Eventual Poor Outcome Research Articles

Pediatric spinal cord infarction following a minor trauma: a case report.

Pediatric spinal cord infarction is a rare entity that presents a diagnostic challenge at the emergency department. Ischemic spinal cord infarction can occur in the setting of trauma, cardiovascular malformation, or postoperatively. We report a case of anterior spinal artery infarction following seemingly minor trauma in an otherwise healthy 14-year-old male. A 14-year-old male presented with unprovoked sudden-onset stabbing back pain earlier that day. The patient then demonstrated bilateral lower extremities weakness while at the emergency department. After extensive diagnostic workup, the patient was diagnosed with anterior spinal artery territory infarction involving the thoracic spinal cord. Minor trauma to the thoracic spinal cord was detected on imaging and was believed to be the culprit of this event. Given the rarity of spinal cord ischemia, a high index of suspicion and extensive workup of patients presenting with clinical weakness are needed for accurate diagnosis and to avoid the eventual poor outcome. With so few reports in the literature regarding spinal cord ischemia in the pediatric population, accurate diagnosis is often delayed until after irreversible events have already taken place. Our case report of anterior spinal artery distribution thoracic cord infarct following a minor trauma was diagnosed by axial thin-slice DWI MRI with an otherwise negative workup.

Increased Plasma Galectin-3 Preceding the Development of Delayed Cerebral Infarction and Eventual Poor Outcome in Non-Severe Aneurysmal Subarachnoid Hemorrhage.

A matricellular protein galectin-3 is involved in tissue injury and inflammation, but the role of galectin-3 remains unclear in aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to assess whether acute-stage galectin-3 levels were associated with the subsequent development of neurovascular events and outcome after SAH. This study included 83 consecutive patients diagnosed with aneurysmal SAH of resuscitated World Federation of Neurological Surgeons (WFNS) grades 1-3. Plasma galectin-3 levels were once measured on days 1-3 (the day after clipping or coiling). Fifteen patients had poor outcomes, which were associated with increasing age, female, pre-onset morbidity, worse WFNS grade, modified Fisher computed tomography scale, acute hydrocephalus, and higher galectin-3 levels compared with good outcomes. Multivariate analyses revealed that plasma galectin-3 was an independent determinant for poor outcome (odds ratio, 3.08; 95% confidence interval, 1.58-6.00; p=0.001). Among post-SAH neurovascular events occurring on day 4 and thereafter, delayed cerebral ischemia and infarction, but not angiographic vasospasm and shunt-dependent hydrocephalus, showed significantly higher plasma galectin-3 levels on days 1-3. The receiver operating characteristic curve indicated that plasma galectin-3 with a cutoff value of 3.30 or 3.48ng/ml predicted delayed cerebral infarction development or poor outcome (specificity, 62.5%, 70.6%; sensitivity, 90.9%, 73.3%, respectively). The findings suggest that plasma galectin-3 levels on days 1-3 would be a useful biomarker for predicting subsequent development of delayed cerebral infarction and eventual poor outcome and provide a new candidate, which may mediate between post-SAH early brain injury or inflammation and delayed cerebral infarction without vasospasm.

Lumboperitoneal shunt for the treatment of leptomeningeal metastasis

Leptomeningeal metastasis (LM) is thought to be a devastating and increasingly frequent neurological complication of cancer characterized by infiltration of malignant cells into the leptomeninges and the subarachnoid space. Intracranial hypertension and hydrocephalus are observed in about half of patients with LM. They are responsible for rapidly declining neurological status and eventual poor outcome in many patients with LM. Impediment of CSF circulation is considered the pathophysiological basis of increased intracranial pressure and hydrocephalus related to LM, which makes ventriculoperitoneal shunt (VP shunt) an acceptable palliative approach for LM now. It is noteworthy that LM generally causes communicating hydrocephalus. Lumboperitoneal shunt (LP shunt) has been demonstrated to be effective in the treatment of communicating hydrocephalus secondary to hemorrhage or infection, idiopathic intracranial hypertension and normal pressure hydrocephalus. And LP shunt has several advantages over VP shunt. Therefore we hypothesize that LP shunt can be used in the treatment of intracranial hypertension and hydrocephalus related to LM and should be given greater priority over VP shunt.

Short term outcomes following clipping and coiling of ruptured intracranial aneurysms: does some of the benefit of coiling stem from less procedural impact on deranged physiology at presentation?

BackgroundEndovascular coiling (EVC) has been shown to yield superior clinical outcomes to surgical clipping (SC) in the treatment of ruptured cerebral aneurysms. The reasons for these differences remain obscure. We...

Nucleotide Excision Repair (NER) Is Frequently Impaired and Affects Outcome in Multiple Myeloma (MM)

IntroductionMultiple Myeloma (MM) is a heterogeneous disease characterized by genomic instability and eventual poor outcome. Aberrations in DNA repair-related pathways have been considered to explain the instability. Nucleotide excision repair (NER) is an important pathway involved in the removal of bulky adducts and DNA crosslinks induced by various genotoxins. Little is known about the relationship between NER in MM biology and patient outcomes. Here we assess the role of NER in MM.MethodsWe evaluated NER efficiency in a panel of MM cell lines (n=18), with a functional assay based on the purified DNA-Damage Binding protein 2 (DDB2) complex (DDB2 proteo-probe, Dreze et al. 2014). NER proficiency was correlated with cytogenetic characteristics, p53 status, sequencing data, gene expression profile, and with melphalan (MLP) sensitivity evaluated by CellTiterGlo (CTG). We then evaluated NER efficiency in patient samples and interrogated the role of NER in MM patients by correlating expression of NER genes with survival (OS) in a cohort of 170 patients (IFM 2005-01) homogeneously treated with alkylating agents.ResultsNER, measured as the amount of (6-4) photoproducts remaining 2 hours after UV irradiation, showed variability between MM cell lines. Out of 18 cell lines, 7 exhibited various levels of NER deficiencies, defined as less than 90% repair at 2 hours (4 cell lines 90-70% and 3 cell lines <60%). The other 11 cell lines presented more than 90% of repair.P53 loss of function did not associate with NER deficiency. Notably, all t(4;14) cell lines tested (n=5) showed a NER repair rate > 90%. NER deficient cell lines (NER <90%) were sensitive to melphalan. However all melphalan sensitive cells did not exhibit NER deficiency, This suggests that other DNA repair pathways are involved in the repair of melphalan-induced lesions. Furthermore, we performed the assay in patient samples showing variable levels of NER, which may reflect different disease status and prognosis. Whole genome sequencing data from 6 NER deficient cell lines revealed missense mutations in critical NER genes in 2 of these cell lines. MM1S and MM1R cells showed mutations in the Xeroderma Pigmentosum Complementation Group A (XPA) gene (mutation D70H), and MM1R was also mutated in the Cockayne syndrome, ERCC6 gene (mutation L682I). Gene expression profile comparison in 12 of these showed a positive correlation between expression of NER genes and NER efficiency.We next studied expression of 20 NER genes in 170 patients treated with high dose melphalan (IFM 2005-01). The analysis revealed a significant negative correlation between 5 overexpressed NER genes (ERCC3, ERCC4, ERCC6, MMS19 and NTHL1) and overall survival (OS).ConclusionNER efficiency is heterogeneous in MM, in part due to acquired mutations. Impairment of NER is associated with outcome as well as may contribute to genomic instability. Ability to proficiently measure NER in patient samples provides us an opportunity to now evaluate NER as a prognostic marker in myeloma. DisclosuresNo relevant conflicts of interest to declare.

Treatment Patterns and Outcomes in Elderly Patients with Multiple Myeloma,

Abstract 3980 Background:Nearly half of patients with multiple myeloma (MM) are over 70 years at the time of diagnosis. While the survival of patients with myeloma has improved in the last decade, several studies have suggested no significant change for the elderly patients. These patients often have other comorbidities and are less likely to tolerate standard treatment approaches. We retrospectively studied the treatment patterns, outcomes, and prognostic factors in patients over 75 years of age. PATIENTS AND METHODS:We identified 212 patients who were older than 75 years from among 1545 patients seen at the Mayo Clinic within 90 days of diagnosis during 1999 to 2008. We only included 139 patients in whom complete treatment details were available. RESULTS:The median age was 80 years (range: 76–94) with 20 (14%) patients older than 85 years; 79 (57%) were male. Thirty-five patients (25%) had a history or coexistence of one or more malignancies. Chromosome analysis and FISH were performed in 65% and 22% respectively. Abnormal cytogenetics were seen in 30 (33%) of the 90 tested patients. The median survival of the 139 elderly patients was 27 months (95% CI: 20∼35) compared to 62 months (56∼68) for 1,290 patients ≤ 75 years of age seen during the same period. Sixty-nine (50%) patients received one or more novel agents (thalidomide, lenalidomide, pomalidomide, bortezomib) and showed longer median survival (40 months vs 13 months) compared with those not receiving these agents (p=0.0008). Age over 85, initial poor performance score > 1, thrombocytopenia, elevated serum LDH or beta2-microglobulin, response more than stable disease to first therapy resulted in inferior survival. Among them, only performance status had the persistent significance in multivariate analysis. CONCLUSION:Older patients receiving newer therapies appear to have a better outcome, which is still lagging behind the younger patients. A poor performance score at diagnosis predicts for eventual poor outcome. Disclosures:No relevant conflicts of interest to declare.

Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure.

Although sepsis is the major cause of mortality and morbidity in the critically ill, precise mechanism(s) causing multiorgan dysfunction remain unclear. Findings of impaired oxygen utilization in septic patients and animals implicate nitric oxide-mediated inhibition of the mitochondrial respiratory chain. We recently reported a relationship between skeletal muscle mitochondrial dysfunction, clinical severity, and poor outcome in patients with septic shock. We thus developed a long-term, fluid-resuscitated, fecal peritonitis model utilizing male Wistar rats that closely replicates human physiological, biochemical, and histological findings with a 40% mortality. As with humans, the severity of organ dysfunction and eventual poor outcome were associated with nitric oxide overproduction and increasing mitochondrial dysfunction (complex I inhibition and ATP depletion). This was seen in both vital (liver) and nonvital (skeletal muscle) organs. Likewise, histological evidence of cell death was lacking, suggesting the possibility of an adaptive programmed shutdown of cellular function. This study thus supports the hypothesis that multiorgan dysfunction induced by severe sepsis has a bioenergetic etiology. Despite the well-recognized limitations of laboratory models, we found clear parallels between this long-term model and human disease characteristics that will facilitate future translational research.