bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromatin‐associated sphingomyelin: metabolism in relation to cell function
Authors: Albi E. , Magni MP. Viola
Published: August 2003

After the first histochemical demonstration by Chayen and Gahan of the presence of phospholipids and especially of sphingomyelin in chromatin, this became the object of long debate and of contradictory results. The general conclusion was that the presence of phospholipids may due to contamination during the isolation of chromatin. More recently the existence of a phospholipid chromatin fraction was confirmed by demonstrating that isolated hepatocyte nuclei, labelled by saturated and unsaturated radioiodination method, showed the presence of radioactivity only in the membrane and not in the isolated chromatin. The phospholipid composition showed an enrichment in sphingomyelin which increased during hepatocyte maturation or erythroleukemic cell differentiation induced by DMSO. A decrease in sphingomyelin was observed at the beginning of the S‐phase in regenerating liver or in cultured proliferating cells. These changes were due to the presence of sphingomyelinase and sphingomyelin synthase in the chromatin, the activity of which paralleled the variation in sphingomyelin content. The sphingomyelin was co‐localized with RNA as shown by biochemical and electron microscopy methods. Using bromo‐uridine it was demonstrated that labelled RNA and sphingomyelin were present in actively transcribing nuclear regions. Isolated nuclear complexes after DNase and RNase digestion contained not only protein, but also RNA and sphingomyelin. After hydrolysis of sphingomyelin the RNAse‐resistant RNA becomes RNAse sensitive. It can therefore be concluded that sphingomyelin and the related enzymes are present in the chromatin; sphingomyelin may have a role in RNA transcription protecting RNA by RNAse digestion before its transfer to the cytoplasm. Copyright © 2003 John Wiley & Sons, Ltd.
Annexin 1: a paracrine/juxtacrine mediator of glucorticoid action in the neuroendocrine system
Authors: Buckingham Julia C. , Solito Egle , John Christopher , Tierney Tanya , Taylor Amanda , Flower Rod , Christian Helen , Morris John
Published: August 2003

Glucocorticoids (GCs) play an essential role in the maintenance of homeostasis. In normal circumstances their secretion is tightly regulated by a complex servo mechanism through which the steroids suppress the synthesis and release of ACTH and its hypothalamic releasing factors (CRH and AVP) and thereby reduce the positive drive to the adrenal cortex. The feedback actions of GCs on hormone release develop rapidly (within minutes), well before any changes in hormone synthesis are apparent. By using immunoneutralization, gene targeting and pharmacological strategies in in vivo and in vitro models, we have identified annexin 1, a Ca2+‐ and phospholipid‐binding protein, as a key mediator of the early inhibitory actions of GCs on peptide release. This brief review outlines this work and describes molecular and cellular studies which have provided insight into the mechanism of annexin 1‐dependent GC signalling in the neuroendocrine system. Copyright © 2003 John Wiley & Sons, Ltd.
A cytochemical assay for osteoclast cathepsin K activity
Authors: Dodds Robert A.
Published: August 2003

Cathepsin K is a member of the papain superfamily of cysteine proteases and plays a pivotal role in osteoclast‐mediated bone resorption. This enzyme is an excellent target for antiresorptive therapies for osteopenic disorders such as osteoporosis.1 Although isolated inhibitor studies on purified enzymes is required to discover potent and selective inhibitors of cathepsin K, a quantitative cytochemical assay2 for cathepsin K would allow inhibitors to be tested on actual osteoclasts within sections of bone. Furthermore cathepsin K activity could be used to identify and analyse osteoclasts at definitive stages of their lifespan. A cytochemical assay is described that localizes osteoclast cathepsin K activity in unfixed, undecalcified cryostat sections of animal and human bone. Copyright © 2003 John Wiley & Sons, Ltd.
Identifying and characterizing the joint cavity‐forming cell
Authors: Pitsillides Andrew A.
Published: August 2003

For many years, a large body of circumstantial evidence supported the notion that the synovial membrane produced the hyaluronan‐rich synovial fluid. A quantitative cytochemical technique for uridine‐diphospho glucose dehydrogenase (UDPGD) activity established that fibroblast‐like cells on the intimal surface of the synovial lining made a specific contribution to maintaining these glycosaminoglycan levels. Our studies have aimed to determine the mechanisms that control the attainment and persistence of this differentiated phenotype, and have recently focused on their appearance during joint cavity development in the embryonic limb; a process that is dependent upon skeletal movement. These in situ micro‐biochemical studies have shown that cells bordering the presumptive joint cavity exhibit raised UDPGD activity, are associated with a matrix rich in hyaluronan and show immobilization‐induced loss in such characteristics. Together with complimentary studies in adult joints, this suggests that mechanical stimuli promote the acquisition of this joint line‐forming phenotype. For this reason our studies have attempted to identify the ‘up‐stream’ mechano‐dependent factors that control these events. Endothelial cells respond to mechanical stimuli by activating, via phosphorylation, mitogen activated protein kinase/extracellular signal‐regulated kinase (MAPkinase/ERK). Using phospho‐specific anti‐ERK‐1/2 antibodies we have shown that immunolabelling of developing limbs shows a clear joint line‐selective activation during cavitation, with little if any labelling within neighbouring elements, and that this is abolished in immobilized limbs. In an attempt to facilitate the final mechanistic deciphering of these responses we have used an in vitro‐based approach and found by Western blotting that active ERK‐1/2 expression was increased in cultured articular surface cells following application of dynamic mechanical strain. Intriguingly, the use of a selective inhibitor (PD98059) of ERK activation by its classical activating kinase, Mek, to restrict such strain‐induced increases, produced an enhanced strain‐related increase in UDPGD mRNA expression. This suggests that mechano‐dependent ERK activation serves a feedback regulatory role during differentiation of these cells. Whilst it is clear that these in vitro experiments serve a useful function, it is clear that they generally take little regard of the influence that might be provided by cell–cell and cell–matrix interactions within the developing limb's complex and dynamic environment and architecture. It is therefore imperative that we attempt to bridge the gap between the cell biology of such phenomena on the one hand, and the morphological approach to this same problem on the other. Copyright © 2003 John Wiley & Sons, Ltd.
Wild type p53 gene causes reorganization of cytoskeleton and, therefore, the impaired deformability and difficult migration of murine erythroleukemia cells
Authors: Yao Weijuan , Gu Li , Sun Dagong , Ka Weibo , Wen Zongyao , Chien Shu
Published: August 2003

We studied the role of p53 gene in the biophysics and biology in murine erythroleukemia cell line (MEL), with the goal of understanding the influence of this tumor suppressor gene on the deformability and metastasis of tumor cells. Experiments were performed on MEL and p53‐transfected MEL (MEL‐M with mutant p53 gene and MEL‐W with wild‐type p53 gene). The cell growth curves indicated that the over‐expression of wild‐type p53 gene significantly suppressed the growth of MEL, with G0‐G1 arrest and apoptosis shown by flow cytometric assays. Confocal laser scanning microscopy revealed that the MEL‐W had a more compact organization of the F‐Actin cytoskeleton than MEL and MEL‐M. Fluorescence polarization measurement indicated a higher membrane fluidity of MEL‐W than the other two groups. Fourier transform infrared spectroscopy (FT‐IR) showed changes in the composition and/or structure of membrane lipids in MEL‐W, with decreases in secondary structures of proteins such as α‐helix, turns and bends and random coil, in comparison to MEL and MEL‐M. The osmotic fragility curves indicated that MEL‐W was more fragile and micropipette experiments showed that they had increased elasticity and reduced deformability in comparison to MEL and MEL‐M. The adhesion assay with the use of the flow chamber revealed a lower adhesion rate of MEL‐W to endothelial cells at high shear stress. The present study on the molecular biology with biophysics of MEL cells contributes to our knowledge on the tumor suppressor gene p53. Cell Motil. Cytoskeleton 56:1–12, 2003. © 2003 Wiley‐Liss, Inc.
Expression of class III β‐tubulin reduces microtubule assembly and confers resistance to paclitaxel
Authors: Hari Malathi , Yang Hailing , Zeng Changqing , Canizales Martin , Cabral Fernando
Published: August 2003

Human brain and testis specific βIII‐tubulin was amplified from a cDNA library, modified to encode a C‐terminal hemagglutinin antigen epitope tag, and cloned into a vector that allows tetracycline regulated expression in mammalian cells. Immunofluorescence analysis of transfected Chinese hamster ovary cells demonstrated that expressed HA‐tagged βIII‐tubulin is able to assemble with endogenous tubulin into microtubules even though βIII‐tubulin is not a normal constituent of these cells. A stable G418‐resistant clone with moderate HAβIII‐tubulin expression displayed weak (1.5–2‐fold) resistance to paclitaxel. A second clone with higher HAβIII‐tubulin expression could not grow unless tetracycline was present to repress transcription of the transfected cDNA. Analysis of cellular microtubules in each of these clones indicated that incorporation of HAβIII‐tubulin led to a significant expression‐dependent decrease in assembled tubulin. Paclitaxel resistant cells were also directly selected from the transfected cell population using a paclitaxel concentration 4 times higher than the minimum toxic dose. Few cells were able to survive the selection and they grew very slowly. Western blot analysis of these resistant cells revealed very high HAβIII‐tubulin expression that led to almost complete replacement of endogenous β‐tubulin at steady state. Transfected βIII‐tubulin with no epitope tag behaved in a very similar fashion indicating that presence of the HA tag had no discernible functional effect. The results demonstrate that βIII‐tubulin diminishes microtubule assembly, is toxic when present at high levels, but is able to confer weak resistance to paclitaxel when expressed at moderate levels in mammalian cells. Cell Motil. Cytoskeleton 56:45–56, 2003. © 2003 Wiley‐Liss, Inc.
Human polymorphonuclear leukocytes respond to waves of chemoattractant, like Dictyostelium
Authors: Geiger Jeremy , Wessels Deborah , Soll David R.
Published: August 2003

It has been assumed that the natural chemotactic signal that attracts human polymorphonuclear leukocytes (PMNs) over long distances to sites of infection is in the form of a standing spatial gradient of chemoattractant. We have questioned this assumption on the grounds, first, that standing spatial gradients may not be stable over long distances for long periods of time and, second, that in the one animal cell chemotaxis system in which the natural chemotactic signal has been described in space and time, aggregation of Dicytostelium discoideum, the signal is in the form of an outwardly relayed, nondissipating wave of attractant. Here, it is demonstrated that PMNs alter their behavior in each of the four phases of a wave of PMN chemoattractant, fashioned after the Dictyostelium wave, in a manner similar to Dictyostelium. These results demonstrate that PMNs have all of the machinery to respond to a natural wave of attractant, providing support to the hypothesis that the natural signal that attracts PMNs over large distances to sites of infection in the human body may also be in the form of a wave. Cell Motil. Cytoskeleton 56:27–44, 2003. © 2003 Wiley‐Liss, Inc.
Changes in the abundance and distribution of conserved centrosomal, cytoskeletal and ciliary proteins during spermiogenesis in Marsilea vestita
Authors: Klink Vincent P. , Wolniak Stephen M.
Published: August 2003

Spermiogenesis in the male gametophytes of the water fern Marsilea vestita is a precise and rapid process resulting in the production of ciliated gametes. Development begins from a single cell within the microspore wall that undergoes nine rapid cell division cycles in distinct planes to produce 32 spermatids that are surrounded by 7 sterile cells. Thereafter, the de novo formation of basal bodies occurs in a discrete cytoplasmic particle known as a blepharoplast, with the subsequent formation of a complex ciliary apparatus in elongating spermatids. The rate and extent of development appear to be controlled at a post‐transcriptional level, where the sudden translation of specific stored mRNAs (e.g., centrin) results in the formation of particular structures in the cells (e.g., blepharoplasts). We show here that additional centrosomal and cytoskeletal antigens known as SF assemblin, p95 kDa protein, δ tubulin, γ tubulin, Xgrip109, Aik, CTR453, RanBPM, BX63, RSP6, and α tubulin each exhibit specific localization patterns both on immunoblots of gametophyte protein isolates and in fixed cells. BAp90, PP4, and RLC exhibit specific localization patterns in fixed cells. We show that the antigens exhibit complex patterns of abundance during spermiogenesis. In an attempt to identify regulatory agents involved in spermiogenesis, we employed a RNAi‐based screen of 41 randomly selected gametophyte cDNAs on developing populations of synchronously growing gametophytes. The gametophytes treated with each of the RNAi probes exhibited arrest at a specific stage of development. A consequence of anomalous development was the block to assembly of the ciliary apparatus, an effect highlighted by altered staining with anti‐centrin, anti‐β‐tubulin, and anti‐RSP6 antibodies. Our results show that complex, integrated processes of translation and protein partitioning apparently underlie the assembly of the ciliary apparatus during spermiogenesis in male gametophytes of M. vestita. Cell Motil. Cytoskeleton 56:57–73, 2003. © 2003 Wiley‐Liss, Inc.
Long‐term adjustment of survivors of early‐stage breast carcinoma, 20 years after adjuvant chemotherapy
Authors: Kornblith Alice B. , Herndon James E. , Weiss Raymond B. , Zhang Chunfeng , Zuckerman Enid L. , Rosenberg Sylvia , Mertz Magriet , Payne David , Jane Massie Mary , Holland James F. , Wingate Patti , Norton Larry , Holland Jimmie C.
Published: August 2003

BACKGROUND

The long‐term impact of breast carcinoma and its treatment was assessed in 153 breast carcinoma survivors previously treated on a Phase III randomized trial (Cancer and Leukemia Group B [CALGB 7581]) a median of 20 years after entry to CALGB 7581.

METHODS

Survivors were interviewed by telephone using the following standardized measures: Brief Symptom Inventory (BSI), PostTraumatic Stress Disorder Checklist with the trauma defined as survivors' response to having had cancer (PCL‐C), Conditioned Nausea, Vomiting and Distress, European Organization for Research and Treatment of Cancer QLQ‐C30 (quality of life), Life Experience Survey (stressful events), MOS Social Support Survey, comorbid conditions (Older Americans Resources and Services Questionnaire), and items developed to assess long‐term breast carcinoma treatment side effects and their interference with functioning.

RESULTS

Only 5% of survivors had scores that were suggestive of clinical levels of distress (BSI), 15% reported 2 or more posttraumatic stress disorder (PTSD) symptoms (PCL‐C) that were moderately to extremely bothersome, 1–6% reported conditioned nausea, emesis, and distress as a consequence of sights, smells, and tastes triggered by reminders of their treatment, 29% reported sexual problems attributed to having had cancer, 39% reported lymphedema, and 33%, reported numbness. Survivors who reported greater lymphedema and numbness that interfered with functioning had significantly worse PTSD (PCL‐C;P= 0.008) com‐ pared with survivors who reported less lymphedema and numbness. Survivors with a lower level of education (P= 0.026), less adequate social support (P= 0.0033), more severe negative life events (P= 0.0098), and greater dissatisfaction with their medical care (P= 0.037) had worse PTSD compared with other survivors.

CONCLUSIONS

Twenty years after the initial treatment, the impact of breast carcinoma on survivors' adjustment was minimal. However, the higher prevalence of PTSD symptoms in response to having had cancer is indicative of continuing psychologic sequelae long after treatment completion. Findings related to lymphedema and numbness and continued symptoms of PTSD suggest that the long‐term psychologic and medical sequelae on adjustment may be underrecognized. To establish in more detail whether survivors' overall psychologic state is any different from that of individuals without cancer, a population of community residents without cancer would need to be studied. Cancer 2003;98:679–89. © 2003 American Cancer Society.

DOI 10.1002/cncr.11531
Androgen receptors frequently are expressed in breast carcinomas
Authors: Moinfar Farid , Okcu Murat , Tsybrovskyy Oleksiy , Regitnig Peter , Lax Sigurd F. , Weybora Wolfgang , Ratschek Manfred , Tavassoli Fattaneh A. , Denk Helmut
Published: August 2003

BACKGROUND

Several studies have demonstrated the biologic and therapeutic significance of estrogen and progesterone receptors (ER and PR) in breast carcinomas. The aim of the current study was to examine the presence of androgen receptors (AR) in breast carcinomas.

METHODS

Two hundred cases of breast carcinoma, consisting of 145 invasive and 55 noninvasive (ductal carcinoma in situ [DCIS]) lesions, were examined using a monoclonal antibody against AR on formalin‐fixed, paraffin‐embedded archival material. The results were analyzed for correlations with immunohistochemically determined ER, PR, and HER‐2/neu expression.

RESULTS

Eighty‐seven of the 145 cases (60%) of invasive carcinoma and 45 of the 55 cases (82%) of DCIS were AR‐positive according to internationally standardized guidelines. The vast majority of Grade 1 carcinomas were positive for AR (90% of invasive Grade 1 carcinomas and 95% of Grade 1 DCIS), whereas in Grade 3 invasive carcinomas and DCIS, positive immunoreactions for AR were observed in 46% and 76% of cases, respectively. Among the cases of Grade 3 carcinoma, 33 invasive carcinomas (39%) and 17 DCIS lesions (68%) were ER‐negative but AR‐positive. Among Grade 1 carcinomas (invasive and DCIS), not a single case was positive for HER‐2/neu, but most cases were intensely positive for AR. In contrast, many invasive Grade 3 carcinomas exhibited agreement between AR status and HER‐2/neu status (AR‐positive and HER‐2/neu‐positive, 30.5%; AR‐negative and HER‐2/neu‐negative, 42.5%).

CONCLUSIONS

Androgen receptors are commonly expressed in DCIS and in invasive breast carcinoma. A significant number of poorly differentiated carcinomas are ER‐negative and PR‐negative but AR‐positive. Immunohistochemical examination of AR would be desirable because it would provide additional information about steroid receptors in breast carcinomas. Cancer 2003;98:703–11. © 2003 American Cancer Society.

DOI 10.1002/cncr.11532
Identification of fibroblast growth factor receptor 3 mutations in urine sediment DNA samples complements cytology in bladder tumor detection
Authors: Rieger‐Christ Kimberly M. , Mourtzinos Arthur , Lee Peter J. , Zagha Ralph M. , Cain Jason , Silverman Mark , Libertino John A. , Summerhayes Ian C.
Published: August 2003

BACKGROUND

Mutations in fibroblast growth factor 3 receptor (FGFR3) are frequent events in low‐grade bladder tumors. To assess the potential utility of the detection of FGFR3 mutations in a screening modality, the authors analyzed urine sediment DNA samples from 192 patients in a retrospective study.

METHODS

Urine sediment DNA samples from 192 patients were prepared. Seventy‐two patients had undergone transurethral resection (TURBT group) of mainly Ta lesions and 120 patients had undergone cystectomy (cystectomy group). The majority of patients in the cystectomy group had more advanced tumors compared with patients in the TURBT group. DNA preparations were screened for FGFR3 mutations in exons 7, 10, and 15 using single‐strand conformation polymorphism (SSCP) and DNA sequencing.

RESULTS

Using SSCP, 67% of patients in the TURBT group and 28% in the cystectomy group displayed FGFR3 mutations. Comparative analysis of cytology results and FGFR3 mutational analysis were performed in 122 cases. Within the TURBT group, FGFR3 mutation analysis outperformed cytology. FGFR3 mutation analysis identified change in 68% of urine sediment DNA samples whereas cytology recorded the presence of tumor cells in 32% of the DNA samples. In the cystectomy group, cytology outperformed FGFR3 mutation analysis. Cytology recorded tumor detection in 90% of patients, while SSCP identified mutational change in 24%.

CONCLUSIONS

Combining FGFR3 mutation results with cytology in both groups correctly identified tumor presence in 105 of 122 (86%) of patients. The greater sensitivity of FGFR3 mutation detection over cytology in identifying the presence of low‐grade, superficial bladder tumors represents a potential new tool to complement standard cytology in screening patients for bladder tumors and recurrent disease. Cancer 2003;98:737–44. © 2003 American Cancer Society.

DOI 10.1002/cncr.11536
Radiotherapy for extranodal, marginal zone, B‐cell lymphoma of mucosa‐associated lymphoid tissue originating in the ocular adnexa
Authors: Uno Takashi , Isobe Koichi , Shikama Naoto , Nishikawa Atsushi , Oguchi Masahiko , Ueno Naoyuki , Itami Jun , Ohnishi Hiroshi , Mikata Atsuo , Ito Hisao
Published: August 2003

BACKGROUND

Due to the small number of patients and differences in the pathologic classification in most radiotherapy series, information regarding the adequacy of tumor control in patients with ocular‐adnexal marginal zone B‐cell lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma) is limited.

METHODS

A multiinstitutional, retrospective study was performed on 50 patients with Stage IE ocular‐adnexal MALT lymphoma who were treated with radiotherapy between 1989 and 1999. The impact of patient characteristics and other variables on tumor control was analyzed.

RESULTS

Responses to radiotherapy include a complete response (CR) in 26 patients, a partial response (PR) in 20 patients, and no change in 4 patients. Forty‐nine of 50 patients obtained tumor control in the ocular adnexa at 24 months. Overall, 6 patients exhibited disease recurrence at 4–97 months. Three patients developed recurrence in the ocular adnexa. Two patients had isolated extranodal failure involving the oral floor and the submandibular gland, and one patient experienced failure in the neck lymph node. The initial tumor response had a marginal impact on the development of recurrence. None of the 26 patients who achieved a CR experienced ocular‐adnexal recurrence. All three patients who experienced local treatment failure belonged to the initial PR group. In total, five of six patients who developed recurrent disease had obtained a PR after initial radiotherapy. Age, gender, tumor location, and dose of radiotherapy did not influence the development of recurrence. There was only one death due to lymphoma. The 5‐year overall survival rate was 91% with a median follow‐up of 46 months.

CONCLUSIONS

Radiotherapy offers excellent local control with a prolonged clinical course for patients with MALT lymphoma in the ocular adnexa. The initial response to radiotherapy marginally influenced the probability of recurrence. Cancer 2003;98:865–71. © 2003 American Cancer Society.

DOI 10.1002/cncr.11539
Short‐term morbidity of the upper limb after sentinel lymph node biopsy or axillary lymph node dissection for Stage I or II breast carcinoma
Authors: Rietman Johan S. , Dijkstra Pieter U. , Geertzen Jan H. B. , Baas Peter , de Vries Jaap , Dolsma Wil , Groothoff Johan W. , Eisma Willem H. , Hoekstra Harald J.
Published: August 2003

BACKGROUND

The goals of sentinel lymph node biopsy (SLNB) are to improve axillary staging and reduce unnecessary axillary lymph node dissections (ALND), thereby reducing treatment‐related upper‐limb morbidity. In the current prospective study, short‐term upper‐limb morbidity was assessed after SLNB and/or ALND.

METHODS

The study comprised 204 patients with Stage I/II breast carcinoma. Mean patient age was 55.6 years (standard deviation, 11.6). Sixty‐six patients (32%) underwent SLNB only, and 138 (68%) underwent a Level I–II ALND. Assessment (preoperative [t0] and 6 weeks postoperative [t1]) included evaluation of shoulder range of motion, muscle strength, grip strength, pain, upper/forearm circumference, shoulder disability, and activities of daily life (ADL).

RESULTS

Considerable treatment‐related upper‐limb morbidity was observed. Significant (P < 0.001) changes were found for pain, range of motion in forward flexion, abduction and abduction/external rotation, strength of shoulder abductors and elbow flexors, and in perceived disability in ADL. However, no significant difference in change of upper‐limb function and ADL was found between the SLNB and ALND groups.

CONCLUSIONS

Significant short‐term treatment‐related upper‐limb morbidity exists after SLNB or ALND. There is no significant difference in short‐term treatment‐related morbidity between SLNB and ALND. Cancer 2003;98:690–6. © 2003 American Cancer Society.

DOI 10.1002/cncr.11545
The impact of age on toxicity, response rate, quality of life, and survival in patients with advanced, Stage IIIB or IV nonsmall cell lung carcinoma treated with carboplatin and paclitaxel
Authors: Hensing Thomas A. , Peterman Amy H. , Schell Michael J. , Lee Ji‐Hyun , Socinski Mark A.
Published: August 2003

BACKGROUND

The optimal treatment strategy for elderly patients with advanced nonsmall cell lung carcinoma has not been defined to date. The authors performed a retrospective analysis of a Phase III trial that treated patients who had Stage IIIB or IV nonsmall cell lung carcinoma with carboplatin and paclitaxel and analyzed the impact of age on response rate, survival, toxicity, and quality of life.

METHODS

Patients with Stage IIIB or IV NSCLC were randomized to receive either 4 cycles of carboplatin at an area under the curve (AUC) of 6 and paclitaxel at a dose of 200 mg/m2 every 21 days or treatment with carboplatin and paclitaxel (C/P) until they developed disease progression. At the time of disease progression, all patients on both arms were to receive second‐line weekly paclitaxel at a dose of 80 mg/m2 per week. In this analysis, patients age 70 years and older were compared with patients younger than age 70 years. In addition, a minimum log rank P value analysis was performed in an attempt to identify other potential age splits that may have been significant.

RESULTS

Two hundred thirty patients were randomized. Sixty‐seven patients were age 70 years or older (29%). The median number of cycles delivered for both age groups was 4 cycles (range, 0–19 cycles). No statistically significant differences in any of the most common toxicities (Grade ≥ 2) associated with C/P were identified (data from Cycles 1–4) for patients younger than age 70 years compared with patients age 70 years and older, respectively, including neutropenia (38% vs. 35%), neuropathy (13% vs. 16%), leukopenia (7% vs. 13%), myalgia/arthralgia (15% vs. 9%), malaise (8% vs. 15%), anemia (9% vs. 4%), thrombocytopenia (7% vs. 9%), anorexia (8% vs. 4%), and nausea/emesis (14% vs. 15%). In addition, no potential age splits that may have been significant were found using a minimum log rank P value analysis.

CONCLUSIONS

The current analysis demonstrated that C/P exhibited similar toxicity profiles in patients age 70 years and older compared with patients younger than age 70 years. The survival rates were not different between the two age groups, and there was no difference in progression of quality‐of‐life outcomes. In fit, elderly patients, C/P represented a reasonable standard regimen. Cancer 2003;98:779–88. © 2003 American Cancer Society.
Phase II study of alemtuzumab in chronic lymphoproliferative disorders
Authors: Ferrajoli Alessandra , O'Brien Susan M. , Cortes Jorge E. , Giles Francis J. , Thomas Deborah A. , Faderl Stefan , Kurzrock Razelle , Lerner Susan , Kontoyiannis Dimitrios P. , Keating Michael J.
Published: August 2003

BACKGROUND

Pilot studies showed that alemtuzumab is active in lymphoproliferative disorders. The authors conducted a Phase II trial to evaluate the efficacy and safety of alemtuzumab in advanced or refractory chronic lymphoproliferative disorders.

METHODS

Seventy‐eight patients were enrolled. The most common diagnoses were chronic lymphocytic leukemia (n = 42 patients) and T‐cell prolymphocytic leukemia (n = 18 patients). Before entering the study, the patients had received multiple therapies (median, three therapies) and the median time from diagnosis was 7 years. Alemtuzumab was given intravenously at doses of 3 mg, 10 mg, and 30 mg on 3 consecutive days, after which 30 mg was administered 3 times a week. Patients were treated for 4–12 weeks depending on disease response. All patients received prophylactic trimethoprim/sulfamethoxazole and valacyclovir.

RESULTS

The overall response rate was 35%, the complete response (CR) rate was 13%, and the partial response (PR) rate was 22%. The median duration of response was 18 months for patients achieving a CR and 7 months for patients achieving a PR. The median duration of survival was 25 months for patients who had a response and 12 months for the entire population. Normalization of the lymphocyte count was observed in 84% of patients and resolution of bone marrow involvement was observed in 49% of patients. The most common infusion‐related adverse events were fever, rigors, skin rash, nausea, and dyspnea. These were most common during the first week of therapy. Hematologic toxicity was comprised of long‐lasting lymphocytopenia and transient neutropenia and thrombocytopenia. Thirty‐six patients (46%) experienced at least one episode of fever or infection.

CONCLUSIONS

Alemtuzumab has a high response rate in patients with chronic lymphoproliferative disorders. Cancer 2003;98:773–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11551
Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin‐1 by epidermal growth factor in human pancreatic carcinoma
Authors: Parikh Alexander A. , Liu Wen Biao , Fan Fan , Stoeltzing Oliver , Reinmuth Niels , Bruns Christiane J. , Bucana Corazon D. , Evans Douglas B. , Ellis Lee M.
Published: August 2003

BACKGROUND

It was recently shown that neuropilin‐1 (NRP‐1), which was described originally as a receptor for the semaphorins/collapsins (ligands involved in neuronal guidance), is a coreceptor for vascular endothelial growth factor (VEGF) and increases the affinity of specific isoforms of VEGF to its receptor, VEGF‐R2.

METHODS

The authors investigated the expression and regulation of NRP‐1 in human pancreatic adenocarcinoma specimens and cell lines.

RESULTS

Immunohistochemical analysis revealed that NRP‐1 was expressed in 12 of 12 human pancreatic adenocarcinoma specimens but was absent in nonmalignant pancreatic tissue. Northern blot analysis revealed NRP‐1 mRNA expression in 8 of 11 human pancreatic adenocarcinoma cell lines. NRP‐1 mRNA expression was increased by epidermal growth factor (EGF) but not by tumor necrosis factor α in several of the human pancreatic adenocarcinoma cell lines studied. Treating human Panc‐48 adenocarcinoma cells with EGF activated Akt and Erk but not P‐38. Blockade of the phosphatidylinositol‐3 kinase (PI‐3K)/Akt, mitogen‐activated protein kinase (MAPK)/Erk, or P‐38 pathways abrogated EGF‐induced NRP‐1 expression. Finally, EGF receptor blockade in vivo led to a decrease in NRP‐1 expression in an orthotopic model of human pancreatic carcinoma.

CONCLUSIONS

NRP‐1 is expressed in most human pancreatic adenocarcinomas and cell lines but not in nonmalignant pancreatic tissue. EGF regulates NRP‐1 expression through the PI‐3K/Akt and MAPK/Erk signaling pathways, and blockade of the EGF receptor is associated with decreased expression of NRP‐1 in vivo. NRP‐1 may act as a coreceptor for VEGF in pancreatic carcinoma, as it does in other tumor systems, thereby enhancing angiogenesis and the effect of VEGF on the growth of pancreatic adenocarcinoma. Cancer 2003;98:720–9. © 2003 American Cancer Society.

DOI 10.1002/cncr.11560
Expression of c‐ABL, c‐KIT, and platelet‐derived growth factor receptor‐β in ovarian serous carcinoma and normal ovarian surface epithelium
Authors: Schmandt Rosemarie E. , Broaddus Russell , Lu Karen H. , Shvartsman Hyun , Thornton Angela , Malpica Anais , Sun Charlotte , Bodurka Diane C. , Gershenson David M.
Published: August 2003

BACKGROUND

Tyrosine kinases, such as c‐KIT, c‐ABL, and platelet‐derived growth factor‐beta (PDGFR‐β), are important regulators of cell growth. Highly potent and selective inhibitors of tyrosine kinases are being investigated as alternatives to standard chemotherapy. One such inhibitor, imatinib mesylate, is being used to treat gastrointestinal stromal tumors and chronic myelogenous leukemia. Ovarian carcinomas frequently develop resistance to conventional chemotherapeutic agents. Immunohistochemical expression of c‐ABL, PDGFR‐β, and c‐KIT was evaluated in ovarian carcinomas to determine whether treatment with imatinib mesylate might be feasible.

METHODS

The expression of c‐ABL, c‐KIT, and PDGFR‐β in tumors was evaluated by immunohistochemical analysis of 52 ovarian serous carcinomas, including 21 low‐grade (well differentiated) and 31 high‐grade (poorly differentiated) tumors. Fourteen normal ovaries were also evaluated.

RESULTS

In normal ovarian surface epithelium, c‐ABL was expressed universally. PDGFR‐β was expressed in the majority (93%) of samples of normal ovarian epithelium, whereas the c‐KIT protein was undetectable in normal ovarian surface epithelium. Overall, c‐ABL was expressed in 71% of serous carcinomas. c‐ABL was expressed more frequently in the low‐grade serous carcinomas (81%) compared with the high‐grade serous carcinomas (65%). PDGFR‐β expression was observed in 81% of serous carcinomas overall and was observed more frequently in higher‐grade tumors. c‐KIT immunohistochemical staining was absent in low‐grade tumors but was present in 26% of high‐grade serous carcinomas.

CONCLUSIONS

The majority of ovarian serous carcinomas express one or more of the kinases targeted by the tyrosine kinase inhibitor, imatinib mesylate, suggesting the potential usefulness of this drug in the treatment of ovarian carcinoma. Cancer 2003;98:758–64. © 2003 American Cancer Society.

DOI 10.1002/cncr.11561
Characterization of the neoplastic phenotype in the familial atypical multiple‐mole melanoma–pancreatic carcinoma syndrome
Authors: Rulyak Stephen J. , Brentnall Teresa A. , Lynch Henry T. , Austin Melissa A.
Published: August 2003

BACKGROUND

Previous studies suggest that the familial atypical multiple‐mole melanoma (FAMMM) syndrome may predispose affected families to nonmelanoma carcinomas, including adenocarcinoma of the pancreas. It has been found that many of these families harbor mutations in the CDKN2A gene on chromosome 9p21. The phenotypic expression of CDKN2A mutations in these families has not been characterized fully.

METHODS

The authors studied eight families that appeared to inherit multiple nevi, cutaneous melanomas, and pancreatic carcinomas in association with a CDKN2A germline mutation. The expression of disease within these families was examined, and segregation ratios were estimated to assess the patterns of inheritance according to various definitions of phenotype.

RESULTS

Either multiple nevi or pancreatic carcinoma was diagnosed in 53% of first‐degree relatives of the probands. The offspring of parents affected with multiple nevi, melanoma, or pancreatic carcinoma were significantly more likely to be affected themselves compared with the offspring of unaffected parents (48.9% vs. 16.7%; P = 0.004).

CONCLUSIONS

The current results provide additional evidence that multiple nevi, melanoma, or pancreatic carcinoma may be inherited as autosomal‐dominant traits in families known to harbor CDKN2A mutations. Other malignancies may be a part of the phenotype in these families, although this hypothesis requires additional study. Cancer 2003;98:798–804. © 2003 American Cancer Society.

DOI 10.1002/cncr.11562
Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma
Authors: Laverdiere Caroline , Kolb E. Anders , Supko Jeffrey G. , Gorlick Richard , Meyers Paul A. , Maki Robert G. , Wexler Leonard , Demetri George D. , Healey John H. , Huvos Andrew G. , Goorin Allen M. , Bagatell Rochelle , Ruiz‐Casado Ana , Guzman Cecilia , Jimeno Jose , Harmon David
Published: August 2003

BACKGROUND

Recurrent osteosarcoma is a drug‐resistant disease with a dismal prognosis. The objective of this Phase II study was to evaluate the activity of ecteinascidin 743 (ET‐743) as a salvage therapy in these patients.

METHODS

Patients with recurrent osteosarcoma who had received standard chemotherapeutic agents were eligible. ET‐743 was administered at a dose of 1500 μg/m2 as a 24‐hour infusion every 3 weeks. Pharmacokinetic studies were performed during the first cycle.

RESULTS

Twenty‐five patients were enrolled, 23 of whom were assessable for response (median age of 18 years; range, 12–67 years). The median number of previous chemotherapeutic agents was five (range, three to eight previous agents). Sixty‐one cycles were administered (median number of cycles per patient was 2; range, 1–9 cycles per patient). Three patients (12%) achieved minor responses (49% 36% and 25%, respectively). Fifteen patients (60%) developed a transient elevation of hepatic transaminases (Grade 3 or 4 [according to the National Cancer Institute Common Toxicity Criteria]), which was not cumulative. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 12 patients (48%) and 6 patients (24%), respectively. The mean area under the curve (AUC) in 4 patients experiencing Grade 4 toxicity (76.4 ± 29.3 ng × hr/mL) was significantly greater (P = 0.034) than that in those for whom the most severe toxicity was Grade 3 (39.5 ± 17.2 ng × hr/mL [n = 12]) or Grade 1‐2 (52.6 ± 15.6 ng × hr/mL [n = 5]). There were no other significant correlations found between pharmacokinetic variables and patient characteristics, toxicity, or therapeutic response.

CONCLUSIONS

ET‐743 was found to be well tolerated in heavily pretreated osteosarcoma patients but had limited antitumor activity as a single agent. The combination of ET‐743 with cisplatin or doxorubicin should be considered. Cancer 2003;98:832–40. © 2003 American Cancer Society.

DOI 10.1002/cncr.11563
Obesity as a potential risk factor for adenocarcinomas and squamous cell carcinomas of the uterine cervix
Authors: Lacey James V. , Swanson Christine A. , Brinton Louise A. , Altekruse Sean F. , Barnes Willard A. , Gravitt Patti E. , Greenberg Mitchell D. , Hadjimichael Olympia C. , McGowan Larry , Mortel Rodrigue , Schwartz Peter E. , Kurman Robert J. , Hildesheim Allan
Published: August 2003

BACKGROUND

Hormonal factors may play a more prominent role in cervical adenocarcinoma than squamous cell carcinoma. The authors evaluated whether obesity, which can influence hormone levels, was associated with adenocarcinoma and squamous cell carcinoma.

METHODS

This case–control study included 124 patients with adenocarcinoma, 139 matched patients with squamous cell carcinoma, and 307 matched community control participants. All participants completed interviews and provided cervicovaginal samples for human papillomavirus (HPV) testing. Polytomous logistic regression‐generated odds ratios (ORs) and 95% confidence intervals (95% CIs) for self‐reported height and weight, body mass index (BMI; kg/m2), and measured waist‐to‐hip ratio (WHR) for both histologic types were adjusted and stratified for HPV and other confounders.

RESULTS

Height, weight, BMI, and WHR were positively associated with adenocarcinoma. BMI ≥ 30 kg/m2 (vs. BMI < 25 kg/m2; OR, 2.1 and 95% CI, 1.1–3.8) and WHR in the highest tertile (vs. the lowest tertile; OR, 1.8 and 95% CI, 0.97–3.3) were associated with adenocarcinoma. Neither height nor weight was found to be associated with squamous cell carcinoma, and associations for BMI ≥ 30 kg/m2 (OR, 1.6) and WHR in the highest tertile (OR, 1.6) were weaker and were not statistically significant. Analyses using only HPV positive controls showed similar associations. The data were adjusted for and stratified by screening, but higher BMI and WHR were associated with higher disease stage at diagnosis, even among recently and frequently screened patients with adenocarcinoma. Thus, residual confounding by screening could not be excluded as an explanation for the associations.

CONCLUSIONS

Obesity and body fat distribution were associated more strongly with adenocarcinoma than with squamous cell carcinoma. Although questions about screening remain, obesity may have a particular influence on the risk of glandular cervical carcinoma. Cancer 2003;98:814–21. Published 2003 by the American Cancer Society.

DOI 10.1002/cncr.11567
The significance of thymidine phosphorylase/platelet‐derived endothelial cell growth factor activity in renal cell carcinoma
Authors: Mizutani Yoichi , Wada Hiromi , Yoshida Osamu , Fukushima Masakazu , Kawauchi Akihiro , Nakao Masahiro , Miki Tsuneharu
Published: August 2003

BACKGROUND

Thymidine phosphorylase (TP) is identical to platelet‐derived endothelial cell growth factor (PDECGF) and has angiogenic activity. Little is known about the significance of TP/PDECGF activity in patients with renal cell carcinoma (RCC). The authors examined the enzymatic activity of TP in 66 RCC specimens and investigated the association between the level of TP activity and the stage/grade status of patients with RCC. Furthermore, the authors examined the correlation between TP/PDECGF activity and prognosis.

METHODS

TP activity levels in nonfixed, fresh‐frozen RCC specimens and in specimens of normal kidney were determined using a thin‐layer chromatography assay.

RESULTS

The activity of TP was approximately 3.5‐fold greater in RCC specimens compared with normal kidney specimens. TP activity in patients with Stage III–IV RCC was 2.6‐fold greater compared with TP activity in patients with Stage I–II RCC. In addition, the level of TP activity was correlated with a higher grade of RCC. Patients who had RCC with low TP activity had a longer postoperative disease‐specific survival compared with patients who had RCC with high TP activity in the 5‐year follow‐up.

CONCLUSIONS

The current study is the first to demonstrate a correlation between levels of TP activity and both disease progression and a higher grade of RCC. It also is the first to show that elevated TP activity in patients with RCC predicts a poor prognosis. The results suggest that high TP/PDECGF activity may be associated with the malignant potential of RCC and that TP/PDECGF may be a molecular therapeutic target in patients with RCC. Cancer 2003;98:730–6. © 2003 American Cancer Society.

DOI 10.1002/cncr.11570
Does retroperitoneal lymph node dissection have a curative role for patients with sex cord–stromal testicular tumors?
Authors: Mosharafa Ashraf A. , Foster Richard S. , Bihrle Richard , Koch Michael O. , Ulbright Thomas M. , Einhorn Lawrence H. , Donohue John P.
Published: August 2003

BACKGROUND

Sex cord–stromal tumors account for < 5% of all adult testicular tumors, and 10% are malignant. Due to the limited reported experience, there is no agreement on the best management, especially in patients who have tumors with malignant pathologic features or who present with metastatic disease. The authors attempt to evaluate the role of retroperitoneal lymph node dissection (RPLND) in the management of patients with these malignant sex cord–stromal tumors.

METHODS

Reviewing the Indiana University testis cancer registry revealed 17 patients who underwent RPLND for sex cord–stromal tumors. Pathology was reviewed for features suggestive of malignancy. The data examined included clinical and pathologic stage, surgical procedure, additional therapy received, and outcome.

RESULTS

Pathology included Leydig tumors in six patients, Sertoli tumors in four patients, sex cord–stromal tumors in five patients, a granulosa cell tumor in one patient, and a poorly differentiated non–germ cell tumor in one patient. Nine patients had histologic features suggestive of malignancy. Clinical stage at surgery was Stage I in nine patients and Stage IIA–IIIA in eight patients. Patients underwent modified or bilateral RPLND. Nine patients had pathologic Stage I tumors, and the remaining eight patients and had pathologic Stage IIB–IIIA tumors. Follow‐up ranged from 8 months to 11 years. Of the eight patients with Stage II–III disease, six patients eventually died of metastatic disease despite additional radiotherapy and/or chemotherapy.

CONCLUSIONS

Sex cord–stromal tumors have a potentially aggressive malignant behavior that is difficult to predict based on clinical and pathologic features. Although the therapeutic role of RPLND in patients with small‐volume metastatic retroperitoneal tumors is unclear, RPLND remains an option to be performed immediately after orchiectomy, especially in patients who have tumors with malignant features and/or small‐volume metastatic disease. Cancer 2003;98:753–7. © 2003 American Cancer Society.
Advanced seminoma—Treatment results and prognostic factors for survival after first‐line, cisplatin‐based chemotherapy and for patients with recurrent disease
Authors: Gholam Dany , Fizazi Karim , Terrier‐Lacombe Marie‐Jose , Jan Pascale , Culine Stephane , Theodore Christine
Published: August 2003

BACKGROUND

Advanced seminoma is a rare clinicopathologic entity. To the authors' knowledge, very few sizeable reports published to date have studied the outcome of patients with advanced seminoma after first‐line and salvage therapy, and few have dealt with prognostic factors initially or in patients with recurrent disease.

METHODS

The records of 145 men with advanced seminoma who were treated with cisplatin‐based first‐line chemotherapy regimens were reviewed. Six patient characteristics, including age, prior radiotherapy, primary tumor site, initial serum lactate dehydrogenase and human chorionic gonadotropin levels, and disease stage, were studied as initial prognostic factors. In patients with recurrent disease, outcome according to the site of recurrence and the salvage treatment was also reviewed.

RESULTS

A complete response was obtained in 130 patients (90%) after cisplatin‐based first‐line chemotherapy, and the 5‐year overall survival rate was 81% (95% confidence interval [95% CI], 73–87%). Nonpulmonary visceral metastasis at diagnosis was the only initial adverse prognostic factor. Thirty‐one patients (21%) developed recurrent disease. Recurrence in the liver or the central nervous system was a major adverse prognostic factor, with a 5‐year overall survival rate of 7% (95% CI, 1–32%), compared with 58% (95% CI, 33–79%) in patients who had lymph node, lung, or bone recurrences. The only durable complete remission after a liver recurrence was obtained with high‐dose chemotherapy followed by autologous stem cell transplantation. All 12 patients who were treated for primary mediastinal seminoma with cisplatin‐based chemotherapy alone were long‐term disease free survivors.

CONCLUSIONS

Overall, the prognosis of patients with advanced seminoma was good after cisplatin‐based, first‐line chemotherapy. Metastasis in the liver or the central nervous system, initially or at recurrence, is currently the only proven adverse prognostic factor. Cancer 2003;98:745–52. © 2003 American Cancer Society.

DOI 10.1002/cncr.11574