Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage.

BACKGROUND: Since the first observations of patients with COVID-19, significant hypoalbuminaemia was detected. Its causes have not been investigated yet. OBJECTIVE: We hypothesized that pulmonary capillary leakage affects the severity of respiratory failure, causing a shift of fluids and proteins through the epithelial-endothelial barrier. METHODS: One hundred seventy-four COVID-19 patients with respiratory symptoms, 92 admitted to the intermediate medicine ward (IMW) and 82 to the intensive care unit (ICU) at Luigi Sacco Hospital in Milan, were studied. RESULTS: Baseline characteristics at admission were considered. Proteins, interleukin 8 (IL-8) and interleukin 10 (IL-10) in bronchoalveolar lavage fluid (BALF) were analysed in 26 ICU patients. In addition, ten autopsy ultrastructural lung studies were performed in patients with COVID-19 and compared with postmortem findings in a control group (bacterial pneumonia-ARDS and H1N1-ARDS). ICU patients had lower serum albumin than IMW patients [20 (18-23) vs 28 (24-33) g L-1 , P < 0.001]. Serum albumin was lower in more compromised groups (lower PaO2 -to-FiO2 ratio and worst chest X-ray findings) and was associated with 30 days of probability of survival. Protein concentration was correlated with IL-8 and IL-10 levels in BALF. Electron microscopy examinations of eight out of ten COVID-19 lung tissues showed loosening of junctional complexes, quantitatively more pronounced than in controls, and direct viral infection of type 2 pneumocytes and endothelial cells. CONCLUSION: Hypoalbuminaemia may serve as severity marker of epithelial-endothelial damage in patients with COVID-19. There are clues that pulmonary capillary leak syndrome plays a key role in the pathogenesis of COVID-19 and might be a potential therapeutic target.

Adjuvant chemotherapy in average-risk adult medulloblastoma patients improves survival: a long term study.

BACKGROUND: Medulloblastoma is extremely rare in adults. The role of chemotherapy for average-risk adult patients remains controversial. Surgery and radiotherapy provide a significant disease control and a good prognosis, but about 25% of average-risk patients have a relapse and die because of disease progression. No data in average-risk adult patients are available to compareradiotherapy alone and radiotherapyfollowed byadjuvant chemotherapy. METHODS: We analyzed 48 average-risk patients according to Chang classification diagnosed from 1988 to 2016. RESULTS: Median age was 29 years (range 16-61). Based on histological subtypes, 15 patients (31.3%) had classic, 15 patients (31.3%) had desmoplastic, 5 patients (10.4%) had extensive nodularity and 2 patients (4.2%) had large cells/anaplastic medulloblastoma. Twenty-four patients (50%) received adjuvant radiotherapy alone and 24 (50%) received radiotherapy and chemotherapy. After a median follow-up of 12.5 years, we found that chemotherapyincreases progression-free survival (PFS-15 82.3 ± 8.0% in patients treated with radiotherapy and chemotherapyvs. 38.5% ± 13.0% in patients treated with radiotherapy alone p = 0.05) and overall survival (OS-15 89.3% ± 7.2% vs. 52.0% ± 13.1%, p = 0.02). Among patients receiving chemotherapy, the reported grade ≥ 3 adverse events were: 9 cases of neutropenia (6 cases of G3 neutropenia [25%] and 3 cases of G4 neutropenia [13%]), 1 case of G3 thrombocytopenia (4%) and 2 cases of G3 nausea (8%). CONCLUSIONS: Our study with a long follow up period suggests that adding adjuvant chemotherapy to radiotherapy might improve PFS and OS in average-risk adult medulloblastoma patients.

Hospital reengineering against COVID-19 outbreak: 1-month experience of an Italian tertiary care center.

OBJECTIVE: The recent outbreak of SARS-CoV-2 infection in Italy has resulted in a sudden and massive flow of patients into emergency rooms, and a high number of hospitalizations with the need for respiratory isolation. Massive admission of patients to the Policlinico "Agostino Gemelli" Foundation of Rome, Italy, determined the need for reengineering the entire hospital. MATERIALS AND METHODS: In this article, we consider some of the structural and organizational changes that have been necessary to deal with the emergency, with particular reference to non-intensive medicine wards, and the preventive measures aimed at limiting the spread of SARS-CoV-2 infection among hospital staff and patients themselves. RESULTS: 577 staff members were subjected to molecular tests in 1-month period and 3.8% of the total were positive. 636 patients admitted to the COVID-19 pathway were included and analyzed: 45.4% were identified as SARS-CoV-2 positive. More SARS-CoV-2 negative patients were discharged in comparison to SARS-CoV-2 positive patients (59% vs. 41%, respectively). On the other hand, more SARS-CoV-2 positive patients were transferred to ICUs in comparison to SARS-CoV-2 negative patients (16% vs. 1%, respectively). Occurrence of death was similar between the two groups, 11% vs. 7%, for SARS-CoV-2 negative and positive patients, respectively. 25% of ≥80 years old SARS-CoV-2 positive patients died during the hospitalization, while death rate was lower in other age groups (5% in 70-79 years old patients and 0% in remaining age groups). CONCLUSIONS: Rapid hospital reengineering has probably had an impact on the management of patients with and without SARS-CoV-2 infection, and on in-hospital mortality rates over the reporting period.

Madelung's disease and acute alcoholic hepatitis: case report and review of literature.

Madelung's disease is a rare condition characterized by symmetric growth of fatty tumors (lipomas) around the neck, shoulders, upper arms, and trunk. It often affects men with a history of alcohol abuse. Here we report a review of the literature about this disease together with the description of a patient affected by Madelung's disease and acute alcoholic hepatitis.

MEDS score and vitamin D status are independent predictors of mortality in a cohort of Internal Medicine patients with microbiological identified sepsis.

OBJECTIVE: Sepsis is a life-threatening disease resulting from the interaction between pathogen and host response; its dysregulation causes organ dysfunction, high morbidity, and mortality. Despite the increase of septic patients admitted to Internal Medicine wards, data about clinical predictors of mortality in this setting are still lacking. The aim of this study was to evaluate the role of MEDS score and vitamin D as predictors of mortality (28-day and 90-day) in septic patients admitted to the Internal Medicine department. PATIENT S AND METHODS: Prospectively collected clinical data, lab tests including vitamin D, and clinical scores (SIRS, MEDS, SCS, REMS, SOFA, qSOFA) were retrospectively analyzed. Eighty-eight microbiologically identified septic patients (median age 75 years old, IQR 65-82 years old; range 37-94 years old) were evaluated. RESULTS: Twenty-three patients (26.1%) died at 28 days, 33 (37.5%) died at 90 days. The logistic regression showed a positive effect of MEDS score (p=0.006; OR 1.24, 95% CI 1.08-1.49), and a negative effect of low vitamin D levels (p=0.008, OR 0.83, 95% CI 0.72-0.94) on mortality. Moreover, the cut-off of 7 points for MEDS score and of 7 ng/ml for vitamin D levels significantly predicted poor prognosis at 28 and 90 days. CONCLUSIONS: MEDS score and vitamin D levels represent independent predictors of mortality in a cohort of Internal Medicine septic patients. Further studies on larger samples are needed to confirm our results and to clarify the pathophysiological mechanisms at the basis of vitamin D deficiency as a predictor of mortality in septic patients.

Human Rickettsia aeschlimannii infection: first case with acute hepatitis and review of the literature.

OBJECTIVE: Rickettsia conorii is responsible for the Mediterranean Spotted Fever. Recently, new rickettsial species have been recognized in Europe and implicated in human diseases. Clinical features often differ greatly from each other, but non-severe liver involvement is frequently observed during any rickettsial infection. CASE REPORT: We describe the unique case of a patient presented with significant high aminotransferase levels due to the first human R. aeschlimannii infection ever detected in Italy. The hypothesis of rickettsiosis was made on the basis of a comprehensive medical history and was confirmed by serological tests. Molecular analyses made on a sample of hepatic tissue revealed the presence of a rickettsial species never found before in human liver. CONCLUSIONS: A brief review of the literature is reported to highlight how relevant this case is and to remind that rickettsioses should be in the differential diagnoses of acute hepatitis, considering mostly the recent spread of new rickettsial species.

Primary Cutaneous Coccidioidomycosis in an Italian Nun Working in South America and Review of Published Literature.

Coccidioidomycosis is a systemic disease caused by the dimorphic fungus Coccidioides, endemic in parts of the Southwestern USA and Central and South America. Two species, Coccidioides immitis and Coccidioides posadasii, were differentiated. Primary cutaneous coccidioidomycosis (PCC) has been reported rarely. An unusual case of PCC characterized by a persistent solitary lesion diagnosed in Italy in an immunocompetent Italian nun living in Argentina is described. The isolate was identified by sequence analysis as C. posadasii. Antibody screening was negative. A total of 39 cases of PCC have been reported in the literature. Infections occurred as a consequence of traumatic implantation in a natural setting in endemic areas or of accidental inoculation in laboratory workers. Importance of accurate investigation of travel history and of occupational hazards to laboratory workers is outlined.

Pattern of care and effectiveness of treatment for glioblastoma patients in the real world: Results from a prospective population-based registry. Could survival differ in a high-volume center?

BACKGROUND: As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. METHODS: Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. RESULTS: Two hundred sixty-seven GBM patients (median age, 64 y; range, 29-84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2-12.4). The 139 patients ≤aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0-18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248-0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388-0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328-0.986; P = .0446). CONCLUSIONS: The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged ≤70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor.

The human homologue of macaque area V6A.

In macaque monkeys, V6A is a visuomotor area located in the anterior bank of the POs, dorsal and anterior to retinotopically-organized extrastriate area V6 (Galletti et al., 1996). Unlike V6, V6A represents both contra- and ipsilateral visual fields and is broadly retinotopically organized (Galletti et al., 1999b). The contralateral lower visual field is over-represented in V6A. The central 20°-30° of the visual field is mainly represented dorsally (V6Ad) and the periphery ventrally (V6Av), at the border with V6. Both sectors of area V6A contain arm movement-related cells, active during spatially-directed reaching movements (Gamberini et al., 2011). In humans, we previously mapped the retinotopic organization of area V6 (Pitzalis et al., 2006). Here, using phase-encoded fMRI, cortical surface-based analysis and wide-field retinotopic mapping, we define a new cortical region that borders V6 anteriorly and shows a clear over-representation of the contralateral lower visual field and the periphery. As with macaque V6A, the eccentricity increases moving ventrally within the area. The new region contains a non-mirror-image representation of the visual field. Functional mapping reveals that, as in macaque V6A, the new region, but not the nearby area V6, responds during finger pointing and reaching movements. Based on similarity in position, retinotopic properties, functional organization and relationship with the neighboring extrastriate visual areas, we propose that the new cortical region is the human homologue of macaque area V6A.

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

BACKGROUND: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. PATIENTS AND METHODS: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. RESULTS: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. CONCLUSIONS: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Glomerular lesions in HIV-positive patients: a 20-year biopsy experience from Northern Italy.

AIM: Glomerular involvement in HIV-positive patients is quite heterogeneous. In the present paper we reviewed 73 renal biopsies performed during a period of more than 20 years in a single Nephrology Unit, Milan, Northern Italy, in order to evaluate the aspects of single types of glomerular lesions (including HIV associated nephropathy-HIVAN), grouped according to histological patterns and clinical presentation. Moreover, in the group of non-HIVAN patients, the possible differences in histological characteristics from non-HIV lesions were investigated. MATERIALS AND METHODS: Renal tissues were obtained by percutaneous biopsies and were studied by light microscopy, immunofluorescence and electron microscopy. For the histological description three histological groups were identified: HIVAN, immune complex glomerulonephritis (GN) and glomerulopathies not related to immune-mediated mechanisms (so-called "various" glomerulopathies). RESULTS: HIVAN was observed in 9 cases, immune complex GNs in 40 cases (10 mesangial proliferative GN, 8 membranoproliferative GN, 5 lupus-like GN, 4 "acute" GN, 2 crescentic GN, 4 IgA nephropathy, 4 membranous GN and 3 immunotactoid GN) and "various" glomerulopathies in 24 cases (13 non-collapsing focal segmental glomerulosclerosis, 3 minimal changes, 3 end-stage renal disease, 4 diabetic nephropathy and one amyloidosis). CONCLUSIONS: Our 20-year biopsy series of HIV-related glomerular involvement confirmed the heterogeneity of lesions. In our series, the vast majority of HIV-related GN are the so-called immune complex GNs, with some peculiar aspects, as multiple site location of deposits and a frequent tendency towards sclerosis, in agreement with experimental data regarding HIV and fibrosis.

Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

BACKGROUND: Standardized salvage treatment has not yet proved effective in glioblastoma multiforme (GBM) patients who receive prior standard radiotherapy plus concomitant and adjuvant temozolomide. METHODS: Patients with progressive GBM after radiotherapy plus concomitant and/or adjuvant temozolomide received three-weekly doses (100-75 mg m(2)) of fotemustine followed, after a 5-week rest, by fotemustine (100 mg m(2)) every 3 weeks for < or =1 year. RESULTS: Forty-three patients (29 M, 14 F; median age 51 years, range 34-68; median KPS 90) were enrolled. Progression-free survival at 6 months (PFS-6) was 20.9% (95% CI: 9-33%); three patients (7.1%) had partial response (PR); 15 (34.9%), disease stabilization (SD). The median survival was 6 months (95% CI: 5-7). MGMT promoter status was methylated in 8 (18.6%) and unmethylated in 26 (60.5%) and not assessable in 9 (20.9%) patients, respectively. Disease control was 75% versus 34.6% in methylated and unmethylated MGMT patients (P = 0.044); no significant difference was found between groups for PFS-6 and survival. Grade 3 and 4 thrombocytopenia and neutropenia were observed in 20.9 and 16.3% of patients, during the induction phase, and in 0 and 9.5% patients during the maintenance phase, respectively. CONCLUSIONS: The findings of the present trial, that evaluate fotemustine in a homogeneous population, may represent a new benchmark for nitrosourea activity. Moreover, this is the first study to evaluate correlation between MGMT promoter status and outcome of fotemustine for relapsing GBM previously treated with radiotherapy and temozolomide.

Setting the conditions for efficient, robust and reproducible generation of functionally active neurons from adult subventricular zone-derived neural stem cells.

Although new culture conditions enable homogeneous and long-term propagation of radial glia-like neural stem (NS) cells in monolayer and serum-free conditions, the efficiency of the conversion of NS cells into terminally differentiated, functionally mature neurons is relatively limited and poorly characterized. We demonstrate that NS cells derived from adult mouse subventricular zone robustly develop properties of mature neurons when exposed to an optimized neuronal differentiation protocol. A high degree of cell viability was preserved. At 22 days in vitro, most cells (65%) were microtubule-associated protein 2(+) and coexpressed gamma-aminobutyric acid (GABA), GAD67, calbindin and parvalbumin. Nearly all neurons exhibited sodium, potassium and calcium currents, and 70% of them fired action potentials. These neurons expressed functional GABA(A) receptors, whereas activable kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartic acid receptors were present in approximately 80, 30 and 2% of cells, respectively. Antigenic and functional properties were efficiently and reliably reproduced across experiments and cell passages (up to 68). This is the first report showing a consistent and reproducible generation of large amounts of neurons from long-term passaged adult neural stem cells. Remarkably, the neuronal progeny carries a defined set of antigenic, biochemical and functional characteristics that make this system suitable for studies of NS cell biology as well as for genetic and chemical screenings.

Temozolomide three weeks on and one week off as first line therapy for patients with recurrent or progressive low grade gliomas.

BACKGROUND: Patients with recurrent or progressive low grade gliomas survive for a decade or more following diagnosis, and may be at a higher risk for treatment-related complications, such as cognitive impairment from radiotherapy. PURPOSE: The aim of the present study was to determine in patients with progressive or recurrent low grade gliomas, the response rate and toxicity incurred by a continued schedule of temozolomide chemotherapy administered before radiation therapy, and to explore correlations between response and survival with 1p/19q deletions and MGMT promoter methylation status. METHODS: Progressive radio and chemotherapy naïve low grade glioma patients with O(6)-methyl-guanine-DNA-methyl-tranferase (MGMT) promoter status evaluation were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m(2)/daily for 21 days every 28 days for 12 cycles. RESULTS: A total of 30 patients (median age 45 [range: 24.2-68.6] years) with a median KPS of 90 (range 60-90) were accrued. The overall response rate was 30% (9 partial responses); 17 patients (56.7%) had disease stabilization. CONCLUSION: The prolonged temozolomide schedule considered in the present study is followed by a high response rate; toxicity is acceptable. Further randomized trials should therefore be conducted to confirm the efficacy of this regimen as first-line therapy in patients with progressive low grade glioma.

Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mg day(-1)) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1-36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2-104+) weeks and PFS-6 was 14.3% (95% CI 4.0-32.7%). The median overall survival was 24.6 weeks (range 4-104+). No grade 3-4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO).

The efficacy of temozolomide strongly depends on O(6)-alkylguanine DNA-alkyl transferase (AGAT), which repairs DNA damage caused by the drug itself. Low-dose protracted temozolomide administration can decrease AGAT activity. The main end point of the present study was therefore to test progression-free survival at 6 months (PFS-6) in glioblastoma patients following a prolonged temozolomide schedule. Chemonaïve glioblastoma patients with disease recurrence or progression after surgery and standard radiotherapy were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m(2)/daily for 21 days every 28 days until disease progression. O(6)-methyl-guanine-DNA-methyl-tranferase (MGMT) was determined in 22 patients (66.7%). A total of 33 patients (median age 57 years, range 31-71) with a median KPS of 90 (range 60-100) were accrued. The overall response rate was 9%, and PFS-6 30.3% (95% CI:18-51%). No correlation was found between the MGMT promoter methylation status of the tumours and the overall response rate, time to progression and survival. In 153 treatment cycles delivered, the most common grade 3/4 event was lymphopoenia. The prolonged temozolomide schedule considered in the present study is followed by a high PFS-6 rate; toxicity is acceptable. Further randomised trials should therefore be conducted to confirm the efficacy of this regimen.

MATILDE regimen followed by radiotherapy is an active strategy against primary CNS lymphomas.

The authors assessed MATILDE chemotherapy followed by response-tailored radiation therapy in 41 patients aged 70 years or younger with primary CNS lymphoma in a Phase II trial. With response rates of 76% after MATILDE and 83% after chemotherapy with or without radiation therapy, this was an active strategy, particularly in low- to intermediate-risk patients (International Extranodal Lymphoma Study Group [IELSG] score). Myelosuppression was the dose-limiting toxicity, with 9.5% of lethal complications. After a median follow-up of 49 months, a plateau in the survival curve (5-year overall survival: 41 +/- 7%) was obtained.

Is protracted low-dose temozolomide feasible in glioma patients?

The authors investigated the safety of 75 mg/m2 temozolomide for 21 days every 28 days in glioma patients. This schedule could lead to DNA repair enzyme O6-alkylguanine-DNA alkyltransferase depletion, contributing to overcoming drug resistance. Although Phase III studies are forthcoming, no data are available on the long-term toxicity of temozolomide, which, in this series, incurred prolonged, cumulative lymphopenia, which leads to a high incidence of infections.

Ultrastructural study of renal involvement in two females with Anderson-Fabry disease.

Anderson-Fabry disease (AFD) is a rare X-linked lipid storage disorder due to a deficient lysosomal a-galactosidase A (a-Gal) activity. In males with the classic form of the disease the enzymatic defect leads to progressive accumulation of glycosphingolipids (GL) in different organs, mainly in the kidney, heart, and brain, causing severe multisystem failure. AFD is usually mild in heterozygous females, but severe cerebrovascular, renal, and cardiac manifestations have been rarely described. The aim of this study is to describe renal involvement of mild symptomatic female carriers by ultrastructural analysis focusing to microvascular lesions, considered to be one of the major causes of systemic disease in AFD. Resin-embedded renal biopsies from 2 sisters with isolated mild proteinuria and belonging to a family group with AFD were observed by light and electron microscopy. In spite of the mild clinical symptoms, diffuse GL storages were demonstrated in all types of glomerular cells and in interstitial endothelial cells. Moreover, platelets were frequently observed in glomerular vassels, a feature coherent with a possible role of prothrombotic state, and platelet activation, in early glomerular lesions.

How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial.

BACKGROUND: The initial studies on nitrosoureas were performed >30 years ago. These drugs remain the standard chemotherapy for glioblastoma. However, because the criteria used to evaluate the activity of nitrosoureas in a neuro-oncologic setting have changed, new data on their activity are needed. METHODS: The authors conducted a phase II study on 40 patients with recurrent glioblastoma following surgery and standard radiotherapy. They analyzed progression-free survival at 6 months (PFS-6), time to progression (TTP), response rate, and toxicity. Patients were treated with 80 mg/m2 carmustine on days 1 to 3, every 8 weeks for a maximum of six cycles. RESULTS: Median TTP was 13.3 weeks (95% CI, 10.26 to 16.86 weeks), and PFS-6 was 17.5% (95% CI, 8.9 to 34.3). Response to chemotherapy, age < or =40 years, and performance status > or =90 were significant prognostic factors for TTP; however, with multivariate analysis, only response to chemotherapy was significant. The major side effects were reversible hematologic and long-lasting hepatic and pulmonary toxicity. CONCLUSION: The activity of this BCNU regimen is comparable with that reported in the past and with the newest therapies, such as temozolomide. However, BCNU toxicity is high and recovery is slow, thus compromising the administration of further drugs in patients with progressive disease.