bluuebunny/crossref_metadata_2025 huggingface dataset:
Silent Lacunar Lesions Detected by Magnetic Resonance Imaging of Children With Brain Tumors: A Late Sequela of Therapy
Authors: Fouladi Maryam , Langston James , Mulhern Raymond , Jones Dana , Xiong Xiaoping , Yang Jianping , Thompson Stephen , Walter Andrew , Heideman Richard , Kun Larry , Gajjar Amar
Published: February 2017

BACKGROUND: Cerebral lacunes, which generally appear on magnetic resonance imaging as foci of white matter loss, usually occur in adults after ischemic infarcts. We report the development of lacunes in children after therapy for brain tumors.

PATIENTS AND METHODS: We reviewed the clinical characteristics and radiologic studies of 524 consecutive children with brain tumors treated over a 10-year period. We documented the neuropsychologic findings associated with lacunes and the factors predictive of lacunar development.

RESULTS: Lacunes developed in none of the 103 patients observed or treated with surgery alone. Twenty-five of the 421 patients treated with chemotherapy or radiation therapy or both had lacunes. Patients were a median of 4.5 years old at the time of both diagnosis (range, 0.3 to 19.8 years) and radiotherapy (range, 1.5 to 20 years). Fourteen patients were treated with craniospinal irradiation, and 11 were treated with local radiotherapy. The median time from radiotherapy to the appearance of lacunes was 2.01 years (range, 0.26 to 5.7 years). For all patients, lacunes were an incidental finding with no corresponding clinical deficits. The factor most predictive of lacunar development was age less than 5 years at the time of radiotherapy (P = .010). There was no significant difference in estimated decline in intelligence quotient scores between patients with lacunes and age and diagnosis-matched controls.

CONCLUSION: Lacunes may be caused by therapy-induced vasculopathy in children with brain tumors, with the most significant predictor being age less than 5 years at the time of radiotherapy.
Primary Mediastinal Germ Cell Tumors in Children and Adolescents: Results of the German Cooperative Protocols MAKEI 83/86, 89, and 96
Authors: Schneider Dominik T. , Calaminus Gabriele , Reinhard Harald , Gutjahr Peter , Kremens Bernhard , Harms Dieter , Göbel Ulrich
Published: February 2017

PURPOSE: To evaluate children and adolescents with primary mediastinal teratoma and malignant germ cell tumors (GCTs).

PATIENTS AND METHODS: Forty-seven patients from the German nontesticular GCT studies were analyzed (median age, 2.5 years; range, neonate to 17 years). Teratoma (n = 21) were resected, and no adjuvant treatment was given. Malignant GCTs (n = 26) were treated with cisplatin-based chemotherapy and resection. Three of 26 patients underwent radiotherapy.

RESULTS: In all patients with teratoma, tumor markers were normal. Surgery of teratoma was complete in 17 of 21 patients and microscopically incomplete in four of 21 patients, and we observed no relapse after a median follow-up of 29 months. In 23 of 26 patients with malignant GCTs, alpha-fetoprotein and/or beta-human chorionic gonadotropin were elevated. Twelve of 26 patients received adjuvant chemotherapy after initial resection, which was complete in six of 12 patients, whereas delayed resection after preoperative chemotherapy was complete in 10 of 11 patients (P = .03). Four of six patients underwent second-look thoracotomy after incomplete primary surgery. Three of 26 patients did not undergo tumor resection. The final completeness of resection was the strongest prognostic indicator (event-free survival [EFS], 0.94 ± 0.06 v 0.42 ± 0.33; P < .002). Local stage and distant metastases were not prognostically significant at the .05 level. For all malignant GCTs, the 5-year survival rate was 0.87 ± 0.05 (median follow-up, 51 months), with an EFS of 0.83 ± 0.05.

CONCLUSION: The prognosis of mediastinal teratoma is excellent after complete or microscopically incomplete resection. In children with malignant GCT, the prognosis is favorable with a therapeutic strategy of delayed resection after preoperative chemotherapy. In most children, the diagnosis can be based on elevated tumor markers and imaging. Biopsy is indicated in nonsecreting GCT.
Phase I Evaluation of Sequential Doxorubicin Gemcitabine Then Ifosfamide Paclitaxel Cisplatin for Patients With Unresectable or Metastatic Transitional-Cell Carcinoma of the Urothelial Tract
Authors: Dodd Paul M. , McCaffrey John A. , Hilton Susan , Mazumdar Madhu , Herr Harry , Kelly W. Kevin , Icasiano Evelyn , Boyle Mary G. , Bajorin Dean F.
Published: February 2017

PURPOSE: This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma.

PATIENTS AND METHODS: Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m2 and gemcitabine 2,000 mg/m2, to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m2 (days 1 to 3); paclitaxel 200 mg/m2 (day 1); and cisplatin 70 mg/m2 (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy.

RESULTS: Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses).

CONCLUSION: AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.
Etoposide and Cisplatin/Etoposide, Methotrexate, and Actinomycin D (EMA) Chemotherapy for Patients With High-Risk Gestational Trophoblastic Tumors Refractory to EMA/Cyclophosphamide and Vincristine Chemotherapy and Patients Presenting With Metastatic Placental Site Trophoblastic Tumors
Authors: Newlands E.S. , Mulholland P.J. , Holden L. , Seckl M.J. , Rustin G.J. S.
Published: February 2017

PURPOSE: To evaluate the results of etoposide, cisplatin/etoposide, methotrexate, and actinomycin D (EP/EMA) chemotherapy in patients with gestational trophoblastic tumors (GTTs), who have relapsed after or who have become refractory to EMA/cyclophosphamide and vincristine (CO) chemotherapy, and in patients presenting with metastatic placental site trophoblastic tumors (PSTTs).

PATIENTS AND METHODS: We have treated a total of 34 patients with GTT and eight patients with metastatic PSTT with the EP/EMA chemotherapy schedule.

RESULTS: Twenty-two patients received EP/EMA because of apparent drug resistance to EMA/CO, and because the human chorionic gonadotropin (hCG) was near normal, they were not assessable for response. Twenty-one of these patients (95%) are alive and in remission. In the group where the hCG was high enough to confirm a response (greater than one log fall in hCG) to EP/EMA, all 12 patients responded and nine of these patients (75%) are alive and in remission. We have treated three patients with PSTT where the interval from antecedent pregnancy was less than 2 years, and all patients (100%) are alive and in remission. We have treated five patients where the interval from antecedent pregnancy was greater than 2 years and one fifth (20%) remain in remission. The survival for patients with GTT is 30 (88%) out of 34 patients and four (50%) out of eight patients for PSTT, giving an overall survival for these two cohorts of 34 (81%) out of 42 patients. The toxicity of this schedule is significant, with grade 3 or 4 toxicity (National Cancer Institute common toxicity criteria) recorded in hemoglobin (21%), WBC (68%), and platelets (40%). The role of surgery in this group of patients is important and contributed to sustained remission in five patients (23%) and possibly helped an additional seven patients (32%).

CONCLUSION: EP/EMA is an effective but moderately toxic regimen for patients with high-risk GTT who become refractory to or relapse from EMA/CO chemotherapy. Also, EP/EMA clearly has activity in patients with metastatic PSTT.
Depression in Patients With Lung Cancer: Prevalence and Risk Factors Derived From Quality-of-Life Data
Authors: Hopwood Penelope , Stephens Richard J. ,   for the British Medical Research Council Lung Cancer Working Party
Published: February 2017

PURPOSE: To evaluate self-reported depression rates in patients with inoperable lung cancer and to explore demographic, clinical, and quality-of-life (QOL) factors associated with depression and thus identify patients at risk.

PATIENTS AND METHODS: Nine hundred eighty-seven patients from three palliative treatment trials conducted by the Medical Research Council Lung Cancer Working Party formed the study sample. 526 patients (53%) had poor prognosis small-cell lung cancer (SCLC) and 461 patients (47%) had good prognosis non–small-cell lung cancer (NSCLC). Hospital Anxiety and Depression Scale data and QOL items from the Rotterdam Symptom Checklist were analyzed, together with relevant demographic and clinical factors.

RESULTS: Depression was self-rated in 322 patients (33%) before treatment and persisted in more than 50% of patients. SCLC patients had a three-fold greater prevalence of case depression than those with NSCLC (25% v 9%; P < .0001). An increased rate for women was found for good performance status (PS) patients (PS of 0 or 1) but the sex difference reduced for poor PS patients (PS of 3 or 4) because of increased depression rates for men (χ2 for trend, P < .0001). Multivariate analysis showed that functional impairment was the most important risk factor; depression increased by 41% for each increment on the impairment scale. Pretreatment physical symptom burden, fatigue, and clinician-rated PS were also independent predictors, but cell type was not.

CONCLUSION: Depression is common and persistent in lung cancer patients, especially those with more severe symptoms or functional limitations. Psychologic screening and appropriate intervention is an essential part of palliative care.
Phase I and Pharmacokinetic Study of Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer
Authors: Zujewski J. , Horak I.D. , Bol C.J. , Woestenborghs R. , Bowden C. , End D.W. , Piotrovsky V.K. , Chiao J. , Belly R.T. , Todd A. , Kopp W.C. , Kohler D.R. , Chow C. , Noone M. , Hakim F.T. , Larkin G. , Gress R.E. , Nussenblatt R.B. , Kremer A.B. , Cowan K.H.
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks.

PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1.

RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months.

CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1,000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.
“Low-Risk” Prediction Rule for Pediatric Oncology Patients Presenting With Fever and Neutropenia
Authors: Klaassen Robert J. , Goodman T. Robin , Pham Ba , Doyle John J.
Published: February 2017

PURPOSE: To prospectively derive and validate a clinical prediction rule to allow a more tailored approach to the management of pediatric oncology outpatients presenting with fever and neutropenia.

PATIENTS AND METHODS: The clinical prediction rule was derived over a 1-year period and then validated over the following 8 months in a new set of fever and neutropenia episodes. Patients were excluded if they presented with comorbidity or an abnormal chest x-ray (CXR).

RESULTS: Significant bacterial infection (SBI; defined as any blood or urine culture positive for bacteria, interstitial or lobar consolidation on CXR, or unexpected death from infection) was documented in 43 of the 227 episodes. Multivariate analysis found four significant factors: bone marrow disease, general appearance unwell on initial examination, monocyte count less than 0.1 × 109/L, and peak oral or oral equivalent temperature greater than 39°C. Only the monocyte count contributed to determining a low-risk group, excluding SBI with 84% sensitivity (95% confidence interval [CI], 61% to 100%), 42% specificity (95% CI, 38% to 46%), and a negative predictive value of 92% (95% CI, 76% to 100%). If the monocyte count was ≥ 0.1 × 109/L at the time of presentation (low risk), the incidences of SBI and bacteremia were 8% and 5%, respectively, versus 25% and 17% in the high-risk group. When validated in a new population of 136 episodes of fever and neutropenia, the incidences of SBI and bacteremia in the low-risk group were 12% and 5%, respectively, and 25% and 19% in the high-risk group.

CONCLUSION: Pediatric oncology outpatients with fever and neutropenia who present with an initial monocyte count of ≥ 0.1 × 109/L and do not have comorbidity or an abnormal CXR at the time of presentation are at lower risk for SBI and can be considered for less aggressive initial therapy.
Phase II Study of Cisplatin and Paclitaxel in Advanced Carcinoma of the Urothelium: An Eastern Cooperative Oncology Group Study
Authors: Dreicer Robert , Manola Judith , Roth Bruce J. , Cohen Michael B. , Hatfield Alan K. , Wilding George
Published: February 2017

PURPOSE: Cisplatin and paclitaxel are active agents in advanced urothelial cancer. A phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multi-institutional setting.

PATIENTS AND METHODS: Fifty-two patients with advanced urothelial carcinoma were treated on one day with paclitaxel 175 mg/m2 over 3 hours followed by cisplatin 75 mg/m2, both intravenously, every 21 days. Cycles were repeated every 21 days until progression or a maximum of six cycles.

RESULTS: Twenty-six patients obtained an objective response, for an overall response rate of 50% (95% confidence interval, 36% to 64%). Four patients achieved complete clinical responses. The median overall survival time for the group was 10.6 months. Toxicity was moderate, with granulocytopenia and neurotoxicity being the most common side effects noted.

CONCLUSION: The combination of cisplatin and paclitaxel is active in advanced urothelial cancer. Responses in visceral, nodal, and soft tissues sites were observed. Granulocytopenia without fever and grade 2/3 neurotoxicity were common. The confidence interval of the overall response rate in this study overlaps most of the other reported regimens. The optimal therapy for advanced urothelial cancer remains undefined.
Evaluation of Soy Phytoestrogens for the Treatment of Hot Flashes in Breast Cancer Survivors: A North Central Cancer Treatment Group Trial
Authors: Quella Susan K. , Loprinzi Charles L. , Barton Debra L. , Knost James A. , Sloan Jeff A. , LaVasseur Beth I. , Swan Debra , Krupp Kenneth R. , Miller Kathy D. , Novotny Paul J.
Published: February 2017

PURPOSE: Hot flashes represent a significant clinical problem for some breast cancer survivors. Safe, effective treatment is needed for this prominent clinical problem. Although it has been shown that estrogen or progesterone replacement therapy can alleviate this problem, there are continued safety concerns regarding the use of hormonal therapies in these women. Based on anecdotal information, we hypothesized that soy-derived phytoestrogens, weak estrogen-like substances in the soybean that demonstrate estrogen agonist and/or antagonist effects when they bind to estrogen receptors, could alleviate hot flashes. This current trial was designed to investigate this hypothesis.

PATIENTS AND METHODS: This double-blind clinical trial involved breast cancer survivors with substantial hot flashes. After randomization, patients underwent a 1-week baseline period with no therapy. This was followed by 4 weeks of either soy tablets or placebo. The patients then crossed over to the opposite arm in a double-blind manner for the last 4 weeks. Patients completed a daily questionnaire documenting hot flash frequency, intensity, and perceived side effects.

RESULTS: Of the 177 women who were randomized and started the study substance, 155 (88%) provided useable data over the first 5 weeks; 149 provided usable data over the entire 9 weeks. There was no suggestion that the soy product was more effective in reducing hot flashes than the placebo. At study completion, patients preferred the soy product 33% of the time, the placebo 37% of the time, and neither substance 31% of the time. No toxicity was observed.

CONCLUSION: The soy product did not alleviate hot flashes in breast cancer survivors.
Long-Term Prognosis After Resection of Hepatocellular Carcinoma Associated With Hepatitis B–Related Cirrhosis
Authors: Poon Ronnie Tung-Ping , Fan Sheung-Tat , Lo Chung-Mau , Liu Chi-Leung , Ng Irene Oi-Lin , Wong John
Published: February 2017

PURPOSE: The optimum management of hepatocellular carcinoma (HCC) associated with cirrhosis has not yet been clarified. Very few data are available in the literature regarding the prognosis after resection of HCC associated with hepatitis B virus (HBV)–related cirrhosis. This study evaluated the long-term results and prognostic factors after resection of HCC complicating HBV-related cirrhosis.

PATIENTS AND METHODS: One hundred forty-six patients with HBV-related Child’s A or B cirrhosis who had undergone resection of HCC over a 10-year period were prospectively studied for long-term results. They were compared with 155 noncirrhotic patients with HBV-related HCC resected in the same period.

RESULTS: The overall survival results of cirrhotic patients after resection of HCC were comparable to those of noncirrhotic patients (5-year survival, 44.3% v 45.6%, respectively; P = .216), but the former group had significantly smaller tumors. Stratified according to tumor size, the survival results were similar between cirrhotic and noncirrhotic patients with tumors ≤ 5 cm (5-year survival, 60.7% v 61.7%, respectively; P = .327) but were worse in cirrhotic compared with noncirrhotic patients with tumors greater than 5 cm (5-year survival, 27.8% v 39.5%, respectively; P = .034). Stage by stage, there were no significant differences in survival results between cirrhotic and noncirrhotic patients. Preoperative serum AST level greater than 100 IU/L (P = .004), perioperative transfusion (P = .015), and venous invasion (P < .001) were independent adverse prognostic factors.

CONCLUSION: The prognosis after resection of HCCs less than 5 cm in patients with compensated HBV-related cirrhosis was comparable to that of noncirrhotic patients, which suggests that surgical resection may be considered a first-line treatment for these patients. Patients with underlying active hepatitis as indicated by a high preoperative transaminase level are less favorable candidates for resection. Further studies are needed to define the relative roles of resection and transplantation for HCC associated with hepatitis B cirrhosis.
Pharmacokinetics of Nelarabine and 9-Beta-d-Arabinofuranosyl Guanine in Pediatric and Adult Patients During a Phase I Study of Nelarabine for the Treatment of Refractory Hematologic Malignancies
Authors: Kisor David F. , Plunkett William , Kurtzberg Joanne , Mitchell Beverly , Hodge Jeffrey P. , Ernst Timothy , Keating Michael J. , Gandhi Varsha
Published: February 2017

PURPOSE: To characterize the pharmacokinetics of nelarabine (506U78), the water-soluble prodrug of 9-beta-d-arabinofuranosyl guanine (ara-G), and ara-G in pediatric and adult patients with refractory hematologic malignancies. Ara-G is phosphorylated within leukemic cells to form ara-G triphosphate (ara-GTP), which acts to terminate DNA chain elongation, resulting in cell death.

PATIENTS AND METHODS: The pharmacokinetics of nelarabine and/or ara-G were evaluated in 71 patients (25 pediatric and 46 adult patients) on the first day of therapy. Blood was collected at specified times for the determination of plasma nelarabine and ara-G concentrations.

RESULTS: There were no statistically significant differences in the pharmacokinetics of nelarabine between any of the groups of patients. The harmonic mean half-life (t1/2) of nelarabine in pediatric and adult patients was 14.1 minutes and 16.5 minutes, respectively. The maximum concentrations (Cmax) of ara-G occurred at or near the end of the nelarabine infusion. The Cmax of ara-G ranged from 11.6 μmol/L to 308.7 μmol/L at nelarabine doses of 5 to 75 mg/kg and was linearly related to the nelarabine dose. No statistically significant differences were noted for the pharmacokinetic parameter estimates of ara-G between adult male and female patients. In children versus adults, the dose-normalized Cmax, time of the Cmax, and the steady-state volume of distribution of ara-G were similar. However, the clearance of ara-G was higher in pediatric patients (0.312 L·h−1·kg−1) as compared with adult patients (0.213 L·h−1·kg−1) (P < .001). The t1/2 of ara-G was shorter in pediatric patients as compared with adult patients (2.1 hours v 3.0 hours; P < .01).

CONCLUSION: Nelarabine is an effective prodrug of ara-G, allowing systemic concentrations of ara-G that result in clinical activity.
Does Locoregional Radiation Therapy Improve Survival in Breast Cancer? A Meta-Analysis
Authors: Whelan Timothy J. , Julian Jim , Wright Jim , Jadad Alejandro R. , Levine Mark L.
Published: February 2017

PURPOSE: Recent randomized trials in women with node-positive breast cancer who received systemic treatment report that locoregional radiation therapy improves survival. Previous trials failed to detect a difference in survival that results from its use. A systematic review of randomized trials that examine the effectiveness of locoregional radiation therapy in patients treated by definitive surgery and adjuvant systemic therapy was conducted.

METHODS: Randomized trials published between 1967 and 1999 were identified through MEDLINE database, CancerLit database, and reference lists of relevant articles. Relevant data was abstracted. The results of randomized trials were pooled using meta-analyses to estimate the effect of treatment on any recurrence, locoregional recurrence, and mortality.

RESULTS: Eighteen trials that involved a total of 6,367 patients were identified. Most trials included both pre- and postmenopausal women with node-positive breast cancer treated with modified radical mastectomy. The type of systemic therapy received, sites irradiated, techniques used, and doses of radiation delivered varied between trials. Data on toxicity were infrequently reported. Radiation was shown to reduce the risk of any recurrence (odds ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.83), local recurrence (odds ratio, 0.25; 95% CI, 0.19 to 0.34), and mortality (odds ratio, 0.83; 95% CI, 0.74 to 0.94).

CONCLUSION: Locoregional radiation after surgery in patients treated with systemic therapy reduced mortality. Several questions remain on how these results should be translated into current-day clinical practice.
Therapeutic Relevance of CD34 Cell Dose in Blood Cell Transplantation for Cancer Therapy
Authors: Siena Salvatore , Schiavo Roberta , Pedrazzoli Paolo , Carlo-Stella Carmelo
Published: February 2017

PURPOSE: To review recent advances in peripheral-blood progenitor-cell (PBPC) transplantation in order to define the optimal cell dose required for autologous and allogeneic transplantation.

MATERIALS AND METHODS: A search of MEDLINE was conducted to identify relevant publications. Their bibliographies were also used to identify further articles and abstracts for critical review.

RESULTS: The CD34+ cell content of a graft is regarded as an accurate predictor of engraftment success. Postchemotherapy autologous PBPC transplantation with ≥ 5 × 106 CD34+ cells/kg body weight leads to more rapid engraftment than does transplantation of lower cell doses. Further increases in transplant cell dose further accelerate platelet but not neutrophil engraftment. Evidence that long-term hematopoietic recovery may be more accurately predicted by the subpopulation of primitive progenitors transplanted suggests that the content of CD34+CD33− and long-term culture-initiating cells in cell collection samples may be important for predicting successful engraftment, particularly in patients with poor mobilization. Allogeneic transplantation has been limited by concerns regarding graft-versus-host disease and the use of hematopoietic growth factors in donors. The risk of graft rejection and engraftment failure after HLA-mismatched allogeneic transplantation may be overcome by intensive chemoradiotherapy and the infusion of large numbers of T cell–depleted hematopoietic stem cells.

CONCLUSION: An optimal cell dose of ≥ 8 × 106 CD34+ cells/kg seems to be recommended for autologous PBPC transplantation. This dose facilitates the administration of scheduled chemotherapy on time and reduces the demand for other supportive therapies. A combination of growth factors may enable patients with poor mobilization to achieve a collection sufficient to allow transplantation. The optimum PBPC dose for allogeneic transplantation remains to be defined.
Burdens and Benefits of Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil and Tamoxifen for Elderly Patients With Breast Cancer: The International Breast Cancer Study Group Trial VII
Authors: Crivellari Diana , Bonetti Marco , Castiglione-Gertsch Monica , Gelber Richard D. , Rudenstam Carl-Magnus , Thürlimann Beat , Price Karen N. , Coates Alan S. , Hürny Christoph , Bernhard Jürg , Lindtner Jurij , Collins John , Senn Hans-Jörg , Cavalli Franco , Forbes John , Gudgeon Anne , Simoncini Edda , Cortes-Funes Hernan , Veronesi Andrea , Fey Martin , Goldhirsch Aron ,   for the International Breast Cancer Study Group
Published: February 2017

PURPOSE: Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer Study Group Trial VII.

PATIENTS AND METHODS: Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m2 orally days 1 to 14), methotrexate (40 mg/m2 intravenous days 1 and 8), and fluorouracil (600 mg/m2 intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years.

RESULTS: Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P = .004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P = .0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.65 to 1.52; P = .99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P = .008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received.

CONCLUSION: CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.
Correlation of Vascular Endothelial Growth Factor Content With Recurrences, Survival, and First Relapse Site in Primary Node-Positive Breast Carcinoma After Adjuvant Treatment
Authors: Linderholm Barbro , Grankvist Kjell , Wilking Nils , Johansson Mikael , Tavelin Björn , Henriksson Roger
Published: February 2017

PURPOSE: To determine the predictive value of vascular endothelial growth factor (VEGF) for relapse-free survival (RFS) and overall survival (OS) in primary node-positive breast cancer (NPBC) after adjuvant endocrine treatment or adjuvant chemotherapy.

MATERIALS AND METHODS: VEGF was quantitatively measured in tumor cytosols from 362 consecutive patients with primary NPBC using an enzyme immunoassay for human VEGF165. Adjuvant treatment was given to all patients, either as endocrine therapy (n = 250) or chemotherapy (n = 112). The median follow-up time was 56 months.

RESULTS: Univariate analysis showed VEGF to be a significant predictor of RFS (P = .0289) and OS (P = .0004) in the total patient population and in patients who received adjuvant endocrine treatment (RFS, P = .0238; OS, P = .0121). In the group of patients who received adjuvant chemotherapy, no significant difference was seen in RFS, but a difference was seen in OS (P = .0235). Patients with bone recurrences tended to have lower VEGF expression (median, 2.17 pg/μg DNA) than patients with visceral metastasis (4.41 pg/μg), brain metastasis (8.29 pg/μg), or soft tissue recurrences (3.16 pg/μg). Multivariate analysis showed nodal status (P = .0004), estrogen receptor (ER) status (P < .0001), and tumor size (P = .0085) to be independent predictors of RFS. VEGF was found to be an independent predictor of OS (P = .0170; relative risk [RR] = 1.82), as were ER (P < .0001; RR = 5.19) and nodal status (P = .0002; RR = 2.58). For patients receiving adjuvant endocrine treatment, multivariate analysis showed VEGF content to be an independent predictor of OS (P = .0420; RR = 1.90) but not of RFS.

CONCLUSION: The results suggest that VEGF165 content in tumor cytosols is a predictor of RFS and OS in primary NPBC. VEGF content might also predict outcome after adjuvant endocrine treatment, but further studies in a prospective setting with homologous treatments are required.
Response of Circulating Tumor Cells to Systemic Therapy in Patients With Metastatic Breast Cancer: Comparison of Quantitative Polymerase Chain Reaction and Immunocytochemical Techniques
Authors: Smith Brendan M. , Slade Martin J. , English Jacqueline , Graham Helen , Lüchtenborg Margreet , Sinnett H. Dudley , Cross Nicholas C. P. , Coombes R. Charles
Published: February 2017

PURPOSE: We previously developed a quantitative system for the detection of cytokeratin 19 (CK-19) transcripts using reverse transcriptase polymerase chain reaction (PCR) to detect breast carcinoma cells in blood and bone marrow. The aim of this study was to determine the value of this system in monitoring patients with metastatic disease and to compare it with an established immunocytochemical method.

PATIENTS AND METHODS: Patients with progressive, locally advanced, and metastatic breast cancer (all stage IV) who were due to start systemic treatment were recruited. Blood samples were analyzed for CK-19 transcripts using quantitative PCR (QPCR) and immunocytochemistry (ICC) throughout their course of treatment.

RESULTS: One hundred forty-five blood samples were obtained from 22 patients over 13 months. Seventy-two (49.6%) of these samples were positive by QPCR, and 56 (42%) of 133 were positive by ICC. Of the 133 specimens analyzed by both techniques, 95 (71.4%) had the same results for each, and of the 71 samples that were positive, 40 (56%) were positive by both methods. The relationship between the number of cells detected and the QPCR values was statistically significant (P < .0001). Of the 25 courses of assessable treatment, 17 (68%) of 25 treatment outcomes (either response or disease progression) were reflected by QPCR measurements, and 12 (57%) of 21 were reflected by ICC. During the course of the study, five patients showed a response, and of these, ICC was in agreement in four cases (80%) and QPCR in three cases (60%). Eighteen courses of treatment resulted in progression of the disease; however, only 15 of these were assessable by ICC. ICC was in agreement in eight (53%) of 15 of these cases, and QPCR in 15 (83%) of 18 cases.

CONCLUSION: Circulating carcinoma cells are frequently found in patients with metastatic breast cancer. In the majority of patients, cancer cell numbers as evaluated by QPCR or ICC reflected the outcome of systemic treatment.
p53 Alterations Predict Tumor Response to Neoadjuvant Chemotherapy in Head and Neck Squamous Cell Carcinoma: A Prospective Series
Authors: Cabelguenne Arnauld , Blons Hélène , de Waziers Isabelle , Carnot Françoise , Houllier Anne-Marie , Soussi Thierry , Brasnu Daniel , Beaune Phillipe , Laccourreye Ollivier , Laurent-Puig Pierre
Published: February 2017

PURPOSE: The tumor suppressor gene p53 plays a crucial role in cell cycle control and apoptosis in response to DNA damages. p53 gene mutations and allelic losses at 17p are one of the most common genetic alterations in primary head and neck squamous cell carcinoma (HNSCC). Alterations of the p53 gene have been shown to contribute to carcinogenesis and drug resistance.

PATIENTS AND METHODS: In this prospective series, patients with HNSCC were treated with cisplatin-fluorouracil neoadjuvant chemotherapy. p53 status was characterized in 106 patients with HNSCC (p53 mutations, allelic losses at p53 locus, and plasma anti-p53 antibodies) to determine the existence of a relationship between p53 gene status and response to neoadjuvant chemotherapy.

RESULTS: Exons 4 to 9 of the p53 gene were analyzed, and mutations were found in 72 of 106 patients with HNSCC. p53 mutations were associated with loss of heterozygosity at chromosome 17p (P < .001). The prevalence of p53-mutated tumors was higher in the group of patients with nonresponse to neoadjuvant chemotherapy than in the group of responders (81% v 61%, respectively; P < .04). When compiling p53 mutations and anti-p53 antibodies in plasma, the correlation between p53 status and response to chemotherapy was significant (87% v 57%, respectively; P = .003). A multivariate analysis showed that p53 status is an independent predictive factor of response to chemotherapy.

CONCLUSION: This prospective study suggests that p53 status may be a useful indicator of response to neoadjuvant chemotherapy in HNSCC.
Post Hoc Economic Analysis of Temozolomide Versus Dacarbazine in the Treatment of Advanced Metastatic Melanoma
Authors: Hillner Bruce E. , Agarwala Sanjiv , Middleton Mark R.
Published: February 2017

PURPOSE: To determine the potential economic implications resulting from oral temozolomide (TEM) compared with intravenous (IV) dacarbazine (DTIC) for metastatic melanoma.

PATIENTS AND METHODS: We performed a cost-effectiveness (CE) analysis using hazard ratios (HRs) from the phase III (Schering I95–018) trial comparing TEM 200 mg/m2/d orally for 5 days every 28 days with DTIC 250 mg/m2/d IV for 5 days every 21 days. Sensitivity analyses assessed a range of TEM’s efficacy and costs, direct nonmedical costs, and the DTIC schedule.

RESULTS: The trial found an overall survival trend favoring TEM; median survival times of patients treated with DTIC and TEM were 6.4 and 7.7 months, respectively (HR = 1.18; 95% confidence interval [CI], 0.92 to 1.52; intention to treat, P = .20). The mean increase in survival of TEM over DTIC was 1.1 months. The projected average costs per patient were greater with TEM than DTIC ($6,902 v $3,697, respectively). The incremental CE ratio using TEM was $36,990 per life-year or $101 per day of life gained. The CE ratio’s 95% CI ranged from −$65,180 (DTIC is more effective) to $18,670 per year of life gained. The CE ratios decreased 50% if direct nonmedical costs were included and increased 50% if DTIC’s efficacy was unchanged if given as a single daily dosage. Sixty percent of simulations found TEM with a CE threshold of less than $50,000 per life-year gained.

CONCLUSION: Although the base-case efficacy of TEM compared with DTIC was not statistically significant, its associated incremental CE would be comparable with many interventions. TEM for metastatic melanoma illustrates the tension confronting providers choosing between similar agents that markedly differ in convenience and costs.
Second Malignant Neoplasms After Treatment for Hodgkin’s Disease in Childhood or Adolescence
Authors: Green Daniel M. , Hyland Andrew , Barcos Maurice P. , Reynolds Julie A. , Lee R. Jeffrey , Hall Brenda C. , Zevon Michael A.
Published: February 2017

PURPOSE: To determine the frequency of and risk factors for second malignant neoplasms (SMNs) after treatment for Hodgkin’s disease diagnosed in children and adolescents.

PATIENTS AND METHODS: One hundred eighty-two consecutive, previously untreated patients with Hodgkin’s disease who were younger than 20 years of age at diagnosis and who were referred to Roswell Park Cancer Institute (Buffalo, NY) for treatment between January 1, 1960, and December 31, 1989, were studied. Sex-specific standardized incidence ratios (SIRs) were calculated. Kaplan-Meier survival estimates and Cox regression analyses were performed to determine the relationship of several demographic and treatment variables to SMN incidence.

RESULTS: Twenty-eight patients developed an SMN at a mean of 14.93 ± 8.09 years (range, 2.65 to 29.88 years) after diagnosis of Hodgkin’s disease. The cumulative percentage of patients who developed an SMN was 26.27 ± 6.75% at 30 years after diagnosis. The SIR was 9.39 (95% confidence interval [CI], 4.05 to 18.49) for male patients and 10.16 (95% CI, 5.56 to 17.05) for female patients. The most frequent SMNs were thyroid cancer, breast cancer, nonmelanoma skin cancer, non-Hodgkin’s lymphoma, and acute leukemia. Multivariate analysis of sex, treatment with any alkylating agent, treatment with doxorubicin, splenectomy, and relapse (as a time-dependent covariate) with time to SMN onset gave nonsignificant results.

CONCLUSION: Successfully treated children and adolescents with Hodgkin’s disease have a substantial risk for the occurrence of subsequent neoplasms. The most frequent SMNs (skin, thyroid, and breast) are readily detected by physical examination and available screening procedures.
Hypersensitivity or Development of Antibodies to Asparaginase Does Not Impact Treatment Outcome of Childhood Acute Lymphoblastic Leukemia
Authors: Woo Michael H. , Hak Lawrence J. , Storm Michael C. , Sandlund John T. , Ribeiro Raul C. , Rivera Gaston K. , Rubnitz Jeffrey E. , Harrison Patricia L. , Wang Bo , Evans William E. , Pui Ching-Hon , Relling Mary V.
Published: February 2017

PURPOSE: Development of antibodies and hypersensitivity to asparaginase are common and may attenuate asparaginase effect. Our aim was to determine the relationship between antiasparaginase antibodies or hypersensitivity reactions and event-free survival (EFS).

PATIENTS AND METHODS: One hundred fifty-four children with acute lymphoblastic leukemia received Escherichia coli asparaginase 10,000 IU/m2 intramuscularly three times weekly for nine doses during multiagent induction and reinduction phases and for seven monthly doses during continuation treatment. Erwinia asparaginase was used in case of clinical hypersensitivity to E coli but not for subclinical development of antibodies. Plasma antiasparaginase antibody concentrations were measured on day 29 of induction in 152 patients.

RESULTS: Antibodies were detectable in 54 patients (35.5%), of whom 30 (55.6%) exhibited hypersensitivity to asparaginase. Of the 98 patients who had no detectable antibodies, 18 (18.4%) had allergic reactions. Patients with antibodies were more likely to have a reaction than those without antibodies (P < .001). Among the 50 patients who experienced allergic reactions (including two for whom antibodies were not measured), 36 (72.0%) were subsequently given Erwinia asparaginase; seven (19.4%) reacted to this preparation. EFS did not differ among patients who did and did not have antibodies (P = .54), with 4-year EFS (± 1 SE) of 83% ± 6% and 76% ± 5%, respectively. Similarly, EFS did not differ among patients who did and did not develop allergic reactions (P = .68), with 4-year estimates of 82% ± 6% and 78% ± 5%, respectively.

CONCLUSION: In this setting, in which most patients with allergy were switched to another preparation, there was no adverse prognostic impact of clinical or subclinical allergy to asparaginase.
Vinorelbine Is an Effective and Safe Drug for AIDS-Related Kaposi’s Sarcoma: Results of a Phase II Study
Authors: Nasti Guglielmo , Errante Domenico , Talamini Renato , Rizzardini Giuliano , Fasan Marco , Landonio Giuseppe , Zeroli Claudia , Chichino Guido , Nigra Ezio , Vaccher Emanuela , Tirelli Umberto
Published: February 2017

PURPOSE: To assess the safety and efficacy of vinorelbine in patients with AIDS-related Kaposi’s sarcoma (KS).

PATIENTS AND METHODS: From December 1994 to May 1997, within the Italian Cooperative Group on AIDS and Tumors, we enrolled 36 patients with AIDS-related KS who experienced disease progression after one or more regimens of systemic chemotherapy. Patients were treated with vinorelbine 30 mg/m2 every 2 weeks by intravenous bolus.

RESULTS: Of 35 assessable patients, three (9%) had a clinical complete response and 12 (34%) had a partial remission, for an overall objective response rate of 43% (95% confidence interval, 26% to 61%). For the 15 patients with objective responses, the median duration of response from the beginning of therapy until the development of progression was 176 days, whereas the median progression-free survival and the median survival durations for 35 assessable patients were 151 days and 216 days, respectively. Vinorelbine also induced responses in patients who had become resistant to regimens that included other vinca alkaloids. Overall, vinorelbine was well tolerated. Toxicity, including neurologic toxicity, was mild and reversible. Neutropenia was the most frequent dose-limiting toxicity.

CONCLUSION: Vinorelbine is safe and effective in the treatment of patients with advanced KS who have been previously treated with one or more chemotherapy regimens.
Chromosome Instability as an Indicator of Malignant Progression in Laryngeal Mucosa
Authors: Veltman Joris A. , Bot Fredrik J. , Huynen Ference C. , Ramaekers Frans C. S. , Manni Johannes J. , Hopman Anton H. N.
Published: February 2017

PURPOSE: Routine histologic examination cannot predict whether premalignant laryngeal lesions will progress toward invasive growth. The acquisition of changes in chromosome constitution has been suggested to be essential for driving tumor progression by enhancing mutagenic mechanisms. The aim of the present study was to determine whether chromosomal changes occur in the subsequent stages of early laryngeal carcinogenesis and, if so, whether these changes can be of prognostic value.

MATERIALS AND METHODS: Numerical aberrations for chromosomes 1 and 7 were detected in tissue sections from archival material using an improved in situ hybridization protocol. In total, eight benign laryngeal lesions, 37 premalignant laryngeal lesions, and 16 specimens containing histologically normal epithelia adjacent to laryngeal squamous cell carcinomas were studied. Both the histologic and the cytogenetic classifications were correlated with progression to laryngeal cancer.

RESULTS: No evidence for chromosome alterations was obtained in the control group, nor in histologically normal epithelia adjacent to laryngeal squamous cell carcinomas, nor in all but one hyperplastic lesion (n = 11). In contrast, 14 of 15 dysplastic lesions and nine of 11 carcinomas-in-situ contained numerical chromosomal aberrations. Tetrasomy was present in the majority of the dysplastic lesions. An unstable chromosome content (indicated by the presence of chromosome imbalances and/or polyploidization) in the premalignant lesion strongly predicted its malignant progression.

CONCLUSION: Our results show that laryngeal tumor development involves chromosome tetraploidization. The further change from a stable to an unstable chromosome constitution is of importance for malignant progression.