'MRI-tis' in the early diagnosis of axial SpA: issues and limitations

Sacroiliitis on conventional radiography, a key diagnostic feature of axial spondyloarthritis (SpA), often appears only late in the disease course. With the introduction of potent biologic agents that may also be effective in early disease, diagnostic techniques that can identify SpA early in the disease course would be highly beneficial to patients. MRI has been proposed as a novel diagnostic tool for early axial SpA based on the visualization of active inflammatory lesions in established axial SpA, as well as in pre-radiographic axial SpA. Accordingly, MRI is already widely used in clinical practice and has been included in new classification criteria. However, the specificity and predictive value of MRI lesions for the development of axial SpA remain to be fully defined and validated. Most data come from cross-sectional analyses and have not been validated in prospective studies, and the few available prospective studies were performed in highly selected patient populations and have assessed the value of MRI for the prediction of sacroiliitis rather than axial SpA. Also, some studies have indicated considerable diversity in the pattern and extent of MRI lesions, and suggest that many lesions are not specific for SpA. Prospective, longitudinal studies are needed to validate the utility of this new imaging modality for the diagnosis of axial SpA.     

Optimization of Hyperthermic Intraperitoneal Chemotherapy With Oxaliplatin Plus Irinotecan at 43°C After Compete Cytoreductive Surgery: Mortality and Morbidity in 106 Consecutive Patients

Background Peritoneal carcinomatosis (PC), which has hitherto been regarded as a lethal entity, can now be cured with surgery (treating macroscopic tumor seeding) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) (treating residual microscopic disease). The purpose of this study was to analyze the morbidity and mortality of a particular approach associating optimal (R0–R1) cytoreduction, optimal HIPEC combining oxaliplatin and irinotecan, and an optimal homogeneous intraperitoneal temperature of 43°C. Methods A total of 106 consecutive patients were included in this prospective phase 2 study. After complete resection of the PC, HIPEC was performed by the Coliseum technique with oxaliplatin (360 mg/m²) combined with irinotecan (360 mg/m²) in 2 L/m² of 5% dextrose, over 30 minutes at a real intraperitoneal temperature of 43°C. During the hour preceding HIPEC, patients received 5-fluorouracil (400 mg/m²) and leucovorin (20 mg/m²) intravenously, resulting in tritherapy. Results Postoperative mortality and morbidity rates were 4% and 66%, respectively. The most frequent complications were digestive fistula (24%), lung infection (16%), and severe hematological toxicity (11%). Statistical correlation was evidenced between morbidity and the carcinomatosis score (P = .0008), the number of resected organs (P = .0001), the duration of surgery (P = .0001), and blood loss (P = .0001). Conclusions This new approach, optimized in three respects (complete cytoreduction, combination oxaliplatin with irinotecan, and high temperature) has resulted in a relatively high but acceptable incidence of adverse events considering the expected advantage for survival.     

Prognosis and histopathologic features in papillary tumors of the pineal region: a retrospective multicenter study of 31 cases

Papillary tumor of the pineal region (PTPR) is a recently described tumor entity thought to arise from the specialized ependyma of the subcommissural organ. Whereas histologic features of PTPR are well defined, data on the prognostic value of PTPR remain scarce. We therefore investigated clinicopathologic features, including data on progression-free survival and overall survival, in a retrospective series of 31 PTPR. The age of the 14 males and 17 females ranged from 5 to 66 years (median age, 29 years). Histologically, all tumors were characterized by an epithelial-like growth pattern in which the vessels were covered by layers of columnar or cuboidal tumor cells forming perivascular pseudorosettes. Most of the tumor cells showed strong expression of neuron-specific enolase, cytokeratins (particularly CK18), S-100 protein, and vimentin. Most PTPRs examined also expressed microtubule-associated protein-2. Expression of synaptophysin, epithelial membrane antigen, transthyretin, neural cell adhesion molecule, and nestin was encountered in some tumors. Gross total resection could be achieved in 21 of 31 cases; 15 patients received radiotherapy on resection of the primary tumor. Nevertheless, the majority of patients experienced recurrences; 5-year estimates for overall survival and progression-free survival were 73% and 27%, respectively. To conclude, the clinical course of PTPR is characterized by frequent local recurrence, and the value of radiotherapy on disease progression will need to be investigated in future prospective trials.     

Glutamate receptor changes associated with transient anoxia/hypoglycaemia in hippocampal slice cultures

Transient anoxia/hypoglycaemia in organotypic hippocampal slice cultures, a model of transient brain ischaemia, ultimately results in delayed cell death. Although the mechanisms underlying this delayed death remain unknown, an increase in excitatory drive has been postulated. We report here that transient anoxia/hypoglycaemia in rat hippocampal slice cultures resulted in a 70-80% enhancement of evoked, alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) receptor-mediated, excitatory responses lasting over 60 min. This effect was prevented by blockade of N-methyl-d-aspartate (NMDA) receptors, did not involve changes of paired-pulse facilitation ratio, but was associated with a 50% increase in amplitude, but not frequency, of spontaneous miniature excitatory postsynaptic currents (mEPSCs). Consistent with this, paired recordings revealed the appearance of AMPA receptor-mediated EPSCs at previously silent synapses and occlusion by prior induction of long-term potentiation (LTP). Transient anoxia/hypoglycaemia further resulted in a 63% potentiation of evoked NMDA receptor-dependent synaptic responses, accounting for the 20% increase in ratio of AMPA to NMDA responses. No change in rectification properties of AMPA receptor-mediated currents could be detected within the first hour following anoxia/hypoglycaemia-induced potentiation. Western blot analyses of slice cultures exposed to either control conditions or a short anoxia/hypoglycaemia revealed a marked, 50-70% increase of GluR1, GluR2/3 and NR1 subunits 1 h, but not 15 min, after the anoxic/hypoglycaemic episode. This increase was blocked by an inhibitor of protein synthesis. Together these results indicate that a transient anoxia/hypoglycaemia is associated with a marked enhancement of excitatory transmission sharing similarities with the mechanisms underlying LTP, and is correlated with an increased synthesis of excitatory receptor subunits.     

Bone Mineral Density in Young Women on Methadone Substitution

Little is known about bone mineral density (BMD) in patients with heroin addiction and subsequent methadone substitution. The goal of this study was to compare bone mass density of young HIV-negative women on long-term methadone treatment to a local group of young healthy women. Eleven women (aged 20–29) with previous heroin dependence and current methadone substitution (20–140 mg, median 60, daily) for 1.5–9 (median 3) years were compared to 30 healthy women (aged 20–28). Participants were examined with dual-energy X-ray absorptiometry of the lumbar spine (L2–L4), of the total proximal hip area, and of the femoral neck. Patients and controls had neither current nor lifetime underweight condition, had comparable ages at menarche, and did not differ significantly in current body mass index (21.9 ± 4.0, respectively, 20.5 ± 1.5 kg/m²) in spite of a largely unhealthy lifestyle (cigarette, alcohol, and cocaine consumption in patients). Patients’ total-hip parameters were marginally lower than those of controls (BMD P = 0.054, T score P = 0.049), whereas the femoral neck and lumbar spine parameters did not differ significantly between the two groups. Long-term methadone substitution in HIV-negative women seems to slightly affect bone mass density.     

In vitro mitogen-stimulated T-cell from hepatitis C virus-positive liver transplantation candidates, increases T-cell activation markers and T-cell proliferation

The incidence of acute rejection is significantly higher in hepatitis C virus (HCV) liver-transplant patients than in patients who have received a graft for other liver diseases, i.e., mainly alcoholic cirrhosis. The aim of this study was to assess T-cell function, i.e., intralymphocyte cytokine expression (IL-2 and TNF-alpha), T-cell activation [i.e., transferrin receptor (CD71) and interleukin (IL)-2 alpha-chain (CD25) expression], and T-cell proliferation using a flow-cytometry whole-blood assay in patients waiting for a liver transplantation (n=49). Our data suggest that, in mitogen-stimulated T-cells, (i) intra-lymphocyte cytokine expression is significantly higher in patients with liver disease than in healthy volunteers (n=25); (ii) the expression of T-cell activation markers is decreased in patients with liver cirrhosis compared to healthy volunteers, and (iii) the expression of T-cell activation markers and T-cell proliferation are increased in patients with HCV infection (n=15) compared to those without HCV infection (n=34), particularly compared to patients with alcoholic liver disease (n=19). Circulating CD19-positive cells count was also significantly higher in HCV-positive patients. In conclusion, in vitro, mitogen-stimulated T-cell seem to induce a higher immune response in the blood from patients waiting for a liver transplant for HCV-related liver disease than those without HCV infection, and particularly those with alcoholic liver disease.     

A prognostic system applicable to patients with resectable liver metastasis from colorectal carcinoma staged by positron emission tomography with [18F]fluoro-2-deoxy-D-glucose: role of primary tumor variables

BACKGROUND: The purpose of this study was to develop a prognostic system applicable to patients with hepatic metastasis from colorectal cancer in whom extrahepatic disease was excluded by preoperative PET with [(18)F]fluoro-2-deoxy-D-glucose (FDG-PET). Data from two institutions were analyzed separately and together to improve general applicability of results. STUDY DESIGN: Data were analyzed for 285 consecutive patients undergoing liver resection for colorectal metastases from 1995 to 2005 at 2 institutions routinely using preoperative FDG-PET with. Fifteen clinicopathologic variables of the primary and secondary tumors were examined to identify factors predictive of survival. RESULTS: Outcomes were correlated with poorly differentiated tumor grade in both data sets. Because patients with poorly differentiated tumors comprised a small proportion (16%) of the population, patients with well-differentiated or moderately differentiated tumors were analyzed independently. In this subgroup, positive lymph node status in the primary colorectal tumor resection specimen was the only characteristic that predicted survival of patients in both institutions. Consequently, patients were sorted into three prognostic categories: poor tumor differentiation; well-differentiated or moderately differentiated tumors and node positive; and well-differentiated or moderately differentiated tumors and node negative. These groups had significantly different overall survival on Kaplan-Meier analysis (p=0.0014). CONCLUSIONS: In patients with colorectal liver metastases staged with FDG-PET with overall survival can be predicted directly from data in the pathology report of the colorectal primary tumor. This study also indicates the need for new molecular tumor markers of prognosis to complement clinicopathologic markers if the goal of prediction of outcomes in individual patients is to be reached.     

Allosensitization in bridge to transplant Novacor left ventricular assist device patients: analysis of long-term outcomes with regard to acute rejection and chronic allograft vasculopathy

BACKGROUND: The true relevance of allosensitization in patients benefiting from left ventricular assist device (LVAD) as bridge to transplant (BTT) is still debated. Available registry data referred to numerous devices precluding LVAD-specific analysis. Therefore, we studied all patients with Novacor LVAD prior to transplantation. METHODS: From 1985 to 2006, 37 Novacor LVADs were implanted as BTT, with 30 patients surviving to transplantation (81%). Post-LVAD sensitization was determined for anti-HLA-class I and class II IgGs. Study endpoints were overall survival and/or graft loss, > or =3A cellular rejection and chronic allograft vasculopathy (CAV). The results from LVAD patients were compared to non-LVAD primary heart transplant recipients (n=318). RESULTS: After LVAD insertion, 5 out of 27 patients available for analysis developed anti-HLA antibodies (18.5%). The mean anti-HLA titer after Novacor LVAD implantation was 14% [SD 31]. Actuarial 5- and 10-year patient/graft survival for LVAD and non-LVAD transplant recipients were 73% and 55%, and 70% and 55%, respectively (p=NS). Overall prevalence of rejection > or =3A was 23.3 % (LVAD group) and 18.9% (non-LVAD group) (p=NS). At follow-up, the respective incidence of CAV was 8% (LVAD group) and 32.4% (non-LVAD group) (p<0.01). However, mean follow-up was significantly different for LVAD and non-LVAD patients, 46 vs 90 months (p<0.001). CONCLUSION: In this study, allosensitization occurred infrequently after Novacor LVAD implantation. Secondly, analysis of outcome variables shows that Novacor-LVAD BTT patients can anticipate similar survival to non-LVAD patients, thus minimizing the impact of allosensitization after LVAD implantation.     

Human fetal bone cells associated with ceramic reinforced PLA scaffolds for tissue engineering

Fetal bone cells were shown to have an interesting potential for therapeutic use in bone tissue engineering due to their rapid growth rate and their ability to differentiate into mature osteoblasts in vitro. We describe hereafter their capability to promote bone repair in vivo when combined with porous scaffolds based on poly(l-lactic acid) (PLA) obtained by supercritical gas foaming and reinforced with 5 wt.% beta-tricalcium phosphate (TCP). Bone regeneration was assessed by radiography and histology after implantation of PLA/TCP scaffolds alone, seeded with primary fetal bone cells, or coated with demineralized bone matrix. Craniotomy critical size defects and drill defects in the femoral condyle in rats were employed. In the cranial defects, polymer degradation and cortical bone regeneration were studied up to 12 months postoperatively. Complete bone ingrowth was observed after implantation of PLA/TCP constructs seeded with human fetal bone cells. Further tests were conducted in the trabecular neighborhood of femoral condyles, where scaffolds seeded with fetal bone cells also promoted bone repair. We present here a promising approach for bone tissue engineering using human primary fetal bone cells in combination with porous PLA/TCP structures. Fetal bone cells could be selected regarding osteogenic and immune-related properties, along with their rapid growth, ease of cell banking and associated safety.