Adjuvant radioimmunotherapy trial with iodine-131-labeled anti-carcinoembryonic antigen monoclonal antibody F6 F(ab')2 after resection of liver metastases from colorectal cancer.

PURPOSE: To evaluate the feasibility of radioimmunotherapy (RIT) with radiolabeled anti-carcinoembryonic antigen antibodies after complete resection of liver metastases (LM) from colorectal cancer. Patients and Methods: Twenty-two patients planned for surgery of one to four LM received a preoperative diagnostic dose of a 131I-F(ab')2-labeled anti-carcinoembryonic antigen monoclonal antibody F6 (8-10 mCi/5 mg). 131I-F(ab')2 uptake was analyzed using direct radioactivity counting, and tumor-to-normal liver ratios were recorded. Ten patients with tumor-to-normal liver ratios of >5 and three others were treated with a therapeutic injection [180-200 mCi 131I/50 mg F(ab')2] 30 to 64 days after surgery. RESULTS: Median 131I-F(ab')2 immunoreactivity in patient serum remained at 91% of initial values for up to 96 hours after injection. The main and dose-limiting-toxicity was hematologic, with 92% and 85% grades 3 to 4 neutropenia and thrombocytopenia, respectively. Complete spontaneous recovery occurred in all patients. No human anti-mouse antibody response was observed after the diagnosis dose; however, 10 of the 13 treated patients developed human anti-mouse antibody approximately 3 months later. Two treated patients presented extrahepatic metastases at the time of RIT (one bone and one abdominal node) and two relapsed within 3 months of RIT (one in the lung and the other in the liver). Two patients are still alive, and one of these is disease-free at 93 months after resection. At a median follow-up of 127 months, the median disease-free survival is 12 months and the median overall survival is 50 months. CONCLUSION: RIT is feasible in an adjuvant setting after complete resection of LM from colorectal cancer and should be considered for future trials, possibly in combination with chemotherapy, because of the generally poor prognosis of these patients.

Systematic review and meta-analysis of risk factors for survival after lung metastasectomy in colorectal cancer patients

Objective: Resection of lung metastases (LM) from colorectal cancer (CRC)¦is increasingly performed with a curative intent.Most series report small groups¦of patients, and it is currently not possible to identify those CRC patients who¦may benefit the most of surgical management. It is clinically relevant to assess¦risk factors for prolonged survival after this type of procedures.¦Methods: A meta analysis of 24 series published between 2000 and 2011¦which focused on surgical management of LM from CRC and included more¦than 40 patients each, with or without prior resection of in transit liver¦metastases. Random effects were calculated for five variables considered as¦potential prognostic factors.¦Results: A total of 2815 patients who underwent surgery with a curative¦intent were considered in this analysis. Four parameters were associated with¦a decreased survival: 1) a short disease-free interval between primary tumor¦resection and development of LM (HR = 1·59, 95% CI 1·27-1·98); 2) multiple¦LM (HR = 2·04, 95%CI 1·72-2·41); 3) positive hilar/mediastinal lymph nodes¦(HR = 1·65, 95% CI 1·35-2·02); and 4) a high prethoracotomy CEA value (HR¦=1·91, 95% CI 1·57-2·32). By comparison, a history of resected liver metastases¦(HR = 1·36, 95% CI 0·92-2·03) did not achieve statistical significance.¦Conclusion: Risk factors for poor clinical outcome after surgery for lung¦metastases in CRC patients include: 1) synchronous lung metastases; 2) high¦pre-thoracotomy CEA; 3) hilar nodes involvement; and 4) multiple pulmonary¦lesions.

Liver Transplantation for Neuroendocrine Tumors in Europe-Results and Trends in Patient Selection: A 213-Case European Liver Transplant Registry Study.

OBJECTIVE:: The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. BACKGROUND:: LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. METHODS:: This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1-149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. RESULTS:: Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. CONCLUSIONS:: LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.

Primary percutaneous coronary intervention for unprotected left main disease in patients with acute ST-segment elevation myocardial infarction the AMIS (Acute Myocardial Infarction in Switzerland) plus registry experience.

OBJECTIVES: This study sought to assess outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI) for unprotected left main (LM) disease. BACKGROUND: Limited data are available on outcomes in patients with ST-segment elevation myocardial infarction undergoing LM PCI. METHODS: Of 9,075 patients with ST-segment elevation myocardial infarction enrolled in the AMIS (Acute Myocardial Infarction in Switzerland) Plus registry between 2005 and June 30, 2010, 6,666 underwent primary PCI. Of them, 348 (5.2%; mean age: 63.5 ± 12.6 years) underwent LM PCI, either isolated (n = 208) or concomitant to PCI for other vessel segments (n = 140). They were compared with 6,318 patients (94.8%; mean age: 61.9 ± 12.5 years) undergoing PCI of non-LM vessel segments only. RESULTS: The LM patients had higher rates of cardiogenic shock (12.2% vs. 3.5%; p < 0.001), cardiac arrest (10.6% vs. 6.3%; p < 0.01), in-hospital mortality (10.9% vs. 3.8%; p < 0.001), and major adverse cardiac and cerebrovascular events (12.4% vs. 5.0%; p < 0.001) than non-LM PCI. Rates of mortality and major adverse cardiac and cerebrovascular events were highest for concurrent LM and non-LM PCI (17.9% and 18.6%, respectively), intermediate for isolated LM PCI (6.3% and 8.3%, respectively), and lowest for non-LM PCI (3.8% and 5.0%, respectively). Rates of mortality and major adverse cardiac and cerebrovascular events for LM PCI were higher than for non-LM multivessel PCI (10.9% vs. 4.9%, p < 0.001, and 12.4% vs. 6.4%, p < 0.001, respectively). LM disease independently predicted in-hospital death (odds ratio: 2.36; 95% confidence interval: 1.34 to 4.17; p = 0.003). CONCLUSIONS: Emergent LM PCI in the context of acute myocardial infarction, even including 12% cardiogenic shock, appears to have a remarkably high (89%) in-hospital survival. Concurrent LM and non-LM PCI has worse outcomes than isolated LM PCI.

Human CD8(+) T cells engineered with supraphysiological TCRs are functionally inhibited via PD-1 and SHP-1 phosphatase

Purpose/Objective: Protective CD8+ T cell responses rely on TCRdependent recognition of immunogenic peptides presented by MHC I. Cytolytic T lymphocytes directed against self/tumor antigens express TCRs of lower affinity/avidity than pathogen-derived T lymphocytes and elicit less protective immune responses due to mechanisms of central and peripheral tolerance. Anti-tumor T cell reactivity can be improved by increasing the TCR-pMHC affinity within physiological limits, while intriguingly further increase in the supraphysiological range (KD < 1 lM) leads to drastic functional declines. We aim at identifying the molecular mechanisms underlying the loss of T cell responsiveness associated with supraphysiological TCRpMHC affinities in order to improve effectiveness of TCR-engineered T cells used in adoptive cell transfer (ACT) cancer immunotherapy. Materials and methods: Using a panel of human CD8+ T cells engineered with TCRs of incremental affinity for the HLA-A2-resticted tumor cancer testis antigen NY-ESO-1, we performed comparative gene expression microarray and TCR-mediated signaling analysis together with membrane receptors level analysis. Results: As compared to cells expressing TCR affinities generating optimal function (KD from 5to 1 lM), those with supraphysiological affinity (KD from 1 lM to 15 nM) had an overall reduced expression of genes implied in signaling, cell activation and proliferation, and showed impaired proximal and distal TCR signaling capacity. This correlated with a decline in surface expression of CD8b, CD28 and activatory TNFR superfamily members. Importantly, expression of inhibitory receptor PD-1 and SHP-1 phosphatase was upregulated in a TCR affinity-dependent manner. Consequently, PD-L1 and SHP-1 blockade restored the function of T cells with high TCRs affinity. Moreover, SHP-1 inhibition also augmented functional efficacy of T cells with TCRs of optimal affinity. Conclusions: Our findings indicate that TCR affinity-associated regulatory mechanisms control T cells responsiveness at various levels to limit potential auto-reactive cytotoxic effects. They also support the development of ACT therapies combined with blockade of inhibitory molecules such as SHP-1 to enhance effectiveness of T cell immunotherapy.

Ultrastructural and molecular analysis of Bowman's layer corneal dystrophies: an epithelial origin?

PURPOSE: Two mutations (R555Q and R124L) in the BIGH3 gene have been described in anterior or Bowman's layer dystrophies (CDB). The clinical, molecular, and ultrastructural findings of five families with CDB was reviewed to determine whether there is a consistent genotype:phenotype correlation. METHODS: Keratoplasty tissue from each patient was examined by light and electron microscopy (LM and EM). DNA was obtained, and exons 4 and 12 of BIGH3 were analyzed by polymerase chain reaction and single-stranded conformation polymorphism/heteroduplex analysis. Abnormally migrating products were analyzed by direct sequencing. RESULTS: In two families with type I CDB (CDBI), the R124L mutation was defined. There were light and ultrastructural features of superficial granular dystrophy and atypical banding of the "rod-shaped bodies" ultrastructurally. Patients from three families with "honeycomb" dystrophy were found to carry the R555Q mutation and had characteristic features of Bowman's dystrophy type II (CDBII). CONCLUSIONS: There is a strong genotype:phenotype correlation among CBDI (R124L) and CDBII (R555Q). LM and EM findings suggest that epithelial abnormalities may underlie the pathology of both conditions. The findings clarify the confusion over classification of the Bowman's layer dystrophies.

Integration of olfactory information in a spatial representation enabling accurate arm choice in the radial arm maze

The aim of the present study was to determine whether and how rats can use local olfactory cues for spatial orientation. Rats were trained in an eight-arm radial maze under different conditions as defined by the presence or absence of supplementary olfactory cues marking each arm, the availability of distant visuospatial information, and the illumination of the maze (light or darkness). The different visual conditions were designed to dissociate among the effects of light per se and those of visuospatial cues, on the use of olfactory cues for accurate arm choice. Different procedures with modifications of the arrangement of olfactory cues were used to determine if rats formed a representation of the spatial configuration of the olfactory cues and if they could rely on such a representation for accurate arm choice in the radial maze. The present study demonstrated that the use of olfactory cues to direct arm choice in the radial arm maze was critically dependent on the illumination conditions and implied two different modes of processing of olfactory information according to the presence or the absence of light. Olfactory cues were used in an explicit manner and enabled accurate arm choice only in the absence of light. Rats, however, had an implicit memory of the location of the olfactory cues and formed a representation of the spatial position of these cues, whatever the lighting conditions. They did not memorize the spatial configuration of the olfactory cues per se but needed these cues to be linked to the external spatial frame of reference.

Permo-Triassic stratigraphy of the pelagonian zone in central Evia island (Greece)

A new subdivision of the pre-Jurassic Pelagonian Units in central Evia island is proposed these units are represented by syn- and post rift sequences, separated by a volcano-sedimentary episode. The syn-rift sequences comprise Permian siliciclastic sediments in Verrucano tectofacies, (Ano Mavropoulon Formation) and a small carbonate platform (Zigos Limestones) developed from the Permian to the Middle Anisian. The Ano Mavropoulon Fro, is subdivided into three members: the lower member (Permian s.l.) lying on the basement and characterised by medium-coarse elastic terrigenous sedimentation the middle member (Late Permian) Koprises limestones, made up of shallow-water limestones; the upper member (Latest Permian-Early Triassic) comprising elastic terrigenous and minor reworked carbonate sediments. A regional unconformity (earliest Triassic) separates the Zigos Lm. from the top of the Ano Mavropoulon Fm. The peritidal carbonates belonging to the Zigos Lm, have been subdivided into three lithofacies ranging in age from Spathian to Pelsonian (late Early Triassic to Middle Anisian). The volcanic episode is well constrained in all the Pelagonian domain. In central Evia, it has been dated from Middle Anisian to Early Carnian. The sub-alkaline to alkaline basalts comprised in the volcano-sedimentary sequence (Volcano-sedimentary Complex) have a within-plate affinity. The volcanism occurs between the syn-rift and post-rift stages, and it is probably not linked to the passive margin evolution proper. The post-rift sequences are represented by the onset of the Pelagonian platform aggradation (''Pantokrator'' Carnian to Middle-Late? Jurassic) The northern passive margin sequence of Pelagonia (palaeogeographic sense) is interpreted as related to the Maliak ocean opening during the Early Mesozoic.

Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.

BACKGROUND: Resection of lung metastases (LM) from colorectal cancer (CRC) is increasingly performed with a curative intent. It is currently not possible to identify those CRC patients who may benefit the most from this surgical strategy. The aim of this study was to perform a systematic review of risk factors for survival after lung metastasectomy for CRC. METHODS: We performed a meta-analysis of series published between 2000 and 2011, which focused on surgical management of LM from CRC and included more than 40 patients each. Pooled hazard ratios (HR) were calculated by using random effects model for parameters considered as potential prognostic factors. RESULTS: Twenty-five studies including a total of 2925 patients were considered in this analysis. Four parameters were associated with poor survival: (1) a short disease-free interval between primary tumor resection and development of LM (HR 1.59, 95 % confidence interval [CI] 1.27-1.98); (2) multiple LM (HR 2.04, 95 % CI 1.72-2.41); (3) positive hilar and/or mediastinal lymph nodes (HR 1.65, 95 % CI 1.35-2.02); and (4) elevated prethoracotomy carcinoembryonic antigen (HR 1.91, 95 % CI 1.57-2.32). By comparison, a history of resected liver metastases (HR 1.22, 95 % CI 0.91-1.64) did not achieve statistical significance. CONCLUSIONS: Clinical variables associated with prolonged survival after surgery for LM in CRC patients include prolonged disease-free interval between primary tumor and metastatic spread, normal prethoracotomy carcinoembryonic antigen, absence of thoracic node involvement, and a single pulmonary lesion.

VGLUT1 is Present in Cortical, Hippocampal and Striatal Astrocytes

The last decade has presented studies providing evidence for astrocytic exocytosis of glutamate potentiating nerve signals. To make further investigations into this astrocytic attribute we investigated the localization of the vesicular glutamate transporter 1 (VGLUT1) in small processes of astrocytes close to glutamatergic terminals in frontal cortex, striatum, molecular layer of hippocampus and stratum radiatum of hippocampus. According to the importance of VGLUT1 in glutamate exocytosis the presence of VGLUT1 in astrocytic processes indicates the ability to exocytose glutamate. METHODS: For qualitative analysis we used immunoflourescence histochemistry. Sections from rat frontal cortex, striatum, molecular layer of hippocampus and stratum radiatum of hippocampus were labeled with antibodies against glutamine synthetase (an astrocytic marker) and VGLUT1. Z-stacks of 4.5-5 lm obtained by confocal microscopy from each section were deconvolved and 3D reconstructed in Amira. Small astrocytic processes were analysed for the presence of VGLUT1 inside the processes. The quantitative analysis was done by immunogold labeling. Ultrathin sections from each brain region were labeled for GLT (an astrocytic marker) and VGLUT1. Pictures obtained by electron microscopy were analysed and the point density (gold particles/nm2) for VGLUT1 in astrocytic processes was measured. RESULTS: Using confocal 3D reconstructions we were qualitatively able to identify VGLUT1 within small processes of astrocytes in all four brain regions. Reflecting our qualitative findings the electron microscopical immunogold quantifications showed a significant density of gold particles signaling VGLUT1 in astrocytic processes in all four brain regions. CONCLUSION: We extend the results of previous studies on glutamate release from astrocytes, which have focused on the hippocampus, proposing that astrocytic exocytosis of glutamate is a global phenomenon in the brain.

A fast 3D approach for coronary MRA.

Two-dimensional (2D)-breath-hold coronary magnetic resonance angiography (MRA) has been shown to be a fast and reliable method to depict the proximal coronary arteries. Recent developments, however, allow for free-breathing navigator gated and navigator corrected three-dimensional (3D) coronary MRA. These 3D approaches have potential for improved signal-to-noise ratio (SNR) and allow for the acquisition of adjacent thin slices without the misregistration problems known from 2D approaches. Still, a major impediment of a 3D acquisition is the increased scan time. The purpose of this study was the implementation of a free-breathing navigator gated and corrected ultra-fast 3D coronary MRA technique, which allows for scan times of less than 5 minutes. Twelve healthy adult subjects were examined in the supine position using a navigator gated and corrected ECG triggered ultra-fast 3D interleaved gradient echo planar imaging sequence (TFE-EPI). A 3D slab, consisting of 20 slices with a reconstructed slice thickness of 1.5 mm, was acquired with free-breathing. The diastolic TFE-EPI acquisition block was preceded by a T2prep pre-pulse, a diaphragmatic navigator pulse, and a fat suppression pre-pulse. With a TR of 19 ms and an effective TE of 5.4 ms, the duration of the data acquisition window duration was 38 ms. The in-plane spatial resolution was 1.0-1.3 mm*1.5-1.9 mm. In all cases, the entire left main (LM) and extensive portions of the left anterior descending (LAD) and right coronary artery (RCA) could be visualized with an average scan time for the entire 3D-volume data set of 2:57 +/- 0:51 minutes. Average contiguous vessel length visualized was 53 +/- 11 mm (range: 42 to 75 mm) for the LAD and 84 +/- 14 mm (range: 62 to 112 mm) for the RCA. Contrast-to-noise between coronary blood and myocardium was 5.0 +/- 2.3 for the LM/LAD and 8.0 +/- 2.9 for the RCA, resulting in an excellent suppression of myocardium. We present a new approach for free-breathing 3D coronary MRA, which allows for scan times superior to corresponding 2D coronary MRA approaches, and which takes advantage of the enhanced SNR of 3D acquisitions and the post-processing benefits of thin adjacent slices. The robust image quality and the short average scanning time suggest that this approach may be useful for screening the major coronary arteries or identification of anomalous coronary arteries. J. Magn. Reson. Imaging 1999;10:821-825.

Free-breathing 3D coronary MRA: the impact of "isotropic" image resolution.

During conventional x-ray coronary angiography, multiple projections of the coronary arteries are acquired to define coronary anatomy precisely. Due to time constraints, coronary magnetic resonance angiography (MRA) usually provides only one or two views of the major coronary vessels. A coronary MRA approach that allowed for reconstruction of arbitrary isotropic orientations might therefore be desirable. The purpose of the study was to develop a three-dimensional (3D) coronary MRA technique with isotropic image resolution in a relatively short scanning time that allows for reconstruction of arbitrary views of the coronary arteries without constraints given by anisotropic voxel size. Eight healthy adult subjects were examined using a real-time navigator-gated and corrected free-breathing interleaved echoplanar (TFE-EPI) 3D-MRA sequence. Two 3D datasets were acquired for the left and right coronary systems in each subject, one with anisotropic (1.0 x 1.5 x 3.0 mm, 10 slices) and one with "near" isotropic (1.0 x 1.5 x 1.0 mm, 30 slices) image resolution. All other imaging parameters were maintained. In all cases, the entire left main (LM) and extensive portions of the left anterior descending (LAD) and the right coronary artery (RCA) were visualized. Objective assessment of coronary vessel sharpness was similar (41% +/- 5% vs. 42% +/- 5%; P = NS) between in-plane and through-plane views with "isotropic" voxel size but differed (32% +/- 7% vs. 23% +/- 4%; P < 0.001) with nonisotropic voxel size. In reconstructed views oriented in the through-plane direction, the vessel border was 86% more defined (P < 0.01) for isotropic compared with anisotropic images. A smaller (30%; P < 0.001) improvement was seen for in-plane reconstructions. Vessel diameter measurements were view independent (2.81 +/- 0.45 mm vs. 2.66 +/- 0.52 mm; P = NS) for isotropic, but differed (2.71 +/- 0.51 mm vs. 3.30 +/- 0.38 mm; P < 0.001) between anisotropic views. Average scanning time was 2:31 +/- 0:57 minutes for anisotropic and 7:11 +/- 3:02 minutes for isotropic image resolution (P < 0.001). We present a new approach for "near" isotropic 3D coronary artery imaging, which allows for reconstruction of arbitrary views of the coronary arteries. The good delineation of the coronary arteries in all views suggests that isotropic 3D coronary MRA might be a preferred technique for the assessment of coronary disease, although at the expense of prolonged scan times. Comparative studies with conventional x-ray angiography are needed to investigate the clinical utility of the isotropic strategy.

Hemodialysis for cefepime intoxication: A case report

Introduction: We report a case of cefepime intoxication with acute severe neurologic symptoms, which was treated by temporary hemodialysis. Patients (or Materials) and Methods: Cefepime 2 g BID for endovascular prosthesis infection was prescribed to a frail, chronically ill 88-year-old woman with a serum creatinine of 199 μmol/L and an estimated creatinine clearance of 13 mL/min (Cockroft formula). Two days later, she was transferred to a neurocritical care unit because of acute aphasia, myoclonic jerks, and delirium with a Glasgow coma scale score of 12/15. The following day, in the absence of other causes, cefepime intoxication was hypothesized, and cefepime was withdrawn after a total of 7 doses = 14 g. Over the next 24 hours, two 3-hour hemodialysis (HD) sessions were performed under cefepime concentration monitoring. Results: Cefepime plasma levels were measured by liquid chromatography/ mass spectrometry. There is no validated reference range, but a study (Chapuis T et al, Critical Care, 2010) found a 50% risk of neurotoxicity with residual levels > 15 mg/L. In our patient, levels were 83.3 mg/L 10 hours after last dose, 24.1 mg/L immediately after the first HD session, 13.4 mg/L immediately before the second HD session, and 2.5 mg/L immediately after the second HD session. The patient made a full clinical recovery over the next 48 hours. The 70% to 80% fall in plasmatic levels observed during each HD session is in accordance with literature data (Schmaldienst S et al, Eur J Clin Pharmacol, 2000, and Manyor LM et al, Pharmacotherapy, 2008). According to kinetic simulation, cefepime dropped at a concentration < 15 mg/L 15 hours earlier with HD than it would have without. Conclusion: Neuropsychiatric adverse effects of beta-lactam antibiotics can be easily overlooked by clinicians. One should be especially cautious with their use in very old and frail patients in whom plasma creatinine poorly estimates renal function and cognitive impairment is highly prevalent. Temporary hemodialysis effectively clears cefepime, but its role in hastening clinical recovery may be limited.