bluuebunny/crossref_metadata_2025 huggingface dataset:
Prohibitionist Protests by Women in India’s Northeast
Authors: Deka Kaustubh
Published: February 2017

The body of women in India’s northeast is both racialized and gendered as the region continues to be constructed through the binaries of post-colonial sate-society conflicts and often treated as the ‘other’ of the nation state. A conflict centric approach however has mostly focused on women’s interventions in the society from the perspective of their ‘peace making’ capacities and thus obscuring some other significant roles performed historically by organized women power in the region: activities that predate and, in fact, in some crucial ways influence their gradual mobilization towards the role of peace making. Some of the prominent women led social movements that began in the decades of 1970s and 1980s around the issue of alcohol prohibition had gradually transformed into movements taking up issues of human rights violations and peace negotiations besides others. In this context it is interesting to look into the instances of anti-alcohol or prohibitionist protests undertaken by women in India’s northeast, specially focusing on prominent women’s groups in the states of Manipur and Nagaland, that points at the complex roles played by women’s groups in crafting a public space for the women to articulate their opinion in these societies even when they face challenges from within and without and come to terms with the dilemmas of having to take some difficult position both against the state and the community.
Satyagraha of Common People
Authors: Jha Jyotsna
Published: February 2017

One often comes across women and men who are satyagrahis without being part of any movement. This is a piece on such satyagrahis: to celebrate them and to think about the ways and means in which satyagraha unfolds, and inspires. The article narrates stories of four different people who decided to follow the path of resistance – against the mainstream current – to be able to stand up to their own conviction and beliefs. The article argues that these and probably thousand of others who are practicing some or the other aspect of satyagraha in their daily lives, are also satyagrahis. It is time to celebrate the survival and flourishing of satyagrahi instincts of common people who are living and also dying in some cases – for their principles and conviction. This is their search for and insistence on truth, and indeed a tribute to Gandhi’s satyagraha.
Contextualizing Satyagraha within the Feminist Movement in the US
Authors: Sharma Ayesha
Published: February 2017

The author argues that the mainstream US feminist historical documentation framework—the feminist waves—have organized feminist history to primarily record historical events that involve high status women (i.e white middle-class cisgender women). This paper dissects the feminist waves to suggest that their key events and actors represent the centering of a socially privileged group. The author analyzes the framework to understand the ways in which the waves may encourage this privileging—largely through the erasure and exclusion of the personal and political truths of the most vulnerable feminists and their satyagraha against intertwining inequalities at the grassroots.
PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells
Authors: Naudin Cécile , Hattabi Aurore , Michelet Fabio , Miri-Nezhad Ayda , Benyoucef Aissa , Pflumio Françoise , Guillonneau François , Fichelson Serge , Vigon Isabelle , Dusanter-Fourt Isabelle , Lauret Evelyne
Published: February 2017

Key Points

The RNA regulators PUMILIO sustain HSPC and acute myeloid leukemia cell growth by upregulating FOXP1 expression through direct binding to 2 FOXP1-3′UTR PUMILIO-binding elements. FOXP1 mediates PUMILIO growth-promoting activities by repressing expression of p21CIP1 and p27KIP1cell cycle inhibitors.
Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry
Authors: Jo Helen E. , Glaspole Ian , Grainge Christopher , Goh Nicole , Hopkins Peter M.A. , Moodley Yuben , Reynolds Paul N. , Chapman Sally , Walters E. Haydn , Zappala Christopher , Allan Heather , Keir Gregory J. , Hayen Andrew , Cooper Wendy A. , Mahar Annabelle M. , Ellis Samantha , Macansh Sacha , Corte Tamera J.
Published: February 2017

The prevalence of idiopathic pulmonary fibrosis (IPF), a fatal and progressive lung disease, is estimated at 1.25–63 out of 100 000, making large population studies difficult. Recently, the need for large longitudinal registries to study IPF has been recognised.

The Australian IPF Registry (AIPFR) is a national registry collating comprehensive longitudinal data of IPF patients across Australia. We explored the characteristics of this IPF cohort and the effect of demographic and physiological parameters and specific management on mortality.

Participants in the AIPFR (n=647, mean age 70.9±8.5 years, 67.7% male, median follow up 2 years, range 6 months–4.5 years) displayed a wide range of age, disease severity and co-morbidities that is not present in clinical trial cohorts. The cumulative mortality rate in year one, two, three and four was 5%, 24%, 37% and 44% respectively. Baseline lung function (forced vital capacity, diffusing capacity of the lung for carbon monoxide, composite physiological index) and GAP (gender, age, physiology) stage (hazard ratio 4.64, 95% CI 3.33–6.47, p<0.001) were strong predictors of mortality. Patients receiving anti-fibrotic medications had better survival (hazard ratio 0.56, 95% CI 0.34–0.92, p=0.022) than those not on anti-fibrotic medications, independent of underlying disease severity.

The AIPFR provides important insights into the understanding of the natural history and clinical management of IPF.
Is the lower return to immigrants’ foreign schooling a postarrival problem in Canada?
Authors: Aydede Yigit , Dar Atul
Published: February 2017

Using the 2006 Canadian Census, this paper investigates the lower return to immigrants’ foreign education credentials after adjusting for their occupational matching in hosting labor markets. We develop two continuous indices that quantify the matching quality of the native-born in both horizontal (fields of study) and vertical (educational degrees) dimensions. This allows us to separate the effects of immigrants’ occupational attainment and their foreign schooling quality on wage earnings by measuring immigrants’ occupational match relative to that of native-born. Our findings indicate that the lack of portability in immigrants’ foreign credentials may not be addressed effectively by postarrival policies as the results show that a significant and persistent poor matching quality for internationally educated immigrants cannot substantiate the lower return to their foreign education credentials.

JEL Classification:J6, J15, J61
Experiences of Judeo-Christian Students in Undergraduate Biology
Authors: Barnes M. Elizabeth , Truong Jasmine M. , Brownell Sara E.
Published: February 2017

A major research thrust in science, technology, engineering, and mathematics (STEM) education is focused on how to retain students as STEM majors. The accumulation of seemingly insignificant negative experiences in STEM classes can, over time, lead STEM students to have a low sense of belonging in their disciplines, and this can lead to lower retention. In this paper, we explore how Judeo-Christian students in biology have experiences related to their religious identities that could impact their retention in biology. In 28 interviews with Judeo-Christian students taking undergraduate biology classes, students reported a religious identity that can conflict with the secular culture and content of biology. Some students felt that, because they are religious, they fall within a minority in their classes and would not be seen as credible within the biology community. Students reported adverse experiences when instructors had negative dispositions toward religion and when instructors were rigid in their instructional practices when teaching evolution. These data suggest that this may be a population susceptible to experiences of cultural conflict between their religious identities and their STEM identities, which could have implications for retention. We argue that more research should explore how Judeo-Christian students’ experiences in biology classes influence their sense of belonging and retention.
Sparse-promoting full-waveform inversion based on online orthonormal dictionary learning
Authors: Zhu Lingchen , Liu Entao , McClellan James H.
Published: February 2017

Full-waveform inversion (FWI) delivers high-resolution images of the subsurface by minimizing iteratively the misfit between recorded and calculated seismic data. We have attacked this misfit successfully with the Gauss-Newton method and sparsity-promoting regularization based on fixed multiscale transforms that permit significant subsampling of the seismic data when the model perturbation at each FWI data-fitting iteration can be represented with sparse coefficients. Rather than using analytical transforms with predefined dictionaries to achieve sparse representation, we developed an adaptive transform called the sparse orthonormal transform (SOT), whose dictionary is learned from many small training patches taken from the model perturbations in previous iterations. The patch-based dictionary is constrained to be orthonormal and trained with an online approach to provide the best sparse representation of the complex features and variations in the entire model perturbation. The complexity of the training method is proportional to the cube of the number of samples in one small patch. By incorporating compressive subsampling and the adaptive SOT-based representation into the Gauss-Newton least-squares problem for each FWI iteration, the model perturbation can be recovered after an [Formula: see text]-norm sparsity constraint is applied on the SOT coefficients. Numerical experiments on synthetic models determined that the SOT-based sparsity-promoting regularization can provide robust FWI results with reduced computation.
Graphs to estimate an individualized risk of breast cancer.
Authors: Benichou J , Gail M H , Mulvihill J J
Published: February 2017

PURPOSE

Clinicians who counsel women about their risk for developing breast cancer need a rapid method to estimate individualized risk (absolute risk), as well as the confidence limits around that point. The Breast Cancer Detection Demonstration Project (BCDDP) model (sometimes called the Gail model) assumes no genetic model and simultaneously incorporates five risk factors, but involves cumbersome calculations and interpolations. This report provides graphs to estimate the absolute risk of breast cancer from the BCDDP model.

PATIENTS AND METHODS

The BCDDP recruited 280,000 women from 1973 to 1980 who were monitored for 5 years. From this cohort, 2,852 white women developed breast cancer and 3,146 controls were selected, all with complete risk-factor information. The BCDDP model, previously developed from these data, was used to prepare graphs that relate a specific summary relative-risk estimate to the absolute risk of developing breast cancer over intervals of 10, 20, and 30 years.

RESULTS

Once a summary relative risk is calculated, the appropriate graph is chosen that shows the 10-, 20-, or 30-year absolute risk of developing breast cancer. A separate graph gives the 95% confidence limits around the point estimate of absolute risk. Once a clinician rules out a single gene trait that predisposes to breast cancer and elicits information on age and four risk factors, the tables and figures permit an estimation of a women's absolute risk of developing breast cancer in the next three decades.

CONCLUSION

These results are intended to be applied to women who undergo regular screening. They should be used only in a formal counseling program to maximize a woman's understanding of the estimates and the proper use of them.
Two schedules of teniposide with or without cisplatin in advanced non-small-cell lung cancer: a randomized study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.
Authors: Splinter T A , Sahmoud T , Festen J , van Zandwijk N , Sörenson S , Clerico M , Burghouts J , Dautzenberg B , Kho G S , Kirkpatrick A , Giaccone G
Published: February 2017

PURPOSE

We conducted a randomized trial to investigate the value of the addition of cisplatin to teniposide (VM26) and to investigate the schedule dependence of the topoisomerase II inhibitor VM26, in advanced non-small-cell lung cancer (NSCLC) patients.

PATIENTS AND METHODS

Two hundred twenty-five NSCLC patients were randomized to receive VM26 120 mg/m2 on days 1, 3, and 5 or 360 mg/m2 on day 1 only, either as a single drug or in combination with cisplatin 80 mg/m2 on day 1. Cycles were repeated every 3 weeks. Response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study.

RESULTS

The response rate of the two cisplatin-containing arms was superior to that of the two arms that contained VM26 only (22% v 6%, P < .001); progression-free survival and survival times were also longer in the cisplatin-containing arms (median, 4.3 v 2.2 months, P = .003; median 7.2 v 5.9 months, P = .008, respectively). Toxicity was significantly higher in the cisplatin-containing arms; the most frequent side effects were leukopenia, nausea and vomiting, and alopecia. The schedule of VM26 did not significantly influence the response rate, progression-free survival interval, or survival duration. However, the response rate of the 1-day administration was significantly lower than that of the 3-day administration when given as single drugs.

CONCLUSION

The addition of cisplatin to VM26 improves the response rate, progression-free survival interval, and survival duration over VM26 alone, although at the cost of a significant increase in toxicity. Cisplatin should be considered as the basis for combination chemotherapies in advanced NSCLC.
Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: a North Central Cancer Treatment Group study.
Authors: Rowland K M , Loprinzi C L , Shaw E G , Maksymiuk A W , Kuross S A , Jung S H , Kugler J W , Tschetter L K , Ghosh C , Schaefer P L , Owen D , Washburn J H , Webb T A , Mailliard J A , Jett J R
Published: February 2017

PURPOSE

Megestrol acetate has been reported to improve appetite and quality of life and to decrease nausea and vomiting in patients with cancer anorexia/cachexia. The present trial was formulated to evaluate the impact of megestrol acetate on quality of life, toxicity, response, and survival in individuals with extensive-stage small-cell lung cancer who received concomitant chemotherapy.

PATIENTS AND METHODS

Patients were randomized to receive megestrol acetate 800 mg/d orally or placebo. In addition, all patients were scheduled to receive a maximum of four cycles of cisplatin and etoposide chemotherapy. Quality of life was self-assessed at entry onto study, with every cycle of chemotherapy, and 4 months thereafter with a linear visual analog scale. Toxicity was evaluated by patient questionnaire and investigator reports.

RESULTS

A total of 243 eligible patients were randomized. Those who received megestrol acetate had increased nonfluid weight gain (P = .004) and significantly less nausea (P = .0002) and vomiting (P = .02). Significant thromboembolic phenomena occurred more often in patients who received megestrol acetate versus placebo (9% v 2%, P = .01). Patients who received megestrol acetate had more edema (30% v 20%, P = .002), an inferior response rate to chemotherapy (68% v 80%, P = .03), and a trend for inferior survival duration (median, 8.2 v 10.0 months, P = .49). These findings may have been influenced by a poorer quality of life of the megestrol acetate group at study initiation. There were no significant changes in quality of life scores over time between either of the study arms.

CONCLUSION

Megestrol acetate cannot be routinely recommended for all patients with small-cell lung cancer at the time of chemotherapy initiation. Rather, its therapeutic ratio may be more favorable for patients with problematic cancer anorexia/cachexia.
Neoadjuvant chemotherapy plus concurrent chemotherapy and high-dose radiation for squamous cell carcinoma of the esophagus: a preliminary analysis of the phase II intergroup trial 0122.
Authors: Minsky B D , Neuberg D , Kelsen D P , Pisansky T M , Ginsberg R , Benson A
Published: February 2017

PURPOSE

To determine the preliminary acute toxicity and survival results of neoadjuvant chemotherapy followed by concurrent chemotherapy plus high-dose radiation therapy in patients with local/regional squamous cell carcinoma of the esophagus.

MATERIALS AND METHODS

Forty-five patients with clinical stage T1-4N0-1M0 squamous cell carcinoma were entered onto the trial. Eight patients were declared ineligible after registration. Patients received three monthly cycles of fluorouracil (5-FU; 1,000 mg/m2/24hr for 5 days) and cisplatin (100 mg/m2 on day 1) (neoadjuvant segment) followed by two additional monthly cycles of 5-FU (1,000 mg/m2/24hr for 5 days) and cisplatin (75 mg/m2 on day 1) plus concurrent 64.8 Gy (combined modality segment).

RESULTS

With a median follow-up of 15 months in surviving patients, the incidence of total grade 3+ toxicity during the neoadjuvant chemotherapy segment was 61%, and during the combined modality segment was 72%. Of the 33 patients who started radiation therapy, 91% were able to complete the full course. There were six deaths during treatment, five of which (11%), because of nadir sepsis and/or dehydration, were treatment-related. For the 37 eligible patients, the median disease-free survival duration was 9 months, and the overall median survival was 20 months.

CONCLUSION

The preliminary analysis of this trial demonstrated that the incidence of grade 3+ toxicity was similar to that reported in the combined modality arm of the prior Radiation Therapy Oncology Group (RTOG) intergroup esophageal trial RTOG 85-01. However, because of the increased incidence of treatment-related mortality, this treatment program will not be used as an experimental arm of intergroup trial INT 0123 (RTOG 94-05).
Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival.
Authors: Lenz H J , Leichman C G , Danenberg K D , Danenberg P V , Groshen S , Cohen H , Laine L , Crookes P , Silberman H , Baranda J , Garcia Y , Li J , Leichman L
Published: February 2017

PURPOSE

We tested the hypothesis that polymerase chain reaction (PCR) quantitation of the enzyme thymidylate synthase (TS) within a primary adenocarcinoma of the stomach, has an inverse relationship to response and survival for patients who receive fluorouracil (5FU)-based chemotherapy.

PATIENTS AND METHODS

Before systemic chemotherapy, the genetic expression of TS (TSmRNA level) was determined using a PCR method. Gene expression was calculated by determining the ratio between the amount of radiolabeled PCR product with the linear amplification range of the TS gene and the beta-actin gene. Chemotherapy consisted of two cycles of protracted infusion (PI) 5FU 200 mg/m2/d administered for 3 weeks with leucovorin 20 mg/m2/w. Cisplatin 100 mg/m2 was administered on day 1.

RESULTS

Sixty-five patients with primary gastric cancer had a median TS mRNA level of 4.6 x 10(-3) (range, 0.9 to 20.1 x 10(-3)). Thirty-five percent of patients had measurable responses in their primary tumors. The mean gastric cancer TSmRNA level in responding and resistant patients is statistically significant (P < .001). The median survival time was 43+ months for treated patients with TSmRNA levels less than the median and 6 months for those with TS m-RNA levels greater than the median (P = .003).

CONCLUSION

The genetic expression of TS (TSmRNA level) influences response to 5FU-based chemotherapy and survival for a cohort of patients with primary gastric cancer. Confirmation of these data could lead to therapeutic decisions based on specific molecular properties within a tumor.
Significance of cytogenetic clonal evolution in chronic myelogenous leukemia.
Authors: Majlis A , Smith T L , Talpaz M , O'Brien S , Rios M B , Kantarjian H M
Published: February 2017

PURPOSE

To describe the incidence and significance of clonal evolution patterns.

PATIENTS AND METHODS

We analyzed 264 patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who developed clonal evolution between 1967 and 1993.

RESULTS

The median survival time following clonal evolution was 19 months. Factors associated with worse survival (P < .01) were as follows: chromosome 17 abnormality or chromosomal translocations other than Ph, high percentage of abnormal metaphases, longer time to clonal evolution, and presence of other accelerated-phase features. A recursive partitioning technique (CART) identified different risk groups. The best group (37 patients; no chromosome 17 abnormality, abnormal metaphases < 16%, and interval to clonal evolution < or = 24 months) had an estimated median survival time of 54 months. The worst two groups included 27 patients with chromosome 17 abnormalities and > or = 36% abnormal metaphases (estimated median survival time, 6 months), and 22 patients with other accelerated features and > or = 16% abnormal metaphases (estimated median survival time, 7 months). The intermediate group had an estimated median survival time that ranged from 13 to 24 months. Prior interferon therapy evaluated within risk groups showed a significant survival advantage only in the intermediate-risk group. A multivariate analysis showed similar results, and identified the following independent poor prognostic variables: chromosome 17 abnormality, percentage of abnormal metaphases (cutoff, 24%), longer time to clonal evolution (cutoff, 24 months), other accelerated-phase features, and no prior interferon therapy. Patients with none, one, two, three, or more of the first four features had median survivals times of 51, 24, 14, and 7 months, respectively.

CONCLUSION

The prognostic significance of clonal evolution in CML is not uniform and is related to the specific abnormality, time to its development, its predominance in metaphases, and the presence of other accelerated features, and it may be modified by specific therapies.
Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia. The Japan Leukemia Study Group.
Authors: Kobayashi T , Miyawaki S , Tanimoto M , Kuriyama K , Murakami H , Yoshida M , Minami S , Minato K , Tsubaki K , Ohmoto E , Oh H , Jinnai I , Sakamaki H , Hiraoka A , Kanamaru A , Takahashi I , Saito K , Naoe T , Yamada O , Asou N , Kageyama S , Emi N , Matsuoka A , Tomonaga M , Ohno R
Published: February 2017

PURPOSE

We analyzed complete remission (CR), disease-free survival (DFS), and event-free survival (EFS) rates in two groups of patients treated with either N4-behenoyl-1-beta-D-arabinosylcytosine (BHAC) or cytarabine, and analyzed DFS with or without ubenimex, a biologic response modifier.

PATIENTS AND METHODS

Newly diagnosed patients with acute myeloid leukemia (AML) were randomized to receive either BHAC or cytarabine as remission-induction combination chemotherapy and two courses of consolidation therapy. After maintenance/intensification therapy, patients in CR were randomized to receive either ubenimex and no drug.

RESULTS

Of 341 patients registered, 326 were assessable. The age of assessable patients ranged from 15 to 82 years (median, 48). The overall CR rate was 77%: 72% in the BHAC group and 81% in the cytarabine group, and there was a significant difference between the two groups (P = .035, chi 2 test). The predicted 55-month EFS rate of all patients was 30%: 23% in the BHAC group and 35% in the cytarabine group, with a significant difference between groups (P = .0253). The predicted 55-month DFS rate of all CR patients was 38% and that of CR patients less than 50 years of age was 47%. There was no significant difference in DFS between the ubenimex group and the group that did not receive ubenimex.

CONCLUSION

Analyses of our clinical trial showed that the use of BHAC in remission-induction therapy and in consolidation therapy resulted in poorer CR and EFS rates in adult AML patients compared with the use of cytarabine at the doses and schedules tested. Immunotherapy with ubenimex after the end of all chemotherapy did not improve DFS.
Allogeneic marrow transplantation for myelodysplastic syndrome with advanced disease morphology: a phase II study of busulfan, cyclophosphamide, and total-body irradiation and analysis of prognostic factors.
Authors: Anderson J E , Appelbaum F R , Schoch G , Gooley T , Anasetti C , Bensinger W I , Bryant E , Buckner C D , Chauncey T , Clift R A
Published: February 2017

PURPOSE

To determine if an intensive preparative regimen of busulfan (BU), cyclophosphamide (CY), and total-body irradiation (TBI) could improve outcome after marrow transplantation for advanced morphology myelodysplasia (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-T], and chronic myelomonocytic leukemia [CMML]) compared with that obtained with conventional CY/TBI and to analyze prognostic factors for transplantation for myelodysplasia.

PATIENTS AND METHODS

A phase II study was conducted of 31 patients (median age, 41 years) treated with BU (7 mg/kg), CY (50 mg/kg), TBI (12 Gy), and human leukocyte antigen (HLA)-matched (n = 23) or -mismatched (n = 2) related or unrelated donor (n = 6) marrow transplantation. Results were compared with 44 historical control patients treated with CY (120 mg/kg) and TBI.

RESULTS

The 3-year actuarial disease-free survival (DFS) rate was similar for the BU/CY/TBI group and the CY/TBI group (23% v 30%, P = .6), but there were trends toward lower relapse rates (28% v 54%, P = .27) and higher nonrelapse mortality rates (68% v 36%, P = .12) among the current patients compared with historical controls. Multivariate analysis showed that a normal karyotype pretransplant and the use of methotrexate as part of posttransplant immunosuppression were associated with improved survival and reduced nonrelapse mortality. Univariate analysis showed significant differences in relapse rates based on marrow source (57% for HLA genotypically matched marrow v 18% for all others, P = .04) and on disease morphology (66% for RAEB-T v 38% for RAEB and CMML, P = .05).

CONCLUSION

Patients with advanced morphology myelodysplasia tolerated the intensified BU/CY/TBI preparative regimen and reduced posttransplant immunosuppression poorly. Novel transplant procedures are needed to reduce relapse rates without increasing nonrelapse mortality rates. In addition, transplantation before progression to RAEB-T, if possible, may reduce the risk of relapse.
Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer.
Authors: O'Dwyer P J , Hamilton T C , LaCreta F P , Gallo J M , Kilpatrick D , Halbherr T , Brennan J , Bookman M A , Hoffman J , Young R C , Comis R L , Ozols R F
Published: February 2017

PURPOSE AND METHODS

Resistance to alkylating agents and platinum compounds is associated with elevated levels of glutathione (GSH). Depletion of GSH by buthionine sulfoximine (BSO) restores the sensitivity of resistant tumors to melphalan in vitro and in vivo. In a phase I trial, each patient received two cycles as follows: BSO alone intravenously (i.v.) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L-PAM) 15 mg/m2 i.v. 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients.

RESULTS

The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required an L-PAM dose reduction to 10 mg/m2 at BSO 7.5 g/m2. We measured GSH in peripheral mononuclear cells (PMN), and in tumor biopsies when available, at intervals following BSO dosing. In PMNs, GSH content decreased over 36 to 72 hours to reach a nadir on day 3; at the highest dose, recovery was delayed beyond day 7. The mean PMN GSH nadirs were approximately 10% of control at BSO doses > or = 7.5 g/m2; at 13 and 17 g/m2, all but two patients had nadir values in this range. GSH was depleted in sequential tumor biopsies to a variable extent, but with a similar time course. At BSO doses > or = 13 g/m2, tumor GSH was < or = 20% of starting values on day 3 in five of seven patients; recovery had not occurred by day 5. We measured plasma concentrations of R- and S-BSO by high-performance liquid chromatography (HPLC) in 22 patients throughout the dosing period. Total-body clearance (CLt) and volume of distribution at steady-state (Vss) for both isomers were dose-independent. The CLt of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in Vss were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-BSO and S-BSO, respectively.

CONCLUSION

A biochemically appropriate dose of BSO for use on this schedule is 13 g/m2, which will be used in phase II trials to be conducted in ovarian cancer and melanoma.
Clinical relevance of CD44 cell-surface expression and N-myc gene amplification in a multicentric analysis of 121 pediatric neuroblastomas.
Authors: Combaret V , Gross N , Lasset C , Frappaz D , Peruisseau G , Philip T , Beck D , Favrot M C
Published: February 2017

PURPOSE

In contrast to other human tumors, a repression of the cell-surface glycoprotein CD44 on neuroblastoma is a marker of aggressiveness that usually correlates to N-myc amplification. We thus compared the prognostic value of both markers in the initial staging of 121 children treated for neuroblastoma in collaborative institutions.

METHODS

Frozen samples were analyzed by a rapid and well-standardized technique of immunostaining with monoclonal antibodies (MoAbs) against epitopes in the CD44 constant region.

RESULTS

In this retrospective series, CD44 was expressed on 102 specimens and strongly correlated with favorable tumor stages and histology, younger age, and normal N-myc copy numbers. In univariate analysis, CD44 expression and normal N-myc were the most powerful markers of favorable clinical outcome (P < 10(-6) and chi 2 = 65.40 and P < 10(-6) and chi 2 = 42.56, respectively), but analysis of CD44 affords significant prognostic discrimination in subgroups of patients with or without N-myc-amplified tumors. In the subgroup of stage IV neuroblastomas, CD44 was the only significant prognostic marker (P < .02, chi 2 = 5.76), whereas N-myc status was not discriminant. In multivariate analysis of five factors, ie, N-myc amplification, CD44 expression, age, tumor stage, and histology, the only independent prognostic factors of event-free survival were CD44 expression and tumor stage.

CONCLUSION

The analysis of CD44 cell-surface expression must be recommended as an additional biologic marker in the initial staging of the disease.
Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684.
Authors: Kirkwood J M , Strawderman M H , Ernstoff M S , Smith T J , Borden E C , Blum R H
Published: February 2017

PURPOSE

Interferon alfa-2b (IFN alpha-2b) exhibits antitumor activity in metastatic melanoma and on this basis has been evaluated as an adjuvant therapy following surgery for deep primary (T4) or regionally metastatic (N1) melanoma.

METHODS

A randomized controlled study of IFN alpha-2b (Schering-Plough, Kenilworth, NJ) administered at maximum-tolerated doses of 20 MU/m2/d intravenously (i.v.) for 1 month and 10 MU/m2 three times per week subcutaneously (SC) for 48 weeks versus observation, was conducted by the Eastern Cooperative Oncology Group (ECOG) in 287 patients.

RESULTS

A significant prolongation of relapse-free survival (P = .0023, one-sided) and prolongation of overall survival (P = .0237, one-sided) was observed with IFN alpha-2b therapy in this trial, which is now mature with a median follow-up time of 6.9 years. The impact of treatment on relapse rate is most pronounced early during the treatment interval. The overall benefit of treatment in this trial was analyzed stratified by tumor burden and the presence or absence of microscopic nonpalpable and palpable regional lymph node metastasis. The benefit of therapy with IFN alpha-2b was greatest among node-positive strata. Toxicity of IFN alpha-2b required dose modification in the majority of patients, but treatment at > or = 80% of the scheduled dose was feasible in the majority of patients through the IV phase of treatment, and for more than 3 months of SC maintenance therapy. Discontinuation of treatment due to toxicity was infrequent after the fourth month of therapy.

CONCLUSION

IFN alpha-2b prolongs the relapse-free interval and overall survival of high-risk resected melanoma patients. The increment in median disease-free survival (from 1 to 1.7 years) and overall survival (from 2.8 to 3.8 years) that results from this therapy is associated with a 42% improvement in the fraction of patients who are continuously disease-free after treatment with IFN (from 26% to 37%) in comparison to observation. IFN alpha-2b is the first agent to show a significant benefit in relapse-free and overall survival of high-risk melanoma patients in a randomized controlled trial.
p53 nuclear protein overexpression in colorectal cancer: a dominant predictor of survival in patients with advanced hepatic metastases.
Authors: Belluco C , Guillem J G , Kemeny N , Huang Y , Klimstra D , Berger M F , Cohen A M
Published: February 2017

PURPOSE

To determine whether p53 protein expression is similar within primary colorectal cancer (CRC) and synchronous regional and distant metastases and to assess whether p53 nuclear protein expression could predict outcome in patients with synchronous unresectable liver metastases treated by hepatic artery infusional (HAI) chemotherapy.

MATERIALS AND METHODS

Paraffin sections from tumor and corresponding normal mucosa representative of 50 consecutive advanced CRC cases were examined for p53 nuclear protein expression by immunohistochemistry using the monoclonal antibody PAb 1801. Patterns of p53 nuclear expression were correlated with standard clinicopathologic variables and outcome, including response to HAI and survival. In a subset analysis, the pattern of nuclear p53 immunoreactivity was compared between primary CRC and lymph node and liver metastases.

RESULTS

Positive nuclear immunoreactivity for p53 protein was found in 72% of cases. The pattern of p53 protein expression in lymph node and liver metastases was identical to that of the primary tumor. The median survival time was 21.0 months in patients with p53-positive tumors and 53.2 months in patients with p53-negative tumors (Wilcoxon test P = .038). Two-year survival rates were 41.7% and 78.6%, respectively (P < .01). No significant difference was found in the response rates to HAI chemotherapy between the two groups. By multivariate analysis, p53 protein status was the single best predictor of survival, with a relative risk of 6.312.

CONCLUSION

Our results indicate that nuclear p53 protein status in primary CRC is similar to that in metastatic sites and may be the dominant predictor of survival in patients with advanced hepatic metastases.
c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases.
Authors: Carlomagno C , Perrone F , Gallo C , De Laurentiis M , Lauria R , Morabito A , Pettinato G , Panico L , D'Antonio A , Bianco A R , De Placido S
Published: February 2017

PURPOSE

We studied retrospectively the interaction between c-erbB2 overexpression and adjuvant tomoxifen in node-negative breast cancer patients enrolled in the Gruppo Universitario Napoletano 1 (GUN-1) trial.

PATIENTS AND METHODS

c-erbB2, evaluated by immunohistochemistry in 145 of 173 patients randomly assigned to 2-year adjuvant tamoxifen or no further therapy, was considered overexpressed if greater than 10% of the cells showed specific membrane staining. The role of each prognostic variable and their independent effect were studied using the Cox model. Disease-free (DFS) and overall (OAS) survival curves were estimated by the Kaplan-Meier method.

RESULTS

As of November 30, 1994, the median follow-up period was 12 years. c-erbB2 was overexpressed in 43 of 145 patients (29.7%), which directly correlated with tumor size and inversely with estrogen receptor (ER) level. At univariate analysis, overexpression of c-erbB2 did not affect either DFS or OAS; tamoxifen had a greater effect on reducing the risk of recurrence than of death. Addition of c-erbB2 to a multivariate Cox model that contained menopausal status, tumor size, nuclear grade, and treatment as covariates did not affect the significance of the model for DSF or OAS, whereas addition of the first-order interaction between c-erbB2 and tamoxifen was statistically significant both for DFS and OAS. The same result was obtained when the model contained ER status and ER-tamoxifen interaction. Indeed, adjuvant tamoxifen significantly prolonged DFS and OAS in c-erbB2-negative cases, whereas it had no effect on DFS and OAS in c-erbB2-positive patients.

CONCLUSION

In early-stage breast cancer patients, overexpression of c-erbB2 is a marker of lack of efficacy of adjuvant tamoxifen.
Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: the University of Texas M.D. Anderson Cancer Center experience.
Authors: Diamandidou E , Buzdar A U , Smith T L , Frye D , Witjaksono M , Hortobagyi G N
Published: February 2017

PURPOSE

Adjuvant chemotherapy for breast cancer has been the routine practice in the past decade. A number of studies have observed an increased incidence of treatment-related leukemias following chemotherapy with alkylating agents and/or topoisomerase II inhibitors. We evaluated the incidence of treatment-related leukemias in breast cancer patients treated in four adjuvant and two neoadjuvant chemotherapy trials at The University of Texas M.D. Anderson Cancer Center.

PATIENTS AND METHODS

Between 1974 and 1989, 1,474 patients with stage II or III breast cancer were treated in six prospective trials of adjuvant (n = 4) or neoadjuvant (n = 2) chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (CTX) (FAC) with or without other drugs. The median observation time was 97 months. In 1,107 patients, FAC chemotherapy was given postoperatively; 367 patients received induction chemotherapy, as well as postoperative chemotherapy. Eight hundred ten patients had surgery followed by radiotherapy and chemotherapy; 664 patients had surgery and chemotherapy only. Patients in two adjuvant and one neoadjuvant study received higher cumulative doses of CTX compared with those in the other studies.

RESULTS

Fourteen cases of leukemia were observed. Twelve of these patients had received radiotherapy and chemotherapy, and two had received chemotherapy only. Six of the reported patients with leukemia were treated with a cumulative CTX dose of greater than 6 g/ m2. Five of these patients had received both radiotherapy and chemotherapy. The median latency period in the 14 patients was 66 months (range, 22 to 113). Six of 10 patients with adequate cytogenetic analyses had abnormalities that involved chromosomes 5 and/or 7. The rest of the patients had nonspecific cytogenetic abnormalities or lacked cytogenetic information. The 10-year estimated leukemia rate was 1.5% (95% confidence interval [CI], 0.7% to 2.9%) for all patients treated, 2.5% (95% CI, 1.0% to 5.1%) for the radiotherapy-plus-chemotherapy group, and 0.5% (95% CI, 0.1% to 2.4%) for the chemotherapy-only group; this difference was statistically significant (P = .01). The 10-year estimated leukemia risk for the higher-dose (> 6 g/m2) CTX group was 2% (95% CI, 0.5% to 5.0%) compared with 1.3% (95% CI, 0.4% to 3.0%) for the lower-dose group, a difference that was not statistically significant (P = .53).

CONCLUSION

These data illustrate that patients treated with adjuvant FAC chemotherapy plus radiotherapy have a slightly increased risk of leukemia. This information needs to be considered in the treatment plans for patients with breast cancer. However, for most patients, the benefits of adjuvant therapy exceed the risk of treatment-related leukemia.
Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer.
Authors: Crawford J , O'Rourke M , Schiller J H , Spiridonidis C H , Yanovich S , Ozer H , Langleben A , Hutchins L , Koletsky A , Clamon G , Burman S , White R , Hohneker J , Spiridonitis C H
Published: February 2017

PURPOSE

This prospective randomized trial was performed to compare the effectiveness of intravenous vinorelbine tartrate with intravenous fluorouracil and leucovorin (5-FU/LV) on the primary end points of survival, quality of life (QOL), and relief of cancer-related symptoms in patients with advanced non-small-cell lung cancer (NSCLC). Secondary end points included tumor response rates and time to treatment failure. In addition, the safety of both treatment regimens was evaluated in this multicenter study.

PATIENTS AND METHODS

Two hundred sixteen patients with stage IV NSCLC were enrolled onto this study from 18 centers. Vinorelbine was administered at a dose of 30 mg/m2/wk. 5-FU/LV was administered at a dose of 425 mg/m2 and 20 mg/m2, respectively, for 5 consecutive days every 4 weeks. Patients with progressive disease or toxicity were removed from study while responding and stable patients were continued on therapy.

RESULTS

The median survival time of patients who received vinorelbine was 30 weeks, with 25% of patients alive at 1 year, compared with a median survival time of 22 weeks and 16% of patients alive at 1 year for those treated with 5-FU/LV (P = .03, log-rank test). This improvement in survival was associated with a higher objective response rate (12% v 3%) and time to treatment failure (10 weeks v 8 weeks) for vinorelbine versus 5-FU/LV. The dose-limiting toxicity of vinorelbine was granulocytopenia, with 54% of patients experiencing grade 3/4 granulocytopenia. Nonhematologic toxicity of vinorelbine was generally grade 1 or 2. The most common grade 3 toxicities were related to injection-site reactions.

CONCLUSION

This trial confirms the efficacy of vinorelbine in patients with advanced NSCLC. The clinical activity and relatively favorable toxicity profile of this agent make it a reasonable and useful treatment option in the management of patients with this disease.
Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas.
Authors: Kuttesch J F , Wexler L H , Marcus R B , Fairclough D , Weaver-McClure L , White M , Mao L , Delaney T F , Pratt C B , Horowitz M E , Kun L E
Published: February 2017

BACKGROUND

An excess risk of second malignancies has been reported in survivors of Ewing's sarcoma. We examined a multiinstitutional data base to reevaluate the risk among survivors of Ewing's sarcoma and to identify possible causal factors.

METHODS

Information was derived from a data base that included 266 survivors of Ewing's sarcoma. Cumulative incidence rates of second malignancies were calculated. Contributions of clinical features, type and dose of chemotherapy, and cumulative radiation dose to the risk of second malignancies were evaluated.

RESULTS

After a median follow-up duration of 9.5 years (range, 3.0 to 30), 16 patients have developed second malignancies, which included 10 sarcomas (five osteosarcomas, three fibrosarcomas, and two malignant fibrous histiocytomas) and six other malignancies (acute myeloblastic leukemia, acute lymphoblastic leukemia, meningioma, bronchioalveolar carcinoma, basal cell carcinoma, and carcinoma-in-situ of the cervix). The median latency to the diagnosis of the second malignancy was 7.6 years (range, 3.5 to 25.7). The estimated cumulative incidence rates at 20 years for any second malignancy and for secondary sarcoma were 9.2% (SD = 2.7%) and 6.5% (SD = 2.4%), respectively. The cumulative incidence rate of secondary sarcoma was radiation dose-dependent (P = .002). No secondary sarcomas developed among patients who had received less than 48 Gy, while the absolute risk of secondary sarcoma was 130 cases per 10,000 person-years of observation among patients who had received > or = 60 Gy.

CONCLUSION

The overall risk of second malignancies after Ewing's sarcomas is similar to that associated with treatment for other childhood cancers. The radiation dose-dependency of secondary sarcomas justifies modification in therapy to reduce radiation doses.
Prostate-specific antigen nadir: the optimum level after irradiation for prostate cancer.
Authors: Critz F A , Levinson A K , Williams W H , Holladay D A
Published: February 2017

PURPOSE

The prostate-specific antigen (PSA) nadir that reflects potential cure of prostate cancer by irradiation has not been established. This report attempts to demonstrate the PSA nadir goal for radiotherapy.

MATERIALS AND METHODS

From January 1984 through April 1994, 536 stage T1T2NO prostate cancer patients were treated with radioactive iodine 125 (125I) prostate implants followed by external-beam radiation. All were staged node-negative: 68% by pelvic node dissection and the remainder by computed tomographic (CT) scan. The mean pretreatment PSA level was 12.4 ng/mL (median, 8.4 ng/mL; range, 0.3 to 188 ng/mL). The median follow-up duration is 40 months (range, 12 to 138). An increasing posttreatment PSA level defined recurrence.

RESULTS

Patients who achieved a PSA nadir < or = 0.5 ng/mL had a 95% (+/- 4%) 5-year and an 84% (+/- 12%) 10-year disease-free survival rate, compared with a 5-year disease-free survival rate of 29% (+/- 30%) for those who reached a nadir of 0.6 to 1.0 ng/mL (P = .0001). All patients with a nadir greater than 1.0 ng/mL ultimately failed. Eighty percent of all 536 patients are projected to achieve a nadir < or = 0.5 ng/mL and 90% of patients who achieve this PSA level do so within 48 months of treatment (median, 18 months). Compared with pretreatment PSA level and histologic grade, the PSA nadir is the most significant factor associated with disease-free survival.

CONCLUSION

For most patients to be successfully treated for prostate cancer with radiotherapy, at least with this combination technique, the PSA nadir should become undetectable (< or = 0.5 ng/mL), similar to that after radical prostatectomy. A PSA nadir of < or = 0.5 ng/mL after radiotherapy for prostate cancer may be used as a reasonable indicator of 10-year disease-free survival.