Background
While growing evidence supports the use of hypothermic oxygenated machine perfusion (HOPE) in liver transplantation, its effects on liver metabolism are still incompletely understood.
...Methods
To assess liver metabolism during HOPE using microdialysis (MD), we conducted an open‐label, observational pilot study on 10 consecutive grafts treated with dual‐HOPE (D‐HOPE). Microdialysate and perfusate levels of glucose, lactate, pyruvate, glutamate, and flavin mononucleotide (FMN) were measured during back table preparation and D‐HOPE and correlated to graft function and patient outcome.
Results
Median (IQR) MD and D‐HOPE time was 228 (210, 245) and 116 (103, 143) min. Three grafts developed early allograft dysfunction (EAD), with one requiring retransplantation. During D‐HOPE, MD glucose and lactate levels increased (ANOVA = 9.88 p = 0.01 and 3.71 p = 0.08). Their 2nd‐hour levels were higher in EAD group and positively correlated with L‐GrAFT score. 2nd‐hour MD glucose and lactate were also positively correlated with cold ischemia time, macrovesicular steatosis, weight gain during D‐HOPE, and perfusate FMN. These correlations were not apparent when perfusate levels were considered. In contrast, MD FMN levels invariably dropped steeply after D‐HOPE start, whereas perfusate FMN was higher in dysfunctioning grafts.
Conclusion
MD glucose and lactate during D‐HOPE are markers of hepatocellular injury and could represent additional elements of the viability assessment.
In this study, Patrono et al. explore release of metabolites in extracellular space during hypothermic oxygenated machine perfusion by the mean of microdialysis. Levels of glucose and lactate in the microdialysate correlate with ischemia‐reperfusion injury and could represent additional markers of liver viability during hypothermic perfusion.
Purpose
Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib ...sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma.
Methods
Patients with recurrent or progressive WHO grade I–III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18–75 years, ECOG performance status 0–2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient’s refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9).
Results
Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (
N
= 7; Arm A) or HU alone (
N
= 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75 %, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75 %, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0.
Conclusion
The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.
Purpose
Aggressive pituitary adenomas (APAs) and pituitary carcinomas (PCs) are challenging for their invasive nature, resistance to treatment and recurrences. Temozolomide (TMZ) is used with benefit ...and well-tolerated toxicity profile in APAs and PCs. In most studies patients received ≤ 12 cycles but the best length of treatment is debated since other options after discontinuation are scarce and a second course is mainly unsuccessful.
Methods
We report outcomes of 8 patients with APAs and PCs treated with TMZ for more than 12 continuous cycles with a literature review. Data were retrospectively collected from Padua and Milan University Hospitals. TMZ was used as a single agent (150–200 p.o. mg/m2 daily, 5/28 days) for 14 to 45 cycles.
Results
Eight patients (7 M), 7 APAs and 1 PC. Previous treatments included neurosurgery and radiotherapy in all cases except two giant masses (ACTH-silent APA and prolactinoma). No patient had progression disease (PD) during long-term treatment nor toxicities. No one had complete response (CR) but four had partial response (PR). Four ACTH+ tumors maintained stable disease (SD) but the secretion pattern improved in all. After drug withdrawal, three had delayed PD (2 after 18 and one after 29 months, all ACTH+); two are still in SD.
Conclusions
TMZ may be useful and well-tolerated in APAs and PCs as a long-term therapy. PR appears within the first cycles with no escape throughout the treatment; most patients achieve SD. We suggest extended protocols particularly in responsive ACTH+ PAs and PCs, when further therapies may be unsuccessful.
Abstract Integrity of brain white matter (WM) tracts in adulthood could be detrimentally affected by exposure to adverse childhood experiences (ACE). Changes of diffusion tensor imaging (DTI) ...measures suggesting WM disruption have been reported in patients with schizophrenia together with a history of childhood maltreatment. We therefore hypothesized that ACE could be associated with altered DTI measures of WM integrity in patients with schizophrenia. We tested this hypothesis in 83 schizophrenia patients using whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial, radial, and mean diffusivity (MD), and fractional anisotropy (FA). We observed an inverse correlation between severity of ACE and DTI measures of FA, and a positive correlation with MD in several WM tracts including corona radiata, thalamic radiations, corpus callosum, cingulum bundle, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus. Lower FA and higher MD are indexes of a reduction in fibre coherence and integrity. The association of ACE to reduced FA and increased MD in key WM tracts contributing to the functional integrity of the brain suggests that ACE might contribute to the pathophysiology of schizophrenia through a detrimental action on structural connectivity in critical cortico-limbic networks.
Decreased availability of serotonin in the central nervous system has been suggested to be a central factor in the pathogenesis of depression. Activation of indoleamine 2–3 dioxygenase following a ...pro-inflammatory state could reduce the amount of tryptophan converted to serotonin and increase the production of tryptophan catabolites such as kynurenic acid, an antagonist of ionotropic excitatory aminoacid receptors, whose levels are reduced in bipolar disorder. Abnormalities in white matter (WM) integrity have been widely reported in BD. We then hypothesized that metabolites involved in serotoninergic turnover in BD could influence DTI measures of WM microstructure. Peripheral levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxy-kynurenine, and 5-HIAA were analysed in 22 patients affected by BD and 15 healthy controls. WM microstructure was evaluated using diffusion tensor imaging and tract-based spatial statistics with threshold-free cluster enhancement only in bipolar patients. We observed that kynurenic acid and 5-HIAA were reduced in BD and associated with DTI measures of WM integrity in several association fibres: inferior and superior longitudinal fasciculus, cingulum bundle, corpus callosum, uncus, anterior thalamic radiation and corona radiata. Our results seem to suggest that higher levels of 5-HIAA, a measure of serotonin levels, and higher levels of kynurenic acid, which protects from glutamate excitotoxicity, could exert a protective effect on WM microstructure. Reduced levels of these metabolites in BD thus seem to confirm a crucial role of serotonin turnover in BD pathophysiology.
OBJECTIVE:This international multicenter study by the Upper GI International Robotic Association (UGIRA) aimed to gain insight in current techniques and outcomes of RAMIE worldwide.
...BACKGROUND:Current evidence for RAMIE originates from single-center studies, which may not be generalizable to the international multicenter experience.
METHODS:20 centers from Europe, Asia, North-America, and South-America participated from 2016- 2019. Main endpoints included the surgical techniques, clinical outcomes, and early oncological results of RAMIE.
RESULTS:A total of 856 patients undergoing transthoracic RAMIE were included. Robotic surgery was applied for both the thoracic and abdominal phase (45%), only the thoracic phase (49%), or only the abdominal phase (6%). In most cases, the mediastinal lymphadenectomy included the low para-esophageal nodes (n=815, 95%), subcarinal nodes (n = 774, 90%), and paratracheal nodes (n = 537, 63%). When paratracheal lymphadenectomy was performed during an Ivor Lewis or a McKeown RAMIE procedure, recurrent laryngeal nerve injury occurred in 3% and 11% of patients, respectively. Circular stapled (52%), hand-sewn (30%), and linear stapled (18%) anastomotic techniques were used. In Ivor Lewis RAMIE, robot-assisted hand-sewing showed the highest anastomotic leakage rate (33%), while lower rates were observed with circular stapling (17%) and linear stapling (15%). In McKeown RAMIE, a hand-sewn anastomotic technique showed the highest leakage rate (26%), followed by linear stapling (18%) and circular stapling (6%).
CONCLUSION:This study is the first to provide an overview of the current techniques and outcomes of transthoracic RAMIE worldwide. Although these results indicate high quality of the procedure, the optimal approach should be further defined.
To prospectively investigate the role of apparent diffusion coefficient (ADC) calculated from diffusion-weighted magnetic resonance (MR) imaging as a potential prognostic biomarker in the evaluation ...of the aggressiveness of gastric cancer.
This prospective study had institutional review board approval. Informed consent was obtained from all patients. Between October 2009 and December 2013, a total of 99 patients (65 men, 34 women; mean age, 62.02 years; age range, 32.33-85.15 years) with biopsy-proved cancer (28 esophagogastric junction and 71 gastric cancers) were examined with a 1.5-T MR imaging system, including T1-, T2-, and diffusion-weighted sequences. ADC measurements were obtained. Seventy-one patients were directly treated with surgery, while 28 underwent neoadjuvant chemotherapy beforehand. Pathologic ADC, pathologic T and N stages, tumor location, surgical approach, and histologic subtype were investigated with univariate and multivariate analyses by using the Cox regression model.
At a total median follow-up period of 21 months, 31 patients had died. The median follow-up was 25 months for the surgery-only group (19 of 31 events 61%) and 28 months for the chemotherapy group (12 of 31 events 39%). In the multivariate analysis, ADC values of 1.5 × 10(-3) mm(2)/sec or lower were associated with a negative prognosis, both in the total population (log-relative risk, 1.73; standard error, 0.56; P = .002) and in the surgery-only (log-relative risk, 1.97; standard error, 0.66; P = .003) and chemotherapy (log-relative risk, 2.93; standard error, 1.41; P = .03) groups, along with other significant prognostic factors (in particular, pathologic T and N stages).
Pathologic ADC represents a strong independent prognostic factor in the evaluation of the aggressiveness of gastric cancer, in addition to clinical and surgical variables.
Pain is the most powerful motivating force that guides treatment-seeking behaviors in patients. This applies especially to those who are suffering from chronic pain, whose treatment is a difficult ...challenge for health professionals. Objective. To evaluate the effectiveness of Therapeutic Education in the treatment of pain and disability, and the effects on the psycological outcomes in patients with chronic musculoskeletal pain. The analysed educational intervention namely "Pain Neurophysiology Education", is a promising tool according to results of the neuroscientific investigation in pain pathophysiology, during the last two decades. Methods. Literature search was conducted on PubMed, Pedro and Cochrane Library. All experimental studies including reviews, randomized controlled trials (RCTs), non-randomized clinical trials, and evaluating the effect of Pain Neurophysiology Education (PNE) on pain, disability, anxiety, and stress in chronic musculoskeletal pain disorders, (e.g. fibromyalgia and chronic fatigue syndrome) were considered for inclusion. Additional limitations: studies publishedin English or French within the last 10 years, adult patients (18-65 years). No limitations were set on specific outcome measures of pain, disability, anxiety, and stress. Data were extracted using the participants' interventions, comparisons, and outcomes (PICO) approach. Methodological quality was assessed following actual scientific literature guidelines: the "Oxford Centre for Evidence-based Medicine Levels of Evidence" to assess the level of evidence, the CASP to assess methodological quality properly. Results. This review includes 8 studies RCTs and 2 Systematic Reviews, involving 951 subjects totally. Most studies were of good quality (at least 7 out of 10), with no studies rated as poor or fair. Heterogeneity across the studies with respect to participants, evaluated interventions, and outcome measures used, allowed just a narrative synthesis of results based on effect size. Conclusions. Despite the few studies and some methodological critiques, there is compelling evidence that rehabilitative intervention that includes the Therapeutic Education, in particular PNE, can have a positive effect on pain, disability, catastrophization, and physical function. The PNE effectiveness may be due to the shift of the focus from tissue damage to central processing of nociception, with the aim to increase the patient's awareness of the no-correlation between nociception and pain. Therefore it could be conceived as an intervention that can decrease both the alertness and, as a consequence, the patient's perception of pain. Key words: chronic pain, musculoskeletal pain, education, neurophysiology, biology, neuroscience. Il dolore e una delle maggiori cause che spingono alla continua ricerca del trattamento adeguato. Questo vale ancor piu per coloro che sono affetti da dolore cronico, la cui gestione rappresenta una sfida difficile per gli operatori sanitari. Molto si parla del dolore cronico da cancro, meno di quello provocato da altre patologie. In questo lavoro si intende trattare il dolore cronico muscoloscheletrico di natura non maligna, alla luce delle nuove conoscenze neuroscientifiche, e indagare quanto e se, l'Educazione Terapeutica, rivolta al paziente cronico, sia efficace nella sua gestione. Il lavoro si e focalizzato sui recenti studi che hanno affrontato l'Educazione Terapeutica alla luce del concetto di "sensibilizzazione centrale" (disfunzione dei neuro-circuiti legati alla percezione, trasmissione e processazione delle afferenze nocicettive). E stata effettuata una revisione della letteratura, svolgendo la ricerca degli articoli sui database PubMed, Pedro e Cochrane Library e includendo Randomized-controlled trial (RCT) e reviews, pubblicati negli ultimi 10 anni. Gli studi valutavano gli effetti dell'Educazione del paziente alla Neurofisiologia del Dolore (END) sul miglioramento funzionale e/o sintomatico, percezione della disabilita, la percezione del dolore, attivita funzionali e prestazioni fisiche, in pazienti adulti (18-65 anni) con dolori muscolo-scheletrici cronici, comprese le sindromi muscolo-scheletriche quali fibromialgia e fatigue cronica. L'analisi dei dati e stata effettuata secondo la metodologia PICO. La qualita degli studi, e stata valutata seguendo le linee guida presenti in letteratura. Degli articoli risultanti dalla ricerca sui databases, sono stati inclusi nella revisione 8 studi clinici randomizzati e 2 revisioni sistematiche, con un livello di evidenza medio-alto e qualita metodologica buona per almeno 7 studi su 10. L'eterogeneita degli studi rispetto a popolazione, intervento studiato e misure di outcome usate ha impedito la metanalisi. L'analisi dei risultati e stata quindi descritta narrativamente, tenendo conto della dimensione dell'effetto, e ha mostrato, con notevole evidenza, che l'END puo indurre un effetto di riduzione dell'intensita del dolore, aumento della funzionalita, riduzione dell'atteggiamento catastrofico e miglioramento del movimento nei pazienti con dolore cronico muscoloscheletrico. L'efficacia potrebbe essere data dal fatto che un intervento di END, spostando l'attenzione dal danno tissutale all'elaborazione centrale della nocicezione, mira ad aumentare la consapevolezza del paziente riguardo alla non correlazione tra nocicezione e dolore, di conseguenza potrebbe essere concepito come un intervento in grado di diminuire lo stato di allerta e quindi la percezione del dolore nel paziente. Parole chiave: dolore cronico, dolore muscolo-scheletrico, educazione, neurofisiologia, biologia, neuroscienze.
The Homer family of postsynaptic scaffolding proteins plays a crucial role in glutamate-mediated synaptic plasticity, a phenotype associated with Bipolar Disorder (BD). Homer is a target for ...antidepressants and mood stabilizers. The AA risk genotype of the Homer rs7713917 A>G SNP has been associated with mood disorders and suicide, and in healthy humans with brain function. Despite the evidence linking Homer 1 gene and function to mood disorder, as well as its involvement in animal models of depression, no study has yet investigated the role of Homer in bipolar depression and treatment response.
We studied 199 inpatients, affected by a major depressive episode in course of BD. 147 patients were studied with structural MRI of grey and white matter, and 50 with BOLD functional MRI of emotional processing. 158 patients were treated with combined total sleep deprivation and light therapy.
At neuroimaging, patients with the AA genotype showed lower grey matter volumes in medial prefrontal cortex, higher BOLD fMRI neural responses to emotional stimuli in anterior cingulate cortex, and lower fractional anisotropy in bilateral frontal WM tracts. Lithium treatment increased axial diffusivity more in AA patients than in G*carriers. At clinical evaluation, the same AA homozygotes showed a worse antidepressant response to combined SD and LT.
rs7713917 influenced brain grey and white matter structure and function in BD, long term effects of lithium on white matter structure, and antidepressant response to chronotherapeutics, thus suggesting that glutamatergic neuroplasticity and Homer 1 function might play a role in BD psychopathology and response to treatment.
•rs7713917 significantly influenced grey and white matter structure and function.•AA homozygotes showed smaller medial prefrontal cortex than G carriers.•AA homozygotes showed higher signal responses in right dorsal anterior cingulate cortex.•AA homozygotes showed significantly lower FA in frontal tracts than G carriers.•rs7713917 also influenced severity of depression and response to treatment.
Abstract Biliary tract cancer is a rare malignant tumor. Accordingly, to perform prospective and randomized trials is difficult and the knowledge of its natural history and optimal management remains ...limited. Chemotherapy is commonly used to improve the outcome and to delay tumor progression in advanced disease. Only recently, cisplatin–gemcitabine combination was identified as the new standard first-line therapy. Despite the outcome improvement, disease progression is a constant and approximately half of patients failing upfront treatment maintain a good performance status and are willing to undergo further treatment. No standard salvage chemotherapy regimen has been identified yet. Experiences of salvage therapy in advanced biliary tract cancer are sparse and yielded disappointing results. Well designed multi-institutional randomized trials are warranted to clarify the role and the activity of a second-line therapy.
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