bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic Flare: Indicator of Hormone Responsiveness in Advanced Breast Cancer
Authors: Mortimer Joanne E. , Dehdashti Farrokh , Siegel Barry A. , Trinkaus Kathryn , Katzenellenbogen John A. , Welch Michael J.
Published: February 2017

PURPOSE: The purpose of this study was to investigate whether positron emission tomography (PET) with the glucose analog [18F]fluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-[18F]fluoroestradiol-17 beta (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (metabolic flare) and changes in available levels of estrogen receptor (ER). In addition, we investigated whether these PET findings would predict hormonally responsive breast cancer.

PATIENTS AND METHODS: Forty women with biopsy-proved advanced ER-positive (ER+) breast cancer underwent PET with FDG and FES before and 7 to 10 days after initiation of tamoxifen therapy; 70 lesions were evaluated. Tumor FDG and FES uptake were assessed semiquantitatively by the standardized uptake value (SUV) method. The PET results were correlated with response to hormonal therapy.

RESULTS: In the responders, the tumor FDG uptake increased after tamoxifen by 28.4% ± 23.3% (mean ± SD); only five of these patients had evidence of a clinical flare reaction. In nonresponders, there was no significant change in tumor FDG uptake from baseline (mean change, 10.1% ± 16.2%; P = .0002 v responders). Lesions of responders had higher baseline FES uptake (SUV, 4.3 ± 2.4) than those of nonresponders (SUV, 1.8 ± 1.3; P = .0007). All patients had evidence of blockade of the tumor ERs 7 to 10 days after initiation of tamoxifen therapy; however, the degree of ER blockade was greater in the responders (mean percentage decrease, 54.8% ± 14.2%) than in the nonresponders (mean percentage decrease, 19.4% ± 17.3%; P = .0003).

CONCLUSION: The functional status of tumor ERs can be characterized in vivo by PET with FDG and FES. The results of PET are predictive of responsiveness to tamoxifen therapy in patients with advanced ER+ breast cancer.
Clinical Evaluation of Once-Weekly Dosing of Epoetin Alfa in Chemotherapy Patients: Improvements in Hemoglobin and Quality of Life Are Similar to Three-Times-Weekly Dosing
Authors: Gabrilove Janice L. , Cleeland Charles S. , Livingston Robert B. , Sarokhan Brenda , Winer Eric , Einhorn Lawrence H.
Published: February 2017

PURPOSE: To prospectively evaluate the effectiveness, safety, and clinical benefits of once-weekly epoetin alfa therapy as an adjunct to chemotherapy in anemic cancer patients.

PATIENTS AND METHODS: A total of 3,012 patients with nonmyeloid malignancies who received chemotherapy were enrolled onto this multicenter, open-label, nonrandomized study conducted in 600 United States community-based practices. Patients received epoetin alfa 40,000 U once weekly, which could be increased to 60,000 U once weekly after 4 weeks dependent on hemoglobin response. Treatment was continued for a maximum of 16 weeks.

RESULTS: Among the 2,964 patients assessable for efficacy, epoetin alfa therapy resulted in significant increases in hemoglobin levels, decreases in transfusion requirements, and improvements in functional status and fatigue as assessed by the linear analog scale assessment (energy level, ability to perform daily activities, and overall quality of life) and the anemia subscale of the Functional Assessment of Cancer Therapy–Anemia questionnaire. Improvements in quality-of-life parameters correlated significantly (P < .001) with increased hemoglobin levels. The direct relationship between hemoglobin and quality-of-life improvement was sustained during the 16-week study period, which is similar to findings of large community-based trials of three-times-weekly dosing. Once-weekly epoetin alfa was well tolerated, with most adverse events attributed to the underlying disease or concomitant chemotherapy.

CONCLUSION: The results from this large, prospective, community-based trial suggest that once-weekly epoetin alfa therapy increases hemoglobin levels, decreases transfusion requirements, and improves quality of life in patients with cancer and anemia who undergo concomitant chemotherapy. Based on the results of this study, the clinical benefits and the adverse event profile of once-weekly epoetin alfa therapy in community-based practice are similar to those observed in the historical experience with the three-times-weekly dosage schedule.
Gene Discovery Using the Serial Analysis of Gene Expression Technique: Implications for Cancer Research
Authors: Polyak Kornelia , Riggins Gregory J.
Published: February 2017

ABSTRACT: Cancer is a genetic disease. As such, our understanding of the pathobiology of tumors derives from analyses of the genes whose mutations are responsible for those tumors. The cancer phenotype, however, likely reflects the changes in the expression patterns of hundreds or even thousands of genes that occur as a consequence of the primary mutation of an oncogene or a tumor suppressor gene. Recently developed functional genomic approaches, such as DNA microarrays and serial analysis of gene expression (SAGE), have enabled researchers to determine the expression level of every gene in a given cell population, which represents that cell population’s entire transcriptome. The most attractive feature of SAGE is its ability to evaluate the expression pattern of thousands of genes in a quantitative manner without prior sequence information. This feature has been exploited in three extremely powerful applications of the technology: the definition of transcriptomes, the analysis of differences between the gene expression patterns of cancer cells and their normal counterparts, and the identification of downstream targets of oncogenes and tumor suppressor genes. Comprehensive analyses of gene expression not only will further understanding of growth regulatory pathways and the processes of tumorigenesis but also may identify new diagnostic and prognostic markers as well as potential targets for therapeutic intervention.
Combined Interferon-Alfa, 13-cis-Retinoic Acid, and Alpha-Tocopherol in Locally Advanced Head and Neck Squamous Cell Carcinoma: Novel Bioadjuvant Phase II Trial
Authors: Shin Dong M. , Khuri Fadlo R. , Murphy Barbara , Garden Adam S. , Clayman Gary , Francisco Marites , Liu Diane , Glisson Bonnie S. , Ginsberg Lawrence , Papadimitrakopoulou Vassiliki , Myers Jeffrey , Morrison William , Gillenwater Ann , Ang K. Kian , Lippman Scott M. , Goepfert Helmuth , Hong Waun Ki
Published: February 2017

PURPOSE: Retinoids and interferons (IFNs) have single-agent and synergistic combined effects in modulating cell proliferation, differentiation, and apoptosis in vitro and clinical activity in vivo in the head and neck and other sites. Alpha-tocopherol has chemopreventive activity in the head and neck and may decrease 13-cis-retinoic acid (13-cRA) toxicity. We designed the present phase II adjuvant trial to prevent recurrence or second primary tumors (SPTs) using 13-cRA, IFN-α, and α-tocopherol in locally advanced-stage head and neck cancer.

PATIENTS AND METHODS: After definitive local treatment with surgery, radiotherapy, or both, patients with locally advanced SCCHN were treated with 13-cRA (50 mg/m2/d, orally, daily), IFN-α (3 × 106 IU/m2, subcutaneous injection, three times a week), and α-tocopherol (1,200 IU/d, orally, daily) for 12 months, with a dose modification. Screening for recurrence or SPTs was performed every 3 months.

RESULTS: Tumors of 11 (24%) of the 45 treated patients were stage III, and 34 (76%) were stage IV. Thirty-eight (86%) of 44 patients completed the full 12-month treatment (doses modified as needed). Toxicity generally was consistent with previous IFN and 13-cRA reports and included mild to moderate mucocutaneous and flu-like symptoms; occasional significant fatigue (grade 3 in 7% of patients), mild to moderate hypertriglyceridemia in 30% of patients who continued treatment along with antilipid therapy, and mild hematologic side effects. Six patients did not complete the planned treatment because of intolerable toxicity or social problems. At a median 24-months of follow-up, our clinical end point rates were 9% for local/regional recurrence (four patients), 5% for local/regional recurrence and distant metastases (two patients), and 2% for SPT (one patient), which was acute promyelocytic leukemia (ie, not of the upper aerodigestive tract). Median 1- and 2-year rates of overall survival were 98% and 91%, respectively, and of disease-free survival were 91% and 84%, respectively.

CONCLUSION: The novel biologic agent combination of IFN-α, 13-cRA, and α-tocopherol was generally well tolerated and promising as adjuvant therapy for locally advanced squamous cell carcinoma of the head and neck. We are currently conducting a phase III randomized study of this combination (v no treatment) to confirm these phase II study results.
Prognostic Significance of Reverse Transcriptase Polymerase Chain Reaction for Prostate-Specific Antigen in Men With Hormone-Refractory Prostate Cancer
Authors: Kantoff Philip W. , Halabi Susan , Farmer Deborah A. , Hayes Daniel F. , Vogelzang Nicholas A. , Small Eric J.
Published: February 2017

PURPOSE: To evaluate the prognostic significance of reverse transcriptase polymerase chain reaction (RT-PCR) detection of prostate-specific antigen (PSA) mRNA in the blood of men with hormone-refractory prostate cancer (HRPC).

PATIENTS AND METHODS: Peripheral blood was obtained from 193 men enrolled on Cancer and Leukemia Group B Study 9480, a prospective randomized comparison of three doses of suramin. RNA was isolated from the samples and assayed for the presence of PSA transcripts by RT-PCR.

RESULTS: RNA could be isolated in 156 (83%) of samples. PSA transcripts as measured by RT-PCR were detectable in 75 (48%) of the 156 patients. The median survival for those patients in whom no transcripts were detectable was 18 months (95% confidence interval [CI], 14 to 22 months) compared with 13 months (95% CI, 11 to 15 months) (P = .004) for those in whom transcripts were detectable. In a multivariate analysis in which other factors predictive of survival were used, RT-PCR for PSA provided independent prognostic information.

CONCLUSION: RT-PCR for PSA predicts survival duration in a population of men with HRPC.
Clinical Impact of Germ Cell Tumor Cells in Apheresis Products of Patients Receiving High-Dose Chemotherapy
Authors: Bokemeyer C. , Gillis A. J.M. , Pompe K. , Mayer F. , Metzner B. , Schleucher N. , Schleicher J. , Pflugrad-Jauch G. , Oosterhuis J. W. , Kanz L. , Looijenga L. H.J.
Published: February 2017

PURPOSE: High-dose chemotherapy (HD-Ctx) followed by autologous peripheral-blood stem-cell (PBSC) transplantation is currently investigated in patients with poor prognosis or relapsed metastatic germ cell tumor (GCTs). This study analyzed the presence and the clinical importance of contaminating tumor cells in PBSC preparations used to support HD-Ctx in GCT patients.

PATIENTS AND METHODS: Seven targets for reverse transcription polymerase chain reaction (RT-PCR)-based detection of GCT cells were able to detect seminomatous and different histologic variants of nonseminomatous tumor cells. PBSC preparations from 57 patients were investigated for the presence of contaminating tumor cells using this set of targets, including beta human chorionic gonadotropin (β-hCG), fibronectin (EDB variant), epidermal growth factor receptor (EGFR), CD44 (v8 to 10 variant), germ cell and placental alkaline phosphatase (AP), human endogenous retrovirus type K (ENV and GAG), and XIST. Samples of PBSC preparations from four healthy donors for allogenic transplantations as well as blood specimens from 10 healthy volunteers served as negative controls.

RESULTS: Fifty patients (43 first-line and seven second-line Ctx) were assessable. Combining all RT-PCR results, 29 PBSC preparations (58%) were positive for tumor-specific amplification products (HERV-K 0, fibronectin 4, XIST 14, β-hCG 19, AP 19, CD44 24, EGFR 26). Ten (35%) of 29 patients who underwent transplantation with positive PBSC preparations and seven (33%) of 21 patients with negative PBSC preparations have suffered relapse or progression (not significant [ns]). With a median follow-up of 22 months (2 to 66) post–HD-Ctx projected 3-year survival rates are 68% (RT-PCR+) and 58% (RT-PCR−) (ns). None of the 10 control peripheral-blood samples showed positivity for any of the targets studied.

CONCLUSION: GCT cells can be detected in more than 50% of PBSC preparations using a RT-PCR approach with multiple targets. Despite the presence of tumor cells, retransplantation of the PBSC products did not effect long-term outcome. Factors such as responsiveness to chemotherapy and tumor mass seem to overcome the importance of potentially re-infused tumor cells.
Bony Morbidity in Children Treated for Acute Lymphoblastic Leukemia
Authors: Strauss Adam J. , Su Joyce T. , Dalton Virginia M. Kimball , Gelber Richard D. , Sallan Stephen E. , Silverman Lewis B.
Published: February 2017

PURPOSE: Corticosteroids are widely used in the treatment of acute lymphoblastic leukemia (ALL). To determine the frequency of corticosteroid-associated bony morbidity in children with ALL, we retrospectively evaluated the incidence of fractures and osteonecrosis (ON) on two consecutive pediatric ALL protocols.

PATIENTS AND METHODS: One hundred seventy-six consecutive children were treated for ALL between 1987 and 1995 at the Dana-Farber Cancer Institute and Children’s Hospital. Prednisone was used as the corticosteroid during postremission therapy from 1987 to 1991, and dexamethasone was used from 1991 to 1995. Medical records for all patients were reviewed to assess the occurrence of fractures and ON.

RESULTS: With a median follow-up of 7.6 years, the 5-year cumulative incidence (CI) ± SE of any bony morbidity for the 176 patients was 30% ± 4%, with a 5-year CI of fractures of 28% ± 3% and of ON of 7% ± 2%. With multivariate analysis, independent predictors of bony morbidity included age 9 to 18 years at diagnosis (P < .01), male sex (P < .01), and treatment with dexamethasone (P = .01). Dexamethasone was associated with a higher risk of fractures (5-year CI, 36% ± 5% v 20% ± 4% with prednisone; P = .04), but not ON (P = .40). The 5-year event-free survival for the 176 patients was 79% ± 3%.

CONCLUSION: Children treated for ALL had a high incidence of fractures and ON. Older children, boys, and patients receiving dexamethasone were at increased risk for the development of bony morbidity. Future studies should attempt to minimize corticosteroid-associated bony morbidity without compromising clinical efficacy.
Delay of the Diagnostic Lumbar Puncture and Intrathecal Chemotherapy in Children With Acute Lymphoblastic Leukemia Who Undergo Routine Corticosteroid Testing: Tokyo Children’s Cancer Study Group Study L89-12
Authors: Manabe A. , Tsuchida M. , Hanada R. , Ikuta K. , Toyoda Y. , Okimoto Y. , Ishimoto K. , Okawa H. , Ohara A. , Kaneko T. , Koike K. , Sato T. , Sugita K. , Bessho F. , Hoshi Y. , Maeda M. , Kinoshita A. , Saito T. , Tsunematsu Y. , Nakazawa S.
Published: February 2017

PURPOSE: To determine the effects of eliminating initial lumbar punctures in 418 consecutively treated children with acute lymphoblastic leukemia (ALL).

PATIENTS AND METHODS: Patients were enrolled onto a trial conducted in central Japan between 1989 and 1992. Treatment consisted of standard four-drug induction therapy followed by a risk-based intensification phase, reinduction therapy, late intensification, and remission maintenance therapy (total of 104 weeks). The initial lumbar puncture, with an intrathecal injection of chemotherapy, was performed after 1 week of prednisolone sensitivity testing (day 8). End points included response to prednisolone, CNS status at the time of the day 8 lumbar puncture, subsequent adverse events in CNS and bone marrow, and event-free survival (EFS).

RESULTS: The remission induction rate was 93.1% with a 6-year EFS rate (± SE) of 68.7% ± 2.4%, which is similar to historical results for patients who received their diagnostic lumbar puncture and first instillation of intrathecal chemotherapy on day 0. Overall, 84.5% of the patients had good responses to prednisolone, whereas 15.5% had poor responses. Clinical outcome was strikingly better for the good responders (6-year EFS, 74.1% ± 2.5% compared with 40.1% ± 6.4% for patients with poor responses), suggesting that omission of intrathecal chemotherapy did not alter the predictive value of drug sensitivity testing. Eighteen patients experienced CNS relapse as their first adverse event (cumulative risk, 5.1%; 95% confidence interval, 2.7% to 7.4%), coincident with reports from groups using conventional strategies of CNS clinical management. Bleeding into the CSF at the time of the day 8 lumbar puncture was apparent in 29 cases (8.1%), but leukemic blasts were identified in only two.

CONCLUSION: Delay of the initial lumbar puncture and intrathecal injection of chemotherapy seems to be feasible in children with ALL. Further controlled evaluations are needed to establish the validity of this conclusion.
Phase I Study of Anti–Epidermal Growth Factor Receptor Antibody Cetuximab in Combination With Radiation Therapy in Patients With Advanced Head and Neck Cancer
Authors: Robert Francisco , Ezekiel Mark P. , Spencer Sharon A. , Meredith Ruby F. , Bonner James A. , Khazaeli M. B. , Saleh Mansoor N. , Carey Delicia , LoBuglio Albert F. , Wheeler Richard H. , Cooper Michael R. , Waksal Harlan W.
Published: February 2017

PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti–epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck.

PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m2, followed by weekly infusions of 100 to 250 mg/m2 for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events.

RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions).

CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m2 and a maintenance weekly dose of 250 mg/m2.
Eligibility for Hematopoietic Stem-Cell Transplantation for Primary Systemic Amyloidosis Is a Favorable Prognostic Factor for Survival
Authors: Dispenzieri Angela , Lacy Martha Q. , Kyle Robert A. , Therneau Terry M. , Larson Dirk R. , Rajkumar S. Vincent , Fonseca Rafael , Greipp Philip R. , Witzig Thomas E. , Lust John A. , Gertz Morie A.
Published: February 2017

PURPOSE: Based on the success of hematopoietic stem-cell transplantation (HSCT) for multiple myeloma, HSCT is being used to treat patients with primary systemic amyloidosis (AL). This article addresses the extent to which eligibility to undergo HSCT is a favorable prognostic feature and explores prognostic factors within the subset of eligible patients.

PATIENTS AND METHODS: The Mayo Clinic amyloid database was queried for all patients with AL seen at the Mayo Clinic from 1983 through 1997 who would have been eligible for peripheral-blood stem-cell transplantation. Inclusion criteria included biopsy-proven amyloid, symptomatic disease, absence of a clinical diagnosis of multiple myeloma, age ≤ 70 years, cardiac interventricular septal thickness ≤ 15 mm, cardiac ejection fraction more than 55%, serum creatinine ≤ 2 mg/dL, and direct bilirubin ≤ 2.0 mg/dL.

RESULTS: Median age was 56 years (range, 25 to 70) with 79 (34%) older than 60 years. One hundred patients had early cardiac involvement; 41, hepatic involvement; 167, renal involvement; and 39, nerve involvement. The 229 patients have had a median follow-up of 52 months, and 151 have died. The median survival was 42 months with 5- and 10-year survival rates of 36% and 15%, respectively. Important predictors of survival were size of M-component in 24-hour urine, number of involved organs, alkaline phosphatase, performance score, and weight loss.

CONCLUSION: The same patients who are eligible for HSCT are a good-risk population who do relatively well with chemotherapy (median survival, 42 months), substantially better than the expected median survival of 18 months for all patients with AL. A randomized trial is needed to assess the true effect of HSCT.
Cancer-Related Fatigue: Prevalence of Proposed Diagnostic Criteria in a United States Sample of Cancer Survivors
Authors: Cella David , Davis Kimberly , Breitbart William , Curt Gregory ,   for the Fatigue Coalition
Published: February 2017

PURPOSE: To evaluate the proposed cancer-related fatigue (CRF) diagnostic criteria in a sample of cancer survivors. More accurate prevalence estimates of CRF may result in improved diagnosis and management of one of the most common symptoms associated with cancer and its treatment.

METHODS: Three hundred seventy-nine individuals who had been treated with chemotherapy, either alone or in combination with radiation therapy, were surveyed. Patients were asked background questions about their current condition, their medical history, and the frequency of fatigue during their chemotherapy. Additionally, patients who reported experiencing fatigue at least a few days each month during treatment were asked a series of questions about the impact of fatigue on their daily functioning.

RESULTS: One hundred forty-one (37%) individuals reported at least 2 weeks of fatigue in the previous month. Of the respondents who had received their last treatment more than 5 years ago, 33% still reported at least a 2-week period of fatigue in the month before the interview. Evaluation of the proposed criteria revealed that 17% of respondents met at least two criteria for CRF.

CONCLUSION: The prevalence of diagnosable CRF in the individuals in this sample, most of whom had completed treatment more than 1 year ago, was 17%—lower than expected based on previous reports that have used less-strict criteria. In a sizable number of people, CRF persists well beyond active treatment and should be a focus of intervention. Although they will require replication in other samples and clinical validation, these formal diagnostic criteria can be a step toward common language and a better understanding of the severity range and persistence of CRF.
Funding New Cancer Drugs in Ontario: Closing the Loop in the Practice Guidelines Development Cycle
Authors: Pater J. L. , Browman G. P. , Brouwers M. C. , Nefsky M. F. , Evans W. K. , Cowan D. H.
Published: February 2017

PURPOSE: The previously described practice guidelines development cycle follows an iterative model in which recommendations are reached by a process that incorporates practitioners at all phases. A key feature is the separation of the evidence-based systematic review and the generation of recommendations from policy decisions surrounding implementation. This article describes how this implementation phase has evolved in Ontario and how implementation has affected the guidelines process.

METHODS: The development of the New Drug Funding Program in Ontario and the appointment of a policy advisory committee (PAC) to make funding recommendations were reviewed. The decision-making framework of the PAC is described in this article.

RESULTS: The PAC has had to address a number of issues in making funding recommendations. These issues have included dealing with evidence arising solely from phase II versus phase III trials, using economic information, and involving community representatives in its deliberations. Its activities have had a substantial impact on the practice guidelines initiative.

CONCLUSION: It is possible to integrate an evidence-based, practitioner-driven approach to clinical guideline development with a funding program that takes policy considerations into account. However, even though these two roles are conceptually separate, the needs of the funding program have inevitably had an impact on the guidelines process.
Intellectual Outcome After Reduced-Dose Radiation Therapy Plus Adjuvant Chemotherapy for Medulloblastoma: A Children’s Cancer Group Study
Authors: Ris M. Douglas , Packer Roger , Goldwein Joel , Jones-Wallace Dana , Boyett James M.
Published: February 2017

PURPOSE: To investigate the intellectual outcomes of children with medulloblastomas/primitive neuroectodermal tumors (MB/PNET) treated with reduced-dose craniospinal radiotherapy (RT) plus adjuvant chemotherapy.

PATIENTS AND METHODS: Forty-three children with average-risk posterior fossa MB/PNETs underwent longitudinal intelligence testing. All had been treated with a reduced-dose craniospinal RT regimen (23.4 Gy to the neuraxis, 32.4-Gy boost to the posterior fossa) and adjuvant chemotherapy.

RESULTS: The estimated rate of change from baseline was significant for Full Scale Intelligence Quotient (FSIQ), Verbal IQ (VIQ), and Nonverbal IQ (NVIQ) (P < .001 for all three outcomes). The rate of change was estimated to be −4.3 FSIQ points per year, −4.2 VIQ points per year, and −4.0 NVIQ points per year. Females were more subject to VIQ decline than were males (P = .008), and young children (< 7 years of age) were more negatively affected than were older children, with a significant decline in NVIQ (P = .016). Finally, patients with higher baseline evaluations suffered greater declines in IQ than did those with lower baseline scores.

CONCLUSION: This study represents the largest series of patients with average-risk MB/PNETs treated with a combination of reduced-dose RT and adjuvant chemotherapy whose intellectual development has been followed prospectively. Intellectual loss was substantial but suggestive of some degree of intellectual preservation compared with effects associated with conventional RT doses. However, this conclusion remains provisional, pending further research.
Treatment of Waldenstrom’s Macroglobulinemia With Thalidomide
Authors: Dimopoulos Meletios A. , Zomas Athanassios , Viniou Nora A. , Grigoraki Vassiliki , Galani Eleni , Matsouka Charis , Economou Olga , Anagnostopoulos Nikolaos , Panayiotidis Panayiotis
Published: February 2017

PURPOSE: We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstrom’s macroglobulinemia (WM).

PATIENTS AND METHODS: Twenty patients with WM were treated with thalidomide at a starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated.

RESULTS: On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance.

CONCLUSION: Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant.
Immunomagnetic Purging of Ewing’s Sarcoma From Blood and Bone Marrow: Quantitation by Real-Time Polymerase Chain Reaction
Authors: Merino Margret E. , Navid Fariba , Christensen Barbara L. , Toretsky Jeffrey A. , Helman Lee J. , Cheung Nai-Kong V. , Mackall Crystal L.
Published: February 2017

PURPOSE: A propensity for hematogenous spread with resulting contamination of autologous cell products complicates cellular therapies for Ewing’s sarcoma. We used a new approach to purge artificially contaminated cellular specimens of Ewing’s sarcoma and show the capacity for real-time polymerase chain reaction (PCR) to quantify the contamination level of Ewing’s sarcoma in such specimens.

PATIENTS AND METHODS: Binding of monoclonal antibody (MoAb) 8H9 to Ewing’s sarcoma cell lines and normal hematopoietic cells was studied using flow cytometry. Using real-time PCR–based amplification of t(11;22), levels of Ewing’s contamination of experimental and clinical cellular products were monitored. Purging was accomplished using immunomagnetic-based depletion. Monitoring of the function of residual hematopoietic progenitors and T cells was performed using functional assays.

RESULTS: MoAb 8H9 shows binding to Ewing’s sarcoma but spares normal hematopoietic tissues. Nested real-time PCR is capable of detecting contaminating Ewing’s sarcoma cells with a sensitivity of one cell in 106 normal cells. After 8H9-based purging, a 2- to 3-log reduction in contaminating Ewing’s sarcoma was shown by real-time PCR, with purging to PCR negativity at levels of contamination of 1:106. Levels of contamination in clinical samples ranged from 1:105 to 106. Therefore, 8H9-based purging of clinical samples is predicted to reduce tumor cell contamination to a level below the limit of detection of PCR.

CONCLUSION: These results demonstrate a new approach for purging contaminated cellular products of Ewing’s sarcoma and demonstrate the capacity of real-time PCR to provide accurate quantitative estimates of circulating tumor burden in this disease.
Who Gets Adjuvant Treatment for Stage II and III Rectal Cancer? Insight From Surveillance, Epidemiology, and End Results–Medicare
Authors: Schrag Deborah , Gelfand Sarah E. , Bach Peter B. , Guillem Jose , Minsky Bruce D. , Begg Colin B.
Published: February 2017

PURPOSE: To examine the relationship between patient characteristics and the use of adjuvant pelvic radiation with and without chemotherapy among patients aged 65 years and older with stage II and III rectal cancer.

PATIENTS AND METHODS: A retrospective cohort study using the Surveillance, Epidemiology, and End Results–Medicare linked database identified 1,411 patients aged 65 and older with resected stage II and III rectal cancers diagnosed between 1992 and 1996. From claims submitted to Medicare, we measured the use of pelvic radiation therapy with or without chemotherapy and pre- or postoperatively.

RESULTS: Fifty-seven percent of patients received radiation, 42% received chemotherapy and radiation, and 7% had treatment delivered preoperatively. Age was the strongest determinant of treatment: 73% of patients aged 65 to 69, 66% aged 70 to 75, 52% aged 75 to 79, 39% aged 80 to 84, and 21% aged 85 to 89 received radiation. The age trend remained strong after adjusting for other factors that predict receipt of treatment and after exclusion of patients with any evident comorbidity (P < .001). Patients were more likely to receive radiation treatment if they had an abdominal perineal resection, stage III disease, or a T4 tumor.

CONCLUSION: Because pelvic recurrences are a substantial cause of morbidity, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding adjuvant treatment.
Predictive Impact of 2-18Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography for Residual Postchemotherapy Masses in Patients With Bulky Seminoma
Authors: De Santis Maria , Bokemeyer Carsten , Becherer Alexander , Stoiber Franz , Oechsle Karin , Kletter Kurt , Dohmen Bernhard M. , Dittrich Christian , Pont Jörg
Published: February 2017

PURPOSE: To establish the predictive potential of 2-18fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) for detecting viable tumor tissue in residual postchemotherapy masses of seminoma patients.

PATIENTS AND METHODS: In this prospective multicenter trial, results of FDG PET studies in seminoma patients with postchemotherapy masses ≥ 1 cm were correlated with either the histology of the resected lesion or the clinical outcome on follow-up without resection. Negative PET scans of residual lesions that were devoid of viable tumor tissue on resection or disappeared, shrunk, or remained stable in size for at least 2 years were rated as true-negative (TN). Positive scans without histologic or clinical evidence of tumor tissue were classified as false-positive. In patients with histologically positive or progressive lesions, positive PET scans were defined as true-positive (TP) and negative scans, false-negative (FN).

RESULTS: Thirty-seven PET scans of 33 patients were assessable at a median follow-up time of 23 months (range, 2 to 46 months). Histologic data were available from nine patients who had undergone resection. Twenty-eight patients were followed-up clinically and radiologically. Twenty-eight scans were TN, eight were TP, and one was FN. All 14 residual lesions more than 3 cm and 22 (96%) of the 23 ≤ 3 cm were correctly predicted by FDG PET. The specificity (100%; 95% confidence interval [CI], 87.7% to 100%), sensitivity (89%; 95% CI, 51.7% to 99.7%), positive predictive value (100%), and the negative predictive value (97%) of FDG PET were superior to data obtained by assessing residual tumor size (≤ or > 3 cm).

CONCLUSION: FDG PET is a clinically useful predictor of viable tumor in postchemotherapy residuals of pure seminoma, especially those greater than 3 cm.
Primary Gastrointestinal Non-Hodgkin’s Lymphoma: I. Anatomic and Histologic Distribution, Clinical Features, and Survival Data of 371 Patients Registered in the German Multicenter Study GIT NHL 01/92
Authors: Koch Peter , del Valle Francisco , Berdel Wolfgang E. , Willich Normann A. , Reers Berthold , Hiddemann Wolfgang , Grothaus-Pinke Bernward , Reinartz Gabriele , Brockmann Jens , Temmesfeld Altfried , Schmitz Rudolf , Rübe Christian , Probst Andreas , Jaenke Gert , Bodenstein Heinrich , Junker Arved , Pott Christiane , Schultze Jürgen , Heinecke Achim , Parwaresch Reza , Tiemann Markus ,   for the German Multicenter Study Group
Published: February 2017

PURPOSE: The study was initiated to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, and treatment results in patients with primary gastrointestinal non-Hodgkin’s lymphomas (PGI NHL).

PATIENTS AND METHODS: Between October 1992 and November 1996, 371 PGI NHL patients were eligible to evaluate clinical features. Radiotherapy and chemotherapy were stratified according to histologic grading, stage, and whether surgery had been carried out or not.

RESULTS: A total of 74.8% patients had gastric NHL (PGL). Within the intestine, the small bowel and the ileocecal region were involved in 8.6% and 7.0% of the cases, respectively. Multiple GI involvement (MGI) was 6.5%. Approximately 90% of the GI NHL were in stages IE/IIE. Aggressive NHL accounted for the majority, with a distinguishable pattern in several sites. Forty percent of PGL were of low-grade mucosa-associated lymphatic tissue type. One third of large-cell lymphomas had low-grade components. Most intestinal NHL were germinal-center lymphomas. The site of origin was prognostic. In gastric and ileocecal lymphoma, event-free (EFS) and overall survival (OS) were significantly higher as compared with the small intestine or MGI (median time of observation, 51 months). In PGL, localized disease was prognostic for EFS and OS. Histologic grade influenced only EFS significantly. Numbers in intestinal lymphomas were too small for subanalyses.

CONCLUSION: PGI NHL are heterogeneous diseases. The number of localized PGL allowed for detailed analyses. Larger studies are needed for stages III and IV and for intestinal NHL. A uniform reporting system for PGI NHL, in terms of definitions and histologic and staging classifications, is needed to facilitate comparison of treatment results.
Randomized Trial of Preoperative Chemoradiation Versus Surgery Alone in Patients With Locoregional Esophageal Carcinoma
Authors: Urba Susan G. , Orringer Mark B. , Turrisi Andrew , Iannettoni Mark , Forastiere Arlene , Strawderman Myla
Published: February 2017

PURPOSE: A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone.

MATERIALS AND METHODS: One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42.

RESULTS: At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power.

CONCLUSION: This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.
Response to Cyclophosphamide, Methotrexate, and Fluorouracil in Lymph Node–Positive Breast Cancer According to HER2 Overexpression and Other Tumor Biologic Variables
Authors: Ménard Sylvie , Valagussa Pinuccia , Pilotti Silvana , Gianni Luca , Biganzoli Elia , Boracchi Patrizia , Tomasic Gorana , Casalini Patrizia , Marubini Ettore , Colnaghi Maria I. , Cascinelli Natale , Bonadonna Gianni
Published: February 2017

PURPOSE: There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up.

PATIENTS AND METHODS: Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgroups defined by HER2 and the status of other variables using a Bayesian approach. The end points considered were relapse-free survival (RFS) and cause-specific survival (CSS).

RESULTS: Bayesian analysis of the treatment effect for HER2 and other variables indicated a clinical benefit from CMF treatment in all subgroups defined according to variables status. In particular regarding HER2 status, Bayesian estimates of RFS hazard ratios were equal to 0.484 and 0.641 and estimates of CSS hazard ratios were equal to 0.495 and 0.730 for HER2-positive and -negative tumors, respectively.

CONCLUSION: CMF treatment showed a clinical benefit in the considered subgroups, defined according to HER2 and other tumor variables status. Patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, and the poor prognosis associated with the HER2 overexpression in the untreated group could be completely overcome by the chemotherapy treatment.
Risks of Young Age for Selected Neurocognitive Deficits in Medulloblastoma Are Associated With White Matter Loss
Authors: Mulhern Raymond K. , Palmer Shawna L. , Reddick Wilburn E. , Glass John O. , Kun Larry E. , Taylor June , Langston James , Gajjar Amar
Published: February 2017

PURPOSE: To test the hypothesis that inadequate development of normal-appearing white matter (NAWM) is associated with the relationship between young age at the time of craniospinal irradiation (CRT) and deficient neurocognitive performance in survivors of childhood medulloblastoma.

PATIENTS AND METHODS: Forty-two patients treated since 1985 participated in this cross-sectional study. All had been treated with CRT with or without chemotherapy and had survived 1 or more years after treatment. Neurocognitive evaluations were conducted with tests of intellect (intelligent quotient; IQ), verbal memory, and sustained attention. Quantitative magnetic resonance imaging, using a hybrid neural network, assessed the volume of NAWM.

RESULTS: Neurocognitive test results were below normal expectations for age at the time of testing. A young age at CRT was significantly associated with worse performance on all neurocognitive tests except that of verbal memory. An increased time from completion of CRT was significantly associated with worse performance on all neurocognitive tests except that of sustained attention. After statistically controlling for the effects of time from CRT, we examined the association of NAWM with neurocognitive test results. These analyses revealed that NAWM accounted for a significant amount of the association between age at CRT and IQ, factual knowledge, and verbal and nonverbal thinking, but not sustained attention or verbal memory.

CONCLUSION: The present results suggest that, at least for some cognitive functions, deficient development and/or loss of NAWM after CRT may provide a neuroanatomical substrate for the adverse impact of a young age at the time of CRT.
Phase I and Pharmacokinetic Study of Photodynamic Therapy for High-Grade Gliomas Using a Novel Boronated Porphyrin
Authors: Rosenthal Mark A. , Kavar Bhadu , Hill John S. , Morgan Denis J. , Nation Roger L. , Stylli Stanley S. , Basser Russell L. , Uren Shannon , Geldard Howard , Green Michael D. , Kahl Stephen B. , Kaye Andrew H.
Published: February 2017

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of a novel boronated porphyrin (BOPP) for photodynamic therapy (PDT) of intracranial tumors.

PATIENTS AND METHODS: BOPP was administered alone in increasing doses (0.25, 0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg) preoperatively in patients with intracranial tumors undergoing postresection PDT until dose-limiting toxicity (DLT) was observed.

RESULTS: Twenty-nine assessable patients with intracranial tumors received BOPP intravenously 24 hours before surgery. The recommended dose was 4 mg/kg. Dose escalation was limited by thrombocytopenia. The most common nonhematologic toxicity was skin photosensitivity. Pharmacokinetic parameters showed increased area under the plasma concentration-time curve and maximum concentration with increased dose. Tumor BOPP concentrations also increased with increased dose.

CONCLUSION: BOPP at a dose of 4 mg/kg was well tolerated. DLT was thrombocytopenia, and photosensitivity was the only other toxicity of note. The efficacy of PDT using BOPP requires further exploration.
Comparison of Diameter and Perimeter Methods for Tumor Volume Calculation
Authors: Sorensen A. Gregory , Patel Shveta , Harmath Carla , Bridges Sarah , Synnott Jennifer , Sievers Amy , Yoon Young-Ho , Lee E. John , Yang Michael C. , Lewis Robert F. , Harris Gordon J. , Lev Michael , Schaefer Pamela W. , Buchbinder Bradley R. , Barest Glenn , Yamada Kei , Ponzo John , Kwon H. Young , Gemmete Joseph , Farkas Jeff , Tievsky Andrew L. , Ziegler Richard B. , Salhus Megan R.C. , Weisskoff Robert
Published: February 2017

PURPOSE: Lesion volume is often used as an end point in clinical trials of oncology therapy. We sought to compare the common method of using orthogonal diameters to estimate lesion volume (the diameter method) with a computer-assisted planimetric technique (the perimeter method).

METHODS: Radiologists reviewed 825 magnetic resonance imaging studies from 219 patients with glioblastoma multiforme. Each study had lesion volume independently estimated via the diameter and perimeter methods. Cystic areas were subtracted out or excluded from the outlined lesion. Inter- and intrareader variability was measured by using multiple readings on 48 cases. Where serial studies were available in noncystic cases, a mock response analysis was used.

RESULTS: The perimeter method had a reduced interreader and intrareader variability compared with the diameter method (using SD of differences): intrareader, 1.76 mL v 7.38 mL (P < .001); interreader, 2.51 mL v 9.07 mL (P < .001) for perimeter and diameter results, respectively. Of the 121 noncystic cases, 23 had serial data. In six (26.1%) of those 23, a classification difference occurred when the perimeter method was used versus the diameter method.

CONCLUSION: Variability of measurements was reduced with the computer-assisted perimeter method compared with the diameter method, which suggests that changes in volume can be detected more accurately with the perimeter method. The differences between these techniques seem large enough to have an impact on grading the response to therapy.