bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Etoposide for Refractory and Relapsed Neuroblastoma
Authors: Kushner Brian H. , Kramer Kim , Cheung Nai-Kong V.
Published: February 2017

PURPOSE: To describe the efficacy of oral etoposide against resistant stage 4 neuroblastoma.

PATIENTS AND METHODS: Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide 50 mg/m2 taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Extent-of-disease studies included imaging with 131-iodine-metaiodobenzylguanidine and extensive bone marrow (BM) sampling.

RESULTS: Oral etoposide was used in 20 children between the ages of 2 and 11 years (median, 6 years). Prior treatment included high doses of alkylating agents and a median of 4.5 cycles of etoposide-containing chemotherapy, with cumulative etoposide doses of 1,800 mg/m2 to 3,935 mg/m2 (median, 2,300 mg/m2). Oral etoposide produced antineuroblastoma effects in four of four children with disease refractory to intensive induction treatment; sampling variability could account for resolution (n = 3) or reduction (n = 1) of BM involvement, but improvement in other markers also occurred. Antineuroblastoma effects were also evident in five of five children with asymptomatic relapses after a long chemotherapy-free interval: BM disease resolved and all other disease markers significantly improved in two patients, and disease markers improved or stabilized in three patients on treatment for more than 6 months. In these nine patients, extramedullary toxicity was absent, neutropenia did not occur, transfusional support was not needed, and preliminary data suggested little immunosuppression (phytohemagglutinin responses). Oral etoposide was ineffective in all (11 of 11) patients with rapidly growing tumor masses.

CONCLUSION: Given the absence of toxicity to major organs, the minimal myelosuppression or immunosuppression, and the antineoplastic activity in patients with low tumor burdens after high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.
Long-Term Outcomes After Function-Sparing Surgery Without Radiotherapy for Soft Tissue Sarcoma of the Extremities and Trunk
Authors: Baldini Elizabeth H. , Goldberg Joel , Jenner Christopher , Manola Judith B. , Demetri George D. , Fletcher Christopher D.M. , Singer Samuel
Published: February 2017

PURPOSE: To define the rate of local recurrence (LR) and identify prognostic factors for LR for patients with soft tissue sarcoma (STS) treated with function-sparing surgery (FSS) without radiotherapy (RT).

PATIENTS AND METHODS: Between 1970 and 1994, 242 patients with STS of the trunk and extremity presented with primary localized disease, 74 of whom were treated with FSS without RT (31%). The median tumor size was 4 cm (range, 0.5 to 31 cm). There were 40 patients with grade 1 tumors and 34 with grade 2 and 3 tumors. Median follow-up was 126 months.

RESULTS: The 10-year actuarial local control rate was 93% ± 4%. Resection margin status was a significant predictor for LR. Patients with closest histologic resection margins of less than 1 cm had a 10-year local control rate of 87% ± 6% compared with 100% for patients with closest histologic resection margins of ≥ 1 cm (P = .04). There was no significant association between LR and tumor grade, size, site (truncal v extremity), or depth (superficial v deep). For all patients, the 10-year actuarial survival rate was 73% ± 6%.

CONCLUSION: The 7% LR rate after treatment of STS with FSS without RT reported herein is comparable to published rates following treatment where adjuvant RT is used. These results suggest there may be a select subset of patients with STS in whom carefully performed FSS may serve as definitive therapy and in whom adjuvant RT may not be necessary. However, further study is needed to carefully define this subset of patients and to identify the optimal surgical approach and technique for patients treated without RT.
Neoadjuvant Chemotherapy With Doxorubicin and Cisplatin in Malignant Fibrous Histiocytoma of Bone: A European Osteosarcoma Intergroup Study
Authors: Bramwell Vivien H.C. , Steward William P. , Nooij Marianne , Whelan Jeremy , Craft Alan W. , Grimer Robert J. , Taminau Antonie H.M. , Cannon Steven R. , Malcolm Archie J. , Hogendoorn Pancras C.W. , Uscinska Barbara , Kirkpatrick Anne L. , Machin David , Van Glabbeke Martine M.
Published: February 2017

PURPOSE: Studies involving small case series have suggested that malignant fibrous histiocytoma of bone (MFH-B) is a chemosensitive tumor and that chemotherapy may improve survival. In this study, we evaluated clinical and pathologic response rates and survival in a series of patients treated with a consistent chemotherapy regimen of doxorubicin and cisplatin (DOX/DDP).

PATIENTS AND METHODS: Study patients were required to have biopsy-proven MFH-B, no previous chemotherapy, and primary or metastatic measurable disease and to be ≤ 65 years of age. Treatment consisted of doxorubicin 25 mg/m2/d days 1 through 3 and cisplatin 100 mg/m2 by 4-hour intravenous infusion every 3 weeks for six cycles. In patients with operable primary tumors, chemotherapy was planned to start within 42 days of biopsy, with definitive surgery performed after three cycles.

RESULTS: Forty-one patients had operable nonmetastatic limb sarcomas, and 23 (56%) completed six chemotherapy cycles. Limb salvage was possible in 33 patients (80%), and 16 (42%) of 38 assessable specimens showed a good pathologic response (≥ 90% necrosis). Median time to progression was 56 months, and the 5-year progression-free survival rate was 56% (95% confidence interval [CI], 40% to 72%). Median survival time was 63 months, and the 5-year survival rate was 59% (95% CI, 41% to 77%). Patients with a good pathologic response had longer survival times and times to progression than did those with a poor response. Also treated were two patients with locally recurrent and nine with metastatic disease, and these patients had a median survival time of 17.5 months.

CONCLUSION: Our study suggests that adjuvant or neoadjuvant chemotherapy with DOX/DDP is beneficial in MFH-B. Good pathologic response rates and survivals are quite comparable with those for osteosarcoma, a related bone tumor for which adjuvant or neoadjuvant chemotherapy is an accepted practice.
Immunotherapy of Advanced Malignancy by Direct Gene Transfer of an Interleukin-2 DNA/DMRIE/DOPE Lipid Complex: Phase I/II Experience
Authors: Galanis E. , Hersh E. M. , Stopeck A. T. , Gonzalez R. , Burch P. , Spier C. , Akporiaye E. T. , Rinehart J. J. , Edmonson J. , Sobol R. E. , Forscher C. , Sondak V. K. , Lewis B. D. , Unger E. C. , O'Driscoll M. , Selk L. , Rubin J.
Published: February 2017

PURPOSE: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl-phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally.

PATIENTS AND METHODS: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 μg, 30 μg, or 300 μg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 μg twice a week for 3 weeks, 750 μg weekly for 6 weeks, and 1,500 μg weekly for 6 weeks.

RESULTS: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority ofpatients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8+ infiltration after treatment in the tumor samples of several patients (12 and 16, respectively).

CONCLUSION: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.
Strategic Physician Communication and Oncology Clinical Trials
Authors: Albrecht Terrance L. , Blanchard Christina , Ruckdeschel John C. , Coovert Michael , Strongbow Rebecca
Published: February 2017

PURPOSE: Clinical trials are the primary means for determining new, effective treatments for cancer patients, yet the number of patients that accrue is relatively limited. The purpose of this study was to explore the relationship between physician behavior and patient accrual to a clinical trial by videotaping the interaction.

PATIENTS AND METHODS: Forty-eight patient-physician interactions involving 12 different oncologists were videotaped in several clinics at the H. Lee Moffitt Cancer Center and Research Institute (Tampa, FL). The purpose of each interaction was to present the possibility of a clinical trial to the patient. A coding system, the Moffitt Accrual Analysis System, was developed by the authors to code behaviors that represented both the legal-informational and social influence models of communication behavior. Thirty-two patients agreed to participate in the clinical trial.

RESULTS: Videotaping was found to be a viable, valid, and reliable method for studying the interaction. Physicians who were observed to use both models of influence were found to enroll more patients. Thus, patients were more likely to accrue to the trial when their physician verbally presented items normally included in an informed consent document and when they behaved in a reflective, patient-centered, supportive, and responsive manner. Discussion of benefits, side effects, patient concerns and resources to manage the concerns were all associated with accrual.

CONCLUSION: This research has implications for modifying physician behavior and, thus, increasing the numbers of patients accruing to oncology clinical trials.
Randomized Trial of 3-Hour Versus 24-Hour Infusion of High-Dose Paclitaxel in Patients With Metastatic or Locally Advanced Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26
Authors: Smith Roy E. , Brown Ann M. , Mamounas Eleftherios P. , Anderson Stewart J. , Lembersky Barry C. , Atkins James H. , Shibata Henry R. , Baez Luis , DeFusco Patricia A. , Davila Enrique , Tipping Stuart J. , Bearden James D. , Thirlwell Michael P.
Published: February 2017

PURPOSE: Paclitaxel is an active drug for the treatment of breast cancer; however, the appropriate duration of administration is unknown. We assessed and compared the response rate, event-free survival, survival, and toxicity of paclitaxel 250 mg/m2 delivered every 3 weeks as a 3-hour or 24-hour infusion.

PATIENTS AND METHODS: A total of 563 women with stage IV or IIIB breast cancer were randomized into one of two groups: 279 received 3-hour paclitaxel and 284 received 24-hour paclitaxel. Patients were stratified by age, stage of disease, and prior therapy.

RESULTS: A significantly higher rate of tumor response occurred in the first four cycles of therapy in patients who received the 24-hour infusion of paclitaxel (51% v 41%, respectively; P = .025). Tumor response over all cycles was also significantly higher in the group that received 24-hour infusion (54% v 44%, respectively; P = .023). There were no significant differences in event-free survival or survival between the two arms of the study (P = .9 and .8, respectively). No treatment by stage or by age interactions were observed. During the first four cycles of therapy, at least one episode of ≥ grade 3 toxicity (excluding nadir hematologic values, alopecia, and weight change) occurred in 45% of patients who received the 3-hour paclitaxel infusion and in 50% of those who received the 24-hour paclitaxel infusion. Febrile neutropenia, ≥ grade 3 infection, and ≥ grade 3 stomatitis were less frequent, and severe neurosensory toxicity was more frequent in those who received the 3-hour paclitaxel infusion. Ten treatment-related deaths occurred in the first four cycles. Age, stage, and prior chemotherapy did not influence the effect of treatment.

CONCLUSION: When administered as a continuous 24-hour infusion, high-dose paclitaxel results in a higher tumor response rate than when administered as a 3-hour infusion but does not significantly improve event-free survival or survival. Paclitaxel as a 24-hour infusion results in increased hematologic toxicity and decreased neurosensory toxicity.
Multicenter, Phase II Trial of Exemestane as Third-Line Hormonal Therapy of Postmenopausal Women With Metastatic Breast Cancer
Authors: Jones S. , Vogel C. , Arkhipov A. , Fehrenbacher L. , Eisenberg P. , Cooper B. , Honig S. , Polli A. , Whaley F. , di Salle E. , Tiffany J. , Consonni A. , Miller L.
Published: February 2017

PURPOSE: To assess the antitumor activity, safety, and hormone-suppressive effects of the irreversible aromatase inactivator, exemestane (Aromasin, Pharmacia & Upjohn, Kalamazoo, MI), administered as third-line hormone therapy to postmenopausal women with metastatic breast cancer that is refractory to tamoxifen and megestrol acetate.

PATIENTS AND METHODS: Exemestane was administered at a dose of 25 mg/d orally until patients experienced disease progression. The efficacy and safety of exemestane were clinically and radiographically evaluated. The impact of exemestane treatment on tumor-related signs and symptoms was assessed. The effect of exemestane on serum levels of estrogens and other steroidal hormones was determined.

RESULTS: Ninety-one patients were treated. There were four complete responses (CR) and eight partial responses (PR), for an objective response rate of 13% in the entire treated population. The overall success rate (CR, PR, or stable disease [SD] ≥ 24 weeks) was 30%. The median duration of response and overall success was 9 months and 8 months, respectively. Most patients with CR/PR (83%; 10 of 12 patients) and SD ≥ 24 weeks (80%; 12 of 15 patients) had improved or stable tumor-related signs and symptoms. Mean levels of circulating estrone (E1), estradiol (E2), and estrone sulfate decreased to 11%, 22%, and 13% of baseline levels, respectively (at week 8 or 16 of treatment). One half of the patients had undetectable E1 and E2 levels during treatment, including at the time of disease progression. Mild nausea (20% of patients) and hot flashes (20%) were the most common drug-related adverse events and were generally grade 1.

CONCLUSION: Exemestane is an active and well-tolerated third-line hormonal therapy that represents a new treatment option for postmenopausal patients with advanced breast cancer that has become refractory to standard first- and second-line hormonal therapies.
Positron Emission Tomography Scans in the Evaluation of Postchemotherapy Residual Masses in Patients With Seminoma
Authors: Ganjoo Kristen N. , Chan Rebecca J. , Sharma Matt , Einhorn Lawrence H.
Published: February 2017

PURPOSE: To assess the ability of positron emission tomography (PET) scans in differentiating between necrosis and viable seminoma in postchemotherapy (PC) residual disease.

PATIENTS AND METHODS: We conducted a prospective study of 29 patients with seminoma at Indiana University. All patients had PC residual disease. Computed tomography and PET scans were performed for 19 patients after primary chemotherapy (group A) and for 10 patients after salvage chemotherapy (group B).

RESULTS: In group A, the PC masses were ≥ 3 cm in 14 patients, less than 3 cm in three patients, and not quantified in two patients. All of the patients in group A had negative PET scan results and have had stable or decreasing residual mass size (median follow-up duration, 11.5 months; range, 6 to 26 months). In group B, the PC masses were ≥ 3 cm in four patients, less than 3 cm in five patients, and not quantified in one patient. One patient had a positive PET scan result for a posterior mediastinal mass. Pathologic diagnosis of the PET-positive mass showed only necrotic tissue. The same patient had a negative PET scan of the retroperitoneal mass but relapsed in that area. Overall, of patients in group B, five have stable or decreasing mass (median follow-up duration, 8 months; range, 7 to 22 months), and five had relapsed disease.

CONCLUSION: PET scans have no apparent benefit in PC evaluation of residual masses in bulky seminoma.
Indications for Radiotherapy and Chemotherapy After Complete Resection in Rhabdomyosarcoma: A Report From the Intergroup Rhabdomyosarcoma Studies I to III
Authors: Wolden Suzanne L. , Anderson James R. , Crist William M. , Breneman John C. , Wharam, Jr Moody D. , Wiener Eugene S. , Qualman Stephen J. , Donaldson Sarah S.
Published: February 2017

PURPOSE: To evaluate the outcome of patients with rhabdomyosarcoma (RMS) treated with complete surgical resection and multiagent chemotherapy, with or without local radiotherapy (RT).

PATIENTS AND METHODS: Four hundred thirty-nine patients with completely resected (ie, group I) RMS were further treated with chemotherapy (vincristine and actinomycin D ± cyclophosphamide, doxorubicin, and cisplatin) on Intergroup Rhabdomyosarcoma Studies (IRS) I to III between 1972 and 1991. Eighty-three patients (19%) also received local RT as a component of initial treatment.

RESULTS: Eighty-six patients relapsed (10-year failure-free survival [FFS] 79%, overall survival 89%). Six percent of failure sites were local, 6% were regional, and 7% were distant. Poor prognostic factors were tumor size greater than 5 cm, alveolar or undifferentiated histology, primary tumor sites other than genitourinary, and treatment on IRS-I or II. For patients with embryonal RMS who were treated with RT, there was a trend for improved FFS but no difference in overall survival. On IRS-I and II, patients with alveolar or undifferentiated sarcoma who received RT compared with those who did not receive RT had greater 10-year FFS rates (73% v 44%, respectively; P = .03) and overall survival rates (82% v 52%, respectively; (P = .02). Such patients who received RT on IRS III also benefited more than those who did not receive RT (10-year FFS, 95% v 69%; P = .01; overall survival, 95% v 86%; P = .23).

CONCLUSION: Patients with group I embryonal RMS have an excellent prognosis when treated with adjuvant multiagent chemotherapy without RT. Patients with alveolar RMS or undifferentiated sarcoma fare worse; however, FFS and overall survival are substantially improved when RT is added to multiagent chemotherapy (IRS-I and II). The best outcome occurred in IRS-III, when RT was used in conjunction with intensified chemotherapy.
Phase II Trial of Docetaxel, Cisplatin, Fluorouracil, and Leucovorin as Induction for Squamous Cell Carcinoma of the Head and Neck
Authors: Colevas A. D. , Norris C. M. , Tishler R. B. , Fried M. P. , Gomolin H. I. , Amrein P. , Nixon A. , Lamb C. , Costello R. , Barton J. , Read R. , Adak S. , Posner M. R.
Published: February 2017

PURPOSE: To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL4) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN).

PATIENTS AND METHODS: Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4. Postchemotherapy support included prophylactic growth factors and antibiotics. Patients who achieved a complete response (CR) or partial response (PR) to three cycles of TPFL4 received definitive twice-daily radiation therapy. The primary end points were toxicity and response to TPFL4.

RESULTS: Eighty-five cycles were administered to 30 patients. The major acute toxicities to TPFL4 were mucositis and nausea. One patient died of neutropenic sepsis during therapy. Additional major toxicities were neutropenia, anorexia, nephropathy, neuropathy, and diarrhea. Fourteen percent of all cycles were associated with hospitalization for toxicity. The overall clinical response rate to TPFL4 was 93%, with 63% CRs and 30% PRs. Primary tumor site clinical and pathologic response rates were 93% and 68%, respectively.

CONCLUSION: TPFL4 has an acceptable toxicity profile in good-performance-status patients. Modification of the 5-day TPFL regimen (TPFL5: shorter chemotherapy infusion time, earlier intervention with growth factors and antibiotics) led to fewer episodes of febrile neutropenia and hospitalization. Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials.
Quality-of-Life Measurement in Advanced Cancer: Assessing the Individual
Authors: Waldron Dympna , O'Boyle Ciaran A. , Kearney Michael , Moriarty Michael , Carney Desmond
Published: February 2017

PURPOSE: Despite the increasing importance of assessing quality of life (QoL) in patients with advanced cancer, relatively little is known about individual patient's perceptions of the issues contributing to their QoL. The Schedule for the Evaluation of Individual Quality of Life (SEIQoL) and the shorter SEIQoL–Direct Weighting (SEIQoL-DW) assess individualized QoL using a semistructured interview technique. Here we report findings from the first administration of the SEIQoL and SEIQoL-DW to patients with advanced incurable cancer.

PATIENTS AND METHODS: QoL was assessed on a single occasion using the SEIQoL and SEIQoL-DW in 80 patients with advanced incurable cancer.

RESULTS: All patients were able to complete the SEIQoL-DW, and 78% completed the SEIQoL. Of a possible score of 100, the median QoL global score was as follows: SEIQoL, 61 (range, 24 to 94); SEIQoL-DW, 60.5 (range, 6 to 95). Psychometric data for SEIQoL indicated very high levels of internal consistency (median r = .90) and internal validity (median R2= 0.88). Patients' judgments of their QoL were unique to the individual. Family concerns were almost universally rated as more important than health, the difference being significant when measured using the SEIQoL-DW (P = .002).

CONCLUSION: Patients with advanced incurable cancer were very good judges of their QoL, and many patients rated their QoL as good. Judgments were highly individual, with very high levels of consistency and validity. The primacy given to health in many QoL questionnaires may be questioned in this population. The implications of these findings are discussed with regard to clinical assessment and advance directives.
Subjective and Objective Prospective, Long-Term Analysis of Quality of Life During Inhaled Interleukin-2 Immunotherapy
Authors: Heinzer Hans , Mir Thomas S. , Huland Edith , Huland Hartwig
Published: February 2017

PURPOSE: We conducted both a subjective and objective, prospective quality-of-life analysis during high-dose (36 × 106immunizing units/d) inhalational interleukin (IL)-2 treatment (mean treatment time, 13.4 months) of 15 patients with metastatic renal cell carcinoma (mRCC). Additionally, quality of life for 10 patients with mRCC receiving low-dose (9 × 106IU/m2/d for 5 days) intravenous IL-2 treatment also was evaluated.

PATIENTS AND METHODS: Patients responded to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30 before and during inhalational IL-2 treatment at 1, 3, 6, 9, and 12 months and before and once during intravenous IL-2 treatment. A clinician assessed patient well-being using the Quality of Well-Being scale to calculate once weekly quality-adjusted life-years (QALYs) during inhalational IL-2 treatment.

RESULTS: Patients completed 103 questionnaires and clinicians performed 892 QALY calculations. For patients treated with inhalational IL-2, the mean quality-of-life score deteriorated modestly but significantly 1 month after treatment initiation (15.1%, P = .01) but did not differ significantly from pretreatment scores after 3, 6, 9, and 12 months of treatment. Inhalational IL-2 therapy stabilized patient quality of life for a mean of 13.4 months. The resulting QALY calculation for patients on inhalation IL-2 was 70.1% of 13.4 months, representing 9.4 months of QALY. In comparison, patients who received intravenous IL-2 showed a more marked, statistically significant deterioration in mean quality-of-life score during treatment (27%, P = .006); moreover, three of these 10 patients experienced treatment-related toxicity that prevented questionnaire completion.

CONCLUSION: Quality-of-life analysis during immunotherapy provides valuable information regarding cancer treatment outcomes.
Breast Carcinomas Arising in Carriers of Mutations in BRCA1 or BRCA2: Are They Prognostically Different?
Authors: Phillips Kelly-Anne , Andrulis Irene L. , Goodwin Pamela J.
Published: February 2017

PURPOSE: To review the preclinical and clinical studies relevant to the prognosis and prognostic associations of BRCA1- and BRCA2-associated breast carcinomas, with an emphasis on research methodology.

METHODS: Reports of relevant studies obtained from a MEDLINE search, and references from these articles, were critically reviewed.

RESULTS: Consistent associations with both favorable (medullary or atypical medullary carcinoma) and unfavorable (high tumor grade, hormone receptor negativity, somatic p53 mutation) prognostic characteristics have been found for BRCA1-associated breast carcinomas. Inconsistent results have been demonstrated for prognostic associations of BRCA2-associated breast tumors. Clinical studies that have directly assessed the prognosis of these tumors have not shown a clear effect of BRCA1 or BRCA2 mutation, but no study has used optimal methodology. In vitro and animal model data suggest a possible influence of these mutations on response to agents that cause double-strand DNA breaks, but clinical data are limited.

CONCLUSION: The elucidation of an identifiable subgroup of breast carcinomas that result from germline mutations in BRCA1 or BRCA2 may be an important step toward genotype-based understanding of prognosis and choice of therapy in this disease. However, currently there are inadequate data to support use of BRCA1 or BRCA2 status to counsel individuals regarding their prognosis or to select treatment. Well-designed studies of population-based inception cohorts of breast cancer patients, which have adequate sample size and complete follow-up, and which use objective outcome criteria and blinding of outcome assessment, are required to optimally address this question.
Survival and Neurodevelopmental Outcome of Young Children With Medulloblastoma at St Jude Children's Research Hospital
Authors: Walter Andrew W. , Mulhern Raymond K. , Gajjar Amar , Heideman Richard L. , Reardon David , Sanford R. Alex , Xiong Xiaoping , Kun Larry E.
Published: February 2017

PURPOSE: Young children treated for medulloblastoma are at especially high risk for morbidity and mortality from their disease and therapy. This study sought to assess the relationship, if any, between patient outcome and M stage. Neuropsychologic and endocrine outcomes were also assessed.

PATIENTS AND METHODS: Twenty-nine consecutively diagnosed infants and young children were treated for medulloblastoma at St Jude Children's Research Hospital between November 1984 and December 1995. All patients were treated with the intent of using postoperative chemotherapy to delay planned irradiation.

RESULTS: The median age at diagnosis was 2.6 years. Six patients completed planned chemotherapy without progressive disease and underwent irradiation at completion of chemotherapy. Twenty-three children experienced disease progression during chemotherapy and underwent irradiation at the time of progression. The 5-year overall survival rate for the entire cohort was 51% ± 10%. The 5-year progression-free survival rate was 21% ± 8%. M stage did not impact survival. All patients lost cognitive function during and after therapy at a rate of −3.9 intelligence quotient points per year (P = .0028). Sensory functions declined significantly after therapy (P = .007). All long-term survivors required hormone replacement therapy and had growth abnormalities.

CONCLUSION: The majority of infants treated for medulloblastoma experienced disease progression during initial chemotherapy. However, more than half of these patients can be cured with salvage radiation therapy, regardless of M stage. The presence of metastatic disease did not increase the risk of dying from medulloblastoma. All patients treated in this fashion have significant neuropsychologic deficits. Our experience demonstrates that medulloblastoma in infancy is a curable disease, albeit at a significant cost.
Total-Body Irradiation and Melphalan Is a Safe and Effective Conditioning Regimen for Autologous Bone Marrow Transplantation in Children With Acute Myeloid Leukemia in First Remission
Authors: Bonetti F. , Zecca M. , Pession A. , Messina C. , Montagna D. , Lanino E. , Fagioli F. , Santoro N. , Prete A. , Cesaro S. , Rondelli R. , Giorgiani G. , De Stefano P. , Locatelli F.
Published: February 2017

PURPOSE: To evaluate the safety and efficacy of a preparative regimen consisting of fractionated total-body radiation (9.9 to 12 Gy) and melphalan (140 mg/m2 in a single dose) in children with acute myeloid leukemia in first complete remission (CR) given autologous bone marrow transplantation (ABMT).

PATIENTS AND METHODS: Fifty-three children (30 males and 23 females; age range, 1.5 to 18 years) were enrolled onto the study. The median time from first CR to ABMT was 3.5 months (range, 1.4 to 13 months), with 45 patients (85%) undergoing transplantation within 6 months from the diagnosis. Forty-five patients received in vitro marrow purging with standard-dose mafosfamide (100 μg/mL), seven patients were treated with interleukin-2 before marrow collection, and in the remaining child, the marrow was unmanipulated. The median infused cell dose was 1.8 × 108/kg (range, 0.4 to 5.8 × 108/kg).

RESULTS: All patients but one achieved hematopoietic engraftment, with a median time to neutrophil recovery of 24 days (range,11 to 66 days). Treatment-related toxicity was moderate and consisted mainly of mucositis. One patient died from cytomegalovirus interstitial pneumonia, and one died from pulmonary hemorrhage. Fourteen patients (26%) relapsed at a median time of 6 months after ABMT (range, 2 to 17 months), with a cumulative relapse probability of 29% (95% confidence interval, 16% to 42%). The 5-year Kaplan-Meier estimate of survival for all 53 patients was 78% (range, 65% to 90%), whereas the overall 5-year disease-free survival was 68% (range, 55% to 81%), with a median follow-up duration of 40 months (range, 7 to 130 months).

CONCLUSIONS: These data suggest that, in our cohort of patients, the combination of total-body irradiation and melphalan is safe and associated with good antileukemia activity, making ABMT an appealing alternative for postremission therapy in children with acute myeloid leukemia in first CR.
Expression of Aberrantly Spliced Oncogenic Ikaros Isoforms in Childhood Acute Lymphoblastic Leukemia
Authors: Sun Lei , Goodman Patricia A. , Wood Carla M. , Crotty Mya-Lisa , Sensel Martha , Sather Harland , Navara Christopher , Nachman James , Steinherz Peter G. , Gaynon Paul S. , Seibel Nita , Vassilev Alexei , Juran Brian D. , Reaman Gregory H. , Uckun Fatih M.
Published: February 2017

PURPOSE: We sought to determine if molecular abnormalities involving the Ikaros gene could contribute to the development of acute lymphoblastic leukemia (ALL) in children.

PATIENTS AND METHODS: We studied Ikaros gene expression in normal human bone marrow, normal thymocytes, normal fetal liver–derived immature lymphocyte precursor cell lines, eight different ALL cell lines, and leukemic cells from 69 children with ALL (T-lineage ALL, n = 18; B-lineage ALL, n = 51). Expression of Ikaros protein and its subcellular localization were examined by immunoblotting and confocal laser-scanning microscopy, respectively. Polymerase chain reaction (PCR) and nucleotide sequencing were used to identify the specific Ikaros isoforms expressed in these cells. Genomic sequencing of splice junction regions of the Ikaros gene was performed in search for mutations.

RESULTS: In each of the ALL cases, we found high-level expression of a non–DNA-binding or aberrant DNA-binding isoform of Ikaros with abnormal subcellular compartmentalization patterns. In contrast, only wild-type Ik-1 and Ik-2 isoforms with normal subcellular localization were found in normal bone marrow cells and thymus-derived or fetal liver–derived normal lymphocyte precursors. In leukemic cells expressing the aberrant Ikaros coding sequences with the 30-base-pair deletion, genomic sequence analysis of the intron-exon junctions between exons 6 and 7 yielded the wild-type sequence. We identified a single nucleotide polymorphism (SNP) affecting the third base of the triplet codon for a proline (CCC or CCA) in the highly conserved bipartite activation region (viz, A or C at position 1002 numbering from the translation start site of Ik-1) within our Ikaros clones. Bi-allelic expression of truncated and/or non–DNA-binding isoforms along with wild-type isoforms was observed in leukemic cells, which implicates trans-acting factor(s) affecting splice site recognition.

CONCLUSION: Our findings link specific molecular defects involving the Ikaros gene to childhood ALL. Posttranscriptional regulation of alternative splicing of Ikaros RNA seems to be defective in leukemic lymphocyte precursors from most children with ALL. Consequently, leukemic cells from ALL patients, in contrast to normal lymphocyte precursors, express high levels of non–DNA-binding Ikaros isoforms that are reminiscent of the non–DNA-binding Ikaros isoforms that lead to lymphoblastic leukemia in mice.
Gemcitabine as a Single Agent in the Treatment of Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma
Authors: Fosså A. , Santoro A. , Hiddemann W. , Truemper L. , Niederle N. , Buksmaui S. , Bonadonna G. , Seeber S. , Nowrousian M. R.
Published: February 2017

PURPOSE: A multicenter phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL).

PATIENTS AND METHODS: Thirty-one patients with B-cell intermediate or high-grade NHL (Working Formulation) were enrolled onto the study. The median age was 61 years, with a Karnofsky performance status of ≤ 80% in 65% of patients. Forty-eight percent had stage III or IV (Ann Arbor Classification) at study entry. Pretreatment consisted of one, two, or three chemotherapeutic regimens in nine, 11, and 11 patients, respectively. Gemcitabine 1,250 mg/m2 was administered intravenously over 30 minutes on days 1, 8, and 15 of a 28-day schedule.

RESULTS: Thirty patients were assessable for efficacy, and 31 were assessable for toxicity. No complete responses were observed, but six patients showed a partial response, 11 stable disease, and 13 progressive disease. The overall response rate was 20% (95% confidence interval, 8% to 39%) for assessable patients and 19% (95% confidence interval, 8% to 34%) for the intent-to-treat analysis. The median duration of partial response was 6 months (range, 3.7 to 15+ months). Nonhematologic World Health Organization grade 3 toxicity included hepatic toxicity in four patients and infection in two. Hematologic toxicity was observed as grade 3 anemia in three patients, grade 3 leukopenia in two patients, grade 3/4 neutropenia in two patients, and grade 3/4 thrombocytopenia in six patients.

CONCLUSION: The present schedule of gemcitabine displays modest efficacy and mild toxicity in pretreated aggressive NHL.
Phase I/II Trial of IDEC-Y2B8 Radioimmunotherapy for Treatment of Relapsed or Refractory CD20+B-Cell Non-Hodgkin's Lymphoma
Authors: Witzig Thomas E. , White Christine A. , Wiseman Gregory A. , Gordon Leo I. , Emmanouilides Christos , Raubitschek Andrew , Janakiraman Nalini , Gutheil John , Schilder Russell J. , Spies Stewart , Silverman Daniel H.S. , Parker Elizabeth , Grillo-López Antonio J.
Published: February 2017

PURPOSE: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy.

PATIENTS AND METHODS: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20+B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass ≥ 5 cm.

RESULTS: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/μL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease (≥ 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody).

CONCLUSION: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.
Classical Hodgkin's Disease and Follicular Lymphoma Originating From the Same Germinal Center B Cell
Authors: Marafioti Theresa , Hummel Michael , Anagnostopoulos Ioannis , Foss Hans-Dieter , Huhn Dieter , Stein Harald
Published: February 2017

PURPOSE: Classical Hodgkin's disease and non-Hodgkin's B-cell lymphoma occasionally occur in the same patient. To clarify whether these different diseases share a common precursor cell, we analyzed the immunoglobulin rearrangements in tumor cells of the classical Hodgkin's disease and the follicular lymphoma that developed in the same patient 2 years apart.

PATIENTS AND METHODS: Polymerase chain reaction (PCR) for the detection of rearranged immunoglobulin genes was carried out on single Reed-Sternberg cells and on whole tissue DNA extracted from the follicular lymphoma. PCR products were sequenced and compared with each other and with germ line immunoglobulin variable segments. Immunoglobulin heavy- and light-chain transcripts were analyzed by radioactive in-situ hybridization.

RESULTS: The same monoclonal immunoglobulin gene rearrangement was found in both neoplasms. The variable region of the immunoglobulin heavy-chain genes of the Reed-Sternberg and of the follicular lymphoma cells were differently mutated, but six somatic mutations were shared by both lymphoma cells. Although the coding capacity of the immunoglobulin genes was preserved in both neoplastic cell populations, immunoglobulin heavy- (μ) and light- (κ) chain expression was restricted to the follicular lymphoma cells, except for small amounts of kappa light-chain mRNA in some Reed-Sternberg cells.

CONCLUSIONS: The neoplastic cells of the Hodgkin's disease and the follicular lymphoma that occurred in this patient derived from a common precursor B cell. Its differentiation stage could be identified as that of a germinal center B cell. Thus, transforming events can be more important than the cell of origin in determining a disease entity.
Comparison of Mitotic Index, In Vitro Bromodeoxyuridine Labeling, and MIB-1 Assays to Quantitate Proliferation in Breast Cancer
Authors: Thor Ann D. , Liu Shuqing , Moore II Dan H. , Edgerton Susan M.
Published: February 2017

PURPOSE: To investigate the hypothesis that in vitro bromodeoxyuridine (BrDu) labeling might be superior to MIB-1 immunostaining for prognostic value, because it more selectively labels cells during the S phase.

METHODS: Four hundred eighty-six patients with breast cancers (59% lymph node-negative, 41% lymph node-positive) surgically excised between 1988 and 1993 (median follow-up, 62 months) were evaluated for cellular proliferation using prospective in vitro BrDu uptake assays, retrospective mitotic indices, and MIB-1 labeling.

RESULTS: MIB-1, BrDu labeling, and mitotic index–derived proliferation data were highly correlated. Each was similarly associated with most other markers of prognosis, although these relationships were not identical. By univariate analysis, nodal status was the most significant prognostic variable for all patients. Higher BrDu labeling index, MIB-1 immunolabeling, and mitotic index were also associated with shortened disease-free survival (DFS) and disease-specific survival for the entire patient group, as well as for node-negative patients. The association between cellular proliferation and survival was much weaker for node-positive patients. Multivariate models confirmed that nodal status, tumor size, and proliferation data predicted survival in all patients as well as those with node-negative disease, although MIB-1 was somewhat more closely associated with outcome than mitotic index or in vitro BrDu data. For patients with T1N0M0 disease (n = 172), the only significant predictors of DFS were proliferation rate (mitotic index or MIB-1) and tumor grade.

CONCLUSIONS: Proliferation rate predicts recurrence and survival in breast cancer. This effect is more pronounced in node-negative patients. In vitro BrDu data are not superior to MIB-1 and mitotic counting.
Randomized Phase II Study of BR96-Doxorubicin Conjugate in Patients With Metastatic Breast Cancer
Authors: Tolcher Anthony W. , Sugarman Steven , Gelmon Karen A. , Cohen Roger , Saleh Mansoor , Isaacs Claudine , Young Leslie , Healey Diane , Onetto Nicole , Slichenmyer William
Published: February 2017

PURPOSE: BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric human/mouse monoclonal antibody linked to approximately eight doxorubicin molecules. The antibody is directed against the Lewis-Y antigen, which is expressed on 75% of all breast cancers but is limited in expression on normal tissues. Preclinical xenograft models demonstrated significant antitumor activity, including cures. A randomized phase II design was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer in a study population with confirmed sensitivity to single-agent doxorubicin.

PATIENTS AND METHODS: Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m2 IV over 24 hours or doxorubicin 60 mg/m2 every 3 weeks. Patients were stratified on the basis of prior doxorubicin exposure, visceral disease, and institution. Cross-over to the opposite treatment arm was allowed with progressive or persistently stable disease.

RESULTS: Twenty-three patients who had received a median of one prior chemotherapy regimen were assessable. There was one partial response (7%) in 14 patients receiving the BR96-doxorubicin conjugate and one complete response and three partial responses (44%) in nine assessable patients receiving doxorubicin. No patient experienced a clinically significant hypersensitivity reaction. The toxicities were significantly different between the two treatment groups, with the BR96-doxorubicin conjugate group having limited hematologic toxicity, whereas gastrointestinal toxicities, including marked serum amylase and lipase elevations, nausea, and vomiting with gastritis, were prominent.

CONCLUSION: The BR96-doxorubicin immunoconjugate has limited clinical antitumor activity in metastatic breast cancer. The gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the target antigen and may have compromised the delivery of the immunoconjugate to the tumor sites.
Sarcomatoid Renal Cell Carcinoma: Biologic Behavior, Prognosis, and Response to Combined Surgical Resection and Immunotherapy
Authors: Cangiano Thomas , Liao Joseph , Naitoh John , Dorey Frederick , Figlin Robert , Belldegrun Arie
Published: February 2017

PURPOSE: Sarcomatoid variants of renal cell carcinoma (RCC) are aggressive tumors that respond poorly to immunotherapy. We report the outcomes of 31 patients with sarcomatoid RCC treated with a combination of surgical resection and immunotherapy.

PATIENTS AND METHODS: Patients were identified from the database of the University of California Los Angeles Kidney Cancer Program. We retrospectively reviewed the cases of 31 consecutive patients in whom sarcomatoid RCC was diagnosed between 1990 and 1997. Clinical stage, sites of metastasis, pathologic stage, and type of immunotherapy were abstracted from the medical records. The primary end point analyzed was overall survival, and a multivariate analysis was performed to distinguish any factors conferring an improved survivorship.

RESULTS: Twenty-six percent of patients were male and 74% were female, and the median age was 59 years (range, 34 to 73 years). Length of follow-up ranged from 2 to 77 months (mean, 21.4 months). Twenty-eight patients (84%) had known metastases at the time of radical nephrectomy (67% had lung metastases and 40% had bone, 21% had liver, 33% had lymphatic, and 15% had brain metastases). Twenty-five patients (81%) received immunotherapy, including low-dose interleukin (IL)-2–based therapy (five patients), tumor-infiltrating lymphocyte–based therapy plus IL-2 (nine patients), high-dose IL-2–based therapy (nine patients), dendritic cell vaccine–based therapy (one patient), and interferon alpha–based therapy alone (one patient). Two patients (6%) achieved complete responses (median duration, 46+ months) and five patients (15%) achieved partial responses (median duration, 36 months). One- and 2-year overall survival rates were 48% and 37%, respectively. Using a multivariate analysis, age, sex, and percentage of sarcomatoid tumor (< or > 50%) did not significantly correlate with survival. Improved survival was found in patients receiving high-dose IL-2 therapy compared with patients treated with surgery alone or any other form of immunotherapy (P = .025). Adjusting for age, sex, and percentage of sarcomatoid tumor, the relative risk of death was 10.4 times higher in patients not receiving high-dose IL-2 therapy. Final pathologic T stage did not correlate significantly with outcome, but node-positive patients had a higher death rate per year of follow-up than did the rest of the population (1.26 v 0.76, Cox regression analysis).

CONCLUSION: Surgical resection and high-dose IL-2–based immunotherapy may play a role in the treatment of sarcomatoid RCCs in select patients.