Residual Pure Intralymphatic Breast Carcinoma Following Neoadjuvant Chemotherapy Is Indicative of Poor Clinical Outcome, Even in Node-Negative Patients.

Residual carcinoma confined to lymphovascular spaces following neoadjuvant chemotherapy (NAC) for invasive breast carcinoma is an uncommon finding. We studied pathologic features and outcome for patients with pure intralymphatic carcinoma (PIC) following NAC, a pattern of residual disease reported to have a poor outcome in the only previously published series of this entity. Six of 284 (2.1%) patients treated with NAC were studied. All 6 patients had axillary lymph node involvement before NAC. Tumors were triple-negative (n=3) and HER2+ (n=3: 2 ER+, 1 ER-). Two patients presented with clinical findings of inflammatory carcinoma. Three of 5 pre-NAC core biopsies showed lymphovascular invasion. Three patients showed complete clinical response to NAC, and 3 showed partial response. Post-NAC surgical specimens showed foci of intralymphatic carcinoma in the breast spanning an extent of 0.5 mm to 0.5 cm. Residual ductal carcinoma in situ was present in 2 cases. Four of 6 patients converted to node-negative following NAC. One patient had distant metastasis at presentation and 1 patient died of pulmonary embolism 2 months after surgery. Three of the 4 remaining patients developed distant metastasis, of which 2 first recurred locally (in mean follow-up of 46.5 mo). Patients with PIC had significant greater risk for relapse (hazard ratio, 10.18 [1.97, 52.58]; P=0.006) compared with other NAC-treated patients, after controlling for residual lymph node involvement, tumor size, tumor subtype, histologic grade, and age. Residual PIC following NAC is associated with poor outcome, including in patients that are node-negative following NAC.

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials.

Transplantation of alginate-encapsulated islets has the potential to treat patients suffering from type I diabetes, a condition characterized by an autoimmune attack against insulin-secreting beta cells. However, there are multiple immunological challenges associated with this procedure, all of which must be adequately addressed prior to translation from trials in small animal and nonhuman primate models to human clinical trials. Principal threats to graft viability include immune-mediated destruction triggered by immunogenic alginate impurities, unfavorable polymer composition and surface characteristics, and release of membrane-permeable antigens, as well as damage associated molecular patterns (DAMPs) by the encapsulated islets themselves. The lack of standardization of significant parameters of bioencapsulation device design and manufacture (i.e., purification protocols, surface-modification grafting techniques, alginate composition modifications) between labs is yet another obstacle that must be overcome before a clinically effective and applicable protocol for encapsulating islets can be implemented. Nonetheless, substantial progress is being made, as is evident from prolonged graft survival times and improved protection from immune-mediated graft destruction reported by various research groups, but also with regard to discoveries of specific pathways involved in explaining observed outcomes. Progress in the latter is essential for a comprehensive understanding of the mechanisms responsible for the varying levels of immunogenicity of certain alginate devices. Successful translation of encapsulated islet transplantation from in vitro and animal model testing to human clinical trials hinges on application of this knowledge of the pathways and interactions which comprise immune-mediated rejection. Thus, this review not only focuses on the different factors contributing to provocation of the immune reaction by encapsulated islets, but also on the defining characteristics of the response itself.

Perampanel in the treatment of partial seizures: Time to onset and duration of most common adverse events from pooled Phase III and extension studies.

Perampanel (PER) is a novel noncompetitive AMPA-receptor antagonist approved in over 40 countries for treatment of partial seizures. The safety and tolerability of PER have been well-documented in three double-blind, randomized, placebo (PBO)-controlled Phase III studies and an open-label extension (OLE). This post hoc analysis evaluated the occurrence and characteristics of the most common treatment-emergent adverse events (TEAEs) associated with PER. Results from the Phase III studies were pooled; post hoc analyses on the double-blind phase and up to 1 year of the OLE were performed on the four most common TEAEs for which incidence was higher for PER than PBO. The four most common TEAEs were dizziness, somnolence, fatigue, and irritability. For most subjects in the Phase III double-blind studies, these TEAEs were observed during 6-week titration and were mild or moderate in severity. For severe AEs, no dose-response relationship was observed. Patients in the PBO group during Phase III (who therefore received their first PER treatment during OLE) experienced these TEAEs with incidence and timing similar to that of PER-treated patients in Phase III. The first onset of these TEAEs occurred during the early weeks of PER conversion in the OLE. After 6months and up to 1 year of PER treatment, low to no incidence of the first onset of the four TEAEs was observed. Post hoc analyses of data from pooled Phase III studies provide greater insight into occurrence/duration of TEAEs. Phase III double-blind and OLE data showed that dizziness, somnolence, fatigue, and irritability were the most common TEAEs reported by patients taking PER. Additionally, these results suggest consistency between studies in patient responses to onset of these TEAEs. Although concomitant antiepileptic drugs (AEDs) might be predicted to affect development of TEAEs in patients taking PER, an effect was not observed in this analysis. The low incidence of TEAEs in these studies provides additional support for long-term PER treatment.

Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model.

Multiple sclerosis (MS) is characterized by central nervous system (CNS) inflammation, demyelination, and axonal degeneration. CXCL10 (IP-10), a chemokine for CXCR3+ T cells, is known to regulate T cell differentiation and migration in the periphery, but effects of CXCL10 produced endogenously in the CNS on immune cell trafficking are unknown. We created floxed cxcl10 mice and crossed them with mice carrying an astrocyte-specific Cre transgene (mGFAPcre) to ablate astroglial CXCL10 synthesis. These mice, and littermate controls, were immunized with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide) to induce experimental autoimmune encephalomyelitis (EAE). In comparison to the control mice, spinal cord CXCL10 mRNA and protein were sharply diminished in the mGFAPcre/CXCL10fl/fl EAE mice, confirming that astroglia are chiefly responsible for EAE-induced CNS CXCL10 synthesis. Astroglial CXCL10 deletion did not significantly alter the overall composition of CD4+ lymphocytes and CD11b+ cells in the acutely inflamed CNS, but did diminish accumulation of CD4+ lymphocytes in the spinal cord perivascular spaces. Furthermore, IBA1+ microglia/macrophage accumulation within the lesions was not affected by CXCL10 deletion. Clinical deficits were milder and acute demyelination was substantially reduced in the astroglial CXCL10-deleted EAE mice, but long-term axon loss was equally severe in the two groups. We concluded that astroglial CXCL10 enhances spinal cord perivascular CD4+ lymphocyte accumulation and acute spinal cord demyelination in MOG peptide EAE, but does not play an important role in progressive axon loss in this MS model.

Outcomes of anal fistula surgery in patients with inflammatory bowel disease.

BACKGROUND: Anal fistulas in patients with Crohn's disease are especially difficult to manage because of nonhealing and incontinence. We reviewed our outcomes for the newer sphincter-preserving techniques of anal fistula plug and fibrin glue compared with standard treatments of advancement flap closure and seton drain insertion. METHODS: This was a retrospective study of patients with inflammatory bowel disease treated for high transsphincteric anal fistulas. The primary outcome was healing and continence at 12 weeks postoperatively. RESULTS: Between 1997 and 2009, 51 patients with anal fistulas and inflammatory bowel disease were identified in the St Paul's Hospital Anal Fistula Database. Postoperative healing rates at 12 weeks for the fistula plug, fibrin glue, flap advancement, and seton drain groups were 75%, 0%, 20%, and 28%, respectively. Continence scores were not altered by these procedures. CONCLUSIONS: Closure of the primary fistula opening in patients with inflammatory bowel disease using a biologic anal fistula plug had improved healing compared with fibrin glue, seton drain, and flap advancement. Given its low morbidity and relative simplicity, the anal fistula plug should be considered for treating high transsphincteric anal fistulas in patients with inflammatory bowel disease.

Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague-Dawley and Long-Evans rats.

RATIONALE: Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is heritable and deficient in certain psychiatric disorders, including schizophrenia. Sprague-Dawley (SD) rats are more sensitive to PPI disruptive effects of dopamine (DA) agonists at long interstimulus intervals (60-120 ms) and less sensitive to their PPI-enhancing effects at short (10-30 ms), compared with Long-Evans (LE) rats. These heritable strain differences in sensitivity to the PPI disruptive effects of DA agonists must ultimately reflect neural changes "downstream" from forebrain DA receptors. OBJECTIVE: The current study evaluated the effects of the DA agonist, apomorphine (APO), on ventral pallidal (VP) gamma-aminobutyric acid (GABA) and glutamate efflux and PPI in SD and LE rats. METHODS: PPI was tested in SD and LE rats after vehicle or APO (0.5 mg/kg, subcutaneously (s.c.)) in a within-subject design. In different SD and LE rats, VP dialysate was collected every 10 min for 120 min after vehicle or APO (0.5 mg/kg, s.c.) and analyzed for GABA and glutamate content by capillary electrophoresis (CE) coupled with laser-induced fluorescence (LIF). RESULTS: As predicted, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared to LE rats. APO significantly reduced VP GABA efflux in SD but not in LE rats; glutamate efflux was unaffected in both strains. CONCLUSION: Heritable strain differences in PPI APO sensitivity in SD vs LE rats parallel, and may be mediated by, strain differences in the VP GABA efflux.

Anal fistula plug and fibrin glue versus conventional treatment in repair of complex anal fistulas.

INTRODUCTION: High transsphincteric fistulas are difficult to treat because fistulotomy of involved sphincter muscle results in incontinence. We compare our outcomes for anal fistula plug, fibrin glue, advancement flap closure, and seton drain insertion. METHODS: This is a retrospective study of patients treated for high transsphincteric anal fistulas. The primary outcome was full healing at 12 weeks postoperatively. RESULTS: Between 1997 and 2008, 232 patients with anal fistula were identified in the St. Paul's Hospital Anal Fistula Database. Postoperative healing rates at the 12-week follow-up for the fistula plug, fibrin glue, flap advancement, and seton drain groups were 59.3%, 39.1%, 60.4%, and 32.6%, respectively (P < .0001). CONCLUSIONS: Closure of the primary fistula opening using a biological anal fistula plug and anal flap advancement result in similar fistula healing rates in patients with high transsphincteric fistulae. These 2 strategies are superior to seton placement and fibrin glue. Given the low morbidity and relative simplicity of the procedure, the anal fistula plug is a viable alternative treatment for patients with high transsphincteric anal fistulas.

Isolated fatty liver from prolonged propofol use in a pediatric patient with refractory status epilepticus.

Propofol is a widely used rapidly acting sedating or hypnotic agent in the intensive care setting. It is generally considered safe in both pediatric and adult patients and has been used frequently in cases of refractory status epilepticus. The formulation of propofol is highly lipophilic to facilitate central nervous system penetration and has a high fat content, and prolonged infusions have been known to cause both extrahepatic complications and hepatomegaly secondary to fatty liver. Whereas extrahepatic manifestations of prolonged propofol infusions have been well reported in non-neurologic intensive care patients, cases of pathologically confirmed fatty liver in patients with status epilepticus are relatively few. Furthermore, these cases of hepatomegaly and fatty liver have been also in the context of concomitant extrahepatic side effects. We report on a pediatric patient with refractory status epilepticus treated with a prolonged propofol infusion who developed isolated pathologically confirmed fatty liver without the usually reported extrahepatic manifestations.

Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation.

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is deficient in several brain disorders and is disrupted in rats by dopamine (DA) agonists. Robust heritable strain differences are observed between Sprague-Dawley (SD) and Long-Evans (LE) strains in sensitivity to the PPI-disruptive effects of DA agonists associated with differential gene expression in the nucleus accumbens. Here, we compared the contribution of D2 versus D3 receptors with this heritable difference, using the D3-preferential agonist (pramipexole), the mixed D3/D2 agonist (quinpirole), the mixed D1/D2-like agonist (apomorphine), and the preferential D2 antagonist (L741,626). All DA agonists disrupted PPI in SD and LE rats. Greater sensitivity for this effect was evident with apomorphine and quinpirole in SD than LE rats, but not with pramipexole. The selective D2 antagonist L741,626 preferentially reversed apomorphine-induced PPI deficits at a dose that did not alter pramipexole-induced PPI deficits. We conclude that the heritable pattern of greater PPI 'disruptability' by DA agonists in SD versus LE rats reflects differences in D2 but not D3 receptor-associated mechanisms.

A novel rat strain with enhanced sensitivity to the effects of dopamine agonists on startle gating.

BACKGROUND: Compared to outbred Sprague Dawley (SD) rats, inbred Brown Norway (BN) rats exhibit less prepulse inhibition of startle (PPI) at long prepulse intervals, and more PPI at short intervals. Sensitivity to dopaminergic drug effects on PPI differs substantially across strains, and is heritable within SD and other outbred strains. To further understand the heritability of PPI and its sensitivity to dopamine agonists, we assessed PPI and apomorphine sensitivity in SD, BN and F1 (SD x BN) rats. METHODS: PPI was measured in BN, SD and F1 rats under a variety of stimulus conditions, and after treatment with apomorphine. RESULTS: Findings confirmed significantly more PPI in BN compared to SD rats at short prepulse intervals, and significantly more PPI in SD compared to BN rats at long intervals. F1s were "supersensitive" to both the PPI-disruptive effects of apomorphine at longer intervals, and the PPI-enhancing effects of apomorphine at shorter intervals, compared to either parental strain. CONCLUSION: Differences in sensorimotor gating between SD and BN rats are robust, time-locked and consistent across studies. Unlike patterns in other strains, heritability of PPI apomorphine sensitivity phenotypes in SD x BN F1s cannot be easily explained by simple additive effects.

Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease.

Kidney podocytes and their foot processes maintain the ultrafiltration barrier and prevent urinary protein loss (proteinuria). Here we show that the GTPase dynamin is essential for podocyte function. During proteinuric kidney disease, induction of cytoplasmic cathepsin L leads to cleavage of dynamin at an evolutionary conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria. Dynamin mutants that lack the cathepsin L site, or render the cathepsin L site inaccessible through dynamin self-assembly, are resistant to cathepsin L cleavage. When delivered into mice, these mutants restored podocyte function and resolve proteinuria. Our study identifies dynamin as a critical regulator of renal permselectivity that is specifically targeted by proteolysis under pathological conditions.

Physical and functional connection between auxilin and dynamin during endocytosis.

During clathrin-mediated endocytosis, the GTPase dynamin promotes formation of clathrin-coated vesicles, but its mode of action is unresolved. We provide evidence that a switch in three functional states of dynamin (dimers, tetramers, rings/spirals) coordinates its GTPase cycle. Dimers exhibit negative cooperativity whereas tetramers exhibit positive cooperativity with respect to GTP. Our study identifies tetramers as the kinetically most stable GTP-bound conformation of dynamin, which is required to promote further assembly into higher order structures such as rings or spirals. In addition, using fluorescence lifetime imaging microscopy, we show that interactions between dynamin and auxilin in cells are GTP-, endocytosis- and tetramer-dependent. Furthermore, we show that the cochaperone activity of auxilin is required for constriction of clathrin-coated pits, the same early step in endocytosis known to be regulated by the lifetime of dynamin:GTP. Together, our findings support the model that the GTP-bound conformation of dynamin tetramers stimulates formation of constricted coated pits at the plasma membrane by regulating the chaperone activity of hsc70/auxilin.

Increased CXCL8 (IL-8) expression in Multiple Sclerosis.

Multiple Sclerosis (MS) is a chronic inflammatory disease of the CNS which is characterized by large mononuclear cell infiltration and significant demyelination. CXCL8 is a chemo-attractant for both neutrophils and monocytes and triggers their firm adhesion to endothelium. In this study, we demonstrate that serum CXCL8 and CXCL8 secretion from PBMCs are significantly higher in untreated MS patients compared to controls and are significantly reduced in MS patients receiving interferon-beta1a therapy. We suggest that CXCL8 may serve as a marker of monocyte activity in MS and may play a role in monocyte recruitment to the CNS.

Clinical evaluation of patients with head trauma.

Head trauma is a very common and sometimes life-threatening medical condition that involves sports medicine physicians, emergency room physicians, neurologists, neurosurgeons, orthopedists, anesthesiologists, rehabilitation physicians, psychiatrists, and radiologists; as well as allied health care workers such as physical, occupational, and speech therapists, clinical psychologists, neuropsychologists, and many others. Head trauma needs to be approached by a mutlidisciplinary team because it is complex. Specialized trauma centers incorporate all of these specialists and the best medical technology for optimal management of head trauma. The following chapters cover the use of different neuroimaging techniques, including CT scan and MRI, that greatly aid clinicians in evaluation and management of head trauma patients. These advances have truly revolutionized medicine and it has happened rapidly--pneumoencephalography was the neuroimaging study of choice less than half a century ago. The future of neuroimaging in head trauma will undoubtedly include advances we can not yet foresee but that will allow clinicians to continue to improve patient care.