bluuebunny/crossref_metadata_2025 huggingface dataset:
Prolonged Infusion of Gemcitabine: Clinical and Pharmacodynamic Studies During a Phase I Trial in Relapsed Acute Myelogenous Leukemia
Authors: Gandhi Varsha , Plunkett William , Du Min , Ayres Mary , Estey Elihu H.
Published: February 2017

PURPOSE: To determine the maximum tolerated duration of infusions at the fixed gemcitabine dose rate of 10 mg/m2/min and to analyze the pharmacodynamic actions in leukemia blasts during gemcitabine therapy.

PATIENTS AND METHODS: The study was conducted in a phase I trial by escalating the duration of gemcitabine infusion at a fixed-dose rate of 10 mg/m2/min. Patients with relapsed or refractory acute myelogenous leukemia (AML) received gemcitabine for 8.0 (n = 3), 10.0 (n = 3), 12.5 (n = 8), 15.5 (n = 3), or 18.0 hours (n = 2). Pharmacokinetic and pharmacodynamic investigations were undertaken in circulating AML blasts.

RESULTS: Gemcitabine was infused for up to 18 hours at the fixed-dose rate. Four patients had grade 3 toxicities at longer infusion schedules. One patient had a partial remission; two others had a reduction in blasts and concomitant rise in neutrophils. Gemcitabine triphosphate was detectable in AML cells even at 1 hour after the start of infusion in eight patients. The concentration ranged from 130 to 900 μmol/L at the end of the infusion. Consistently, there was a rapid decline in DNA synthesis, which remained suppressed at 85% to 95% during and for at least 10 hours after the end of the infusion. Compared with levels in cells measured before therapy, at 8 hours after the start of the infusion, there was a decline in the cellular purine deoxynucleotide pools.

CONCLUSION: At the fixed-dose rate of 10 mg/m2/min, gemcitabine could be administered for longer than 12 hours without untoward toxicity. The favorable toxicity profile and pharmacokinetic and pharmacodynamic features warrant combination with DNA-damaging agents.
High-Dose Versus Standard Chemotherapy in Metastatic Breast Cancer: Comparison of Cancer and Leukemia Group B Trials With Data From the Autologous Blood and Marrow Transplant Registry
Authors: Berry Donald A. , Broadwater Gloria , Klein John P. , Antman Karen , Aisner Joseph , Bitran Jacob , Costanza Mary , Freytes Cesar O. , Stadtmauer Edward , Gale Robert Peter , Henderson I. Craig , Lazarus Hillard M. , McCarthy Philip L. , Norton Larry , Parnes Howard , Pecora Andrew , Perry Michael C. , Rowlings Philip , Spitzer Gary , Horowitz Mary M.
Published: February 2017

PURPOSE: To assess survival of patients with metastatic breast cancer treated with high-dose chemotherapy (HDC) versus standard-dose chemotherapy (SDC).

PATIENTS AND METHODS: SDC in four Cancer and Leukemia Group B (CALGB) trials was compared with hematopoietic stem-cell support in patients from the Autologous Blood and Marrow Transplant Registry. Cox proportional hazard regression incorporated potentially confounding effects. A total of 1,509 women were enrolled onto CALGB trials, and 1,188 women received HDC. No significant survival differences existed by CALGB trial or HDC regimen. Consideration was restricted to candidates for both SDC and HDC. The resulting sample included 635 SDC and 441 HDC patients. The outcome of interest was overall survival.

RESULTS: The HDC group displayed better performance status. The SDC group had slightly better survival in first year after treatment. The HDC group had lower hazard of death from years 1 to 4 and had somewhat higher probability of 5-year survival (adjusted probabilities [95% confidence intervals], 23% [17% to 29%] v 15% [11% to 19%], P = .03).

CONCLUSION: After controlling for known prognostic factors in this nonrandomized analysis of two large independent data sets, women receiving HDC versus SDC for metastatic breast cancer have a similar short-term probability of survival, and might have a modestly higher long-term probability of survival.
Prognostic Factors in High-Grade Osteosarcoma of the Extremities or Trunk: An Analysis of 1,702 Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols
Authors: Bielack Stefan S. , Kempf-Bielack Beate , Delling Günter , Exner G. Ulrich , Flege Silke , Helmke Knut , Kotz Rainer , Salzer-Kuntschik Mechthild , Werner Matthias , Winkelmann Winfried , Zoubek Andreas , Jürgens Heribert , Winkler Kurt
Published: February 2017

PURPOSE: To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas, extending well beyond those of the typical young patient with seemingly localized extremity disease.

PATIENTS AND METHODS: A total of 1,702 consecutive newly diagnosed patients with high-grade osteosarcoma of the trunk or limbs registered into the neoadjuvant studies of the Cooperative Osteosarcoma Study Group before July 1998 were entered into an analysis of demographic, tumor-related, and treatment-related variables, response, and survival. The intended therapeutic strategy included preoperative and postoperative chemotherapy with multiple agents as well as surgery of all operable lesions.

RESULTS: Axial tumor site, male sex, and a long history of symptoms were associated with poor response to chemotherapy in univariate and multivariate analysis. Actuarial 10-year overall and event-free survival rates were 59.8% and 48.9%. Among the variables assessable at diagnosis, patient age (actuarial 10-year survival ≥ 40, 41.6%; < 40, 60.2%; P = .012), tumor site (axial, 29.2%; limb, 61.7%; P < .0001), and primary metastases (yes, 26.7%; no, 64.4%; P < .0001), and for extremity osteosarcomas, also size (≥ one third, 52.5%; < one third, 66.7%; P < .0001) and location within the limb (proximal, 49.3%; other, 63.9%; P < .0001), had significant influence on outcome. Two additional important prognostic factors were treatment related: response to chemotherapy (poor, 47.2%; good, 73.4%; P < .0001) and the extent of surgery (incomplete, 14.6%; macroscopically complete, 64.8%; P < .0001). All factors except age maintained their significance in multivariate testing, with surgical remission and histologic response emerging as the key prognostic factors.

CONCLUSION: Tumor site and size, primary metastases, response to chemotherapy, and surgical remission are of independent prognostic value in osteosarcoma.
Postoperative Nomogram for 12-Year Sarcoma-Specific Death
Authors: Kattan Michael W. , Leung Denis H.Y. , Brennan Murray F.
Published: February 2017

PURPOSE: Few published studies have analyzed risk factors for sarcoma-specific death. We developed and internally validated a nomogram that combines the factors to predict the probability of 12-year sarcoma-specific death using a database of 2,136 prospectively followed adult patients treated at a single institution.

PATIENTS AND METHODS: Nomogram predictor variables included age at diagnosis, tumor size (≤ 5, 5 to 10, or > 10 cm), histologic grade (high or low), histologic subtype (fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve tumor, synovial, or other), depth (superficial or deep), and site (upper extremity, lower extremity, visceral, thoracic or trunk, retrointraabdominal, or head or neck). Death from sarcoma or treatment complication was the predicted end point. Three prediction methods were compared, Kaplan-Meier analysis of all possible subsets, recursive partitioning, and Cox proportional hazards regression analysis. The concordance index was used as an accuracy measure with bootstrapping to correct for optimistic bias.

RESULTS: Sarcoma-specific death at 12 years was 36% (95% confidence interval, 33% to 39%). The bootstrap-corrected concordance indices were as follows: Kaplan-Meier, 0.69; recursive partitioning, 0.74; and Cox regression, 0.77. A nomogram was drawn on the basis of the Cox regression model. This nomogram was internally validated using bootstrapping and shown to have excellent calibration.

CONCLUSION: A nomogram has been developed to predict 12-year sarcoma-specific death. This tool may be useful for patient counseling, follow-up scheduling, and clinical trial eligibility determination.
Bax Expression Decreases Significantly From Primary Tumor to Metastasis in Colorectal Cancer
Authors: Jansson Agneta , Sun Xiao-Feng
Published: February 2017

PURPOSE: Bax is a proapoptotic member of the bcl-2 family. Previous studies about Bax have shown that the expression increases from normal to tumor tissue, but the clinical significance is contradictory. Our aims were to analyze the expression of Bax from normal mucosa to primary tumor and to metastases in colorectal cancer patient. We further investigated whether low Bax expression in the primary tumor or changed expression from normal mucosa to primary tumor and to metastases had biologic and clinical significance.

PATIENTS AND METHODS: The study included 135 patients with primary colorectal adenocarcinoma, of whom 31 had metastases in the lymph nodes and 75 had normal mucosa. Immunohistochemistry, DNA sequencing, and microsatellite analysis were used to detect Bax expression, mutations, and microsatellite instability.

RESULTS: The protein was observed in 132 of 135 tumors, all normal epithelial cells and metastases. The frequencies of weak expression were greater from well/moderately to poorly differentiated and to mucinous carcinomas. Bax expression was stronger from normal to tumor tissue, but subsequently decreased in metastases. The matched cases with lower expression in the metastases than in the primary tumor showed a more infiltrative growth pattern and more distal metastases.

CONCLUSION: The association of Bax expression with tumor differentiation/histologic types and a decreased expression in the metastases, suggests that Bax expression may be involved in tumor differentiation/histologic types and metastatic progression. We also propose the novel notion that changed Bax expression in the metastases compared with the primary tumors might provide information to determine the clinicopathologic characteristics of the tumor.
Dietary Change After Breast Cancer: Extent, Predictors, and Relation With Psychological Distress
Authors: Maunsell Elizabeth , Drolet Mélanie , Brisson Jacques , Robert Jean , Deschênes Luc
Published: February 2017

PURPOSE: Some women may try to cope with breast cancer by making lifestyle modifications, possibly in the hope of improving disease outcome. We assessed extent, predictors, and effect on psychological distress of dietary changes in the year after diagnosis among 250 women with newly diagnosed, nonmetastatic breast cancer.

PATIENTS AND METHODS: Data came from medical records, and from interviews 3 days and 12 months after initial treatment.

RESULTS: At 12 months, 41% (n = 103) reported dietary changes at some time since diagnosis, with decreases in meat (77%) and increases in fruit and vegetable intake (72%) being the most frequent. Women reporting changes were more likely to be younger, to have positive nodes, to be receiving adjuvant therapy, and to be more distressed initially. The mean 0 to 12 month decrease in psychological distress was greater in women who reported changes (9 points) than those who did not (4.7 points) (P = .03), although regression toward the mean cannot be excluded.

CONCLUSION: A sizable proportion of women made dietary changes on their own initiative. Most changes reported were generally consistent with current scientific hypotheses about dietary changes that might favorably affect prognosis. The profile of women reporting changes suggests a group with more concerns about recurrence, who may have initiated dietary change to help cope with and gain a sense of control over the disease, and possibly to improve prognosis. Our results suggest that newly diagnosed women could be receptive to explicit attention to diet as part of psychosocial care. However, this interest in dietary change may not, as yet, have been maximally channeled into trying to improve the care and quality of life of women facing diagnosis, treatments, and fears about recurrence.
Assessment of Coronary Heart Disease Morbidity and Mortality After Radiation Therapy for Early Breast Cancer
Authors: Vallis Katherine A. , Pintilie Melania , Chong Nelson , Holowaty Eric , Douglas Pamela S. , Kirkbride Peter , Wielgosz Andreas
Published: February 2017

PURPOSE: To assess the risk of fatal and nonfatal myocardial infarction (MI) after breast-conserving surgery (BCS) and radiation therapy (RT) for left-sided breast cancer.

PATIENTS AND METHODS: A hospital-based retrospective cohort linkage study of all breast cancer patients registered at the Princess Margaret Hospital (PMH), Toronto, Canada, between 1982 and 1988 who were treated with postlumpectomy RT was performed. Available identifiers for the study cohort were linked to two province-wide health files: the Canadian Institute for Health Information Hospitalization File and the Ontario Mortality Database. Admissions to hospital for MI and deaths attributable to MI were identified. The relevant original health records were abstracted to verify the diagnosis of MI according to diagnostic criteria used in the World Health Organization multinational monitoring of trends and determinants in cardiovascular disease (MONICA) project. We compared incidence of MI in the study cohort with the general population and incidence of MI after therapy for left- versus right-sided breast cancer.

RESULTS: A cohort of 2,128 patients was identified. The median length of follow-up was 10.2 years. The incidence of MI in the study cohort was comparable to that in an age-matched general population of women in Ontario. There were 70 coronary events among 56 patients after breast irradiation. According to MONICA criteria, 53 and six events were characterized as definite and possible MIs, respectively. Eleven events did not satisfy MONICA criteria for MI. Twenty-six patients treated for left-sided and 23 patients treated for right-sided breast cancer experienced at least one definite or possible MI (log-rank test, P = .66). There were eight fatal MIs among the left-sided group and six among the right-sided group. There was no excess of other cardiac diseases among patients who received left-sided radiotherapy compared to the right-sided group.

CONCLUSION: We have found no evidence for excess morbidity and mortality from coronary artery disease among women treated with RT to the left breast after BCS at 10.2 years of follow-up. Longer follow-up is required to confirm that excess cardiac disease has been completely avoided.
Phase I Trial of Adoptive Immunotherapy With Cytolytic T Lymphocytes Immunized Against a Tyrosinase Epitope
Authors: Mitchell Malcolm S. , Darrah Denise , Yeung David , Halpern Samuel , Wallace Anne , Voland Joseph , Jones Vicky , Kan-Mitchell June
Published: February 2017

PURPOSE: To study distribution and toxicity of cytolytic T lymphocytes (CTLs) against a single melanoma epitope.

PATIENTS AND METHODS: CD8+T cells obtained by leukapheresis from 10 patients with disseminated HLA-A2.1+, tyrosinase-positive melanomas were immunized in vitro against tyrosinase369-377(YMNGTMSQV). Drosophila cells transduced with HLA-A2.1, CD80, and CD54 (intracellular adhesion molecule-1) were used for priming, followed by two rounds of immunization with mononuclear cells as antigen-presenting cells. 1 × 108CTL were infused intravenously (IV) on day 1. CTL frequency was measured by limiting dilutions in five patients.111In labeling and scintigraphy measured distribution of CTL in next five. Five days later, 1 × 108CTLs were infused on 4 successive days to both groups. Immunohistology of response was judged by biopsies.

RESULTS: Infusions were nontoxic. CTLs were undetectable in the blood, going to lungs within 5 minutes. At 4, 24, and 72 hours, they were found in liver and spleen. Lesions were visualized by scintiscans in one responding patient where two subcutaneous nodules were noted at 4 and 24 hours. A second patient had a partial response and remains alive with disease 2 years later. CD8+T cells were found in lesions of responders, associated with the presence of HLA-A2 molecules and tyrosinase. Two nonresponders without tyrosinase and HLA-A2 molecules had a paucity of CD8+T cells in their lesions. Whether the CD8+T cells in lesions of responders were those we had reinfused is uncertain.

CONCLUSION: CTLs immunized against a single melanoma epitope were nontoxic but did not specifically localize to tumor sites. Nevertheless, two patients had disease regression. Additional therapeutic studies with specifically immunized CTL seem justified.
Minimal Residual Disease Tests Provide an Independent Predictor of Clinical Outcome in Adult Acute Lymphoblastic Leukemia
Authors: Mortuza Forida Y. , Papaioannou Mary , Moreira Ilidia M. , Coyle Luke A. , Gameiro Paula , Gandini Domenica , Prentice H. Grant , Goldstone Anthony , Hoffbrand A. Victor , Foroni Letizia
Published: February 2017

PURPOSE: Investigation of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) using molecular markers has proven superior to other standard criteria (age, sex, and WBC) in distinguishing patients at high, intermediate, and low risk of relapse. The aim of our study was to determine whether MRD investigation is valuable in predicting outcome in Philadelphia-negative adult patients with ALL.

PATIENTS AND METHODS: MRD was assessed in 85 adult patients with B-lineage ALL by semiquantitative immunoglobulin H gene analysis on bone marrow samples collected during four time bands in the first 24 months of treatment. Fifty patients received chemotherapy only and 35 patients received allogeneic (n = 19) or autologous (n = 16) bone marrow transplantation (BMT) in first clinical remission. The relationship between MRD status and clinical outcome was investigated and compared with age, sex, immunophenotype, and presenting WBC count.

RESULTS: Fisher’s exact test established a statistically significant concordance between MRD results and clinical outcome at all times. Disease-free survival (DFS) rates for MRD-positive and -negative patients and log-rank testing established that MRD positivity was associated with increased relapse rates at all times (P < .05) but was most significant at 3 to 5 months after induction and beyond. MRD status after allogeneic BMT rather than before was found to be an important predictor of outcome in 19 adult patients with ALL tested. In patients receiving autologous BMT (n = 16), the MRD status before BMT was more significant (P = .005).

CONCLUSION: The association of MRD test results and DFS was independent of and greater than other standard predictors of outcome and is therefore important in determining treatment for individual patients.
Phase I Clinical and Pharmacologic Trial of Intravenous Estramustine Phosphate
Authors: Hudes Gary , Haas Naomi , Yeslow Gwen , Gillon Thomas , Gunnarsson Per Olov , Ellman Marianne , Nordle Orjan , Eriksson Brigitta , Miller Langdon , Cisar Laura , Kopreski Michael , Viaro Donatella , Hartley-Asp Beryl
Published: February 2017

PURPOSE: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP).

PATIENTS AND METHODS: A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m2. Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment.

RESULTS: The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m2, and cumulative fatigue developed after multiple cycles at 2,500 mg/m2. Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 μmol/L after IV EMP doses ≥ 2,000 mg/m2.

CONCLUSION: High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.
Epithelial Ovarian Cancer Metastasizing to the Brain: A Late Manifestation of the Disease With an Increasing Incidence
Authors: Kolomainen Desiree F. , Larkin James M.G. , Badran Mohammad , A’Hern Roger P. , King D. Michael , Fisher Cyril , Bridges Jane E. , Blake Peter R. , Barton Desmond P.J. , Shepherd John H. , Kaye Stanley B. , Gore Martin E.
Published: February 2017

PURPOSE: We present the Royal Marsden Hospital experience of cerebral metastases from primary epithelial ovarian carcinoma (EOC) over the last 20 years and examine the evidence for an increasing incidence of EOC metastasizing to this site.

PATIENTS AND METHODS: A total of 3,690 women with EOC were seen at the Royal Marsden Hospital from 1980 to 2000. Eighteen of these patients developed cerebral metastases.

RESULTS: Median age at diagnosis of EOC was 52 years (range, 39 to 67). All patients received at least one line of platinum-based chemotherapy; 56% (10 of 18) received more than one line of treatment; 17% (three of 18), two lines; 11% (two of 18), three lines; and 28% (five of 18), four lines. The median treatment interval between each line of chemotherapy was 12, 18, and 4 months. The median interval between diagnosis and CNS relapse was 46 months (range, 12 to 113), in comparison with 5 and 7.5 months for hematogenous relapse in lung or liver, respectively (P < .001). The incidence of CNS metastases in our population from 1980 to 1984 was 0.2%; from 1985 to 1989, 0%; from 1990 to 1994, 0.3%; and from 1995 to 1999, 1.3% (P < .001). An analysis of data from the literature also suggests that the incidence of cerebral metastases from EOC has increased over time.

CONCLUSION: CNS metastases in EOC are a rare and late manifestation of the disease, occurring in patients with a prolonged survival caused by repeated chemosensitive relapses. An analysis of our data and the data from the literature suggests that the incidence of metastasis at this site in patients with EOC is increasing.
Mutations of hMLH1 and hMSH2 in Patients With Suspected Hereditary Nonpolyposis Colorectal Cancer: Correlation With Microsatellite Instability and Abnormalities of Mismatch Repair Protein Expression
Authors: Scartozzi Mario , Bianchi Francesca , Rosati Saverio , Galizia Eva , Antolini Annalisa , Loretelli Cristian , Piga Andrea , Bearzi Italo , Cellerino Riccardo , Porfiri Emilio
Published: February 2017

PURPOSE: The relationship between germ-line mutations of hMSH2 and hMLH1, microsatellite instability (MSI), and loss of DNA mismatch repair (MMR) gene expression were studied to formulate an effective selection protocol for patients with suspected hereditary nonpolyposis colorectal cancer who should be offered genetic testing.

PATIENTS AND METHODS: Patients eligible for germ-line analysis of hMLH1 and hMSH2 were selected. Tumor specimens were obtained to assess MSI and loss of MMR gene expression.

RESULTS: Among 37 patients who participated in the study, two hMSH2 and two hMLH1 missense mutations (11%) were detected, none of which was found in a panel of 60 healthy volunteers. High MSI was found in five tumors (19%) and low MSI in 10 tumors (39%); 12 tumors (46%) were microsatellite stable. Four tumors demonstrated loss of hMLH1, and three tumors demonstrated loss of hMSH2 protein expression.

CONCLUSION: No relationship was found between MMR gene mutations and MSI; low or no MSI was found in the four patients with germ-line mutations, and none of the five patients with high MSI demonstrated abnormalities of MMR genes. On the contrary, loss of hMLH1 or hMSH2 expression was found in the tumors from three of the four patients demonstrating germ-line mutations. These data suggest that germ-line mutations of the MMR gene can occur in people with MSI-negative tumors. Sensitive clinical criteria and the study of MMR gene expression may be useful to identify this subset of patients.
Outcome of Preventive Surgery and Screening for Breast and Ovarian Cancer in BRCA Mutation Carriers
Authors: Scheuer Lauren , Kauff Noah , Robson Mark , Kelly Bridget , Barakat Richard , Satagopan Jaya , Ellis Nathan , Hensley Martee , Boyd Jeff , Borgen Patrick , Norton Larry , Offit Kenneth
Published: February 2017

PURPOSE: To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer.

PATIENTS AND METHODS: Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians.

RESULTS: Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker–based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing.

CONCLUSION: This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.
Improved Outcome of Allogeneic Transplantation in High-Risk Multiple Myeloma Patients After Nonmyeloablative Conditioning
Authors: Badros Ashraf , Barlogie Bart , Siegel Eric , Cottler-Fox Michele , Zangari Maurizio , Fassas Athanasios , Morris Christopher , Anaissie Elias , Van Rhee Frits , Tricot Guido
Published: February 2017

PURPOSE: We present our experience with relapsed and recently diagnosed patients with high-risk multiple myeloma (MM) receiving immunosuppressive, nonmyeloablative melphalan (MEL)-based conditioning regimens (mini-allograft).

PATIENTS AND METHODS: Thirty-one MM patients received allografts from HLA-matched siblings (n = 25) or unrelated donors (n = 6) using a mini-allograft. Seventeen had progressive disease (PD) and 14 had responsive disease (RD) (six with primary RD and eight with responsive relapse). Thirty patients had received one (n = 13) or two or more (n = 17) prior autologous transplantations (ATs). Median age was 56 years (range, 38 to 69 years). Twenty-one patients had chromosome 13 abnormality. Two patients were hemodialysis dependent. Blood and bone marrow grafts were administered to 28 and three patients, respectively. Donor lymphocyte infusions were given to 18 patients either to attain full donor chimerism (n = 6) or to eradicate residual disease (n = 12).

RESULTS: By day 100, 25 (89%) of 28 patients were full donor chimeras, one was a mixed chimera, and two had autologous reconstitution. Acute graft-versus-host disease (GVHD) developed in 18 patients (58%), and 10 progressed to chronic GVHD (limited in six and extensive in four). At a median follow-up of 6 months, 19 (61%) of 31 patients achieved complete/near complete remission. Twelve patients (39%) have died: three of PD, three of early treatment-related mortality (TRM) (before day 100), and six of late TRM. Median overall survival (OS) was 15 months. At 1 year, there was a significantly longer event-free survival (86% v 31%, P = .01) and OS (86% v 48%, P = .04) when a mini-allograft was performed after one versus two or more prior ATs, respectively. When compared with historical MM controls (n = 93) receiving conventional allografts, early TRM was significantly lower (10% v 29%, P = .03), and OS at 1 year was better (71% v 45%; P = .08) in the mini-allograft MM patients.

CONCLUSION: Mini-allograft induced excellent disease control in MM patients with high-risk disease, but is still associated with a significant GVHD.
Phase III Trial of Fluorouracil, Interferon Alfa-2b, and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Metastatic or Unresectable Urothelial Cancer
Authors: Siefker-Radtke Arlene O. , Millikan Randall E. , Tu Shi-Ming , Moore Dennis F. , Smith Terry L. , Williams Dallas , Logothetis Christopher J.
Published: February 2017

PURPOSE: Previously, we developed a novel biochemotherapy regimen combining interferon alfa-2b with fluorouracil and cisplatin (FAP). We now report the results of a prospective randomized trial comparing FAP with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), the standard chemotherapy regimen for locally advanced and metastatic urothelial cancer. The purpose of this study was to compare the response rates and overall survival of patients with metastatic or unresectable urothelial cancer treated with these two chemotherapy regimens.

PATIENTS AND METHODS: Between October 1992 and September 1999, 172 previously untreated patients were registered and randomly assigned to treatment with either FAP or M-VAC. Patients were followed until their death.

RESULTS: The pretreatment clinical characteristics of the groups were similar except for sex (P < .01). Sex did not affect prognosis or survival. The objective response rate for patients assigned to FAP was 42% (35 of 83 patients), with complete response observed in eight (10%) of 83 patients. Among the patients assigned to M-VAC, 51 (59%) of 86 had an objective response, with complete response observed in 21 (24%) of 86. The Kaplan-Meier estimate of median survival was 12.5 months for both groups. Both regimens were quite toxic, with more mucocutaneous toxicity in the FAP arm and more myelosuppression in the M-VAC arm.

CONCLUSION: Although overall survival was not significantly different, patients assigned to M-VAC had a much better chance of responding to front-line therapy. Thus, FAP is very likely to be inferior to M-VAC and is certainly no less toxic. FAP cannot be recommended as part of the standard armamentarium for urothelial cancer.
Promising Survival for Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Concomitant Radiation Plus Temozolomide Followed by Adjuvant Temozolomide
Authors: Stupp Roger , Dietrich Pierre-Yves , Kraljevic Sandrine Ostermann , Pica Alessia , Maillard Ivan , Maeder Phillipe , Meuli Reto , Janzer Robert , Pizzolato Gianpaolo , Miralbell Raymond , Porchet François , Regli Luca , de Tribolet Nicolas , Mirimanoff René O. , Leyvraz Serge
Published: February 2017

PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM.

PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m2/d × 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy × 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m2/d × 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival.

RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome.

CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.
Phase II Trial of Murine 131I-Labeled Antitenascin Monoclonal Antibody 81C6 Administered Into Surgically Created Resection Cavities of Patients With Newly Diagnosed Malignant Gliomas
Authors: Reardon David A. , Akabani Gamal , Edward Coleman R. , Friedman Allan H. , Friedman Henry S. , Herndon James E. , Cokgor Ilkcan , McLendon Roger E. , Pegram Charles N. , Provenzale James M. , Quinn Jennifer A. , Rich Jeremy N. , Regalado Lorna V. , Sampson John H. , Shafman Timothy D. , Wikstrand Carol J. , Wong Terence Z. , Zhao Xiao-Guang , Zalutsky Michael R. , Bigner Darell D.
Published: February 2017

PURPOSE: To assess the efficacy and toxicity of intraresection cavity 131I-labeled murine antitenascin monoclonal antibody 81C6 and determine its true response rate among patients with newly diagnosed malignant glioma.

PATIENTS AND METHODS: In this phase II trial, 120 mCi of 131I-labeled murine 81C6 was injected directly into the surgically created resection cavity of 33 patients with previously untreated malignant glioma (glioblastoma multiforme [GBM], n = 27; anaplastic astrocytoma, n = 4; anaplastic oligodendroglioma, n = 2). Patients then received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy.

RESULTS: Median survival for all patients and those with GBM was 86.7 and 79.4 weeks, respectively. Eleven patients remain alive at a median follow-up of 93 weeks (range, 49 to 220 weeks). Nine patients (27%) developed reversible hematologic toxicity, and histologically confirmed, treatment-related neurologic toxicity occurred in five patients (15%). One patient (3%) required reoperation for radionecrosis.

CONCLUSION: Median survival achieved with 131I-labeled 81C6 exceeds that of historical controls treated with conventional radiotherapy and chemotherapy, even after accounting for established prognostic factors including age and Karnofsky performance status. The median survival achieved with 131I-labeled 81C6 compares favorably with either 125I interstitial brachy-therapy or stereotactic radiosurgery and is associated with a significantly lower rate of reoperation for radionecrosis. Our results confirm the efficacy of 131I-labeled 81C6 for patients with newly diagnosed malignant glioma and suggest that a randomized phase III study is indicated.
Neoadjuvant Chemotherapy in Breast Cancer: Significantly Enhanced Response With Docetaxel
Authors: Smith Ian C. , Heys Steven D. , Hutcheon Andrew W. , Miller Iain D. , Payne Simon , Gilbert Fiona J. , Ah-See Antoinne K. , Eremin Oleg , Walker Leslie G. , Sarkar Tarun K. , Eggleton S. Peter , Ogston Keith N.
Published: February 2017

PURPOSE: To compare the efficacy of neoadjuvant (NA) docetaxel (DOC) with anthracycline-based therapy and determine the efficacy of NA DOC in patients with breast cancer initially failing to respond to anthracycline-based NA chemotherapy (CT).

PATIENTS AND METHODS: Patients with large or locally advanced breast cancer received four pulses of cyclophosphamide 1,000 mg/m2, doxorubicin 50 mg/m2, vincristine 1.5 mg/m2, and prednisolone 40 mg (4 × CVAP) for 5 days. Clinical tumor response was assessed. Those who responded (complete response [CR] or partial response [PR]) were randomized to receive further 4 × CVAP or 4 × DOC (100 mg/m2). All nonresponders received 4 × DOC.

RESULTS: One hundred sixty-two patients were enrolled; 145 patients completed eight cycles of NA CT. One hundred two patients (66%) achieved a clinical response (PR or CR) after 4 × CVAP. After randomization, 50 patients received 4 × CVAP and 47 patients received 4 × DOC. In patients who received eight cycles of CT, the clinical CR (cCR) and clinical PR (cPR) (94% v 66%) and pathologic CR (pCR) (34% v 16%) response rates were higher (P = .001 and P = .04) in those who received further DOC. Intention-to-treat analysis demonstrated cCR and cPR (85% v 64%; P = .03) and pCR (31% v 15%; P = .06). Axillary lymph node examination revealed residual tumor in 33% of patients who received 8 × CVAP and 38% of patients who received further DOC. In patients who failed to respond to the initial CVAP, 4 × DOC resulted in a cCR and cPR rate of 55% and a pCR rate of 2%. Forty-four percent of these patients had residual tumor within axillary lymph nodes.

CONCLUSION: NA DOC resulted in substantial improvement in responses to DOC.
Effect of Graded Testicular Doses of Radiotherapy in Patients Treated for Carcinoma-In-Situ in the Testis
Authors: Petersen Peter Meidahl , Giwercman Aleksander , Daugaard Gedske , Rørth Mikael , Petersen Jørgen Holm , Skakkebæk Niels E. , Hansen Steen W. , von der Maase Hans
Published: February 2017

PURPOSE: To determine the effect of radiotherapy in doses 14 to 20 Gy on eradication of carcinoma-in-situ (CIS) testis and on the Leydig cell function.

PATIENTS AND METHODS: Forty-eight patients presented with unilateral testicular germ cell cancer and CIS of the contralateral testis. The CIS-bearing testis was treated with daily irradiation doses of 2 Gy, 5 days a week, to a cumulative dose of 20 Gy (21 patients), 18 Gy (three patients), 16 Gy (10 patients), and 14 Gy (14 patients).

RESULTS: All patients treated at dose levels 20 Gy to 16 Gy achieved histologically verified complete remission without signs of recurrence of CIS after an observation period of more than 5 years. One of 14 patients treated at dose level 14 Gy had a relapse of CIS 20 months after irradiation. Leydig cell function was examined before and regularly after radiotherapy in 44 of 48 patients. The levels of testosterone were lower after radiotherapy than before. Testosterone showed a stable decrease for more than 5 years after treatment (3.6% per year) without dose dependency. The levels of luteinizing hormone and follicle-stimulating hormone were increased after radiotherapy. The need of androgen substitution therapy was similar at all dose levels.

CONCLUSION: Testicular irradiation is a safe treatment at dose level 20 Gy (10 × 2 Gy). Decrease of dose to 14 Gy (7 × 2 Gy) might lead to risk of relapse of CIS. Impairment of hormone production without clinically significant dose dependency is seen in the dose range 14 to 20 Gy.
Phase III Evaluation of Fluoxetine for Treatment of Hot Flashes
Authors: Loprinzi Charles L. , Sloan Jeff A. , Perez Edith A. , Quella Susan K. , Stella Phillip J. , Mailliard James A. , Halyard Michele Y. , Pruthi Sandhya , Novotny Paul J. , Rummans Teresa A.
Published: February 2017

PURPOSE: Hot flashes can be a prominent problem in women with a history of breast cancer. Given concerns regarding the use of hormonal therapies in such patients, other nonhormonal means for treating hot flashes are required. Based on anecdotal information regarding the efficacy of fluoxetine and other newer antidepressants for treating hot flashes, the present trial was developed.

PATIENTS AND METHODS: This trial used a double-blinded, randomized, two-period (4 weeks per period), cross-over methodology to study the efficacy of fluoxetine (20 mg/d) for treating hot flashes in women with a history of breast cancer or a concern regarding the use of estrogen (because of breast cancer risk). Eligible patients had to have reported that they averaged at least 14 hot flashes per week; they could have received tamoxifen or raloxifene as long as they were on a stable dose. The major outcome measure was a bivariate construct representing hot flash frequency and hot flash score, analyzed by a classic sums and differences cross-over analysis.

RESULTS: Eighty-one randomized women began protocol therapy. By the end of the first treatment period, hot flash scores (frequency × average severity) decreased 50% in the fluoxetine arm versus 36% in the placebo arm. Cross-over analysis demonstrated a significantly greater marked hot flash score improvement with fluoxetine than placebo (P = .02). The results were not adjusted for potential confounding influences, including age and tamoxifen use. The fluoxetine was well tolerated.

CONCLUSION: This dose of fluoxetine resulted in a modest improvement in hot flashes.
Prognostic Factors for Malignant Transformation in Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma
Authors: Cesana Clara , Klersy Catherine , Barbarano Luciana , Nosari Anna Maria , Crugnola Monica , Pungolino Ester , Gargantini Livio , Granata Simonetta , Valentini Marina , Morra Enrica
Published: February 2017

PURPOSE: To evaluate the natural history of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), identify early predictors of evolution, and assess whether associated conditions correlate with disease progression.

PATIENTS AND METHODS: A total of 1,231 consecutive patients with either MGUS (n = 1,104) or SMM (n = 127) diagnosed from July 1975 to March 1998 were included in the study. Cumulative survival probability and cumulative probability of transformation into lymphoproliferative disease were calculated by means of the Kaplan-Meier estimator. Univariate and multivariate Cox models were used to identify possible predictors of malignant evolution.

RESULTS: Cumulative transformation probability at 10 and 15 years was 14% and 30%, respectively. At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenström’s macroglobulinemia (n = 12), non-Hodgkin’s lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247 months), 25 SMMs (19.7%) evolved to overt MM. A lower evolution risk was observed in MGUS than in SMM (P < .0001). Greater than 5% marrow plasmacytosis, detectable Bence Jones proteinuria, polyclonal serum immunoglobulin reduction, and high erythrocyte sedimentation rate (ESR) were independent factors influencing MGUS transformation. SMM progression correlated with greater than 10% marrow plasma cells, detectable Bence Jones proteinuria, and immunoglobulin (Ig) A isotype. Neither concomitant diseases nor immunosuppression correlated with progression.

CONCLUSION: Careful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.
Hepatic Drug Targeting: Phase I Evaluation of Polymer-Bound Doxorubicin
Authors: Seymour Leonard W. , Ferry David R. , Anderson David , Hesslewood Stuart , Julyan Peter J. , Poyner Richard , Doran Jayne , Young Annie M. , Burtles Sally , Kerr David J.
Published: February 2017

PURPOSE: Preclinical studies have shown good anticancer activity following targeting of a polymer bearing doxorubicin with galactosamine (PK2) to the liver. The present phase I study was devised to determine the toxicity, pharmacokinetic profile, and targeting capability of PK2.

PATIENTS AND METHODS: Doxorubicin was linked via a lysosomally degradable tetrapeptide sequence to N-(2-hydroxypropyl)methacrylamide copolymers bearing galactosamine. Targeting, toxicity, and efficacy were evaluated in 31 patients with primary (n = 25) or metastatic (n = 6) liver cancer. Body distribution of the radiolabelled polymer conjugate was assessed using gamma-camera imaging and single-photon emission computed tomography.

RESULTS: The polymer was administered by intravenous (IV) infusion over 1 hour, repeated every 3 weeks. Dose escalation proceeded from 20 to 160 mg/m2(doxorubicin equivalents), the maximum-tolerated dose, which was associated with severe fatigue, grade 4 neutropenia, and grade 3 mucositis. Twenty-four hours after administration, 16.9% ± 3.9% of the administered dose of doxorubicin targeted to the liver and 3.3% ± 5.6% of dose was delivered to tumor. Doxorubicin-polymer conjugate without galactosamine showed no targeting. Three hepatoma patients showed partial responses, with one in continuing partial remission 47 months after therapy.

CONCLUSION: The recommended PK2 dose is 120 mg/m2, administered every 3 weeks by IV infusion. Liver-specific doxorubicin delivery is achievable using galactosamine-modified polymers, and targeting is also seen in primary hepatocellular tumors.
Doxorubicin Administration by Continuous Infusion Is Not Cardioprotective: The Dana-Farber 91-01 Acute Lymphoblastic Leukemia Protocol
Authors: Lipshultz Steven E. , Giantris Amy L. , Lipsitz Stuart R. , Dalton Virginia Kimball , Asselin Barbara L. , Barr Ronald D. , Clavell Luis A. , Hurwitz Craig A. , Moghrabi Albert , Samson Yvan , Schorin Marshall A. , Gelber Richard D. , Sallan Stephen E. , Colan Steven D.
Published: February 2017

PURPOSE: Acute doxorubicin-induced cardiotoxicity can be prevented in adults by continuous infusion of the drug, but mechanisms of cardiotoxicity are different in children. We compared cardiac outcomes in children receiving bolus or continuous infusion of doxorubicin.

PATIENTS AND METHODS: In a randomized study, children with high-risk acute lymphoblastic leukemia received doxorubicin 360 mg/m2 in 30-mg/m2 doses every 3 weeks either by bolus (within 1 hour, n = 57) or by continuous infusion (over 48 hours, n = 64). Echocardiograms obtained before doxorubicin and at longest follow-up times were centrally remeasured, and z scores of cardiac measurements were calculated based on a healthy population.

RESULTS: The groups were similar in age, sex distribution, doxorubicin dose, and duration of follow-up. Before treatment, measures of left ventricular (LV) structure and function did not reveal dilated cardiomyopathy and were not statistically different between bolus and continuous-infusion groups. The follow-up echocardiograms demonstrated no significant difference between the two groups for any cardiac characteristic, but both groups showed significant abnormalities of LV structure and function compared with normal and with baseline. For example, the mean LV fractional shortening fell by approximately two SD in both groups between the two echocardiograms. LV contractility was depressed in both groups (for bolus patients, median z score = −0.70 SD, P = .006; for continuous-infusion patients, median z score = −0.765, P = .005). Dilated cardiomyopathy and inadequate LV hypertrophy were noted in both groups. Clinical cardiac manifestations and event-free survival did not differ.

CONCLUSION: Continuous doxorubicin infusion over 48 hours for childhood leukemia did not offer a cardioprotective advantage over bolus infusion. Both regimens were associated with progressive subclinical cardiotoxicity. Other cardioprotective strategies should be explored.