Morbidity and outcome after sentinel lymph node dissection in patients with early-stage malignant cutaneous melanoma.

OBJECTIVE: Prospective analysis of the morbidity and outcome of the sentinel lymph node (SLN) technique in a consecutive series of patients with early-stage melanoma. METHODS: Between 1997 and 1998, 60 patients with stage IB-II malignant melanoma underwent SLN dissection. Preoperative dynamic lymphoscintigraphy with mapping of the lymph vessels and lymph nodes and location of the sentinel node was performed the day before SLN dissection. SLN was identified by use of the blue dye technique. SLN was assessed for histopathological and immunohistochemical examination. Postoperative morbidity and mortality were recorded. Follow-up consisted of repetitive clinical examination with lymph nodes status, laboratory and radiologic findings. RESULTS: Tumor-positive SLN was observed in 18% of the patients and stage II disease was found in 91% of the patients with positive SLN. Breslow thickness was the only significant factor predicting involvement of a SLN (p = 0.02). In 36% of the positive SLN, metastases could be assessed only by immunohistochemical examination. Postoperative complications after SLN dissection were observed in 5% in comparison with 36% after elective lymph node dissection. After a mean follow-up of 32 months, recurrence was observed in 3% with a mean disease-free survival of 8 months. Overall survival was 82% and 90% in patients with positive and negative SLN, respectively. Overall mortality was 15%, due to distant metastases in 78% of the cases. CONCLUSIONS: Staging of early-stage melanoma with the SLN dissection by use of the blue dye technique combined to lymphoscintigraphy and immunohistochemistry is reliable and safe, with less morbidity than elective lymphadenectomy. Long-term follow-up is mandatory to establish the exact reliability of SLN dissection.

Radiation therapy and concurrent plus adjuvant temsirolimus (CCI-779) versus chemoirradiation with temozolomide in newly diagnosed glioblastoma without methylation of the MGMT gene promoter.

Background: Preclinical data indicate activity of mammalian target of rapamycin inhibitors and synergistic activity together with radiotherapy in glioblastoma. The aim of this trial is to assess the therapeutic activity of temsirolimus (CCI-779), an intravenous mTOR inhibitor, in patients with newly diagnosed glioblastoma with unmethylated O6 methlyguanine-DNA-methlytransferase (MGMT)promoter. Methods: Patients (n=257) with newly diagnosed glioblastoma after open surgical biopsy or resection fulfilling basic eligibility criteria underwent a central MGMT promoter analysis using quantitative methylation specific PCR. Patients with glioblastoma harboring an unmethylated MGMT promoter (n=111) were randomized 1:1 between radiotherapy (60 Gy; 5 times 2 Gy per week) plus concomitant and six cycles of maintenance temozolomide or radiotherapy plus weekly temsirolimus at 25 mg flat dose to be continued until progression or undue toxicity. Primary endpoint was overall survival at 12 months (OS12). Sample size of the investigational treatment arm required 54 patients to assess adequacy of temsirolimus activity set at 80%. More than 38 patients alive at 12 months in the per protocol population was considered a positive signal. A control arm of 54 patients treated with the standard of care was implemented to evaluate the assumptions on OS12. Results: Between December 2009 and October 2012, 111 pts in 14 centers were randomized and treated. Median age was 55 and 58 years in the temsirolimus and standard arm, respectively. Most patients (95.5%) had a WHO performance status of 0 or 1. Both therapies were properly administered with a median of 13 cycles of maintenance temsirolimus. In the per protocolpopulation, exactly 38 patients treated with temsirolimus (out of 54 eligible) reached OS12. In the intention to treat population OS12 was 72.2% [95% CI (58.2, 82.2)] in the temozolomide arm and 69.6% [95% CI (55.8, 79.9) in the temsirolimus arm [HR=1.16 95% CI (0.77, 1.76), p=0.47]. Conclusions: The therapeutic activity of temsirolimus in patients with newly diagnosed glioblastoma with an unmethylated MGMT promoter is too low.

Early Stage Primary Bone Lymphoma: A Retrospective, Multicenter Rare Cancer Network Study

PURPOSE/OBJECTIVE(S): Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas, and 4-5% of all extranodal lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with stage I and II PBL. MATERIALS/METHODS: Between 1987 and 2008, 116 consecutive patients with PBL treated in 13 RCNinstitutions were included in this study. Inclusion criteriawere: age.17 yrs, PBLin stage I and II, andminimum6months follow-up. The median agewas 51 yrs (range: 17-93).Diagnosticwork-up included plain boneXray (74%of patients), scintigraphy (62%), CT-scan (65%),MRI (58%), PET (18%), and bone-marrow biopsy (84%).All patients had biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). The histopathological type was predominantly diffuse large B-cell lymphoma (78%) and follicular lymphoma (6%), according to theWHOclassification. One hundred patients had a high-grade, 7 intermediate and 9 low-gradeNHL. Ninety-three patients had anAnn-Arbor stage I, and 23 had a stage II. Seventy-seven patients underwent chemoradiotherapy (CXRT), 12 radiotherapy (RT) alone, 10 chemotherapy alone (CXT), 9 surgery followed by CXRT, 5 surgery followed by CXT, and 2 surgery followed by RT. One patient died before treatment.Median RT dosewas 40Gy (range: 4-60).Themedian number ofCXTcycleswas 6 (range, : 2-8).Median follow-upwas 41months (range: 6-242). RESULTS: Following treatment, the overall response rate was 91% (CR 74%, PR 17%). Local recurrence was observed in 12 (10%) patients, and systemic recurrence in 17 (15%) patients. Causes of death included disease progression in 16, unrelated disease in 6, CXT-related toxicity in 1, and secondary cancer in 2 patients. The 5-yr overall survival (OS), disease-free survival (DFS), lymphoma- specific survival (LSS), and local control (LC) were 76%, 69%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for survival were: age\50 years (p = 0.008), IPI score #1 (p = 0.009), complete response (p\0.001), CXT (p = 0.008), number of CXT cycles $6 (p = 0.007), and RT dose . 40 Gy (p = 0.005). In multivariate analysis age, RT dose, complete response, and absence of B symptoms were independent factors influencing the outcome. There were 3 patients developing grade 3 or more (CTCAE.V3.0) toxicities. CONCLUSIONS: This large multicenter study, confirms the relatively good prognosis of early stage PBL, treated with combined CXRT. Local control was excellent, and systemic failure occurred infrequently. A sufficient dose of RT (. 40 Gy) and complete CXT regime (. 6 cycles) were associated with a better outcome. Combined modality appears to be the treatment of choice.

Listeria brain abscess, Pneumocystis pneumonia and Kaposi's sarcoma after temozolomide.

BACKGROUND: A 55-year-old man with glioblastoma multiforme was treated with continuous, dose-dense temozolomide. This therapy was curtailed after three cycles because of nausea, asthenia, and neuropsychological deterioration. During a subsequent course of radiotherapy, the patient developed fever, headaches, and cutaneous lesions. INVESTIGATIONS: Physical examination, cerebral MRI, brain biopsy, skin biopsy, immunohistochemistry, bronchoscopy with bronchoalveolar lavage, and laboratory tests. DIAGNOSIS: Severe temozolomide-induced immunosuppression, exacerbated by corticosteroids, with profound T-cell lymphocytopenia and simultaneous opportunistic infections with Pneumocystis jiroveci pneumonia, brain abscess with Listeria monocytogenes, and cutaneous Kaposi's sarcoma. MANAGEMENT: Discontinuation of temozolomide, discontinuation of radiotherapy, antibiotic treatment with amoxicillin and gentamicin, and administration of atovaquone and pentamidine.

Three short perioperative infusions of n-3 PUFAs reduce systemic inflammation induced by cardiopulmonary bypass surgery: a randomized controlled trial.

BACKGROUND: Fish oil (FO) has antiinflammatory effects, which might reduce systemic inflammation induced by a cardiopulmonary bypass (CPB). OBJECTIVE: We tested whether perioperative infusions of FO modify the cell membrane composition, inflammatory responses, and clinical course of patients undergoing elective coronary artery bypass surgery. DESIGN: A prospective randomized controlled trial was conducted in cardiac surgery patients who received 3 infusions of 0.2 g/kg FO emulsion or saline (control) 12 and 2 h before and immediately after surgery. Blood samples (7 time points) and an atrial biopsy (during surgery) were obtained to assess the membrane incorporation of PUFAs. Hemodynamic data, catecholamine requirements, and core temperatures were recorded at 10-min intervals; blood triglycerides, nonesterified fatty acids, glucose, lactate, inflammatory cytokines, and carboxyhemoglobin concentrations were measured at selected time points. RESULTS: Twenty-eight patients, with a mean ± SD age of 65.5 ± 9.9 y, were enrolled with no baseline differences between groups. Significant increases in platelet EPA (+0.86%; P = 0.0001) and DHA (+0.87%; P = 0.019) were observed after FO consumption compared with at baseline. Atrial tissue EPA concentrations were higher after FO than after control treatments (+0.5%; P < 0.0001). FO did not significantly alter core temperature but decreased the postoperative rise in IL-6 (P = 0.018). Plasma triglycerides increased transiently after each FO infusion. Plasma concentrations of glucose, lactate, and blood carboxyhemoglobin were lower in the FO than in the control group on the day after surgery. Arrhythmia incidence was low with no significant difference between groups. No adverse effect of FO was detected. CONCLUSIONS: Perioperative FO infusions significantly increased PUFA concentrations in platelet and atrial tissue membranes within 12 h of the first FO administration and decreased biological and clinical signs of inflammation. These results suggest that perioperative FO may be beneficial in elective cardiac surgery with CPB. This trial was registered at clinicaltrials.gov as NCT00516178.

Acute life-threatening extrinsic allergic alveolitis in a paint controller.

BACKGROUND: Occupational diisocyanate-induced extrinsic allergic alveolitis (EAA) is a rare and probably underestimated diagnosis. Two acute occupational EAA cases have been described in this context, but neither of them concerned hexamethylene diisocyanate (HDI) exposure. AIMS: To investigate the cause of a life-threatening EAA arising at work in a healthy 30-year-old female paint quality controller. METHODS: Occupational medical assessment, workplace evaluation, airborne and biological monitoring and immunodermatological tests. RESULTS: Diagnosis of EAA relied on congruent clinical and radiological information, confirmed occupational HDI exposure and positive IgG antibodies and patch tests. The patient worked in a small laboratory for 7 years, only occasionally using HDI-containing hardeners. While working with HDI for 6 h, she developed breathlessness, rapidly progressing to severe respiratory failure. Workplace HDI airborne exposure values ranged from undetectable levels to 4.25 p.p.b. Biological monitoring of urinary hexamethylene diamine in co-workers ranged from <1.0 to 15.4 μg/g creatinine. Patch tests 8 months later showed delayed skin reaction to HDI at 48 h. Subsequent skin biopsy showed spongiotic dermatitis with infiltration of CD4(+) and CD8(+) T cells. CONCLUSIONS: We believe this is the first reported case of acute life-threatening EAA following exposure to HDI. Low concentrations of airborne HDI and relatively high urinary hexamethylene diamine suggest significant skin absorption of HDI could have significantly contributed to the development of this acute occupational EAA.

Human epidermal Langerhans cells express the tight junction protein claudin-1 and are present in human genetic claudin-1 deficiency (NISCH syndrome).

Claudin-1 (CLDN1) is a structural tight junction (TJ) protein and is expressed in differentiating keratinocytes and Langerhans cells in the epidermis. Our objective was to identify immunoreactive CLDN1 in human epidermal Langerhans cells and to examine the pattern of epidermal Langerhans cells in genetic human CLDN1 deficiency [neonatal ichthyosis, sclerosing cholangitis (NISCH) syndrome]. Epidermal cells from healthy human skin labelled with CLDN1-specific antibodies were analysed by confocal laser immunofluorescence microscopy and flow cytometry. Skin biopsy sections of two patients with NISCH syndrome were stained with an antibody to CD1a expressed on epidermal Langerhans cells. Epidermal Langerhans cells and a subpopulation of keratinocytes from healthy skin were positive for CLDN1. The gross number and distribution of epidermal Langerhans cells of two patients with molecularly confirmed NISCH syndrome, however, was not grossly altered. Therefore, CLDN1 is unlikely to play a critical role in migration of Langerhans cells (or their precursors) to the epidermis or their positioning within the epidermis. Our findings do not exclude a role of this TJ molecule once Langerhans cells have left the epidermis for draining lymph nodes.

Parésie trochléaire transitoire comme signe neurologique inaugural d'une panartérite noueuse [Transient trochlear nerve palsy as the presenting neurological sign of panarteritis nodosa]

INTRODUCTION: Panarteritis nodosa (PAN) is a systemic vasculitis affecting small and medium-sized arteries. Neuro-ophthalmological complications of PAN are rare but numerous, and may affect the eye, the visual and the oculomotor pathways. Such complications occur mainly in patients previously diagnosed with PAN. OBSERVATION: A 51-year-old woman presented with an isolated right trochlear (IV) palsy, in the setting of headaches and fluctuating fever of unknown etiology. Erythrocyte sedimentation rate was 13 mm and full blood cell count was normal. Previous chest X-ray and blood studies were negative for an infection or inflammation. Orbital and cerebral CT scan was normal. Spontaneous recovery of diplopia ensued over four days. Two days later, paresthesia and sensory paresis of the dorsal portion of the left foot were present. Lumbar puncture revealed 14 leucocytes (76 percent lymphocytes) with elevated proteins, but blood studies and serologies were negative. A diagnosis of undetermined meningo-myelo-radiculoneuritis was made. Because of a possible tick bite six weeks previously the patient was empirically treated with 2 g intravenous ceftriaxone for 3 weeks. Fever rapidly dropped. Six weeks after the onset of diplopia, acute onset of blindness in her right eye, diffuse arthralgias and fever motivated a new hospitalization. There was a central retinal artery occlusion of the right eye. Blood studies now revealed signs of systemic inflammation (ESR 30 mm, CRP 12 mg/L, ANA 1/80, pANCA 1/40, leucocytosis 12.4 G/L, Hb 111 g/L, Ht 33 percent). Biopsy of the left sural nerve revealed arterial fibrinoid necrosis. A diagnosis of PAN was made. CONCLUSIONS: Transient diplopia can be the heralding symptom of a systemic vasculitis such as PAN, giant cell arteritis and Wegener granulomatosis. In this patient the presence of accompanying systemic symptoms raised a suspicion of systemic inflammation, but the absence of serologic and imaging abnormalities precluded a specific diagnosis initially. A few weeks later, the presence of a second ischemic event (retinal) and positive blood studies led to a further diagnostic procedure. Oculomotor and abducens palsies have rarely been reported in association with PAN. We report the first case of trochlear nerve paresis as the inaugural neurological sign of PAN. This case highlights the importance of considering inflammatory systemic disorders in patients with acute diplopia particularly when they are young, lack vascular risk factors or cause, and complain of associated systemic symptoms.

Unusual association of diseases/symptoms: Encephalitis with herpes simplex-2 in the cerebrospinal fluid and anti-RI (ANNA-2) antibodies: an infectious or a paraneoplastic syndrome?

We report on a 70-year-old woman with partial complex status epilepticus who was initially diagnosed with herpes simplex-2 (HSV-2) encephalitis, based on brain magnetic resonance imaging (MRI) findings, cerebrospinal fluid (CSF) lymphocytic pleocytosis and HSV-2 DNA detection by polymerase chain reaction (PCR) in the CSF, but without improvement on intravenous acyclovir. Anti-Ri antibodies were positive and computed tomography (CT) investigations revealed a small cell carcinoma at biopsy suggesting paraneoplastic encephalitis. The outcome was unfavourable and the autopsy showed typical features of paraneoplastic encephalitis but no evidence of viral inclusions. This case report is interesting because: (1) it is the first report of an autopsy proven paraneoplastic widespread encephalitis with anti-Ri antibodies; (2) despite a positive HSV-2 PCR in the CSF, there was no sign of herpetic infections of the nervous system; and (3) it illustrates the fact that if paraneoplastic antibodies are usually good markers of the underlying tumour, they are not always predictive of neurological deficits.

Mitotic figure counts are overrated in resection specimen of invasive breast carcinoma

In order for some patients to benefit from aggressive chemotherapy for invasive breast carcinoma, many patients are currently being treated without little or no benefit. Enormous effort is hence being directed towards the identification of those patients who will need chemotherapy and those who will not. Since chemotherapy targets proliferating cells pathologists focus on the proliferative activity of tumors, as assessed by mitotic figure counts or by cell cycle specific immunohistochemical markers, such as Ki-67 and H3 histone. As far as the tumor grade is concerned, many of these studies have reported a tendency to up-grade carcinomas in resection specimen when compared to the initial diagnosis on the biopsy material, and most studies have noted that the upgrade in resection specimen is due solely or to a large extent to an increase in the mitotic figure count. In the present study, we propose a different explanation for the divergence in mitotic figure counts between biopsy and resection material. We assessed the proliferative activity of 52 invasive ductal carcinomas and confirm that the number of mitotic figures significantly increased by a factor of more than 3 in resection specimen over the biopsy material, while at the same time the pan-cell cycle specific marker MIB-1 yieldes comparable results. we propose that the delayed formalin fixation of resection specimen allows cell cycle activities to continue for a long time, up to many hours, and that this leads to an arrest of mitoses in metaphase where they are readily identified by the pathologist. We propose that the mitotic figure count in the rapidly fixed biopsy cores better represent the tumor biology and should be used as a basis for chemotherapy therapeutic decisions.

The role of focal therapy in the management of localised prostate cancer: a systematic review.

CONTEXT: The incidence of localised prostate cancer is increasing worldwide. In light of recent evidence, current, radical, whole-gland treatments for organ-confined disease have being questioned with respect to their side effects, cancer control, and cost. Focal therapy may be an effective alternative strategy. OBJECTIVE: To systematically review the existing literature on baseline characteristics of the target population; preoperative evaluation to localise disease; and perioperative, functional, and disease control outcomes following focal therapy. EVIDENCE ACQUISITION: Medline (through PubMed), Embase, Web of Science, and Cochrane Review databases were searched from inception to 31 October 2012. In addition, registered but not yet published trials were retrieved. Studies evaluating tissue-preserving therapies in men with biopsy-proven prostate cancer in the primary or salvage setting were included. EVIDENCE SYNTHESIS: A total of 2350 cases were treated to date across 30 studies. Most studies were retrospective with variable standards of reporting, although there was an increasing number of prospective registered trials. Focal therapy was mainly delivered to men with low and intermediate disease, although some high-risk cases were treated that had known, unilateral, significant cancer. In most of the cases, biopsy findings were correlated to specific preoperative imaging, such as multiparametric magnetic resonance imaging or Doppler ultrasound to determine eligibility. Follow-up varied between 0 and 11.1 yr. In treatment-naïve prostates, pad-free continence ranged from 95% to 100%, erectile function ranged from 54% to 100%, and absence of clinically significant cancer ranged from 83% to 100%. In focal salvage cases for radiotherapy failure, the same outcomes were achieved in 87.2-100%, 29-40%, and 92% of cases, respectively. Biochemical disease-free survival was reported using a number of definitions that were not validated in the focal-therapy setting. CONCLUSIONS: Our systematic review highlights that, when focal therapy is delivered with intention to treat, the perioperative, functional, and disease control outcomes are encouraging within a short- to medium-term follow-up. Focal therapy is a strategy by which the overtreatment burden of the current prostate cancer pathway could be reduced, but robust comparative effectiveness studies are now required.

Giant cell arteritis: A rare cause of posterior vasculitis.

PURPOSE: To report three cases of posterior vasculitis associated with subacute giant cell arteritis (GCA). METHODS: Three patients with decreased vision underwent complete ophthalmologic examination and fluorescein angiography. RESULTS: All patients presented posterior vasculitis. Patient 1 had an erythrocyte sedimentation rate (ESR) of 38 mm/hr and a C-reactive protein (CRP) of 28mg/L. Patient 2 and 3 had an ESR of 104 and 95 mm/hr and a CRP of 42 and 195 mg/L accordingly. Diagnosis was established by temporal artery biopsy. Resolution was observed after systemic prednisolone therapy. CONCLUSION: GCA should be suspected when posterior vasculitis and relatively high ESR and CRP are present.

Wide resection of the lateral malleolus and adjacent tibial, talar and calcanear bones with ankle fusion and allograft reconstruction for an osteosarcoma.

Introduction: Primary bone sarcomas around the ankle are rare. Due to the proximity of neurovascular structures and limited soft tissue reserves, limb salvage is often not possible. Case report: A 19 yo male presented with pain and a progressive swelling of his ankle. X-rays revealed cortical erosions and an extensive periosteal reaction (sunburst) of the distal fibula. MRI showed a large mass of the fibula invading adjacent soft tissue. The lesion appeared close to the ankle joint, but with the articular cartilage as a barrier and without joint effusion. Core-needle biopsy revealed a high-grade chondroblastic osteosarcoma. No metastases were detected. After presentation at our multidisciplinary sarcoma board, the patient was subjected to neo-adjuvant chemotherapy (AOST 03-331). Without any sign of intra-articular contamination of the ankle joint, surgical treatment consisted of wide resection of the lateral malleolus including a large skin patch, the distal third of the fibula, the lateral surfaces of the tibia and talus as well as the insertion of the lateral ligament on the calcaneus. The distal parts of the anterior, peroneal, and posterior muscular compartments were resected en bloc with the tumor. The defect was reconstructed with tibio-talar and talo-calcanear fusion, bony allograft and a plate. Soft-tissue coverage was achieved with a free fascio-cutaneous flap from the controlateral thigh. Histological analysis revealed clear margins and 50% of tumor necrosis. The oncologic treatment was completed with adjuvant chemotherapy. Conclusion: Wide resection and reconstruction of the lateral malleolus is technically demanding but possible in selected cases. Despite some important functional loss, limb salvage is superior to an amputation.

Dermatofibrosarcoma presenting as a nodule in the breast of a 75-year-old woman: a case report.

ABSTRACT: INTRODUCTION: Dermatofibrosarcoma protuberans is a rare neoplasm of soft tissues and its location in the breast is extremely uncommon. Confusion is possible with other primary breast lesions. CASE PRESENTATION: A 75-year-old Caucasian woman presented with a mass in her left breast 21 years after being diagnosed with invasive ductal carcinoma of the right breast, treated by a right mastectomy and axillary dissection followed by radiotherapy and breast reconstruction. Mammography revealed a dish-shaped skin nodule formation in the upper outer quadrant of her left breast. Echography confirmed the presence of a lesion measuring 1.4 x 0.8 cm. Based on imaging, the diagnosis was a probable angiosarcoma. Due to the presence of a pacemaker for cardiac arrhythmia and full anticoagulation therapy for a pulmonary embolism, magnetic resonance imaging and a biopsy were not done. We proceeded directly to a quadrantectomy and the final diagnosis revealed a dermatofibrosarcoma protuberans, 1. 8 cm in its greatest microscopic dimension, located 0.1 cm from the upper surgical margin. To ensure the wide resection margins required for this type of neoplasm, a re-excision was performed. CONCLUSION: A dermatofibrosarcoma protuberans of the breast is an uncommon discovery. The aim of this case report is to highlight the importance of the surgical procedure in cases of the discovery of dermatofibrosarcoma protuberans. Re-excision may be necessary to ensure adequate resection margins.

Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide.

PURPOSE: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. EXPERIMENTAL DESIGN: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. RESULTS: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P = 0.002; Fisher's exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P = 0.017; Cox regression). CONCLUSIONS: This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.