bluuebunny/crossref_metadata_2025 huggingface dataset:
Ecological and genetic evidence of the vulnerability of shallow‐water populations of the stylasterid hydrocoral Errina novaezelandiae in New Zealand's fiords
Authors: J. Miller Karen , Mundy Craig N. , Lindsay Chadderton W.
Published: January 2004

Some of the key life history characteristics that make modular marine invertebrates such as corals vulnerable to disturbance and stress are susceptibility to damage, slow growth, longevity, and philopatry. This may be particularly so for marginal populations at the limits of their range and, for instance, that are attractive to scuba divers.

In this study we examined the population structure and incidence of damage, quantified growth rates and estimated gene flow to assess the effects of divers on the deep‐water emergent populations of the fragile red coral Errina novaezelandiae in the Te Awaatu Marine Reserve in Fiordland, New Zealand.

We found that population structure in red corals is skewed, with small colonies the most abundant. Damage was up to eight times higher in dived than in non‐dived populations of red coral, and large colonies were more likely to be damaged. Growth in red corals can be high (up to 7 cm −1), although net growth is much lower (0.7 cm yr−1) due to the effects of partial mortality. On the basis of the slow growth rate, we estimate that large corals (>20 cm diameter) will be in excess of 30 yr old. We also found high genetic subdivision among red coral populations and evidence of inbreeding, indicative of limited larval dispersal among neighbouring populations.

Overall, our results indicate the shallow‐water populations of red coral in Fiordland will be susceptible to impacts from scuba diving, and the development of a management strategy to ensure ecologically sustainable tourism and to minimize the effects of divers will be essential for their conservation.

Copyright © 2003 John Wiley & Sons, Ltd.
Comparative pharmacokinetics of acetyl salicylic acid and its metabolites in children suffering from autoimmune diseases
Authors: Juárez Olguín Hugo , Flores Pérez Janett , Lares Asseff Ismael , Loredo Abdalá Arturo , Carbajal Rodríguez Luis
Published: January 2004

The aim of the present study was to compare the effect produced by juvenile rheumatoid arthritis (JRA) or rheumatic fever (RF) on the pharmacokinetics of acetyl salicylic acid (ASA) and its metabolites in children with autoimmune diseases (AD). Methods—A prospective, open labelled study was performed in 17 children with JRA and 17 with RF who received a single dose of 25 mg ASA/kg orally. The pharmacokinetics of ASA and its metabolites were determined. The blood and urine levels of each salicylate collected during 24 h were measured by HPLC. A group of 15 healthy teenage volunteers was included as a control group. Results—The maximum plasma concentration, half‐life time, area under the curve and the amount of salicylates excreted were statistically different between the JRA and the RF groups, as well as between the RF group and the controls, however, there were no significant differences between the JRA group and the controls. Conclusions—Dosage schemes must be adjusted for JRA patients, since the half life in these patients is longer than in RF patients. However, due to ample variability of pharmacokinetic parameters it is recommended that dose schemes are individualized on the type of autoimmune disease considered. Copyright © 2004 John Wiley & Sons, Ltd.
Disposition of WR‐1065 in the liver of tumor‐bearing rats following regional vs systemic administration of amifostine
Authors: Levi Micha , DeRemer Susan J. , Dou Chunzhi , Ensminger William D. , Smith David E.
Published: January 2004

Purpose—Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR‐1065, in normal tissues as a result of differences in membrane‐bound alkaline phosphatase activity. It was hypothesized that amifostine may be a good candidate for regional drug delivery to the liver because of its large hepatic extraction and total body clearance. Methods—Rat livers were implanted with Walker‐256 tumors. The tumor‐bearing rats received 15 min infusions of amifostine (200 mg/kg) via the portal vein or the femoral vein. WR‐1065 concentrations in the blood, liver and tumor were measured at various times. Results—The WR‐1065 tumor portal dosing AUC15−60 was 40% of systemic dosing, and tumor concentrations following portal dosing were one‐fifth of that following systemic dosing. The portal dosing WR‐1065 liver AUC15−60 was 60% higher than the values for systemic dosing. The liver/tumor concentration ratios of WR‐1065 following portal dosing were up to 8‐fold higher than the ratio following systemic administration. Unfortunately, systemic exposure to WR‐1065 was greater following portal vs systemic amifostine. Conclusions—Amifostine may provide increased liver protection and decreased tumor protection from radio‐ or chemotherapy when administered by the portal vein. However, portal dosing also increases systemic exposure to WR‐1065, which is associated with hypotension. Copyright © 2004 John Wiley & Sons, Ltd.
Transdermal delivery system for zidovudine: in vitro, ex vivo and in vivo evaluation
Authors: Narishetty Sunil Thomas Kumar , Panchagnula Ramesh
Published: January 2004

The objective of this study was to prepare a transdermal delivery system (TDS) for zidovudine (AZT) with a combination of menthol and oleic acid as penetration enhancers incorporated in hydroxypropyl methylcellulose, and to evaluate ex vivo as well as in vivo permeation across rat skin. It was found that AZT in gel formulation was stable in both refrigerated as well as accelerated stability conditions for 3 months and further, the gel did not significantly retard the permeability of AZT across the skin in comparison with solution formulation. Ex vivo steady state flux of AZT across rat skin from gel was 2.26 mg cm−2 h−1, which is sufficient to achieve therapeutic plasma concentrations. Intravenous pharmacokinetic parameters of AZT in rats were determined and used together with ex vivo flux data to generate theoretical plasma profiles of AZT and compared with plasma concentrations achieved after application of TDS. Further, steady state plasma concentrations of drug following multiple applications of TDS were determined and good correlations between ex vivo and in vivo data were observed. In addition, the combination of penetration enhancers used at 2.5% w/w in this study proved efficient in achieving sufficient enhancement in the transdermal permeability of AZT across rat skin with reduced skin irritation potential when compared with individual penetration enhancers at higher concentrations. Copyright © 2004 John Wiley & Sons, Ltd.
Comparative evaluation of digoxin concentrations determined by three assay systems: TDx, IMx and OPUS
Authors: Kagawa Yoshiyuki , Iwamoto Takuya , Matsuda Hiroaki , Mukohara Rika , Sawada Jun‐ichi , Kojima Michio
Published: January 2004

Digoxin concentrations measured by three automated immunoassay systems, i.e. OPUS, TDx and IMx assays, were compared in order to evaluate precision and accuracy performance, and data compatibility. Coefficients of variation for all methods in within‐run and between‐run precision were less than 10% at weighed‐in concentrations of 0.545, 1.090 and 2.180 ng/ml. The accuracy relative to the three weighed‐in concentrations ranged from 97% to 123% for all methods. One hundred and three plasma samples from 60 patients receiving digoxin were used to evaluate the data compatibility. Digoxin concentrations measured by the three immunoassay systems correlated well with one another. These results suggest that there are few problems when switching between digoxin assay methods, and that IMx and OPUS are more useful than TDx because they do not require sample pretreatment. The digoxin concentrations of the plasma samples from one patient receiving both digoxin and potassium canrenoate were investigated as a case report. The digoxin concentrations measured by TDx and IMx became higher than those measured by OPUS after starting the combination treatment. In another patient suffering from bilirubinaemia, the digoxin concentrations measured by TDx or IMx were higher than those measured by OPUS. These results suggest that OPUS has a higher specificity for measuring the plasma digoxin concentrations compared with TDx or IMx. Copyright © 2003 John Wiley & Sons, Ltd.
In vitro investigation on the impact of the surface‐active excipients Cremophor EL, Tween 80 and Solutol HS 15 on the metabolism of midazolam
Authors: Bravo González Roberto C. , Huwyler Jörg , Boess Franziska , Walter Isabelle , Bittner Beate
Published: January 2004

The impact of the surface‐active formulation ingredients Cremophor EL, Tween 80 and Solutol HS 15 on the intrinsic clearance (Clint) of midazolam (MDZ) was investigated in rat hepatocytes and microsomes. In rat hepatocytes with 0.003%, 0.03% and 0.3% (w/v) Solutol HS 15 already present in the incubation medium, the Clint was significantly reduced in a dose‐dependent manner by about 25%, 30% and 50%, respectively. In the presence of Cremophor EL and Tween 80 a significant reduction in Clint by about 30% and 25%, respectively, was observed at 0.03% surfactant concentration. At 0.3% of Cremophor EL and Tween 80, Clint was reduced by about 50% and 20%, respectively. A reduction in Clint was also observed in experiments with rat liver microsomes. At surfactant concentrations up to 0.03%, cytotoxicity assays (lactate dehydrogenase release, adenosine triphosphate content) as well as light microscope investigations did not reveal any cytotoxic impact of the surfactants on the hepatocyte monolayer. A potential interaction of the surfactants with biological membranes was determined using phosphatidylcholine‐cholesterol liposomes loaded with self‐quenching concentrations of carboxyfluorescein. No marked release of carboxyfluorescein from the liposomes (that would be an indication for a surfactant‐dependent disruption of membrane integrity) was observed up to concentrations of 0.03% of the different surfactants. It is concluded that cytochrome P450 3A mediated metabolism of MDZ seems to be prevented by all surfactants at concentrations above 0.03%. In our experiments the surfactants did not show toxic effects at concentrations that resulted in a decreased Clint of MDZ. Thus, a direct inhibition of the metabolizing enzymes, a molecular interaction with the microsomes as well as an alteration of membrane properties that did not yet result in a release of LDH have to be taken into consideration as reasons for the observed changes in the metabolism of MDZ. Copyright © 2004 John Wiley & Sons, Ltd.
A clinically comprehensive ethical framework for offering and recommending cancer treatment before and during pregnancy
Authors: Chervenak Frank A. , McCullough Laurence B. , Knapp Robert C. , Caputo Thomas A. , Barber Hugh R. K.
Published: January 2004

The authors describe a clinically comprehensive ethical framework for addressing the challenges of managing cancer during pregnancy. The framework is based on the ethical principles of beneficence and respect for autonomy and the concept of the fetus as a patient.
Chemotherapy‐induced neutropenia
Authors: Crawford Jeffrey , Dale David C. , Lyman Gary H.
Published: January 2004

Cytotoxic chemotherapy suppresses the hematopoietic system, impairing host protective mechanisms and limiting the doses of chemotherapy that can be tolerated. Neutropenia, the most serious hematologic toxicity, is associated with the risk of life‐threatening infections as well as chemotherapy dose reductions and delays that may compromise treatment outcomes. The authors reviewed the recent literature to provide an update on research in chemotherapy‐induced neutropenia and its complications and impact, and they discuss the implications of this work for improving the management of patients with cancer who are treated with myelosuppressive chemotherapy. Despite its importance as the primary dose‐limiting toxicity of chemotherapy, much concerning neutropenia and its consequences and impact remains unknown. Recent surveys indicate that neutropenia remains a prevalent problem associated with substantial morbidity, mortality, and costs. Much research has sought to identify risk factors that may predispose patients to neutropenic complications, including febrile neutropenia, in an effort to predict better which patients are at risk and to use preventive strategies, such as prophylactic colony‐stimulating factors, more cost‐effectively. Neutropenic complications associated with myelosuppressive chemotherapy are a significant cause of morbidity and mortality, possibly compromised treatment outcomes, and excess healthcare costs. Research in quantifying the risk of neutropenic complications may make it possible in the near future to target patients at greater risk with appropriate preventive strategies, thereby maximizing the benefits and minimizing the costs. Cancer 2004;100:228–37. © 2003 American Cancer Society.
Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project
Authors: Fisher Edwin R. , Land Stephanie R. , Fisher Bernard , Mamounas Eleftherios , Gilarski Linda , Wolmark Norman
Published: January 2004

BACKGROUND

The current report represents a 12‐year clinicopathologic update of an earlier 5‐year analysis of 180 patients with lobular carcinoma in situ (LCIS) who were treated with local excision and subsequent surveillance only.

METHODS

Nineteen pathologic characteristics of LCIS were assessed as potential predictors of invasive and noninvasive ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR) as well as mortality.

RESULTS

Overall, only 26 IBTRs (14.4%) and 14 CBTRs (7.8%) were observed. Nine IBTRs (5.0% of the total cohort) and 10 CBTRs (5.6% of the total cohort) were invasive carcinomas. Eight of 9 IBTRs (88.9%) and 6 of 8 invasive CBTRs (75%) that had histologic sections available for review were of the lobular invasive type. Ninety‐six percent of all IBTRs and 100% of invasive IBTRs occurred within the same site as the index LCIS. The numbers of invasive IBTRs were comparable within and after 5 years (5 invasive IBTRs vs. 4 IBTRs). Recurrences of invasive CBTR occurred later than recurrences of invasive IBTR, with 70% of invasive CBTRs recognized after 5 years compared with 44% of invasive IBTRs. It was found that Grade 2–3 LCIS was significantly predictive for invasive IBTR when combined with the number of recurrences of ductal carcinoma in situ (DCIS) alone or with LCIS. Only 2 patients in the cohort (1.1%) succumbed to breast carcinoma; 1 patient had a prior invasive IBTR, and the other patient had an invasive CBTR. The reasons for the lower frequency of invasive recurrences and the higher proportions of the lobular invasive phenotype than noted by others are discussed along with the impact of the findings on the nomenclature, precursor nature, and treatment of LCIS.

CONCLUSIONS

LCIS is a more indolent form of in situ breast carcinoma than DCIS, with which it shares other features of its natural history, particularly very low mortality rates. There is no compelling reason to surgically treat LCIS other than conservatively. The values of other adjuvant modalities in the management of LCIS are discussed. The authors acknowledge that their findings are based on relatively few events and, even at 12 years, may be regarded as ‘preliminary’. Nonetheless, their findings may reflect the true biologic nature of LCIS. Cancer 2004;100:238–44. © 2003 American Cancer Society.
Phase II study of alpha‐tocopherol in improving the cognitive function of patients with temporal lobe radionecrosis
Authors: Chan Agnes S. , Cheung Mei‐Chun , Law Stephen C. , Chan John H.
Published: January 2004

BACKGROUND

Radiotherapy is an important treatment modality for brain tumors and is the standard radical treatment for nasopharyngeal carcinoma (NPC). However, the treatment is not free of side effects, and one possible neurologic sequela is the occurrence of temporal lobe radionecrosis (TLN) associated with cognitive dysfunction. Currently, there is no effective intervention to improve patients' cognitive performance.

METHODS

Twenty‐nine patients with TLN after radiotherapy for NPC were recruited on a voluntary basis. Among them, 19 patients (15 males and 4 females) received a megadose of alpha‐tocopherol (vitamin E) (2000 international units per day) for 1 year, whereas the other 10 (5 males and 5 females) served as control patients. Their cognitive function (i.e., global cognitive ability, attention, memory, language, and executive function) was evaluated by a battery of neuropsychological tests before and after treatment.

RESULTS

Significant improvement in global cognitive ability (P = 0.035) and memory (verbal: P = 0.036; visual: P = 0.007) occurred among patients in the treatment group after a 1‐year medication period. In addition, the executive function of the treatment group improved significantly (P = 0.04). No difference was found between the two groups with respect to attention or language.

CONCLUSIONS

The current investigation was a preliminary study on the effect of alpha‐tocopherol on the cognitive function of patients with TLN after radiotherapy for NPC. In view of the absence of effective treatment for patients with cerebral radionecrosis, alpha‐tocopherol has the potential to be a complementary intervention for patients with cognitive dysfunction due to TLN. Cancer 2004;100:398–404. © 2003 American Cancer Society.
Long‐term outcomes after radical prostatectomy performed in a community‐based health maintenance organization
Authors: Zhang M.S. Ying , Glass Andrew , Bennett Nicole , Oyama Karen A. , Gehan Edmund , Gelmann Edward P.
Published: January 2004

BACKGROUND

Radical prostatectomy is used widely for the treatment of patients with localized prostate carcinoma. No long‐term analysis has been reported on a series of radical prostatectomies performed in a community‐based health maintenance organization.

METHODS

Charts and histologic slides were reviewed from 750 patients who underwent radical prostatectomy between 1970 and 1996 at a community‐based health maintenance organization. The influences of a number of variables were analyzed for their impact on progression free survival (PFS) and overall survival (OS).

RESULTS

With a median follow‐up of 6.2 years among survivors, 137 patients (18%) had progressive disease, and 149 patients (20%) died from all causes. The median OS from the date of diagnosis was 15.7 years (95% confidence interval, 13.6–17.2), similar to the expected median survival of 16.2 years. The median PFS from diagnosis was not reached, but 75% of patients were progression free ≥ 10.6 years after undergoing prostatectomy. The prognostic factors included Gleason score, age at diagnosis, and T stage. Outcomes were comparable with reports of surgical series from university‐based practices.

CONCLUSIONS

The patient characteristics that had important, favorable correlation with survival included Gleason score ≤ 6, T1 or T2 tumor status, and younger age at diagnosis. Lower prostate‐specific antigen values at diagnosis, together with the former two parameters, also had a favorable correlation with PFS. Radical prostatectomy in a community‐based health maintenance organization was followed by long‐term PFS and OS comparable to outcomes reported from university‐based practices. The impact of radical prostatectomy on survival remains to be demonstrated. Cancer 2004;100:300–7. © 2003 American Cancer Society.
Stereotactic vacuum‐assisted breast biopsy in 2874 patients
Authors: Kettritz Ute , Rotter Kerstin , Schreer Ingrid , Murauer Margarete , Schulz‐Wendtland Rüdiger , Peter Daniela , Heywang‐Köbrunner Sylvia H.
Published: January 2004

BACKGROUND

Vacuum‐assisted breast biopsy (VAB) can replace surgical biopsy for the diagnosis of breast carcinoma. The authors evaluated the accuracy and clinical utility of VAB in a multicenter setting using a strict quality assurance protocol.

METHODS

In the current study, VABs were performed successfully for 2874 patients at 5 sites. Benign lesions were verified by follow‐up. Surgery was recommended for malignant and borderline lesions. VAB was performed on patients with lesions rated as highly suspicious (6%), intermediate to suspicious (85%), or probably benign (9%). Fifty‐eight percent of the lesions were < 10 mm and 70% had microcalcifications.

RESULTS

The authors identified 7% of patients with invasive carcinomas, 15% with ductal carcinomas in situ (DCIS), 5% with atypical ductal hyperplasias (ADH), and 0.6% with lobular carcinomas in situ. The results of the VAB necessitated an upgrade of 24% of patients with ADH to DCIS or DCIS and invasive carcinoma. Twelve percent of patients with DCIS proved to have invasive carcinoma. Seventy‐three percent of the patients had benign lesions. Only 1 false‐negative result was encountered (negative predictive value, 99.95%). Minor side effects were reported to occur in 1.4% of patients and 0.1% of patients required a subsequent intervention. Scarring relevant for mammography was rare among patients (i.e., 0.3% of patients had relevant scarring).

CONCLUSIONS

Quality‐assured VAB was found to be highly reliable. VAB effectively identified patients with benign lesions and assisted therapeutic decisions. Most important, only a single case of malignancy was missed. A close interdisciplinary approach assured optimal results. Cancer 2004;100:245–51. © 2003 American Cancer Society.
Phase II study of pentostatin in advanced T‐cell lymphoid malignancies
Authors: Tsimberidou Apostolia‐Maria , Giles Francis , Duvic Madeleine , Fayad Luis , Kurzrock M.D. Razelle
Published: January 2004

BACKGROUND

The goal of the current study was to assess the toxicity, safety, and efficacy of pentostatin in patients with T‐cell lymphoid malignancies.

METHODS

Patients were eligible if they had biopsy‐proven T‐cell lymphoma or leukemia and failure to respond to previous therapy or an expected complete response rate to conventional therapy of < 20%. Pentostatin was administered at an initial dose of 3.75 or 5.0 mg/m2 by intravenous bolus daily over a consecutive 3‐day period every 3 weeks.

RESULTS

Forty‐two of 44 patients enrolled in the study were evaluable. The median age of the patients was 62 years (range, 38–86 years). Patients received a median of 3 previous therapies (range, 0–10 previous therapies). Of these patients, 32 (76%) had mycosis fungoides/Sézary syndrome and 10 patients (24%) had other T‐cell leukemias or lymphomas. The overall response rate was 54.8% (complete remission, 6 patients [14.3%]; partial remission, 17 patients [40.5%]). Durable responses were observed mainly in patients with Sézary syndrome or peripheral T‐cell lymphoma. The median follow‐up period for surviving patients was 20 months (range, 1–83+ months). The median duration of response was 4.3 months (range, 1–61 months). The most common toxicities were neutropenia, nausea, and CD4 suppression. A transient early ‘flare’ of disease was observed in some responders.

CONCLUSIONS

At these doses, pentostatin was reasonably well tolerated and is an effective drug for the treatment of T‐cell lymphomas. Cancer 2004;100:342–9. © 2003 American Cancer Society.
Expression of matrix metalloproteinase 9 is a prognostic factor in patients with non‐Hodgkin lymphoma
Authors: Sakata Koh‐ichi , Satoh Masaaki , Someya Masanori , Asanuma Hiroko , Nagakura Hisayasu , Oouchi Atushi , Nakata Kensei , Kogawa Katsuhisa , Koito Kazumitsu , Hareyama Masato , Himi Tetsuo
Published: January 2004

BACKGROUND

Non‐Hodgkin lymphoma (NHL) represents a heterogeneous group of tumors that vary with regard to their biologic aggressiveness and clinical course. In in vitro studies, matrix metalloproteinase 9 (MMP9) was reportedly expressed by human NHL cells and elevated levels of MMP9 have been observed in a subset of patients with high‐grade NHL.

METHODS

The expression of MMP2 and MMP9 was evaluated in 158 patients with NHL and the relation between the expression of these proteins and clinicopathologic factors was analyzed. All but 1 patient had received radiation therapy and 92 patients also were treated with intensive combination chemotherapy.

RESULTS

Nearly all the patients with extranodal natural killer NK/T‐cell lymphoma nasal type and anaplastic large cell lymphoma, T‐cell/null cell type expressed MMP9. In contrast, only a small fraction of the patients with mucosa‐associated lymphoid tissue (MALT) lymphomas and follicular lymphomas expressed MMP9. Approximately 50% of the diffuse large B‐cell lymphoma (DLBCL) cases expressed MMP9. The expression of MMP2 was noted in some of the patients with DLBCL and nasal NK/T‐cell lymphoma. The overall survival rates of patients who expressed MMP9 were significantly lower than that of those who did not. Such a correlation was not demonstrated in MMP2 expression. When MMP9 expression was analyzed in DLBLC patients, the overall survival rates of patients who expressed MMP9 were significantly lower than those who did not express MMP9. Chemotherapy was associated with better overall survival in DLBCL patients who expressed MMP9. Overall survival rates of T‐cell/NK‐cell lymphoma patients who expressed MMP9 appeared to be lower than that in those who did not express MMP9. However, chemotherapy was not found to improve overall survival in patients who expressed MMP9.

CONCLUSIONS

MMP9 expression was observed in patients with aggressive NHL and was characterized by poor overall survival. Cancer 2004;100:356–65.© 2003 American Cancer Society.
Long‐term follow‐up of patients with intermediate or high‐grade non‐Hodgkin lymphoma treated with a combination of cyclophosphamide, epirubicin, vincristine, and prednisone
Authors: Rossini Fausto , Terruzzi Elisabetta , Perego Daniele , Miccolis Isabella , Rivolta Franca , Manca Elena , Pogliani Enrico M.
Published: January 2004

BACKGROUND

Doxorubicin cardiotoxicity is one of the most serious side effects of the cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, regimen, especially among elderly patients. In the CEOP regimen, epirubicin was substituted for doxorubicin to reduce cardiotoxicity.

METHODS

Between March 1984 and September 1998, 186 previously untreated patients with a histologically confirmed diagnosis of intermediate‐ or high‐grade non‐Hodgkin lymphoma according to the Working Formulation were treated with CEOP (cyclophosphamide, 750 mg/m2, epirubicin, 75 mg/m2, vincristine, 1.4 mg/m2; and prednisone, 60 mg per day orally on Days 1–5). Of 186 patients, 85 (45.7%) had Stage IV disease, and 60 (32.3%) had an International Prognostic Index score > 2. Comorbidity was present in 36 patients (19.3%).

RESULTS

Complete remission (CR) was achieved in 119 patients (64.3%), and partial remission was achieved in 30 patients (16.2%). Among the patients who achieved a CR, 95 (79.8%) were still disease free at a median follow‐up time of 86.9 months (range, 14–200 months). The remaining 24 patients experienced disease recurrence, at a median follow‐up time of 19 months (range, 3–101 months). The relative dose intensities were 0.69, 0.89, and 0.80 for vincristine, epirubicin, and cyclophosphamide, respectively. Two patients died of toxicity due to infection. Two patients, 59 and 73 years old, respectively, experienced arrhythmia. Another patient, age 64 years, who had a myocardial infarction 10 years earlier, had angina. One patient with hypertension experienced cardiac failure. No patients died of cardiac toxicity.

CONCLUSION

Long‐term follow‐up confirmed that CEOP is an effective and well‐tolerated chemotherapy regimen for intermediate‐ and high‐grade lymphoma. The Results were promising, especially among elderly patients. Cancer 2004;100:350–5. © 2003 American Cancer Society.
Treatment outcome and pattern of failure in 77 patients with sinonasal natural killer/T‐cell or T‐cell lymphoma
Authors: Li Chi‐Cheng , Tien Hwei‐Fang , Tang Jih‐Luh , Yao Ming , Chen Yao‐Chang , Su Ih‐Jen , Hsu Su‐Ming , Hong Ruey‐Long
Published: January 2004

BACKGROUND

Sinonasal natural killer (NK)/T‐cell or T‐cell lymphoma behaves quite differently from other lymphomas. The objective of this study was to investigate clinical features, treatment outcomes, and failure patterns in patients with this type of sinonasal lymphoma.

METHODS

From September, 1977 to December, 2000, 77 patients with sinonasal NK/T‐cell lymphoma or T‐cell lymphoma who had received radiotherapy (R/T), chemotherapy (C/T), or both (R/T and C/T) were evaluated retrospectively.

RESULTS

Fifty‐six patients (73%) had locoregional disease only, and 21 patients (27%) had systemic involvement. Forty‐four patients (57%) achieved a complete remission (CR). The 5‐year overall survival rate was 36% (median follow‐up, 89 months). Achievement of CR was the only prognostic factor for survival in multivariate analysis. Among patients with locoregional disease, the CR rate was 63%, and the 5‐year overall survival rate was 42%. Combined R/T and C/T or R/T alone resulted in better survival compared with C/T alone (5‐year survival rates, 59%, 50%, and 15%, respectively; P = 0.01). Incidences of locoregional and systemic failure were 43% and 30%, respectively. Outcome was dismal for patients with systemic disease, with a CR rate of 43% and a 5‐year survival rate of 25%. Only 2 of 21 patients had sustained remissions. The locoregional and systemic failure rates were 57% and 71%, respectively.

CONCLUSIONS

Treatment outcomes were unsatisfactory for patients with locoregional and systemic sinonasal NK/T‐cell or T‐cell lymphoma. R/T could not control locoregional disease satisfactorily, and C/T was unable to eradicate systemic disease in many patients. High‐dose therapy may be worth studying in these patients. New treatments should be investigated to increase remission rates, prevent failure, and improve survival. Cancer 2004;100:366–75. © 2003 American Cancer Society.
A Phase II trial of aprinocarsen, an antisense oligonucleotide inhibitor of protein kinase C α, administered as a 21‐day infusion to patients with advanced ovarian carcinoma
Authors: Advani Ranjana , Peethambaram Prema , Lum Bert L. , Fisher George A. , Hartmann Lynn , Long Harry J. , Halsey Joanne , Holmlund Jon T. , Dorr Andrew , Sikic Branimir I.
Published: January 2004

BACKGROUND

It has been postulated that protein kinase C α (PKC‐α) plays a pivotal role in signal transduction in tumor cancer cells. Aprinocarsen, a 20‐base antisense oligonucleotide, has shown ability to inhibit PKC‐α protein expression and inhibit tumor growth in human xenograft models. In a previous Phase I trial, the authors demonstrated the safety and some evidence of activity in ovarian carcinoma of aprinocarsen administered as a 21‐day, continuous, intravenous infusion.

METHODS

In this Phase II trial, 36 patients with advanced ovarian carcinoma were treated with aprinocarsen at a dose of 2 mg/kg per day delivered as a 21‐day, continuous, intravenous infusion. The primary objective was to determine the antitumor response, and the secondary objectives were to evaluate toxicity and to evaluate effects on quality of life (QOL).

RESULTS

Between September 1997 and December 1999, 36 patients (median age, 58 years) were enrolled in this trial. Patients were stratified into 2 groups: a platinum‐sensitive group (n = 12 patients) and a platinum‐resistant group (n = 24 patients). All 36 patients were evaluable for toxicity, and 27 patients were fully assessable for antitumor response after 2 cycles of therapy. All patients had received prior treatments. No objective responses were noted in the platinum‐sensitive group. In the platinum‐resistant group, 1 patient had some evidence of antitumor activity indicated by a decrease in serum CA 125 and stable disease on imaging studies for 8 months. No changes were noted in overall patient ratings for any of the five QOL domains.

CONCLUSIONS

When it was administered as a single agent, aprinocarsen did not have significant clinical activity in patients with advanced ovarian carcinoma. Further study may be warranted in combination with platinum‐based regimens. Cancer 2004;100:321–6. © 2003 American Cancer Society.
Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first‐line treatment in metastatic colorectal carcinoma
Authors: Bajetta Emilio , Di Bartolomeo Maria , Mariani Luigi , Cassata Antonio , Artale Salvatore , Frustaci Sergio , Pinotti Graziella , Bonetti Andrea , Carreca Ignazio , Biasco Guido , Bonaglia Luigi , Marini Giovanni , Iannelli Antonio , Cortinovis Diego , Ferrario Ermina , Beretta Elena , Lambiase Antonio , Buzzoni Roberto ,   for the Italian Trials in Medical Oncology (I.T.M.O.) Group
Published: January 2004

BACKGROUND

The aim of the current randomized Phase II study was to investigate the efficacy and safety of capecitabine combined with irinotecan as first‐line treatment in metastatic colorectal carcinoma (CRC).

METHODS

A total of 140 patients received capecitabine at a dose of 1250 mg/m2 twice daily on Days 2–15 and irinotecan at a dose of either 300 mg/m2 on Day 1 (Arm A) or 150 mg/m2 on Days 1 and 8 (Arm B) every 3 weeks. During the course of the study, enrollment was continued using lower doses of capecitabine (1000 mg/m2 twice daily) and irinotecan (Arm A: 240 mg/m2; Arm B: 120 mg/m2) to improve the safety profile of the combinations.

RESULTS

Efficacy was evaluable in 134 patients (68 in Arm A, 66 in Arm B). Objective responses were observed in 46% of the patients (8% complete response [CR]), including 47% in Arm A (9% CR; 38% partial response [PR]) and 44% in Arm B (8% CR; 36% PR). The median progression‐free survival was 8.3 months in Arm A and 7.6 months in Arm B. Among the first 52 patients treated with the higher doses, the most frequent Grade 3–4 adverse event was diarrhea (27%). The lower doses adopted in the subsequent 88 patients led to better diarrhea control, particularly in Arm A, and significant reductions in the incidence of all‐grade hand‐foot syndrome and abdominal pain.

CONCLUSIONS

The capecitabine and irinotecan combination was a highly active first‐line therapy in metastatic CRC. An acceptable safety profile was observed after dose reduction, particularly when irinotecan was administered on 1 day. Cancer 2004;100:279–87. © 2003 American Cancer Society.
Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma
Authors: De Vita Ferdinando , Orditura Michele , Lieto Eva , Infusino Stefania , Morgillo Floriana , Martinelli Erika , Castellano Paolo , Romano Ciro , Ciardiello Fortunato , Catalano Giuseppe , Pignatelli Carlo , Galizia Gennaro
Published: January 2004

BACKGROUND

To the authors' knowledge, little is known to date regarding the prognostic relevance of measuring serum levels of vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis, in patients with colon carcinoma who undergo surgery.

METHODS

Preoperative and postoperative VEGF serum levels were determined by enzyme‐linked immunoadsorbent assay in 81 patients with colon carcinoma who were undergoing surgery. Fifty healthy individuals served to define normal VEGF serum levels.

RESULTS

Preoperative VEGF serum levels were significantly higher in the group of patients with colon carcinoma (mean, 504.1 pg/mL ± 223 pg/mL; range, 285–1390 pg/mL; 95% confidence interval [95%CI], 49 pg/mL) compared with the control group (mean, 78.1 pg/mL ± 22 pg/mL; range, 40–110 pg/mL; 95%CI, 4.3 pg/mL; P < 0.001). Multiple regression analysis demonstrated a significant correlation (r) between preoperative VEGF serum levels and age (r = − 0.275; P = 0.013), Dukes stage (r = 0.488; P < 0.001), and carcinoembryonic antigen (CEA) levels (r = 0.285; P < 0.018). No significant correlation was found between preoperative VEGF serum levels and disease site, patient gender, tumor size, tumor grade, or performance status. Moreover, preoperative VEGF serum levels were significantly lower in patients who underwent curative surgery compared with patients who underwent noncurative surgery (443 pg/mL ± 117 pg/mL vs. 821 ± 353 pg/mL, respectively; P < 0.0001). Logistic regression analysis selected preoperative VEGF and CEA serum levels as the only good prognostic indicators of curative and noncurative surgery (P < 0.001; relative risk, 2.98 and 2.03, respectively). Furthermore, VEGF serum levels dropped significantly after surgery, with a further downward trend until the 30th postoperative day (P < 0.001). Stepwise regression analysis selected preoperative VEGF serum level as the only variable associated significantly with the prediction of both disease‐specific survival and disease‐free survival (P = 0.001).

CONCLUSIONS

Preoperative serum VEGF levels may be useful for predicting outcome in patients with colon carcinoma who undergo surgery. Cancer 2004;100:270–8. © 2003 American Cancer Society.
Genetic polymorphisms in the Hmong population
Authors: Kiffmeyer William R. , Langer Erica , Davies Stella M. , Envall Julie , Robison Leslie L. , Ross Julie A.
Published: January 2004

BACKGROUND

The Hmong, an isolated, agrarian people from southern China, migrated to the mountainous regions of what are today Vietnam, Cambodia, and Laos. Minnesota has the second largest Hmong population in the United States. The authors compared frequencies of common genetic polymorphisms believed to influence risk of malignancy to determine whether frequencies in the Hmong are different from those in other Asian populations and in white Minnesotans.

METHODS

Genotyping for glutathione S‐transferase μ1 (GSTM1), glutathione S‐transferase θ1 (GSTT1), myeloperoxidase (MPO) (C−463T), nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase (NQO1) (C609T), 5,10‐methylenetetrahydrofolate reductase (MTHFR) (C677T), MTHFR (A1298C), methionine synthase reductase (MTRR) (A66G), X‐ray repair cross complementing 1 (XRCC1) 194 (Arg194Trp), XRCC1 280 (Arg280His), and XRCC1 399 (Arg399Gln) alleles was performed by TaqMan analysis using DNA isolated from newborn heel‐stick spots provided by the Minnesota Department of Health.

RESULTS

The Hmong had significantly higher frequencies of the NQO1 T allele and the XRCC1 Trp polymorphism (Arg194Trp) and had significantly lower frequencies of the G allele in MTRR (A66G) and the T allele in MTHFR (C677T) compared with white Minnesotans. The Hmong also were significantly more likely to lack the GSTM1 and GSTT1 genes compared with whites (82% vs. 54% and 61% vs. 18%, respectively). Genotype frequencies were similar for MTHFR (A1298C), MPO (C−463T), and XRCC1 (Arg280His, Arg399Gln). Genotype frequencies at these loci also were compared with those reported for other Asian populations and showed notable differences between the Hmong and Chinese/Taiwanese, Korean, and Japanese populations.

CONCLUSIONS

The genetic differences identified have implications for both cancer etiology and prognosis in this unique population. Cancer 2004;100:411–7. © 2003 American Cancer Society.
Frequency of HLA‐C alleles in differentiated thyroid carcinoma in southeastern Spain
Authors: Ríos Antonio , Rodríguez José Manuel , Moya María Rosa , Galindo Pedro José , Canteras Manuel , Alvarez María Rocío , Parrilla Pascual
Published: January 2004

BACKGROUND

The development of thyroid carcinoma may be influenced genetically and has been associated with certain HLA alleles. HLA‐C alleles have not been studied in depth, because available serology techniques have not been very reliable in detecting them. However, the development of molecular biology provided an efficient and reliable technique for allele detection. The aims of the current study were to determine whether there is a significant association between any HLA‐C allele and differentiated thyroid carcinoma and to establish the possible susceptibility or protection alleles related to these tumors.

METHODS

HLA‐C genotyping was performed in 63 patients undergoing surgery for differentiated thyroid carcinoma (57 patients with the papillary subtype and 6 patients with the follicular subtype). A representative sample of 100 nonrelated healthy Caucasians was used as a control group from the same geographic area. The polymerase chain reaction–sequence‐specific primer technique was used for HLA‐C genotyping. The clinical variables analyzed were age, gender, family history of thyroid pathology, residence in areas of endemic goiter, asymptomatic status, presence of hyperthyroidism, compressive symptoms, presence of an intrathoracic thyroid component, histologic variables of the tumor, and evolution. The chi‐square test, the Mantel–Haenszel test, and the Bonferroni correction were used for the statistical analysis.

RESULTS

In the control group, a significant correlation was observed between the lower frequency of the HLA‐Cw7 allele and the development of differentiated thyroid carcinoma (P < 0.05). Analysis of the different clinical variables revealed a relation between HLA‐C alleles and three clinical situations: cervical lymph node involvement with HLA‐Cw7 and HLA‐Cw2, vascular involvement with HLA‐Cw7 and HLA‐Cw1, and cervical carcinoma recurrence with HLA‐Cw1. However, after application of the Bonferroni correction, only the association between HLA‐Cw7 and lymphatic (Pc = 0.0483) or vascular involvement (Pc = 0.0324) persisted.

CONCLUSIONS

The results revealed a relation between HLA‐Cw7 and differentiated thyroid carcinoma. In future investigations, HLA‐C typing may help to identify patients with a poor prognosis. Cancer 2004;100:264–9. © 2003 American Cancer Society.
Molecular markers for prognosis after isolated postmastectomy chest wall recurrence
Authors: Haffty Bruce G. , Hauser Analene , Ho Choi Doo , Parisot Nicole , Rimm David , King Bonnie , Carter Darryl
Published: January 2004

BACKGROUND

Local chest wall recurrence after mastectomy occurs in 10–20% of patients with operable breast carcinoma. The objective of the current study was to assess the prognostic value of molecular markers at the time of local recurrence and to compare these markers with clinical variables.

METHODS

Between 1975 and 1999, the authors treated 113 patients at their institution for postmastectomy chest wall recurrences with full‐course external beam radiotherapy. Patients who presented primarily with lymph node recurrences or with simultaneous distant metastasis were excluded. Follow‐up from the time of chest wall recurrence was 10.13 years. All clinical and pathologic data from the original diagnosis and from the time of chest wall recurrence were entered into a computerized database. Paraffin‐embedded tumor specimens from the chest wall recurrences were available for 43 patients and were constructed into tissue microarrays for immunohistochemical staining of estrogen receptor, progesterone receptor (PR), p53, HER‐2/neu, and cyclin D.

RESULTS

Overall survival after chest wall recurrence for the entire cohort was 46% at 5 years and 28% at 10 years. The distant metastasis–free survival rate was 49% at 5 years and 40% at 10 years. Local‐regional control of disease was achieved in 79% of patients at 10 years. In multivariate analysis, significant factors for distant metastasis after local recurrence were time to recurrence (< 2 years from the original diagnosis to chest wall recurrence) and PR status (distant metastasis–free survival rate: 84% [PR‐positive] vs. 38% [PR‐negative]; P = 0.007). The only significant factor for local‐regional disease progression was HER‐2/neu status. Patients with positive HER‐2/neu status had a local‐regional progression‐free rate of 59%, compared with 92% for patients with negative HER‐2/neu status.

CONCLUSIONS

The prognosis for patients after local‐regional recurrence of breast carcinoma is relatively poor. Longer time to local recurrence and positive PR status were associated with favorable distant metastasis–free rates and long‐term survival. Positive HER‐2/neu status was associated with poorer local‐regional control of disease. Implications for systemic therapy and further studies are discussed. Cancer 2004;100:252–63. © 2003 American Cancer Society.
Elective radiotherapy provides regional control for patients with cutaneous melanoma of the head and neck
Authors: Bonnen Mark D. , Ballo Matthew T. , Myers Jeffrey N. , Garden Adam S. , Diaz Eduardo M. , Gershenwald Jeffrey E. , Morrison William H. , Lee Jeffrey E. , Oswald Mary Jane , Ross Merrick I. , Ang K. Kian
Published: January 2004

BACKGROUND

In the current study, the authors assessed the efficacy of elective radiotherapy in providing regional (lymph node) control in patients with cutaneous melanoma of the head and neck who were at high risk for lymph node involvement. Toxicity was also assessed.

METHODS

From 1983 to 1998, 157 patients with Stage I or II cutaneous melanoma of the head and neck received elective regional radiotherapy after wide local excision of the primary lesion. None of the patients had received sentinel lymph node biopsy or dissection of the lymph nodes. Their medical records were reviewed retrospectively and analyzed for outcome.

RESULTS

The median follow‐up for the current review was 68 months (range, 7–185 months). The disease recurred locally in 9 patients, in the neck lymph nodes in 15 patients, and distantly in 57 patients. The actuarial regional control rate was 89% at both 5 years and 10 years. The actuarial disease‐specific survival and distant metastasis‐free survival rates were 68% and 63%, respectively, at 5 years and 58% and 49%, respectively, at 10 years. Breslow thickness was a significant determinant of disease‐specific survival and distant metastasis‐free survival rates. At 10 years, 6% of patients had developed a symptomatic treatment‐related complication. There were no treatment‐related deaths.

CONCLUSIONS

The results of the current study confirmed the efficacy and safety of elective regional radiotherapy for patients with cutaneous head and neck melanoma predicted to have a high rate of lymph node involvement. Elective irradiation was a viable alternative to elective lymph node dissection. It may also serve as an alternative to sentinel lymph node biopsy, particularly for patients for whom dissection and systemic therapy are not therapeutic options. Cancer 2004;100:383–9. © 2003 American Cancer Society.
Stereotaxic implantation of 5‐fluorouracil‐releasing microspheres in malignant glioma
Authors: Menei Philippe , Jadaud Eric , Faisant Nathalie , Boisdron‐Celle Michèle , Michalak Sophie , Fournier Dominique , Delhaye Manuel , Benoit Jean‐Pierre
Published: January 2004

BACKGROUND

The authors developed a new method of drug delivery into the brain using implantable, biodegradable microspheres. The strategy was evaluated initially to provide localized and sustained delivery of the radiosensitizer 5‐fluorouracil (5‐FU) after patients underwent surgical resection of malignant glioma. In this study, the microspheres were implanted by stereotaxy into deeply situated and inoperable brain tumors.

METHODS

Ten patients with newly diagnosed, inoperable, malignant gliomas were included in the study, and 1 dose of 5‐FU was studied (132 mg). After histologic confirmation, a suspension of poly(D‐L lactide‐co‐glycolide) 5‐FU‐loaded microspheres was implanted by stereotaxy into the tumor in one or several trajectories with one to seven deposits per trajectory. External beam radiation (59.4 grays) was started before postoperative Day 7. Patients were followed by clinical examination, computed tomography scanning, magnetic resonance imaging, and 5‐FU assays in blood and cerebrospinal fluid (CSF).

RESULTS

The number of trajectories was adapted to the size and shape of the tumor. Microsphere implantation was tolerated well, except in four patients who received a single trajectory and experienced a transitory worsening of preexisting neurologic symptoms. There were no episodes of edema or hematologic complications. 5‐FU was detected in CSF and blood in some patients at very low concentrations. The median overall survival was 40 weeks, with 2 patients who had longer survival (71 weeks and 89 weeks, respectively).

CONCLUSIONS

In this study, the authors demonstrated that biodegradable microspheres could be implanted by stereotaxy and were efficient systems for drug delivery into brain tumors. This method may have future applications in the treatment of patients other malignancies. Cancer 2004;100:405–10. © 2003 American Cancer Society.