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.

Causes and place of death in Italian patients with amyotrophic lateral sclerosis.

OBJECTIVES: To determine the causes and place of death in a cohort of Italian patients with amyotrophic lateral sclerosis (ALS). A better understanding of the likely causes of death in ALS might improve the palliative care at the end-of-life, whereas knowing the place of death will help to verify the need for highly specialized care services, e.g. hospice and nursing home. PATIENTS AND METHODS: Between 2000 and 2008, 182 ALS patients (onset: spinal, 127; bulbar, 55; M/F: 1.6) were followed in a single ALS Tertiary Centre in Palermo, Sicily, Italy until death. Medical data for each individual patient were recorded in a large database throughout the disease course. Information concerning causes and place of death were obtained by consultation with relatives or the family physician. RESULTS: Respiratory failure (terminal respiratory insufficiency, pneumonia) was the most frequent cause of death (81.3%), which included six cases (3.3%) who requested a terminal sedation. Sudden death and death during sleep accounted for by 6.0% and 6.6% of all deaths, respectively. Heart-related causes of death were relatively infrequent in our cohort, accounting for by 7.1% of all deaths (i.e. sudden death: 6.0% and myocardial infarct: 1.1%). Patients (85.2%) died at home. CONCLUSIONS: The leading cause of death in ALS remains the respiratory failure, followed by the sudden death and death during sleep. Most patients in our cohort died at home, a choice that might be only partially driven by cultural factors. These findings might have a great impact on the development of the advanced and end-of-life palliative care and in the planning of specialized care services, as hospice and nursing home.

Subduction hides high-pressure sources of energy that may feed the deep subsurface biosphere.

Geological sources of H2 and abiotic CH4 have had a critical role in the evolution of our planet and the development of life and sustainability of the deep subsurface biosphere. Yet the origins of these sources are largely unconstrained. Hydration of mantle rocks, or serpentinization, is widely recognized to produce H2 and favour the abiotic genesis of CH4 in shallow settings. However, deeper sources of H2 and abiotic CH4 are missing from current models, which mainly invoke more oxidized fluids at convergent margins. Here we combine data from exhumed subduction zone high-pressure rocks and thermodynamic modelling to show that deep serpentinization (40-80 km) generates significant amounts of H2 and abiotic CH4, as well as H2S and NH3. Our results suggest that subduction, worldwide, hosts large sources of deep H2 and abiotic CH4, potentially providing energy to the overlying subsurface biosphere in the forearc regions of convergent margins.

Lung cancer management: monitoring and treating resistance development in third-generation EGFR TKIs.

INTRODUCTION: Patients treated with third-generation EGFR TKIs will develop resistance to treatment at a certain point. Early detection of resistance occurrence could allow more options for treatment. AREAS COVERED: We discuss the development of third-generation EGFR TKIs, focusing on osimertinib and discuss the most common resistance mechanisms under evaluation. We also debate how this resistance can be detected; particularly we review the possible application of liquid biopsy in this scenario. Lastly we discuss available treatment options when resistance occurs, with an eye on ongoing trials and possible future developments. EXPERT OPINION: As resistance will ultimately develop, a strict instrumental follow-up as per international guidelines is required with the aim of detecting this resistance in an early phase. Detecting an oligoprogression could allow the integration of local ablative therapies while further delaying the need for a systemic therapy change. By exploiting the increasing potentiality of liquid biopsy, in the near future, physicians could be able to understand why a patient develops resistance and therefore can choose the best possible individualized treatment option.

Cerebrospinal fluid tau protein is not a biological marker in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to progressive motor neuron cell death. Etiopathogenesis is still imperfectly known and much effort have been undertaken to find a biological marker that could help in the early diagnosis and in the monitoring of disease progression. Cerebrospinal fluid (CSF) concentrations of tau, an axonal microtubule-associated protein, have been measured in ALS with levels found increased in some studies and unchanged in others. METHODS: Total CSF tau level was assayed in a population of ALS patients (n = 57) and controls (n = 110) using a specific ELISA method. RESULTS: No significant differences in the median CSF tau levels between ALS cases and controls were found [ALS: 126 pg/ml (78-222); controls: 112 pg/ml (71-188), P = ns]. In the ALS group, the bulbar-onset patients showed increased CSF tau levels as compared with the spinal-onset cases. These differences might be related to the higher age of the bulbar-onset patients. Further, no correlations were found between CSF tau concentrations and the rate of progression of the disease. CONCLUSIONS: These results do not support the hypothesis that total CSF tau protein is a reliable biological marker for ALS.

[Extra-auditory effects of noise]. / Effetti extrauditivi del rumore.

In the last thirty years, several studies have demonstrated a correlation between exposure to noise and the development of alterations and/or pathologies in organs and apparatus, apart from the auditory one. Exposure to noise can induce biochemical, physiological, or psychosocial modifications that can remain either inside the range of biological normality or alter and compromise the psychophysical well-being of the individual depending on the extent of the functional alterations of organic systems and psychosocial functions; both the reversibility and duration of the alterations and the adaptation could be related to the recovery capabilitiy of the human organism and to the environmental condition. Among the factors that can influence the effects of noise we can find: intrinsic characteristics of the physical insult (pressure, sound intensity, emission frequency), extrinsic characteristics (duration of the exposure, way of emission, presence of impulsive components, masking effects), spectral characteristics (infrasounds, ultrasounds, time of recovery) genetic factors (susceptibility) and acquired factors of the human organism (acoustic isolation of the living houses and the social necessity for the industrial activities that generate noise). Other factors that influence the damage are the surprise effect, the semantic content and the identification of the noise source. It can be hypothesized that the extra-auditory effects of noise show themselves through a series of nervous circuits that use the autonomic nervous system and interfere on neuro-immune-endocrine parameters. The organs which are more studied are: cardiovascular, gastro-enteric and endocrine systems, nervous system and psychological effects, respiratory system, fetus and effects on reproductive system, immune system and genetic material.

Subducting serpentinites release reduced, not oxidized, aqueous fluids.

The observation that primitive arc magmas are more oxidized than mid-ocean-ridge basalts has led to the paradigm that slab-derived fluids carry SO2 and CO2 that metasomatize and oxidize the sub-arc mantle wedge. We combine petrography and thermodynamic modelling to quantify the oxygen fugacity (fO2) and speciation of the fluids generated by serpentinite dehydration during subduction. Silicate-magnetite assemblages maintain fO2 conditions similar to the quartz-fayalite-magnetite (QFM) buffer at fore-arc conditions. Sulphides are stable under such conditions and aqueous fluids contain minor S. At sub-arc depth, dehydration occurs under more reducing conditions producing aqueous fluids carrying H2S. This finding brings into question current models in which serpentinite-derived fluids are the cause of oxidized arc magmatism and has major implications for the global volatile cycle, as well as for redox processes controlling subduction zone geodynamics.

Telephone follow-up for patients with amyotrophic lateral sclerosis.

The relentless evolution of amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disorder of the upper and lower motoneurons, leads to an increasing level of disability. Most patients, during the course of the disease, become unable to attend the tertiary clinical care center and are thus prevented from enrolling in clinical trials or benefiting from specialized care and management. The main objective of this study was to verify whether the ALS functional rating scale (ALSFRS) could be reliably administered by telephone to patients, when unable to attend the ALS clinic, or to their caregivers. ALSFRS is a validated instrument that assesses the functional status and the disease progression in ALS. We first administered the functional rating scale directly in the clinic to 30 patients, with definite or probable ALS, and to their respective caregivers, and found a very high agreement between the two groups for the total score and the majority of the rating items. Next, we showed, in both patients and caregivers, a high degree of correlation between the total score of the ALSFRS measured by telephone and that reported in the clinic. This indicates that ALSFRS is a reliable instrument for monitoring the disease progression in homebound patients, even when the person contacted by telephone is the caregiver. We also performed a telephone clinic, based on an unstructured interview, with 16 ALS patients at an advanced stage of the disease and unable to attend the ALS clinic. On some occasions, the person interviewed was the caregiver. The symptoms most frequently reported were a worsening of muscle strength, swallowing and breathing problems, constipation, and inability to clear lung secretions. Several patients asked for assistive and adaptive equipment. All patients and caregivers found the telephone clinic very useful and considered it a good complement to the management and care programme.

[Night workers and plasmatic cortisol]. / Lavoratori notturni e cortisolo plasmatico.

The aim of the study is to evaluate whether occupational exposure to night work could cause alterations in the levels of plasmatic cortisol. The interest toward this argument arises form several studies in scientific literature referring the presence of an alteration in the synthesis and release of cortisol in workers exposed to night work. We studied a population of workers employed in night security service and monitoring service of alarm systems in different museums compared to a control group not performing shift-work and/or night work. The exposed and control subjects were compared by age, length of service, smoking habit (n. cigarettes per day), habitual consumption of alcoholic drinks (n. glass of wine/beer per day). We evaluated the levels of plasmatic cortisol on 50 workers exposed to night work, all males of whom 30 smokers and 20 non-smokers and on 50 controls of whom 30 smokers and 20 non-smokers.

Differential effect of beta-N-oxalylamino-L-alanine, the Lathyrus sativus neurotoxin, and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate on the excitatory amino acid and taurine levels in the brain of freely moving rats.

We studied the effect of beta-oxalylamino-L-alanine, a glutamate analog present in Lathyrus sativus seeds and implicated in the etiopathogenesis of neurolathyrism, and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate on the extracellular levels of aspartate, glutamate and taurine in the primary motor cortex of freely moving rats. We found that while both neurotoxins increase the level of aspartate and glutamate, only (+/-)-alpha(-amino-3-hydroxy-5-methylisoxazole-4-propionate is able to modulate the level of taurine. GYKI-52466, a non-competitive non-NMDA antagonist, inhibited beta-oxalylamino-L-alanine-induced increase of aspartate, but not that of glutamate. Conversely, this antagonist proved to be very efficient in blocking the stimulating effect of (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate on all three amino acids. We suggest that beta-oxalylamino-L-alanine increases the level of glutamate in vivo by a mechanism not connected to its effect on the non-NMDA receptors, which might involve the inhibition of glutamate transport. This would allow the excitatory neurotransmitter to reach a concentration sufficient to stimulate the non-NMDA receptors, which in their turn mediate the specific release of aspartate. Although the role of aspartate as a neurotransmitter is still under discussion, it might indeed amplify the excitotoxic cascade through its action on NMDA receptors. We speculate that this sequence of events might represent an important step in the molecular cascade leading to the appearance of the selective motoneuron degeneration in neurolathyrism.

Effects of exogenous gangliosides on the pattern of respiratory enzymes in experimental diabetic retino-pathy in the rat.

The prevalence of LDH1 in the retina let us think that this tissue, in normal conditions, is particularly resistant to anoxia; yet the datum relative to the variations, of LDH1 pattern in the degenerating retina with decrease of LDH1, makes more probable the hypothesis of a variable sensitivity of the enzyme in the normal metabolic conditions. This consideration, which can also be extended to the other enzymatic systems, justifies our research line.

Protective effect of the cochlear efferent system during noise exposure.

The aim of the present study was to confirm the hypothesis that the cochlear efferent system is involved in the mechanisms underlying the "toughening" effect at high frequencies. The toughening effect is defined as a progressive threshold shift reduction when repeated exposures to the same noise are applied. Vestibular neurectomy was performed through a posterior cranial fossa approach in six healthy pigmented guinea pigs, and it assured the interruption of both crossed and uncrossed olivocochlear bundles to one ear only, before their entrance in the internal auditory meatus. The animals were then implanted with permanent electrodes for the electrocochleographic findings. Ten days after the operation the animals were exposed to octave-band toughening noise, centered at 4 kHz, at 85-dB SPL, for 10 consecutive days, 6 hours on/18 hours off. The hearing threshold was registered before and at the end of each exposure session. The behavior of the hearing threshold in the operated ears was then compared to that of the controlateral, nonoperated ears. Complete recovery from TS in the control ear began after four days of exposure, whereas in the operated ear hearing loss increased to day 7 (55 dB), with only a partial reduction (45 dB) beyond ten days of exposure. The results of the present study clearly demonstrated that sectioning of the OCB in guinea pigs causes persistent hearing loss during noise-exposure conditioning, in comparison to the contralateral, nonoperated ear. Thus, one can assume that the lack of decrease of TS during intermittent noise exposure could be due to the loss of the protective effect of the efferent fibers, perhaps mediated by the lateral OC neurons that synapse beneath the IHCs.

Neurosteroids in the retina: neurodegenerative and neuroprotective agents in retinal degeneration.

Steroids may have a powerful role in neuronal degeneration. Recent research has revealed that steroids may influence the onset and progression of some retinal disorders as well as neurodegenerative diseases and, as in brain, they accumulate in the retina via a local synthesis (neurosteroids) and metabolism of blood-circulating steroid hormones. Their crucial role as neurodegenerative and neuroprotective agents has been also upheld in a retinal excitotoxic paradigm. These findings are reviewed especially from the emerging perspective that after an insult local changes in steroidogenic responses and consequent neurosteroid availability might turn out to be offensive or defensive cellular adaptations for the potentiation or prevention of neuronal death.

gamma-Aminobutyric acid type A/benzodiazepine receptors regulate rat retina neurosteroidogenesis.

It has been previously shown that retinal ganglion cells have the ability to synthesize steroids including neuroactive steroids such as pregnenolone sulfate. Since ganglion cells possess GABAA/benzodiazepine (BZ) receptors and neurosteroids modulate retinal GABAA receptor function, we investigated the role of these receptors in isolated rat retina neurosteroidogenesis. Ligands for central-type BZ receptors stimulated retinal pregnenolone synthesis. Clonazepam was the most potent ligand examined acting at nanomolar concentrations. Moreover, the effective steroidogenesis stimulatory dose (ED50) for these ligands and the Ki to inhibit [3H]flunitrazepam binding showed a coefficient of correlation of r = 0.87, suggesting the involvement of the central-type BZ receptors in this event. Ro 5-4864, which preferentially binds to peripheral-type BZ receptors, was less efficacious and potent whereas PK 11195 did not affect the basal pregnenolone formation and did not antagonize the Ro 5-4864 stimulated steroid synthesis. The GABAergic agonist muscimol, stimulated neurosteroid synthesis and this effect was reversed by the GABAergic antagonists bicuculline and picrotoxinin. In addition, these antagonists decreased basal pregnenolone formation, suggesting a tonic GABAergic control of the steroidogenic pathway, and reduced clonazepam-stimulated steroidogenesis. These results, together with the reported ability of neurosteroids to modulate GABAA receptor function, suggest a novel regulatory mechanism to control the inhibitory transmission.

Dopaminergic agonists in the treatment of Parkinson's disease: a review.

Dopaminergic agonists represent an important class of drugs in Parkinson's Disease, useful: a) in delaying the beginning of L-dopa therapy; b) in supporting it, reducing its dosage and widen the therapeutic window; c) moreover, as the disease advances, in trying to treat motor fluctuations. Authors describe briefly the problems caused by long term L-dopa therapy, and analyze, separately, the characteristics of the most important dopaminergic agonists currently utilized in the treatment of PD.

Long term results of extra anatomical bypasses.

The authors discuss their own experience with extra anatomical bypasses. It is composed by 214 patients who underwent 224 extra anatomical bypasses: 167 axillofemoral bypasses, 50 femorofemoral bypasses and 7 trans-obturator bypasses. The indications included the presence of infections, or a previously thrombosed aortic prosthesis, or infected aneurysm, in 12.1% of the cases; in 6.2% of the cases the extra anatomical bypass was due to acute ischaemia of limb. In 81.7% it was chosen because of the presence of some general or local contraindication to direct aortoiliac reconstruction. The results are comparable to those reported in the literature. The only unusually high datum is the rate of early infections in femorofemoral bypasses (12%). On the ground of these results, the Authors stress the value of extra-anatomical bypasses as an alternative to direct aortoiliac reconstructions.

CDP-choline in the treatment of chronic cerebrovasculopathies.

Ninety-two patients affected by chronic cerebrovasculopathy were treated with cytidine diphosphate choline (CDP-choline) 1000 mg/day i.m. or with placebo, in a double-blind study. Two cycles of therapy of 4 weeks each were performed, with an interval of 1 week. There were 46 patients in each group with chronic cerebrovascular diseases, and the two groups were comparable as far as mental deterioration was concerned. The following psychometric tests were administered: Toulouse-Piéron (attention to non-verbal stimuli), Randt Memory test (memory), Sandoz Clinical Assessment of Geriatrics (SCAG, measurement of the behavioral and emotional control). The comparison between the two groups revealed significant improvements in the CDP-choline group compared with the placebo group in some of the attention capabilities (decrease in the number of wrong answers at the Toulouse-Piéron test), of the mnemonic capabilities ('General Information' subtest of Randt Memory test) and behavioral capabilities (SCAG 'affective disturbances' score). No side-effects were detected in the CDP-choline group.

Vestibular neurectomy in the guinea-pig: a retrosigmoid approach.

The efferent cochlear system, composed of both ipsi- and contralateral bundles, runs along with the vestibular nerve and may serve as protection for the inner ear. Sectioning of the vestibular nerve could thus create an experimental model for further in-depth study of such a protective role. A personal surgical approach is described, involving a suboccipital (or retrosigmoid) route to the postero-medial aspect of the guinea-pig temporal bone, chosen because of its use for the induction of endolymphatic hydrops in the same species. The crucial step in this approach is the separation of the sigmoid sinus in its entirety, through an intra-dural access with a minimal removal/retraction of cerebellar tissue. This did not affect either the post-operative recovery of the animal or its hearing threshold level as assessed via auditory brainstem responses.

Laser Doppler measurement of cochlear blood flow changes during conditioning noise exposure.

Using laser Doppler flowmetry, cochlear blood flow was assessed in Mongolian gerbils exposed to noise. Anesthetized animals were surgically implanted with permanent electrodes and then exposed for 10 consecutive days (6 h on/18 h off) to an octave band noise centered at 4 kHz (85 dB SPL). The auditory brainstem responses and the blood flow in the basal turn of the cochlea were compared with those of gerbils not exposed to noise. The exposed animals developed an initial threshold shift, followed by a progressive reduction in threshold shift up to complete recovery at the end of the test. In the exposed animals, a reduction in the cochlear blood flow during the first 4 days of exposure was observed, which was then followed by a progressive increase up to the end of the test. The results of this study exclude a possible role of the microvasculature of the lateral cochlear wall in determining the resistance to 4 kHz frequency noise exposure.