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Quality of radiotherapy reporting in randomized controlled trials of Hodgkin's lymphoma and non-Hodgkin's lymphoma: in regard to Bekelman and Yahalom (Int J Radiat Oncol Biol Phys 2009;73:492-498)

Tue, 06/17/2014 - 11:16am

Comment on Quality of radiotherapy reporting in randomized controlled trials of Hodgkin's lymphoma and non-Hodgkin's lymphoma: a systematic review. [Int J Radiat Oncol Biol Phys. 2009]

Don Lawrence and the "k-capture" revolution

Tue, 06/17/2014 - 11:16am

PURPOSE: The practice of brachytherapy was in steep decline in the mid-20th century, largely because of safety issues. This article explores the innovations that revitalized brachytherapy with special attention to the introduction of low-energy seeds for permanent implantation.

METHODS AND MATERIALS: Literature review; interviews; and the memos, records, and correspondence of Donald C. Lawrence.

RESULTS: Paul Harper first proposed the use of radionuclides that decay by k-capture in the 1950s. But it was the vision and tenacity of health physicist Donald Lawrence that led to the successful implementation of I-125 (in the 1960s) and Cs-131 (40 years later).

Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02

Tue, 06/17/2014 - 11:16am

PURPOSE: To report the impact of radiotherapy quality on outcome in a large international phase III trial evaluating radiotherapy with concurrent cisplatin plus tirapazamine for advanced head and neck cancer.

PATIENTS AND METHODS: The protocol required interventional review of radiotherapy plans by the Quality Assurance Review Center (QARC). All plans and radiotherapy documentation underwent post-treatment review by the Trial Management Committee (TMC) for protocol compliance. Secondary review of noncompliant plans for predicted impact on tumor control was performed. Factors associated with poor protocol compliance were studied, and outcome data were analyzed in relation to protocol compliance and radiotherapy quality.

RESULTS: At TMC review, 25.4% of the patients had noncompliant plans but none in which QARC-recommended changes had been made. At secondary review, 47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control. Major deficiencies were unrelated to tumor subsite or to T or N stage (if N+), but were highly correlated with number of patients enrolled at the treatment center (< five patients, 29.8%; > or = 20 patients, 5.4%; P < .001). In patients who received at least 60 Gy, those with major deficiencies in their treatment plans (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant (n = 502): -2 years overall survival, 50% v 70%; hazard ratio (HR), 1.99; P < .001; and 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001, respectively.

CONCLUSION: These results demonstrate the critical importance of radiotherapy quality on outcome of chemoradiotherapy in head and neck cancer. Centers treating only a few patients are the major source of quality problems.

Treatment results for patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III and IV, 1984-1997: a report from the Children's Oncology Group

Tue, 06/17/2014 - 11:16am

PURPOSE: To assess local control, event-free survival (EFS), and overall survival (OS) rates in 71 patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma (ALV RMS) and their relation to radiation therapy (RT) on IRSG Protocols III and IV, 1984-1997. METHODS: Chart review and standard statistical procedures.

PATIENTS AND TUMORS: Patients were 1-18 years at diagnosis (median, 6 years). Primary tumor sites were extremity/trunk (N = 54), head/neck (N = 9), genitourinary tract (N = 7), and perineum (N = 1). Thirty patients received VA +/- C with RT; 41 received VA +/- C alone. RT was assigned, not randomized.

RESULTS: Fifty-four patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site, < or = 5 cm) tumors. Eight-year EFS was 90%, with 100% local control for 17 patients given RT. Eight-year EFS was 88%, with 92% local control for 37 patients without RT; P = 0.52 for EFS comparisons, 0.3 for local control comparisons. In 17 Stage 3 patients (unfavorable site, tumors >5 cm, N0), 8-year EFS was 84% with 100% local control in 13 patients given RT; 8-year EFS was only 25% and local control 50% in 4 patients without RT. Local recurrence was the most common site of first failure in non-irradiated patients.

CONCLUSION: Patients with Stage 1-2 ALV RMS had slightly but statistically insignificantly improved local control, EFS, and OS rates when local RT was given. The need for local RT in Stage 1-2 patients deserves evaluation in a randomized study. Local control, EFS, and OS rates were significantly improved in Stage 3 patients receiving local RT.

Impact of tumor viability at second-look procedures performed before completing treatment on the Intergroup Rhabdomyosarcoma Study Group protocol IRS-IV, 1991-1997: a report from the children's oncology group

Tue, 06/17/2014 - 11:16am

PURPOSES: The aims of the study were to compare results of clinical/radiographic studies before second-look procedures (SLP) with SLP specimens from patients with gross residual sarcoma at diagnosis and to relate tumor viability to outcome.

PATIENTS: Seventy-three patients underwent SLP before completing chemotherapy, with (n = 59) or without (n = 14) radiotherapy. Tumor sites were bladder/prostate (n = 27), head/orbit/parameningeal (n = 22), extremity/trunk (n = 14), and retroperitoneum/pelvis (n = 10).

RESULTS: Of 14 patients, 1 (7%) with clinical/radiographic complete response (CR) had viable tumor. Of 59 patients, 35 (59%) without CR had viable tumor. Five-year failure-free survival (FFS) rates were 81% in 37 patients without viable tumor and 53% in 36 patients with viable tumor (Cox proportional hazards adjusted P = .05). Five-year FFS rates were 67% in 15 patients with clear margins and 43% in 21 patients with tumor-involved margins (n = 18) or viable gross tumor (n = 3) (Cox proportional hazards adjusted P = .04). Five-year survival was 78% to 79% among 73 patients with and 333 patients without SLP during treatment.

CONCLUSIONS: Second-look procedures can show whether viable tumor is present and may be beneficial in selected patients with rhabdomyosarcoma. Disappearance of tumor (CR) usually correlated with no viable tumor at SLP. However, 41% of patients without CR had no viable tumor. Those without viable tumor had increased FFS but not survival compared to those with viable tumor.

Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft

Tue, 06/17/2014 - 11:16am

PURPOSE: Patients with localized, grossly resected, or gross residual (orbital only) embryonal rhabdomyosarcoma (ERMS) had 5-year failure-free survival (FFS) rates of 83% and overall survival rates of 95% on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III/IV. IRSG D9602 protocol (1997 to 2004) objectives were to decrease toxicity in similar patients by reducing radiotherapy (RT) doses and eliminating cyclophosphamide for the lowest-risk patients.

PATIENTS AND METHODS: Subgroup A patients (lowest risk, with ERMS, stage 1 group I/IIA, stage 1 group III orbit, stage 2 group I) received vincristine plus dactinomycin (VA). Subgroup B patients (ERMS, stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, stage 3 group I/II) received VA plus cyclophosphamide. Patients in group II/III received RT. Compared with IRS-IV, doses were reduced from 41.4 to 36 Gy for stage 1 group IIA patients and from 50 or 59 to 45 Gy for group III orbit patients.

RESULTS: Estimated 5-year FFS rates were 89% (95% CI, 84% to 92%) for subgroup A patients (n = 264) and 85% (95% CI, 74%, 91%) for subgroup B patients (n = 78); median follow-up: 5.1 years. Estimated 5-year FFS rates were 81% (95% CI, 68% to 90%) for patients with stage 1 group IIA tumors (n = 62) and 86% (95% CI, 76% to 92%) for patients with group III orbit tumors (n = 77).

CONCLUSION: Five-year FFS and OS rates were similar to those observed in comparable IRS-III patients, including patients receiving reduced RT doses, but were lower than in comparable IRS-IV patients receiving VA plus cyclophosphamide. Five-year FFS rates were similar among subgroups A and B patients.

Precedence for prostate brachytherapy

Tue, 06/17/2014 - 11:16am

PURPOSE: To identify the earliest practitioners of prostate brachytherapy.

METHODS AND MATERIALS: Review of contemporary literature.

RESULTS: Radiotherapy has been used for benign prostatic ailments as early as 1902. Prostate cancer was first treated by teletherapy in 1904. Several urologists, in Paris and Vienna, applied intracavitary radium for prostate disease in 1908-1909. We present evidence that Henri Minet was the first to perform prostate brachytherapy, as early as 1908.

CONCLUSION: Brachytherapy has been used to treat prostate cancer for more than a century.

Influence of noncompliance with radiation therapy protocol guidelines and operative bed recurrences for children with rhabdomyosarcoma and microscopic residual disease: a report from the Children's Oncology Group

Tue, 06/17/2014 - 11:16am

PURPOSE: Postoperative radiation therapy (RT) is recommended for patients with rhabdomyosarcoma having microscopic disease. Sometimes RT dose/volume is reduced or omitted in an attempt to avoid late effects, particularly in young children. We reviewed operative bed recurrences to determine if noncompliance with RT protocol guidelines influenced local-regional control.

METHODS AND MATERIALS: All operative bed recurrences among 695 Group II rhabdomyosarcoma patients in Intergroup Rhabdomyosarcoma Study Group (IRS) I through IV were reviewed for deviation from RT protocol. Major/minor dose deviation was defined as >10% or 6-10% of the prescribed dose (40-60 Gy), respectively. Major/minor volume deviation was defined as tumor excluded from the RT field or treatment volume not covered by the specified margin (preoperative tumor volume and 2- to 5-cm margin), respectively. No RT was a major deviation.

RESULTS: Forty-six of 83 (55%) patients with operative bed recurrences did not receive the intended RT (39 major and 7 minor deviations). RT omission was the most frequent RT protocol deviation (19/46, 41%), followed by dose (17/46, 37%), volume (9/46, 20%), and dose and volume deviation (1/46, 2%). Only 7 operative bed recurrences occurred in IRS IV (5% local-regional failure) with only 3 RT protocol deviations. Sixty-three (76%) patients with recurrence died of disease despite retrieval therapy, including 13 of 19 nonirradiated children.

CONCLUSION: Over half of the operative bed recurrences were associated with noncompliance; omission of RT was the most common protocol deviation. Three fourths of children die when local-regional disease is not controlled, emphasizing the importance of RT in Group II rhabdomyosarcoma.

Partial breast irradiation by brachytherapy, 1927

Tue, 06/17/2014 - 11:16am

PURPOSE: Examination of Geoffrey Keynes's contributions to brachytherapy and the management of breast cancer.

METHODS AND MATERIALS: Review of publications and texts of the era.

RESULTS: In an era when radical mastectomy was accepted as standard treatment for breast cancer, Keynes demonstrated that brachytherapy (with or without local excision) was equally effective, while sparing body form and function.

CONCLUSIONS: Keynes established that conservative surgery, combined with radiotherapy, was the preferable option for managing breast cancer.

Pulmonary toxicity in Stage III non-small cell lung cancer patients treated with high-dose (74 Gy) 3-dimensional conformal thoracic radiotherapy and concurrent chemotherapy following induction chemotherapy: a secondary analysis of Cancer and Leukemia Grou

Tue, 06/17/2014 - 11:16am

PURPOSE: Cancer and Leukemia Group B (CALGB) 30105 tested two different concurrent chemoradiotherapy platforms with high-dose (74 Gy) three-dimensional conformal radiotherapy (3D-CRT) after two cycles of induction chemotherapy for Stage IIIA/IIIB non-small cell lung cancer (NSCLC) patients to determine if either could achieve a primary endpoint of >18-month median survival. Final results of 30105 demonstrated that induction carboplatin and gemcitabine and concurrent gemcitabine 3D-CRT was not feasible because of treatment-related toxicity. However, induction and concurrent carboplatin/paclitaxel with 74 Gy 3D-CRT had a median survival of 24 months, and is the basis for the experimental arm in CALGB 30610/RTOG 0617/N0628. We conducted a secondary analysis of all patients to determine predictors of treatment-related pulmonary toxicity.

METHODS AND MATERIALS: Patient, tumor, and treatment-related variables were analyzed to determine their relation with treatment-related pulmonary toxicity.

RESULTS: Older age, higher N stage, larger planning target volume (PTV)1, smaller total lung volume/PTV1 ratio, larger V20, and larger mean lung dose were associated with increasing pulmonary toxicity on univariate analysis. Multivariate analysis confirmed that V20 and nodal stage as well as treatment with concurrent gemcitabine were associated with treatment-related toxicity. A high-risk group comprising patients with N3 disease and V20 >38% was associated with 80% of Grades 3-5 pulmonary toxicity cases.

CONCLUSIONS: Elevated V20 and N3 disease status are important predictors of treatment related pulmonary toxicity in patients treated with high-dose 3D-CRT and concurrent chemotherapy. Further studies may use these metrics in considering patients for these treatments.

Underscreened and undertreated

Tue, 06/17/2014 - 11:16am

Molecular targets for radiation oncology in prostate cancer

Tue, 06/17/2014 - 11:16am

Recent selected developments of the molecular science of prostate cancer (PrCa) biology and radiation oncology are reviewed. We present potential targets for molecular integration treatment strategies with radiation therapy (RT), and highlight potential strategies for molecular treatment in combination with RT for patient care. We provide a synopsis of the information to date regarding molecular biology of PrCa, and potential integrated research strategy for improved treatment of PrCa. Many patients with early-stage disease at presentation can be treated effectively with androgen ablation treatment, surgery, or RT. However, a significant portion of men are diagnosed with advanced stage/high-risk disease and these patients progress despite curative therapeutic intervention. Unfortunately, management options for these patients are limited and are not always successful including treatment for hormone refractory disease. In this review, we focus on molecules of extracellular matrix component, apoptosis, androgen receptor, RUNX, and DNA methylation. Expanding our knowledge of the molecular biology of PrCa will permit the development of novel treatment strategies integrated with RT to improve patient outcome.

Effect of radiotherapy techniques (IMRT vs. 3D-CRT) on outcome in patients with intermediate-risk rhabdomyosarcoma enrolled in COG D9803--a report from the Children's Oncology Group

Tue, 06/17/2014 - 11:16am

PURPOSE: To compare the dosimetric parameters of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in patients with intermediate-risk rhabdomyosarcoma and to analyze their effect on locoregional control and failure-free survival (FFS).

METHODS AND MATERIALS: The study population consisted of 375 patients enrolled in the Children's Oncology Group protocol D9803 study, receiving IMRT or 3D-CRT. Dosimetric data were collected from 179 patients with an available composite plan. The chi-square test or Fisher's exact test was used to compare the patient characteristics and radiotherapy parameters between the two groups. The interval-to-event outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards regression analysis was used to examine the effect of the treatment technique on FFS after adjusting for primary site and risk group.

RESULTS: The median follow-up time was 5.7 and 4.2 years for patients receiving 3D-CRT and IMRT, respectively. No differences in the 5-year failure of locoregional control (18% vs. 15%) or FFS (72% vs. 76%) rates were noted between the two groups. Multivariate analysis revealed no association between the two techniques and FFS. Patients with primary tumors in parameningeal sites were more likely to receive IMRT than 3D-CRT. IMRT became more common during the later years of the study. Patients receiving IMRT were more likely to receive >50 Gy, photon energy of 5 radiation fields than those who received 3D-CRT. The coverage of the IMRT planning target volume by the prescription dose was improved compared with the coverage using 3D-CRT with similar target dose heterogeneity.

CONCLUSIONS: IMRT improved the target dose coverage compared with 3D-CRT, although an improvement in locoregional control or FFS could not be demonstrated in this population. Future studies comparing the integral dose to nontarget tissue and late radiation toxicity between the two groups are warranted.

Clustering is a feature of the spiral ganglion in the basal turn

Tue, 06/17/2014 - 11:16am

OBJECTIVE: To demonstrate the organization of the spiral ganglion in the mammalian species.

METHODS: Temporal bone (TB) specimens from man (n = 2), monkey (n = 2), lion (n = 2) and cat (n = 20) were stained, decalcified and dissected according to the Sudan black B method of Rasmussen. These TB specimens were examined under a Zeiss operating microscope and photographed with a Canon 100 camera interfaced with the microscope.

RESULTS: Spiral ganglion cells occurred in clusters within Rosenthal's canal in all four species. The location of the clusters was marked by the interface between axon and dendritic bundles as well as groups of ganglion cells. In monkey and man the clusters were more separated than in lion and cat.

CONCLUSIONS: These observations indicate that the spiral ganglion forms clusters of neurons within Rosenthal's canal at the basal cochlear turn in the mammals investigated here. The formation of clusters may be related to the principles of neurogenesis.

PSA regulates androgen receptor expression in prostate cancer cells

Tue, 06/17/2014 - 11:16am

BACKGROUND: Prostate-specific antigen (PSA) is a pivotal downstream target gene of the androgen receptor (AR), and a serum biomarker to monitor prostate cancer (PrCa) progression. It has been reported that PSA transactivates AR, but the mechanistic requirements of this response have not been investigated.

METHODS: We studied the localization of PSA, AR, and Src in intracellular compartments of synthetic androgen (R1881)-stimulated LNCaP and C4-2B PrCa cells, using immunofluorescence and subcellular fractionation approaches. We also investigated the effect of downregulation of PSA on AR expression by immunoblotting and real-time PCR using short hairpin RNA (shRNA) and small interfering RNA (siRNA). Src activity was analyzed by immunoblotting.

RESULTS: R1881 stimulation induced nuclear localization of both PSA and AR in LNCaP and C4-2B PrCa cells as well as increased phosphorylation of Src. Stable shRNA or transient siRNA knockdown of PSA resulted in reduced AR protein levels as well as AR mRNA levels in C4-2B cells. Similar to C4-2B cells, ablation of AR levels upon silencing of PSA was also confirmed in VCaP cells, another androgen-independent cell line. Silencing of PSA did not cause significant changes in Src activation; besides, Src regulation by integrins did not appear to affect AR transcriptional activity.

CONCLUSIONS: PSA localizes to nuclei of androgen-stimulated PrCa cells, and controls AR mRNA and protein levels. This regulatory loop is specific for PSA, does not involve known AR activators such as Src and AKT, and may contribute to AR signaling under conditions of increasing PSA levels in patients.

Local control with reduced-dose radiotherapy for low-risk rhabdomyosarcoma: a report from the Children's Oncology Group D9602 study

Tue, 06/17/2014 - 11:15am

PURPOSE: To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated in the Children's Oncology Group D9602 study.

METHODS AND MATERIALS: Patients with low-risk RMS were nonrandomly assigned to receive radiotherapy doses dependent on the completeness of surgical resection of the primary tumor (clinical group) and the presence of involved regional lymph nodes. After resection, most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primary tumors received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets with a higher risk of relapse in Intergroup Rhabdomyosarcoma Study Group III and IV studies.

RESULTS: Three hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol-specified omission of radiotherapy in girls with Group IIA vaginal tumors (n = 5) resulted in three failures for this group.

CONCLUSIONS: In comparison with Intergroup Rhabdomyosarcoma Study Group III and IV results, reduced-dose radiotherapy does not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected nonbladder genitourinary tumors require radiotherapy for postsurgical residual tumor for optimal local control to be achieved.

What we have learned: the impact of quality from a clinical trials perspective

Tue, 06/17/2014 - 11:15am

In this review article, we address the radiation oncology process improvements in clinical trials and review how these changes improve the quality for the next generation of trials. In recent years, we have progressed from a time of limited data acquisition to the present in which we have real-time influence of clinical trials quality. This enables immediate availability of the important elements, including staging, eligibility, response, and outcome for all trial investigators. Modern informatics platforms are well designed for future adaptive clinical trials. We review what will be needed in the informatics architecture of current and future clinical trials.

Evaluation of diagnostic performance of CT for detection of tumor thrombus in children with Wilms tumor: a report from the Children's Oncology Group

Tue, 06/17/2014 - 11:15am

BACKGROUND: Pre-operative assessment of intravascular extension of Wilms tumor is essential to guide management. Our aim is to evaluate the diagnostic performance of multidetector CT in detection of tumor thrombus in Wilms tumor.

PROCEDURE: The study population was drawn from the first 1,015 cases in the AREN03B2 study of the Children's Oncology Group. CT scans of children with (n = 62) and without (n = 111) tumor thrombus at nephrectomy were independently reviewed by two radiologists, blinded to patient information. Doppler sonography results were obtained from institutional radiology reports, as Doppler requires real-time evaluation. The diagnostic performance of CT and Doppler for detection of tumor thrombus was determined using nephrectomy findings as reference standard.

RESULTS: In the primary nephrectomy group, tumor thrombus detection sensitivity, specificity of CT was 65.6, 84.8%, and Doppler was 45.8, 95.7%, respectively. In this group, sensitivity of CT, Doppler for detection of cavoatrial thrombus was 84.6 and 70.0%, respectively. In the secondary nephrectomy group, tumor thrombus detection sensitivity, specificity of CT was 86.7, 90.6%, and Doppler was 66.7, 100.0%, respectively. In this group, sensitivity of CT, Doppler for detection of cavoatrial thrombus was 96.0 and 68.8%, respectively. Pre-operative Doppler evaluation performed in 108/173 cases, detected 3 cases with intravenous extension (2 in renal vein, 1 in IVC at renal vein level) that were missed at CT.

CONCLUSIONS: CT can accurately identify cavoatrial tumor thrombus that will impact surgical approach. Routine Doppler evaluation, after CT has already been performed, is not required in Wilms tumor.

Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study

Tue, 06/17/2014 - 11:15am

PURPOSE: The primary objective of this study was to compare the survival of patients with unresectable stage III non-small-cell lung cancer (NSCLC) treated with combined chemoradiotherapy with or without thalidomide.

PATIENTS AND METHODS: Patients were randomly assigned to the control arm (PC) involving two cycles of induction paclitaxel 225 mg/m(2) and carboplatin area under the curve (AUC) 6 followed by 60 Gy thoracic radiation administered concurrently with weekly paclitaxel 45 mg/m(2) and carboplatin AUC 2, or to the experimental arm (TPC), receiving the same treatment in combination with thalidomide at a starting dose of 200 mg daily. The protocol allowed an increase in thalidomide dose up to 1,000 mg daily based on patient tolerability.

RESULTS: A total of 546 patients were eligible, including 275 in the PC arm and 271 in the TPC arm. Median overall survival, progression-free survival, and overall response rate were 15.3 months, 7.4 months, and 35.0%, respectively, for patients in the PC arm, in comparison with 16.0 months (P = .99), 7.8 months (P = .96), and 38.2% (P = .47), respectively, for patients in the TPC arm. Overall, there was higher incidence of grade 3 toxicities in patients treated with thalidomide. Several grade 3 or higher events were observed more often in the TPC arm, including thromboembolism, fatigue, depressed consciousness, dizziness, sensory neuropathy, tremor, constipation, dyspnea, hypoxia, hypokalemia, rash, and edema. Low-dose aspirin did not reduce the thromboembolic rate.

CONCLUSION: The addition of thalidomide to chemoradiotherapy increased toxicities but did not improve survival in patients with locally advanced NSCLC.

Fatty acid binding protein 4 is expressed in distinct endothelial and non-endothelial cell populations in glioblastoma

Tue, 06/17/2014 - 11:15am

AIMS: Glioblastoma (GBM) is the most common and aggressive primary brain tumour in adults. Angiogenesis and vasculogenesis play key roles in progression of GBMs. Fatty acid binding protein 4 (FABP4) is an intracellular chaperone for free fatty acids. FABP4 is detected in microvascular endothelial cells (ECs) in several normal tissues and promotes proliferation of ECs. The goal of this study was to characterize the tissue distribution pattern of FABP4 in GBMs.

METHODS: Immunohistochemistry for FABP4 was performed on paraffin-embedded tumour sections and the intensity and distribution of FABP4 immunoreactivity were analysed. Double immunofluorescence was employed for detailed characterization of FABP4-positive cells. RESULTS: FABP4 immunoreactivity was absent in normal brain tissue sections. FABP4-positive cells were detected in 33%, 43%, 64% and 89% of Grade I, Grade II, Grade III and Grade IV glial tumours, respectively. Thus, the percentage of FABP4-positive cells in GBMs was significantly higher than lower-grade gliomas. In general, FABP4-expressing cells were distributed in a non-homogenous pattern, as 'hot spots' in glial tumours. FABP4 expression was detected in a subset of vascular ECs as well as some non-ECs.

CONCLUSION: FABP4 is expressed in a significantly higher percentage of GBMs in comparison to both normal brain tissues and lower-grade glial tumours. FABP4 is expressed in some tumour ECs as well as non-ECs in glial tumours. As FABP4 promotes proliferation of ECs, detection of FABP4 in GBM-ECs, but not normal brain ECs suggests that FABP4 may play a role in the robust angiogenesis associated with GBMs. Neuropathological Society.