, yeasts and molds, and lactic acid bacteria, except in samples stored at 25 degrees C, increased irrespective of storage temperature. The pH of samples decreased, titratable acidity and percentage of free whey increased, and texture defects were detected at a later stage than flavor changes during storage. Shelf-life data of labneh was adequately described by the Weibull distribution. The nominal shelf life determined using sensory changes and yeast counts as failure criteria ranged from 8.5 to 10.5, 4.7 to 5.8 and 2.3 to 2.7 d at 5, 15 and 25 degrees C, respectively. Q10 (shelf life at T degrees C/shelf life at T+10 degrees C) for flavor quality loss was 1.98 at 5 degrees C, and the corresponding activation energy was 11.3 kcal/mol.