bluuebunny/crossref_metadata_2025 huggingface dataset:
Couples Who Get Closer After Breast Cancer: Frequency and Predictors in a Prospective Investigation
Authors: Dorval Michel , Guay Stéphane , Mondor Myrto , Mâsse Benoît , Falardeau Maurice , Robidoux André , Deschênes Luc , Maunsell Elizabeth
Published: May 2005

Purpose

Although some couples report an improved relationship since coping with breast cancer together, little quantitative information exists about this phenomenon. We assessed extent to which both couple members report that breast cancer brought them closer and characteristics that predicted this.

Patients and Methods

This prospective study was based on all women with newly diagnosed nonmetastatic disease first treated during recruitment in four Quebec hospitals, in addition to their spouses. Participation was 87% among eligible patients and 91% among spouses of participating patients. Both couple partners were interviewed individually about quality of life at 2 weeks and 3 and 12 months after treatment start. At 12 months, each was asked whether the disease had brought them closer, distanced them, or had no effect.

Results

Overall, 42% of the 282 couples said breast cancer brought them closer, 6% had one or other partner reporting feeling distanced, and less than 1% of couples had both partners reporting feeling distanced. Characteristics assessed explained 31% of variance in the proportion of couples getting closer (P < .0001). After taking into account partners' prediagnosis characteristics and the woman's treatment, the spouse reporting the patient as confidant (P = .003), getting advice from her in the first 2 weeks about coping with breast cancer (P = .03), accompanying her to surgery (P = .057), the patient's reporting more affection from her spouse at 3 months since diagnosis (P = .003) predicted both partners saying the disease brought them closer.

Conclusion

Breast cancer can be a growth experience for couples under certain conditions. This information may help reassure patients and their spouses confronting this disease.
Phase II Study of 9-Nitro-Camptothecin in Patients With Advanced Chordoma or Soft Tissue Sarcoma
Authors: Chugh Rashmi , Dunn Rodney , Zalupski Mark M. , Biermann J. Sybil , Sondak Vernon K. , Mace Joseph R. , Leu Kirsten M. , Chandler William F. , Baker Laurence H.
Published: May 2005

Purpose

The purpose of this trial was to assess the objective clinical response, toxicity, and time to progression of treatment with 9-Nitro-Camptothecin (9-NC) in patients with advanced chordoma, soft tissue sarcoma (STS), and gastrointestinal stromal tumor (GIST).

Patients and Methods

Patients with locally advanced and/or metastatic chordoma, STS, or GIST received 9-NC 1.25 mg/m2 orally for 5 consecutive days followed by 2 days of rest. Patients continued on therapy until disease progression, uncontrollable toxicity, or withdrawal of consent.

Results

From January 2000 to May 2003, 51 patients (15 chordoma, 23 STS, 13 GIST patients) enrolled. One patient (7%) with chordoma and one patient (4%) with STS had an objective response. Median time to progression was 9.9, 8.0, and 8.3 weeks for chordoma, STS, and GIST patients, respectively. Three- and 6-month progression-free survival rates were 47% and 33% for chordoma patients, 26% and 22% for STS patients, and 31% and 23% for GIST patients, respectively. Ten patients (10%) stopped study drug before disease progression secondary to toxicity. Common adverse events included anemia (42 patients, seven with grade 3/4 toxicity), leukopenia (33 patients, nine with grade 3/4 toxicity), fatigue (30 patients, three with grade 3/4 toxicity), nausea (34 patients, six with grade 3/4 toxicity), and diarrhea (28 patients, five with grade 3/4 toxicity).

Conclusion

9-NC has modest activity in delaying progression in patients with unresectable or metastatic chordoma. 9-NC is associated with moderate toxicity and shows little benefit in patients with advanced STS and GIST.
Mapping Molecular Networks Using Proteomics: A Vision for Patient-Tailored Combination Therapy
Authors: Petricoin Emanuel F. , Bichsel Verena E. , Calvert Valerie S. , Espina Virginia , Winters Mary , Young Lynn , Belluco Claudio , Trock Bruce J. , Lippman Marc , Fishman David A. , Sgroi Dennis C. , Munson Peter J. , Esserman Laura J. , Liotta Lance A.
Published: May 2005

Mapping tumor cell protein networks in vivo will be critical for realizing the promise of patient-tailored molecular therapy. Cancer can be defined as a dysregulation or hyperactivity in the network of intracellular and extracellular signaling cascades. These protein signaling circuits are the ultimate targets of molecular therapy. Each patient's tumor may be driven by a distinct series of molecular pathogenic defects. Thus, for any single molecular targeted therapy, only a subset of cancer patients may respond. Individualization of therapy, which tailors a therapeutic regimen to a tumor molecular portrait, may be the solution to this dilemma. Until recently, the field lacked the technology for molecular profiling at the genomic and proteomic level. Emerging proteomic technology, used concomitantly with genomic analysis, promises to meet this need and bring to reality the clinical adoption of molecular stratification. The activation state of kinase-driven signal networks contains important information relative to cancer pathogenesis and therapeutic target selection. Proteomic technology offers a means to quantify the state of kinase pathways, and provides post-translational phosphorylation data not obtainable by gene arrays. Case studies using clinical research specimens are provided to show the feasibility of generating the critical information needed to individualize therapy. Such technology can reveal potential new pathway interconnections, including differences between primary and metastatic lesions. We provide a vision for individualized combinatorial therapy based on proteomic mapping of phosphorylation end points in clinical tissue material.
Irinotecan in Combination With Fluorouracil in a 48-Hour Continuous Infusion As First-Line Chemotherapy for Elderly Patients With Metastatic Colorectal Cancer: A Spanish Cooperative Group for the Treatment of Digestive Tumors Study
Authors: Sastre Javier , Marcuello Eugenio , Masutti Bartomeu , Navarro Matilde , Gil Silvia , Antón Antonio , Abad Albert , Aranda Enrique , Maurel Joan , Valladares Manuel , Maestu Inmaculada , Carrato Alfredo , Vicent José María , Díaz-Rubio Eduardo
Published: May 2005

Purpose

Elderly patients constitute a subpopulation with special characteristics that differ from those of the nonelderly and have been underrepresented in clinical trials. This study was performed to determine the efficacy and safety of irinotecan (CPT-11) in combination with fluorouracil (FU) administered as a 48-hour continuous infusion twice a month in elderly patients.

Patients and Methods

Patients ≥ 72 years old with metastatic colorectal cancer, Eastern Cooperative Oncology Group performance status of 0 to 1, no geriatric syndromes, and no prior treatment were treated every 2 weeks with CPT-11 180 mg/m2 plus FU 3,000 mg/m2 in a 48-hour continuous infusion.

Results

By intent-to-treat analysis, in 85 assessable patients, the objective response rate was 35% (95% CI, 25% to 46%), and stable disease was 33% (95% CI, 23% to 44%). Median time to progression was 8.0 months (95% CI, 6.0 to 10.0 months), and median overall survival time was 15.3 months (95% CI, 13.8 to 16.9 months). Toxicity was moderate. Grade 3 and 4 neutropenia, diarrhea, and asthenia were observed in 21%, 17%, and 13% of patients, respectively. Only one case of neutropenic fever occurred. There were two toxic deaths, one was a result of grade 4 diarrhea and acute kidney failure, and the other was a result of massive intestinal hemorrhage in the first cycle. The study of prognostic factors did not reveal any predictive factor of response. Response to treatment and baseline lactate dehydrogenase were the main factors conditioning progression-free and overall survival.

Conclusion

Twice a month continuous-infusion CPT-11 combined with FU is a valid therapeutic alternative for elderly patients in good general condition.
Home-Based Physical Activity Intervention for Breast Cancer Patients
Authors: Pinto Bernardine M. , Frierson Georita M. , Rabin Carolyn , Trunzo Joseph J. , Marcus Bess H.
Published: May 2005

Purpose

The efficacy of a home-based physical activity (PA) intervention for early-stage breast cancer patients was evaluated in a randomized controlled trial.

Patients and Methods

Eighty-six sedentary women (mean age, 53.14 years; standard deviation, 9.70 years) who had completed treatment for stage 0 to II breast cancer were randomly assigned to a PA or contact control group. Participants in the PA group received 12 weeks of PA counseling (based on the Transtheoretical Model) delivered via telephone, as well as weekly exercise tip sheets. Assessments were conducted at baseline, after treatment (12 weeks), and 6 and 9 month after baseline follow-ups. The post-treatment outcomes are reported here.

Results

Analyses showed that, after treatment, the PA group reported significantly more total minutes of PA, more minutes of moderate-intensity PA, and higher energy expenditure per week than controls. The PA group also out-performed controls on a field test of fitness. Changes in PA were not reflected in objective activity monitoring. The PA group was more likely than controls to progress in motivational readiness for PA and to meet PA guidelines. No significant group differences were found in body mass index and percent body fat. Post-treatment group comparisons revealed significant improvements in vigor and a reduction in fatigue in the PA group. There was a positive trend in intervention effects on overall mood and body esteem.

Conclusion

The intervention successfully increased PA and improved fitness and specific aspects of psychological well-being among early-stage breast cancer patients. The success of a home-based PA intervention has important implications for promoting recovery in this population.
Phase I Study of 506U78 Administered on a Consecutive 5-Day Schedule in Children and Adults With Refractory Hematologic Malignancies
Authors: Kurtzberg J. , Ernst T.J. , Keating M.J. , Gandhi V. , Hodge J.P. , Kisor D.F. , Lager J.J. , Stephens C. , Levin J. , Krenitsky T. , Elion G. , Mitchell B.S.
Published: May 2005

Purpose

A phase I study was conducted to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of a novel purine nucleoside, nelarabine, a soluble prodrug of 9-beta-D-arabinosylguanine (araG; Nelarabine), in pediatric and adult patients with refractory hematologic malignancies.

Patients and Methods

Between April 1994 and April 1997, 93 patients with refractory hematologic malignancies were treated with one to 16 cycles of study drug. Nelarabine was administered daily, as a 1-hour intravenous infusion for 5 consecutive days, every 21 to 28 days. First-cycle pharmacokinetic data, including plasma nelarabine and araG levels, were obtained on all patients treated. Intracellular phosphorylation of araG was studied in samples of leukemic blasts from selected patients.

Results

The MTDs were defined at 60 mg/kg/dose and 40 mg/kg/dose daily × 5 days in children and adults, respectively. Dose-limiting toxicity (DLT) was neurologic in both children and adults. Myelosuppression and other significant organ toxicities did not occur. Pharmacokinetic parameters were similar in children and adults. Accumulation of araGTP in leukemic blasts was correlated with cytotoxic activity. The overall response rate was 31%. Major responses were seen in patients with T-cell malignancies, with 54% of patients with T-lineage acute lymphoblastic leukemia achieving a complete or partial response after one to two courses of drug.

Conclusion

Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged.
Phase II Study of Nelarabine (compound 506U78) in Children and Young Adults With Refractory T-Cell Malignancies: A Report From the Children’s Oncology Group
Authors: Berg Stacey L. , Blaney Susan M. , Devidas Meenakshi , Lampkin Tom A. , Murgo Anthony , Bernstein Mark , Billett Amy , Kurtzberg Joanne , Reaman Greg , Gaynon Paul , Whitlock James , Krailo Mark , Harris Michael B.
Published: May 2005

Purpose

Nelarabine (compound 506U78), a water soluble prodrug of 9-b-d-arabinofuranosylguanine, is converted to ara-GTP in T lymphoblasts. We sought to define the response rate of nelarabine in children and young adults with refractory or recurrent T-cell disease.

Patients and Methods

We performed a phase II study with patients stratified as follows: stratum 1: ≥ 25% bone marrow blasts in first relapse; stratum 2: ≥ 25% bone marrow blasts in ≥ second relapse; stratum 3: positive CSF; stratum 4: extramedullary (non-CNS) relapse. The initial nelarabine dose was 1.2 g/m2 daily for 5 consecutive days every 3 weeks. There were two dose de-escalations due to neurotoxicity on this or other studies. The final dose was 650 mg/m2/d for strata 1 and two patients and 400 mg/m2/d for strata 3 and four patients.

Results

We enrolled 121 patients (106 assessable for response) at the final dose levels. Complete plus partial response rates at the final dose levels were: 55% in stratum 1; 27% in stratum 2; 33% in stratum 3; and 14% in stratum 4. There were 31 episodes of ≥ grade 3 neurologic adverse events in 27 patients (18% of patients).

Conclusion

Nelarabine is active as a single agent in recurrent T-cell leukemia, with a response rate more than 50% in first bone marrow relapse. The most significant adverse events associated with nelarabine administration are neurologic. Further studies are planned to determine whether the addition of nelarabine to front-line therapy for T-cell leukemia in children will improve survival.
Randomized Comparison of Group Versus Individual Genetic Education and Counseling for Familial Breast and/or Ovarian Cancer
Authors: Calzone Kathleen A. , Prindiville Sheila A. , Jourkiv Oxana , Jenkins Jean , DeCarvalho Maria , Wallerstedt Dawn B. , Liewehr David J. , Steinberg Seth M. , Soballe Peter W. , Lipkowitz Stan , Klein Pamela , Kirsch Ilan R.
Published: May 2005

Purpose

An efficient approach to education and counseling before BRCA1 and BRCA2 mutation testing is necessary for effective utilization of testing in the community. Education and counseling, when delivered individually, are limited by a shortage of trained health care providers as well as by financial and time constraints. The purpose of this study was to determine whether pretest education and counseling for breast cancer genetics in a group setting is equivalent to that provided on an individual basis.

Patients and Methods

One hundred forty-two patients at high risk for harboring a BRCA mutation were randomly assigned to group or individual education and counseling sessions. Group education was followed by brief individual counseling. Knowledge and Impact of Events Scales (IES) were administered at baseline and after education and counseling and at 1 week and 3, 6, and 12 months. Satisfaction with education and counseling was measured at completion of the session. Preferred method of education and counseling was solicited at 3 months.

Results

There was no difference in knowledge or IES scores between groups. When stratified by genetic test results, knowledge scores showed no difference. Regardless of group, post-test IES scores in patients with positive results were higher than patients with negative or uninformative results but returned to baseline by 12 months. Participants were equally satisfied with either method they were assigned. Significantly more time was spent per patient in individual sessions (1.25 hours) than in group education (0.74 hours).

Conclusion

Our data suggest that group education and counseling may confer similar benefits compared with traditional individual sessions. Additional investigation of this approach in larger numbers of patients is warranted.
Patient Online Self-Reporting of Toxicity Symptoms During Chemotherapy
Authors: Basch Ethan , Artz David , Dulko Dorothy , Scher Kevin , Sabbatini Paul , Hensley Martee , Mitra Nandita , Speakman John , McCabe Mary , Schrag Deborah
Published: May 2005

Purpose

Tracking symptoms related to treatment toxicity is standard practice in routine care and during clinical trials. Currently, clinicians collect symptom information via complex and often inefficient mechanisms, but there is growing interest in collecting outcome information directly from patients.

Patients and Methods

The National Cancer Institute Common Terminology Criteria for Adverse Events schema for seven common symptoms was adapted into a Web-based patient-reporting system, accessible from desktop computers in outpatient clinics and from home computers. Eighty patients with gynecologic malignancies beginning standard chemotherapy regimens were enrolled between April and September 2004. During an 8-week observation period, participants were encouraged to log in and report symptoms at each follow-up visit, or alternatively, to access the system from home.

Results

All patients completed an initial log in. At each subsequent appointment, most enrollees (80% to 85%) reported symptoms using the online system, with a mean of three follow-up visits per patient during the observation period (range, one to six). Sixty of 80 patients (75%) logged in at least once from home. Use was significantly associated with prior Internet experience. Forty-two severe toxicities (grade 3 to 4) entered from home prompted seven clinician interventions. Most patients (96%) found the system useful and would recommend it to others.

Conclusion

Patients are capable of reporting symptoms experienced during chemotherapy using a Web-based interface. Assessment in the clinical trial setting and comparison of direct patient- versus clinician-based approaches for reporting symptoms and their severity are warranted.
Evaluation of Five Radiation Schedules and Prognostic Factors for Metastatic Spinal Cord Compression
Authors: Rades Dirk , Stalpers Lukas J.A. , Veninga Theo , Schulte Rainer , Hoskin Peter J. , Obralic Nermina , Bajrovic Amira , Rudat Volker , Schwarz Rudolf , Hulshof Maarten C. , Poortmans Philip , Schild Steven E.
Published: May 2005

Purpose

To study five radiotherapy (RT) schedules and potential prognostic factors for functional outcome in metastatic spinal cord compression (MSCC).

Patients and Methods

One thousand three hundred four patients who were irradiated from January 1992 to December 2003 were included in this retrospective review. The schedules of 1 × 8 Gy in 1 day (n = 261), 5 × 4 Gy in 1 week (n = 279), 10 × 3 Gy in 2 weeks (n = 274), 15 × 2.5 Gy in 3 weeks (n = 233), and 20 × 2 Gy in 4 weeks (n = 257) were compared for motor function, ambulatory status, and in-field recurrences. The following potential prognostic factors were investigated: age, sex, performance status, histology, number of involved vertebra, interval from cancer diagnosis to MSCC, pretreatment ambulatory status, and time of developing motor deficits before RT. A multivariate analysis was performed with the ordered logit model.

Results

Motor function improved in 26% (1 × 8 Gy), 28% (5 × 4 Gy), 27% (10 × 3 Gy), 31% (15 × 2.5 Gy), and 28% (20 × 2 Gy); and posttreatment ambulatory rates were 69%, 68%, 63%, 66%, and 74% (P = .578), respectively. On multivariate analysis, age, performance status, primary tumor, involved vertebra, interval from cancer diagnosis to MSCC, pretreatment ambulatory status, and time of developing motor deficits were significantly associated with functional outcome, whereas the RT schedule was not. Acute toxicity was mild, and late toxicity was not observed. In-field recurrence rates at 2 years were 24% (1 × 8 Gy), 26% (5 × 4 Gy), 14% (10 × 3 Gy), 9% (15 × 2.5 Gy), and 7% (20 × 2 Gy) (P < .001). Neither the difference between 1 × 8 Gy and 5 × 4 Gy (P = .44) nor between 10 × 3 Gy, 15 × 2.5 Gy, and 20 × 2 Gy (P = .71) was significant.

Conclusion

The five RT schedules provided similar functional outcome. The three more protracted schedules seemed to result in fewer in-field recurrences. To minimize treatment time, the following two schedules are recommended: 1 × 8 Gy for patients with poor predicted survival and 10 × 3 Gy for other patients. Results should be confirmed in a prospective randomized trial.
Quality of Life Among Younger Women With Breast Cancer
Authors: Avis Nancy E. , Crawford Sybil , Manuel Janeen
Published: May 2005

Purpose

To describe quality of life (QOL) of younger women 4 to 42 months after breast cancer diagnosis and to identify factors associated with impaired QOL.

Methods

A total of 202 women diagnosed with stage I to III breast cancer at age 50 or younger from 4 to 42 months after breast cancer diagnosis previously completed a mailed survey. Global QOL; health-related QOL as measured by the Functional Assessment of Cancer Therapy–Breast Cancer (FACT-B); medical history; symptoms; days of work/activity missed after diagnosis; relationship, sexual, and body image problems; coping strategies; and feelings of preparedness were measured.

Results

General aches and pains and unhappiness with appearance were reported by more than 70% of women. Hot flashes (P = .0007), pain with sexual intercourse (P = .02), and difficulty with bladder control (P = .002) all significantly increased with age. Global QOL was significantly lower than for a nonpatient sample of younger women (P < .0001). In general, few sociodemographic and medical factors were related to QOL. In multivariate analyses, days of work/usual activity missed immediately after diagnosis; relationship, sexual, or body image problems after diagnosis; and coping strategies were related to almost all QOL domains. Ongoing treatment, vaginal dryness, and feeling unprepared for the impact of breast cancer were related to some domains.

Conclusion

Younger breast cancer survivors are at risk for impaired QOL up to several years after diagnosis. Younger women, especially those at high risk for lower QOL, may need interventions that specifically target their needs related to menopausal symptoms and problems with relationships, sexual functioning, and body image. Preparing younger woman for the impact of breast cancer may also prove beneficial.
Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma Modulates Intratumoral CD4/CD8 Ratio and Tumor Microenvironment: A Multicenter Phase II Clinical Trial
Authors: Tímár József , Ladányi Andrea , Forster-Horváth Csaba , Lukits Júlia , Döme Balázs , Remenár Éva , Gődény Mária , Kásler Miklós , Bencsik Beáta , Répássy Gábor , Szabó György , Velich Norbert , Suba Zsuzsa , Élő János , Balatoni Zsuzsa , Pócza Károly , Zemplén Béla , Chretien Paul , Talor Eyal
Published: May 2005

Purpose

To investigate the clinicopathologic effects of local neoadjuvant Leukocyte Interleukin Injection (LI) regimen in oral squamous cell carcinoma (OSCC) patients. Treatment regimen included LI 800 IU/d as interleukin-2 (IL-2), administered half peritumorally and half perilymphatically five times per week for 3 weeks; low-dose cyclophosphamide; indomethacin; zinc; and multivitamins.

Patients and Methods

Thirty-nine patients diagnosed with T2-3N0-2M0 OSCC participated in the pathology portion of this phase II multicenter study (19 LI-treated patients and 20 historical controls). Clinical responses were determined by imaging. Paraffin-embedded tumor samples were obtained at surgery for all patients. Surgery for the LI-treated group was performed between days 14 and 54 after the end of treatment. Histologic evaluation, pathologic staging, necrosis, and American Joint Committee on Cancer grading were performed from hematoxylin and eosin sections. Immunohistochemistry and morphometry determined cellular infiltrate.

Results

Two pathologically complete, two major (> 50%), and four minor responses (> 30% but < 50%) resulted from LI treatment (overall response rate, 42%). Histopathology showed that the intratumoral CD4+:CD8+ ratio was low (< 1) in patients not treated with LI (controls). An increase in tumor-infiltrating CD4+ and a decrease of CD8+ T cells was observed in LI-treated patients, leading to a significantly (P < .05) higher intratumoral CD4+:CD8+ ratio (> 2.5). This was paralleled by dendritic cell transition from tumor surface toward stromal interface (P < .05), with macrophage decrease and neutrophil accumulation, multifocal microscopic necrosis, and significant (P < .05) increase in tumor stroma of LI-treated patients compared with controls.

Conclusion

LI-treated OSCC patients were characterized by a markedly altered composition of tumor-infiltrating mononuclear cells, increased CD4+:CD8+ ratio, and increased tumor stroma to epithelial ratio, all of which were distinct from controls.
Gemcitabine in Combination With Oxaliplatin Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GISCAD Phase III Trial
Authors: Louvet C. , Labianca R. , Hammel P. , Lledo G. , Zampino M.G. , André T. , Zaniboni A. , Ducreux M. , Aitini E. , Taïeb J. , Faroux R. , Lepere C. , de Gramont A.
Published: May 2005

Purpose

Gemcitabine (Gem) is the standard treatment for advanced pancreatic cancer. Given the promising phase II results obtained with the Gem-oxaliplatin (GemOx) combination, we conducted a phase III study comparing GemOx with Gem alone in advanced pancreatic cancer.

Patients and Methods

Patients with advanced pancreatic cancer were stratified according to center, performance status, and type of disease (locally advanced v metastatic) and randomly assigned to either GemOx (gemcitabine 1 g/m2 as a 100-minute infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2 every 2 weeks) or Gem (gemcitabine 1 g/m2 as a weekly 30-minute infusion).

Results

Three hundred twenty-six patients were enrolled; 313 were eligible, and 157 and 156 were allocated to the GemOx and Gem arms, respectively. GemOx was superior to Gem in terms of response rate (26.8% v 17.3%, respectively; P = .04), progression-free survival (5.8 v 3.7 months, respectively; P = .04), and clinical benefit (38.2% v 26.9%, respectively; P = .03). Median overall survival (OS) for GemOx and Gem was 9.0 and 7.1 months, respectively (P = .13). GemOx was well tolerated overall, although a higher incidence of National Cancer Institute Common Toxicity Criteria grade 3 and 4 toxicity per patient was observed for platelets (14.0% for GemOx v 3.2% for Gem), vomiting (8.9% for GemOx v 3.2% for Gem), and neurosensory symptoms (19.1% for GemOx v 0% for Gem).

Conclusion

These results confirm the efficacy and safety of GemOx, but this study failed to demonstrate a statistically significant advantage in terms of OS compared with Gem. Because GemOx is the first combined treatment to be superior to Gem alone in terms of clinical benefit, this promising regimen deserves further development.
Clinical Examination Following Preoperative Chemoradiation for Rectal Cancer Is Not a Reliable Surrogate End Point
Authors: Guillem Jose G. , Chessin David B. , Shia Jinru , Moore Harvey G. , Mazumdar Madhu , Bernard Bianca , Paty Philip B. , Saltz Leonard , Minsky Bruce D. , Weiser Martin R. , Temple Larissa K.F. , Cohen Alfred M. , Wong W. Douglas
Published: May 2005

Purpose

Clinical assessment of rectal cancer response to preoperative combined-modality therapy (CMT) using digital rectal examination (DRE) has been proposed as a means of assessing efficacy of therapy. However, because the accuracy of this approach has not been established, we conducted a prospective analysis to determine the operating surgeon's ability to assess response using DRE.

Patients and Methods

Ninety-four prospectively accrued patients with locally advanced rectal cancer (T3/4 or N1) were evaluated with DRE and sigmoidoscopy in order to determine the following tumor characteristics: size, location, mobility, morphology, and circumference. Following preoperative CMT (50.40 Gy with fluorouracil-based chemotherapy) and under general anesthesia, the same surgeon estimated tumor response based on changes in these tumor characteristics, assessed via DRE. Percent pathologic tumor response was determined prospectively by a single pathologist using whole mount sections of the resected cancer.

Results

Clinical assessment using DRE underestimated pathologic response in 73 cases (78%). In addition, DRE was able to identify only 3 of 14 cases (21%) with a pathologic complete response. There were no clinical overestimates of response. None of the clinicopathologic tumor characteristics examined had a significant impact on DRE estimation of response.

Conclusion

Clinical examination underestimates the extent of rectal cancer response to preoperative CMT. Given the inaccuracy of DRE following preoperative CMT, it should not be used as a sole means of assessing efficacy of therapy nor for selecting patients following CMT for local surgical therapies.
Clinical Value of Mitochondrial Mutations in Colorectal Cancer
Authors: Lièvre Astrid , Chapusot Caroline , Bouvier Anne-Marie , Zinzindohoué Franck , Piard Françoise , Roignot Patrick , Arnould Laurent , Beaune Philippe , Faivre Jean , Laurent-Puig Pierre
Published: May 2005

Purpose

Prognostic factors that could select high-risk recurrence colorectal cancer patients and predict chemosensitivity are needed. Since mutations of mitochondrial DNA (mtDNA) have been described in different types of cancers and since they may play a role in response to anticancer agents, we investigated in a population-based series of colorectal cancer patients the clinical value of mtDNA mutations.

Patients and Methods

The displacement loop (D-loop) region of mtDNA was sequenced on a series of 365 patients recorded in the Digestive Cancer Registry of Côte-d'Or (France) between 1998 and 2000. Clinicopathologic characteristics were correlated to the presence of a D-loop mutation. Survival rates were compared with the log-rank test. A multivariate survival analysis was performed.

Results

D-loop mutations were found in 38.3% of the tumors. The 3-year survival rate was 53.5% in patients with D-loop mutation versus 62.1% in patients without (P = .05). After adjustment for age, stage, and microsatellite instability status, the relative risk of death in patients with D-loop mutation was 1.40 (95% CI, 1.02 to 1.93; P = .034) as compared with those without. In stage III colon cancers, adjuvant chemotherapy was beneficial only for patients without D-loop mutation (3-year survival, 78.3% v 45.4%, P < .02). In those with D-loop mutation who received adjuvant chemotherapy, the relative risk of death was 4.30 (95% CI, 1.23 to 15.00; P < .02).

Conclusion

The D-loop region is a hotspot for somatic mutations in colorectal tumors. Moreover, presence of tumor D-loop mutation appears to be a factor of poor prognosis in colorectal patients and a factor of resistance to fluorouracil-based adjuvant chemotherapy in stage III colon cancers.
Bendamustine Plus Rituximab Is Effective and Has a Favorable Toxicity Profile in the Treatment of Mantle Cell and Low-Grade Non-Hodgkin's Lymphoma
Authors: Rummel Mathias J. , Al-Batran Salah E. , Kim Soo-Z. , Welslau Manfred , Hecker Ralf , Kofahl-Krause Dorothea , Josten Klaus-M. , Dürk Heinz , Rost Andreas , Neise Michael , von Grünhagen Ulrich , Chow Kai U. , Hansmann Martin-L. , Hoelzer Dieter , Mitrou Paris S.
Published: May 2005

Purpose

The aim of this multicenter-study was to evaluate the progression-free survival, response rate and toxicity of the combination of bendamustine and rituximab (BR) in patients with mantle cell or low-grade lymphomas in first to third relapse or refractory to previous treatment.

Patients and Methods

A total of 245 courses (median, four courses per patient) were administered to 63 patients. Bendamustine was given at a dose of 90 mg/m2 as a 30-minute infusion on days 1 and 2, combined with 375 mg/m2 rituximab on day 1, for a maximum of four cycles every 4 weeks. Histologies were 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, and six marginal zone lymphoma.

Results

Fifty-seven of 63 patients responded to BR, corresponding to an overall response rate of 90% (95% CI, 80% to 96%) with a complete remission rate (CR) of 60% (95% CI, 47% to 72%). The median time of progression-free survival was 24 months (range, 5 to 44+ months), and the median duration of overall survival has not yet been reached. In mantle cell lymphomas, BR showed a considerable activity, achieving a response rate of 75% (95% CI, 48% to 93%) with a CR rate of 50%. Myelosuppression was the major toxicity, with 16% grade 3 and 4 leukocytopenia. Thrombocytopenia was rare, with only 3% grade 3 and 4.

Conclusion

These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas.
The Cutaneous B-Cell Lymphoma Prognostic Index: A Novel Prognostic Index Derived From a Population-Based Registry
Authors: Smith Benjamin D. , Smith Grace L. , Cooper Dennis L. , Wilson Lynn D.
Published: May 2005

Purpose

Three classification and prognostic systems exist for primary cutaneous B-cell lymphoma (PCBCL). Whereas the WHO classification defines its categories based on histology, both the European Organisation for Research and Treatment of Cancer classification and the conventional staging system consider skin site. We sought to incorporate both histology and skin site into a single prognostic index designed to predict survival in patients with PCBCL.

Methods

The associations between histology, skin site, and survival were determined using adjusted proportional hazards analysis conducted on 926 patients with PCBCL identified in the Surveillance, Epidemiology, and End Results data, spanning 1973 to 2001.

Results

Four primary CBCL prognostic index (CBCL-PI) groups were identified. Group IA included indolent histologies involving any skin site. Group IB included diffuse large B-cell histology involving favorable skin sites (head/neck, arm). Group II included diffuse large B-cell histology involving unfavorable skin sites (trunk, legs, disseminated) or immunoblastic large B-cell histology involving favorable skin sites. Group III included immunoblastic large B-cell histology involving unfavorable skin sites. The adjusted mortality hazards ratios were 1.0, 1.3 (95% CI, 0.99 to 1.7), 2.1 (95% CI, 1.6 to 2.7), and 4.5 (95% CI, 2.8 to 7.2) for groups IA/B to III, respectively. The corresponding 5-year relative survivals were 94%, 86%, 60%, and 34%.

Conclusion

The CBCL-PI identifies adverse combinations of histology and skin site, helping to reconcile differences in current classification and prognostic systems for PCBCL.
Changes in Gene Expression Associated With Response to Neoadjuvant Chemotherapy in Breast Cancer
Authors: Hannemann Juliane , Oosterkamp Hendrika M. , Bosch Cathy A.J. , Velds Arno , Wessels Lodewyk F.A. , Loo Claudette , Rutgers Emiel J. , Rodenhuis Sjoerd , van de Vijver Marc J.
Published: May 2005

Purpose

At present, clinically useful markers predicting response of primary breast carcinomas to either doxorubicin-cyclophosphamide (AC) or doxorubicin-docetaxel (AD) are lacking. We investigated whether gene expression profiles of the primary tumor could be used to predict treatment response to either of those chemotherapy regimens.

Patients and Methods

Within a single-institution, randomized, phase II trial, patients with locally advanced breast cancer received six courses of either AC (n = 24) or AD (n = 24) neoadjuvant chemotherapy. Gene expression profiles were generated from core-needle biopsies obtained before treatment and correlated with the response of the primary tumor to the chemotherapy administered. Additionally, pretreatment gene expression profiles were compared with those in tumors remaining after chemotherapy.

Results

Ten (20%) of 48 patients showed a (near) pathologic complete remission of the primary tumor after treatment. No gene expression pattern correlating with response could be identified for all patients or for the AC or AD groups separately. The comparison of the pretreatment biopsy and the tumor excised after chemotherapy revealed differences in gene expression in tumors that showed a partial remission but not in tumors that did not respond to chemotherapy.

Conclusion

No gene expression profile predicting the response of primary breast carcinomas to AC- or AD-based neoadjuvant chemotherapy could be detected in this interim analysis. More subtle differences in gene expression are likely to be present but can only be reliably identified by studying a larger group of patients. Response of a breast tumor to neoadjuvant chemotherapy results in alterations in gene expression.
Molecular Determinants of Cetuximab Efficacy
Authors: Vallböhmer Daniel , Zhang Wu , Gordon Michael , Yang Dong Yun , Yun Jim , Press Oliver A. , Rhodes Katrin E. , Sherrod Andy E. , Iqbal Syma , Danenberg Kathleen D. , Groshen Susan , Lenz Heinz-Josef
Published: May 2005

Purpose

To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab.

Patients and Methods

Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction.

Results

There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment.

Conclusion

This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment.
Bevacizumab in Combination With Fluorouracil and Leucovorin: An Active Regimen for First-Line Metastatic Colorectal Cancer
Authors: Hurwitz Herbert I. , Fehrenbacher Louis , Hainsworth John D. , Heim William , Berlin Jordan , Holmgren Eric , Hambleton Julie , Novotny William F. , Kabbinavar Fairooz
Published: May 2005

Purpose

In a phase III trial, combining bevacizumab (BV)—a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor—with irinotecan, bolus fluorouracil (FU), and leucovorin (LV; IFL) increased survival compared with IFL alone in first-line treatment of patients with metastatic colorectal cancer (CRC). Results for the parent study of IFL/BV versus IFL/placebo are reported elsewhere. Here, we describe efficacy and safety results for the third patient cohort in this trial, who received BV combined with FU/LV, and compare them with results for concurrently enrolled patients who received IFL.

Methods

Patients (N = 923) were randomly assigned to receive IFL/placebo (control), IFL/BV, or FU/LV/BV. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) 5 mg/kg was administered intravenously every 2 weeks. Before an interim analysis confirmed acceptable safety for IFL/BV, 313 patients were concurrently randomly assigned to these three arms; after this analysis, the FU/LV/BV arm was discontinued.

Results

Median overall survivals were 18.3 and 15.1 months with FU/LV/BV (n = 110) and IFL/placebo (n = 100), respectively. Median progression-free survivals were 8.8 and 6.8 months, respectively. Overall response rates were 40.0% and 37.0%, and median response durations were 8.5 and 7.2 months, respectively. Adverse events consistent with those expected from FU/leucovorin- or IFL-based regimens were seen, as were modest increases in hypertension and bleeding in the bevacizumab arm, which were generally easily managed.

Conclusion

The FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile. FU/LV/BV is an active alternative treatment regimen for patients with previously untreated metastatic CRC.
Phase II Trial of Postoperative Adjuvant Paclitaxel/Carboplatin and Thoracic Radiotherapy in Resected Stage II and IIIA Non–Small-Cell Lung Cancer: Promising Long-Term Results of the Radiation Therapy Oncology Group—RTOG 9705
Authors: Bradley Jeffrey D. , Paulus Rebecca , Graham Mary V. , Ettinger David S. , Johnstone David W. , Pilepich Miljenko V. , Machtay Mitchell , Komaki Ritsuko , Atkins James , Curran Walter J.
Published: May 2005

Purpose

To determine the overall survival, progression-free survival, and toxicity associated with concurrent paclitaxel/carboplatin and thoracic radiotherapy for completely resected patients with stage II and IIIA non–small-cell lung cancer (NSCLC).

Patients and Methods

Eighty-eight eligible patients had surgical resection for pathologic stage II or IIIA disease and received postoperative paclitaxel and carboplatin. Concurrent thoracic radiotherapy at 50.4 Gy in 28 fractions for 6 weeks (1.8 Gy/d, 5 days/wk) was given during cycles 1 and 2. A boost of 10.8 Gy in six fractions was given for extracapsular nodal extension or T3 lesions.

Results

Treatment compliance was acceptable, with 93% compliance for radiation therapy and 86% for chemotherapy completion. The median duration of follow-up was 56.7 months (range, 17 to 61 months). The median overall survival time was 56.3 months, with 1-, 2-, and 3-year survival rates of 86%, 70%, and 61%, respectively. The 1-, 2-, and 3- year progression-free survival rates were 70%, 57%, and 50%, respectively. Brain metastasis occurred as the sole site of first failure in 11%, and 9% failed in other metastatic sites as first failure. Of the 43 patients who died, the cause of death was the treated cancer in 31 (35%). Local failure was a component of first failure in 15% of patients. Toxicities were acceptable. An overall survival comparison to Eastern Cooperative Oncology Group 3590 is favorable.

Conclusion

The mature results of this trial suggest an improved overall and progression-free survival in this group of resected NSCLC patients, compared with previously reported trials. A phase III trial comparing this treatment regimen with standard therapy seems warranted.
Maternal Food Restriction Enhances Insulin-Induced GLUT-4 Translocation and Insulin Signaling Pathway in Skeletal Muscle from Suckling Rats
Authors: Gavete M. L. , Martín M. A. , Alvarez C. , Escrivá F.
Published: May 2005

Restriction of protein calories during stages of immaturity has a major influence on glucose metabolism and increases the risk of type 2 diabetes in adulthood. However, it is known that reduction of food intake alleviates insulin resistance. We previously demonstrated an improved insulin-induced glucose uptake in skeletal muscle of chronically undernourished adult rats. The purpose of this work was to investigate whether this condition is present during suckling, a period characterized by physiological insulin resistance as well as elucidate some of the underlying mechanisms. With this aim, 10-d-old pups from food-restricted dams were studied. We showed that undernourished suckling rats are glucose normotolerants, despite their depressed insulin secretion capacity. The content of the main glucose transporters in muscle, GLUT-4 and GLUT-1, was not affected by undernutrition, but fractionation studies showed an improved insulin-stimulated GLUT-4 translocation. p38MAPK protein, implicated in up-regulation of intrinsic activity of translocated GLUT-4, was increased. These changes suggest an improved insulin-induced glucose uptake associated with undernutrition. Insulin receptor content as well as that of both regulatory and catalytic phosphoinositol 3-kinase subunits was increased by food restriction. Insulin receptor substrate-1-associated phosphoinositol 3-kinase activity after insulin was enhanced in undernourished rats, as was phospho-glycogen synthase kinase-3, in line with insulin hypersensitivity. Surprisingly, protein tyrosine phosphatase-1B association with insulin receptor was also increased by undernutrition. These adaptations to a condition of severely limited nutritional resources might result in changes in the development of key tissues and be detrimental later in life, when a correct amount of nutrients is available, as the thrifty phenotype hypothesis predicts.
Sex Difference in the Response of Melanin-Concentrating Hormone Neurons in the Lateral Hypothalamic Area to Glucose, as Revealed by the Expression of Phosphorylated Cyclic Adenosine 3′,5′-Monophosphate Response Element-Binding Protein
Authors: Mogi Kazutaka , Funabashi Toshiya , Mitsushima Dai , Hagiwara Hiroko , Kimura Fukuko
Published: May 2005

Because there are sex differences in feeding behavior in rats, we looked for a possible sex difference in the response to glucose of melanin-concentrating hormone (MCH) neurons in the lateral hypothalamic area using phosphorylated cAMP response element-binding protein (pCREB) as a marker of neural activity. Intact male rats and female rats at diestrus 2, proestrus, or estrus were fed normally or fasted for 48 h and injected with saline or glucose (400 mg/kg). Thereafter, preparations were subjected to immunohistochemical processing for the double staining of MCH and pCREB. Fasting increased the ratio of MCH neurons with pCREB (double-stained cells) in both male and female rats. In fasted rats, glucose injection decreased the ratio of double-stained cells more promptly in females than in males. The magnitude of decrease caused by glucose was greater at proestrus and estrus than at diestrus 2. Gonadectomy in males enhanced and in females attenuated the response of MCH neurons to glucose. Testosterone and estrogen replacement in males and females, respectively, restored the response of MCH neurons to glucose. The demonstrated sex differences in the response of MCH neurons to glucose correlated well with the gonadal steroid milieu; thus, MCH neurons may play an important role in sex differences in feeding behavior.