Correlations between perfusion MR imaging cerebral blood volume, microvessel quantification, and clinical outcome using stereotactic analysis in recurrent high-grade glioma.

BACKGROUND AND PURPOSE: Quantifying MVA rather than MVD provides better correlation with survival in HGG. This is attributed to a specific "glomeruloid" vascular pattern, which is better characterized by vessel area than number. Despite its prognostic value, MVA quantification is laborious and clinically impractical. The DSC-MR imaging measure of rCBV offers the advantages of speed and convenience to overcome these limitations; however, clinical use of this technique depends on establishing accurate correlations between rCBV, MVA, and MVD, particularly in the setting of heterogeneous vascular size inherent to human HGG. MATERIALS AND METHODS: We obtained preoperative 3T DSC-MR imaging in patients with HGG before stereotactic surgery. We histologically quantified MVA, MVD, and vascular size heterogeneity from CD34-stained 10-µm sections of stereotactic biopsies, and we coregistered biopsy locations with localized rCBV measurements. We statistically correlated rCBV, MVA, and MVD under conditions of high and low vascular-size heterogeneity and among tumor grades. We correlated all parameters with OS by using Cox regression. RESULTS: We analyzed 38 biopsies from 24 subjects. rCBV correlated strongly with MVA (r = 0.83, P < .0001) but weakly with MVD (r = 0.32, P = .05), due to microvessel size heterogeneity. Among samples with more homogeneous vessel size, rCBV correlation with MVD improved (r = 0.56, P = .01). OS correlated with both rCBV (P = .02) and MVA (P = .01) but not with MVD (P = .17). CONCLUSIONS: rCBV provides a reliable estimation of tumor MVA as a biomarker of glioma outcome. rCBV poorly estimates MVD in the presence of vessel size heterogeneity inherent to human HGG.

Predictors of the response to treatment in anemic hemodialysis patients with high serum ferritin and low transferrin saturation.

Treating hemodialysis patients to combat anemia corrects hemoglobin but exacerbates iron deficiency by utilizing iron stores. Patients needing iron should receive this by intravenous (i.v.) means. The Dialysis patients' Response to IV iron with Elevated ferritin (DRIVE) trial investigated the role of i.v. iron in anemic patients with high ferritin, low transferrin saturation, and adequate epoetin doses. We examined whether baseline iron and inflammation markers predict the response of hemoglobin to treatment. Patients (134) were randomized to no added iron or to i.v. ferric gluconate for eight consecutive hemodialysis sessions spanning 6 weeks with epoetin increased by 25% in both groups. The patients started with hemoglobin less than or equal to 11 g/dl, ferritin between 500 and 1200 ng/ml, and transferrin saturation of less than 25%. Significantly, patients with a reticulocyte hemoglobin content greater than or equal to 31.2 pg were over five times more likely to achieve a clinically significant increase in hemoglobin of greater than 2 g/dl. Lower reticulocyte hemoglobin contents did not preclude a response to i.v. iron. Significantly higher transferrin saturation or lower C-reactive protein but not ferritin or soluble transferrin receptor levels predicted a greater response; however their influence was not clinically significant in either group. We conclude that none of the studied markers is a good predictor of response to anemia treatment in this patient sub-population.

Season of birth and risk of brain tumors in adults.

BACKGROUND: Recent studies demonstrated an excess of winter births in children with brain tumors and in adults with various neurologic or psychiatric diseases relative to the general population. OBJECTIVE: To investigate a possible association between month of birth and risk of brain tumors in adults using data from a large, hospital-based case-control study. METHODS: Cases were patients with incident glioma (n = 489) or meningioma (n = 197) diagnosed at hospitals in Boston, MA, Phoenix, AZ, and Pittsburgh, PA. Controls (n = 799) were patients hospitalized for a variety of nonmalignant conditions and frequency matched to cases by hospital, age, sex, race/ethnicity, and distance of residence from hospital. Odds ratios (ORs) were calculated using multivariate unconditional logistic regression allowing for cyclic variation in risk with month of birth. RESULTS: A relationship between month of birth and risk of adult glioma and meningioma was found, best described by a 12-month periodic function with peaks in February and January and troughs in August and July. The association between month of birth and risk of glioma differed significantly by handedness, with left-handed and ambidextrous subjects born during late fall through early spring being at particularly high risk of adult glioma as compared with those born at other times of the year. CONCLUSION: These findings suggest the importance of seasonally varying exposures during the pre- or postnatal period in the development of brain tumors in adults.

Occupation and the risk of adult glioma in the United States.

OBJECTIVE: Previous studies have observed increased glioma incidence associated with employment in the petroleum and electrical industries, and in farming. Several other occupations have also been associated with increased risk, but with inconsistent results. We evaluated associations between occupational title and glioma incidence in adults. METHODS: Cases were 489 patients with glioma diagnosed from 1994 to 1998 at three United States hospitals. Controls were 799 patients admitted to the same hospitals for non-malignant conditions. An experienced industrial hygienist grouped occupations that were expected to have similar tasks and exposures. The risk of adult glioma was evaluated for those subjects who ever worked in an occupational group for at least six months, those who worked longer than five years in the occupation, and those with more than ten years latency since starting work in the occupation. RESULTS: Several occupational groups were associated with increased glioma incidence for having ever worked in the occupation, including butchers and meat cutters (odds ratio [OR] = 2.4; 95% confidence limits [CL]: 1.0, 6.0), computer programmers and analysts (OR = 2.0; 95% CL: 1.0, 3.8), electricians (OR = 1.8; 95% CL: 0.8, 4.1), general farmers and farmworkers (OR = 2.5; 95% CL: 1.4, 4.7), inspectors, checkers, examiners, graders, and testers (OR = 1.5; 95% CL: 0.8, 2.7), investigators, examiners, adjustors, and appraisers (OR = 1.7; 95% CL: 0.8, 3.7), physicians and physician assistants (OR = 2.4; 95% CL: 0.8, 7.2), and store managers (OR = 1.6; 95% CL: 0.8, 3.1), whereas occupation as a childcare worker was associated with decreased glioma incidence (OR = 0.4; 95% CL: 0.2, 0.9). These associations generally persisted when the subjects worked longer than five years in the occupation, and for those with more than ten years latency since starting to work in the occupation. CONCLUSIONS: This is our first analysis of occupation and will guide future exposure-specific assessments.

A randomized trial of iron deficiency testing strategies in hemodialysis patients.

BACKGROUND: Diagnosis of iron deficiency in hemodialysis patients is limited by the inaccuracy of commonly used tests. Reticulocyte hemoglobin content (CHr) is a test that has shown promise for improved diagnosis in preliminary studies. The purpose of this study was to compare iron management guided by serum ferritin and transferrin saturation to management guided by CHr. METHODS: A total of 157 hemodialysis patients from three centers were randomized to iron management based on (group 1) serum ferritin and transferrin saturation, or (group 2) CHr. Patients were followed for six months. Treatment with intravenous iron dextran, 100 mg for 10 consecutive treatments was initiated if (group 1) serum ferritin <100 ng/mL or transferrin saturation <20%, or (group 2) CHr <29 pg. RESULTS: There was no significant difference between groups in the final mean hematocrit or epoetin dose. The mean weekly dose of iron dextran was 47.7 +/- 35.5 mg in group 1 compared to 22.9 +/- 20.5 mg in group 2 (P = 0.02). The final mean serum ferritin was 399.5 +/- 247.6 ng/mL in group 1 compared to 304.7 +/- 290.6 ng/mL in group 2 (P < 0.05). There was no significant difference in final TSAT or CHr. Coefficient of variation was significantly lower for CHr than serum ferritin and transferrin saturation (3.4% vs. 43.6% and 39.5%, respectively). CONCLUSIONS: CHr is a markedly more stable analyte than serum ferritin or transferrin saturation, and iron management based on CHr results in similar hematocrit and epoetin dosing while significantly reducing IV iron exposure.

Cochlear reimplantation: surgical techniques and functional results.

OBJECTIVES/HYPOTHESIS: The most common indication for cochlear reimplantation is device failure. Other, less frequent indications consist of "upgrades" (e.g., single to multichannel), infection, and flap breakdown. Although the percentage of failures has decreased over time, an occasional patient requires reimplantation because of device malfunction. The varying designs of internal receiver/stimulators and electrode arrays mandate an examination of the nature and effects of reimplantation for the individual designs. The purpose of the current study was to investigate the reimplantation of several implant designs and to determine whether differences in surgical technique, anatomical findings, and postoperative performance exist. STUDY DESIGN: Retrospective chart review. METHODS: The subjects were 33 of 618 severely to profoundly deaf adults and children who had implantation at the New York University Medical Center (New York, NY) between February 1984 and December 2000. The subjects had previously had implantation with either a single-channel 3M/House (House Ear Institute, Los Angeles, CA) or 3M/Vienna (Technical University of Vienna, Vienna, Austria) device or with one of the multichannel Clarion (Advanced Bionics, Sylmar, CA), Ineraid (Smith & Nephew Richards, TN), or Nucleus (including the Contour) devices (Cochlear Corp., Englewood, CO) before reimplantation. RESULTS: Length of use before reimplantation ranged from 1 month to 13 years and included traumatic and atraumatic (electronic) failures, as well as device extrusion or infection. Results indicated that postoperative performance was either equal to or better than scores before failure. None of the devices explanted caused damage that precluded the implantation of the same or an upgraded device. These findings support the efficacy and safety of internal implant designs as related to the maintenance of a functional cochlea for the purpose of reimplantation. CONCLUSIONS: Cochlear reimplantation can be performed safely and without decrement to performance. The number of implanted electrodes at reinsertion were either the same or greater in all cases.

Acute renal failure after radiofrequency liver ablation of metastatic carcinoid tumor.

IMPLICATIONS: We report a case of prolonged radiofrequency liver ablation for metastatic carcinoid tumor complicated by hemolysis, rhabdomyolysis, and transient acute renal failure. Brief radiofrequency liver ablation procedures or those for a small number of tumor sites are not associated with these complications.

Intra-arterial cisplatin plus oral etoposide for the treatment of recurrent malignant glioma: a phase II study.

Twenty-five adults with recurrent malignant glioma were enrolled into a phase II clinical study. All patients had undergone surgical resection and had failed radiotherapy and first-line treatment with nitrosourea-based chemotherapy; five had failed second-line chemotherapy. Our objective was to test the efficacy of combining intra-arterially (i.a.) infused cisplatin and oral etoposide. Using conventional angiographic technique to access anterior/posterior cerebral circulation, cisplatin 60 mg/m2 was administered by i.a. infusion on day 1 of treatment. Oral etoposide 50 mg/m2/day was given days 1-21, with a 7 day rest interval between courses. Response to treatment was evaluated in 20 patients. Two patients with anaplastic astrocytoma had partial responses (PR) and six patients experienced stable disease (SD) for an overall response rate (PR +/- SD) of 40%. The median time to disease progression (MTP) following treatment for the responder subgroup was 18 weeks. The median survival time from treatment (MST) for the responders (n = 8) and non-responders (n = 12) was 56.5 weeks and 11 weeks, respectively. Combined i.a. cisplatin and oral etoposide was well-tolerated, but produced an objective response in only a minority of patients. Those considered responders (PR + SD) experienced significant survival advantage when compared to the non-responders. Nonetheless, i.a. delivery of chemotherapy is an expensive and technologically burdensome treatment for most patients to access, requiring proximity to a major center with neuro-oncological and neuroradiological clinical services. This is of special concern for patients suffering recurrent disease with progressive neurological symptoms at a time in their course when quality of life must be safeguarded and palliation of symptoms should be the therapeutic goal. Despite the efforts of previous investigators to use this combination of agents to treat recurrent malignant glioma, we cannot recommend the use of i.a. chemotherapy for salvage treatment of this disease.

The adequacy of basic intraoperative transesophageal echocardiography performed by experienced anesthesiologists.

UNLABELLED: Transesophageal echocardiography (TEE) may improve intraoperative decision-making and patient outcome if it is performed and interpreted correctly. After revising our TEE examination to fulfill the published guidelines for basic TEE practitioners, we prospectively evaluated the ability of our cardiac anesthesiologists (all very experienced with TEE) to record and interpret this revised examination. Educational aids and regular TEE performance feedback were provided to the anesthesiologists. Their interpretations were compared with the independently determined results of experts. Compared with their own historical controls (42% recording rate), all anesthesiologists showed significant improvement in their ability to record a basic intraoperative TEE examination resulting in 81% (P < 0.0001) of all required images being recorded: 88% before cardiopulmonary bypass, 77% immediately after bypass, and 64% after chest closure. Seventy-nine percent of the images recorded at baseline were correctly interpreted, 6% were incorrectly interpreted, and 15% were not evaluated. Our attempt to assess compliance with published guidelines for basic intraoperative TEE resulted in a marked improvement in our intraoperative TEE practice. Most, but not all, standard cross-sections are recorded or interpreted correctly, even by highly experienced and motivated practitioners. IMPLICATIONS: Experienced cardiac anesthesiologists can obtain and correctly interpret most basic intraoperative transesophageal echocardiograms.

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine.

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

Cellular-telephone use and brain tumors.

BACKGROUND: Concern has arisen that the use of hand-held cellular telephones might cause brain tumors. If such a risk does exist, the matter would be of considerable public health importance, given the rapid increase worldwide in the use of these devices. METHODS: We examined the use of cellular telephones in a case-control study of intracranial tumors of the nervous system conducted between 1994 and 1998. We enrolled 782 patients through hospitals in Phoenix, Arizona; Boston; and Pittsburgh; 489 had histologically confirmed glioma, 197 had meningioma, and 96 had acoustic neuroma. The 799 controls were patients admitted to the same hospitals as the patients with brain tumors for a variety of nonmalignant conditions. RESULTS: As compared with never, or very rarely, having used a cellular telephone, the relative risks associated with a cumulative use of a cellular telephone for more than 100 hours were 0.9 for glioma (95 percent confidence interval, 0.5 to 1.6), 0.7 for meningioma (95 percent confidence interval, 0.3 to 1.7), 1.4 for acoustic neuroma (95 percent confidence interval, 0.6 to 3.5), and 1.0 for all types of tumors combined (95 percent confidence interval, 0.6 to 1.5). There was no evidence that the risks were higher among persons who used cellular telephones for 60 or more minutes per day or regularly for five or more years. Tumors did not occur disproportionately often on the side of head on which the telephone was typically used. CONCLUSIONS: These data do not support the hypothesis that the recent use of hand-held cellular telephones causes brain tumors, but they are not sufficient to evaluate the risks among long-term, heavy users and for potentially long induction periods.

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

Family presence during trauma resuscitation: a survey of AAST and ENA members. American Association for the Surgery of Trauma. Emergency Nurses Association.

BACKGROUND: The Emergency Nurses Association (ENA) has formally resolved that family presence (FP) during resuscitation and invasive procedures (TR) is the right of the patient and is beneficial for both patients and family members. Furthermore, FP during TR has been implemented at several trauma centers. Because this policy is controversial, a survey was conducted to assess the opinions of members of the American Association for the Surgery of Trauma (AAST) and ENA in regard to FP. METHODS: A survey instrument regarding FP during TR was mailed to the AAST membership (n = 813) and a random sampling (10%) of ENA members (n = 2,988). Questions regarding membership (AAST vs. ENA), age, gender, years in practice, trauma experience, the patient's right to FP during the primary survey, secondary survey, and invasive procedures, the potential effects of FP on trauma team function, and medicolegal implications were included in the survey. Qualitative and quantitative variables were analyzed by analysis of variance and chi2 analysis, respectively. Responses to questions by using a Likert Scale for degree of agreement were analyzed by using the Kruskal-Wallis test. RESULTS: A total of 1,629 (AAST, n = 368; ENA, n = 1,261) surveys were returned (43.4% response). There were 44 surveys returned as undeliverable (1.2%). The members of the AAST were older, more likely to be male, had been in practice longer, and had greater trauma experience when compared with ENA members (p < 0.001). More AAST than ENA members (97.8% vs. 80.2%) believed that FP during all phases of TR was inappropriate (p < 0.001). Fewer AAST members believed that FP was a patient right when compared with ENA members (p < 0.0001). The AAST members were more likely to believe FP interfered with patient care and increased the stress of trauma team members (p < 0.0001). The majority of AAST and ENA members had experience with FP during TR (55.3 vs. 67.8%; p < 0.001). However, the impressions of their experiences were widely disparate, with 63.6% of ENA and only 17.5% of AAST members, indicating that the experience was beneficial (p < 0.001). CONCLUSION: Attitudes toward FP during TR are significantly different between AAST and ENA members. Because of these differences in opinion, implementation of an FP policy may create conflicts between trauma team members and may interfere with the effectiveness of the trauma team.

Limited utility of routine drug screening in trauma patients.

BACKGROUND: Routine toxicology screening of seriously injured patients has become the standard of care in most trauma centers. However, the benefit of drug screening in acute trauma is unproven. We reviewed the impact of positive drug screening results on patient care within the first 3 days of treatment. METHODS: We retrospectively reviewed the charts of seriously injured patients admitted to an American College of Surgeons-certified level I trauma center over a 5-year period. Modifications of therapeutic regimens based on positive toxicology results were noted. Using current financial data, charges for toxicology were calculated. RESULTS: Between January 1, 1990, and December 31, 1995, 2,678 trauma patients had drug screening. Of these, 414 (15%) had detectable quantities of the following intoxicants: opiates, barbiturates, amphetamines, phencyclidine hydrochloride (PCP), cocaine, marijuana, or benzodiazepines. Review of all 401 available charts failed to identify any cases in which treatment was altered by a positive toxicology result. Hospital costs related to routine screening were $138,587, while charges to patients amounted to $538,278. CONCLUSIONS: Routine toxicology does not alter or improve the immediate care of the injured patient. Routine drug screening is expensive, and benefits were not easily documented. The policy of routine toxicology screening in trauma centers should be reevaluated.

Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

Current therapy for brain tumors: back to the future.

In the last 30 years, while considerable progress has been made in laboratory research of malignant gliomas, fewer clinical breakthroughs can be highlighted. Laboratory research has improved our understanding of the biology, and especially the molecular genetics of this disease. Unfortunately, these successes highlight the difficulties in translating laboratory results into substantive clinical improvements. In part, these difficulties stem from a schizophrenic view of the development and evolution of brain tumors. We believe either that (1) brain tumors are local and therefore the most important research should have as its goal local control, or (2) brain tumors are diffuse, which is to say that the cells rapidly grow beyond their initial locus, and our research goal is the prevention or treatment of the advancing tumor front. Clearly both hypotheses have merit and, in fact, almost certainly, both are true. The question becomes, should we devote our research energies to one hypothesis at the exclusion of the other?