Lesioni non palpabili della mammella: la Mammotome-biopsy nella gestione preoperatoria del cancro della mammella

Premessa: Il tumore del seno è nei paesi occidentali al primo posto per frequenza nelle donne e la sua incidenza è in costante crescita. Grazie soprattutto alla diffusione dello screening mammografico e ad una maggiore consapevolezza del problema, negli ultimi anni è aumentata la diagnosi delle cosiddette lesioni “non palpabili”; parimenti si è assistito ad un importante sviluppo delle metodiche diagnostiche di tipo mininvasivo. Alla tradizionale citologia con ago sottile si sono affiancate infatti varie procedure bioptiche percutanee; tali metodiche microistologiche hanno quasi del tutto sostituito la biopsia chirurgica escissionale e l’esame intra-operatorio al congelatore. Pazienti e metodo: Nella nostra Divisione di Chirurgia Generale, Vascolare e Mininvasiva, dal dicembre 1999 al settembre 2004 abbiamo eseguito, in collaborazione con il servizio di Radiologia, 214 biopsie su guida ecografia utilizzando la vacuum-assisted biopsy (Mammotome® ) con ago 11-Gauge. I risultati ottenuti per ciò che concerne l’accuratezza diagnostica, la quantità e qualità delle informazioni ottenute, il significato delle stesse nella eventuale gestione chirurgica, il discomfort globale per la paziente sono stati analizzati e discussi nel presente lavoro. Risultati: Delle 214 biopsie eseguite con tecnica Mammotome, nell’89,3% dei casi si è trattato di lesioni clinicamente non palpabili, con un diametro medio di 8 mm. L’età media delle pazienti era di 57,6 anni (range 31-88). La positività per patologia maligna è stata di 90 casi (42%). Nei casi di iperplasia duttale atipica e radial scar (6%) è stata effettuata l’exeresi chirurgica della lesione che ha confermato nel 100% dei casi la precedente diagnosi bioptica. Il 19% delle pazienti sottoposte a biopsia Mammotome era stato precedentemente sottoposto ad un prelievo citologico con ago sottile. Confrontando i risultati delle due metodiche, l’attendibilità diagnostica della seconda risulta essere significativamente superiore (p<0,05) come pure il numero di informazioni ottenute (istotipo, invasività, grading, recettori ormonali, etc.); il discomfort legato alla procedura, valutato in termini di dolore (VAS), è risultato inferiore a quello del prelievo con ago sottile (p<0,05). L’unica complicanza della biopsia Mammotome è rappresentata dall’ematoma nella sede del prelievo (8% dei casi). Il numero dei falsi negativi è stato di un caso, dovuto ad un non corretto centraggio del bersaglio. Conclusioni: Allo stato attuale in presenza di una lesione non palpabile della mammella la scelta della metodica diagnostica (agobiopsia o Mammotome) è legata al sospetto radiologico nella prospettiva di un eventuale intervento chirurgico. La biopsia con Mammotome nelle lesioni non palpabil

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS &lt; 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

Bis-Histidyl adducts in tetrameric hemoglobins

In the last decade crystallographic evidence for endogenous coordination at the sixth coordination site of the heme iron has been reported for monomeric haemoglobins (Hbs) in both the ferrous (haemochrome) and ferric (haemichrome) oxidation state. Usually, the sixth ligand is provided by the imidazole side chain of a His, the only putative ligand normally present in the distal site of the heme pocket. More recently, structural and spectroscopic evidence has been reported, which show that the bis-histidyl adduct in the ferric state represents a common accessible ordered state also for several tetrameric Hbs isolated from Antarctic fish, both in the solid and solution state. Bis-histidyl coordination was also discovered in the crystals of horse met-Hb exposed to acidic pH. All these crystal structures are characterised by a different binding state of α and β chains. Tetrameric Hbs with all chains in the bis-histidyl coordination state have not yet been found. Herein we review the structural details of the recent results in this field, together with solution studies on the pathway of haemichrome formatio

Reduction of ferric hemoglobin from Trematomus bernacchii in a partial bis-histidyl state produces a deoxy coordination even when encapsulated into the crystal phase

Crystallographic and spectroscopic evidences on Antarctic fish hemoglobins (AFHbs) revealed that their ferric tetramers at physiological pH are in a mixed α(aquo-met)/β(bis-histidyl) coordination state and show a quaternary structure intermediate between the classical R and T states (H state). Ferric bis-histidyl adducts (hemichromes) have been also observed in some mammalian Hbs. In order to reveal if hemichrome in AFHbs can be converted into a hemochrome, at least in the crystal phase, chemical reduction on single crystals of ferric Hb from Trematomus bernacchii (HbTb) has been followed via Raman microscopy. The results of this analysis reveal that in HbTb, upon reduction, the bis-histidyl coordination is loosened in favor of a penta-coordinated ferrous deoxy state, with no evidence of ferrous bis-histidyl state. These data are in agreement with UV/Vis absorption spectra in solution. Furthermore, our data are also indirectly supported by the observation that upon reduction with dithionite, the ferric HbTb crystals crack and lose their diffraction power: in the crystalline state, the quaternary structure transition from the H to the T state is not compatible with the crystal packing. Altogether these data indicate that if bis-histidyl adducts have a functional significance in AFHbs, this function refers to a stable ferric state, or to a transient, though never detected, ferrous species

The Root effect - a structural and evolutionary perspective

Haemoglobin carries oxygen from the environment to tissues; in vertebrates, it is contained in specialized cells, called erythrocytes. Over the last century, the study of the chemical properties of this haemoprotein has provided a wealth of information. One of its most important and ancient physiological features is the Root effect, found in many teleost fish (and some amphibians). The Root effect corresponds to an extreme pH sensitivity and can be described as an exaggerated Bohr effect: it dictates to what extent the oxygen tension can be raised in acid-producing tissues. It is likely that the eye choroid rete represents the most ancient anatomical structure associated with the presence of Root effect haemoglobins. This review describes our overall understanding of the molecular properties, biological occurrence, physiological role and evolutionary origin of Root effect haemoglobins. The current knowledge of the structural properties of Root effect haemoglobins is discussed in the light of recent results obtained on the haemoglobins of the coldadapted notothenioids Trematomus newnesi and T. bernacchii

Multiple coordination and quaternary states of fish hemoglobin re-open the Root effect question

The Root effect is a widespread property in fish hemoglobins (Hbs) that produces a drastic reduction of cooperativity and oxygen-binding ability at acidic pH. Up to now, the structural explanation of the Root effect has been based on the two-state model, and is related to an over-stabilization of the T quaternary structure. Here, we report the crystal structure of the deoxy and carbomonoxy form of the non-Root effect major component Hb isolated from the Antarctic fish Trematomus newnesi (Hb1Tn). In the deoxy state, the inter-aspartic hydrogen bond at the α1β2 interface between Asp95α and Asp101β is observed. In the carbomonoxy Hb1Tn crystals, both a T-like state and a R/T intermediate quaternary structure are observed. In these crystals, three of four independent CO coordination states are not assisted by the hydrogen bond with the distal histidine, that goes out of the heme pocket. This un-assisted CO coordination states are associated with unusually small thermal fluctuations which characterise both α and β CD corners. The accessibility of ligated states within three different quaternary structure (T, R and R/T intermediate) suggests a novel structural explanation of protein allostery based on a three state Edelstein’s model

Combined Raman and X-ray crystallography reveals multiple coordinations and quaternary states of fish hemoglobins

Many fish hemoglobins (Hbs) are endowed with Root effect, that produces a decrease in oxygen affinity at low pH, associated with complete loss of cooperativity. Over the years, several hypotheses on the structural determinants of the Root effect have been suggested. Up to now, all the structural explanations of the Root effect have been based on the two-state model, in which the Root effect is related to an increase of the allosteric equilibrium between the R and T state at acidic pH [1-3]. Here, we report the crystal structures of the deoxy and carbomonoxy forms of the non-Root-effect major component Hb 1 isolated from the Antarctic fish (Af) Trematomus newnesi (Hb1Tn). Surprisingly, in the deoxy state of the non-Root effect Hb1Tn, the inter-aspartic hydrogen bond between Asp95α and Asp101β at the α1β2 interface, which is believed to be important in Root effect [2], is observed. A combined Resonance Raman / x-ray crystallography of this AfHb has revealed heterogeneity in the deoxy coordination. Novel ligated states are observed in both a T-like state and a R/T intermediate quaternary state. Three of four independent CO coordination states are not assisted by the hydrogen bond of the distal histidyl, that swings out of the heme pocket. These un-assisted CO coordination states (supported by FT-IR spectroscopy solution studies) are associated with unusually small thermal fluctuations which characterise both α and β CD corners. The accessibility of ligated states within three different quaternary structures (T, R and R/T intermediate [4]) suggests a novel structural explanation of protein allostery, based on a three-state Edelstein’s model [5]. Grant Sponsors: PRIN , PNRA. [1] Mazzarella et al. Proteins, 2006, 65(2), 490-498. [2] Mazzarella et al. Proteins, 2006, 62(2), 316-321 [3] Yokoyama et al. J. Biol. Chem. 2004, 279, 28632-28640. [4] Vitagliano et al. J. Am. Chem. Soc., 2008, 130, 10527-10535. [5] Edelstein, J. Mol. Biol., 1996, 256, 737-744

Riparazione laparoscopica dei laparoceli e delle ernie ombelicali. Nostra esperienza

Introduzione - Il laparocele rappresenta una complicanza frequente dopo una laparotomia (2-20%). Il tasso di recidive dopo una riparazione semplice non protesica è ancora maggiore. L’utilizzo delle protesi ha comportato una riduzione delle recidive. Nell’ultimo decennio, la riparazione laparoscopica dei laparoceli e delle ernie ombelicali è divenuta una interessante alternativa alla procedura open. Pazienti - Scopo di questo studio retrospettivo è quello di valutare l’efficacia, la sicurezza ed i vantaggi dell’approccio laparoscopico relativamente al trattamento laparoscopico dei laparoceli e delle ernie ombelicali. Dal febbraio 2000 al giugno 2006, complessivamente 127 laparoceli (primari e recidivi), 21 ernie ombelicali e 19 ernie epigastriche sono state trattate con approccio mininvasivo. I criteri di esclusione sono stati: dimensioni del difetto inferiore a 2 cm o superiore a 20 cm, problematiche anestesiologiche, disordini emo-coagulativi. Il rapporto femmine/maschi è stato di 0.7, l’età media di 59 anni (24-83). Le patologie addominali associate, trattate contemporaneamente, sono state 26. Tre casi sono stati operati in condizioni di urgenza (laparoceli strozzati). Risultati - Il tasso di conversione in chirurgia open è stato di 2 casi (1.2%). Il tempo operatorio medio di 78 minuti (25-170) e la degenza media post-operatoria di 2.1 giorni (1-5). Le complicanze intra- e post-operatorie sono state del 5% (soprattutto sieromi), le recidive osservate 1.8% (3 casi). Conclusioni - Ulteriori studi con follow-up adeguati sono necessari per poter dimostrare i reali vantaggi della tecnica laparoscopica, tuttavia l’esperienza riportata di oltre 5 anni dimostra che in casi selezionati l’approccio laparoscopico può rappresentare un’ interessante ed efficace alternativa alla tecnica open