Risk Factor Analysis for the Mal-Positioning of Thoracic Aortic Stent Grafts.

OBJECTIVE: The present study aimed at quantifying mal-positioning during thoracic endovascular aortic repair and analysing the extent to which anatomical factors influence the exact stent graft positioning. METHODS: A retrospective review was conducted of patients treated between 2007 and 2014 with a stent graft for whom proximal landing zones (LZ) could be precisely located by anatomical fixed landmarks, that is LZ 1, 2, or 3. The study included 66 patients (54 men; mean age 51 years, range 17-83 years) treated for traumatic aortic rupture (n = 27), type B aortic dissection (n = 21), thoracic aortic aneurysm (n = 8), penetrating aortic ulcer (n = 5), intramural hematoma (n = 1), and floating aortic thrombus (n = 4). Pharmacologic hemodynamic control was systematically obtained during stent graft deployment. Pre- and post-operative computed tomographic angiography was reviewed to quantify the distance between planned and achieved LZ and to analyze different anatomical factors: iliac diameter, calcification degree, aortic angulation at the proximal deployment zone, and tortuosity index (TI). RESULTS: Primary endoleak was noted in seven cases (10%): five type I (7%) and two type II (3%). Over a mean 35 month follow up (range 3-95 months), secondary endoleak was detected in two patients (3%), both type I, and stent graft migration was seen in three patients. Mal-positioning varied from 2 to 15 mm. A cutoff value of 11 mm was identified as an adverse event risk. Univariate analysis showed that TI and LZ were significantly associated with mal-positioning (p = .01, p = .04 respectively), and that aortic angulation tends to reach significance (p = .08). No influence of deployment mechanism (p = .50) or stent graft generation (p = .71) or access-related factors was observed. Multivariate analysis identified TI as the unique independent risk factor of mal-positioning (OR 241, 95% CI 1-6,149, p = .05). A TI >1.68 was optimal for inaccurate deployment prediction. CONCLUSION: TI calculation can be useful to anticipate difficulties during stent graft deployment and to reduce mal-positioning.

Risk Factor Analysis of Bird Beak Occurrence after Thoracic Endovascular Aortic Repair.

OBJECTIVES: The aim was to analyze the role played by anatomy and stent graft in the incidence of incomplete apposition to aortic arch. METHODS: Between 2007 and 2014 data including available and suitable computed tomographic angiography (CTA) imaging of patients who had undergone thoracic endovascular aortic repair were reviewed. The study included 80 patients (65 men, 54 ± 21 years) treated for traumatic aortic rupture (n = 27), thoracic aortic aneurysm (n = 15), type B aortic dissection (n = 24), penetrating aortic ulcer (n = 5), intramural hematoma (n = 2), aorto-oesophageal fistula (n = 2), and aortic mural thrombus (n = 5). Pre- and post-operative CTA images were analyzed to characterize bird beak in terms of length and angle, and to calculate aortic angulation within a 30 mm range at the proximal deployment zone. RESULTS: Bird beak configuration was detected in 46 patients (57%): mean stent protrusion length was 16 mm (range: 8-29 mm) and mean bird beak angle was 20° (range: 7-40°). The bird beak effect was significantly more frequent after traumatic aortic rupture treatment (p = .05) and in landing zone 2 (p = .01). No influence of either stent graft type or generation, or degree of oversizing was observed (p = .29, p = .28, p = .81 respectively). However, the mean aortic angle of patients with bird beak was higher in the Pro-form group than that in the Zenith TX2 group (62° vs. 48°, p = .13). Multivariate analysis identified the aortic angle of the deployment zone as the unique independent risk factor of malapposition (HR = 1.05, 95% CI 1-1.10, p = .005). The cutoff value of 51° was found to be predictive of bird beak occurrence with a sensitivity of 58% and a specificity of 85%. CONCLUSIONS: Assessment of proximal landing zone morphology to avoid deployment zones generating an aortic angle of over 50° can be recommended to improve aortic curvature apposition with the current available devices.

A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer.

BACKGROUND: A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. METHODS: In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1-3 along with cisplatin on day 1 and etoposide on days 1-3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. RESULTS: Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1-3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. CONCLUSIONS: AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.

Cytotoxic Evaluation of 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, 3-AP, in Peripheral Blood Lymphocytes of Patients with Refractory Solid Tumors using Electron Paramagnetic Resonance.

PURPOSE: 3-AP (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP) is a metal chelator that potently inhibits the enzyme ribonucleotide reductase, RR, which plays a key role in cell division and tumor progression. A sub-unit of RR has a non-heme iron and a tyrosine free radical, which are required for the enzymatic reduction of ribonucleotides to deoxyribonucleotides. The objective of the study was to determine whether 3-AP affects its targeted action by measuring EPR signals formed either directly or indirectly from low molecular weight ferric-3-AP chelates. METHODS: Peripheral blood lymphocytes were collected from patients with refractory solid tumors at baseline and at 2, 4.5 and 22 hours after 3-AP administration. EPR spectra were used to identify signals from high-spin Fe-transferrin, high-spin heme and low-spin iron or copper ions. RESULTS: An increase in Fe-transferrin signal was observed, suggesting blockage of Fe uptake. It is hypothesized that formation of reactive oxygen species by FeT(2) or CuT damage transferrin or the transferrin receptor. An increase in heme signal was also observed, which is a probable source of cytochrome c release from the mitochondria and potential apoptosis. In addition, increased levels of Fe and Cu were identified. CONCLUSION: These results, which were consistent with our earlier study validating 3-AP-mediated signals by EPR, provide valuable insights into the in vivo mechanism of action of 3-AP.

The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors.

PURPOSE: 3-AP is a ribonucleotide reductase inhibitor and has been postulated to act synergistically with other chemotherapeutic agents. This study was conducted to determine the toxicity and antitumor activity of 3-AP with irinotecan. Correlative studies included pharmacokinetics and the effects of ABCB1 and UGT1A1 polymorphisms. METHODS: The treatment plan consisted of irinotecan on day 1 with 3-AP on days 1-3 of a 21-day cycle. Starting dose was irinotecan 150 mg/m(2) and 3-AP 85 mg/m(2) per day. Polymorphisms of ABCB1 were evaluated by pyrosequencing. Drug concentrations were determined by HPLC. RESULTS: Twenty-three patients were enrolled, 10 men and 13 women. Tumor types included seven patients with pancreatic cancer, four with lung cancer, two with cholangiocarcinoma, two with mesothelioma, two with ovarian cancer, and six with other malignancies. Two patients experienced dose-limiting toxicity (DLT) at dose level 1, requiring amendment of the dose-escalation scheme. Maximal tolerated dose (MTD) was determined to be 3-AP 60 mg/m(2) per day and irinotecan 200 mg/m(2). DLTs consisted of hypoxia, leukopenia, fatigue, infection, thrombocytopenia, dehydration, and ALT elevation. One partial response in a patient with refractory non-small cell lung cancer was seen. Genotyping suggests that patients with wild-type ABCB1 have a higher rate of grade 3 or 4 toxicity than those with ABCB1 mutations. CONCLUSIONS: The MTD for this combination was 3-AP 60 mg/m(2) per day on days 1-3 and irinotecan 200 mg/m(2) on day 1 every 21 days. Antitumor activity in a patient with refractory non-small cell lung cancer was noted at level 1.

Phase I trial of 2-methoxyestradiol NanoCrystal dispersion in advanced solid malignancies.

PURPOSE: 2-methoxyestradiol (2ME2; Panzem) is an endogenous, estradiol-17beta metabolite that at pharmacologic doses exerts antimitotic and antiangiogenic activities. Studies with a 2ME2 capsule formulation showed limited oral bioavailability. We report the results of a phase I study using a NanoCrystal Dispersion formulation of 2ME2 (2ME2 NCD). EXPERIMENTAL DESIGN: Patients with refractory solid tumors received 2ME2 NCD orally. Patients received drug either every 6 hours (part A) or every 8 hours (part B). Doses were escalated in successive cohorts until the maximum tolerated dose (MTD) was identified. The primary objective was identifying the MTD. Secondary objectives were to evaluate the plasma pharmacokinetics of 2ME2 and efficacy. RESULTS: In part A, 16 patients received a median of 4 cycles of 2ME2 NCD. Dose-limiting toxicities (DLT) included fatigue (2), hypophosphatemia (2), increased alanine aminotransferase (1), and muscle weakness (1). Trough levels at steady-state reached the minimum effective concentration in all cohorts. The MTD was determined to be 1,000 mg orally every 6 hours. In part B, 10 patients received a median of 1 cycle. DLTs included elevated gamma-glutamyltransferase (1), hyponatremia (1), fatigue (1), and anorexia (1). An MTD could not be defined for part B because 4 of 10 patients had DLTs at the initial dose level and dose reduction was not pursued. Thirteen patients had stable disease (A, 11; B, 2); there were no confirmed responses. CONCLUSION: For 2ME2 NCD, the MTD and recommended phase II regimen is 1,000 mg orally every 6 hours. Treatment was generally well-tolerated.

Dose-escalation study of fixed-dose rate gemcitabine combined with capecitabine in advanced solid malignancies.

PURPOSE: To define dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of capecitabine with fixed-dose rate (FDR) gemcitabine. METHODS: Eligible adults (advanced solid tumor; performance status or=3 toxicity was myelosuppression, particularly neutropenia. At dose level 4 (1,000 mg/m(2) gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropenia >or=7 days). At dose level 3 (800 mg/m(2) gemcitabine), one patient had a DLT (grade 3 neutropenia >or=7 days) among six evaluable patients. Therefore, the MTD and recommended phase II dose was designated as capecitabine 500 mg/m(2) PO BID days 1-14 with 800 mg/m(2) FDR gemcitabine days 1 and 8 infused at 10 mg/m(2) per min on a 21-day cycle. Partial responses occurred in pretreated patients with esophageal, renal cell and bladder carcinomas. CONCLUSIONS: This regimen was well tolerated and may deserve evaluation in advanced gastrointestinal and genitourinary carcinomas.

[Is endovascular treatment of acute thoracic aortic disease possible in centers where extracorporal circulation is not available?]. / Le traitement endovasculaire des lésions urgentes de l'aorte thoracique descendante est-il possible dans un centre ne disposant pas de circulation extracorporelle?

OBJECTIVE: To determine whether access to extra-corporal circulation (ECC) is necessary to treat acute descending thoracic aorta disease. METHOD: From January 2004 to May 2006, 16 patients underwent endovascular stent-graft repair of the descending thoracic aorta, among them 13 (81%) were treated in an emergency setting (nine men, mean age: 75.4 years, range 30-94 years). The indication was traumatic aortic rupture (n=3, 23%), complicated acute type B dissection (n=4; 31%), symptomatic or ruptured thoracic aortic aneurysm (n=4; 31%), aorto-esophageal fistula (n=1; 7,5%) and aortic intramural haematoma (n=1; 7,5%). Computed tomography showed hemomediastin and/or hemothorax in five patients (38%). Transesophageal echocardiography and angiography were performed in two (15%) and one patients respectively. Cerebrospinal fluid drainage was performed for two patients (15%). RESULTS: Endovascular repair was successfully completed in 92.3% of cases. The 30-day mortality was 7.5% (n=1). There was one case (7.5%) of delayed paraplegia. Follow-up ranged between two and 24 months (mean 10.2), no rupture occurred. Three type I endoleaks were detected and only two were treated. Two none related additional mortalities were observed. None of these patients has needed ECC. CONCLUSION: The unavailability of ECC does not seem to be a compromising factor in the management of thoracic aorta disease, however a good experience in endovascular techniques is required.

Electron paramagnetic resonance study of peripheral blood mononuclear cells from patients with refractory solid tumors treated with Triapine.

The metal chelator Triapine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, is a potent inhibitor of ribonucleotide reductase. EPR spectra consistent with signals from Fe-transferrin, heme, and low-spin iron or cupric ion were observed in peripheral blood mononuclear cells (PBMCs) obtained from patients treated with Triapine. One signal that is unequivocally identified is the signal for Fe-transferrin. It is hypothesized that Fe uptake is blocked by reactive oxygen species generated by FeT(2) or CuT that damage transferrin or transferrin receptor. A potential source for the increase in the heme signal is cytochrome c released from the mitochondria. These results provide valuable insight into the in vivo mechanism of action of Triapine.

Phase I trial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors.

PURPOSE: To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacodynamics, and antitumor activity of continuous weekly-administered paclitaxel and BMS-214662, a novel farnesyl transferase inhibitor. EXPERIMENTAL DESIGN: Patients were treated every week as tolerated with i.v. paclitaxel (fixed dose, 80 mg/m(2)/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80-245 mg/m(2)/wk) over 1 h starting 30 min after completion of paclitaxel. RESULTS: Twenty-six patients received 94 courses (one course, 21 days) of study treatment. Two patients received five courses of BMS-214662 as a weekly 24-h infusion (209 mg/m(2)/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m(2)/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m(2)/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m(2)/wk). Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (>80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion. CONCLUSIONS: Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m(2) over 1 h) and BMS-214662 (160 mg/m(2) over 1 h) administered weekly.

[Laparoscopic surgery of varicocele. Role of total endovenous anesthesia in same-day discharge]. / Chirurgia laparoscopica del varicocele. Ruolo dell'anestesia totalmente endovenosa nella dimissione in giornata.

The success of out-patients laparoscopic surgery depends on a careful selection of patients and the ability of anesthetic technique to ensure a rapid emergence from anesthesia, with a satisfactory control of postoperative pain and the absence of side effects. This study was undertaken to investigate the influence of a total intravenous anesthetic management on the recovery process after laparoscopic varicocelectomy. Fifty-three ASA 1 patients aged 12-41 yrs (mean 26.02) scheduled to undergo laparoscopic varicocelectomy as day surgery procedure were included in this study. Propofol was used as inductor agent and in variable-rate infusion (170-100 mcg/Kg/min) to maintain anesthesia supplemented with Fentanyl (FNT) before endotracheal intubation, incision surgery and if the patient manifested clinical signs of inadequate analgesia. Local anesthesia was infiltrated into the skin before incision. Tramadol 100 mg and Ketorolac 30 mg were administered before the end of surgery to delay the onset of the postoperative pain. Pain was evaluated using a self-rating visual analoque scale (VAS) ranging from 0 to 10 at 0-0.5 hrs postoperatively and every 2 hrs until discharge. At the same time nausea was clinically evaluated using a scale ranging from 0 to 3. Postoperative pain and nausea (PONV) treatment were standardized. Patients were discharged by Post-Anesthesia Discharge Scoring System (PADS). Mean operating time was 34.2 min and mean estubation time was 11.6 min. At time 0 all patients had VAS pain score < 3, on the same time 2 of patients was treated for mild PONV; mean time to first request for postoperative analgesia treatment in 89% of patients was more than 6 hrs, 5 patients required pain treatment before discharge in a mean time 216' +/- 156'. Using the PADS system, 64% of patients were discharged at 4 hrs and 89% at 6 hrs after surgery. One patient was admitted to hospital for an overnight stay for walking dizziness; another was readmitted for surgical complications. This results suggest that the proposed anesthetic management provided adequate pain control with minimun postoperative nausea and a good recovery rate. This permitted a short postoperative hospital stay without compromising in safety, efficacy, or patient satisfaction.

The inhibitory effect of combining chlorhexidine and hydrogen peroxide on 3-day plaque accumulation.

In a blind, randomised, 4-cell, cross-over study, the effect of rinsing with a perborate solution (1.9 g sodium perborate-monohydrate dissolved in 30 ml water/Bocasan, Oral-B) on the in vivo plaque-inhibiting effect of 0.12% chlorhexidine (Oral-B) was examined. After a thorough professional prophylaxis including interdental cleaning, 12 subjects started to rinse according to 4 different regimens: regimen (C-P-C): chlorhexidine in the morning, perborate at noon and chlorhexidine in the evening; regimen (CP-CP): chlorhexidine immediately followed by perborate in the morning and in the evening; regimen (PC-PC): perborate immediately followed by chlorhexidine in the morning and in the evening; regimen (C-C): chlorhexidine in the morning and in the evening. No further oral hygiene measures were allowed for the next 72 h. After 72 h, the subjects were scored for plaque, and a washout period of 4 days followed; cross-over was randomly assigned according to a Latin square design. Following this procedure, all subjects went through all 4 regimens. The regimens C-P-C and PC-PC resulted in significantly lower plaque-scores, 0.27 and 0.28 respectively, than regimen C-C (0.40). For the regimen CP-CP, the plaque-score was 0.28, which was not significantly different from the C-C regimen. The results suggest a positive interaction between chlorhexidine and hydrogen peroxide. Rinsing with a combination of 0.12% chlorhexidine (Oral-B) and a perborate solution (Bocasan Oral-B) can result in more effective short-term plaque growth inhibition than rinsing with chlorhexidine alone.

EEG monitoring of carotid endarterectomy with routine patch-graft angioplasty: an experience in a large series.

Four hundred and thirty-nine carotid endarterectomies (CEAs) with routine use of patchgraft angioplasty were performed in 375 patients; the indwelling shunt was used only in patients showing clamp-related EEG abnormalities. Five patients showed EEG abnormalities just after head positioning, which reversed after removal of head hyperextension; three cases suffered EEG flattening due to severe bradycardia or cardiac arrest before carotid clamping, which promptly reversed after treatment. Clamp-related EEG abnormalities appeared in 106 operations (24.2%) and all reversed after the insertion of the indwelling shunt; patients with occlusion of the contralateral internal carotid artery showed a 68.8% rate of EEG clamp-related changes. The short term follow-up (one month after the operation) showed six minor strokes with complete recovery (1.37%), one intraoperative stroke (0.23%), three delayed major strokes (0.69%) and three neurological deaths (0.69%). The long-term follow-up over an average of 42 months showed a 3.7% rate of relevant neurological complications (ie permanent deficits + death) and a 3.16% rate significant restenosis or occlusion of the operated carotid artery. Our results show that the routine use of EEG monitoring and patch-graft angioplasty allow to perform CEAs with a very high degree of safety, improving the clinical course of the disease.

Sensorimotor central conduction time in comatose patients.

Motor evoked potentials (MEPs) following magnetic stimulation were recorded in 22 patients comatose as a result of head injury (13 cases), stroke (7 cases) or anoxia (2 cases). Somatosensory evoked potentials (SEPs) from median nerve were recorded as well in 19 cases in the same session. Thirteen patients died or remained vegetative (59.1%), 3 were severely disabled (13.6%) and 6 showed a good recovery (27.3%). MEPs were significantly related to the outcome; they appeared to be a more accurate prognostic indicator than the Glasgow Coma Scale (GCS). However, 1 out of 6 patients with bilaterally absent MEPs (16.7%) showed a good recovery. SEPs were significantly related to the outcome as well, but the combined use of SEP and MEP improved the outcome prediction, decreasing the rate of false negatives. Two patients had normal sensorimotor function, 13 a combined sensorimotor dysfunction, while 4 had a pure motor dysfunction. Our results suggest that SEPs and MEPs may improve the assessment of sensorimotor dysfunction in comatose patients. A significant relationship between MEPs and outcome appears to exist, but the assessment of MEP reliability requires further study.

Spatial mapping of SEP in comatose patients: improved outcome prediction by combined parietal N20 and frontal N30 analysis.

The aim of this study is to evaluate whether SEP spatial mapping can improve outcome prediction in comparison to the conventional SEP recordings. Twenty patients comatose as a result of head injury or cerebral vascular disorders were submitted to 19-channel SEP mapping from median nerve stimulation. SEP recording were performed within the 4th hospital day in 18 cases and over one month from the insult in the remaining two. Nine patients (45%) showed a good recovery or a mild disability, 3 (15%) a severe disability and the rest (40%) died or remained in a vegetative state. Five patients (28%) had bilaterally normal SEP, 5 (28%) the absence of both parietal N20 and frontal N30, while the others (44%) had a dissociation N20/N30 (namely, preserved N20 with absent N30). The SEP mapping was significantly related to the outcome (P = 0.0087) and improved the outcome prediction in comparison to the conventional SEP recordings, allowing to check the presence of frontal N30: in patients with bilaterally present N20 the outcome appeared to depend upon the N30. SEP mapping proved to be a far superior prognostic indicator than the Glasgow Coma Scale. In 3 patients with midline shift on CT scan an abnormal spatial distribution of N20 was disclosed by SEP mapping. Our preliminary results suggest that SEP mapping may improve the assessment of comatose patients in comparison to the use of parietal derivations only.