Lymph node ratio and surgical quality are strong prognostic factors of rectal cancer: results from a single referral centre.

AIM: Nodal stage is a strong prognostic factor of oncological outcome of rectal cancer. To compensate for the variation in total number of harvested nodes, calculation of the lymph node ratio (LNR) has been advocated. The aim of the study was to compare the impact, on the long-term oncological outcome, of the LNR with other predictive factors, including the quality of total mesorectal excision (TME) and the state of the circumferential resection margin. METHOD: Consecutive patients having elective surgery for nonmetastatic rectal cancer were extracted from a prospectively maintained database. Retrospective uni- and multivariate analyses were performed based on patient-, surgical- and tumour-related factors. The prognostic value of the LNR on overall survival (OS) and on overall recurrence-free survival (ORFS) was assessed and a cut-off value was determined. RESULTS: From 1998 to 2013, out of 456 patients, 357 with nonmetastatic disease were operated on for rectal cancer. Neoadjuvant radiochemotherapy was administered to 66.7% of the patients. The mean number of lymph nodes retrieved was 12.8 ± 8.78 per surgical specimen. A lower lymph node yield was obtained in patients who received neoadjuvant chemoradiotherapy (11.8 vs 14.2; P = 0.014). The 5-year ORFS was 71.8% and the 5-year OS was 80.1%. Multivariate analysis confirmed LNR, the quality of TME and age to be independent prognostic factors of OS. LNR, age and perineural infiltration were independently associated with ORFS. Low- and high-risk patients could be discriminated using an LNR cut-off value of 0.2. CONCLUSION: LNR is an independent prognostic factor of OS and ORFS. In line with the principles of optimal surgical management, the quality of TME and lymph node yield are essential technical requirements.

Estimation of coronary flow reserve by sestamibi imaging in patients with mild hypertension and normal coronary arteries.

AIM: Patients with hypertension may exhibit abnormal vasodilator capacity during pharmacological vasodilatation. We assessed coronary flow reserve (CFR) by sestamibi imaging in hypertensive patients with normal coronary vessels. METHODS: Twenty-five patients with untreated mild essential hypertension and normal coronary vessels and 10 control subjects underwent dipyridamole-rest Tc-99m sestamibi imaging. Myocardial blood flow (MBF) was estimated by measuring first transit counts in pulmonary artery and myocardial counts from tomograhic images. CFR was expressed as the ratio of stress to rest MBF. Coronary vascular resistances (CVR) were computed as the ratio between mean arterial pressure and MBF. RESULTS: Estimated MBF at rest was not different in patients and controls (1.11 ± 0.59 vs. 1.14 ± 0.28 counts/pixel/s; P=0.87). Conversely, stress MBF was lower in patients than in controls (1.55 ± 0.47 vs. 2.68 ± 0.53 counts/pixel/s; P<0.001). Thus, CFR was reduced in patients compared to controls (1.61 ± 0.58 vs. 2.43 ± 0.62; P<0.001). Rest and stress CVR values were higher in patients (P<0.001), while stress-induced changes in CVR were not different (P=0.08) between patients (-51%) and controls (-62%). In the overall study population, a significant relation between CFR and stress-induced changes in CVR was observed (r=-0.86; P<0.001). CONCLUSION: Sestamibi imaging may detect impaired coronary vascular function in response to dipyridamole in patients with untreated mild essential hypertension and normal coronary arteries. A mild increase in arterial blood pressure does not affect baseline MBF, but impairs coronary reserve due to the amplified resting coronary resistances.

Energy deposition in liquid scintillators composed of CsPbBr3 colloidal nanocrystal dispersions.

Liquid scintillation processes are commonly used for various applications involving radioactivity levels analysis, as well as experiments in the field of high energy physics, most commonly in the form of organic scintillating cocktails. In this paper, we explore the potential of halide perovskite nanocrystal colloidal dispersions as an alternative to those organic mixtures. After an optimization of the nanocrystals' mean size and surface chemistry, the scintillation yield of these composite mixtures is evaluated through Compton - Triple to Double Coincidence Ratio experiments and compared with commercial liquid scintillator. The obtained results shine a light on the energy deposition mechanisms in nanocrystals-based liquid scintillators.

Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.

Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC.

Tricuspid atresia with double-outlet left atrium.

Clinical and pathologic findings of an unusual case of cardiac malformation are presented. The main features were those of atresia of the right atrioventricular valve associated with two distinct atrioventricular orifices connecting the morphologically left atrium to the underlying morphologically left ventricle. Other distinguishing characteristics were ostium secundum atrial septal defect, normally related great arteries, with the aorta arising from the main ventricular chamber and the pulmonary artery from the anterior and right-sided outlet chamber, and infundibular and valvular pulmonary atresia.

Percutaneous transluminal coronary angioplasty in refractory unstable angina pectoris: are new devices useful?

This study was undertaken to assess if the introduction of new angioplasty devices (autoperfusion balloon catheters, stent and atherectomy) could ameliorate early and late results of prompt percutaneous transluminal coronary angioplasty (PTCA) in patients with refractory unstable angina. From January 1993 to June 1995, 59 of 278 patients (14 female, 45 male; mean age: 61 +/- 10 years; range: 38-78) admitted to our Coronary Care Unit with the diagnosis of unstable angina had more than one episode of chest pain at rest with dynamic electrocardiographic ST-T changes and without signs of cardiac necrosis while on medical therapy including oxygen, aspirin, heparin, nitroglycerin and either a beta-blocker or a calcium-antagonist. Coronary angiography was performed within 48 h from the last ischemic attack and a culprilesion technically suitable for PTCA was identified. PTCA was performed in 73 lesions. Elective stent implantation was considered for 16 type B or C lesions in 14 patients. The procedure was initially successful in 52/59 patients (88%), uncomplicated unsuccessful in 4/59 (7%) and complicated in 3/59 (5%). Elective stent insertions were all successful (16/16, 100%). All successfully treated patients were followed up for a mean of 12 +/- 7 months (range: 6-27): 2/52 patients (3.8%) suffered from non-transmural myocardial infarction, 14/52 (26.9%) had a recurrence of angina and 2/52 (3.8%), asymptomatic, had a positive stress test. We conclude that prompt PTCA in refractory unstable angina using 1990s 'state of the art' equipment compares favorably to previous study and that stent delivery might become the elective treatment of complex lesions in this subset of patients.

Troponin T, creatine kinase MB mass, and creatine kinase MB isoform ratio in the detection of myocardial damage during non-surgical coronary revascularization.

The presence of myocardial injury during non-surgical coronary revascularization has been evaluated by means of highly specific and sensitive biochemical markers. Troponin T, creatine kinase-MB isoenzyme mass concentration, and creatine kinase MB2/MB1 isoform ratio have been determined in 80 patients who underwent coronary revascularization with percutaneous transluminal coronary angioplasty (PTCA). Forty-five patients underwent balloon angioplasty, 15 rotational atherectomy, 10 directional atherectomy, and 10 elective coronary stenting. Serum concentration of the evaluated markers did not increase significantly after 57 uncomplicated revascularization procedures, including 15 rotablation procedures, nor after 8 PTCAs complicated by localized coronary type B and C dissections. Significant elevation of all markers above the upper limits of the reference interval (P < 0.05) was detected after occlusion of small side branches (< 0.5 mm diameter) in 5 patients. Creatine kinase MB2/MB1 isoform ratio was the earliest marker to increase. After recanalization of occluded vessels in 8/10 patients with 6-60 days old myocardial infarction only troponin T concentrations increased from a baseline of 0.28 microgram/l to a median peak of 0.80 microgram/l. This increase was statistically not significant (P = 0.12). In conclusion, myocardial damage was not detected following uncomplicated non-surgical revascularization obtained with different techniques. Markers of myocardial injury provide high sensitivity after small side branch occlusion.

Unexpected sudden death during acute myocardial infarction: role of primary electromechanical dissociation.

The causes of death during the acute phase of myocardial infarction were studied in 128 patients. Forty-three of these, who had no clear signs of cardiocirculatory failure, were considered to be cases of sudden and unexpected death. Thirty-two of these patients (74%) had electromechanical dissociation, defined as a sudden disappearance of an effective arterial pressure in the presence of adequate electrocardiographic complexes. Twenty-three patients who had been given this diagnosis were males and 9 females; 53% presented with anterior infarction, 31% with infero-posterior infarction, 3.5% with both anterior and infero-posterior and 12.5% with non-Q wave infarction. A previous episode of infarction was recorded in 31.2% of patients with electromechanical dissociation. Autopsy was performed in 84 patients, 23 of whom died with electromechanical dissociation. Half of the latter cases revealed cardiac rupture (secondary electromechanical dissociation), whereas in the other half death was due to primary electromechanical dissociation. The study stresses the relatively high incidence of this cause of death and the need to differentiate between the two different forms. Although at present the pathophysiology of primary electromechanical dissociation is not completely understood, we believe that recurrence of global or local ischemia may play a more important role than cardiovascular inhibitory reflexes.

Myocardial damage after D.C. countershock: myoglobin and CK-MB radioimmunoassay evaluation.

After D.C. countershock to terminate cardiac arrhythmias, in 3 out of 8 patients studied, an increase in both plasma myoglobin (Mb) and CK-MB (assessed by radioimmunoassay) was found. In 2 patients there was an increase of only plasma Mb and in 1 an increase of only CK-MB. In 2 cases no increase of either parameters was found. It is suggested that the radioimmunoassay technique for measuring Mb and CK-MB might have a greater reliability than other techniques for the detection of myocardial damage.

Creatinephosphokinase and myoglobin monitoring in acute myocardial infarction.

Creatinephosphokinase (CPK) and myoglobin (Mb) were measured in 15 patients admitted to the Coronary Care Unit for acute myocardial infarction (AMI). Blood samples were collected from the right atrium every six hours for 48 hours starting from the time of arrival in the Unit and were tested for CPK by a spectrophotometric technique and for Mb by an RIA method. Mb usually started to increase earlier than CPK and reached the peak plasma level more quickly. In five cases Mb but not CPK subsequently showed further increases during the course of the study. The suggestion is made that Mb measurements might be more reliable than CPK for the early detection and the initial followup of AMI.

[The efficacy and safety of slow-release nicardipine vs nifedipine in angina]. / Efficacia e tollerabilità della nicardipina a lenta liberazione vs nifedipina nell'angina.

This controlled, double-blind, completely randomized study assessed the efficacy and safety of nicardipine and nifedipine, both in slow-release formulations, in patients with unstable angina. Thirty patients (28 M, 2F) were included in the final analysis, mean age 56.5 +/- 9.1 years (SD), mean weight 73.5 +/- 9.2 kg, mean height 171.5 +/- 6.5 cm, all with unstable angina. Nicardipine was given at a daily dosage of 80-120 mg, and nifedipine 40-60 mg, for up to one month. At the end of treatment with nicardipine supine systolic and diastolic blood pressure (SBP and DBP) dropped respectively 7.7% and 5.5% at 8 am and 8.6% and 7.1% at 8 pm. Nifedipine reduced SBP and DBP by respectively 6.5% and 13.1% at 8 am and 5.3% and 9.4% at 8 pm. There was no clinical or statistical difference between the treatments. Heart rate did not change appreciably during either treatment. On completion of nicardipine treatment, 87.5% of patients had suffered no angina attacks, compared with 66.7% for nifedipine. The remaining 12.5% of patients treated with nicardipine presented only one mild angina attack per day, while the other 33.3% of the nifedipine patients had one moderate angina attack per day. No untoward effects were reported with nicardipine; one patient receiving nifedipine presented cardiopalmus and another complained of headache. These results indicate that nicardipine is at least as safe and effective as nifedipine in the treatment of unstable angina.

[Cardiac echinococcosis. Description of a case with cysts localized in the free wall of the left ventricle]. / Echinococcosi cardiaca. Descrizione di un caso con cisti localizzata nella parete libera del ventricolo sinistro.

A case of isolated cardiac echinococcosis is reported. A 19-year-old man was hospitalized for chest pain with electrocardiographic pathological Q waves in D1, aVL, V5, V6. Two-dimensional echocardiography and chest computed tomography documented pericardial effusion and an intramyocardial cyst. Casoni's reaction and immunological tests completed the diagnosis of cardiac hydatidosis. The localization and the etiology of the cyst were confirmed during cardiac surgery.

Translational control in the stress adaptive response of cancer cells: a novel role for the heat shock protein TRAP1.

TNF receptor-associated protein 1 (TRAP1), the main mitochondrial member of the heat shock protein (HSP) 90 family, is induced in most tumor types and is involved in the regulation of proteostasis in the mitochondria of tumor cells through the control of folding and stability of selective proteins, such as Cyclophilin D and Sorcin. Notably, we have recently demonstrated that TRAP1 also interacts with the regulatory protein particle TBP7 in the endoplasmic reticulum (ER), where it is involved in a further extra-mitochondrial quality control of nuclear-encoded mitochondrial proteins through the regulation of their ubiquitination/degradation. Here we show that TRAP1 is involved in the translational control of cancer cells through an attenuation of global protein synthesis, as evidenced by an inverse correlation between TRAP1 expression and ubiquitination/degradation of nascent stress-protective client proteins. This study demonstrates for the first time that TRAP1 is associated with ribosomes and with several translation factors in colon carcinoma cells and, remarkably, is found co-upregulated with some components of the translational apparatus (eIF4A, eIF4E, eEF1A and eEF1G) in human colorectal cancers, with potential new opportunities for therapeutic intervention in humans. Moreover, TRAP1 regulates the rate of protein synthesis through the eIF2α pathway either under basal conditions or under stress, favoring the activation of GCN2 and PERK kinases, with consequent phosphorylation of eIF2α and attenuation of cap-dependent translation. This enhances the synthesis of selective stress-responsive proteins, such as the transcription factor ATF4 and its downstream effectors BiP/Grp78, and the cystine antiporter system xCT, thereby providing protection against ER stress, oxidative damage and nutrient deprivation. Accordingly, TRAP1 silencing sensitizes cells to apoptosis induced by novel antitumoral drugs that inhibit cap-dependent translation, such as ribavirin or 4EGI-1, and reduces the ability of cells to migrate through the pores of transwell filters. These new findings target the TRAP1 network in the development of novel anti-cancer strategies.

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins.

Tumor necrosis factor receptor-associated protein-1 (TRAP1) is a mitochondrial (MITO) antiapoptotic heat-shock protein. The information available on the TRAP1 pathway describes just a few well-characterized functions of this protein in mitochondria. However, our group's use of mass-spectrometric analysis identified TBP7, an AAA-ATPase of the 19S proteasomal subunit, as a putative TRAP1-interacting protein. Surprisingly, TRAP1 and TBP7 colocalize in the endoplasmic reticulum (ER), as demonstrated by biochemical and confocal/electron microscopic analyses, and interact directly, as confirmed by fluorescence resonance energy transfer analysis. This is the first demonstration of TRAP1's presence in this cellular compartment. TRAP1 silencing by short-hairpin RNAs, in cells exposed to thapsigargin-induced ER stress, correlates with upregulation of BiP/Grp78, thus suggesting a role of TRAP1 in the refolding of damaged proteins and in ER stress protection. Consistently, TRAP1 and/or TBP7 interference enhanced stress-induced cell death and increased intracellular protein ubiquitination. These experiments led us to hypothesize an involvement of TRAP1 in protein quality control for mistargeted/misfolded mitochondria-destined proteins, through interaction with the regulatory proteasome protein TBP7. Remarkably, expression of specific MITO proteins decreased upon TRAP1 interference as a consequence of increased ubiquitination. The proposed TRAP1 network has an impact in vivo, as it is conserved in human colorectal cancers, is controlled by ER-localized TRAP1 interacting with TBP7 and provides a novel model of the ER-mitochondria crosstalk.

[Postoperative bacterial endocarditis after cardiac prosthesis (author's transl)]. / L'endocardite batterica postoperatoria su protesi cardiache

The infection of an endocardial prosthesis, either valvular or septal patch, is a frequent and dangerous post-operative complication. Eleven patients having postoperative endocarditis (9 on valve prosthesis and 2 on ventricular septal patch) are the subject of this paper. Six of the 7 infected "early" had Gram-negative bacteria in the blood cultures, while staphylococus aureus, streptococcus viridans and klebsiella pneumoniae were responsible for 3 of the 4 "late" infections. In 2 patients, one "early" and one "late" the causative bacteria were not identified. The definite prevalence of Gram-negative flora in post-operative endocarditis may have been facilitated by the routine use of antibiotics after open-heart surgery. Three of the 11 patients survived, one after replacement of the infected prosthesis and two after prolonged specific antibiotic treatment. On the basic of this experience, compared with other written reports, the authors propose to treat postoperative endocarditis medically for approximately 5 weeks, with full doses of specific antibiotics, reserving for surgical treatment only the cases of prosthetic malfunction, left atrial thrombosis, peripheral embolization and in those patients where the medical treatment fails.

[Anatomically corrected malposition of the great arteries (author's transl)]. / Malposizione anatomicamente corretta delle grandi arterie

Anatomically corrected malposition of the great arteries is defined as a trunco-conal malformation characterized by an aorta arising anteriorly from a morphologically left ventricle and by the presence of a subaortic muscular conus. This malalignment determines a conotruncal-ventricular discordance: d-loop and l-position or l-loop and d-position of the aorta. Two additional cases of this very rate lesion are reported, both associated with left juxtaposition of the atrial appendages, tricuspid atresia, ventricular malrotation and destrocardia in situs solitus with d-loop. Because of the high frequency of this association, observed also in the majority of the previously published cases, its morphogenetic significance and implications are discussed.

[Atrial desynchronization induced by Valsalva's maneuver in a patient with reciprocating supraventricular tachycardia and Wolff-Parkinson-White syndrome]. / Desincronizzazione atriale indotta da manovra di Valsalva in un paziente con tachicardia sopraventricolare reciprocante e sindrome di WPW.

A 22 years old man with ventricular preexcitation syndrome due to a left accessory pathway, was admitted because of orthodromic reciprocating tachycardia, 205 bpm in frequency. The patient was invited to perform a Valsalva Maneuvre, and at its ending, the tachycardia degenerated into atrial fibrillation (AF) associated with high ventricular rate, reverted to sinus rhythm by D.C. shock. The electrophysiologic study documented a left lateral by pass tract, with an anterograde refractory period of 230 msec. AF was inducible and had a minimal RR interval of 220 msec. Vagal stimulation, induced at the end of Valsalva maneuvre, probably caused dispersion of atrial refractorines and intraatrial reentry, converting the orthodromic tachycardia into atrial fibrillation.

[Vectorcardiographic analysis of late potentials]. / L'analisi vettorcardiografica dei postpotenziali.

We analyzed by high amplification vectorcardiography the morphology of the QRS ending loop and the ST segment of patients with previously recorded Lown 4A, 4B ventricular arrhythmias and the healthy subject. Eight patients were affected by ischemic heart disease and 7 by arrhythmogenic right ventricular dysplasia. All had some irregularities at the end of the QRS or in the ST segment, on the standard ECG. The VCG showed one or more of these three morphologies: complete or incomplete ring, rapidly inscripted isodi-triphasic potentials, sinusoidal irregularities. In the 20 healthy subjects, the loop corresponding to the last 30 msec of the QRS, till the end of the afferent portion of T, was regular, without any particular morphology. We think that these aspects could be related to delayed fragmentation of the ventricular depolarization.