bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenal involvement in the antiphospholipid syndrome
Authors: Espinosa G , Cervera R , Font J , Asherson R A
Published: July 2003

Although Addison disease and hypoadrenalismare rare in patients with systemic lupus erythematosus (SLE), early reports of the associationsuggested the presence of antiphospholipidantibodies (aPL) in these patients. Data from literature reveal that adrenal failure was present in between 10 and 26% of patients with catastrophic APS and that one-third of patients presented with adrenal involvement during the course of catastrophic APS. Adrenal involvement may be the first clinical manifestation of this syndrome, whereas a few patients may have a history of Addison’s disease in the past. The pathological mechanisms involved in the production of adrenal insufficiency in APS are still not clearly understood, but the hypercoagulable state in these patients supports the concept that adrenal haemorrhagic infarction may possibly be related to adrenal vein thrombosis. In the present article, we review the pathogenic mechanisms and main clinical, laboratory and treatment features of patients suffering adrenal involvement with aPL to support the idea that APS leads to the development of adrenal insufficiency.
The effects of antiphospholipid antibodies obtained from women with SLE/APS and associated pregnancy loss on rat embryos and placental explants in culture
Authors: Ornoy A , Yacobi S , Matalon S Tartakover , Blank M , Blumenfeld Z , Miller R K , Shoenfeld Y
Published: July 2003

Recurrent fetal loss occurs in approximately 1% of women. Autoimmune causes have been suggested as a factor in some of these cases. High rates of intrauterine fetal growth retardation and increased incidence of prematurity is associated with systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). We found in previous studies that sera from SLE/APS patients when used as a culture medium for rat embryos were found to reduce embryonic growth and development, induce a high rate of embryonic anomalies and death and damage the yolk sac morphologicallyand functionally. In order to investigatethe direct effect of IgG purified from women with SLE/APS on the growth and viability of embryos, we cultured 11.5-day-old rat embryos in their yolk sacs in the presence of IgG purified from SLE/APS patients with recurrent pregnancy loss (RPL). The IgG affected directly the embryo and yolk sac, reducing their growth. The purified IgG positive for anticardiolipin/anti-DNA antibodies reduced yolk sac and embryonic growth more than sera negative for these antibodies but positive for antiphosphatydilserine and for antilaminin. Monoclonal antiphosphatydilserine reduced yolk sac growth but the embryos remained intact. Following the observed damage to the yolk sac we cultured human placental explants at 5.5-8 weeks of pregnancy in sera from SLE/APS patients for 96 hours and found that these sera reduced placental trophoblastic cell growth, reduced their proliferation rate and increased their rate of apoptosis. Successful treatment of the women resulted in a correction of the damage induced in the cultured rat embryos and in the cultured placental explants.
Sacrifice: an ethical dimension of caring that makes suffering meaningful
Authors: Helin Kaija , Lindström Unni Å
Published: July 2003

This article is intended to raise the question of whether sacrifice can be regarded as constituting a deep ethical structure in the relationship between patient and carer. The significance of sacrifice in a patient-carer relationship cannot, however, be fully understood from the standpoint of the consistently utilitarian ethic that characterizes today’s ethical discourse. Deontological ethics, with its universal principles, also does not provide a suitable point of departure. Ethical recommendations and codices are important and can serve as general sources of knowledge when making decisions, but they should be supplemented by an ethic that takes into consideration contextual and situational factors that make every encounter between patient and carer unique. Caring science research literature presents, on the whole, general agreement on the importance of responsibility and devotion with regard to sense of duty, warmth and genuine engagement in caring. That sacrifice may also constitute an important ethical element in the patient-carer relationship is, however, a contradictory and little considered theme. Caring science literature that deals with sacrifice/self-sacrifice indicates contradictory import. It is nevertheless interesting to notice that both the negative and the positive aspects bring out the importance of the concept for the professional character of caring. The tradition of ideas in medieval Christian mysticism with reference to Lévinas’ ethic of responsibility offers a deeper perspective in which the meaningfulness of sacrifice in the caring relationship can be sought. The theme of sacrifice is not of interest merely as a carer’s ethical outlook, but sacrifice can also be understood as a potential process of transformation towards health. The instinctive or conscious experience of sacrifice on the part of the individual patient can, on a symbolic level, be regarded as analogous to the cultic or religious sacrifice aiming at atonement. Sacrifice appears to the patient as an act of transformation to achieve atonement and healing. Atonement then implies finding meaningfulness in one’s suffering. The concept of sacrifice, understood in a novel way, opens up a deeper dimension in the understanding of suffering and makes caring in ‘the patient’s world’ possible.
Gefitinib in Pretreated Non–Small-Cell Lung Cancer (NSCLC): Analysis of Efficacy and Correlation With HER2 and Epidermal Growth Factor Receptor Expression in Locally Advanced or Metastatic NSCLC
Authors: Cappuzzo Federico , Gregorc Vanesa , Rossi Elisa , Cancellieri Alessandra , Magrini Elisabetta , Paties Carlo Terenzio , Ceresoli Giovanni , Lombardo Laura , Bartolini Stefania , Calandri Cesare , De Rosa Marisa , Villa Eugenio , Crinò Lucio
Published: July 2003

Purpose: To evaluate the correlation between HER2 expression and gefitinib (ZD 1839, Iressa; AstraZeneca, London, United Kingdom) efficacy in terms of response rate, time to progression (TTP), and overall survival (OS) time.

Patients and Methods: Patients with pretreated advanced non–small-cell lung cancer (NSCLC) received gefitinib at a daily dose of 250 mg until disease progression. Tumor tissue specimens obtained at the time of primary diagnosis were collected to determine HER2/epidermal growth factor receptor (EGFR) status by immunohistochemistry.

Results: From February 2001 to June 2002, 63 consecutive patients were enrolled onto the study. The overall disease control rate was 58.7% (partial response [PR], 15.9%; stable disease [SD], 42.8%), median TTP was 3.3 months, and median OS was 4.1 months. Among the 43 patients in whom EGFR/HER2 status was determined, we observed six PRs (14%) and 18 SDs (42%). Disease control, including PR and SD, was 40% in the 15 patients overexpressing HER2 and 64.3% in the 28 patients not overexpressing HER2 (P = .126). No difference was found between the two groups in terms of TTP (3.5 v 3.7 months, respectively) and OS (5.7 v 6.8 months, respectively). In addition, we did not find any difference in TTP, OS, toxicity, and symptom outcome in the group of patients overexpressing both HER2 and EGFR compared with patients who had no overexpression of HER2

Conclusion: According to these data, efficacy, toxicity, and symptom outcome in patients with NSCLC treated with gefitinib do not seem to be related to HER2 expression.
DTPACE: An Effective, Novel Combination Chemotherapy With Thalidomide for Previously Treated Patients With Myeloma
Authors: Lee Choon-Kee , Barlogie Bart , Munshi Nikhil , Zangari Maurizio , Fassas Athanasios , Jacobson Joth , van Rhee Frits , Cottler-Fox Michele , Muwalla Firas , Tricot Guido
Published: July 2003

Purpose: To improve outcome in previously treated patients (at least two cycles of standard therapy) with multiple myeloma, thalidomide was combined with cytotoxic chemotherapy as induction therapy.

Patients and Methods: The regimen consisted of 4-days of oral dexamethasone, daily thalidomide, and 4 days of continuous-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide (DTPACE). Response to two cycles of DTPACE for induction was evaluated in 236 patients. Before being treated with DTPACE, 148 patients (63%) had shown progressive disease while receiving standard chemotherapy, and 55 patients (23%) had chromosome 13 abnormalities.

Results: The partial remission rate (PR) after two cycles of DTPACE was 32%, with 16% attaining a complete remission (CR) or near-CR (nCR; defined as only immunofixation electrophoresis–positive). Patients with high lactate dehydrogenase (LDH; n = 98) showed a better response than those with normal LDH (n = 138): PR or better, 43% v 27% (P = .01); CR + nCR, 25% v 11% (P = .01). Patients with chromosome 13 abnormalities (n = 55) responded equally well as the other patients (n = 181): PR or better, 35% v 33% (P = .84); CR + nCR, 17% v 15% (P = .73). Patients who received 100% dose of DTPACE for two cycles (n = 115) achieved higher response rates than those with less than 100% dose (n = 121): PR or better, 49% v 17% (P < .0001); CR + nCR, 27% v 6% (P < .0001).

Conclusion: Combination therapy of oral dexamethasone and thalidomide with infusional chemotherapy is effective as induction therapy before autotransplantation, especially in patients with high-risk features.
Status of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer
Authors: Mendelsohn John , Baselga Jose
Published: July 2003

The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in many epithelial tumors. Receptor activation leads to recruitment and phosphorylation of several downstream intracellular substrates, leading to mitogenic signaling and other tumor-promoting cellular activities. In human tumors, receptor overexpression correlates with a more aggressive clinical course. Taken together, these observations indicate that the EGFR is a promising target for cancer therapy. Monoclonal antibodies directed at the ligand-binding extracellular domain and low–molecular weight inhibitors of the receptor’s tyrosine kinase are currently in advanced stages of clinical development. These agents prevent ligand-induced receptor activation and downstream signaling, which results in cell cycle arrest, promotion of apoptosis, and inhibition of angiogenesis. They also enhance the antitumor effects of chemotherapy and radiation therapy. In patients, anti-EGFR agents can be given safely at doses that fully inhibit receptor signaling, and single-agent activity has been observed against a variety of tumor types, including colon carcinoma, non–small-cell lung cancer, head and neck cancer, ovarian carcinoma, and renal cell carcinoma. Although antitumor activity is significant, responses have been seen in only a minority of the patients treated. In some clinical trials, anti-EGFR agents enhanced the effects of conventional chemotherapy and radiation therapy. Ongoing research efforts are directed at the selection of patients with EGFR-dependent tumors, identification of the differences among the various classes of agents, and new clinical development strategies.
Localized Extremity Soft Tissue Sarcoma: Improved Knowledge With Unchanged Survival Over Time
Authors: Weitz Jürgen , Antonescu Christina R. , Brennan Murray F.
Published: July 2003

Purpose: The objective of this study was to define whether survival of patients with extremity soft tissue sarcoma (STS), stratified for known risk factors, has improved over the last 20 years.

Patients and Methods: From January 1982 to December 2001, 1,706 patients with primary and recurrent STS of the extremities were treated at our institution and were prospectively followed. From this cohort, we selected 1,261 patients who underwent complete macroscopic resection and had one of the following histopathologies: fibrosarcoma, liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, or synovial sarcoma. Median follow-up was 55 months. Patient, tumor, and treatment factors were analyzed as prognostic factors.

Results: The 5-year disease-specific actuarial survival was 79% (78% for patients treated from 1982 to 1986, 79% for patients treated from 1986 to 1991, 79% for patients treated from 1992 to 1996, and 85% for patients treated from 1997 to 2001; P = not significant). For high-risk patients (high-grade, > 10 cm, deep tumors; n = 247), 5-year disease-specific survival was 51% (50% for patients treated from 1982 to 1986, 45% for patients treated from 1986 to 1991, 52% for patients treated from 1992 to 1996, and 61% for patients treated from 1997 to 2001; P = not significant). Tumor depth, size, grade, microscopic margin status, patient age, presentation status (primary tumor versus local recurrence), location (proximal versus distal), and certain histopathologic subtypes were significant prognostic factors for disease-specific survival on multivariate analysis; however, time period of treatment was not.

Conclusion: Prognosis of patients with extremity STS, stratified for known risk factors, has not improved over the last 20 years, indicating that current therapy has reached the limits of efficacy.
Oxaliplatin With Weekly Bolus Fluorouracil and Low-Dose Leucovorin as First-Line Therapy for Patients With Colorectal Cancer
Authors: Hochster Howard , Chachoua Abraham , Speyer James , Escalon Juliette , Zeleniuch-Jacquotte Anne , Muggia Franco
Published: July 2003

Purpose: To determine the activity of biweekly oxaliplatin, combined with weekly bolus fluorouracil (FU) and low-dose leucovorin (LV) chemotherapy (bFOL), as first-line therapy for patients with metastatic colorectal cancer.

Patients and Methods: Patients with measurable metastatic colorectal cancer; no previous therapy for advanced disease (adjuvant therapy allowed if >6 months since completion); and performance status 0, 1, or 2 were eligible and were treated with oxaliplatin 85 mg/m2 days 1 and 15 plus LV 20 mg/m2 over 10 to 20 minutes, followed by a 500 mg/m2 bolus dose of FU on days 1, 8, and 15 every 28 days. Patients underwent response evaluation by computed tomographic scan every 2 months.

Results: Forty-two patients were entered, and 41 patients were treated, including 20 men and 22 women, nine with previous adjuvant chemotherapy and four with radiation therapy. Three patients achieved complete response, and 23 patients achieved partial response, for a response rate of 63% (95% CI, 49% to 78%). Major toxicities included cumulative neuropathy grade 2 (24%) and grade 3 (12%; requiring discontinuation of oxaliplatin), diarrhea grade 3 to 4 (29%) and grade 3 to 4 hematologic toxicity (10%). Median time to progression was 9.0 months (95% confidence interval, 7.1 to 10.8 months) with median survival of 15.9 months (95% confidence interval, 11.4 to 19.7 months).

Conclusion: The bFOL regimen seems to have activity comparable to be infusional programs of FU combined with oxaliplatin. Prospective trials are warranted to determine the relative merits of this schedule compared with the currently indicated schedules.
Long-Term Toxicity After Definitive Chemoradiotherapy for Squamous Cell Carcinoma of the Thoracic Esophagus
Authors: Ishikura Satoshi , Nihei Keiji , Ohtsu Atsushi , Boku Narikazu , Hironaka Shuichi , Mera Kiyomi , Muto Manabu , Ogino Takashi , Yoshida Shigeaki
Published: July 2003

Purpose: To assess the long-term toxicity after definitive chemoradiotherapy (CRT) for squamous cell carcinoma (SCC) of the esophagus.

Patients and Methods: Patients newly diagnosed with SCC of the esophagus and treated with definitive CRT between 1992 and 1999 in our institution were recruited from our database on the basis of the following criteria: age ≤ 75 years, performance status (PS; based on the Eastern Cooperative Oncology Group scale) 0 to 2, and clinical tumor-node-metastasis system stage I to IVA. The CRT consisted of two cycles of cisplatin 40 mg/m2 on days 1 and 8, and continuous infusion of fluorouracil 400 mg/m2/d on days 1 to 5 and 8 to 12, repeated every 5 weeks with concurrent radiotherapy of 60 Gy in 30 fractions. For the assessment of toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme was adopted.

Results: A total of 139 patients were recruited, and their characteristics were as follows: median age, 62 years (range, 38 to 75 years); 121 males and 18 females; 96 patients PS 0, 42 patients PS 1, and one patient PS 2; 15 patients T1, 11 patients T2, 60 patients T3, and 53 patients T4; and 101 patients M0, 38 patients M1a. With a median follow-up of 53 months, the median survival time and 5-year survival rate were 21 months and 29%, respectively. Of 78 patients with complete remission, two patients died as a result of acute myocardial infarction. Grade 2, 3, and 4 late toxicities occurred with the following incidences: pericarditis in eight patients, seven patients, and one patient, respectively; heart failure in zero, zero, and two patients; pleural effusion in seven, eight, and zero patients; and radiation pneumonitis in one patient, three patients, and zero patients, respectively.

Conclusion: Definitive CRT for SCC of the esophagus is effective with substantial toxicities. Additional investigation to minimize the normal tissue toxicities is warranted.
Cluster Analysis of p53 and Ki67 Expression, Apoptosis, Alpha-Fetoprotein, and Human Chorionic Gonadotrophin Indicates a Favorable Prognostic Subgroup Within the Embryonal Carcinoma Germ Cell Tumor
Authors: Mazumdar Madhu , Bacik Jennifer , Tickoo Satish K. , Dobrzynski Deborah , Donadio Alessia , Bajorin Dean , Motzer Robert , Reuter Victor , Bosl George J.
Published: July 2003

Purpose: The prognostic information provided by alpha-fetoprotein and human chorionic gonadotrophin in the management of germ cell tumor (GCT) patients is a biochemical reflection of tumor differentiation. Ki67, p53, and apoptosis have been found to be related to proliferation (Ki67), cell death (p53, apoptosis), and possibly differentiation chemoresistance (p53). We sought to determine whether simultaneous expression of one or more of these markers could identify clinically relevant subgroups of patients with nonseminomatous GCT (NSGCT).

Patients and Methods: These five marker values were obtained for 95 previously untreated patients with embryonal carcinoma with or without other germ cell components. A multivariate cluster analysis was performed to identify patients with similar marker patterns.

Results: One prominent cluster (n = 37; 36 testis retroperitoneum), consisting of 26 (70%) good-risk (GR), nine (24%) intermediate-risk (IR), and two (6%) poor-risk (PR) patients, as defined by the International Germ Cell Consensus Cancer Group (IGCCCG), was observed. The 5-year survival of the prominent cluster (with 30% IR/PR patients) was 94% (95% confidence interval [CI], 86% to 100%), which is comparable to the 91% (95% CI, 89% to 93%) 5-year survival of the IGCCCG GR patients. IGCCCG risk status (P = .005) and cluster affiliation (P = .04) were independent predictors of outcome with hazard ratios of 5.0 (95% CI, 1.6 to 15.4) and 4.6 (95% CI, 1.04 to 20.1), respectively.

Conclusion: These results suggest that there is a subgroup of NSGCT patients with embryonal carcinoma (with or without other histologies) with a specific tumor biology profile (high Ki67, low apoptosis, and low p53) whose survival is better than that of the overall patient group. The unexpectedly good outcome for the prominent cluster and independent-risk status suggest that subgroups of GCT reflecting different abilities to respond to treatment exist within IGCCCG prognostic categories.
HER-2 Expression and Cell Proliferation: Prognostic Markers in Patients With Node-Negative Breast Cancer
Authors: Volpi Annalisa , Nanni Oriana , De Paola Franca , Granato Anna Maria , Mangia Annita , Monti Franco , Schittulli Francesco , De Lena Mario , Scarpi Emanuela , Rosetti Paola , Monti Manlio , Gianni Lorenzo , Amadori Dino , Paradiso Angelo
Published: July 2003

Purpose: We analyzed the clinical relevance of HER-2 expression, widely investigated in breast cancer but with contradictory results, in the largest case series of node-negative breast cancer patients investigated to date.

Patients and Methods: The pure prognostic value of HER-2 expression was investigated in 529 patients treated with locoregional therapy alone until early relapse. Proliferative activity was evaluated as [ 3 H]thymidine labeling index and HER-2 expression by immunohistochemistry. All biologic determinations were conducted within the context of an intra- and interlaboratory National Quality Control Program.

Results: HER-2 expression was not related to relapse-free survival in the overall series but was a significant discriminant of prognosis in the subgroup of patients with rapidly proliferating tumors. Six-year rate of relapse was 40% for patients with highly (≥30%) positive tumors and 26% for those with weakly HER-2-expressing tumors (P = .039).

Conclusion: HER-2 expression in association with proliferative activity identifies a subgroup of node-negative breast cancer patients with the worst prognosis, who are candidates for specific intensive adjuvant therapy.
Intestinal Non-Hodgkin’s Lymphoma: A Multicenter Prospective Clinical Study From the German Study Group on Intestinal Non-Hodgkin’s Lymphoma
Authors: Daum Severin , Ullrich Reiner , Heise Walter , Dederke Bettina , Foss Hans-Dieter , Stein Harald , Thiel Eckhard , Zeitz Martin , Riecken Ernst-Otto
Published: July 2003

Purpose: Intestinal non-Hodgkin’s lymphomas are not well characterized. We therefore studied prospectively their clinical features and response to standardized therapy.

Patients and Methods: Fifty-six patients with primary intestinal lymphoma were included in a prospective, nonrandomized multicenter study. Lymphoma resection was recommended and staging was performed according to the Ann Arbor classification. Patients were scheduled to receive six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy, and at stages EIII to EIV, they received additional involved-field radiotherapy. Corticosteroids were used in patients who could not receive chemotherapy.

Results: Thirty-five patients had intestinal T-cell lymphoma (ITCL), 21 patients had intestinal B-cell lymphoma (IBCL; 18 diffuse large-cell lymphomas, two marginal-cell lymphomas, and one follicle-center lymphoma). Thirty-four patients at stages EI to EII (14 ITCL and 20 IBCL) and nine patients at stages EIII to EIV (all ITCL) received chemotherapy. No patient in stages EIII to EIV received radiotherapy, because death occurred in 12 of 14 patients. Two-year cumulative survival in patients with IBCL was 94% (95% CI, 82% to 100%) and higher than in patients with ITCL (28% [95% CI, 13% to 43%]; P < .0001), even when only stages EI to EII were considered (ITCL, 37.5% [95% CI, 16.5% to 58.5%]; P < .0001). IBCL patients compared with ITCL patients were at lower lymphoma stages (P < .01), had higher Karnofsky status (P < .005), had intestinal perforation less often (P < .05), required emergency operation less often (P < .05), received CHOP (P < .05) more often, and reached complete remission (P < .0005) more frequently.

Conclusion: IBCL patients at stages EI and EII respond well to chemotherapy, but the prognosis and treatment of ITCL patients is unsatisfactory.
Assessment of Quality of Life in Outpatients With Advanced Cancer: The Accuracy of Clinician Estimations and the Relevance of Spiritual Well-Being—A Hoosier Oncology Group Study
Authors: Fisch Michael J. , Titzer Michael L. , Kristeller Jean L. , Shen Jianzhao , Loehrer Patrick J. , Jung Sin-Ho , Passik Steven D. , Einhorn Lawrence H.
Published: July 2003

Purpose: To evaluate the association between quality-of-life (QOL) impairment as reported by patients and QOL impairment as judged by nurses or physicians, with and without consideration of spiritual well-being (SWB).

Patients and Methods: A total of 163 patients with advanced cancer were enrolled onto a therapeutic trial, and cross-sectional data were derived from clinical and demographic questionnaires obtained at baseline, including assessment of patient QOL and SWB. Clinicians rated the QOL impairment of their patients as mild, moderate, or severe. Clinician-estimated QOL impairment and patient-derived QOL categories were compared. Correlation coefficients were estimated to associate QOL scores using different instruments. The analysis of variance method was used to compare Functional Assessment of Cancer Therapy–General scores on categorical variables.

Results: There was no significant association between self-assessment scores and marital status, education level, performance status, or predicted life expectancy. However, a strong relationship between SWB and QOL was noted (P < .0001). Clinician-estimated QOL impairment matched the level of patient-derived QOL correctly in approximately 60% of cases, with only slight variation depending on the method of categorizing patient-derived QOL scores. The accuracy of clinician estimates was not associated with the level of SWB. Interestingly, a subset analysis of the inaccurate estimates revealed an association between lower SWB and clinician underestimation of QOL impairment (P = .0025).

Conclusion: Clinician estimates of QOL impairment were accurate in more than 60% of patients. SWB is strongly associated with QOL, but it is not associated with the overall accuracy of clinicians’ judgments about QOL impairment.
Celecoxib, a Selective Cyclo-Oxygenase-2 Inhibitor, Enhances the Response to Preoperative Paclitaxel and Carboplatin in Early-Stage Non–Small-Cell Lung Cancer
Authors: Altorki N.K. , Keresztes R.S. , Port J.L. , Libby D.M. , Korst R.J. , Flieder D.B. , Ferrara C.A. , Yankelevitz D.F. , Subbaramaiah K. , Pasmantier M.W. , Dannenberg A.J.
Published: July 2003

Purpose: Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non–small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2(PGE2).

Methods: In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib.

Results: All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2detected in primary tumors after treatment with paclitaxel and carboplatin alone.

Conclusion: In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.
The Role of Irradiation of the Internal Mammary Lymph Nodes in High-Risk Stage II to IIIA Breast Cancer Patients After High-Dose Chemotherapy: A Prospective Sequential Nonrandomized Study
Authors: Stemmer Salomon M. , Rizel Shulamith , Hardan Izhar , Adamo Adamous , Neumann Avivit , Goffman Jana , Brenner Harold J. , Pfeffer M. Raphael
Published: July 2003

Purpose: This phase II single-institution prospective, nonrandomized trial investigates high-dose adjuvant chemotherapy and locoregional radiotherapy in patients with breast cancer. We compared the outcome of patients in this study treated with radiotherapy fields including the internal mammary nodes (IMN) to a group of patients who did not receive IMN irradiation.

Patients and Methods: 100 patients with high-risk stage II–III breast cancer received doxorubicin-based adjuvant chemotherapy followed by high-dose chemotherapy, stem-cell support, and locoregional radiotherapy. The radiotherapy included electron-beam irradiation to the IMN. For 20 months during the study, no electron-beam facility was available and we were unable to deliver the IMN irradiation as planned to 33 patients. The remaining 67 patients (32 treated before and 35 treated after this period) received IMN irradiation. Patients with receptor-positive tumors received tamoxifen for 5 years.

Results: At a median follow-up of 77 months for all of the patients, disease-free survival (DFS) was significantly prolonged in patients receiving IMN radiation compared to those without IMN radiation (73% v 52%; P = .02). A trend was seen for overall survival (OS; 78% v 64%; P = .08). Cox regression multivariate analysis found IMN radiotherapy to be significant both for DFS and OS. Estrogen receptor positivity was also significant for DFS. There was no treatment related mortality.

Conclusion: In patients with high-risk stage II to III breast cancer, the inclusion of the IMN in the radiotherapy field was associated with a statistically significant increase in DFS and a borderline increase in OS.
Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents
Authors: Ma Brigette B.Y. , Bristow Robert G. , Kim John , Siu Lillian L.
Published: July 2003

Purpose: Molecular targeted agents have been combined with radiotherapy (RT) in recent clinical trials in an effort to optimize the therapeutic index of RT. The appeal of this strategy lies in their potential target specificity and clinically acceptable toxicity.

Design: This article integrates the salient, published research findings into the underlying molecular mechanisms, preclinical efficacy, and clinical applicability of combining RT with molecular targeted agents. These agents include inhibitors of intracellular signal transduction molecules, modulators of apoptosis, inhibitors of cell cycle checkpoints control, antiangiogenic agents, and cyclo-oxygenase-2 inhibitors.

Results: Molecular targeted agents can have direct effects on the cytoprotective and cytotoxic pathways implicated in the cellular response to ionizing radiation (IR). These pathways involve cellular proliferation, DNA repair, cell cycle progression, nuclear transcription, tumor angiogenesis, and prostanoid-associated inflammation. These pathways can also converge to alter RT-induced apoptosis, terminal growth arrest, and reproductive cell death. Pharmacologic modulation of these pathways may potentially enhance tumor response to RT though inhibition of tumor repopulation, improvement of tumor oxygenation, redistribution during the cell cycle, and alteration of intrinsic tumor radiosensitivity.

Conclusion: Combining RT and molecular targeted agents is a rational approach in the treatment of solid tumors. Translation of this approach from promising preclinical data to clinical trials is actively underway.
Dose-Escalating and Pharmacological Study of Oxaliplatin in Adult Cancer Patients With Impaired Renal Function: A National Cancer Institute Organ Dysfunction Working Group Study
Authors: Takimoto Chris H. , Remick Scot C. , Sharma Sunil , Mani Sridhar , Ramanathan Ramesh K. , Doroshow James , Hamilton Anne , Mulkerin Daniel , Graham Martin , Lockwood Graham F. , Ivy Percy , Egorin Merrill , Schuler Barbara , Greenslade Denis , Goetz Andrew , Knight Ronald , Thomas Rebecca , Monahan Brian P. , Dahut William , Grem Jean L.
Published: July 2003

Purpose: This study was undertaken to determine the toxicities, pharmacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population.

Patients and Methods: Thirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m2 every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL ≥60 mL/min), group B (mild dysfunction, CrCL 40 to 59 mL/min), group C (moderate dysfunction, CrCL 20 to 39 mL/min), and group D (severe dysfunction, CrCL <20 mL/min). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations.

Results: No dose-limiting toxicities were observed in any patient group during the first cycle of therapy. Escalation of oxaliplatin to the maximum dose of 130 mg/m2 was well tolerated in all patient groups with a CrCL ≥20 mL/min (groups A, B, and C). Pharmacokinetic analysis showed that patients with decreased CrCL had a corresponding decrease in the clearance of plasma ultrafiltrable platinum (r2 = 0.765). However, oxaliplatin-induced side effects were not more common or severe in patients with mild to moderate renal dysfunction, despite the decrease in ultrafiltrable platinum clearance.

Conclusion: Oxaliplatin at 130 mg/m2 every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCL greater than 20 mL/min.
Chemotherapy Alone as Initial Treatment for Primary CNS Lymphoma in Patients Older Than 60 Years: A Multicenter Phase II Study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group
Authors: Hoang-Xuan K. , Taillandier L. , Chinot O. , Soubeyran P. , Bogdhan U. , Hildebrand J. , Frenay M. , De Beule N. , Delattre J.Y. , Baron B.
Published: July 2003

Purpose: To assess the efficacy and toxicity of chemotherapy alone in patients older than 60 years with primary CNS lymphoma.

Patients and Methods: Fifty patients with a median age of 72 years and a median Karnofsky performance score (KPS) of 50 were eligible for this multicenter phase II study. The protocol consisted of high-dose methotrexate (MTX), lomustine, procarbazine, methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine. The patients received one induction cycle; if objective response was achieved, five additional maintenance cycles were administered every 6 weeks. The median follow-up of patients was 3 years.

Results: Twenty four patients (48%) achieved an objective response (compete response [CR], 42%; partial response, 6%), with a median duration of CR of 27 months (range, 3 to 47+ months). Overall median survival time was 14.3 months, and 1-year progression-free survival was 40% (95% confidence interval [CI], 26% to 53%). Myelosuppression was the most frequent side effect, with grade 3 to 4 neutropenia in 19% of patients. One patient died during chemotherapy, as a result of pulmonary embolism. Most patients improved or preserved their cognitive functions (47% and 45% of the patients, respectively) and KPS (36% and 52% of the patients, respectively) until relapse, whereas cognitive and KPS decline attributed to delayed treatment neurotoxicity occurred in 8% and 12% patients, respectively.

Conclusion: In the elderly, this chemotherapy regimen compares favorably with radiotherapy (RT) alone and reduces considerably the risk of delayed neurotoxicity associated with combined chemoradiotherapy. Chemotherapy alone is an appropriate strategy in older patients to delay or avoid RT.
Androgen Receptor Mutations in Androgen-Independent Prostate Cancer: Cancer and Leukemia Group B Study 9663
Authors: Taplin Mary-Ellen , Rajeshkumar Barur , Halabi Susan , Werner Cary P. , Woda Bruce A. , Picus Joel , Stadler Walter , Hayes Daniel F. , Kantoff Philip W. , Vogelzang Nicholas J. , Small Eric J.
Published: July 2003

Purpose: The mechanisms responsible for prostate cancer androgen independence are diverse. Mutations of the androgen receptor (AR) gene that broaden ligand specificity have been implicated. Bone marrow specimens containing prostate tumor were obtained from men undergoing antiandrogen withdrawal for AR sequence analysis and clinical correlation.

Materials and Methods: Eligible men enrolled on a trial of antiandrogen withdrawal had a minimum prostate-specific antigen (PSA) level of 5 ng/dL that was increasing on castration therapy including an antiandrogen. With informed consent, marrow biopsies were obtained to collect prostate tumor. Additional samples were obtained from men enrolled on chemotherapy trials. AR cDNA or DNA was polymerase chain reaction–amplified, cloned, and sequenced. The AR CAG repeat length was recorded.

Results: One hundred eighty-four bone marrow biopsies were obtained, and 48 had prostate tumor detected by light microscopy. The ARs from these 48 samples were sequenced. Overall, five (10%) of 48 tumors had mutated ARs. AR point mutations were detected in the hormone-binding domain involved in transcription factor binding. Three mutations were novel in prostate cancer. One tumor sample had a CAG repeat length of 21, compared with germline length of 22 repeats. There was no association between detectability of AR mutations and antiandrogen withdrawal response or survival.

Conclusion: These data suggest that AR mutations are present in approximately 10% of patients with prostate cancer who experience treatment failure with hormone therapy that included an antiandrogen. Mutations in the AR likely confer a growth advantage for a subset of progressive prostate cancers. Correlation of AR mutation with antiandrogen withdrawal response or survival could not be made.
Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma
Authors: Vogelzang Nicholas J. , Rusthoven James J. , Symanowski James , Denham Claude , Kaukel E. , Ruffie Pierre , Gatzemeier Ulrich , Boyer Michael , Emri Salih , Manegold Christian , Niyikiza Clet , Paoletti Paolo
Published: July 2003

Purpose: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone.

Patients and Methods: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days.

Results: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm.

Conclusion: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.
Positron Emission Tomography in Non–Small-Cell Lung Cancer: Prediction of Response to Chemotherapy by Quantitative Assessment of Glucose Use
Authors: Weber Wolfgang A. , Petersen Volker , Schmidt Burkhard , Tyndale-Hines Leishia , Link Thomas , Peschel Christian , Schwaiger Markus
Published: July 2003

Purpose: To prospectively evaluate the use of positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) to predict response to chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods: Patients with stage IIIB or IV NSCLC scheduled to undergo platinum-based chemotherapy were eligible for this study. Patients were studied by FDG-PET before and after the first cycle of therapy. Based on previous studies, a reduction of tumor FDG uptake by more than 20% as assessed by standardized uptake values (SUV) was used as a criterion for a metabolic response. Furthermore, changes in tumor SUVs were compared with changes in FDG net-influx constants (Ki) and tumor/muscle ratios (t/m).

Results: Fifty-seven patients were included in the study. There was a close correlation between metabolic response and best response to therapy according to Response Evaluation Criteria in Solid Tumors (P < .0001; sensitivity and specificity for prediction of best response, 95% and 74%, respectively). Median time to progression and overall survival were significantly longer for metabolic responders than for metabolic nonresponders (163 v 54 days and 252 days v 151 days, respectively). Similar results were obtained when Ki was used to assess tumor glucose use, whereas changes in t/m showed considerable overlap between responding and nonresponding tumors.

Conclusion: In NSCLC, reduction of metabolic activity after one cycle of chemotherapy is closely correlated with final outcome of therapy. Using metabolic response as an end point may shorten the duration of phase II studies evaluating new cytotoxic drugs and may decrease the morbidity and costs of therapy in nonresponding patients.
Evidence of a Graft-Versus-Leukemia Effect in Chronic Lymphocytic Leukemia After Reduced-Intensity Conditioning and Allogeneic Stem-Cell Transplantation: The Cooperative German Transplant Study Group
Authors: Schetelig J. , Thiede C. , Bornhäuser M. , Schwerdtfeger R. , Kiehl M. , Beyer J. , Sayer H.G. , Kröger N. , Hensel M. , Scheffold C. , Held T.K. , Höffken K. , Ho A.D. , Kienast J. , Neubauer A. , Zander A.R. , Fauser A.A. , Ehninger G. , Siegert W.
Published: July 2003

Purpose: To study whether hematopoietic stem-cell transplantation (HSCT) after reduced-intensity conditioning is effective and tolerable in patients with advanced chronic lymphocytic leukemia (CLL).

Patients and Methods: Thirty patients with advanced B-cell CLL were included into the study. After reduced-intensity conditioning with fludarabine, busulfan, and antithymocyte globulin, patients received a transplant from related (n = 15) or unrelated donors (n = 15). Minimal residual disease (MRD) was monitored with a clone-specific polymerase chain reaction.

Results: After a median follow-up of 2 years, 23 patients are alive (to date). Neutrophil and platelet engraftment occurred after a median of 17.5 and 15 days, respectively. Acute graft-versus-host disease (GVHD) grade 2 to 4 was observed in 17 patients (56%), and chronic GVHD was observed in 21 patients (75%). Twelve patients (40%) achieved a complete remission (CR), and 16 patients (53%) achieved a partial remission. Late CR occurred up to 2 years after transplantation. MRD was monitored in eight patients with CR. All patients achieved a molecular CR. At last follow-up, six patients were in ongoing molecular CR. Causes of death were treatment-related complications in four patients and progressive disease in three patients. The probability of overall survival, progression-free survival, and nonrelapse mortality at 2 years was 72% (95% confidence interval [CI], 54% to 90%), 67% (95% CI, 49% to 85%), and 15% (95% CI, 1% to 29%), respectively.

Conclusion: Treatment-related mortality after reduced-intensity conditioning followed by allogeneic HSCT was low. The procedure induced molecular remissions in patients with advanced CLL. The observation of late remissions provided evidence of a graft-versus-leukemia effect.
Prospective, Randomized, Multicenter Trial on the Antiproliferative Effect of Lanreotide, Interferon Alfa, and Their Combination for Therapy of Metastatic Neuroendocrine Gastroenteropancreatic Tumors—The International Lanreotide and Interferon Alfa Study Group
Authors: Faiss Siegbert , Pape Ulrich-Frank , Böhmig Michael , Dörffel Yvonne , Mansmann Ulrich , Golder Werner , Riecken Ernst Otto , Wiedenmann Bertram
Published: July 2003

Purpose: Somatostatin analogs and interferon alfa control hormone-active/functional neuroendocrine gastroenteropancreatic tumors. In addition to hormonal control, variable degrees of antiproliferative effects for both agents have been reported. Until now, however, no prospective, randomized studies in therapy-naive patients have compared somatostatin analogs or interferon alfa alone with a combination of the two.

Methods: Eighty therapy-naive patients with histologically verified neuroendocrine tumor disease (primary localization: foregut, n = 36; midgut, n = 30; hindgut, n = 3; unknown, n = 11; functional, n = 29; nonfunctional, n = 51) were randomly treated either with lanreotide (1 mg three times a day administered subcutaneously [SC]) or interferon alfa (5 × 106 U three times a week SC) or both. All patients had disease progression in the 3 months before study entry, verified with imaging procedures.

Results: Twenty-five patients were treated with lanreotide, 27 patients were treated with interferon alfa, and 28 patients were treated with the combination. Partial tumor remission was seen in four patients (one patient who received lanreotide, one patient who received interferon alfa, and two patients who received the combination). During the 12 months of therapy, stable disease was observed in 19 patients (seven patients who received lanreotide, seven patients who received interferon alfa, and five patients who received the combination), whereas tumor progression occurred in 14 of 25 patients (lanreotide), 15 of 27 patients (interferon alfa), and 14 of 28 patients (combination). Side effects leading to an interruption of therapy were more frequent in the combination group than in the monotherapy arms.

Conclusion: This prospective, randomized, multicenter study shows for the first time that somatostatin analogs, interferon alfa, or the combination of the two had comparable antiproliferative effects in the treatment of metastatic neuroendocrine gastroenteropancreatic tumors. Response rates were lower compared with those published in previous, nonrandomized studies. The antiproliferative effect of the tested substances was similar for functional and nonfunctional neuroendocrine tumors.
Adlayer Structures of Binaphthyl Derivatives on Cu(111)
Authors: Han Mei-Juan , Zeng Qing-Dao , Wan Li-Jun , Bai Chun-Li
Published: July 2003

Adsorption of two binaphthyl derivatives on Cu(111) electrode were investigated by STM and cyclic voltammetry. Both molecules adsorbed on the Cu(111) electrode surface in 0.1 M HClO4 solution and formed well-defined adlayers with a (4 × 4) symmetry in the double layer potential region. With the high resolution STM images, the configurations of individual molecules were determined. According to the experimental results, structural models are proposed for the adlayers.
A Simple, Effective and Highly Selective Cleavage of 3-Methylbut-2-enyl (prenyl) Ethers Using p-Toluenesulfonic Acid
Authors: Babu K Suresh , Raju B China , Srinivas P V , Rao A Sridhar , Kumar S Praveen , Rao J Madhusudana
Published: July 2003

A highly selective cleavage of prenyl ethers has been achieved in high yields using p-toluenesulfonic acid under extremely mild conditions. This method is compatible with a wide variety of functional groups such as methyl, benzyl, allyl ethers and benzyl, methyl, prenyl esters present in the molecules.