3D quantitative assessment of response to fractionated stereotactic radiotherapy and single-session stereotactic radiosurgery of vestibular schwannoma.

OBJECTIVES: To determine clinical outcome of patients with vestibular schwannoma (VS) after treatment with fractionated stereotactic radiotherapy (FSRT) and single-session stereotactic radiosurgery (SRS) by using 3D quantitative response assessment on MRI. MATERIALS: This retrospective analysis included 162 patients who underwent radiation therapy for sporadic VS. Measurements on T1-weighted contrast-enhanced MRI (in 2-year post-therapy intervals: 0-2, 2-4, 4-6, 6-8, 8-10, 10-12 years) were taken for total tumour volume (TTV) and enhancing tumour volume (ETV) based on a semi-automated technique. Patients were considered non-responders (NRs) if they required subsequent microsurgical resection or developed radiological progression and tumour-related symptoms. RESULTS: Median follow-up was 4.1 years (range: 0.4-12.0). TTV and ETV decreased for both the FSRT and SRS groups. However, only the FSRT group achieved significant tumour shrinkage (p < 0.015 for TTV, p < 0.005 for ETV over time). The 11 NRs showed proportionally greater TTV (median TTV pre-treatment: 0.61 cm(3), 8-10 years after: 1.77 cm(3)) and ETV despite radiation therapy compared to responders (median TTV pre-treatment: 1.06 cm(3); 10-12 years after: 0.81 cm(3); p = 0.001). CONCLUSION: 3D quantification of VS showed a significant decrease in TTV and ETV on FSRT-treated patients only. NR had significantly greater TTV and ETV over time. KEY POINTS: Only FSRT not GK-treated patients showed significant tumour shrinkage over time. Clinical non-responders showed significantly less tumour shrinkage when compared to responders. 3D volumetric assessment of vestibular schwannoma shows advantages over unidimensional techniques.

GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis.

BACKGROUND: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) is a global, prospective, non-interventional study undertaken to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice, including Child-Pugh B patients who were excluded from clinical trials. METHODS: Patients with unresectable HCC, for whom the decision to treat with sorafenib, based on the approved label and prescribing guidelines, had been taken by their physician, were eligible for inclusion. Demographic data and disease/medical history were recorded at entry. Sorafenib dosing and adverse events (AEs) were collected at follow-up visits. The second interim analysis was undertaken when ~1500 treated patients were followed up for ≥ 4 months. RESULTS: Of the 1571 patients evaluable for safety, 61% had Child-Pugh A status and 23% Child-Pugh B. The majority of patients (74%) received the approved 800 mg initial sorafenib dose, regardless of Child-Pugh status; however, median duration of therapy was shorter in Child-Pugh B patients. The majority of drug-related AEs were grade 1 or 2, and the most commonly reported were consistent with previous reports. The incidence and nature of drug-related AEs were broadly similar across Child-Pugh, Barcelona Clinic Liver Cancer (BCLC) and initial dosing subgroups, and consistent with the overall population. CONCLUSIONS: Consistent with the first interim analysis, overall safety profile and dosing strategy are similar across Child-Pugh subgroups. Safety findings also appear comparable irrespective of initial sorafenib dose or BCLC stage. Final analyses in > 3000 patients are ongoing.

Impact of a single-day multidisciplinary clinic on the management of patients with liver tumours.

PURPOSE: Multidisciplinary cancer clinics may improve patient care. We examined how a single-day multidisciplinary liver clinic (mdlc) affected care recommendations for patients compared with the recommendations provided before presentation to the mdlc. METHODS: We analyzed the demographic and clinicopathologic data of 343 patients assessed in the Johns Hopkins Liver Tumor Center from 2009 to 2012, comparing imaging and pathology interpretation, diagnosis, and management plan between the outside provider (osp) and the mdlc. RESULTS: Most patients were white (n = 259, 76%); median age was 60 years; and 146 were women (43%). Outside providers referred 182 patients (53%); the rest were self-referred. Patients travelled median of 83.4 miles (interquartile range: 42.7-247 miles). Most had already undergone imaging (n = 338, 99%) and biopsy (n = 194, 57%) at the osp, and a formal management plan had been formulated for about half (n = 168, 49%). Alterations in the interpretation of imaging occurred for 49 patients (18%) and of biopsy for 14 patients (10%). Referral to the mdlc resulted in a change of diagnosis in 26 patients (8%), of management plan in 70 patients (42%), and of tumour resectability in 7 patients (5%). Roughly half the patients (n = 174, 51%) returned for a follow-up, and 154 of the returnees (89%) received treatment, primarily intraarterial therapy (n = 88, 57%), systemic chemotherapy (n = 60, 39%), or liver resection (n = 32, 21%). Enrollment in a clinical trial was proposed to 34 patients (10%), and 21 of the 34 (62%) were accrued. CONCLUSIONS: Patient assessment by our multidisciplinary liver clinic had a significant impact on management, resulting in alterations to imaging and pathology interpretation, diagnosis, and management plan. The mdlc is an effective and convenient means of delivering expert opinion about the diagnosis and management of liver tumours.

First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafeNib) non-interventional study.

AIMS: Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON), a global, non-interventional, surveillance study, aims to evaluate the safety of sorafenib in all patients with unresectable hepatocellular carcinoma (uHCC) under real-life practice conditions, particularly Child-Pugh B patients, who were not well represented in clinical trials. METHODS: Treatment decisions are determined by each physician according to local prescribing guidelines and clinical practice. Patients with uHCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Demographic data and medical and disease history are recorded at entry. Sorafenib dosing and adverse events (AEs) are collected throughout the study. RESULTS: From January 2009 to April 2011, >3000 patients from 39 countries were enrolled. The prespecified first interim analysis was conducted when the initial approximately 500 treated patients had been followed up for ≥4 months; 479 were valid for safety evaluation. Preplanned subgroup analyses indicate differences in patient characteristics, disease aetiology and previous treatments by region. Variation in sorafenib dosing by specialty are also observed; Child-Pugh status did not appear to influence the starting dose of sorafenib. The type and incidence of AEs was consistent with findings from previous clinical studies. AE profiles were comparable between Child-Pugh subgroups. DISCUSSION: The GIDEON study is generating a large, robust database from a broad population of patients with uHCC. First interim analyses have shown global and regional differences in patient characteristics, disease aetiology and practice patterns. Subsequent planned analyses will allow further evaluation of early trends.

Packing technique for endovascular coil embolisation of peripheral arterial pseudo-aneurysms with preservation of the parent artery: safety, efficacy and outcomes.

OBJECTIVES: To evaluate the endovascular treatment of pseudo-aneurysms (PAs) with super-selective coil embolisation using the 3D packing technique. DESIGN: Retrospective study of consecutive patients in one academic centre. MATERIALS: From 2002 to 2009, 16 patients (mean age 51.6 years, range 24-82) underwent PA sac packing with coils. Four patients were asymptomatic, nine had PA rupture, and three had other symptoms. Lesion location was as follows: splenic artery (8), carotid artery (2), hepatic artery (2), superior mesenteric artery (1), cystic artery (1), uterine artery (1), and hypogastric artery (1). METHODS: The sac was packed with 0.018-inch controlled-detachable microcoils, preserving the parent artery. Magnetic resonance angiography was done within 6 months, at 12 months then yearly. RESULTS: Technical success rate was 100%. Complete definitive PA exclusion was achieved with a single procedure in 15 (93.8%) patients. One patient with a secondary bleeding arterio-digestive fistula underwent successful surgery. No major complications or late recanalisations occurred during follow-up (mean, 24.7 months; range 6-49). CONCLUSIONS: Coil PA embolisation by 3D sac packing is safe and effective and may induce less morbidity than complete parent vessel occlusion, stent placement, or open surgery. This procedure should be used whenever possible, as it preserves parent artery patency.

Ca2+ responses to interleukin 1 and tumor necrosis factor in cultured human skin fibroblasts. Possible implications for Reye syndrome.

Elevated concentrations of cytokines were found in the plasma of patients acutely ill with Reye syndrome (RS) but not in control subjects or recovered RS patients. To determine whether this disorder involves a genetically determined abnormal response to cytokines, the effects of tumor necrosis factor (TNF) and IL-1 on intracellular free Ca2+ were compared in cultured skin fibroblasts from control subjects and patients with RS. IL-1 and TNF caused rapid, transient, and concentration-dependent increases in cytosolic free Ca2+. The peak cytosolic free Ca2+ was greater and occurred at higher concentrations of IL-1 and TNF in patient cells than in cells from age-matched controls. In control cells, the Ca2+ transient diminished sharply with increasing amounts of IL-1 or TNF above the maximum stimulatory concentration. In contrast, in patient fibroblast this bell-shaped curve of concentration dependency was much less apparent. Bradykinin-stimulated Ca2+ transients were similar in the two groups and did not exhibit the bell-shaped concentration dependency. Thus, plasma cytokine levels are elevated in RS patients and the Ca2+ response to cytokines is increased in cells derived from these patients. We propose that the increased response reflects a genetic defect in cytokine receptor-modulated signal transduction.

New concepts in embolotherapy of HCC.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide with rapidly growing incidence rates in the USA and Europe. Despite improving surveillance programs, most patients are diagnosed at intermediate to advanced stages and are no longer amenable to curative therapies, such as ablation, surgical resection and liver transplantation. For such patients, catheter-based image-guided embolotherapies such as transarterial chemoembolization (TACE) represent the standard of care and mainstay therapy, as recommended and endorsed by a variety of national guidelines and staging systems. The main benefit of these therapies is explained by the preferentially arterial blood supply of liver tumors, which allows to deliver the anticancer therapy directly to the tumor-feeding artery while sparing the healthy hepatic tissue mainly supplied by the portal vein. The tool box of an interventional oncologist contains several different variants of transarterial treatment modalities. Ever since the first TACE more than 30 years ago, these techniques have been progressively refined, both with respect to drug delivery materials and with respect to angiographic micro-catheter and image-guidance technology, thus substantially improving therapeutic outcomes of HCC. This review will summarize the fundamental principles, technical and clinical data on the application of different embolotherapies, such as bland transarterial embolization, Lipiodol-based conventional transarterial chemoembolization as well as TACE with drug-eluting beads (DEB-TACE). Clinical data on 90Yttrium radioembolization as an emerging alternative, mostly applied for niche indications such as HCC with portal vein invasion, will be discussed. Furthermore, we will summarize the principle of HCC staging, patient allocation and response assessment in the setting of HCC embolotherapy. In addition, we will evaluate the role of cone-beam computed tomography as a novel intra-procedural image-guidance technology. Finally, this review will touch on new technical developments such as radiopaque, imageable DEBs and the rationale and role of combined systemic and locoregional therapies, mostly in combination with Sorafenib.

Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention.

Despite more than 75 years of research by some of the greatest scientists in the world to conquer cancer, the clear winner is still cancer. This is reflected particularly by liver cancer that worldwide ranks fourth in terms of mortality with survival rates of no more than 3-5%. Significantly, one of the earliest discovered hallmarks of cancer had its roots in Bioenergetics as many tumors were found in the 1920s to exhibit a high glycolytic phenotype. Although research directed at unraveling the underlying basis and significance of this phenotype comprised the focus of cancer research for almost 50 years, these efforts declined greatly from 1970 to 1990 as research into the molecular and cell biology of this disease gained center stage. Certainly, this change was necessary as the new knowledge obtained about oncogenes, gene regulation, and programmed cell death once again placed Bioenergetics in the limelight of cancer research. Thus, we now have a much better molecular understanding of the high glycolytic phenotype of many cancers, the pivotal roles that Type II hexokinase-mitochondrial interactions play in this process to promote tumor cell growth and survival, and how this new knowledge can lead to improved therapies that may ultimately turn the tide on our losing war on cancer.

Selective activation of Ca2+ influx by extracellular ATP in a pancreatic beta-cell line (HIT).

The action of exogenous ATP on cytoplasmic free Ca2+ ([Ca2+]i) was studied in insulin secreting cells using fura-2. Stimulation of clonal pancreatic beta-cells (HIT) with ATP (range 2-20 microM) evoked a sustained elevation in [Ca2+]i. ATP selectively promoted Ca2+ influx and not Ca2+ mobilization since (1) the effect required external Ca1+ and (2) was observed in cells in which internal stores were depleted with ionomycin (3) the rate of Mn2+ influx, measured as the quenching of the fura-2 signal, was accelerated by ATP. The action of ATP was unaffected by the voltage-sensitive Ca2+ channel blockers nifedipine and verapamil as well as by a depolarizing concentration of K+. The effect on [Ca2+]i was highly specific for ATP since AMP, ADP, adenosine 5'-[gamma-thio]triphosphate, adenosine 5'-[beta, gamma-methylene]triphosphate, GTP and adenosine were ineffective. In normal pancreatic islet cells, both exogenous ATP (range 0.2-2 microM) and ADP induced a transient Ca2+ elevation that did not require external Ca2+. The nucleotide specificity of the effect on [Ca2+]i suggests that ATP activates P2 gamma purinergic receptors in normal beta-cells. Thus, ATP evokes a Ca2+ signal in clonal HIT cells and normal islet cells by different transducing systems involving distinct purinoreceptors. A novel mechanism for increasing [Ca2+]i by extracellular ATP is reported in HIT cells, since the nucleotide specificity and the selective activation of Ca2+ influx without mobilization of internal Ca2+ stores cannot be explained by mechanisms already described in other cell systems.

Systematic review of catheter-based intra-arterial therapies in hepatocellular carcinoma: state of the art and future directions.

Intra-arterial therapies (IATs) play a pivotal role in the management of patients with primary and secondary liver malignancies. The unique advantages of these treatments are their ability to selectively deliver a high dose of anticancer treatment while preserving healthy liver tissue. The proven efficacy of these catheter-based locoregional therapies in a highly systemic chemoresistant cancer such as hepatocellular carcinoma (HCC), along with the minimally invasive nature of these treatments, quickly yielded wide acceptance in the medical community and revolutionized the field of Interventional Oncology. In this article, we describe the clinical rationale and background of catheter-based IATs. We provide an overview of clinical achievements of these treatments alone and in combination with sorafenib in patients with HCC.

Cyclic AMP raises cytosolic Ca2+ and promotes Ca2+ influx in a clonal pancreatic beta-cell line (HIT T-15).

The effect on cytosolic Ca2+ concentration ([Ca2+]i) of cAMP analogues and the adenylate cyclase-stimulating agents forskolin, isoproterenol and glucagon has been examined in an insulin-secreting beta-cell line (HIT T-15) using fura 2. All these manipulations of the cAMP messenger system promoted a rise in [Ca2+]i which was blocked by the Ca2+ channel antagonists verapamil and nifedipine or by removal of extracellular Ca2+. The action of the adenylate cyclase activator forskolin was glucose-dependent. The results suggest that cAMP elevates [Ca2+]i in HIT cells by promoting Ca2+ entry through voltage-sensitive Ca2+ channels, not through mobilization of stored Ca2+. Activation of Ca2+ influx may be an important component of the mechanisms by which cAMP potentiates fuel-induced insulin release.

Prognostic significance of p53 mutations in non-small cell lung cancer: a meta-analysis of 829 cases from eight published studies.

Mutation of the p53 tumor suppressor gene is considered a possible marker of poor survival among patients with non-small cell lung cancer (NSCLC). This report presents the results of a meta-analysis of the available data addressing this issue. Using previously described methods, a protocol was developed for a meta-analysis examining the prognostic significance of p53 mutations in NSCLC. Two-year survival data derived from 829 patients in eight published studies were analyzed using a general variance-based method employing confidence intervals described by Greenland (Epidemiol. Rev. 9 (1986) 1-30). The outcome of interest was a summary relative risk (RRs) reflecting the risk of death at 2 years associated with p53 mutation positive versus p53 negative disease. Prior to calculation of a RRs, an analysis for homogeneity (Q) showed Q to equal 22.3. With 8 degrees of freedom, this yielded a P value corresponding to P<0.005. This indicated substantial heterogeneity across studies in terms of their estimate of effect. Although a RRs of 1.52 was found when all eight studies were combined (favoring a negative prognostic role for p53 mutation), the validity of this estimate is questionable since the existing heterogeneity indicates that factors other than p53 mutation account for the variability in RRs across studies. Sensitivity analyses suggested that selection bias might represent an important source of variability in that p53 mutations may differ in their effects on biological behavior of NSCL tumors. Other possible confounders include smoking history, race, geographic location of study and socio-economic status. The available data do not support a clear role for p53 mutation as a prognostic marker in NSCLC. It appears that multiple sources of bias may contribute to spurious association of p53 mutation status and survival. Future analyses must control for possible confounders in order to determine whether certain p53 mutations are truly associated with poor clinical outcome.

Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase.

The rabbit VX2 tumor when implanted in the liver has proven convenient as a model for studying hepatocellular carcinomas. However, its metabolic properties have not been well studied. Significantly, studies described here show that the VX2 tumor exhibits a high glycolytic/high hexokinase phenotype that is retained following implantation and growth in rabbit liver. In addition, results of a limited screen show that the glycolytic rate is inhibited best by 2-deoxyglucose (2DOG) and 3-bromopyruvate (3BrPA), the former compound of which is phosphorylated by hexokinase but not further metabolized, while the latter directly inhibits hexokinase. Finally, when tested on hepatoma cells in culture both inhibitors facilitated cell death. These studies underscore the usefulness of the VX2 tumor model for the study of advanced liver cancer and for selecting anti-hepatoma agents.

Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials.

The impact of intravesical chemotherapy prophylaxis on recurrence of superficial transitional cell carcinoma of the bladder is poorly defined. The objective of this report is to present a meta-analysis of the available clinical trial data to quantify the effect of intravesical chemotherapy on tumor recurrence following complete transurethral resection (TURB) in patients with newly diagnosed superficial bladder cancer. A prospective protocol outlining the above meta-analysis was initially developed followed by a thorough search of the existing published literature using strict eligibility criteria. Eleven randomized trials were found that met protocol specifications. These studies contained data on 3703 patients that were statistically combined using a fixed effects model (Peto). The outcome of interest was the proportion of patients recurring at 1, 2, and 3 years post-TURB. Combining all 11 studies using 1-year recurrence as the outcome measure yielded a Peto odds ratio (ORp) of 0.56, demonstrating a 44% reduction in 1-year recurrence among patients treated with intravesical chemotherapy versus those treated with TURB alone. A statistical test for heterogeneity (Q) showed these data to be heterogenous (the studies are not measuring an effect of the same size). Sensitivity analyses were performed to determine sources of heterogeneity. These tests suggest that chemotherapy treatment schedule may account for the wide variation in tumor recurrence rates across studies. When the available clinical trial data were stratified by duration of treatment, the meta-analysis showed that intravesical chemotherapy decreased tumor recurrence from 30% to 80% depending on the outcome of interest (i.e., recurrence at 1, 2, or 3 years post-TURB). Intravesical chemotherapy appears to have a major impact on decreasing the chance of recurrence of superficial transitional cell carcinoma of the bladder. This is in contrast to prior analyses suggesting only modest efficacy in this clinical setting (i.e., on the order of a 14% reduction in recurrence).

Depiction of reperfused myocardial infarction using contrast-enhanced spin echo and gradient echo magnetic resonance imaging.

RATIONALE AND OBJECTIVES: The authors used gadolinium (Gd) chelate as a T1, T2, and T2* enhancing agent in reperfused myocardial infarction to compare the appearance of reperfused myocardial infarction on spin echo and gradient echo magnetic resonance (MR) sequences. METHODS: Rats (n = 28) were subjected to reperfused myocardial infarction and received no contrast medium, 0.2, 0.5, or 1.0 mmol/kg Gd DTPA-BMA. Spin echo and gradient echo MR images of the excised hearts (n = 7 rats per group) were acquired using 2.0 T system: repetition time (TR)/echo time (TE) = 300/20 ms for T1-weighted spin echo, TR/TE = 4000/80 ms for T2-weighted spin echo, and TR/TE = 600/10, 15, 20, and 30 ms for gradient echo imaging. Regional T2 and T2* relaxation times were measured. Triphenyl tetrazolium chloride was used to verify regional infarction. RESULTS: Unenhanced spin echo images failed to distinguish infarcted from normal myocardium. On Gd DTPA-BMA enhanced T1-weighted spin echo images, infarction was depicted as a high-intensity region "hot spot." On the other hand, the infarcted region was visualized as a low-signal region "cold spot" on Gd DTPA-BMA enhanced T2-weighted images. Changes in signal intensity and T2 relaxation time on T2 weighted images were dose dependent. On gradient recalled echo images, the infarcted region was discriminated from normal myocardium by a dark boundary zone, which was visible only at 1.0 mmol/kg. The presence of infarction was documented in every heart. CONCLUSIONS: The contrast between normal and infarcted myocardium was affected greatly by the dose and imaging parameters. The results indicate that spin echo and gradient echo images have greatly differing sensitivities to extracellular gadolinium chelates. Changes in myocardial T2 relaxation time, but not T2*, correlated well with the dose.

Percutaneous management of bile duct strictures and injuries associated with laparoscopic cholecystectomy: a decade of experience.

BACKGROUND: The 1990s were associated with a dramatic increase in bile duct injuries with the widespread use of laparoscopic cholecystectomy (LC). Interventional radiology has an integral role in diagnosing and managing these injuries. Definitive percutaneous management with balloon dilatation might be possible in select patients with intact biliary-enteric continuity, but longterm data are limited. STUDY DESIGN: Data were collected prospectively on 51 consecutive patients with major bile duct stricture or injury associated with LC, treated with percutaneous management, January 1, 1990, to December 31, 1999. Percutaneous transhepatic cholangiography and biliary catheter placement were followed by balloon dilatation and stenting. Outcomes were assessed with direct patient contact or hospital records. RESULTS: All patients completed treatment, and 50 (98%) were stent free at mean followup of 76 months. The success rate of percutaneous management was 58.8%, without need for subsequent intervention. Presenting symptoms, level of injury, and number of stents or dilatations did not predict outcomes. Percutaneous treatment was more likely to fail in patients stented for less than 4 months (p < 0.001). Operative repair at Hopkins before percutaneous management was predictive of a successful outcome (p < 0.05). Including subsequent operations or percutaneous management, successful outcomes were achieved in 98% of patients. CONCLUSIONS: Major bile duct injuries after LC remain a clinical challenge. Although surgical reconstruction is the treatment cornerstone, selected patients with biliary-enteric continuity can achieve successful long-term results with definitive percutaneous management. The combination of percutaneous management and surgical reconstruction results in successful outcomes in virtually all patients.

Behçet's disease complicated by pylephlebitis and hepatic abscesses.

A 22 year old man presented with fever, abdominal pain, weight loss and diarrhea. Past medical history revealed recurrent aseptic meningitis, uveitis, and erythema nodosum. Further inquiry unveiled a prominent history of oral aphthous ulcers; all features of Behçet's disease. Imaging revealed mesenteric arteritis and pylephlebitis, septic thrombophlebitis of the portal vein, a previously unrecognized complication of Behçet's disease, with multiple intrahepatic abscesses. Portal venography demonstrated an extensively diseased, expanded, and obstructed portal venous system. Blood cultures and portal vein aspirate yielded polymicrobial flora. Percutaneous intraportal thrombolytic therapy and mechanical thrombectomy were attempted to restore flow to the portal venous system. This distinctly rare manifestation of Behçet's Disease, pylephlebitis, may result from ischemic injury and structural compromise of the bowel mucosa, resulting from underlying vasculitis.

Perineal application of cosmetic talc and risk of invasive epithelial ovarian cancer: a meta-analysis of 11,933 subjects from sixteen observational studies.

OBJECTIVE: Prior epidemiological studies suggest an association between perineal cosmetic talc use and increased risk of epithelial ovarian cancer. A meta-analysis was performed to evaluate this suspected association. MATERIALS AND METHODS: Using previously described methods, a protocol was developed for a meta-analysis examining the association between perineal talc use versus non-use and the development of invasive epithelial ovarian cancer. Literature search techniques, study inclusion criteria and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer development associated with perineal talc use versus non-use. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. RESULTS: Sixteen observational studies meeting protocol specified inclusion criteria were located via a comprehensive literature search. These studies enrolled a total of 11,933 subjects. Analysis for heterogeneity demonstrated that the data were homogenous (p = 0.17) and could be combined in a meta-analysis. Pooling all sixteen studies yielded a RRs of 1.33 (CI = 1.16-1.45), a statistically significant result suggesting a 33% increased risk of ovarian cancer with perineal talc use. Despite this finding, the data showed a lack of a clear dose-response relationship making the RRs of questionable validity. Further sensitivity analyses showed that hospital-based studies showed no relationship between talc use and ovarian cancer risk, i.e. RRs 1.19 (0.99-1.41) versus population-based studies (RRs = 1.38, CI = 1.25-1.52). This suggests that selection bias and/or uncontrolled confouding may result in a spurious positive association between talc use and ovarian cancer risk in population-based studies. CONCLUSION: The available observational data do not support the existence of a causal relationship between perineal talc exposure and an increased risk of epithelial ovarian cancer. Selection bias and uncontrolled confouding may account for the positive associations seen in prior epidemiological studies.

Multi-drug versus single agent chemotherapy for high grade astrocytoma; results of a meta-analysis.

BACKGROUND: The addition of chemotherapy to postoperative radiation therapy in the treatment of high grade astrocytoma results in a modest increase in 12 and 24 month survival. It is, at present, unclear whether single agent or combination drug therapy constitutes the best drug regimen for these patients. Despite this uncertainty, multi-drug regimens have become standard therapy for some high grade astrocytomas. METHODS: One year survival data derived from over 2,100 patients enrolled in 9 randomized clinical trials were analyzed using the meta-analytic techniques previously described by Peto et al. This analysis compared the proportion of patients surviving one year treated with multi-drug regimens versus single agent treatment (usually BCNU). All patients included in this analysis also underwent surgery and radiation therapy as part of their clinical management. RESULTS: A summary odds ratio was calculated following a statistical analysis showing a lack of heterogeneity among the included studies in terms of their estimate of effect. The calculated Peto odds ratio was 1.22 with a 95% confidence interval of 0.99-1.36. These data indicate that combination drug treatment is associated with an approximately 22% decreased 1 year survival as compared with single agent therapy. CONCLUSION: This analysis suggests that the available data do not support the use of combination chemotherapy regimens in this patient population. Additional randomized clinical trials are needed to clearly determine whether any multidrug treatment scheme is superior to currently available single agent therapies.

Planned preoperative radiation therapy in muscle invasive bladder cancer; results of a meta-analysis.

BACKGROUND: The role of pre-operative radiation therapy in the treatment of muscle invasive bladder cancer is unclear. The objective of this report is to present a meta-analysis of the published clinical trial data on this topic to determine whether pre-operative radiation improves survival in patients with this disease. METHODS: Data from 5 randomized trial were pooled using the meta-analytic techniques previously described by Peto et al. Three and five year survival were compared between patients receiving pre-operative radiation therapy followed by cystectomy versus patients treated with cystectomy alone. RESULTS: A summary odds ratio was calculated following a statistical analysis showing a lack of heterogeneity among the included studies in terms of their estimate of effect. The calculated Peto odds ratio was 0.71 favoring the use of preoperative radiation (95% CI 0.48-1.06). Due to possible biases in this original analysis due to study design deficiencies, a sensitivity analysis showed a "corrected" odds ratio of 0.94 with a 95% confidence interval of 0.57- 1.55, a non-statistically significant result. CONCLUSION: The available clinical trial data do not support a role for routine use of pre-operative radiation therapy in the treatment of muscle invasive bladder cancer. Additional well designed trials are needed to address this issue.