bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure and sequence of the human fast skeletal troponin T (TNNT3) gene: insight into the evolution of the gene and the origin of the developmentally regulated isoforms
Authors: Stefancsik Raymund , Randall Jeffrey D. , Mao Chengjian , Sarkar Satyapriya
Published: December 2003

An Erratum has been published for this article in Comparative and Functional Genomics 5(2) 2004, 205.

We describe the cloning, sequencing and structure of the human fast skeletal troponin T (TNNT3) gene located on chromosome 11p15.5. The single‐copy gene encodes 19 exons and 18 introns. Eleven of these exons, 1–3, 9–15 and 18, are constitutively spliced, whereas exons 4–8 are alternatively spliced. The gene contains an additional subset of developmentally regulated and alternatively spliced exons, including a foetal exon located between exon 8 and 9 and exon 16 or α (adult) and 17 or β (foetal and neonatal). Exon phasing suggests that the majority of the alternatively spliced exons located at the 5′ end of the gene may have evolved as a result of exon shuffling, because they are of the same phase class. In contrast, the 3′ exons encoding an evolutionarily conserved heptad repeat domain, shared by both TnT and troponin I (TnI), may be remnants of an ancient ancestral gene. The sequence of the 5′ flanking region shows that the putative promoter contains motifs including binding sites for MyoD, MEF‐2 and several transcription factors which may play a role in transcriptional regulation and tissue‐specific expression of TnT. The coding region of TNNT3 exhibits strong similarity to the corresponding rat sequence. However, unlike the rat TnT gene, TNNT3 possesses two repeat regions of CCA and TC. The exclusive presence of these repetitive elements in the human gene indicates divergence in the evolutionary dynamics of mammalian TnT genes. Homologous muscle‐specific splicing enhancer motifs are present in the introns upstream and downstream of the foetal exon, and may play a role in the developmental pattern of alternative splicing of the gene. The genomic correlates of TNNT3 are relevant to our understanding of the evolution and regulation of expression of the gene, as well as the structure and function of the protein isoforms. The nucleotide sequence of TNNT3 has been submitted to EMBL/GenBank under Accession No. AF026276. Copyright © 2003 John Wiley & Sons, Ltd.
Gene expression profiling on global cDNA arrays gives hints concerning potential signal transduction pathways involved in cardiac fibrosis of renal failure
Authors: Amann Kerstin , Ridinger Heidrun , Rutenberg Christiane , Ritz Eberhard , Mall Gerhard , Maercker Christian
Published: December 2003

Cardiac remodelling with interstitial fibrosis in renal failure, which so far is only poorly understood on the molecular level, was investigated in the rat model by a global gene expression profiling analysis. Sprague–Dawley rats were subjected to subtotal nephrectomy (SNX) or sham operation (sham) and followed for 2 and 12 weeks, respectively. Heart‐specific gene expression profiling, with RZPD Rat Unigene‐1 cDNA arrays containing about 27 000 gene and EST sequences revealed substantial changes in gene expression in SNX compared to sham animals. Motor protein genes, growth and differentiation markers, and extracellular matrix genes were upregulated in SNX rats. Obviously, not only genes involved in cardiomyocyte hypertrophy, but also genes involved in the expansion of non‐vascular interstitial tissue are activated very early in animals with renal failure. Together with earlier findings in the SNX model, the present data suggest the hypothesis that the local renin–angiotensin system (RAS) may be activated by at least two pathways: (a) via second messengers and G‐proteins (short‐term signalling); and (b) via motor proteins, actins and integrins (long‐term signalling). The study documents that complex hybridization analysis yields reproducible and promising results of patterns of gene activation pointing to signalling pathways involved in cardiac remodelling in renal failure. The complete array data are available via http://www.rzpd.de/cgi‐bin/services/exp/viewExpressionData.pl.cgi Copyright © 2003 John Wiley & Sons, Ltd.
Do we need HER‐2/neu testing for all patients with primary breast carcinoma?
Authors: Taucher Susanne , Rudas Margaretha , Mader Robert M. , Gnant Michael , Dubsky Peter , Bachleitner Thomas , Roka Sebastian , Fitzal Florian , Kandioler Daniela , Sporn Emanuel , Friedl Josef , Mittlböck Martina , Jakesz Raimund
Published: December 2003

BACKGROUND

HER‐2/neu is a valuable prognostic marker in primary breast carcinoma. Controversy surrounds the correlation between HER‐2/neu expression and other prognostic markers, as has been discussed in preclinical and clinical studies. The objective of the current study was to investigate the probability, calculated using parameters that are assessed routinely in clinical practice, that patients with breast carcinoma had positive HER‐2/neu status.

METHODS

The authors evaluated HER‐2/neu status in 923 consecutive patients with breast carcinoma by immunohistochemical methods. Correlations involving HER‐2/neu status, estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade, patient age, lymph node involvement, and tumor size were evaluated using the Mantel–Haenszel chi‐square test and the Spearman correlation. The authors created a simple scoring system (i.e., the diagnostic instrument for validation of HER‐2/neu score) to define subgroups of patients with breast carcinoma and to determine the likelihood of HER‐2/neu positivity.

RESULTS

HER‐2/neu overexpression was correlated significantly with negative ER (P = 0.0001) and PR status (P = 0.0001), Grade 3 (G3) lesions (P = 0.0001), and young age (P = 0.006). The likelihood of HER‐2/neu positivity in a patient with positive ER and PR status and G1/G2 disease was approximately 6.1%.

CONCLUSIONS

The authors demonstrated in a large patient series that HER‐2/neu overexpression was associated with negative hormone receptor status, G3, and young age. In a subgroup of patients presenting with hormone‐responsive and G1/G2 tumors, the likelihood of HER‐2/neu overexpression was very small. Therefore, the assessment of HER‐2/neu status in this subgroup of patients with breast carcinoma may be considered unnecessary, unless the role of HER‐2/neu status in adjuvant treatment has been proven. Cancer 2003;98:2547–53. © 2003 American Cancer Society.
A Phase II study of estramustine, docetaxel, and carboplatin with granulocyte–colony‐stimulating factor support in patients with hormone‐refractory prostate carcinoma
Authors: Oh William K. , Halabi Susan , Kelly W. Kevin , Werner Cary , Godley Paul A. , Vogelzang Nicholas J. , Small Eric J. ,   for the Cancer and Leukemia Group B
Published: December 2003

BACKGROUND

The authors determined the safety and efficacy of estramustine, docetaxel, and carboplatin with granulocyte–colony‐stimulating factor (G‐CSF) support in patients with hormone‐refractory prostate carcinoma.

METHODS

In the current multicenter, cooperative group study, patients with advanced prostate carcinoma whose disease progressed despite androgen deprivation therapy were treated with a combination of oral estramustine(240 mg three times per day for 5 days), 70 mg/m2 of docetaxel, and carboplatin at a dose of (area under the curve) 5. G‐CSF was used to minimize the neutropenia associated with this regimen. Each cycle was repeated every 21 days.

RESULTS

Forty patients were treated with a median of 7 cycles of therapy. Of the 34 evaluable patients with elevated pretreatment prostate‐specific antigen (PSA) levels, 23 (68%) had a ≥ 50% decline in PSA and 20 (59%) had a ≥ 75% decline. Twenty‐one patients had measurable disease, with 1 complete response (5%) and 10 partial responses (47%), for an overall measurable response rate of 52% (95% confidence interval [95% CI], 30–74%). The most common Grade 3 or Grade 4 toxicities (according to the National Cancer Institute Common Toxicity Criteria) included neutropenia in 23% of patients, thrombocytopenia in 13%, and fatigue in 13%. Febrile neutropenia occurred in 1 patient (3%). The overall median time to disease progression was 8.1 months (95% CI, 6–10 months) and the overall survival period was 19 months (95% CI, 13–26 months).

CONCLUSIONS

The combination of estramustine, docetaxel, and carboplatin with G‐CSF support was found to have significant clinical activity with an acceptable toxicity profile in patients with progressive hormone‐refractory prostate carcinoma. Cancer 2003;98:2592–8. © 2003 American Cancer Society.
Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome‐positive chronic myelogenous leukemia in the chronic phase
Authors: Kantarjian Hagop M. , O'Brien Susan , Cortes Jorge , Giles Francis J. , Rios Mary Beth , Shan Jianqin , Faderl Stefan , Garcia‐Manero Guillermo , Ferrajoli Alessandra , Verstovsek Srdan , Wierda William , Keating Michael , Talpaz Moshe
Published: December 2003

BACKGROUND

TheInternationalRandomized study ofInterferon‐alpha plus cytarabine (IFN‐α plus ara‐C) versusSTI571 (imatinib mesylate) [IRIS trial] in patients with newly diagnosed Philadelphia chromosome (Ph)‐positive, chronic‐phase chronic myelogenous leukemia (CML) has not shown (to date) a survival advantage for imatinib. This was most likely because approximately 90% of patients receiving IFN‐α plus ara‐C changed to imatinib therapy after a median of 8 months into therapy.

METHODS

The authors analyzed the results with imatinib therapy in patients with newly diagnosed Ph‐positive CML in chronic phase and compared their outcome with patients who received IFN‐α regimens. A total of 187 patients with Ph‐positive CML in early chronic phase treated with imatinib were compared with a historic group of 650 similar patients treated with IFN‐α regimens from 1982 until 1997.

RESULTS

Patients who received imatinib were significantly older and had significantly more bone marrow basophilia and less leukocytosis. The complete cytogenetic response (Ph 0%) rates were better with imatinib (81% vs. 32%;P< 0.001), as were the survival rates (30‐month estimated survival rates 98% vs. 88%;P= 0.01). A multivariate analysis of the total study group of 837 patients identified imatinib therapy to be a significant independent favorable prognostic factor for survival (P= 0.01).

CONCLUSIONS

The current study is the first to indicate the survival advantage of imatinib compared with IFN‐α, the previous standard of care, in patients with early chronic‐phase CML. Cancer 2003;98:2636–42. © 2003 American Cancer Society.
Short‐term biologic response to withdrawal of hormone replacement therapy in patients with invasive breast carcinoma
Authors: Prasad Ramachandran , Boland Gary P. , Cramer Angela , Anderson Elizabeth , Knox W. Fiona , Bundred Nigel J.
Published: December 2003

BACKGROUND

The biologic effect of continuing hormone replacement therapy (HRT) after a diagnosis of breast carcinoma is unclear. The goal of rhe current study was to determine the short‐term effect of HRT withdrawal on invasive breast carcinoma using biologic surrogate markers of tumor response.

METHODS

The study was performed between 1996 and 2000 and comprised 140 women who had been using HRT at the time of breast carcinoma diagnosis by core needle biopsy. The breast tumors were removed a median of 17 days later (range, 2–31 days). Of these women, 125 women stopped HRT at the time of core needle biopsy and 15 continued to receive HRT until surgery. In addition, 55 women with breast carcinoma from the same time period, who were not receiving HRT at diagnosis, were studied. Changes in expression of Ki‐67 (a measure of epithelial cell proliferation), progesterone receptor (PR), p27KIP‐1 (a cyclin‐dependent kinase inhibitor), and cyclin D1 (a cell cycle‐related protein) were determined by immunohistochemistry on paired sections of the core needle biopsy and surgical specimens from each patient.

RESULTS

In women who stopped HRT, a significant decrease in Ki‐67 expression was observed between core needle biopsy and surgery in estrogen receptor (ER)‐positive (n = 106; P < 0.001), but not in ER‐negative tumors (n = 19; P = 0.58), with an associated reduction in PR (P < 0.001) and cyclin D1 expression (P < 0.001) and an increase in p27KIP‐1 (P = 0.03). These changes in Ki‐67 and PR expression occurred irrespective of c‐erb‐B2 status. No change was observed in any parameter in the other groups of patients.

CONCLUSIONS

ER‐positive invasive breast carcinomas demonstrated a favorable biologic response to withdrawal of HRT. Therefore, HRT should be stopped at the time of diagnosis and was subsequently contraindicated. Cancer 2003;98:2539–46. © 2003 American Cancer Society.
The value of routine follow‐up in patients treated for carcinoma of the vulva
Authors: Oonk Maaike H. M. , de Hullu Joanne A. , Hollema Harry , Mourits Marian J. E. , Pras Elisabeth , Wymenga Anke N. M. , van der Zee Ate G. J.
Published: December 2003

BACKGROUND

Vulvar carcinoma patients traditionally are offered follow‐up after their primary treatment because earlier diagnosis of recurrent disease is believed to improve chances for curative treatment. The objective of the current study was to determine the value of a strict routine follow‐up protocol for the detection of recurrences in a large series of patients who were treated for carcinoma of the vulva.

METHODS

Clinicopathologic data for patients with primary squamous cell carcinoma of the vulva who were treated between January 1990 and July 2000 were prospectively stored in a database. After treatment, patients visited the outpatient clinic at the study institution at gradually increasing intervals. When a recurrence was diagnosed, it was indicated whether the recurrence was local, occurred in the skin bridge, occurred in the inguinal region, or was distant, and this information was registered. Moreover, it was noted whether the diagnosis was made at a routinely scheduled or at an interval follow‐up meeting and whether symptoms as noted by the patient herself led to the diagnosis.

RESULTS

Data from 238 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I–IV vulvar carcinoma were analyzed with a mean follow‐up of 63 months (median, 58 months; range, 6–149 months). Sixty‐five of 238 patients (27%) developed recurrent disease; 49 were local recurrences, 2 recurrences were found in the skin bridge, 6 were found in the inguinal region, and 8 were distant recurrences. Forty‐two of these 65 recurrences (65%) were detected at a routinely scheduled follow‐up meeting, at which time 21 of the 42 patients with recurrent disease (50%) reported symptoms or signs. Local recurrences diagnosed at a routinely scheduled follow‐up meeting were found to have a smaller greater dimension (mean, 2.1 cm and median, 1.6 cm; range, 0.3–8.0 cm) compared with recurrences detected at an interval meeting (mean, 3.1 cm and median, 3.0 cm; range, 0.4–7.0 cm) (P = 0.04).

CONCLUSIONS

The data from the current study indicated that routinely scheduled follow‐up meetings with patients with carcinoma of the vulva result in the detection of smaller recurrences in a substantial proportion of patients compared with self‐reported recurrences, without a measurable effect on morbidity or mortality. Cancer 2003;98:2624–9. © 2003 American Cancer Society.
Long‐term follow‐up of autologous stem cell transplantation in patients with diffuse mantle cell lymphoma in first disease remission
Authors: Khouri Issa F. , Saliba Rima M. , Okoroji Grace‐Julia , Acholonu Sandra A. , Champlin Richard E.
Published: December 2003

BACKGROUND

The current study was conducted to analyze the long‐term results of autologous stem cell transplantation (ASCT) in patients with diffuse mantle cell lymphoma (MCL) in first disease remission.

METHODS

Thirty‐three patients were treated. Thirty‐one patients had Ann Arbor Stage III or Stage IV disease. The hyper‐CVAD regimen (hyperfractionated intense‐dose cyclophosphamide, vincristine, continuous intravenous infusion of doxorubicin, and dexamethasone, alternating with high doses of cytarabine and methotrexate plus leucovorin rescue) was used for cytoreduction before ASCT. Patients were consolidated with high‐dose cyclophosphamide (120 mg/kg), total body irradiation, and ASCT.

RESULTS

At a median follow‐up of 49 months, the overall survival and disease‐free‐survival rates at 5 years were estimated to be 77% and 43%, respectively. Patients whose M. D. Anderson Lymphoma Tumor Score (TS) was ≤ 1 at the time of diagnosis or transplantation experienced longer disease‐free survival compared with those whose TS was > 1 (P = 0.02). A β2‐microglobulin (β2m)level ≤ 3 mg/L at the time of diagnosis or transplantation was also found to be strongly predictive of longer survival (5‐year survival rate of 100% vs. 22% in patients with a β2m level > 3 mg/L) (P = 0.0001).

CONCLUSIONS

ASCT may prolong the overall survival in a subset of patients with MCL. This improvement has been observed for the most part in patients with low β2m levels (≤ 3 mg/L) and TS (≤ 1). Randomized trials are required to fully assess the benefits of this strategy. Cancer 2003;98:2630–5. © 2003 American Cancer Society.
The des‐γ‐carboxy prothrombin index is a new prognostic indicator for hepatocellular carcinoma
Authors: Nagaoka Sakae , Yatsuhashi Hiroshi , Hamada Hisayuki , Yano Koji , Matsumoto Takehiro , Daikoku Manabu , Arisawa Kokichi , Ishibashi Hiromi , Koga Michiaki , Sata Michio , Yano Michitami
Published: December 2003

BACKGROUND

Des‐γ‐carboxy prothrombin (DCP) has been reported to be an important prognostic factor in patients with hepatocellular carcinoma (HCC). Recently, a monoclonal antibody, 19B7, which recognizes the Gla domain of DCP, has been identified. The 19B7 antibody recognizes an epitope different from that recognized by MU‐3, which is another antibody against DCP. In this study, the authors investigated the measurement of DCP using the antibodies MU‐3 and 19B7, respectively, as a prognostic factor for patients with HCC who had solitary, small tumors and or Child Stage A HCC.

METHODS

One hundred four patients with HCC who had solitary, small tumors or Child Stage A tumors were enrolled in the study between 1991 and 2001. All patients were treated and were followed for a mean of 3.2 years. The authors analyzed the correlation between the DCP Index (DCP measured by MU‐3 and DCP measured by 19B7) and patient prognosis. The patients were classified into 3 groups based on their DCP Index: 1) DCP negative (DCP < 40 milli arbitrary unit (mAU)/mL)); 2) low DCP Index (DCP ≥ 40 mAU/mL; MU‐3:19B7 ratio, < 3.0; and 3) high DCP Index (DCP ≥ 40 mAU/mL; MU‐3:19B7 ratio, ≥ 3.0).

RESULTS

The survival rate for patients in the high DCP Index group was lower compared with the survival rate for patients in the DCP‐negative group and was significantly lower compared with the survival rate for patients in the low DCP Index group. In a univariate Cox proportional hazards model, the positive factors were high DCP Index and low DCP Index. Among the positive predictive factors that were analyzed using a multivariate Cox proportional hazards model were age (hazard ratio, 3.27; P = 0.006), low DCP Index (hazard ratio, 2.87; P = 0.012), and high DCP Index (hazard ratio, 12.3; P < 0.0001).

CONCLUSIONS

The prognosis of patients who had a high DCP Index score was poorer compared with patients who had a low DCP Index score and patients who were classified as DCP negative. The authors concluded that the DCP Index is a prognostic indicator for patients with HCC. Cancer 2003;98:2671–7. © 2003 American Cancer Society.
Should molecular testing be required for diagnosing synovial sarcoma?
Authors: Coindre Jean‐Michel , Pelmus Manuela , Hostein Isabelle , Lussan Catherine , Bui Binh N. , Guillou Louis
Published: December 2003

BACKGROUND

The t(X;18) translocation is a specific marker of synovial sarcomas (SS). Detection of SYT‐SSX transcripts by polymerase chain reaction (PCR) was tested on preselected specimens of well‐established histologic types, but to our knowledge, the diagnostic utility of molecular assays on a series of potential SS in comparison with conventional tools has never been reported.

METHODS

Two hundred four consecutive cases of potential SS submitted for a second opinion were studied prospectively. On the basis of clinical context, histologic aspect, and immunohistochemical profile, the tumors were divided into three categories: 1) diagnosis of SS certain, when the only possible diagnosis was SS; 2) diagnosis of SS probable, when SS was the first diagnosis contemplated, but a differential diagnostic issue was raised by other tumors; 3) diagnosis of SS possible, when the diagnosis of SS was not the first diagnosis considered. Detection of SYT‐SSX transcripts was performed using real‐time PCR from fixed, embedded tissue as a systematic test.

RESULTS

Sufficient RNA samples were recovered for PCR from 177 specimens (87%). One hundred four specimens (51%) were positive for SYT‐SSX transcripts. Tumor sites of SS included the extremities (n = 57), lung (n = 13), trunk wall (n = 12), head and neck (n = 6), and other sites (n = 16). There were 61 monophasic, 22 poorly differentiated, 17 biphasic, and 4 predominantly epithelial SS. For 58 tumor specimens (29%), diagnosis of SS was certain before molecular testing; 49 (84.5%) of these 58 contained SYT‐SSX transcripts. For 39 tumor specimens (19%), diagnosis of SS was probable; 29 (74.4%) of these 39 contained SYT‐SSX transcripts. For 107 tumor specimens (52%), diagnosis of SS was only possible and strongly challenged by another histologic type. The issue consisted mainly of making the distinction between an SS and a poorly differentiated spindle cell sarcoma (n = 49), a poorly differentiated round cell sarcoma (n = 34), a carcinoma (n = 11), a myoepithelioma (n = 8), or an epithelioid fibrosarcoma (n = 5).Twenty‐six tumor specimens (24.3%) contained SYT‐SSX transcripts—10, 7, 5, 3, and 1 in the spindle cell tumor, round cell tumor, carcinomalike tumor, myoepitheliomalike tumor, and epithelioid‐fibrosarcoma‐like tumor categories, respectively.

CONCLUSIONS

Molecular testing was not required if the diagnosis of SS was certain or probable on the basis of clinical, histologic, and immunohistochemical evaluation. However, it proved to be very helpful or necessary when the diagnosis of SS was only possible and was challenged by other tumor types, mainly other spindle cell sarcomas, round cell sarcomas, carcinomas, myoepitheliomas, and epithelioid fibrosarcomas. Cancer 2003;98:2700–7. © 2003 American Cancer Society.
Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia
Authors: Raimondi Susana C. , Zhou Yinmei , Mathew Susan , Shurtleff Sheila A. , Sandlund John T. , Rivera Gaston K. , Behm Frederick G. , Pui Ching‐Hon
Published: December 2003

BACKGROUND

The purpose of the current study was to evaluate the cytogenetic features of the hypodiploid leukemic cells of pediatric patients with this rare subgroup of acute lymphoblastic leukemia (ALL). In addition, the authors determined whether subdivision of the hypodiploid category served a prognostic purpose for these patients.

METHODS

The authors evaluated the cytogenetic records of 979 patients with ALL admitted to St. Jude Children's Research Hospital (Memphis, TN) between 1984 and 1999.

RESULTS

Of 67 patients (6.8%) whose leukemic cells contained a modal number (MN) of chromosomes less than or equal to 45 (i.e., hypodiploid leukemic cells), 57 had an MN of 45 and 10 had an MN of less than 45. In 19 patients, cells with an MN of 45 had a whole chromosome missing (42%), which was a sex chromosome in 12 patients (63%). Leukemic cells with an MN of 45 contained dicentric chromosomes (n = 33) formed from chromosome 9p (55%), 12p (18%), or both (21%). The ETV6‐CBFA2 fusion was present in 39% of 28 evaluable B‐lineage cases with an MN of 45. The event‐free survival rate (EFS) for patients with hypodiploid leukemic cells of MN less than 45 (5‐year EFS = 20.0% ± 10.3%) was significantly (P < 0.001) lower than that for patients with leukemic cells of MN greater than or equal to 45 (5‐year EFS = 74.9% ± 1.6%).

CONCLUSIONS

Low hypodiploidy (MN < 45) should be recognized as a high‐risk feature in pediatric ALL. Only two hypodiploid groups (MN < 45 and MN = 45) may be necessary in prognostic assessments. Cancer 2003;98:2715–22. © 2003 American Cancer Society.
Music therapy for mood disturbance during hospitalization for autologous stem cell transplantation
Authors: Cassileth Barrie R. , Vickers Andrew J. , Magill Lucanne A.
Published: December 2003

BACKGROUND

High‐dose therapy with autologous stem cell transplantation (HDT/ASCT) is a commonly used treatment for hematologic malignancies. The procedure causes significant psychological distress and no interventions have been demonstrated to improve mood in these patients. Music therapy has been shown to improve anxiety in a variety of acute medical settings. In the current study, the authors determined the effects of music therapy compared with standard care on mood during inpatient stays for HDT/ASCT.

METHODS

Patients with hematologic malignancy admitted for HDT/ASCT at two sites (Memorial Sloan‐Kettering Cancer Center and Ireland Cancer Center in Cleveland, Ohio) were randomized to receive music therapy given by trained music therapists or standard care. Outcome was assessed at baseline and every 3 days after randomization using the Profile of Mood States.

RESULTS

Of 69 patients registered in the study, follow‐up data were available for 62 (90%). During their inpatient stay, patients in the music therapy group scored 28% lower on the combined Anxiety/Depression scale (P = 0.065) and 37% lower (P = 0.01) on the total mood disturbance score compared with controls.

CONCLUSIONS

Music therapy is a noninvasive and inexpensive intervention that appears to reduce mood disturbance in patients undergoing HDT/ASCT. Cancer 2003;98:2723–9. © 2003 American Cancer Society.
Salvage therapy in patients with glioblastoma
Authors: Hau Peter , Baumgart Ulrike , Pfeifer Katharina , Bock Anne , Jauch Tanya , Dietrich Jörg , Fabel Klaus , Grauer Oliver , Wismeth Caecilia , Klinkhammer‐Schalke Monika , Allgäuer Michael , Schuierer Gerhard , Koch Horst , Schlaier Juergen , Ulrich Winfried , Brawanski Alexander , Bogdahn Ulrich , Steinbrecher Andreas
Published: December 2003

BACKGROUND

Survival after first‐line therapy is poor for patients with glioblastoma. The role of second‐line treatment for recurrent disease is controversial. The authors studied the outcome in a subset of patients with glioblastoma who were selected for an aggressive reintervention strategy at the time of progression. Their objectives were to improve patients' overall survival with sustained quality of life and to make comparisons with overall survival in unselected patients.

METHODS

Overall, 168 patients were eligible for retrospective analysis. Ninety patients received specific therapy for disease recurrence (reintervention group) by specific criteria.

RESULTS

In the reintervention group, promising median overall survival (mOS) results after diagnosis (61.5 weeks) and progression (33 weeks) were obtained. The progression‐free survival (PFS) rate at 12 months and the overall survival rate were superior in the reintervention group (71% at 12 months and 32% at 24 months) compared with the total cohort (45% and 20%, respectively) and the standard group (15% and 5%, respectively). A matched‐pair analysis (n = 46 in each group), with an mOS period of 65.5 versus 28.5 weeks, confirmed these data. Quality of life was stable or slightly improved during reinterventions in a subset of patients treated within clinical studies.

CONCLUSIONS

The majority of patients in the current series were treated with a reintervention strategy, which had an impact on PFS and mOS. A second resection, focal radiotherapy (in selected cases), and additional chemotherapeutic regimens should be considered for patients with recurrent glioblastoma. Cancer 2003;98:2678–86. © 2003 American Cancer Society.
Doxorubicin‐based chemotherapy for diffuse large B‐cell lymphoma in elderly patients
Authors: Lee Keun‐Wook , Kim Dae‐Young , Yun Tak , Kim Dong‐Wan , Kim Tae‐You , Yoon Sung‐Soo , Seog Heo Dae , Bang Yung‐Jue , Park Seonyang , Kook Kim Byoung , Kyeong Kim Noe
Published: December 2003

BACKGROUND

Although many studies of elderly patients with non‐Hodgkin lymphoma have focused on the dose intensity of chemotherapy, few studies have restricted the histologic inclusion criteria such that only patients with diffuse large B‐cell lymphoma (DLCL) are considered. In the current study, treatment outcomes for elderly patients (age ≥ 60 years) were analyzed, with emphasis on the dose intensity of doxorubicin.

METHODS

Between 1994 and 2000, 195 patients with DLCL were treated initially with doxorubicin‐based chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone; or cyclophosphamide, vincristine, bleomycin, doxorubicin, procarbazine, and prednisone). Of these patients, 70 were aged 60 years or older.

RESULTS

Elderly patients had poorer treatment outcomes than did young patients (5‐year survival, 30% vs. 57%;P< 0.001); however, elderly patients who received doxorubicin at dose intensities ≥ 10 mg/m2per week (n= 25) had outcomes (5‐year survival, 52%) that were comparable to those of young patients. Among prognostic factors, only International Prognostic Index score (P= 0.022) and dose intensity of doxorubicin (P= 0.039) were found to have significant effects on the overall survival of elderly patients. When the reasons for doxorubicin dose reduction in 45 elderly patients who ultimately received doxorubicin at dose intensities < 10 mg/m2per week were analyzed, it was found that 20 patients received reduced doses from the start of treatment because of their old age alone; these dose reductions in the 20 cases resulted in poorer treatment outcomes.

CONCLUSIONS

Elderly patients with DLCL who received doxorubicin at dose intensities ≥ 10 mg/m2per week had treatment outcomes that were comparable to those of young patients; however, physician bias associated with patient age was found to be related to unnecessary dose reductions. Efforts to maintain doxorubicin dose intensities ≥ 10 mg/m2per week and more objective standards for the selection of elderly patients capable of tolerating doxorubicin‐based regimens are required. Cancer 2003;98:2651–6. © 2003 American Cancer Society.
Prophylactic oophorectomy
Authors: Schlosshauer Peter W. , Cohen Carmel J. , Penault‐Llorca Frederique , Miranda Carlos R. , Bignon Yves‐Jean , Dauplat Jacques , Deligdisch Liane
Published: December 2003

BACKGROUND

The tumorigenesis of ovarian carcinoma is poorly understood. The authors studied morphologic features and immunohistochemical expression patterns of neoplasia‐associated markers in prophylactically removed ovaries, normal ovaries, and papillary serous ovarian carcinomas to identify possible preneoplastic changes in ovarian surface epithelium.

METHODS

Morphologic features and immunohistochemical expression patterns of CA‐125, Ki‐67, p53, E‐cadherin, and Bcl‐2 were evaluated in 21 normal ovaries, 31 ovaries that were removed prophylactically for increased carcinoma risk, and 7 ovarian papillary serous carcinomas. Representative slides from formalin‐fixed, paraffin‐embedded tissue blocks were submitted to immunohistochemical staining and were evaluated independently by three gynecologic pathologists. For statistical analyses, Fisher exact tests, multivariate analyses, Spearman rank correlation coefficients, Wald statistics, Kruskal–Wallis tests, and Mann–Whitney tests were used. Immunohistochemical staining results were correlated with morphologic findings.

RESULTS

The authors found progressive increases in reactivity with the lowest expression in normal ovarian epithelium, stronger expression in epithelium from prophylactically removed ovaries, and the highest expression in carcinomas for Ki‐67 and p53. A similar trend was observed for CA‐125. Positivity for Ki‐67 and p53 was seen predominantly in the epithelium of inclusion cysts and deep invaginations, including those areas that had been identified as hyperplastic or dysplastic on routine hematoxylin and eosin‐stained sections.

CONCLUSIONS

The current results suggest biologic/molecular evidence for the existence of preneoplastic changes in ovarian surface epithelium and support the previously proposed concept of ovarian dysplasia. Subtle morphologic alterations of the ovarian epithelium may be biologically significant. Cancer 2003;98:2599–606. © 2003 American Cancer Society.
Prognostic significance of Gleason pattern in patients with Gleason score 7 prostate carcinoma
Authors: Rasiah Kris K. , Stricker Phillip D. , Haynes Anne‐Maree , Delprado Warick , Turner Jennifer J. , Golovsky David , Brenner Phillip C. , Kooner Raji , O'Neill Gordon F. , Grygiel John J. , Sutherland Robert L. , Henshall Susan M.
Published: December 2003

BACKGROUND

In the current study, the authors sought to further stratify the prognosis of patients with Gleason score (GS) 7 prostate carcinoma. They assessed the influence on outcome of a predominant poorly differentiated Gleason pattern (primary Gleason pattern [GP] 4) and/or a coincident small focus of poorly differentiated tumor of higher grade (tertiary GP 5).

METHODS

The authors studied 412 patients (mean postoperative follow‐up, 33 months) with GS 7 tumors treated with radical prostatectomy at a single Australian campus between November 1989 and December 2002. The chi‐square test, Kaplan–Meier method, and Cox proportional hazards analyses were used to evaluate the correlation between primary GP 4 and tertiary GP 5 with the occurrence of adverse pathologic features and disease recurrence.

RESULTS

In this cohort, 307 patients (75%) had primary GP 3 tumors, 105 (25%) had primary GP 4 tumors, and 17 (2.3%) had a tertiary element of high‐grade tumor (GP 5). Patients with primary GP 4 tumors displayed higher rates of seminal vesicle involvement and extraprostatic extension and, along with patients with tertiary GP 5, had significantly shorter times to disease recurrence. Univariate analysis demonstrated that primary GP 4 (P = 0.0003) and tertiary GP 5 (P < 0.0001) were strong predictors of disease recurrence. Primary GP 4 (P = 0.0122) remained an independent predictor of disease recurrence on stepwise multivariate analysis.

CONCLUSIONS

Primary GP 4 tumors represented an aggressive subset of GS 7 prostate carcinomas. Primary GP was an easily accessible and clinically relevant predictor of disease recurrence in patients with GS 7 prostate carcinoma. Cancer 2003;98:2560–5. © 2003 American Cancer Society.
Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma
Authors: Leibovich Bradley C. , Han Ken‐ryu , Bui Matthew H. T. , Pantuck Allan J. , Dorey Frederick J. , Figlin Robert A. , Belldegrun Arie
Published: December 2003

BACKGROUND

The objective of this study was to develop an algorithm capable of stratifying the survival of patients with metastatic renal cell carcinoma (RCC) after nephrectomy and immunotherapy.

METHODS

The medical records of 173 patients who underwent radical nephrectomy for metastatic RCC and received recombinant interleukin‐2 (IL‐2)‐based immunotherapy between 1989 and 2000 were evaluated. Survival was the primary endpoint and was assessed based on clinical, surgical, and pathologic parameters. The clinical parameters included age, gender, performance status, existing hypertension, thyroid‐stimulating hormone (TSH) levels, location of metastases, and presenting symptomatology. The surgical features included the requirement for blood transfusion or adrenalectomy. The pathologic factors involved tumor stage, tumor size, nuclear grade, lymph node status, and histologic subtype. Disease‐specific survival was estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards models were used to determine associations between clinical and pathologic features and survival.

RESULTS

The median follow‐up was 3.2 years (range, 0.2–9.3 years). Death due to RCC occurred in 123 patients (71%) at a median of 13 months (range, from 0.1 months to 8.4 years) after nephrectomy. Multivariate analysis revealed that the following features were associated with survival: lymph node status (P = 0.002), constitutional symptoms (P = 0.005), location of metastases (P < 0.001), sarcomatoid histology (P = 0.003), and TSH level (P = 0.038). A scoring system based on the features in the multivariate model was created to stratify patients into low‐risk, intermediate‐risk, and high‐risk groups. Estimated survival rates at 1 years, 3 years, and 5 years were 92%, 61%, and 41%, respectively, for the low‐risk group and 66%, 31%, and 19%, respectively, for the intermediate risk group. The high‐risk group had 1% survival at 1 year and no survivors at 3 years.

CONCLUSIONS

In patients with metastatic RCC who were treated with nephrectomy and IL‐2 immunotherapy, regional lymph node status, constitutional symptoms, location of metastases, sarcomatoid histology, and TSH levels were associated with survival. The authors present a scoring algorithm based on these features that can be used to predict survival in patients who present with metastatic RCC and to stratify such patients for prospective clinical trials. Cancer 2003;98:2566–75. © 2003 American Cancer Society.
Quantitative alterations in nuclear structure predict prostate carcinoma distant metastasis and death in men with biochemical recurrence after radical prostatectomy
Authors: Khan Masood A. , Walsh Patrick C. , Miller M. Craig , Bales Wesley D. , Epstein Jonathan I. , Mangold Leslie A. , Partin Alan W. , Veltri Robert W.
Published: December 2003

BACKGROUND

Microscopic histologic grade has been the best predictor of prostate carcinoma (PCa) progression in men after surgical therapy. The ability to predict accurately, at the time of surgery, which patients are likely to develop metastatic PCa would enable optimization of disease management with adjuvant therapy. The authors assessed the ability of pathologic, nuclear morphometric, and chromatin parameters to predict metastatic PCa progression and/or death in 227 men with biochemical recurrence and long‐term follow‐up after undergoing radical prostatectomy.

METHODS

Multivariate logistic regression (LR) was used to calculate quantitative nuclear grade (QNG) solutions using the variances of 60 nuclear morphometric descriptors (NMDs) of nuclear size, shape, DNA content, and chromatin organization that predicted distant metastasis and/or PCa‐specific death. An LR model also was generated to predict this outcome using a combination of pathologic variables and the best QNG solution. Cox proportional hazards models were generated, and Kaplan–Meier plots were used to display three risk groups based on pathology, QNG, and a combination of these variables.

RESULTS

A multivariate LR model using pathology retained lymph node (LN) status, seminal vesicle status, and prostatectomy Gleason score, yielding an area under the curve–receiver operator characteristic (AUC‐ROC) of 75% with an accuracy of 59% at 90% sensitivity. The best QNG solution used the variance of 25 NMDs, yielding an AUC‐ROC of 84% and an accuracy of 70% at 90% sensitivity. The combined pathology‐QNG model retained LN status, prostatectomy Gleason score, and QNG, yielding an AUC‐ROC of 86% with an accuracy of 76% at 90% sensitivity. The Cox proportional hazards models produced the following significant univariate and multivariate hazard ratios: QNG, 3.5 and 2.9, respectively; LN, 2.7 and 1.8, respectively; and prostatectomy Gleason score, 2.8 and 2.1, respectively.

CONCLUSIONS

Alterations in the structure of tumor nuclei measured by computer‐assisted image analysis were strong predictors of PCa progression and death in men with long‐term follow‐up who had biochemical recurrence after undergoing radical prostatectomy. QNG solutions can serve as a new supplemental biomarker for accurate prediction of PCa progression at the time of surgery. Cancer 2003;98:2583–91. © 2003 American Cancer Society.
Correlation of bcl‐2 and p53 expression in primary breast tumors and corresponding metastatic lymph nodes
Authors: Arun Banu , Kilic Gokhan , Yen Charles , Foster Barbara , Yardley Denise , Gaynor Richard , Ashfaq Raheela
Published: December 2003

BACKGROUND.

The p53 tumor suppressor gene product participated in G1 cell cycle arrest or cell death. Loss of function was associated with poor outcome in patients with breast carcinoma. bcl‐2 prevented apoptosis induced by c‐myc or growth factor deprivation. High bcl‐2 expression in breast tumor tissue specimens appears to be associated with favorable prognostic factors. However, Bcl‐2 and p53 expression in primary tumor tissue specimens versus metastatic lymph node specimens in breast carcinoma has not been studied. The current study compared Bcl‐2 and p53 expression in primary breast carcinoma tissue specimens with Bcl‐2 and p53 expression in axillary lymph node specimens.

METHODS.

Primary breast tumor and corresponding axillary metastatic lymph node tissue specimens were obtained from 60 patients with breast carcinoma. They were evaluated for the presence of Bcl‐2 and p53 expression by immunohistochemistry using standard methods.

RESULTS.

Bcl‐2 expression in primary tumor tissue specimens (53%) was correlated with Bcl‐2 expression in metastatic lymph node specimens (50 %; Pearson correlation = 0.656). p53 expression in primary tumor specimens (72%) was correlated with p53 expression in metastatic lymph node specimens (60 %; Pearson correlation = 0.800). A significant inverse correlation also was found between p53 and Bcl‐2 expression in primary breast tumor tissue specimens (Pearson correlation = −0.310).

CONCLUSIONS.

The current study suggested that Bcl‐2 and p53 expression in axillary metastatic lymph node specimens is correlated with Bcl‐2 and p53 expression in the primary tumor tissue specimens. The prognostic and predictive value of Bcl‐2 and p53 expression in axillary lymph node metastasis in patients with breast carcinoma needs to be further evaluated in larger trials with longer follow‐up. Cancer 2003;98:2554–9. © 2003 American Cancer Society.
Classification of isolated tumor cells
Authors: Singletary S. Eva , Greene Frederick L. , Sobin Leslie H.
Published: December 2003

In May 2002, the 6th edition of the American Joint Committee on Cancer staging manual was published. This new staging system was officially adopted for use in tumor registries in January 2003. The changes adopted for the chapter concerning breast carcinoma were the result of recommendations made by a task force charged with proposing changes that reflected published clinical data and current clinical consensus.
Gemcitabine plus oxaliplatin for patients with advanced hepatocellular carcinoma using two different schedules
Authors: Taïeb Julien , Bonyhay Luminita , Golli Lamia , Ducreux Michel , Boleslawski Emmanuel , Tigaud Jean‐Marie , de Baere Thierry , Mansourbakht Touraj , Delgado Marie Anna , Hannoun Laureut , Poynard Thierry , Boige Valerie
Published: December 2003

BACKGROUND

New therapies are needed to improve the prognosis of patients with advanced hepatocellular carcinoma (HCC). Various gemcitabine‐oxaliplatin combinations have been tested recently in patients with ovarian and pancreatic carcinoma, yielding interesting results with little toxicity. Therefore, the authors evaluated the activity and toxicity of two such combinations in patients with HCC.

METHODS

Twenty‐one patients were enrolled prospectively in the study. Eleven patients received gemcitabine 1000 mg/m2 on Day 1 and oxaliplatin 100 mg/m2 on Day 2 (GEMOX‐1), and 10 patients received gemcitabine 1500 mg/m2 on Day 1 followed by oxaliplatin 85 mg/m2 on Day 1 (GEMOX‐2). Treatment was repeated every 2 weeks until disease progression developed or until unacceptable adverse effects occurred.

RESULTS

All patients were assessable for response and toxicity. Four patients (19%) achieved objective responses (95% confidence interval, 13–26%), including 3 patients in the GEMOX‐1 group and 1 patient in the GEMOX‐2 group. Ten patients (48%) had stable disease, and 7 patients (33%) experienced disease progression. The median progression‐free survival was 5 months, and the median overall survival was 12 months. Fifty‐four percent of patients in the GEMOX‐1 group and 50% of patients in the GEMOX‐2 group had received previous systemic chemotherapy or cisplatin‐based chemoembolization. Grade 3–4 hematologic toxicity, according to National Cancer Institute Common Toxicity Criteria, consisted of thrombocytopenia (GEMOX‐1 vs. GEMOX‐2, 18% vs. 40%) and neutropenia (0% vs. 30%). No Grade 3–4 nonhematologic toxicity was observed, except for 1 episode of Grade 3 diarrhea. Grade 1 neurotoxicity and Grade 2 neurotoxicity (specific scale), respectively, were observed in 4 patients and 7 patients receiving GEMOX‐1 and in 7 patients and 1 patient receiving GEMOX‐2.

CONCLUSIONS

Gemcitabine‐oxaliplatin combination therapy is feasible in patients with advanced HCC. The GEMOX‐1 regimen was tolerated better than the GEMOX‐2 regimen. Currently, the GEMOX‐1 regimen is being evaluated in a Phase II study in previously untreated patients with HCC. Cancer 2003;98:2664–70. © 2003 American Cancer Society.
A two‐arm phase II study of temozolomide in patients with advanced gastrointestinal stromal tumors and other soft tissue sarcomas
Authors: Trent Jonathan C. , Beach Jennifer , Burgess Michael A. , Papadopolous Nicholas , Chen Lei L. , Benjamin Robert S. , Patel Shreyaskumar R.
Published: December 2003

BACKGROUND

The authors conducted a two‐arm Phase II study of temozolomide to determine its efficacy and toxicity in patients with soft tissue sarcomas (STSs) who had received, had refused, or were not eligible for standard chemotherapy with doxorubicin and ifosfamide (Arm 1) and in patients with gastrointestinal stromal tumors (GISTs; Arm 2). Patients with GIST were eligible regardless of prior therapy before imatinib was available.

METHODS

Sixty patients were enrolled in the current study, 19 of whom had GISTs and 41 of whom had other STSs. The patients received temozolomide at a dose of 85 mg/m2 orally for 21 days followed by 7 days without treatment. Standard radiographic imaging after every two cycles was used to assess the treatment response.

RESULTS

Of the 39 patients in Arm 1, there was 1 complete response and 1 partial response of 39 evaluable patients, for a total response rate of 5% (95% confidence interval, 0–12%). The responses lasted 7 months and 8 months, respectively. In Arm 2, there was no response in 17 patients. The disease was stable in 22% of the patients with GISTs and 33% of the patients with other STSs. The median overall survival time was 26.4 months in patients with GISTs and 11 months in patients with other STSs. The median time to disease progression was 2.3 months in patients with GISTs and 3.3 months in patients with other STSs. Grade 3 and Grade 4 adverse effects (according to National Cancer Institute Common Toxicity Criteria) were rare and included fatigue (eight patients), anemia (six patients), constipation (four patients), neutropenia (four patients), and thrombocytopenia (four patients).

CONCLUSIONS

The data from the current study suggest that temozolomide is well tolerated but has only minimal efficacy and a limited role in the treatment of patients with STSs. Cancer 2003;98:2693–9. © 2003 American Cancer Society.