Breast cancer electron intraoperative radiotherapy: assessment of preoperative selection factors from a retrospective analysis of 758 patients and review of literature.

PURPOSE: To report our experience with full-dose 21 Gy IORT in early breast cancer patients after breast-conserving surgery to define most important selection factors. METHODS: Seven hundred and fifty eight patients, subjected to conserving surgery and IORT, were retrospectively analyzed evaluating most important clinical outcomes. RESULTS: Median follow up was 5.2 years. Results from Cox analyses defined 2 groups of patients, "suitable" (age > 50 years, non lobular histology, tumour size ≤ 2 cm, pN0 or pNmic, ki67 ≤ 20%, non triple negative receptor status and G1-G2) and "unsuitable" for IORT, with a higher rate of breast related events moving from "suitable" to "unsuitable" group. The 5 year rate of IBR is 1.8% in suitable group with significant differences versus unsuitable (1.8 vs. 11.6%, p < 0.005). Same differences between two groups were evidenced in true local relapse (0.6 vs. 6.9%, p < 0.005) and in new ipsilateral BC (1.1 vs. 4.7%, p < 0.015). CONCLUSIONS: In our current practice we consider the following preoperative factors to select patients suitable for IORT: age > 50 years, absence of lobular histology, tumor size ≤ 2 cm, pN0 or pNmic, according to APBI consensus statement, including also ki67 ≤ 20%, non triple negative receptor status and G1-G2.

Momentum-dependent scaling exponents of nodal self-energies measured in strange metal cuprates and modelled using semi-holography.

The anomalous strange metal phase found in high-Tc cuprates does not follow the conventional condensed-matter principles enshrined in the Fermi liquid and presents a great challenge for theory. Highly precise experimental determination of the electronic self-energy can provide a test bed for theoretical models of strange metals, and angle-resolved photoemission can provide this as a function of frequency, momentum, temperature and doping. Here we show that constant energy cuts through the nodal spectral function in (Pb,Bi)2Sr2-xLaxCuO6+δ have a non-Lorentzian lineshape, consistent with a self-energy that is k dependent. This provides a new test for aspiring theories. Here we show that the experimental data are captured remarkably well by a power law with a k-dependent scaling exponent smoothly evolving with doping, a description that emerges naturally from anti-de Sitter/conformal-field-theory based semi-holography. This puts a spotlight on holographic methods for the quantitative modelling of strongly interacting quantum materials like the cuprate strange metals.

Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis.

Cystic fibrosis (CF) is caused by dysfunction of the CF transmembrane conductance regulator (CFTR), an anion channel whose dysfunction leads to chronic bacterial and fungal airway infections via a pathophysiological cascade that is incompletely understood. Airway glands, which produce most airway mucus, do so in response to both acetylcholine (ACh) and vasoactive intestinal peptide (VIP). CF glands fail to secrete mucus in response to VIP, but do so in response to ACh. Because vagal cholinergic pathways still elicit strong gland mucus secretion in CF subjects, it is unclear whether VIP-stimulated, CFTR-dependent gland secretion participates in innate defense. It was recently hypothesized that airway intrinsic neurons, which express abundant VIP and ACh, are normally active and stimulate low-level gland mucus secretion that is a component of innate mucosal defenses. Here we show that low levels of VIP and ACh produced significant mucus secretion in human glands via strong synergistic interactions; synergy was lost in glands of CF patients. VIP/ACh synergy also existed in pig glands, where it was CFTR dependent, mediated by both Cl(-) and HCO(3) (-), and clotrimazole sensitive. Loss of "housekeeping" gland mucus secretion in CF, in combination with demonstrated defects in surface epithelia, may play a role in the vulnerability of CF airways to bacterial infections.

Central aponeurosis tears of the rectus femoris: practical sonographic prognosis.

OBJECTIVE: This study is a statistical analysis to establish whether a correlation exists between the level and degree of rectus femoris (RF) central tendon injury and the amount of time that an athlete is unable to participate subsequently, referred to as "sports participation absence" (SPA). DESIGN: Causal-comparative study. PATIENTS: 35 players from two high-level Spanish soccer teams with an injury to the central tendon of the RF based on clinical and ultrasound criteria. MAIN OUTCOME MEASURE: Ultrasound examination was performed with an 8-2 MHz linear multifrequency transducer. All studies included both longitudinal and transverse RF sections. RESULTS: At the proximal level the SPA time is 45.1 days when the injury length is 4.0 cm. This value increases by 5.3 days with each 1 cm increase in the length of injury. In the case of distal level injury, SPA time is 32.9 days when the injury length is 3.9 cm. This value increases by 3.4 days with each 1 cm increase. In the total representative sample, SPA time when the injury length is 4.2 cm corresponds to 39.1 days. This value increases by 4.2 days per length unit. CONCLUSIONS: RF central tendon injury at the proximal level is associated with a greater SPA time than at the distal level. Patients with a grade II injury have an SPA time longer than those with a grade I injury whether the injury is located proximal or distal.

Mesenchymal stem cells encapsulated into biomimetic hydrogel scaffold gradually release CCL2 chemokine in situ preserving cytoarchitecture and promoting functional recovery in spinal cord injury.

Spinal cord injury (SCI) is an acute neurodegenerative disorder caused by traumatic damage of the spinal cord. The neuropathological evolution of the primary trauma involves multifactorial processes that exacerbate the pathology, worsening the neurodegeneration and limiting neuroregeneration. This complexity suggests that multi-therapeutic approaches, rather than any single treatment, might be more effective. Encouraging preclinical results indicate that stem cell-based treatments may improve the disease outcome due to their multi-therapeutic ability. Mesenchymal Stem Cells (MSCs) are currently considered one of the most promising approaches. Significant improvement in the behavioral outcome after MSC treatment sustained by hydrogel has been demonstrated. However, it is still not known how hydrogel contribute to the delivery of factors secreted from MSCs and what factors are released in situ. Among different mediators secreted by MSCs after seeding into hydrogel, we have found CCL2 chemokine, which could account for the neuroprotective mechanisms of these cells. CCL2 secreted from human MSCs is delivered efficaciously in the lesioned spinal cord acting not only on recruitment of macrophages, but driving also their conversion to an M2 neuroprotective phenotype. Surprisingly, human CCL2 delivered also plays a key role in preventing motor neuron degeneration in vitro and after spinal cord trauma in vivo, with a significant improvement of the motor performance of the rodent SCI models.

Painful peripheral neuropathies.

Peripheral neuropathies are a heterogeneous group of diseases affecting peripheral nerves. The causes are multiple: hereditary, metabolic, infectious, inflammatory, toxic, traumatic. The temporal profile includes acute, subacute and chronic conditions. The majority of peripheral neuropathies cause mainly muscle weakness and sensory loss, positive sensory symptoms and sometimes pain. When pain is present, however, it is usually extremely intense and among the most disabling symptoms for the patients. In addition, the neurological origin of the pain is often missed and patients receive inadequate or delayed specific treatment. Independently of the disease causing the peripheral nerve injury, pain originating from axonal pathology or ganglionopathy privileges neuropathies affecting smaller fibres, a clinical observation that points towards abnormal activity within nociceptive afferents as a main generator of pain. Natural activation of blood vessels or perineurial nociceptive network by pathology also causes intense pain. Pain of this kind, i.e. nerve trunk pain, is among the heralding symptoms of inflammatory or ischemic mononeuropathy and for its intensity represents itself a medical emergency. Neuropathic pain quality rekindles the psychophysical experience of peripheral nerves intraneural microstimulation i.e. a combination of large and small fibres sensation temporally distorted compared to physiological perception evoked by natural stimuli. Pins and needles, burning, cramping mixed with numbness, and tingling are the wording most used by patients. Nociceptive pain instead is most often described as aching, deep and dull. Good command of peripheral nerve anatomy and pathophysiology allows timely recognition of the different pain components and targeted treatment, selected according to intensity, type and temporal profile of the pain.

Inhibition of airway surface fluid absorption by cholinergic stimulation.

In upper airways airway surface liquid (ASL) depth and clearance rates are both increased by fluid secretion. Secretion is opposed by fluid absorption, mainly via the epithelial sodium channel, ENaC. In static systems, increased fluid depth activates ENaC and decreased depth inhibits it, suggesting that secretion indirectly activates ENaC to reduce ASL depth. We propose an alternate mechanism in which cholinergic input, which causes copious airway gland secretion, also inhibits ENaC-mediated absorption. The conjoint action accelerates clearance, and the increased transport of mucus out of the airways restores ASL depth while cleansing the airways. We were intrigued by early reports of cholinergic inhibition of absorption by airways in some species. To reinvestigate this phenomenon, we studied inward short-circuit currents (Isc) in tracheal mucosa from human, sheep, pig, ferret, and rabbit and in two types of cultured cells. Basal Isc was inhibited 20-70% by the ENaC inhibitor, benzamil. Long-lasting inhibition of ENaC-dependent Isc was also produced by basolateral carbachol in all preparations except rabbit and the H441 cell line. Atropine inhibition produced a slow recovery or prevented inhibition if added before carbachol. The mechanism for inhibition was not determined and is most likely multi-factorial. However, its physiological significance is expected to be increased mucus clearance rates in cholinergically stimulated airways.

Increased blood concentrations of interleukin-12 are associated with a longer survival in untreatable metastatic solid tumor patients: preliminary observations.

IL-2 and IL-12 are the main antitumor cytokines in humans. Endogenous IL-2 production is generally low in metastatic cancer patients. In contrast, preliminary data suggest a possible increased secretion of IL-12 in a subgroup of metastatic cancer patients, of which the prognostic significance is still to be established. This preliminary study was performed to investigate the survival time in relation to IL-12 blood levels in patients with untreatable metastatic solid tumors. The study included 40 patients (lung cancer: 16; gastrointestinal tumors: 24). Abnormally elevated serum levels of IL-12 were observed in 15/40 (37%) patients, without any apparent relation with tumor histotype. The 1-year survival rate was significantly higher in patients with elevated IL-12 baseline values than in those with normal concentrations (8/15 vs 3/25, p < 0.01). The results of this preliminary study, which need to be confirmed in a greater number of patients by monitoring the clinical course of the neoplastic disease, seem to suggest that abnormally high baseline serum levels of the antitumor cytokine IL-12 may have a favorable prognostic significance, as they appear to be associated with a longer survival time.

Physiopathology of IL-12 in human solid neoplasms: blood levels of IL-12 in early or advanced cancer patients, and their variations with surgery and immunotherapy.

Experimental studies have shown that IL-12 plays an important role in the activation of the anticancer immune defenses. Unfortunately, at present the behavior of IL-12 secretion in human neoplasms remain to be established. In an attempt to draw some preliminary data about IL-12 secretion in human cancer, in the present study we have evaluated serum levels of IL-12 in a group of non-metastatic and metastatic solid tumor patients in relation to the survival time, and their changes in surgically treated cancer patients and in metastatic patients undergoing immunotherapy with IL-2. Mean serum levels of IL-12 were significantly higher metastatic patients (n = 40) than in those with locally limited solid neoplasm (n = 16). Moreover, within the metastatic group, the percent of 1-year survival was significantly higher in patients with abnormally elevated blood concentrations of IL-12 than in those with normal values. In the group of 10 patients surgically treated for gastrointestinal tract tumors, the surgical operation induced a significant decline in IL-12 mean serum levels. Finally, in a group of 23 metastatic renal cell cancer patients treated with IL-12 immunotherapy (6 million IU/day S.C. for 6 days/week for 4 weeks), the treatment was associated with a significant and progressive increase in IL-12 mean values. Moreover, serum mean levels of IL-12 observed in therapy in patients with response or stable disease were significantly higher than those found in progressing patients. This preliminary study seems to suggest that the evidence of high levels of IL-12 may have a favourable prognostic significance in solid tumor patients, either in baseline conditions or in response to IL-2 cancer immunotherapy.

[The endoscopic treatment of postcholecystectomy biliary leakage]. / Tratamiento endoscópico de la fuga biliar poscolecistectomía.

Although there is a decrease in the total number of complications observed on performance of laparoscopy cholecystectomy (LC) there does appear to be an increase in biliary tract lesions. Seven cases of postcholecystectomy biliary leakage treated with endoscopic methods are presented. These cases include 4 patients with leakage from the cystic canal stump and 3 with leakage from the common bile duct. In 5 cases the biliary tract lesion occurred following LC, 1 after conventional cholecystectomy and in 1 reconverted LP. CPRE identified the site of the leakage in the 7 patients and in 2 residual choledocholithiasis. In 5 cases treatment consisted in endoscopic papillotomy and placement of biliary endoprosthesis while only papillotomy was performed in 2 patients. In one of these cases CPRE was repeated and the sphincterotomy widened due to persistence of the leakage at 5 days, with the same finally closing at 15 days of the second CPRE. Closure of the biliary leakage was obtained in the other 6 cases in less than 72 hours post-CPRE. No complications secondary to the technique were observed. It was concluded that CPRE together with endoscopic papillotomy and placement of biliary prostheses is an effective and safe treatment for postcholecystectomy biliary leakages of the common bile duct or cystic duct.

[Variations in interleukin-2 and interleukin-6 due to surgical trauma in cancer patients]. / Variazioni di interleuchina-2 e interleuchina-6 da trauma chirurgico in pazienti oncologici.

Inflammatory response after surgical trauma, which is necessary for infection control and tissue repairing, can actually produce some cytokines suppressive of the antitumoral immunity response. In this study the authors evaluate pre- and post-operative IL-2 (antitumor response activator) and IL-6 (lymphocytic response inhibitor and tumor growth factor) levels in 26 cancer patients undergoing resective surgery. Analysis of the results showed a significative IL-6 increase and a tendency to IL-2 decrease in the post-operative period. It is thus confirmed, even on the basis of the cytokines, the meaningful immunosuppressive effect of the surgical trauma on neoplastic growth control.

Measurement of fluid secretion from intact airway submucosal glands.

Human airways are kept sterile by a mucosal innate defense system that includes mucus secretion. Mucus is secreted in healthy upper airways primarily by submucosal glands and consists of defense molecules mixed with mucins, electrolytes, and water and is also a major component of sputum. Mucus traps pathogens and mechanically removes them via mucociliary clearance while inhibiting their growth via molecular (e.g., lysozyme) and cellular (e.g., neutrophils, macrophages) defenses. Fluid secretion rates of single glands in response to various mediators can be measured by trapping the primary gland mucus secretions in an oil layer, where they form spherical bubbles that can be optically measured at any desired interval to provide detailed temporal analysis of secretion rates. The composition and properties of the mucus (e.g., solids, viscosity, pH) can also be determined. These methods have now been applied to mice, ferrets, cats, pigs, sheep, and humans, with a main goal of comparing gland secretion in control and CFTR-deficient humans and animals.

Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process.

Chronic bacterial airway infections are the major cause of mortality in cystic fibrosis (CF). Normal airway defenses include reflex stimulation of submucosal gland mucus secretion by sensory neurons that release substance P (SubP). CFTR is an anion channel involved in fluid secretion and mutated in CF; the role of CFTR in secretions stimulated by SubP is unknown. We used optical methods to measure SubP-mediated secretion from human submucosal glands in lung transplant tissue. Glands from control but not CF subjects responded to mucosal chili oil. Similarly, serosal SubP stimulated secretion in more than 60% of control glands but only 4% of CF glands. Secretion triggered by SubP was synergistic with vasoactive intestinal peptide and/or forskolin but not with carbachol; synergy was absent in CF glands. Pig glands demonstrated a nearly 10-fold greater response to SubP. In 10 of 11 control glands isolated by fine dissection, SubP caused cell volume loss, lumen expansion, and mucus flow, but in 3 of 4 CF glands, it induced lumen narrowing. Thus, in CF, the reduced ability of mucosal irritants to stimulate airway gland secretion via SubP may be another factor that predisposes the airways to infections.

Acinar origin of CFTR-dependent airway submucosal gland fluid secretion.

Cystic fibrosis (CF) airway disease arises from defective innate defenses, especially defective mucus clearance of microorganisms. Airway submucosal glands secrete most airway mucus, and CF airway glands do not secrete in response to VIP or forskolin. CFTR, the protein that is defective in CF, is expressed in glands, but immunocytochemistry finds the highest expression of CFTR in either the ciliated ducts or in the acini, depending on the antibodies used. CFTR is absolutely required for forskolin-mediated gland secretion; we used this finding to localize the origin of forskolin-stimulated, CFTR-dependent gland fluid secretion. We tested the hypothesis that secretion to forskolin might originate from the gland duct rather than or in addition to the acini. We ligated gland ducts at various points, stimulated the glands with forskolin, and monitored the regions of the glands that swelled. The results supported an acinar rather than ductal origin of secretion. We tracked particles in the mucus using Nomarski time-lapse imaging; particles originated in the acini and traveled toward the duct orifice. Estimated bulk flow accelerated in the acini and mucus tubules, consistent with fluid secretion in those regions, but was constant in the unbranched duct, consistent with a lack of fluid secretion or absorption by the ductal epithelium. We conclude that CFTR-dependent gland fluid secretion originates in the serous acini. The failure to observe either secretion or absorption from the CFTR and epithelial Na(+) channel (ENaC)-rich ciliated ducts is unexplained, but may indicate that this epithelium alters the composition rather than the volume of gland mucus.

Stories from doctors of patients with pain. A qualitative research on the physicians' perspective.

GOAL OF WORK: The aim of this study was to explore the physicians' internal representation of the doctor-patient relationship in the dramatic field of the patient with pain. METHODS: Using an open narrative format, 151 physicians were asked to "Tell us about an episode during your professional experience in which you found yourself in difficulty whilst confronting a patient who was in pain". The narrations were examined in accordance with a clinical-interpretive method. MAIN RESULTS: Three "perspectives of observation" were identified, namely: the biological perspective, the professional perspective, and the personal perspective. The biological perspective is about the biological model and the "depersonalization" of pain. In the professional perspective, the narrative concerns the patient as a "person" and the reattribution of the pain to the suffering person. The personal perspective is about the emotional-relational explosion within the meeting between the doctor as human being and the patient as human being. Most of the narrations did not strictly connect to one or another of the perspectives, but each story seemed a journey without peace back and forth among the perspectives. CONCLUSIONS: The professional perspective seemed to be the only place in which physicians could "stop", a space not extreme in which they seemed to express the need for education about the management of the professional relationship with the other person.

Staphylococcus lugdunensis infective endocarditis: description of 10 cases and analysis of native valve, prosthetic valve, and pacemaker lead endocarditis clinical profiles.

OBJECTIVE: To evaluate the incidence and the clinical and echocardiographic features of infective endocarditis (IE) caused by Staphylococcus lugdunensis and to identify the prognostic factors of surgery and mortality in this disease. DESIGN: Prospective cohort study. SETTING: Study at two centres (a tertiary care centre and a community hospital). PATIENTS: 10 patients with IE caused by S lugdunensis in 912 consecutive patients with IE between 1990 and 2003. METHODS: Prospective study of consecutive patients carried out by the multidisciplinary team for diagnosis and treatment of IE from the study institutions. English, French, and Spanish literature was searched by computer under the terms "endocarditis" and "Staphylococcus lugdunensis" published between 1989 and December 2003. MAIN OUTCOME MEASURES: Patient characteristics, echocardiographic findings, required surgery, and prognostic factors of mortality in left sided cases of IE. RESULTS: 10 cases of IE caused by S lugdunensis were identified at our institutions, representing 0.8% (four of 467), 1.5% (two of 135), and 7.8% (four of 51) of cases of native valve, prosthetic valve, and pacemaker lead endocarditis in the non-drug misusers. Native valve IE was present in four patients (two aortic, one mitral, and one pulmonary), prosthetic valve aortic IE in two patients, and pacemaker lead IE in the other four patients. All patients with left sided IE had serious complications (heart failure, periannular abscess formation, or shock) requiring surgery in 60% (three of five patients) of cases with an overall mortality rate of 80% (four of five patients). All patients with pacemaker IE underwent combined medical treatment and surgery, and mortality was 25% (one patient). In total 59 cases of IE caused by S lugdunensis were identified in a review of the literature. The combined analysis of these 69 cases showed that native valve IE (53 patients, 77%) is characterised by mitral valve involvement and frequent complications such as heart failure, abscess formation, and embolism. Surgery was needed in 51% of cases and mortality was 42%. Prosthetic valve endocarditis (nine of 60, 13%) predominated in the aortic position and was associated with abscess formation, required surgery, and high mortality (78%). Pacemaker lead IE (seven of 69, 10%) is associated with a better prognosis when antibiotic treatment is combined with surgery. CONCLUSIONS: S lugdunensis IE is an uncommon cause of IE, involving mainly native left sided valves, and it is characterised by an aggressive clinical course. Mortality in left sided native valve IE is high but the prognosis has improved in recent years. Surgery has improved survival in left sided IE and, therefore, early surgery should always be considered. Prosthetic valve S lugdunensis IE carries an ominous prognosis.

Treatment of cerebral Aspergillosis with itraconazole: do high doses improve the prognosis?

We describe a 72-year-old woman with chronic asthma who presented with cerebral abscesses due to Aspergillus fumigatus after she received treatment with corticosteroids. Therapy with high-dose itraconazole (800 mg/d for 5 months, followed by 400 mg/d for an additional 4.5 months) resulted in complete resolution of all lesions. Serum concentrations of the drug ranged from 2 micrograms/mL to 30 micrograms/mL. Review of 20 cases of cerebral aspergillosis that were treated with itraconazole revealed that three of the four patients who received high doses (800 mg/d in the adults) of the drug responded favorably, while only two of the 16 patients who received a dose of 400 mg/d were cured. The use of high-dose itraconazole appears to be justified for high-risk patients with cerebral aspergillosis for whom conventional therapy has failed.

[Cerebral SPECT with thallium-201 in the differential diagnosis of focal cerebral lesions in patients with AIDS]. / SPECT cerebral con talio-201 en el diagnóstico diferencial de lesiones cerebrales focales en pacientes con SIDA.

BACKGROUND: The aim of this study was to analyze the usefulness of cerebral SPECT with thallium-201 in patients with the acquired human immunodeficiency syndrome (AIDS) and focal cerebral lesions. METHODS: Six patients with AIDS and focal cerebral lesions in whom a cerebral SPECT was performed with thallium-201 are described. Treatment was initiated with antiToxoplasma drugs in all patients. The clinical response, serology for positive toxoplasma and radiologic improvement were criteria for the diagnosis of encephalitis by Toxoplasma. In the remaining cases, cerebral biopsy and/or necropsy study were carried out. RESULTS: In the 2 patients in whom cerebral SPECT demonstrated enhancement of the lesion, the pathologic diagnosis was cerebral lymphoma. Of the 4 remaining cases in whom no enhancement was observed, three corresponded to cerebral toxoplasmosis and one to progressive multifocal leucoencephalopathy. CONCLUSIONS: Cerebral SPECT with thallium-201 is a simple, specific and useful technique for the differentiation of primary cerebral lymphoma from the remaining inflammatory cerebral lesions which may be present in AIDS patients.