Cholestatic hepatitis C after chemotherapy containing rituximab in diffuse large B cell lymphoma.

Rituximab is a chimeric anti-CD20 monoclonal antibody that is a widely used for the treatment of B cells non-Hodgkin lymphoma. The use of chemotherapy regimens containing rituximab in HCV-positive patients with non-Hodgkin lymphoma has been associated with liver dysfunction, but no cases of cholestatic hepatitis C were described. To our knowledge, this is the first case of cholestatic hepatitis C in an HCV-positive patient with diffuse large B-cell lymphoma describes in the literature. We discuss the pathogenetic mechanisms underlying this severe form of hepatitis and describe its evolution after antiviral treatment.

Long term nucleotide and nucleoside analogs treatment in chronic hepatitis B HBeAg negative genotype D patients and risk for hepatocellular carcinoma.

UNLABELLED: BACKGROUND AND RATIONALE OF THE STUDY: Effect of Long-term nucleoside/nucleotide (NUC) on hepatocellular carcinoma (HCC) incidence in a population of HBeAg-negative genotype D patients has not been adequately studied in real-life cohorts. Our aim was to evaluate the impact of liver fibrosis and other variables on HCC incidence in this population of patients. Of 745 patients with chronic hepatitis B (CHB), 306 HBeAg-negative genotype D were selected and included in this study. All patients received treatment with NUC for at least 18 months. Patients with CHB or compensated cirrhosis were included. Patients with HCC diagnosed before or during the first 18 months of NUC therapy were excluded. RESULTS: HCC was diagnosed in 2 CHB patients (1.0%) and 23 cirrhosis patients (20%) (OR = 24.41, 95% CI 5.40 < OR < 153.2; p < 0.0001). Multivariate analysis revealed that HCC risk was independently associated with age ≥ 60 years (OR = 6.45, 95% CI 1.22 to 34.0; p = 0.02) and liver cirrhosis (OR = 12.1, 95% CI 1.39 to 106.2; p = 0.02), but not with virological response (VR), and previous resistance to NUC, or rescue therapy. Multivariate analysis in cirrhosis patients revealed that only age ≥ 60 years was an independent risk factor associated with HCC (p = 0.003). CONCLUSIONS: Liver cirrhosis and age ≥ 60 years are the stronger risk factors for HCC in genotype D HBeA-gnegative patients. Previous resistance to NUC in patients that achieved a VR after rescue therapy was not a predictive factor regarding HCC. VR does not appear to significantly reduce the overall incidence of HCC when a patient has already progressed to liver cirrhosis.

Stapled trans-anal rectal resection (STARR) in the surgical treatment of the obstructed defecation syndrome: results of STARR Italian Registry.

PURPOSE: This study was designed to evaluate the safety and efficacy of stapled trans-anal rectal resection (STARR) in the treatment of obstructed defecation syndrome ODS by the analysis of the data collected in the STARR Italian Registry (SIR) with a special emphasis on the analysis of symptoms and quality of life. METHODS: Collected data included, preoperative tests findings, and the evaluation of symptoms; the latter was obtained by using dedicated tools such as the Obstructed Defecation Syndrome Score (ODS-S), the Severity Symptom Score (SSS), and the Continence Grading Scale (CGS). Data on the quality of life were collected by Patient Assessment of Constipation Quality of Life (PAC-QoL) and the Euro Quality of Life-5 Domains Visual Analogue Scale (EQ-5D VAS). The evaluation of the symptoms and the quality of life was repeated 6 and 12 months after surgery. RESULTS: The SIR had collected data on 2171 patients (1653 females, 76.1%; mean age 56.2 years; range 20-96 years). A significant improvement (P < .0001) was seen between preoperative and 12-month follow-up in all scores: ODS-S (16.7 vs. 5.0), SSS (15.6 vs. 2.6), CGS (2.0 vs. 0.7), PAC-QoL (51.0 vs. 22.1), and EQ-5D VAS (57.5 vs. 85.7). Complications included defecatory urgency (4.5% at 12 months), bleeding (3.6%), perineal sepsis (3.4%), and one case of rectovaginal fistula (0.05%). CONCLUSION: The analysis of SIR data seems to confirm that STARR is a safe and effective procedure in the treatment of ODS. However, further studies are required to evaluate the long-term stability of results.

Treatment of hepatitis C virus carriers with persistently normal alanine aminotransferase levels with peginterferon alpha-2a and ribavirin: a multicentric study.

BACKGROUND/AIMS: To evaluate, in clinical practice, the efficacy and safety of combined antiviral treatment in hepatitis C virus (HCV) carriers with normal alanine aminotransferase (ALT) levels. METHODS: Eighty-eight HCV carriers with persistently normal ALT levels were enrolled. All patients received peginterferon (PEG-IFN) alpha-2a 180 microg once weekly plus ribavirin (RBV) 800 mg/day for 24 weeks (HCV-2 and -3) or 1000-1200 mg/day for 48 weeks (HCV-1). RESULTS: Rapid virological response (RVR) was seen in 66/88 patients (75%): 19/32 HCV-1 (59%), 40/46 HCV-2 (87%) and 7/10 HCV-3 patients. Younger patients, leaner subjects and patients with non-1 genotype or lower baseline HCV RNA levels were more likely to achieve an RVR. Sustained virological response (SVR) was seen in 69/88 patients (78%): 20/32 HCV-1 patients (62%), 41/46 HCV-2 patients (89%) and 8/10 (80%) HCV-3 patients. The overall SVR rate was 88% in patients with RVR (58/66) and 50% in those without RVR. CONCLUSIONS: The combination of PEG-IFN alpha-2a and RBV produces, in patients with normal ALT, virological response rates that are comparable or even higher than those obtained in patients with elevated ALT levels. Thus, we suggest that in selected cases immediate therapy might be preferred to a 'wait-and-see' policy.

Long-term outcome of sacral nerve stimulation for fecal incontinence.

PURPOSE: Sacral nerve stimulation is a safe and effective procedure for fecal incontinence. We investigated whether its efficacy is maintained long term. PATIENTS AND METHODS: Sixty patients with fecal incontinence underwent permanent sacral nerve stimulation. Patients' data were prospectively recorded in the national registry of the Italian Group of sacral nerve stimulation. The severity of fecal incontinence was evaluated by the Wexner score, and data were collected in a bowel function diary. Quality of life was evaluated by the Italian version of the Medical Outcomes Survey Short Form (SF-36) questionnaire. RESULTS: Fifty-two patients were available for long-term follow-up lasting at least 5 years. Compared with baseline, the Wexner score decreased significantly after definitive implantation (from 15 +/- 4 to 5 +/- 5, P < 0.001). At least 50 percent improvement in continence was achieved in 74 percent of the patients, and at least 70 percent improvement (median value) was achieved in 50 percent. The mean number of solid/liquid incontinence episodes decreased significantly from 0.5 (+/-0.5) to 0.1 (+/-0.3) per day (P = 0.004). Quality of life improved in all domains. The overall mean improvement in SF-36 scores was 39.8 percent. Both mean resting and squeeze anal pressures increased significantly, and maximum volume tolerated decreased significantly. CONCLUSIONS: Sacral nerve stimulation maintains its efficacy long term, not only in regard to control of symptoms but also regarding quality of life.

Is sacral nerve stimulation an effective treatment for chronic idiopathic anal pain?

BACKGROUND: Chronic idiopathic anal pain is a common, benign symptom, the etiology of which remains unclear. Traditional treatments are often ineffective. This study investigated the efficacy of sacral nerve stimulation in treating chronic idiopathic anal pain. METHODS: Twelve patients (10 women and 2 men; mean age, 61.0 +/- 10.3 years; range, 48-82 years) implanted with a permanent device for sacral nerve stimulation were followed in the Italian Group for Sacral Neuromodulation (GINS) Registry. All patients had frequent chronic anal or perianal pain; 75 percent had previously undergone pelvic surgery. Pharmacologic and rehabilitative therapy had yielded poor results. Changes from baseline to last follow-up examination were evaluated for scores on a visual analog pain scale (0-10) and the Short-Form 36 (SF-36) health status questionnaire. Manometric measurements recorded at last follow-up were compared with preimplantation values. RESULTS: In one patient, the permanent device was removed because of technical failure. After a mean follow-up of 15 (range, 3-80) months, visual analog pain scores had significantly improved (from 8.2 +/- 1.7 to 2.2 +/- 1.3, P < 0.001). SF-36 physical component scores increased from 26.27 +/- 5.65 to 38.95 +/- 9.08, P < 0.02). Scores on the mental component showed improvement, although not significant. Postimplantation changes in manometric functional data were not significant, but sensitivity thresholds showed a considerable decrease. CONCLUSIONS: Long-term follow-up data showing improvements in scores on the visual analog pain scale and quality of life questionnaire indicate that, before adopting more aggressive surgical procedures, SNS should be considered for patients with chronic idiopathic anal pain in whom pharmacologic and biofeedback treatments have failed to produce effective results.

Outcomes of stapled transanal rectal resection vs. biofeedback for the treatment of outlet obstruction associated with rectal intussusception and rectocele: a multicenter, randomized, controlled trial.

PURPOSE: This study was designed to assess the safety and outcomes achieved with stapled transanal rectal resection vs. biofeedback training in obstructed defecation patients. METHODS: A total of 119 women patients who suffered from obstructed defecation with associated rectocele and rectal intussusception were randomized to stapled transanal rectal resection or biofeedback training. Stapled transanal rectal resection was performed by using two circular staplers to produce transanal full-thickness rectal resection. Primary outcome was symptoms of obstructed defecation resolution at 12 months; secondary outcomes included safety, change in quality of life score, and anatomic correction of rectocele and rectal intussusception. RESULTS: Fourteen percent (8/59) stapled transanal rectal resection and 50 percent (30/60) biofeedback training patients withdrew early. Eight (15 percent) patients treated with stapled transanal rectal resection and 1 (2 percent) biofeedback patient experienced adverse events. One serious adverse event (bleeding) occurred after stapled transanal rectal resection. Scores of obstructed defecation improved significantly in both groups as did quality of life (both P < 0.0001). Successful treatment was observed in 44 (81.5 percent) stapled transanal rectal resection vs. 13 (33.3 percent) evaluable biofeedback training patients (P < 0.0001). Functional benefit was observed early and remained stable during the study. CONCLUSIONS: In this controlled trial, stapled transanal rectal resection was well tolerated, was more effective than biofeedback training for the resolution of obstructed defecation symptoms, and improved quality of life, with minimal risk of impaired continence. Thus, stapled transanal rectal resection offers a new treatment alternative for obstructed defecation after failure of conservative measures including biofeedback training, a noninvasive approach.

Local intracerebral delivery of endogenous inhibitors by osmotic minipumps effectively suppresses glioma growth in vivo.

The systemic administration of endogenous inhibitors significantly reduced the growth of human glioma in vivo, but required the production of a large amount of biologically active protein. In this study we reduced the amount of protein needed and optimized the therapeutical response by delivering the endogenous inhibitors locally into the brain by osmotic minipumps. Human hemopexin fragment of MMP-2 or COOH-terminal fragment of platelet factor-4 were delivered locally and continuously into the brain of mice implanted intracranially with glioma cells, by osmotic minipumps connected to an intracranial catheter. Local delivery of human hemopexin fragment of MMP-2 and COOH-terminal fragment of platelet factor-4 significantly inhibited the growth of well-established malignant glioma in nude and BALB/C mice. When the inhibitors were given at the same concentration, the efficacy of the local delivery was much higher than that reached with the systemic administration, both when the inhibitor was administered daily or continuously by s.c. minipumps. Moreover, the local delivery reduced the amount of protein needed to reach a significant therapeutic response. Intracerebral delivery maintained a long-term control of glioma growth and inhibited glioma recurrence in a surgical resection model. Treatment showed no side effects. Histochemical analysis of tumors showed that the tumor growth inhibition was the result of a decrease in tumor vasculature and a change in tumor vessel morphology. Our data demonstrate that local intracerebral delivery of endogenous inhibitors effectively inhibits malignant glioma growth and reduces the amount of protein needed to reach a therapeutical response.

Suppression of malignant glioma recurrence in a newly developed animal model by endogenous inhibitors.

Glioma recurrences develop at the borders of the surgical cavity and are the main cause of their poor prognosis. There are no therapeutic advances to reduce the incidence of recurrence or animal models that closely mimic the clinical scenario to evaluate novel therapeutics. This work investigates the efficacy of endogenous inhibitors, in preventing the recurrence of human malignant gliomas, in a newly developed animal model of glioma surgical resection. We developed a nude mice model in which human glioma xenografts were microsurgically removed. After surgery, small islets of tumor cells persisted in the normal brain parenchyma, grew, and formed a recurrence. As inhibitors we used PEX and a fragment of platelet factor 4 (PF-4/CTF), which were administered systemically on a daily basis or in metronomic combination with chemotherapy for 120 days. Treatment was started 1 or 15 days after tumor removal. PEX or PF-4/CTF produced a significant improvement in survival, and delayed the appearance of glioma recurrence. Survival of animals that received daily PEX or PF-4/CTF was similar to that of animals that received metronomic PEX or PF-4/CTF and chemotherapy, respectively. The effect of treatment was dependent on the time at which the treatment was initiated. The highest level of inhibition was observed when the treatment was administered 1 day after surgical resection and when PEX was used as the inhibitor (120 days versus 35 days of the control). Tumors treated with PEX or PF-4/CTF were small and well delineated, with few vessels. Postsurgical administration of PEX or PF-4/CTF significantly reduces the incidence human malignant glioma recurrences for a long period of time.

[Italian translation and prospective validation of fecal incontinence quality of life (FIQL) index]. / Traduzione e validazione prospettica della versione italiana del Fecal Incontinence Quality Of Life (FIQL) index.

The evaluation of any functional disease affecting quality of life requires a purpose-designed quality-of-life index for clinical trials as well as for evaluating the outcomes of treatments. The fecal incontinence quality of life index (FIQL) was developed at Minnesota University (USA) for patients with faecal incontinence but could not be used for Italian patients without appropriate cultural and linguistic adaptation. Therefore this index was translated into italian and prospectively validated on a new series of 73 incontinent patients and 8 healthy controls in order to provide Italian coloproctologists with a useful tool for clinical research. The italian version or the FIQL index met all the statistical criteria of reliability, reproducibility, specificity and convergency required and therefore can be used with confidence in clinical trials on such patients.

IS20I, a specific alphavbeta3 integrin inhibitor, reduces glioma growth in vivo.

OBJECTIVE: The biological features of malignant gliomas include high cell proliferation, extensive local infiltration of tumor cells into normal brain, and marked neovascularization. alphavbeta3 integrin is highly expressed in malignant gliomas and plays a role in glioma growth. This article investigates the in vitro and in vivo effects of a synthetic alphavbeta3 integrin inhibitor called IS20I on human malignant gliomas. METHODS: The in vitro effects of IS20I were studied by performing adhesion assays, competition studies, semi-in vivo angiogenic assays, and migration and proliferation assays. For the in vivo experiments, IS20I was administered systemically in nude mouse intracranial and subcutaneous malignant glioma models. RESULTS: IS20I reacted selectively to alphavbeta3 integrin in glioma cells and tissues. In vitro, IS20I strongly inhibited angiogenesis and simultaneously exhibited potent antimitotic and antimigratory effects on numerous tumor and endothelial cell lines. In addition, at high concentrations, IS20I induced endothelial and tumor cell apoptosis. In vivo, when IS20I was administered intraperitoneally in subcutaneous and intracranial nude mouse glioma models, it potently reduced malignant glioma growth. Inhibition levels of 76 and 82% were observed at concentrations of 1 and 5 mg/kg, respectively, in the U87 intracranial model. The suppression of tumor growth is associated with a decrease in tumor vascularity, an increase in apoptosis, and a decrease in tumor cell proliferation. CONCLUSION: This work expands the understanding of the effects of anti-alphavbeta3 integrin inhibitors on malignant gliomas. In addition to direct proapoptotic and antiangiogenic effects, IS20I inhibits tumor and endothelial cell proliferation and migration, resulting in a potent inhibition of glioma growth in vivo.

Gelastic seizures and low-grade hypothalamic astrocytoma: a case report.

The typical, well recognized childhood epilepsy syndrome caused by hypothalamic hamartoma is characterized by early-onset, stereotyped attacks of uncontrollable laughter, frequent refractory seizures with progressive cognitive deterioration and severe behavioral problems. Here, we report a 17-year-old patient with gelastic phenomenon started in the neonatal period, later on associated with drug resistant polymorphic seizures, intellectual deficit and behavioral disorders, who improved by partial resection of an expected hypothalamic hamartoma that, in turn, resulted to be a hypothalamic low-grade astrocytoma.

Sacral nerve stimulation in the treatment of fecal incontinence - the experience of a pelvic floor center : short term results.

OBJECTIVES: The aim of this paper is to present the data pertinent to the experiences of our Pelvic Floor Center on the utilisation of SNS in the treatment of fecal incontinence and compare these data to the data of current literature. METHODS: All patients who had had SNS treatment for fecal incontinence between the dates of 1st April 2008 and 1st April 2011 were enrolled in the study. We considered a 50% reduction of fecal incontinence episodes as a success of the test phase. The score used for assessment was the Cleveland Clinic Florida-Fecal Incontinence score (CCF-FI). RESULTS: The 21 patients treated for fecal incontinence (19 ♀ and 2 ♂, average age 59.7 [ 26-73] years) were sub-divided on the basis of the presence or absence of sphincter damage (group A1 had damage while group A2 did not). A patient (group A1) was excluded from the study as the result of the external connector breaking during the test phase. Of the 20 remaining patients (9 from group A1 and 11 from A2), 14 (70%) felt benefit and subsequently underwent definitive stimulator implantation. The variation between the pre-operative CCF-FI and the value at 6 months was statistically significant both in group A1 (p=0.009) and in group A2 (p=0.003). The only complication reported was one case (7.1%) of infection of the definitive stimulator. CONCLUSION: SNS represents an effective treatment for patients with fecal incontinence. The results have been encouraging, and in line with current literature.

Hepatitis C virus-related B cell subtypes in non Hodgkin's lymphoma.

AIM: To evaluate if indolent B cell-non Hodgkin's lymphoma (B-NHL) and diffuse large B-cell lymphoma (DLBCL) in hepatitis C virus (HCV) positive patients could have different biological and clinical characteristics requiring different management strategies. METHODS: A group of 24 HCV related B-NHL patients (11 indolent, 13 DLBCL) in whom the biological and clinical characteristics were described and confronted. Patients with DLBCL were managed with the standard of care of treatment. Patients with indolent HCV-related B-NHL were managed with antiviral treatment pegylated interferon plus ribavirin and their course observed. The outcomes of the different approaches were compared. RESULTS: Patients with DLBCL had a shorter duration of HCV infection and a higher prevalence of HCV genotype 1 compared to patients with indolent B-NHL in which HCV genotype 2 was the more frequent genotype. Five of the 9 patients with indolent HCV-related B-NHL treated with only antiviral therapy, achieved a complete response of their onco-haematological disease (55%). Seven of the 13 DLBCL patients treated with immunochemotheraphy obtained a complete response (54%). CONCLUSION: HCV genotypes and duration of HCV infection differed between B-NHL subtypes. Indolent lymphomas can be managed with antiviral treatment, while DLBCL is not affected by the HCV infection.

Plasma cytokines and portopulmonary hypertension in patients with cirrhosis waiting for orthotopic liver transplantation.

Portopulmonary hypertension (PPHTN) is a rare complication in patients with portal hypertension. A role of endothelin 1 (ET-1) and other cytokines was demonstrated in primary pulmonary hypertension but not in PPHTN. We evaluated the possible role of ET-1, interleukin 6 (IL-6), interleukin 1ß (IL-1ß), and tumor necrosis factor alpha (TNF-α) in the pathogenesis of PPHTN. Plasmatic concentrations of ET-1, IL-6, IL-1ß, and TNF-α were measured in patients with pulmonary systolic arterial pressure (PAPs) >30 mm Hg and in patients with cirrhosis. In all, Six out of 11 patients with PAPs >30 mm Hg had PPHTN on right heart catheterization. The remaining 10 patients had an hyperdynamic circulation (HC). In PPHTN patients, ET-1 and IL-6 were significantly higher compared with HC and patients with cirrhosis. Endothelin 1 and IL-6 could be implicated in the pathogenesis of PPHTN. On the basis of these results, ET-1 receptor antagonists or anti-IL-6 could have a rationale in the treatment of PPHTN.

Liver cirrhosis and rhino-orbital mucormycosis, a possible but rare association: description of a clinical case and literature review.

Only few cases of rhino-orbital mucormycosis in patients with liver cirrhosis are described in the literature and most of these patients showed an associated diabetes mellitus. We describe a case of rhino-orbital mucormycosis in a patient with liver cirrhosis without other risk factors.

Adefovir and lamivudine in combination compared with adefovir monotherapy in HBeAg-negative adults with chronic hepatitis B virus infection and clinical or virologic resistance to lamivudine: a retrospective, multicenter, nonrandomized, open-label study.

OBJECTIVES: The aim of this study was to assess the therapeutic effectiveness of adefovir dipivoxil (ADV), administered in combination with lamivudine (LAM) or as monotherapy, and the rate of resistance to ADV, in hepatitis B e antigen (HBeAg)-negative adult patients with chronic hepatitis B virus (HBV) infection and clinical or virologic resistance to LAM. Furthermore, we evaluated in these selected patients the clinical co-variates associated with a sustained virologic response. METHODS: Data from adult outpatients aged >18 years with chronic HBV infection and clinical or virologic resistance to LAM were used in this retrospective, multicenter, nonrandomized, open-label study. Patients were selected if they received ADV 10 mg PO QD + LAM 100 mg QD PO or ADV 10 mg PO QD as monotherapy for 24 to 32 months between June 2003 and July 2006. End points were the proportions of patients who achieved virologic response (undetectable HBV-DNA [<3.3 log(10) copies/mL]) and biochemical response (normalization [<40 IU/L] of alanine aminotransferase [ALT]), and the proportions in whom resistance to ADV (rebound serum HBV-DNA >1 log(10) copies/mL compared with on-treatment nadir, as confirmed on molecular analysis) was found. HBV-DNA and ALT levels were checked every month during the first 3 months of treatment and every 3 months thereafter until 28 months. Data from each center were stored in a centralized database and analyzed by a blinded independent investigator. RESULTS: Data from 70 patients were included (48 men, 22 women; median age, 51 years; ADV + LAM, 36 patients; ADV monotherapy, 34). The median duration of the pharmacologic treatment in the 2 groups of patients was 28 months (range, 24-32 months). By month 3, virologic response was achieved in 30 patients (83%) in the ADV + LAM group and in 26 patients (76%) in the ADV monotherapy group. At 12 months, virologic response was achieved in 5 additional patients in the ADV + LAM group and 2 additional patients in the ADV monotherapy group. Biochemical response was found to be time dependent: in the 2 groups, the rates of biochemical response were, respectively, 56% and 54% at month 3, 80% and 71% at month 6, and 96% and 79% at month 12, persisting up to the end of the study period. The rates of clinical resistance to ADV were 3% with ADV + LAM and 18% with ADV monotherapy (with a 6% rate of resistance due to rtA181 mutation in the monotherapy group). Logistic regression analysis found that pre-treatment levels of HBV-DNA <5 log(10) copies/mL, ALT levels >150 IU/L, an inflammation score >7, and a fibrosis score <2 were the strongest covariates independently associated with a sustained virologic response in both groups of patients. No adverse events were reported in any of the patients. CONCLUSION: ADV, administered in combination with LAM or as monotherapy, appeared to be effective in this small, selected group of HBeAg-negative patients with clinical or virologic resistance to LAM, especially in those with low pretreatment HBV-DNA levels, high ALT levels, and low fibrosis scores.

Lo Spedale di Poveri, the hospital for the poor in Milan: 15th to 20th century.

The construction of the Hospital for the Poor was begun in Milan in 1451 at the instigation of Francesco Sforza, Duke of Milan. In contrast to what had happened during the Dark Ages of the Medieval period, the new hospital was extraordinary both in construction and in medical organization. Wards for the patients were separated according to diseases, infective and noninfective, and according to sex. Each patient had his or her own bed and was fed adequately and kept warm. Patients were no longer treated by astrologers or monks but rather by doctors who had studied medicine at the University of Pavia. Each ward had its own doctor and surgeon, and from 1558 on, there was a doctor on duty in the hospital 24 hours a day. The hospital had its own pharmacy and drug reference book. The Hospital for the Poor, or Cà Granda (Big House), or the Ospedale Maggiore, as it was variously called from the 15th to the 19th centuries, became a training ground for anatomic and clinical studies. It was only in 1929 that a Faculty of Medicine was set up at Ospedale Maggiore.

Add-on phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study.

PURPOSE: To determine the potential effectiveness of phenytoin (PHT) in preventing early postoperative seizures in patients undergoing craniotomy for supratentorial brain tumors. METHODS: Two hundred patients requiring elective craniotomy for supratentorial brain tumors were randomized to two groups of equal size, with a prospective, open-label, controlled design. One group received PHT (18 mg/kg as an intravenous intraoperative load, followed by additional daily doses aimed at maintaining serum PHT concentrations within the 10- to 20-aeg/ml range) for 7 consecutive days. In the other group, PHT was not administered. More than 90% of patients in both groups continued to take preexisting anticonvulsant medication (AEDs) with carbamazepine or phenobarbital throughout the study. The primary efficacy end point was the number of patients remaining free from seizures during the 7-day period after the operation. RESULTS: Of 100 patients allocated to PHT, 13 experienced seizures during the 7-day observation period, compared with 11 of 100 patients in the placebo group (p > 0.05). Most seizures occurred in the first day after surgery in both groups. There were no differences between groups in the proportion of patients experiencing more than one seizure, but there was a trend for generalized seizures to be more common in PHT-treated patients than in controls (11 vs. five patients, respectively). Status epilepticus occurred in one patient in the PHT group and in two patients in the control group. Of the 13 PHT-treated seizure patients, 11 had serum PHT concentrations within the target range, and only two had concentrations below range on the days their seizures occurred. CONCLUSIONS: PHT, given at dosages producing serum concentrations within the target range, failed to prevent early postoperative seizures in patients treated with concomitant AEDs. Prophylactic administration of PHT cannot be recommended in these patients.

Ceramide levels are inversely associated with malignant progression of human glial tumors.

Ceramide represents an important sphingoid mediator involved in the signaling pathways that control cell proliferation, differentiation, and death. To determine whether ceramide levels correlate with the malignant progression of human astrocytomas, we investigated these levels in surgical specimens of glial tumors of low-grade and high-grade malignancy. Tumor samples obtained from 52 patients who underwent therapeutic removal of primary brain tumors were used. The tumors were classified according to standard morphologic criteria and were grouped into tumors of low-grade and high-grade malignancy. Sections of normal brain tissue adjacent to the tumor were also analyzed in 11 of the 52 patients. After extraction and partial purification, ceramide was measured by quantitative derivatization to ceramide-1-phosphate using diacylglycerol kinase and [gamma-(32)P]ATP. Ceramide levels were significantly lower in the combined high-grade tumors compared with low-grade tumors and in both tumor groups compared with peritumoral tissue. The results indicate an inverse correlation between the amount of ceramide and tumor malignancy as assessed by both the histological grading and ganglioside pattern. Moreover, overall survival analysis of 38 patients indicates that ceramide levels are significantly associated with patient survival. The present findings indicate that ceramide is inversely associated with malignant progression of human astrocytomas and poor prognosis. The downregulation of ceramide levels in human astrocytomas emerges as a novel alteration that may contribute to glial neoplastic transformation. The low ceramide levels in high-grade tumors may provide an advantage for their rapid growth and apoptotic resistant features. This study appears to support the rationale for the potential benefits of a ceramide-based chemotherapy.