Overt gastrointestinal bleeding in patients with cancer: Clinical characteristics and outcomes.

BACKGROUND: The aim of this study was to compare the clinical characteristics and outcomes of gastrointestinal bleeding (GIB) between cancer patients (CP) and non-cancer patients (NCP). METHODS: This was a prospective study of patients admitted with overt GIB between 2013 and 2021. GIB etiology, management and outcomes including rebleeding and mortality, were compared between CP and NCP, and among patients with different types of cancer. The associations with categorical variables were assessed with the Chi-square test, and the t-test was used for continuous variables. RESULTS: Of 674 patients admitted for GIB, 144 (21%) had cancer. 121(84%) CP had active disease, 49% had stage 4 cancer, and 78% had solid tumors, of whom 28 (20%) had luminal GI cancers. The most common were colorectal cancer, prostate cancer, and lymphomas. Compared to NCP, CP had higher age-adjusted Charlson Comorbidity Index, and were less likely to undergo endoscopy or endoscopic therapy. Severe GIB was equally prevalent in both groups, but CP had more severe anemia. Peptic ulcer was the most common etiology in both groups. Of 28 luminal cancer patients, 17(59%) bled from their tumors. Nine patients bled from cancer metastasis to the GI lumen. CP had higher in-hospital, one-month, one-year, and end-of-follow-up mortality. Length of hospital stay and re-bleeding rates did not differ between CP and NCP. CONCLUSIONS: CP with GIB are less likely to have diagnostic and therapeutic endoscopy and have higher mortality than NCP. Steps to identify CP at risk for GIB and to improve their outcomes merit further investigation.

Impact of blood transfusion on mortality and rebleeding in gastrointestinal bleeding: an 8-year cohort from a tertiary care center.

Background: The aim of this study was to investigate the impact of blood transfusion (BT) on mortality and rebleeding in patients with gastrointestinal bleeding (GIB) and whether BT at a threshold of ≤7 g/dL may improve these outcomes. Methods: A prospective study was conducted in patients admitted with GIB between 2013 and 2021. Antithrombotic (AT) use and clinical outcomes were compared between transfused and non-transfused patients, and between those transfused at a threshold of ≤7 vs. >7 g/dL. Multivariate analysis was performed to identify predictors of mortality and rebleeding. Results: A total of 667 patients, including 383 transfused, were followed up for a median of 56 months. Predictors of end-of-follow-up mortality included: age-adjusted Charlson Comorbidity Index, stigmata of recent hemorrhage (SRH), and being on anticoagulants only upon presentation (P=0.026). SRH was a predictor of end-of-follow-up rebleeding, while having been on only antiplatelet therapy (AP) upon presentation was protective (P<0.001). BT was not associated with mortality or rebleeding at 1 month or end of follow up. Among transfused patients, being discharged only on AP protected against mortality (P=0.044). BT at >7 g/dL did not affect the risk of short or long-term rebleeding or mortality compared to BT at ≤7 g/dL. Conclusions: Short- and long-term mortality and rebleeding in GIB were not affected by BT, nor by a transfusion threshold of ≤7 vs. >7 g/dL, but were affected by the use of AT. Further studies that account for AT use are needed to determine the best transfusion strategy in GIB.

Clinical characteristics of symptomatic young patients with colonic adenomas.

Background: The incidence of colonic adenomas and colorectal cancer has been on the rise among young patients. In this study, we aimed to describe the characteristics of young patients (<50 years) with adenomatous polyps and to characterize those polyps. We also aimed to determine appropriate surveillance intervals for young patients. Methods: We performed a retrospective chart review of patients <50 years of age who had polypectomy of 1 or more adenomatous polyps on colonoscopy between 2008 and 2021. Patient demographics, colonoscopy indication and polyp characteristics were obtained from the chart. Timing and findings on surveillance colonoscopies were recorded. Results: A total of 610 patients were included: mean age 42.9±5.9 years, 61% males, body mass index 27.5±4.7 kg/m2, and over 50% smokers. The most common indications were abdominal pain (23.3%), rectal bleeding (22.3%), and change in bowel habits (17.6%). Almost half of the patients who had adenomas (299) were younger than 45 years. Tubular adenoma was the most frequently encountered type of polyp (571; 93.6%). Mean polyp size was 1.1±0.9 cm. The most common location of adenomas was the sigmoid colon (41%). Of patients with adenomas, 156 (26%) had surveillance colonoscopy within 2.9±2.3 years; 74 patients (47.4%) were found to have new adenomas. Conclusions: Patients aged <50 years with colonic adenomas were mostly males, overweight, and smokers. Further adenomas were found in 47% of surveillance colonoscopies, and most were encountered within 5 years. High rates of recurrent adenomas in people <50 years of age may warrant frequent surveillance.

Esophageal cancer: a twenty-four-year experience at a tertiary care center with an evaluation of the prognostic significance of the neutrophil-lymphocyte ratio.

BACKGROUND: A high neutrophil-lymphocyte ratio (NLR) may be associated with worse survival in esophageal cancer (EC). Our aims were to describe the demographic and clinical data of EC in a tertiary referral center in Lebanon and to determine the prognostic value of NLR. METHODS: A retrospective cohort study based on chart review of patients diagnosed with EC was conducted at the American University of Beirut Medical Center (AUBMC). The demographic characteristics, clinical presentation and outcomes were described and compared between squamous cell carcinomas (ESCC) and adenocarcinomas (EAC). Data about esophageal cancer incidence were obtained from the National Cancer Registry, the Ministry of Public Health and GLOBOCAN 2020. Cox regression analysis was performed to determine whether the NLR is an independent predictor of survival, using variables based on clinical knowledge and previously established data. RESULTS: 110 patients were diagnosed with EC, which was the least common among other gastrointestinal malignancies. Our follow up rates reached 86.4%. The median survival was 9 months (IQR 3-25.5.) and was comparable between ESCC (median of 7 months, IQR 2-25) and EAC (median of 9 months, IQR 3-26.3), p = 0.803. Advanced stage was associated with a worse prognosis (p = 0.037). The mean NLR(±SD) was 5.20 ± 6.8, with no significant difference between EAC and ESCC (4.5 ± 3.4 vs. 5.9 ± 9.2, p = 0.420) or between early or advanced stages (5.4 ± 8.1 vs. 4.7 ± 6.8, p = 0.732). The area under the curve for the NLR was 0.560 (95% CI: 0.374-0.746, p = 0.488). After adjusting for age, gender, TNM staging and grading, cox regression analysis showed that an increased NLR was a significant predictor of mortality, with an adjusted hazard ratio of 1.095 (p = 0.011). CONCLUSION: EC is quite uncommon in Lebanon despite a high prevalence of smoking and obesity. Advanced stage and high NLR were associated with a negative prognostic value.

Development and Validation of a Novel 1-year Mortality Risk Score That Includes the Use of Antithrombotic in Patients With Overt Gastrointestinal Bleeding.

GOALS AND BACKGROUND: We aimed to develop a novel 1-year mortality risk-scoring system that includes use of antithrombotic (AT) drugs and to validate it against other scoring systems in patients with acute gastrointestinal bleeding (GIB). STUDY: We developed a risk-scoring system from prospectively collected data on patients admitted with GIB between January 2013 and August 2020, who had at least 1- year of follow-up. Independent predictors of 1-year mortality were determined after adjusting for the following confounders: the age-adjusted Charlson Comorbidity Index (CCI) (divided into 4 groups: CCI-0=0, CCI-1=1 to 3, CCI-2=4 to 6, CCI-3 ≥7), need for blood transfusion, GIB severity, need for endoscopic therapy, and type of AT. The risk score was based on independent predictors. RESULTS: Five hundred seventy-six patients were included and 123 (21%) died at 1-year follow-up. Our risk -score was based on the following: CCI-2 (2 points), CCI-3 (4 points), need for blood transfusion (1 point), and no use of aspirin (1 point), as aspirin use was protective (maximum score=6). Patients with higher risk scores had higher mortality. The model had a better predictive accuracy [AUC=0.82, 95% confidence interval (0.78-0.86), P <0.0001] than the Rockall score for upper GIB (Area Under the Curve (AUC)=0.68, P <<0.0001), the Oakland score for lower GIB (AUC=0.69, p =0.004), or the Shock Index for all (AUC=0.54, P <0.0001). CONCLUSION: A simple and novel score that includes use of AT upon admission accurately predicts 1-year mortality in patients with GIB. This scoring system may help guide follow-up decisions and inform the prognosis of patients with GIB.

Total esophageal food impaction in the era of the COVID-19 pandemic: a delayed presentation in a patient with Parkinson's disease.

Total esophageal food impaction is extremely rare. We report a patient with Parkinsonism who presented with total dysphagia to solids and liquids and with inability to swallow her saliva of 3 days duration. She did not present sooner as she was afraid of contracting COVID-19 during hospitalization. Chest CT scan revealed total esophageal food impaction. Awake fiberoptic endotracheal intubation followed by EGD and clearance of the impacted food were performed. This patient illustrates esophageal involvement in Parkinson's disease, delayed presentation with an emergency in the COVID-19 era, and the multidisciplinary approach to minimize the risk of aspiration during endoscopy.

Impact of sedation type on adenoma detection rate by colonoscopy.

BACKGROUND & AIMS: Endoscopic detection of polyps and adenomas decreases the incidence and mortality of colorectal cancer. The available data concerning the relationship between the sedation type and adenoma detection rate (ADR) or polyp detection rate (PDR) is inconclusive. The aim of our study was to evaluate the impact of conscious vs. deep (propofol) sedation on the ADR/PDR in diagnostic and screening colonoscopies. METHODS: This was a retrospective cohort study. Patients aged 50-75 years old presenting for a first screening or diagnostic colonoscopy were included. Baseline demographic characteristics were collected, as well as PDR and ADR. Endoscopic withdrawal time and quality of bowel preparation rated in a binary fashion were also collected. Two multivariate logistic regression models were used to evaluate the independent predictors of endoscopic detection of polyps and adenomas. RESULTS: 574 patients met our inclusion criteria. Mean age was 59.26 ± 7.21 with 52.4% females and an average BMI of 28.08 ± 4.89. 374 patients (65.2%) underwent screening colonoscopies, and deep sedation was performed in 200 patients (34.8%). Only 4.7% had bad bowel preparation. PDR was 70% and ADR was 52%. On bivariate analysis, no significant difference was shown in PDR and ADR between conscious and deep sedation groups (0.70, 0.71; p = 0.712 and 0.50, 0.54; p = 0.394, respectively). On multivariate analysis for PDR, age and withdrawal time were independent predictors. For ADR, age, female sex, and withdrawal time were independent predictors. Sedation type and the indication did not reach statistical significance in both models. CONCLUSION: The use of deep sedation didn't influence the ADR/PDR quality metrics in our mixed cohort of screening and diagnostic colonoscopies.

Validation of the new ABC score for predicting 30-day mortality in gastrointestinal bleeding.

BACKGROUND/AIM: The ABC score is a new pre-endoscopic scoring system that was recently developed to accurately predict one-month mortality in upper and lower gastrointestinal bleeding (GIB). We aim to validate this new score on a cohort of Lebanese patients treated in a tertiary care center and to compare it to currently existing scores. METHODS: Adult patients admitted to the American University of Beirut Medical Center (AUBMC) with overt GIB between January 2013 and August 2020 were included. The area under receiver operating characteristic (AUROC) curves of the ABC score in predicting 30-day mortality was calculated using the SPSS software. Other optimal existing scores for predicting mortality (the Oakland score for lower GIB, the AIMS-65 and the Rockall scores for upper GIB)s were also assessed and compared to the ABC score. RESULTS: A total of 310 patients were included in our study. For upper GIB, the ABC score showed good performance in predicting 30-day mortality (AUROC: 0.79), outperforming both the AIMS-65 score (AUROC 0.67, p < 0.001) and the Rockall score (AUROC: 0.62, p < 0.001). For lower GIB, the ABC score also had good performance which was comparable to the Oakland score (AUROC: 0.70 vs 0.56, p = 0.26). CONCLUSION: In our cohort of patients, the ABC score demonstrated good performance in predicting 30-day mortality for patients with upper and lower GIB compared to other established risk scores, which may help guide management decisions. This simple and novel score provides valuable prognostic information for patients presenting with GIB and appears to be reproducible in different patient populations.

Resuming aspirin in patients with non-variceal upper gastrointestinal bleeding: a systematic review and meta-analysis.

BACKGROUND: Our primary and secondary aims were to analyze the evidence surrounding mortality and re-bleeding risks in patients on aspirin with non-variceal upper gastrointestinal bleeding (NVUGIB) as a function of whether or not aspirin was resumed after the bleeding episode, and to determine whether aspirin intake upon admission affected the outcomes. METHODS: A search for randomized controlled trials (RCTs) and prospective observational studies was performed. Data extraction and risk of bias assessment were done. Generic inverse variance and random-effects model were employed. Heterogeneity across studies was assessed using the I 2 test. Certainty of evidence was assessed using the GRADE approach for each comparison and outcome, and an evidence profile was created. RESULTS: Evidence from 1 RCT and 4 observational studies suggests that early aspirin resumption reduced mortality (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.06-0.63) while increasing re-bleeding risk (HR 1.90, 95%CI 0.60-6.00); moderate certainty of evidence. The observational evidence was inconsistent for both mortality (HR 0.84, 95%CI 0.54-1.33) and re-bleeding (HR 0.85, 95%CI 0.47-1.55); very low certainty of evidence. Nine observational studies addressed our secondary aim: 6 provided inconsistent results regarding mortality (pooled odds ratio [OR] 1.1, 95%CI 0.80-1.50) and 4 provided inconsistent results regarding re-bleeding risk (pooled OR 0.92, 95%CI 0.53-1.59); very low certainty of evidence for both outcomes. CONCLUSION: Evidence supporting a protective effect of aspirin resumption soon after NVUGIB is of low-to-moderate certainty, and is not informative as to the optimal timing of aspirin resumption.

Increased rebleeding and mortality in patients with gastrointestinal bleeding treated with anticoagulant drugs compared to antiplatelet drugs.

BACKGROUND/AIM: We determined the effect of antiplatelet and anticoagulant agents on rebleeding and mortality in patients with gastrointestinal bleeding. METHODS: This was a prospective study of patients admitted with gastrointestinal bleeding between 2013 and 2018. Outcomes were compared among patients on antiplatelet agents only, anticoagulant drugs only, combination therapy, and none. The association between mortality, rebleeding, and type of antithrombotic medication on admission and discharge was determined using multivariate analysis. RESULTS: A total of 509 patients were followed up for a median of 19 months. End of follow-up rebleeding and mortality rates were 19.4% and 23.0%, respectively. Independent predictors of mortality were age [hazard ratio (HR) = 1.025 per year increase, P = 0.002], higher Charlson Comorbidity Index (HR = 1.4, P < 0.0001), severe bleeding (HR = 2.1, P < 0.0001), and being on anticoagulants (HR = 2.3, P = 0.002). Being on antiplatelets was protective against rebleeding (HR = 0.6, P = 0.047). Those on anticoagulants were more likely to die (HR = 2.5, P < 0.0001) and to rebleed (HR = 2.1, P = 0.01) than those on antiplatelets. Antithrombotic drug discontinuation upon discharge was associated with increased mortality in patients with cardiovascular disease. CONCLUSION: In gastrointestinal bleeding, rebleeding and mortality were associated with being on anticoagulant drugs, while being on antiplatelet agents was protective against rebleeding. Discontinuation of antithrombotics upon discharge increased the risk of death. The findings inform risk stratification and decisions regarding continuation or discontinuation of antithrombotics.

Esophageal Cytomegalovirus and Herpes Simplex virus co-infection in an immunocompromised patient: Case report and review of literature.

Herpes simplex virus and Cytomegalovirus co-infection has been reported to occur in a variety of sites in immunocompromised patients. To our knowledge, few cases of such co-infection have been reported to occur in the esophagus. We report a case of a 60-year-old woman who was maintained on immunosuppressive therapy for a presumed diagnosis of pemphigus vulgaris, who presented with odynophagia. Investigations revealed ulcerative esophagitis caused by both HSV and CMV. The patient was treated with valganciclovir with full recovery. We also present the results of various studies on patients with similar presentation particularly those caused by HSV and CMV co-infection.

The impact of age on prognosis in patients with gastric cancer: experience in a tertiary care centre.

BACKGROUND: Gastric cancer (GC) is a leading cause of cancer-related death in the world and most patients have advanced disease upon presentation. The effect of age on prognosis in GC is controversial. We aimed to determine the impact of age on survival in patients with GC. METHODS: This was a retrospective study of the medical records of Lebanese patients diagnosed with GC at the American University of Beirut Medical Center (AUBMC) between 2005 and 2014. Patients were divided into young (<65 years) and older groups (≥65 years). A multivariate analysis was done to determine the independent predictors of survival. Kaplan-Meier method was used for analysis of long-term survival outcomes. RESULTS: The sample consisted of 156 patients. The mean age was 62.15 (SD 13.54). Most patients presented with stage 4 disease (62.2%) and poorly differentiated histology (66.4%). The most common symptoms were abdominal pain and weight loss. On bivariate analysis, advanced stage (P=0.02) and higher grade (P=0.04) were associated with increased mortality. Patients <65 years of age were significantly more likely to have poorly differentiated tumours, while patients ≥65 years had more comorbidities (P=0.001). The 5-year DFS were 35% and 37% for patients <65 years of age and ≥65 years of age, respectively (P=0.15). CONCLUSIONS: Higher grade and advanced stage are associated with worse survival in patients with GC, but age did not seem to have an impact. Screening high risk patients and early diagnosis are necessary to improve survival.

Site specific diagnostic yield of endoscopic biopsies in Gastrointestinal Graft-versus-Host Disease: A tertiary care Center experience.

BACKGROUND: Gastrointestinal (GI) graft versus host disease (GVHD) occurs in up to 40% of patients undergoing allogenic hematopoietic stem cell transplantation (HSCT). However, the optimal endoscopic approach is still unclear and the area of the GI tract with the highest diagnostic yield is still a topic of debate. OBJECTIVE: We compared the diagnostic yield of different anatomic site biopsies in the diagnosis of GI GVHD and assessed the correlation of endoscopic findings with histopathology. METHODS: All cases of biopsy proven GI GVHD were obtained from pathology database AUBMC between 1/1/2005 and 31/8/2017. We retrospectively analyzed the demographical, clinical and endoscopic data. RESULTS: Nineteen patients were diagnosed with GI GVHD over 17.6 years. The most common presenting symptom was severe diarrhea (18 patients, 94.7%). Combining upper endoscopy and sigmoidoscopy with biopsies had the highest diagnostic yield of 90% in diagnosing GI GVHD compared to 63.6%, 78.6% and 77.8% for upper endoscopy, sigmoidoscopy and colonoscopy respectively. In macroscopically normal mucosa, the recto-sigmoid and duodenal biopsies had the highest diagnostic yield (75%). As for the macroscopically abnormal mucosa, the highest yield was for the recto-sigmoid biopsies (100%) in lower endoscopy and duodenal biopsies in the upper endoscopy (60%). CONCLUSION: In a patient suspected to have GI GVHD, the best endoscopic approach is the combination of upper endoscopy and flexible sigmoidoscopy with biopsies of normal as well as abnormal mucosa. It should be emphasized that normal mucosa be biopsied especially in the duodenum and recto-sigmoid for a better diagnostic yield.

Inhibitory effect of luminal saccharides on glucose absorption from an adjacent jejunal site in rats: a newly described intestinal neural reflex.

Nutrients in the lumen of the small intestine are sensed by special cells in the epithelial lining. The ensuing neurohumoral reflexes affect gastrointestinal absorption/secretion, motility, and vascular perfusion. To study in vivo the effect of a monosaccharide (glucose) or polysaccharide (starch) present in the jejunum on glucose absorption from an adjacent part of the intestine and investigate the possible underlying mechanisms. Using the single pass intraluminal perfusion technique, a segment of jejunum (perfusion segment) was continuously perfused with 20 mM glucose to determine glucose absorption. One hour later, a bolus of a saccharide was instilled in an isolated adjacent jejunal segment and the change in glucose absorption was monitored for a further 2 h. The contribution of neural mechanisms in this process was investigated. Instillation of glucose (20 mM or 40 mM) in either distal or proximal jejunal pouch elicited immediate and sustained inhibition of glucose absorption (a decrease by 25%; P < 0.01) from the perfused jejunal segment. Comparable inhibition was obtained with instillation of other monosaccharides or starch in the jejunal pouch. This inhibition was abolished by adding tetrodotoxin to the pouch or to the perfused jejunal segment and also by pretreatment with sympathetic blockers (guanethidine or hexamethonium) and by chemical ablation of capsaicin-sensitive primary afferent fibers. Glucose absorption within the jejunum is auto-regulated through backward and forward mechanisms. This regulation is mediated by neural reflexes involving capsaicin-sensitive afferent and sympathetic efferent fibers. These reflexes might serve to protect against hyperglycemia.

The Natural History of Incidental Colonic Diverticulosis on Screening Colonoscopy.

Background: The natural history of colonic diverticulosis is unclear. Methods: Patients with incidental diverticulosis identified in a previous prospective cross-sectional screening colonoscopy study were evaluated retrospectively for clinic or hospital visit(s) for diverticular disease (DD= acute diverticulitis or diverticular bleeding) using review of electronic health records and patient phone interview. Results: 826 patients were included in the screening colonoscopy study. Three were excluded for prior DD. In all, 224 patients (27.2%; mean age 62.3 ± 8.2) had incidental diverticulosis distributed in the left colon (67.4%), right colon (5.8%), or both (22.8%). Up-to-date information was available on 194 patients. Of those, 144 (74.2%) could be reached for detailed interview and constituted the study population. Over a mean follow-up of 7.0 ± 1.7 years, DD developed in 6 out of 144 patients (4.2%) (4 acute cases of diverticulitis, 1 probable case of diverticular bleeding, and 1 acute case of diverticulitis and diverticular bleeding). Two patients were hospitalized, and none required surgery. The time to event was 5.1 ± 1.6 years and the incidence rate was 5.9 per 1000 patient-years. On multivariate analysis, none of the variables collected at baseline colonoscopy including age, gender, obesity, exercise, fiber intake, alcohol use, constipation, or use of NSAIDs were associated with DD. Conclusion: The natural history of incidental diverticulosis on screening colonoscopy was highly favorable in this well-defined prospectively identified cohort. The common scenario of incidental diverticulosis at screening colonoscopy makes this information clinically relevant and valuable to physicians and patients alike.

Wilson's disease in Lebanon and regional countries: Homozygosity and hepatic phenotype predominance.

AIM: To determine the phenotypes and predominant disease-causing mutations in Lebanese patients with Wilson's disease, as compared to regional non-European data. METHODS: The clinical profile of 36 patients diagnosed in Lebanon was studied and their mutations were determined by molecular testing. All patients underwent full physical exam, including ophthalmologic slit-lamp examination ultrasound imaging of the liver, as well as measurement of serum ceruloplasmin and 24-h urinary-Cu levels. In addition, genetic screening using PCR followed by sequencing to determine disease-causing mutations and polymorphisms in the ATP7B gene was carried on extracted DNA from patients and immediate family members. Our phenotypic-genotypic findings were then compared to reported mutations in Wilson's disease patients from regional Arab and non-European countries. RESULTS: Patients belonged to extended consanguineous families. The majority were homozygous for the disease-causing mutation, with no predominant mutation identified. The most common mutation, detected in 4 out of 13 families, involved the ATP hinge region and was present in patients from Lebanon, Egypt, Iran and Turkey. Otherwise, mutations in Lebanese patients and those of the region were scattered over 17 exons of ATP7B. While the homozygous exon 12 mutation Trp939Cys was only detected in patients from Lebanon but none from the regional countries, the worldwide common mutation H1069Q was not present in the Lebanese and was rare in the region. Pure hepatic phenotype was predominant in patients from both Lebanon and the region (25%-65%). Furthermore, the majority of patients, including those who were asymptomatic, had evidence of some hepatic dysfunction. Pure neurologic phenotype was rare. CONCLUSION: Findings do not support presence of a founder effect. Clinical and genetic screening is recommended for family members with index patients and unexplained hepatic dysfunction.

Chemosensitivity of U251 Cells to the Co-treatment of D-Penicillamine and Copper: Possible Implications on Wilson Disease Patients.

D-Penicillamine (PA), a copper chelator, and one of the recommended drugs for treatment of Wilson disease (WD) has been reported to worsen the symptoms of patients with neurologic presentations. However, the cause of this paradoxical response has not been fully elucidated and requires further investigations. Accordingly, we have studied the in vitro effect of Copper (Cu) and/or PA treatment on human glioblastoma U251 cells as an in vitro model of Cu cytotoxicity. Treatment of U251 cells with either Cu or PA exerted no significant effect on their morphology, viability or ROS level. In contrast, co-treatment with Cu-PA caused a decrease in viability, altered glutathione and ceruloplasmin expression coupled with marked increase in ROS; depolarization of mitochondrial membrane potential; and an increase in Sub G0 phase; along with alpha-Fodrin proteolysis. These findings along with the absence of LDH release in these assays, suggest that combined Cu-PA exposure induced apoptosis in U251 cells. In addition, pre-/or co-treatment with antioxidants showed a protective effect, with catalase being more effective than N-acetyl cysteine or trolox in restoring viability and reducing generated ROS levels. By comparison, a similar analysis using other cell lines showed that rat PC12 cells were resistant to Cu and/or PA treatment, while the neuroblastoma cell line SH-SY5Y was sensitive to either compound alone, resulting in decreased viability and increased ROS level. Taken together, this study shows that glioblastoma U251 cells provide a model for Cu-PA cytotoxicity mediated by H2O2. We postulate that PA oxidation in presence of Cu yields H2O2 which in turn permeates the plasma membrane and induced apoptosis. However, other cell lines exhibited different responses to these treatments, potentially providing a model for cell type- specific cytotoxic responses in the nervous system. The sensitivity of different neural and glial cell types to Cu-PA treatment may therefore underlie the neurologic worsening occurring in some PA-treated WD patients. Our results also raise the possibility that the side effects of PA treatment might be reduced or prevented by administering antioxidants.