Eliminating the breast cancer surgery paradigm after neoadjuvant systemic therapy: current evidence and future challenges.

In patients with operable early breast cancer, neoadjuvant systemic treatment (NST) is a standard approach. Indications have expanded from downstaging of locally advanced breast cancer to facilitate breast conservation, to in vivo drug-sensitivity testing. The pattern of response to NST is used to tailor systemic and locoregional treatment, that is, to escalate treatment in nonresponders and de-escalate treatment in responders. Here we discuss four questions that guide our current thinking about 'response-adjusted' surgery of the breast after NST. (i) What critical diagnostic outcome measures should be used when analyzing diagnostic tools to identify patients with pathologic complete response (pCR) after NST? (ii) How can we assess response with the least morbidity and best accuracy possible? (iii) What oncological consequences may ensue if we rely on a nonsurgical-generated diagnosis of, for example, minimally invasive biopsy proven pCR, knowing that we may miss minimal residual disease in some cases? (iv) How should we design clinical trials on de-escalation of surgical treatment after NST?

Baseline factors predicting a response to neoadjuvant chemotherapy with implications for non-surgical management of triple-negative breast cancer.

BACKGROUND: Patients with triple-negative breast cancer (TNBC) and a pathological complete response (pCR) after neoadjuvant chemotherapy may be suitable for non-surgical management. The goal of this study was to identify baseline clinicopathological variables that are associated with residual disease, and to evaluate the effect of neoadjuvant chemotherapy on both the invasive and ductal carcinoma in situ (DCIS) components in TNBC. METHODS: Patients with TNBC treated with neoadjuvant chemotherapy followed by surgical resection were identified. Patients with a pCR were compared with those who had residual disease in the breast and/or lymph nodes. Clinicopathological variables were analysed to determine their association with residual disease. RESULTS: Of the 328 patients, 36·9 per cent had no residual disease and 9·1 per cent had residual DCIS only. Patients with residual disease were more likely to have malignant microcalcifications (P = 0·023) and DCIS on the initial core needle biopsy (CNB) (P = 0·030). Variables independently associated with residual disease included: DCIS on CNB (odds ratio (OR) 2·46; P = 0·022), T2 disease (OR 2·40; P = 0·029), N1 status (OR 2·03; P = 0·030) and low Ki-67 (OR 2·41; P = 0·083). Imaging after neoadjuvant chemotherapy had an accuracy of 71·7 (95 per cent c.i. 66·3 to 76·6) per cent and a negative predictive value of 76·9 (60·7 to 88·9) per cent for identifying residual disease in the breast and lymph nodes. Neoadjuvant chemotherapy did not eradicate the DCIS component in 55 per cent of patients. CONCLUSION: The presence of microcalcifications on imaging and DCIS on initial CNB are associated with residual disease after neoadjuvant chemotherapy in TNBC. These variables can aid in identifying patients with TNBC suitable for inclusion in trials evaluating non-surgical management after neoadjuvant chemotherapy.

[Parameters influencing the preclinical application of cervical collars]. / Einflussfaktoren auf die präklinische Anlage einer Zervikalstütze.

BACKGROUND: The application of cervical collars is a standard procedure in emergency care of trauma patients. It is often observed that the application of cervical collars is performed incorrectly, which may lead to reduced immobilization of the cervical spine. OBJECTIVES: The objective of this study was to analyze the practical skills of professional emergency care providers concerning the application of cervical collars. MATERIALS AND METHODS: Emergency care professionals (n = 104) were asked to apply a cervical collar to a training doll. Each performance step was assessed separately. Furthermore, personal and occupational data of all study participants were collected using a questionnaire. RESULTS: The study participants included professional rescue personnel and emergency physicians. The average occupational experience of all study participants in out-of-hospital emergency care was 11.1 ± 8.9 years. Most participants had already received training on trauma care (61 %) and felt "very confident" in handling a cervical collar (84 %). The application of the cervical collar was performed correctly in 11 % of the performances. The most common error was incorrect size adjustment of the cervical collar (66 %). No association was found between the correct application of the cervical collar and possible parameters of influence, such as working experience in emergency care or participation in trauma courses. CONCLUSIONS: Despite pronounced subjective confidence regarding the application of cervical collars, this study shows that there are general deficits in the practical skills of applying cervical collars. Therefore, a critical assessment of the current training contents on the subject of trauma care must be demanded.

Can Routine Imaging After Neoadjuvant Chemotherapy in Breast Cancer Predict Pathologic Complete Response?

BACKGROUND: This study evaluated breast imaging procedures for predicting pathologic complete response (pCR = ypT0) after neoadjuvant chemotherapy (NACT) for breast cancer to challenge surgery as a diagnostic procedure after NACT. METHODS: This retrospective, exploratory, monocenter study included 150 invasive breast cancers treated by NACT. The patients received magnetic resonance imaging (MRI), mammography (MGR), and ultrasound (US). The results were classified in three response subgroups according to response evaluation criteria in solid tumors. To incorporate specific features of MRI and MGR, an additional category [clinical near complete response (near-cCR)] was defined. Residual cancer in imaging and pathology was defined as a positive result. Negative predictive values (NPVs), false-negative rates (FNRs), and false-positive rates (FPRs) of all imaging procedures were analyzed for the whole cohort and for triple-negative (TN), HER2-positive (HER2+), and HER2-negative/hormone-receptor-positive (HER2-/HR+) cancers, respectively. RESULTS: In 46 cases (31%), pCR (ypT0) was achieved. Clinical complete response (cCR) and near-cCR showed nearly the same NPVs and FNRs. The NPV was highest with 61% for near-cCR in MRI and lowest with 44% for near-cCR in MGR for the whole cohort. The FNRs ranged from 4 to 25% according to different imaging methods. The MRI performance seemed to be superior, especially in TN cancers (NPV 94%; FNR 5%). The lowest FPR was 10 % in MRI, and the highest FPR was 44% in US. CONCLUSION: Neither MRI nor MGR or US can diagnose a pCR (ypT0) with sufficient accuracy to replace pathologic diagnosis of the surgical excision specimen.

Prevalence of renal dysfunction in ischaemic stroke and transient ischaemic attack patients with or without atrial fibrillation.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is associated with a higher risk of stroke and atrial fibrillation (AF). There are limited data on the comorbidity of renal dysfunction and AF in stroke patients. Our aim was to determine the frequency of kidney dysfunction in ischaemic stroke patients with and without AF. METHODS: In a prospectively collected, single center cohort of acute ischaemic stroke and transient ischaemic attack (TIA) patients, glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease equation on admission. Renal function was graded into five categories (cat.): cat. 1, eGRF ≥90 ml/min/1.73 m(2); cat. 2, 60-89; cat. 3, 30-59; cat. 4, 15-29; cat. 5, <15. The diagnosis of AF was based on medical history, a 12-lead electrocardiogram (ECG) and 24-h Holter or continuous ECG monitoring. RESULTS: In total, 2274 patients (1727 stroke, 547 TIA; median age 71.0) were included. Median eGFR was 78.6 ml/min/1.73 m(2) (interquartile range 61/95); 21.1% were in cat. 3, 2.1% in cat. 4, 0.7% in cat. 5. In all, 535 patients (23.5%) suffered from AF; 28.0% of these were in cat. 3, 2.6% and 0.8% in cat. 4 and cat. 5, respectively. In multivariable analysis, age [odds ratio (OR) 1.1], diabetes (OR 1.8), heart failure (OR 1.7) and AF (OR 1.4) were independently associated with kidney dysfunction (eGFR < 60). CONCLUSIONS: Renal dysfunction is far more common in stroke patients than in the general population and more common in AF-related stroke. These findings may have implications for the choice of anticoagulants.

Prevalence of atrial fibrillation and association of previous antithrombotic treatment in patients with cerebral microbleeds.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are associated with an increased risk of intracerebral hemorrhage. The impact of oral anticoagulation (OAC) on CMBs is not well characterized. Our aim was to assess the prevalence of CMBs in stroke and transient ischaemic attack (TIA) patients with atrial fibrillation (AF) and to analyze the implications of previous treatment with OAC. METHODS: In this retrospective analysis on data from a prospectively recruiting stroke registry, patients with ischaemic stroke or TIA with brain magnetic resonance imaging including susceptibility weighted imaging were consecutively enrolled during a 3-year period. For each patient cardiovascular risk factors, AF history and recent diagnosis of AF, present use of OAC and antiplatelets, the National Institute of Health Stroke Scale and the premorbid modified Rankin Scale score were recorded. Two independent raters identified CMBs according to consensus criteria. CMB location was classified as lobar, deep or in the posterior fossa. RESULTS: In all, 785 patients (mean age 63.9 ± 14.2 years) were included. At least one CMB was detected in 186 (23.7%) patients. CMBs were significantly more frequent in patients with AF (30.5% vs. 22.4%). Patients with previous OAC treatment were more likely to have CMBs (36.7% vs. 22.8%, P = 0.03) and abundant CMBs (n > 10) were more frequent in anticoagulated patients even after adjustment for age. However, age was the only independent factor predicting CMBs (P = 0.001). CONCLUSIONS: Cerebral microbleeds are common in elderly AF patients with acute ischaemic stroke. Previous OAC is associated with a higher number of CMBs predominantly in the lobar location. Establishing a causal relationship requires prospective longitudinal investigation.

Vertically transmitted symbiont reduces host fitness along temperature gradient.

Parasites with exclusive vertical transmission from host parent to offspring are an evolutionary puzzle. With parasite fitness entirely linked to host reproduction, any fitness cost for infected hosts risks their selective elimination. Environmental conditions likely influence parasite impact and thereby the success of purely vertical transmission strategies. We tested for temperature-dependent virulence of Caedibacter taeniospiralis, a vertically transmitted bacterial symbiont of the protozoan Paramecium tetraurelia. We compared growth of infected and cured host populations at five temperatures (16­32 °C). Infection reduced host density at all temperatures, with a peak of −30% at 28 °C. These patterns were largely consistent across five infected Paramecium strains. Similar to Wolbachia symbionts, C. taeniospiralis may compensate fitness costs by conferring to the host a 'killer trait', targeting uninfected competitors. Considerable loss of infection at 32 °C suggests that killer efficacy is not universal and that limited heat tolerance restricts the conditions for persistence of C. taeniospiralis.

Feasibility of the Montreal Cognitive Assessment in acute stroke patients.

BACKGROUND AND PURPOSE: Cognitive deficits are common following stroke. Cognitive function in the acute stroke setting is a predictive factor for mid-term outcome. The Montreal Cognitive Assessment (MoCA) is a screening tool for cognitive impairment. The feasibility of MoCA in the acute phase of stroke was evaluated and factors predictive of cognitive impairment were determined. METHODS: In this prospective, single-centre, explorative and observational study consecutive patients with ischaemic (IS) or haemorrhagic (ICH) stroke were enrolled between March 2011 and September 2012. The routine work-up for each patient encompassed assessment of cardiovascular risk factors, the National Institutes of Health Stroke Scale (NIHSS) and the pre-morbid modified Rankin Scale (mRS) score. Cognitive performance was measured using the German version of the MoCA within the first days of admission. A MoCA score of <26 was considered to indicate cognitive impairment. RESULTS: Between March 2011 and September 2012 a total of 842 patients with IS (89.0%) and ICH (11.0%) were enrolled in our study. MoCA was feasible in 678/842 patients (80.5%). Factors independently associated with non-feasibility were stroke severity (NIHSS), pre-morbid functional status (mRS), age and lower educational level. Mean MoCA was 21.4 (SD 5.7). A total of 498/678 (73.5%) patients appeared cognitively impaired (<26/30). Independent predictive factors for a lower MoCA score were age, educational level, stroke severity (NIHSS) and pre-morbid functional status (mRS). CONCLUSIONS: In the acute phase of stroke, MoCA is feasible in about 80% of eligible patients. At this stage, MoCA identifies a cognitive impairment in 75% of patients.

Small interfering RNA treatment can inhibit Cyprinid herpesvirus 3 associated cell death in vitro.

A Cyprinid herpesvirus 3 infection of carp induces a disease which causes substantial losses in carp culture. Here we present the use of a possible strategy for the management of the virus infection RNA interference based on small interfering RNAs. As a result of in vitro studies, we found that a mixture of short interfering RNAs specific for viral DNA enzyme synthesis and capsid proteins of the CyHV-3 can be a potential inhibitor of virus replication in fibroblastic cells. This gives the basis for the development of a combinatorial RNA interference strategy to treat CyHV-3 infections.

Planning and evaluating clinical trials with composite time-to-first-event endpoints in a competing risk framework.

Composite endpoints combine several events of interest within a single variable. These are often time-to-first-event data, which are analyzed via survival analysis techniques. To demonstrate the significance of an overall clinical benefit, it is sufficient to assess the test problem formulated for the composite. However, the effect observed for the composite does not necessarily reflect the effects for the components. Therefore, it would be desirable that the sample size for clinical trials using composite endpoints provides enough power not only to detect a clinically relevant superiority for the composite but also to address the components in an adequate way. The single components of a composite endpoint assessed as time-to-first-event define competing risks. We consider multiple test problems based on the cause-specific hazards of competing events to address the problem of analyzing both a composite endpoint and its components. Thereby, we use sequentially rejective test procedures to reduce the power loss to a minimum. We show how to calculate the sample size for the given multiple test problem by using a simply applicable simulation tool in SAS. Our ideas are illustrated by two clinical study examples.

A radiation hybrid map of the zebrafish genome.

Recent large-scale mutagenesis screens have made the zebrafish the first vertebrate organism to allow a forward genetic approach to the discovery of developmental control genes. Mutations can be cloned positionally, or placed on a simple sequence length polymorphism (SSLP) map to match them with mapped candidate genes and expressed sequence tags (ESTs). To facilitate the mapping of candidate genes and to increase the density of markers available for positional cloning, we have created a radiation hybrid (RH) map of the zebrafish genome. This technique is based on somatic cell hybrid lines produced by fusion of lethally irradiated cells of the species of interest with a rodent cell line. Random fragments of the donor chromosomes are integrated into recipient chromosomes or retained as separate minichromosomes. The radiation-induced breakpoints can be used for mapping in a manner analogous to genetic mapping, but at higher resolution and without a need for polymorphism. Genome-wide maps exist for the human, based on three RH panels of different resolutions, as well as for the dog, rat and mouse. For our map of the zebrafish genome, we used an existing RH panel and 1,451 sequence tagged site (STS) markers, including SSLPs, cloned candidate genes and ESTs. Of these, 1,275 (87.9%) have significant linkage to at least one other marker. The fraction of ESTs with significant linkage, which can be used as an estimate of map coverage, is 81.9%. We found the average marker retention frequency to be 18.4%. One cR3000 is equivalent to 61 kb, resulting in a potential resolution of approximately 350 kb.

Do patients with invasive lobular breast cancer benefit in terms of adequate change in surgical therapy from a supplementary preoperative breast MRI?

BACKGROUND: Breast magnetic resonance imaging (MRI) has been introduced in the preoperative management of invasive lobular breast cancer (ILC). We analysed if MRI leads to adequate changes in surgical management. PATIENTS AND METHODS: We carried out a single-centre retrospective confirmatory analysis of 92 patients with ILC and a preoperative breast MRI. By applying a blinded tumour board method, we analysed if surgical procedures were altered due to breast MRI. In case of alteration, we analysed whether the change was adequate according to the postoperative pathology findings. We considered an adequate rate of change>5% to be a clinically relevant benefit. RESULTS: A change in surgical therapy due to the MRI findings occurred in 23 of 92 patients (25%). According to the postoperative pathology findings, this change was adequate for 20 of these patients (22%; 95% confidence interval [CI] 14%-31%, P<0.0001). An overtreatment occurred for three patients (3%; 95% CI 0%-6%) who underwent a mastectomy following the results of breast MRI. Patients with larger tumours did likely benefit more from preoperative breast MRI. CONCLUSIONS: Patients with ILC might benefit from a preoperative breast MRI. Possible harm from overtreatment should be minimised by diligent use of preoperative histological clarification.

The histone H1 globular region. A possible supersecondary structure from spectroscopic and statistical studies.

The central region of the basic nuclear protein, histone H1, has a highly conserved amino acid sequence and a globular structure which is still not known at atomic resolution. A possible secondary and supersecondary structure was predicted by combining experimental measurements of circular dichroism and NMR spectroscopy with a statistical method based on the amino acid sequence. Our results showed the protein fragment as being highly structured and having a total alpha-helix content of about 40%.

Risk factors for cerebral hypoperfusion, mild cognitive impairment, and dementia.

Putative risk factors accelerating mild cognitive decline and dementia were correlated with repeated measures of cerebral atrophy, CT, densitometry, perfusions, and cognitive testing among neurologically and cognitively normative aging volunteers. A total of 224 normative subjects at increased risk for cognitive decline were admitted to the study. Mean entry age was 59.5 +/- 15.8 years. Mean follow-up is 5.8 +/- 3.3 years. At follow-up, 22 developed mild cognitive impairment (41 CCSE >/= -3), 19 became demented-8 with Vascular type (VAD), 11 with Alzheimer's type (DAT)-and 183 remain cognitively unchanged. Cerebral atrophy, tissue densities, and perfusions were measured by Xe-CT. After age 60, cerebral atrophy, ventricular enlargement, and polio- and leuko-araiosis geometrically increased as perfusions declined. Risk factors accelerating perfusional decline, cerebral atrophy, polio-araiosis, and leuko-araiosis were: transient ischemic attacks (TIAs), hypertension, smoking, hyperlipidemia, and male gender. At age 71.5 +/- 11.9, mild cognitive impairment began accelerated by TIAs, hypertension and heart disease. Leuko-araiosis began before cognitive decline. TIAs, hypertension, and hyperlipidemia correlated with VAD. Excessive cortical perfusional decrease, gray and white matter hypodensities, and cerebral atrophy correlate with cognitive decline.

Properties of Pseudomonas aeruginosa exotoxin A ionic channel incorporated in planar lipid bilayers.

Acidic conditions induce the incorporation of Pseudomonas aeruginosa exotoxin A into phospholipid planar bilayers and the formation of pores permeable to electrolytes. Channel openings occur as single events, although they may occasionally cluster in bursts. In 100 mM KCl, the elementary single channel current amplitude is 3.1 pA (at a transmembrane voltage of 100 mV), the mean open time is 1.3 ms, while bursts may last for several seconds. Noise analysis gave results identical to single channel analysis. Voltage pulse protocols and continuous cycling voltage ramps showed that the toxin channel is voltage dependent, having a higher probability of being open at positive voltages.

Why emergency XeCT-CBF should become routine in acute ischemic stroke before thrombolytic therapy.

Intravenous thrombolytic therapy using recombinant tissue plasminogen activator (rtpa) has been approved for the treatment of acute ischemic stroke in the USA, if treatment is initiated within 3-hours (NINDS tpa Stroke Study Group) but not 6 hours (ECASS II) after time of onset. Favorable outcome in the placebo arm was much higher than expected possibly because patients with TIA's are likely to be included as progressive ischemic stroke subjects when a brief 3-6 hours duration of stroke is defined as the therapeutic window. Yonas' group at the University of Pittsburg demonstrated that adding stable xenon inhalation to routine CT scanning performed during emergency screening of acute stroke, predicted which cases became irreversibly infarcted if thrombolytic therapy was not administered within a few hours of stroke onset, since non-contrasted CT scans are usually normal this early. Adding a few minutes for inhalation of 26% xenon is justified in order to measure LCBF values which predict size, severity and volumes of impending cerebral infarctions and rule out TIA's which have relatively normal CT-CBF values. CT-CBF measures provide positive indications for thrombolytic therapy. This is not possible by MRI and SPECT methods which are not sufficiently quantitative to discern LCBF values persistently below ischemic thresholds of 16 mls/100 gm/min, thereby predicting impending infarction.

XE-CT CBF changes during normative aging, cognitive decline and dementia.

Factors accelerating cerebral degenerative changes represent potentially modifiable risks for cognitive decline. Putative risk factors accelerating mild cognitive decline and dementia were correlated with repeated measures of cerebral atrophy, CT densitometry, perfusions and cognitive testing among neurologically and cognitively normative volunteers. TIAs, hypertension, smoking and male gender accelerate cerebral degenerative changes, mild cognitive decline and dementia. Intervention by control of risk factors and cholinesterase inhibitors should prevent cerebral atropho-degenerative changes so that optimal cognitive performance is maintained.

Cardiovascular and other risk factors for Alzheimer's disease and vascular dementia.

Factors accelerating cerebral degenerative changes represent potentially modifiable risks for cognitive decline. Putative risks accelerating subtle cognitive decline and dementia were correlated with repeated measures of cerebral atrophy, CT densitometry, perfusions, and cognitive testing among 224 neurologically and cognitively normative aging volunteers. After age 60, cerebral atrophy, ventricular enlargement, polioaraiosis, and leukoaraiosis geometrically increased as perfusions declined. Risks accelerating perfusional decline, cerebral atrophy, polioaraiosis, and leukoaraiosis were: transient ischemic attacks (TIAs), hypertension, smoking, hyperlipidemia, male gender. At age 71.5 +/- 11.9, subtle cognitive decline began, accelerated by TIAs, hypertension, and heart disease. Leukoaraiosis began before cognitive decline. TIAs, hypertension, and hyperlipidemia correlated with vascular dementias. Excessive cortical perfusional decreases and cerebral atrophy correlated with cognitive decline. Family history of neurodegenerative disease correlated with Alzheimer's disease. We concluded that TIAs, hypertension, hyperlipidemia, smoking, and male gender accelerate cerebral degenerative changes, cognitive decline, and dementia.

Coexistent thyroid cancer and pregnancy.

OBJECTIVE: A study was performed to determine the appropriate time for the initiation of therapy for thyroid carcinoma first diagnosed during pregnancy. DATA SOURCES: Material on thyroid cancer cases was obtained from the New Mexico Tumor Registry, Albuquerque, a computerized population-based registry for the state of New Mexico, and the Indian reservation facilities in New Mexico and Arizona (a Surveillance, Epidemiology, and End Results Registry funded by the National Cancer Institute, Bethesda, Md) for the period 1970 to 1991. STUDY SELECTION: All cases of thyroid cancer, except medullary and anaplastic, in patients aged 18 to 46 years were evaluated. Subgroups were established for (1) all women who were noted to be pregnant at the time of their initial diagnosis and (2) all women with thyroid cancer in the 18- to 46-year-old age group. DATA EXTRACTION: The information was extracted by a certified tumor registrar for age, sex, thyroid cancer, specific type of thyroid cancer, period, race, year of diagnosis, accession date, last date seen, tumor status, treatment, and patient status. DATA SYNTHESIS: There have been no deaths in the pregnant group with a follow-up ranging from 0.5 to 20 years. There was no statistically significant difference in observed survival rates between the pregnant group and 465 women, aged 18 to 46 years, with comparable thyroid cancers or in the death rates of women aged 18 to 67 years in the general population. CONCLUSIONS: Surgical treatment for patients with well-differentiated thyroid cancer diagnosed during pregnancy can be delayed until after parturition.

Peptides secondary structure prediction with neural networks: a criterion for building appropriate learning sets.

Artificial neural networks have been recently applied with success for protein secondary structure prediction. So far, one of the two main aspects on which neural net performance depends, the topology of the net, has been considered. The present work addresses the other main aspect, the building up of the learning set. We present a criterion to build up suitable learning sets based on the alpha-helix percentage. Starting from a set of several well known proteins, we formed 7 groups of proteins with similar helix percentages and we used them for the learning of the same neural net. We found that the best secondary structure prediction for each of the tested proteins (not belonging to the initial set) was the one obtained using the learning set whose helix percentage was closest to that of the tested protein. The accuracy of correct prediction of our method on three types of secondary structure (alpha-helix, beta-sheet and coil), has been compared with the accuracy of other secondary structure prediction methods.