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Redesigning radiotherapy quality assurance: opportunities to develop an efficient, evidence-based system to support clinical trials--report of the National Cancer Institute Work Group on Radiotherapy Quality Assurance

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

PURPOSE: In the context of national calls for reorganizing cancer clinical trials, the National Cancer Institute sponsored a 2-day workshop to examine challenges and opportunities for optimizing radiotherapy quality assurance (QA) in clinical trial design.

METHODS AND MATERIALS: Participants reviewed the current processes of clinical trial QA and noted the QA challenges presented by advanced technologies. The lessons learned from the radiotherapy QA programs of recent trials were discussed in detail. Four potential opportunities for optimizing radiotherapy QA were explored, including the use of normal tissue toxicity and tumor control metrics, biomarkers of radiation toxicity, new radiotherapy modalities such as proton beam therapy, and the international harmonization of clinical trial QA.

RESULTS: Four recommendations were made: (1) to develop a tiered (and more efficient) system for radiotherapy QA and tailor the intensity of QA to the clinical trial objectives (tiers include general credentialing, trial-specific credentialing, and individual case review); (2) to establish a case QA repository; (3) to develop an evidence base for clinical trial QA and introduce innovative prospective trial designs to evaluate radiotherapy QA in clinical trials; and (4) to explore the feasibility of consolidating clinical trial QA in the United States.

CONCLUSION: Radiotherapy QA can affect clinical trial accrual, cost, outcomes, and generalizability. To achieve maximum benefit, QA programs must become more efficient and evidence-based.

Postsurgical treatment of early-stage breast cancer with electronic brachytherapy: outcomes and health-related quality of life at 1 year

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

OBJECTIVES: This multicenter registry followed up patients with early-stage breast cancer treated with breast-conserving surgery and electronic brachytherapy (EBT). This report provides 1- and 2-year updates to the initial publication.

METHODS: Patients were of age 50 years or more with invasive carcinoma or ductal carcinoma in situ, tumor size

RESULTS: Of the 69 patients enrolled, 62 were evaluated at 1 year and 20 patients at 2 years after treatment. At 1 year, 28 (45.2%) patients reported adverse events that were possibly, probably, or definitely related to treatment. Most (90%) were grade 1: manageable and typical of radiation therapy. Four events were grade 2: induration/firmness (2), field contracture (1), and seroma (1). One event was grade 3: a draining fistula at the lumpectomy site due to residual effects of a breast infection at 1 month. No recurrences have been reported. Cosmetic ratings were excellent or good in 93.4% of patients at 1 year. Most patients (69%) were energetic most or all of the time. Most patients (69% to 98%) were not affected by individual symptoms of breast disease at 1 year. Generally patients who had an adverse event did not report the corresponding symptom on the quality-of-life questionnaire.

CONCLUSIONS: This registry followed up patients with early-stage breast cancer at 1 and 2 years after breast-conserving surgery and EBT. No recurrences have been reported, and adverse effects were acceptable.

alpha(V)beta(6) integrin expression is induced in the POET and Pten(pc-/-) mouse models of prostatic inflammation and prostatic adenocarcinoma

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

Chronic inflammation is proposed to prime the development of prostate cancer. However, the mechanisms of prostate cancer initiation and development are not completely understood. The alpha(v)beta(6) integrin has been shown to play a role in epithelial development, wound healing and some epithelial cancers [1, 2]. Here, we investigate the expression of alpha(v)beta(6) in mouse models of prostatic inflammation and prostate cancer to establish a possible relationship between inflammation of the prostate, alpha(v)beta(6) expression and the progression of prostate cancer. Using immunohistochemical techniques, we show expression of alpha(v)beta(6) in two in vivo mouse models; the Pten(pc)-/- model containing a prostate- specific Pten tumor suppressor deletion that causes cancer, and the prostate ovalbumin-expressing transgenic (POET) inflammation mouse model. We show that the alpha(v)beta(6) integrin is induced in prostate cancer and inflammation in vivo in these two mouse models. alpha(v)beta(6) is expressed in all the mice with cancer in the Pten(pc-/-) model but not in age-matched wild-type mice. In the POET inflammation model, alpha(v)beta(6) is expressed in mice injected with activated T-cells, but in none of the control mice. In the POET model, we also used real time PCR to assess the expression of Transforming Growth Factor Beta 1 (TGFbeta1), a factor in inflammation that is activated by alpha(v)beta(6). In conclusion, through in vivo evidence, we conclude that alpha(v)beta(6) integrin may be a crucial link between prostatic inflammation and prostatic adenocarcinoma.

Surveillance computed tomography imaging and detection of relapse in intermediate- and advanced-stage pediatric Hodgkin's lymphoma: a report from the Children's Oncology Group

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

PURPOSE Children with Hodgkin's lymphoma (HL) routinely undergo surveillance computed tomography (CT) imaging for up to 5 years after therapy, resulting in cost and radiation exposure, without clear benefit. The objective of this study was to determine the contribution of surveillance CT, as compared with clinical findings, to detection of disease recurrence.

PATIENTS AND METHODS Two hundred sixteen patients, age ≤ 21 years old, were treated on the multicenter Pediatric Oncology Group 9425 trial. Data for patients who experienced relapse were retrospectively reviewed to determine whether imaging or clinical events prompted suspicion of disease recurrence. Correlation was made to disease stage, time to recurrence, relapse site, and overall survival (OS).

RESULTS With a median follow-up time of 7.4 years, 25 (11.6%) of 216 patients had experienced a relapse, of whom 23 experienced local relapse. Median time to relapse was 7.6 months (range, 0.2 to 48.9 months). Nineteen relapses (76%) were detected based on symptoms, laboratory or physical examination findings, and two relapses (8%) were detected by imaging within the first year after therapy. Only four patients (16%) had their recurrence detected exclusively by surveillance imaging after the first year. Six deaths occurred, all in patients who experienced relapse within the first year after therapy. No patient with a recurrence after 1 year off treatment has died, regardless of how the recurrence was detected.

CONCLUSION The majority of pediatric HL relapses occurred within the first year after therapy or were detected based on change in clinical status. Detecting late relapse, whether by imaging or clinical change, did not affect OS. These findings indicate that CT is overused for routine surveillance of patients with HL.

A comparison of the biological effective dose of 50-kV electronic brachytherapy with (192)Ir high-dose-rate brachytherapy for vaginal cuff irradiation

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

PURPOSE: Advantages for electronic brachytherapy (EBT) of the vaginal cuff include decreased physical dose to the bladder and rectum. Here we compare (192)Ir with EBT using biological effective dose (BED) to account for the different radiobiological effectiveness (RBE) predicted for low-energy x-rays.

METHODS AND MATERIALS: Fifteen data sets from five consecutive postoperative endometrial cancer patients treated with EBT were analyzed. Treatment planning was performed using PLATO software. The dose was prescribed as 21Gy in three fractions to a depth of 0.5cm. Physical dose, BED(3), and BED(10) were evaluated for the mucosa, bladder, and rectum. An RBE value of 1.5 was used for BED calculations.

RESULTS: Mucosal physical dose is 28.4% greater with EBT (36.6 vs. 28.5Gy, p<0.05). However, the BED(10) is increased by 79.1% (55.6 vs. 99.6Gy, p<0.05) and the BED(3) by 71.5% (118.8 vs. 203.7Gy, p<0.05). The physical dose (dose to 50% volume of the organ) to the bladder (9.3 vs. 6.6Gy, p<0.05) and rectum (7.2 vs. 4.2Gy, p<0.05) are reduced with EBT. BED(3) to the rectum and bladder are also reduced but to a lesser extent (13 vs. 8.3Gy, p<0.05; 18.9 vs. 14.7Gy, p=0.06, respectively).

CONCLUSIONS: BED takes into account the higher RBE of low-energy photons generated with EBT and provides a more accurate estimate of the biological effect. When using EBT, physical dose may underestimate the biological effect on the vaginal mucosa and overestimate the benefit for the bladder and rectum. Dose adjustment for EBT based on BED should be considered. rights reserved.

Primary mucosa-associated lymphoid tissue lymphoma of the salivary glands: a multicenter Rare Cancer Network study

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

PURPOSE: Involvement of salivary glands with mucosa-associated lymphoid tissue (MALT) lymphoma is rare. This retrospective study was performed to assess the clinical profile, treatment outcome, and prognostic factors of MALT lymphoma of the salivary glands.

METHODS AND MATERIALS: Thirteen member centers of the Rare Cancer Network from 10 countries participated, providing data on 63 patients. The median age was 58 years; 47 patients were female and 16 were male. The parotid glands were involved in 49 cases, submandibular in 15, and minor glands in 3. Multiple glands were involved in 9 patients. Staging was as follows: IE in 34, IIE in 12, IIIE in 2, and IV in 15 patients.

RESULTS: Surgery (S) alone was performed in 9, radiotherapy (RT) alone in 8, and chemotherapy (CT) alone in 4 patients. Forty-one patients received combined modality treatment (S + RT in 23, S + CT in 8, RT + CT in 4, and all three modalities in 6 patients). No active treatment was given in one case. After initial treatment there was no tumor in 57 patients and residual tumor in 5. Tumor progression was observed in 23 (36.5%) (local in 1, other salivary glands in 10, lymph nodes in 11, and elsewhere in 6). Five patients died of disease progression and the other 5 of other causes. The 5-year disease-free survival, disease-specific survival, and overall survival were 54.4%, 93.2%, and 81.7%, respectively. Factors influencing disease-free survival were use of RT, stage, and residual tumor (p < 0.01). Factors influencing disease-specific survival were stage, recurrence, and residual tumor (p < 0.01).

CONCLUSIONS: To our knowledge, this report represents the largest series of MALT lymphomas of the salivary glands published to date. This disease may involve all salivary glands either initially or subsequently in 30% of patients. Recurrences may occur in up to 35% of patients at 5 years; however, survival is not affected. Radiotherapy is the only treatment modality that improves disease-free survival.

IL-1 generated subsequent to radiation-induced tissue injury contributes to the pathogenesis of radiodermatitis

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

Radiation injury in the skin causes radiodermatitis, a condition in which the skin becomes inflamed and the epidermis can break down. This condition causes significant morbidity and if severe it can be an independent factor that contributes to radiation mortality. Radiodermatitis is seen in some settings of radiotherapy for cancer and is also of concern as a complication post-radiation exposure from accidents or weapons, such as a "dirty bomb". The pathogenesis of this condition is incompletely understood. Here we have developed a murine model of radiodermatitis wherein the skin is selectively injured by irradiation with high-energy electrons. Using this model we showed that the interleukin-1 (IL-1) pathway plays a significant role in the development of radiodermatitis. Mice that lack either IL-1 or the IL-1 receptor developed less inflammation and less severe pathological changes in their skin, especially at later time-points. These findings suggest that IL-1 pathway may be a potential therapeutic target for reducing the severity of radiodermatitis.

From the lost radium files: misadventures in the absence of training, regulation, and accountability

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

PURPOSE: Radium was the foundation of brachytherapy in the early decades of the 20th century. Despite being a most precious and perilous substance, it was mislaid with surprising frequency. This essay explores how it was lost, the efforts taken to recover it, and measures instituted to prevent mishandling.

METHODS AND MATERIALS: Review of contemporary literature, government publications, archives, and lay press.

RESULTS: Radium is a particularly dangerous substance because of its long half-life, its gaseous daughter (radon), and the high-energy emissions of its decay products. Despite the hazard, it was unregulated for most of the century. Any physician could obtain and administer it, and protocols for safe handling were generally lacking. Change came with appreciation of the danger, regulation, mandated training, and the institution of a culture of accountability. Unfortunately, careless management of medical radionuclides remains a global hazard.

CONCLUSION: Responsible stewardship of radioactive material was not a high priority, for practitioners or the federal government, for much of the 20th century. As a result, large quantities of radium had gone astray, possibly subjecting the general public to continued radiation exposure. Lessons from the radium era remain relevant, as medical radionuclides are still mishandled.

Early-stage primary bone lymphoma: a retrospective, multicenter Rare Cancer Network (RCN) Study

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

PURPOSE: Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with Stages I and II PBL.

PATIENTS AND METHODS: Thirteen Rare Cancer Network (RCN) institutions enrolled 116 consecutive patients with PBL treated between 1987 and 2008 in this study. Eighty-seven patients underwent chemoradiotherapy (CXRT) without (78) or with (9) surgery, 15 radiotherapy (RT) without (13) or with (2) surgery, and 14 chemotherapy (CXT) without (9) or with (5) surgery. Median RT dose was 40 Gy (range, 4-60). The median number of CXT cycles was six (range, 2-8). Median follow-up was 41 months (range, 6-242).

RESULTS: The overall response rate at the end of treatment was 91% (complete response [CR] 74%, partial response [PR] 17%). Local recurrence or progression was observed in 12 (10%) patients and systemic recurrence in 17 (15%). The 5-year overall survival (OS), lymphoma-specific survival (LSS), and local control (LC) were 76%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for OS and LSS were International Prognostic Index (IPI) score 40 Gy (p = 0.005). For LC, only CR and Stage I were favorable factors. In multivariate analysis, IPI score, RT dose, CR, and CXT were independently influencing the outcome (OS and LSS). CR was the only predicting factor for LC.

CONCLUSION: This large multicenter retrospective study confirms the good prognosis of early-stage PBL treated with combined CXRT. An adequate dose of RT and complete CXT regime were associated with better outcome.

Robert Abbe: early American brachytherapist

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

PURPOSE: To assess Robert Abbe's career and contributions to brachytherapy, in the context of the work of contemporary European and American investigators.

METHODS AND MATERIALS: Examination of his lectures and journal articles, as well as contemporaneous newspaper accounts, textbooks, and archival material.

RESULTS: Although not the first American to apply radium therapeutically, Robert Abbe was among the earliest to acquire and systematically use a clinically significant quantity. He replicated early European experimental and clinical work, and published a large series of cases treated with generally favorable results. Abbe was the first American to emphasize the role of radiobiology in optimizing therapeutic ratio. His eloquence and stature helped legitimize the new therapeutic modality.

CONCLUSIONS: Robert Abbe was probably the nation's most influential early brachytherapist. rights reserved.

Triple negative breast cancer is associated with an increased risk of residual invasive carcinoma after lumpectomy

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

BACKGROUND: To assess the potential mechanisms that may underlie increased local failure in triple negative (TN) breast cancers, an analysis was performed of the risk of residual carcinoma after lumpectomy with correlation to pathologic factors, including molecular phenotype.

METHODS: A review of pathologic specimens was performed for women with invasive breast cancer treated with lumpectomy followed by reexcision. Data were collected on age; tumor size, grade, and nodal stage; estrogen receptor, progesterone receptor, and human endothelial growth factor receptor 2 (Her2); extensive intraductal component; lymphovascular invasion; margins; and reexcision findings. Univariate and multivariate logistic regression analyses were performed to evaluate for associations between pathologic features of the lumpectomy specimen and reexcision findings. Molecular phenotypes were defined by conventionally used immunohistochemical pattern.

RESULTS: Data were collected on 369 patients with breast cancer. The median age was 57 years, median tumor size was 1.5 cm, 36% had positive margins, 32% had positive lymph nodes, 73.5% had the luminal A subtype, 9.5% had the luminal B subtype, 4.5% were Her2-enriched, and 12.5% were TN. Overall, 32% of patients had invasive cancer in their reexcision specimens, and 51% of those with the TN subtype had residual invasive disease on reexcision compared with 30% to 31% for other subtypes. On univariate analysis, age, tumor size, margin status, lymphovascular invasion, nodal status, and TN subtype were associated with elevated risk of residual invasive cancer. On multivariate analysis using a forward stepwise model, TN subtype maintained significance, with an odds ratio of 3.28 (P = .002).

CONCLUSION: TN subtype has a statistically significant association with an increased risk of residual tumor. This suggests the putative increase in the risk of local failure in TN patients may be related to increased residual tumor burden.

Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children's Oncology Group

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

BACKGROUND: Hodgkin lymphoma is highly curable but associated with significant late effects. Reduction of total treatment would be anticipated to reduce late effects. This aim of this study was to demonstrate that a reduction in treatment was possible without compromising survival outcomes.

METHODS: Protocol P9426, a response-dependent and reduced treatment for low risk Hodgkin lymphoma (stages I, IIA, and IIIA(1) ) was designed in 1994 based on a previous pilot project. Patients were enrolled from October 15, 1996 to September 19, 2000. Patients were randomized to receive or not receive dexrazoxane and received two cycles of chemotherapy consisting of doxorubicin, bleomycin, vincristine, and etoposide. After two cycles, patients were evaluated for response. Those in complete response (CR) received 2,550 cGy of involved field radiation therapy (IFRT). Patient with partial response or stable disease, received two more cycles of chemotherapy and IFRT at 2,550 cGy.

RESULTS: There were 294 patients enrolled, with 255 eligible for analysis. The 8-year event free survival (EFS) between the dexrazoxane randomized groups did not differ (EFS 86.8 +/- 3.1% with DRZ, and 85.7 +/- 3.3% without DRZ (P = 0.70). Forty-five percent of patients demonstrated CR after two cycles of chemotherapy. There was no difference in EFS by histology, rapidity of response, or number of cycles of chemotherapy. Six of the eight secondary malignancies in this study have been previously reported.

CONCLUSIONS: Despite reduced therapy and exclusion of most patients with lymphocyte predominant histology, EFS and overall survival are similar to other reported studies. The protocol documents that it is safe and effective to reduce therapy in low-risk Hodgkin lymphoma based on early response to chemotherapy with rapid responding patients having the same outcome as slower-responding patients when given 50% of the chemotherapy.

Prevalence of poor cardiac anatomy in carcinoma of the breast treated with whole-breast radiotherapy: reconciling modern cardiac dosimetry with cardiac mortality data

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

PURPOSE: : The purpose of the study was to identify patient characteristics that predict for increased cardiac exposure through dosimetric analysis of the anatomy of a cohort of women treated with left-sided tangential breast radiation. Statistical analyses estimations for the appropriate sample sizes required for detection of significant differences in cardiac mortality at 15 years were conducted, assuming a threshold V25 for radiation-induced coronary artery disease (CAD) beyond which women are at risk for radiation-induced coronary artery disease.

METHODS AND MATERIALS: : Detailed heart dosimetry was recorded. Clinical factors (age, history of CAD, diabetes, receipt of cardiotoxic agents, weight/body mass index) and anatomic factors (heart volume, breast volume, cardiac contact distance) were recorded for each patient.

RESULTS: : The average heart V25 was 3.57%. The median percentage of the heart included in the tangential beam was 4.02%. There were no clinical or anatomic factors that predict suboptimal heart anatomy (ie, V25 of >/=6%) on multivariate analysis. The sample size calculations using thresholds for induction of CAD of V25 >/=1%, 6%, and 10% yielded sample sizes of 1314, 9504, and 61,342, respectively; considering node-positive breast cancer mortality and 15% loss to follow-up, these change to 2237, 16,166, and 104,334, respectively.

CONCLUSIONS: : Current studies with modern radiotherapy techniques would be underpowered to detect a difference in cardiac mortality where only some women are at risk. The heart, chest wall, and breast have a complex relationship to tangential breast radiation, and their interplay prevented this anatomic metric's success.

Credentialing for participation in clinical trials

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

The National Cancer Institute (NCI) clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence-based clinical trial processes for improvements in patient care. The cooperative groups are undergoing a transformation process to launch, conduct, and publish clinical trials more rapidly. Institutional participation in clinical trials can be made more efficient and include the expansion of relationships with international partners. This paper reviews the current processes that are in use in radiation therapy trials and the importance of maintaining effective credentialing strategies to assure the quality of the outcomes of clinical trials. The paper offers strategies to streamline and harmonize credentialing tools and processes moving forward as the NCI undergoes transformative change in the conduct of clinical trials.

Outcome of patients with localized orbital sarcoma who relapsed following treatment on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-III and -IV, 1984-1997: a report from the Children's Oncology Group

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

BACKGROUND: We wanted to ascertain patterns of recurrence, re-treatment, and outcome among 188 eligible patients treated for localized orbital sarcoma on IRSG Protocols III/IV, 1984-1997.

PROCEDURE: Retrospective chart review.

RESULTS: Twenty-four of 188 patients (12.8%) developed local (n = 22) or distant relapse (n = 2) at 0.057-7.05 years (median, 1.58) after enrollment. Ages at study entry were 0.14-17 years (median, 5 years). Initial tumor operations included biopsy (n = 20) or gross resection with microscopic residual (n = 4). Initial tumor diameters were 0.5-7 cm (median, 3). Pathologic subtypes were embryonal rhabdomyosarcoma (ERMS, n = 19), sarcoma not otherwise specified (n = 2), and alveolar RMS, botryoid ERMS, or undifferentiated sarcoma (n = 1 each). Initial treatment included vincristine/dactinomycin (n = 24) including an alkylator (n = 4) and radiotherapy (RT, n = 21). Twenty patients responded, 14 completely, 6 partially. After recurrence, patients underwent orbital exenteration (n = 10), enucleation (2), tumor excision (3), or biopsy (1); 7 had no operation, and 1 had no data. Post-relapse chemotherapy included combinations of etoposide (n = 14 patients), doxorubicin (14), ifosfamide (12), cyclophosphamide (7), and dacarbazine (n = 1). Six patients received RT, including four previously treated and two not irradiated initially. Two patients died; one at 1.79 years after contralateral brain metastasis followed by local recurrence, and another at 2.49 years after multiple local recurrences. Twenty-two patients (91.7%) survived sarcoma-free for 0.04-17 years (median, 6.9) after relapse, and 18 of 22 (82%) were alive >/=5 years after relapse.

CONCLUSION: Survival following recurrent localized orbital sarcoma appears likely after vigorous re-treatment given with curative intent.

Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: results of a Children's Oncology Group (COG) phase II study

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

BACKGROUND: Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children's Oncology Group.

PROCEDURES: Eligible patients were (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging.

RESULTS: Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10-18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23-0.48) and 96%, respectively. All three deaths were due to progressive DT.

CONCLUSIONS: Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates.

Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group

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

Radiolabeled metaiodobenzylguanidine (mIBG) is a highly sensitive and specific marker for detecting neuroblastoma. A semiquantitative mIBG score (Curie score [CS]) was assessed for utility as a prognostic indicator for a cohort of patients with high-risk metastatic disease.

METHODS: mIBG scans from 280 patients with mIBG-avid, stage 4 neuroblastoma enrolled on the Children's Oncology Group (COG) protocol A3973 were evaluated at diagnosis (n = 280), after induction chemotherapy (n = 237), and after an autologous stem cell transplantation (n = 178). Individual mIBG scans were evaluated at 10 different anatomic regions, with the scoring of each site (0-3) based on the extent of disease at that anatomic region.

RESULTS: There was no correlation between CS at diagnosis and subsequent treatment outcome. Patients with a CS > 2 after induction therapy had a significantly worse event-free survival (EFS) than those with scores 2 identified a cohort of patients at greater risk for an event, independent of other known neuroblastoma factors, including age, MYCN status, ploidy, mitosis-karyorrhexis index, and histologic grade. For MYCN-amplified tumors, the presence (CS > 0) versus absence (CS = 0) of residual mIBG avidity after induction was associated with a significantly worse outcome (3-y EFS: 11.8% +/- 7.8% vs. 49.6% +/- 7.7%, respectively; P = 0.003). After transplantation, patients with a CS > 0 had an EFS inferior to that of patients with a CS of 0 (3-y EFS: 28.9% +/- 6.8% vs. 49.3% +/- 4.9%, respectively [n = 133]; P = 0.009).

CONCLUSION: Curie scoring carries prognostic significance in the management of patients with high-risk neuroblastoma. In particular, patients with CSs > 2 after induction have extremely poor outcomes and should be considered for alternative therapeutic strategies.

Heart rate variability remains reduced and sympathetic tone elevated after temporal lobe epilepsy surgery

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

PURPOSE: There is evidence of autonomic dysregulation in temporal lobe epilepsy. The structures removed during temporal lobectomy are important centers of central cardiovascular control; therefore surgery may conceivably alter the cardiovascular autonomic function. The effects of temporal lobectomy on autonomic cardiac control are controversial. We investigated the effects of temporal lobectomy on heart rate variability (HRV) in the early and late postoperative periods.

METHODS: We used 1-h ECG recordings to assess heart rate variability by spectral analysis in 24 consecutive patients who underwent temporal lobectomy due to intractable temporal lobe epilepsy. ECG recordings were performed before and twice (early and late) after surgery. The results were compared with age and sex matched controls.

RESULTS: When compared with controls, all the time and frequency domain indices (SDRR, RMSSD, TP, LF and HF) were significantly lower in the patient group before surgery. Findings were similar in the early and late post-operative periods except that the LF/HF ratio increased in the patient group after the late post-operative period. Within the patient group, compared to pre-operative results, normalized HF was increased in the early post-operative period; however in the late post-operative period, LF/HF ratio was increased.

CONCLUSIONS: These findings show that in patients with intractable temporal lobe epilepsy, HRV is decreased globally in both sympathetic and parasympathetic domains. While the total HRV remains reduced throughout the postoperative periods, the LF/HF ratio, i.e., sympathovagal balance is altered, in favor of parasympathetic side early after surgery, but towards the sympathetic side after the first postoperative month. rights reserved.

Does quality of radiation therapy predict outcomes of multicenter cooperative group trials? A literature review

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

Central review of radiation therapy (RT) delivery within multicenter clinical trials was initiated in the early 1970s in the United States. Early quality assurance publications often focused on metrics related to process, logistics, and timing. Our objective was to review the available evidence supporting correlation of RT quality with clinical outcomes within cooperative group trials. A MEDLINE search was performed to identify multicenter studies that described central subjective assessment of RT protocol compliance (quality). Data abstracted included method of central review, definition of deviations, and clinical outcomes. Seventeen multicenter studies (1980-2012) were identified, plus one Patterns of Care Study. Disease sites were hematologic, head and neck, lung, breast, and pancreas. Between 0 and 97% of treatment plans received an overall grade of acceptable. In 7 trials, failure rates were significantly higher after inadequate versus adequate RT. Five of 9 and 2 of 5 trials reported significantly worse overall and progression-free survival after poor-quality RT, respectively. One reported a significant correlation, and 2 reported nonsignificant trends toward increased toxicity with noncompliant RT. Although more data are required, protocol-compliant RT may decrease failure rates and increase overall survival and likely contributes to the ability of collected data to answer the central trial question.

A perspective on recurrent vertigo

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

The recurrent nature of the 3 most common vestibulopathies suggests a recurrent cause. Histopathology in temporal bones from patients with these syndromes - vestibular neuronitis (VN, n = 7), Meniere's disease (MD, n = 8) and benign paroxysmal positional vertigo (BPPV, n = 5) - shows focal degeneration of vestibular nerve axons and degenerated nearby facial nerve meatal ganglion cells. Transmission electron microscopic confirmation of intracytoplasmic viral particles in surgically excised vestibular nerves from patients with VN and MD support a viral etiology in these vestibulopathies. Antiviral treatment of these syndromes in a series of 211 patients with a 3- to 8-year follow-up resulted in complete control of vertigo in VN (88%), MD (90%) and BPPV (60%).