Showing papers by "Memorial Sloan Kettering Cancer Center published in 2001"

Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks

Abstract: The purpose of this study was to develop a method of classifying cancers to specific diagnostic categories based on their gene expression signatures using artificial neural networks (ANNs). We trained the ANNs using the small, round blue-cell tumors (SRBCTs) as a model. These cancers belong to four distinct diagnostic categories and often present diagnostic dilemmas in clinical practice. The ANNs correctly classified all samples and identified the genes most relevant to the classification. Expression of several of these genes has been reported in SRBCTs, but most have not been associated with these cancers. To test the ability of the trained ANN models to recognize SRBCTs, we analyzed additional blinded samples that were not previously used for the training procedure, and correctly classified them in all cases. This study demonstrates the potential applications of these methods for tumor diagnosis and the identification of candidate targets for therapy.

IFNγ, and lymphocytes prevent primary tumour development and shape tumour immunogenicity

Abstract: Lymphocytes were originally thought to form the basis of a 'cancer immunosurveillance' process that protects immunocompetent hosts against primary tumour development, but this idea was largely abandoned when no differences in primary tumour development were found between athymic nude mice and syngeneic wild-type mice However, subsequent observations that nude mice do not completely lack functional T cells and that two components of the immune system-IFNgamma and perforin-help to prevent tumour formation in mice have led to renewed interest in a tumour-suppressor role for the immune response Here we show that lymphocytes and IFNgamma collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity The immune response thus functions as an effective extrinsic tumour-suppressor system However, this process also leads to the immunoselection of tumour cells that are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals

Multiclass cancer diagnosis using tumor gene expression signatures

Abstract: The optimal treatment of patients with cancer depends on establishing accurate diagnoses by using a complex combination of clinical and histopathological data. In some instances, this task is difficult or impossible because of atypical clinical presentation or histopathology. To determine whether the diagnosis of multiple common adult malignancies could be achieved purely by molecular classification, we subjected 218 tumor samples, spanning 14 common tumor types, and 90 normal tissue samples to oligonucleotide microarray gene expression analysis. The expression levels of 16,063 genes and expressed sequence tags were used to evaluate the accuracy of a multiclass classifier based on a support vector machine algorithm. Overall classification accuracy was 78%, far exceeding the accuracy of random classification (9%). Poorly differentiated cancers resulted in low-confidence predictions and could not be accurately classified according to their tissue of origin, indicating that they are molecularly distinct entities with dramatically different gene expression patterns compared with their well differentiated counterparts. Taken together, these results demonstrate the feasibility of accurate, multiclass molecular cancer classification and suggest a strategy for future clinical implementation of molecular cancer diagnostics.

Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth

Abstract: The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.

Histone deacetylases and cancer: causes and therapies.

Abstract: Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to cancer, but how do they exert this effect?

Statistics notes: Analysing controlled trials with baseline and follow up measurements.

Abstract: In many randomised trials researchers measure a continuous variable at baseline and again as an outcome assessed at follow up. Baseline measurements are common in trials of chronic conditions where researchers want to see whether a treatment can reduce pre-existing levels of pain, anxiety, hypertension, and the like. Statistical comparisons in such trials can be made in several ways. Comparison of follow up (post-treatment) scores will give a result such as “at the end of the trial, mean pain scores were 15 mm (95% confidence interval 10 to 20 mm) lower in the treatment group.” Alternatively a change score can be calculated by subtracting the follow up score from the baseline score, leading to a statement such as “pain reductions were 20 mm (16 to 24 mm) greater on treatment than control.” If the average baseline scores are the same in each group the estimated treatment effect will be the same using these two simple approaches. If the treatment is effective the statistical significance of the treatment effect by the two methods will depend on the correlation between baseline and follow up scores. If the correlation is low using the change score will …

Protein S-nitrosylation: a physiological signal for neuronal nitric oxide.

Abstract: Nitric oxide (NO) has been linked to numerous physiological and pathophysiological events that are not readily explained by the well established effects of NO on soluble guanylyl cyclase. Exogenous NO S-nitrosylates cysteine residues in proteins, but whether this is an important function of endogenous NO is unclear. Here, using a new proteomic approach, we identify a population of proteins that are endogenously S-nitrosylated, and demonstrate the loss of this modification in mice harbouring a genomic deletion of neuronal NO synthase (nNOS). Targets of NO include metabolic, structural and signalling proteins that may be effectors for neuronally generated NO. These findings establish protein S-nitrosylation as a physiological signalling mechanism for nNOS.

Guidelines 2000 for Colon and Rectal Cancer Surgery

Abstract: Background Oncologic resection techniques affect outcome for colon cancer and rectal cancer, but standardized guidelines have not been adopted. The National Cancer Institute sponsored a panel of experts to systematically review current literature and to draft guidelines that provide uniform definitions, principles, and practices. Methods Methods were similar to those described by the American Society of Clinical Oncology in developing practice guidelines. Experts representing oncology and surgery met to review current literature on oncologic resection techniques for level of evidence (I-V, where I is the best evidence and V is the least compelling) and grade of recommendation (A-D, where A is based on the best evidence and D is based on the weakest evidence). Initial guidelines were drafted, reviewed, and accepted by consensus. Results For the following seven factors, the level of evidence was II, III, or IV, and the findings were generally consistent (grade B): anatomic definition of colon versus rectum, tumor-node-metastasis staging, radial margins, adjuvant R0 stage, inadvertent rectal perforation, distal and proximal rectal margins, and en bloc resection of adherent tumors. For another seven factors, the level of evidence was II, III, or IV, but findings were inconsistent (grade C): laparoscopic colectomy; colon lymphadenectomy; level of proximal vessel ligation, mesorectal excision, and extended lateral pelvic lymph node dissection (all three for rectal cancer); no-touch technique; and bowel washout. For the other four factors, there was little or no systematic empirical evidence (grade D): abdominal exploration, oophorectomy, extent of colon resection, and total length of rectum resected. Conclusions The panel reports surgical guidelines and definitions based on the best available evidence. The availability of more standardized information in the future should allow for more grade A recommendations.

Endothelial Apoptosis as the Primary Lesion Initiating Intestinal Radiation Damage in Mice

Abstract: Gastrointestinal (GI) tract damage by chemotherapy or radiation limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberkuhn to initiate the lethal GI syndrome. Here, we show in mouse models that microvascular endothelial apoptosis is the primary lesion leading to stem cell dysfunction. Radiation-induced crypt damage, organ failure, and death from the GI syndrome were prevented when endothelial apoptosis was inhibited pharmacologically by intravenous basic fibroblast growth factor (bFGF) or genetically by deletion of the acid sphingomyelinase gene. Endothelial, but not crypt, cells express FGF receptor transcripts, suggesting that the endothelial lesion occurs before crypt stem cell damage in the evolution of the GI syndrome. This study provides a basis for new approaches to prevent radiation damage to the bowel.

Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair.

Abstract: The Ku heterodimer (Ku70 and Ku80 subunits) contributes to genomic integrity through its ability to bind DNA double-strand breaks and facilitate repair by the non-homologous end-joining pathway. The crystal structure of the human Ku heterodimer was determined both alone and bound to a 55-nucleotide DNA element at 2.7 and 2.5 A resolution, respectively. Ku70 and Ku80 share a common topology and form a dyad-symmetrical molecule with a preformed ring that encircles duplex DNA. The binding site can cradle two full turns of DNA while encircling only the central 3-4 base pairs (bp). Ku makes no contacts with DNA bases and few with the sugar-phosphate backbone, but it fits sterically to major and minor groove contours so as to position the DNA helix in a defined path through the protein ring. These features seem well designed to structurally support broken DNA ends and to bring the DNA helix into phase across the junction during end processing and ligation.

Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma.

Abstract: Cholangiocarcinoma is a rare disease, accounting for less than 2% of all human malignancies. 1 Although the entire biliary tree is potentially at risk, tumors involving the biliary confluence or the right or left hepatic ducts (hilar cholangiocarcinoma) are most common and account for 40% to 60% of all cases. 2–6 Meaningful clinical experience in managing hilar cholangiocarcinomas has been limited to a few referral centers because of the infrequency with which they are encountered. Although resection has long been recognized as the most effective therapy for hilar cholangiocarcinoma, 7 the importance of partial hepatectomy and the willingness of surgeons to use it routinely are relatively recent developments. 2,8–10 Many clinical series extend over a prolonged period, often greater than 20 years. 4,5,9,11,12 As a result, these reports lack a uniform approach to diagnosis, assessment of disease extent, and resection, and the results are therefore difficult to interpret. Further, most studies originate from surgical departments and tend to focus on surgical findings and results and often do not provide a full accounting of all patients seen. Long-term survival in patients with hilar cholangiocarcinoma depends critically on complete tumor resection. 2,10 In the absence of widespread disease, the likelihood of achieving a complete resection requires examination of all factors related to local tumor extent, which increasingly has become possible with noninvasive imaging studies. 13,14 Tumor location and extent within the biliary tree, as provided by the Bismuth-Corlette classification system, 15,16 is only one component. Additional factors that must be addressed relate to radial tumor growth and its impact on adjacent structures, specifically portal venous involvement and consequent hepatic lobar atrophy. Both the modified Bismuth-Corlette and the American Joint Committee on Cancer 17 staging systems fail to account for all of these local, tumor-related factors, which frequently influence therapy. We have shown previously that a preoperative staging system that accounts fully for local tumor-related factors accurately predicts resectability and correlates with survival. 2 The present study represents an analysis of all patients with hilar cholangiocarcinoma seen and treated at a single institution during a 9-year period. The organizational structure of the hepatobiliary program at Memorial Sloan-Kettering Cancer Center (MSKCC) allows a multidisciplinary review of all patients, regardless of disease stage. Thus, a full accounting of all patients, including those with unresectable tumors, is possible. The relatively short time interval ensures homogeneity with respect to disease assessment and surgical approach. This study also proposes a preoperative staging system, based on imaging data and modified from a previous report, 2 that stratifies patients into treatment groups with predictable resectability rates and survival.

Pancreatic Intraepithelial Neoplasia: A New Nomenclature and Classification System for Pancreatic Duct Lesions

Abstract: Proliferative epithelial lesions in the smaller caliber pancreatic ducts and ductules have been the subject of numerous morphologic, clinical, and genetic studies; however, a standard nomenclature and diagnostic criteria for classifying these lesion have not been established. To evaluate the uniform

Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas

Abstract: Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has not been described. During B-cell development, the immunoglobulin variable (V) region genes are subject to somatic hypermutation in germinal-centre B cells. Here we report that an aberrant hypermutation activity targets multiple loci, including the proto-oncogenes PIM1, MYC, RhoH/TTF (ARHH) and PAX5, in more than 50% of diffuse large-cell lymphomas (DLCLs), which are tumours derived from germinal centres. Mutations are distributed in the 5' untranslated or coding sequences, are independent of chromosomal translocations, and share features typical of V-region-associated somatic hypermutation. In contrast to mutations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, suggesting a DLCL-associated malfunction of somatic hypermutation. Intriguingly, the four hypermutable genes are susceptible to chromosomal translocations in the same region, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis.

Inactivation of the apoptosis effector Apaf-1 in malignant melanoma.

Abstract: Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type.

A Novel Response of Cancer Cells to Radiation Involves Autophagy and Formation of Acidic Vesicles

Abstract: The mechanisms underlying neoplastic epithelial cell killing by ionizing radiation are largely unknown. We discovered a novel response to radiation manifested by autophagy and the development of acidic vesicular organelles (AVO). Acidification of AVO was mediated by the vacuolar H+-ATPase. Staining with the lysosomotropic agent acridine orange enabled us to quantify AVO accumulation and to demonstrate their time- and dose-dependent appearance. The appearance of AVO occurred in the presence of the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethyl ketone, but was inhibited by 3-methyladenine, an inhibitor of autophagy. The accretion of AVO in surviving progenies of irradiated cells, and the increased incidence of clonogenic death after inhibition of vacuolar H+-ATPase suggest that formation of acidic organelles represents a novel defense mechanism against radiation damage.

TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination.

Abstract: Here we used mice lacking tumor necrosis factor-alpha (TNF alpha) and its associated receptors to study a model of demyelination and remyelination in which these events could be carefully controlled using a toxin, cuprizone. Unexpectedly, the lack of TNF alpha led to a significant delay in remyelination as assessed by histology, immunohistochemistry for myelin proteins and electron microscopy coupled with morphometric analysis. Failure of repair correlated with a reduction in the pool of proliferating oligodendrocyte progenitors (bromodeoxyuridine-labeled NG2(+) cells) followed by a reduction in the number of mature oligodendrocytes. Analysis of mice lacking TNF receptor 1 (TNFR1) or TNFR2 indicated that TNFR2, not TNFR1, is critical to oligodendrocyte regeneration. This unexpected reparative role for TNF alpha in the CNS is important for understanding oligodendrocyte regeneration/proliferation, nerve remyelination and the design of new therapeutics for demyelinating diseases.

Recombinational DNA double-strand breaks in mice precede synapsis

Abstract: In Saccharomyces cerevisiae, meiotic recombination is initiated by Spo11-dependent double-strand breaks (DSBs), a process that precedes homologous synapsis. Here we use an antibody specific for a phosphorylated histone (gamma-H2AX, which marks the sites of DSBs) to investigate the timing, distribution and Spo11-dependence of meiotic DSBs in the mouse. We show that, as in yeast, recombination in the mouse is initiated by Spo11-dependent DSBs that form during leptotene. Loss of gamma-H2AX staining (which in irradiated somatic cells is temporally linked with DSB repair) is temporally and spatially correlated with synapsis, even when this synapsis is 'non-homologous'.

Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor

Abstract: Acetylation of core histone tails plays a fundamental role in transcription regulation. In addition to acetylation, other posttranslational modifications, such as phosphorylation and methylation, occur in core histone tails. Here, we report the purification, molecular identification, and functional characterization of a histone H4–specific methyltransferase PRMT1, a protein arginine methyltransferase. PRMT1 specifically methylates arginine 3(Arg 3) of H4 in vitro and in vivo. Methylation of Arg 3 by PRMT1 facilitates subsequent acetylation of H4 tails by p300. However, acetylation of H4 inhibits its methylation by PRMT1. Most important, a mutation in theS-adenosyl-l-methionine–binding site of PRMT1 substantially crippled its nuclear receptor coactivator activity. Our finding reveals Arg 3 of H4 as a novel methylation site by PRMT1 and indicates that Arg 3 methylation plays an important role in transcriptional regulation.

United States Multicenter Study of Arsenic Trioxide in Relapsed Acute Promyelocytic Leukemia

Abstract: PURPOSE: To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Forty patients experiencing first (n = 21) or ≥ second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study. RESULTS: Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients receive...

MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells

Abstract: The mitotic checkpoint protein hsMad2 is required to arrest cells in mitosis when chromosomes are unattached to the mitotic spindle. The presence of a single, lagging chromosome is sufficient to activate the checkpoint, producing a delay at the metaphase-anaphase transition until the last spindle attachment is made. Complete loss of the mitotic checkpoint results in embryonic lethality owing to chromosome mis-segregation in various organisms. Whether partial loss of checkpoint control leads to more subtle rates of chromosome instability compatible with cell viability remains unknown. Here we report that deletion of one MAD2 allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts. Checkpoint-defective cells show premature sister-chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome mis-segregation events in the absence of these agents. Furthermore, Mad2+/- mice develop lung tumours at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.

PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo

Abstract: We present evidence that some low-grade oligodendrogliomas may be comprised of proliferating glial progenitor cells that are blocked in their ability to differentiate, whereas malignant gliomas have additionally acquired other mutations such as disruption of cell cycle arrest pathways by loss of Ink4a–Arf. We have modeled these effects in cell culture and in mice by generating autocrine stimulation of glia through the platelet-derived growth factor receptor (PDGFR). In cell culture, PDGF signaling induces proliferation of glial precursors and blocks their differentiation into oligodendrocytes and astrocytes. In addition, coexpression of PDGF and PDGF receptors has been demonstrated in human gliomas, implying that autocrine stimulation may be involved in glioma formation. In this study, using somatic cell type-specific gene transfer we investigated the functions of PDGF autocrine signaling in gliomagenesis by transferring the overexpression of PDGF-B into either nestin-expressing neural progenitors or glial fibrillary acidic protein (GFAP)-expressing astrocytes both in cell culture and in vivo. In cultured astrocytes, overexpression of PDGF-B caused significant increase in proliferation rate of both astrocytes and neural progenitors. Furthermore, PDGF gene transfer converted cultured astrocytes into cells with morphologic and gene expression characteristics of glial precursors. In vivo, gene transfer of PDGF to neural progenitors induced the formation of oligodendrogliomas in about 60% of mice by 12 wk of age; PDGF transfer to astrocytes induced the formation of either oligodendrogliomas or mixed oligoastrocytomas in about 40% of mice in the same time period. Loss of Ink4a–Arf, a mutation frequently found in high-grade human gliomas, resulted in shortened latency and enhanced malignancy of gliomas. The highest percentage of PDGF-induced malignant gliomas arose from of Ink4a–Arf null progenitor cells. These data suggest that chronic autocrine PDGF signaling can promote a proliferating population of glial precursors and is potentially sufficient to induce gliomagenesis. Loss of Ink4a–Arf is not required for PDGF-induced glioma formation but promotes tumor progression toward a more malignant phenotype.

The Influence of Hospital Volume on Survival after Resection for Lung Cancer

Abstract: Background Among patients who have undergone high-risk operations for cancer, postoperative mortality rates are often lower at hospitals where more of these procedures are performed. We undertook a population-based study to estimate the extent to which the number of procedures performed at a hospital (hospital volume) is associated with survival after resection for lung cancer. Methods We studied patients 65 years old or older who received a diagnosis of stage I, II, or IIIA non–small-cell lung cancer between 1985 and 1996, resided in 1 of the 10 study areas covered by the Surveillance, Epidemiology, and End Results Program, and underwent surgery at a hospital that participates in the Nationwide Inpatient Sample (2118 patients and 76 hospitals). Results The volume of procedures at the hospital was positively associated with the survival of patients (P<0.001). Five years after surgery, 44 percent of patients who underwent operations at the hospitals with the highest volume were alive, as compared with 33 p...

Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial.

Abstract: Raloxifene, a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis, has shown a significant reduction in breast cancer incidence after 3 years in this placebo-controlled, randomized clinical trial in postmenopausal women with osteoporosis This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board A total of 7,705 women were enrolled in the 4-year trial; 2,576 received placebo, 2,557 raloxifene 60mg/day, and 2,572 raloxifene 120mg/day Women were a mean of 665-years old at trial entry, 19 years postmenopause, and osteoporotic (low bone mineral density and/or prevalent vertebral fractures) As of 1 November 1999, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 028, 95% confidence interval (CI) 017, 046) These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR 016, 95% CI 009, 030) Raloxifene was generally safe and well-tolerated, however, thromboembolic disease occurred more frequently with raloxifene compared with placebo (p=0003) We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment, through prevention of new cancers or suppression of subclinical tumors, or both Additional randomized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis, at risk for cardiovascular disease, and at high risk for breast cancer

Mechanism and control of meiotic recombination initiation.

Abstract: Homologous recombination is essential during meiosis in most sexually reproducing organisms. In budding yeast, and most likely in other organisms as well, meiotic recombination proceeds via the formation and repair of DNA double-strand breaks (DSBs). These breaks appear to be formed by the Spo11 protein, with assistance from a large number of other gene products, by a topoisomerase-like transesterase mechanism. Recent studies in fission yeast, multicellular fungi, flies, worms, plants, and mammals indicate that the role of Spo11 in meiotic recombination initiation is highly conserved. This chapter reviews the properties of Spo11 and the other gene products required for meiotic DSB formation in a number of organisms and discusses ways in which recombination initiation is coordinated with other events occurring in the meiotic cell.

Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis.

Abstract: BACKGROUND To the authors' knowledge, there are no long-term cohort studies of lymphedema, despite the substantial morbidity of arm swelling. The goal of this study was to identify prevalence of breast carcinoma–related lymphedema, time of onset, and associated predictive factors. METHODS A cohort of 923 women consecutively treated with mastectomy and complete axillary dissection at our center between 1976 and 1978 was observed intensively for 20 years. Two hundred sixty-three study subjects (28.5%) who were alive and recurrence free constituted the cohort for the current study. A subset of 52 women (20% of study population) with contralateral mastectomy was analyzed separately. Subjects reported circumferential arm measurements taken using a validated instrument. In addition to providing analysis of clinical and treatment variables, this study is the first to the authors' knowledge to analyze possible etiologic factors in the posttreatment years, such as occupation, general physical activity, and sports/leisure activities. Univariate and multivariate analytic methods were used. RESULTS At 20 years after treatment, 49% (128 of 263) reported the sensation of lymphedema. Arm swelling measurements were severe (≥ 2.0 in [5.08 cm]; patients reported measurement in inches) for 13% (33 of 263 women). Seventy-seven percent (98 of 128) noted onset within 3 years after the operation; the remaining percentage developed arm swelling at a rate of almost 1% per year. Of the 15 potential predictive factors analyzed, only 2 were statistically significantly associated with lymphedema: arm infection/injury and weight gain since operation (P < 0.001 and P = 0.02, respectively). CONCLUSIONS This defined cohort, treated by axillary dissection 20 years ago, documents the high prevalence of lymphedema and its time course. Two significantly associated factors, both potentially controllable, are identified. The current study provides further support for treatments that limit lymph node dissection. The authors are prospectively evaluating patients undergoing sentinel lymph node biopsy. Cancer 2001;92:1368–77. © 2001 American Cancer Society.