Showing papers by "Memorial Sloan Kettering Cancer Center published in 2005"

A microRNA polycistron as a potential human oncogene

Abstract: To date, more than 200 microRNAs have been described in humans; however, the precise functions of these regulatory, non-coding RNAs remains largely obscure. One cluster of microRNAs, the mir-17-92 polycistron, is located in a region of DNA that is amplified in human B-cell lymphomas. Here we compared B-cell lymphoma samples and cell lines to normal tissues, and found that the levels of the primary or mature microRNAs derived from the mir-17-92 locus are often substantially increased in these cancers. Enforced expression of the mir-17-92 cluster acted with c-myc expression to accelerate tumour development in a mouse B-cell lymphoma model. Tumours derived from haematopoietic stem cells expressing a subset of the mir-17-92 cluster and c-myc could be distinguished by an absence of apoptosis that was otherwise prevalent in c-myc-induced lymphomas. Together, these studies indicate that non-coding RNAs, specifically microRNAs, can modulate tumour formation, and implicate the mir-17-92 cluster as a potential human oncogene.

Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain

Abstract: Background Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR). Despite initial responses, patients eventually progress by unknown mechanisms of “acquired” resistance. Methods and Findings We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, a mutation analogous to T790M has been observed in other kinases with acquired resistance to another kinase inhibitor, imatinib (Gleevec). Conclusion In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers.

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Abstract: The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

Genes that mediate breast cancer metastasis to lung

Abstract: By means of in vivo selection, transcriptomic analysis, functional verification and clinical validation, here we identify a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumour and in the lung microenvironment. Others contribute to aggressive growth selectively in the lung. Many encode extracellular proteins and are of previously unknown relevance to cancer metastasis.

Smad transcription factors

Abstract: Smad transcription factors lie at the core of one of the most versatile cytokine signaling pathways in metazoan biology-the transforming growth factor-beta (TGFbeta) pathway. Recent progress has shed light into the processes of Smad activation and deactivation, nucleocytoplasmic dynamics, and assembly of transcriptional complexes. A rich repertoire of regulatory devices exerts control over each step of the Smad pathway. This knowledge is enabling work on more complex questions about the organization, integration, and modulation of Smad-dependent transcriptional programs. We are beginning to uncover self-enabled gene response cascades, graded Smad response mechanisms, and Smad-dependent synexpression groups. Our growing understanding of TGFbeta signaling through the Smad pathway provides general principles for how animal cells translate complex inputs into concrete behavior.

Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer

Abstract: In a recent report, [Zhang et al. (2003) N. Engl. J. Med. 348, 203–213], the presence of CD3+ tumor-infiltrating lymphocytes (TILs) was found to correlate with improved survival in epithelial ovarian cancer. We performed immunohistochemical analysis for TILs and cancer testis antigens in 117 cases of epithelial ovarian cancer. The interrelationship between subpopulations of TILs and expression of cancer testis antigens was investigated, as well as between TILs and overall survival. The median follow-up of the patients was 31 months. Patients with higher frequencies of intraepithelial CD8+ T cells demonstrated improved survival compared with patients with lower frequencies [median = 55 versus 26 months; hazard ratio = 0.33; confidence interval (C.I.) = 0.18–0.60; P = 0.0003]. No association was found for CD3+ TILs or other subtypes of intraepithelial or stromal TILs. However, the subgroups with high versus low intraepithelial CD8+/CD4+ TIL ratios had median survival of 74 and 25 months, respectively (hazard ratio = 0.30; C.I. = 0.16–0.55; P = 0.0001). These results indicate that CD4+ TILs influence the beneficial effects of CD8+ TIL. This unfavorable effect of CD4+ T cells on prognosis was found to be due to CD25+forkhead box P3 (FOXP3)+ regulatory T cells (Treg; suppressor T cells), as indicated by survival of patients with high versus low CD8+/Treg ratios (median = 58 versus 23 months; hazard ratio = 0.31; C.I. = 0.17–0.58; P = 0.0002). The favorable prognostic effect of intraepithelial CD8+ TILs did not correlate with concurrent expression of NY-ESO-1 or MAGE antigens. We conclude that intraepithelial CD8+ TILs and a high CD8+/Treg ratio are associated with favorable prognosis in epithelial ovarian cancer.

Cardiovascular Risk Associated With Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention

Abstract: background Selective cyclooxygenase-2 (COX-2) inhibitors have come under scrutiny because of reports suggesting an increased cardiovascular risk associated with their use. Experimental research suggesting that these drugs may contribute to a prothrombotic state provides support for this concern. methods We reviewed all potentially serious cardiovascular events among 2035 patients with a history of colorectal neoplasia who were enrolled in a trial comparing two doses of celecoxib (200 mg or 400 mg twice daily) with placebo for the prevention of colorectal adenomas. All deaths were categorized as cardiovascular or noncardiovascular, and nonfatal cardiovascular events were categorized in a blinded fashion according to a prespecified scheme. results

Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

Abstract: Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro, but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer. Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription. Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers non-lethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age. Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, we detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours.

Cancer/testis antigens, gametogenesis and cancer.

Abstract: Cancer/testis (CT) antigens, of which more than 40 have now been identified, are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumour types, including melanoma, and carcinomas of the bladder, lung and liver These immunogenic proteins are being vigorously pursued as targets for therapeutic cancer vaccines CT antigens are also being evaluated for their role in oncogenesis — recapitulation of portions of the germline gene-expression programme might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, hypomethylation and metastatic capacity

Mutations in the Epidermal Growth Factor Receptor and in KRAS Are Predictive and Prognostic Indicators in Patients With Non–Small-Cell Lung Cancer Treated With Chemotherapy Alone and in Combination With Erlotinib

Abstract: Purpose Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non–small-cell lung cancer (NSCLC). The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described. Patients and Methods Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses. Results EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P < ...

KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib

Abstract: Background Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive.

Identification of microRNAs of the herpesvirus family

Abstract: Epstein-Barr virus (EBV or HHV4), a member of the human herpesvirus (HHV) family, has recently been shown to encode microRNAs (miRNAs). In contrast to most eukaryotic miRNAs, these viral miRNAs do not have close homologs in other viral genomes or in the genome of the human host. To identify other miRNA genes in pathogenic viruses, we combined a new miRNA gene prediction method with small-RNA cloning from several virus-infected cell types. We cloned ten miRNAs in the Kaposi sarcoma-associated virus (KSHV or HHV8), nine miRNAs in the mouse gammaherpesvirus 68 (MHV68) and nine miRNAs in the human cytomegalovirus (HCMV or HHV5). These miRNA genes are expressed individually or in clusters from either polymerase (pol) II or pol III promoters, and share no substantial sequence homology with one another or with the known human miRNAs. Generally, we predicted miRNAs in several large DNA viruses, and we could neither predict nor experimentally identify miRNAs in the genomes of small RNA viruses or retroviruses.

Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis

Abstract: We undertook this study to develop uniformly accepted criteria for the definition of organ involvement and response for patients on treatment protocols for immunoglobulin light-chain amyloidosis (AL). A consensus panel was convened comprising 13 specialists actively involved in the treatment of patients with amyloidosis. Institutional criteria were submitted from each, and a consensus was developed defining each organ involved and the criteria for response. Specific criteria have been developed with agreed on definitions of organ and hematologic response as a result of discussions at the 10th International Symposium on Amyloid and Amyloidosis held in Tours, France, April 2004. These criteria now form the working definition of involvement and response for the purposes of future data collection and reporting. We report criteria that centers can now use to define organ involvement and uniform response criteria for reporting outcomes in patients with light-chain AL.

Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry

Abstract: Purpose To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). Patients and Methods Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximab's commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria. Results Sixteen chemotherapy-refractory, ...

Annual Report to the Nation on the Status of Cancer, 1975–2002, Featuring Population-Based Trends in Cancer Treatment

Abstract: Background: The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide information on cancer rates and trends in the United States. This year’s report updates statistics on the 15 most common cancers in the fi ve major racial/ethnic populations in the United States for 1992 – 2002 and features populationbased trends in cancer treatment. Methods: The NCI, the CDC, and the NAACCR provided information on cancer cases, and the CDC provided information on cancer deaths. Reported incidence and death rates were age-adjusted to the 2000 U.S. standard population, annual percent change in rates for fi xed intervals was estimated by linear regression, and annual percent change in trends was estimated with joinpoint regression analysis. Population-based treatment data were derived from the Surveillance, Epidemiology, and End Results (SEER) Program registries, SEER-Medicare linked databases, and NCI Patterns of Care/Quality of Care studies. Results: Among men, the incidence rates for all cancer sites combined were stable from 1995 through 2002. Among women, the incidence rates increased by 0.3% annually from 1987 through 2002. Death rates in men and women combined decreased by 1.1% annually from 1993 through 2002 for all cancer sites combined and also for many of the 15 most common cancers. Among women, lung cancer death rates increased from 1995 through 2002, but lung cancer incidence rates stabilized from 1998 through 2002. Although results of cancer treatment studies suggest that much of contemporary cancer treatment for selected cancers is consistent with evidencebased guidelines, they also point to geographic, racial, economic, and age-related disparities in cancer treatment. Conclusions: Cancer death rates for all cancer sites combined and for many common cancers have declined at the same time as the dissemination of guideline-based treatment into the community has increased, although this progress is not shared equally across all racial and ethnic populations. Data from population-based cancer registries, supplemented by linkage with administrative databases, are an important resource for monitoring the quality of cancer treatment. Use of this cancer surveillance system, along with new developments in medical informatics and electronic medical records, may facilitate monitoring of the translation of basic science and clinical advances to cancer prevention, detection, and uniformly high quality of care in all areas and populations of the United States. [J Natl Cancer Inst 2005;97:1407 – 27]

Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor-Positive Breast Cancer: Updated Findings from NCIC CTG MA.17

Abstract: BACKGROUND: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. METHODS: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. RESULTS: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P

Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis

Abstract: Prostate cancers that are progressing on medical and surgical therapies designed to ablate the action of androgens continue to express androgen receptor (AR) and to depend on signaling through the receptor for growth. A more clinically relevant classification of castration-resistant disease focuses on the mechanisms of receptor activation, which include (1) changes in the level of ligand(s) in tumor tissue; (2) increased levels of the protein due to gene amplification or altered mRNA expression; (3) activating mutations in the receptor that affect structure and function; (4) changes in coregulatory molecules including coactivators and corepressors; and (5) factors that lead to activation of the receptor independent of the level of ligand or receptor allowing kinase cross talk. From an AR perspective, the term "hormone refractory" is inappropriate. On the basis of this schema, we discuss strategies that are focused on the AR either directly or indirectly, as single agents or in combination, that are in clinical development.

Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG).

Abstract: Background: As more and more cancers occur in elderly people, oncologists are increasingly confronted with the necessity of integrating geriatric parameters in the treatment of their patients. Methods: The International Society of Geriatric Oncology (SIOG) created a task force to review the evidence on the use of a comprehensive geriatric assessment (CGA) in cancer patients. A systematic review of the evidence was conducted. Results: Several biological and clinical correlates of aging have been identified. Their relative weight and clinical usefulness is still poorly defined. There is strong evidence that a CGA detects many problems missed by a regular assessment in general geriatric and in cancer patients. There is also strong evidence that a CGA improves function and reduces hospitalization in the elderly. There is heterogeneous evidence that it improves survival and that it is cost-effective. There is corroborative evidence from a few studies conducted in cancer patients. Screening tools exist and were successfully used in settings such as the emergency room, but globally were poorly tested. The article contains recommendations for the use of CGA in research and clinical care for older cancer patients. Conclusions: A CGA, with or without screening, and with follow-up, should be used in older cancer patients, in order to detect unaddressed problems, improve their functional status, and possibly their survival. The task force cannot recommend any specific tool or approach above others at this point and general geriatric experience should be used.

Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer.

Abstract: Purpose: Ionizing radiation therapy (RT) is an important component in the management of breast cancer. Although the primary tumor can be successfully treated by surgery and RT, metastatic breast cancer remains a therapeutic challenge. Here we tested the hypothesis that the combination of RT to the primary tumor with CTLA-4 blockade can elicit antitumor immunity inhibiting the metastases. Experimental Design: The poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were injected s.c. with 4T1 cells, and treatment was started 13 days later when the primary tumors measured 5 mm in average diameter. Mice were randomly assigned to four treatment groups receiving: (1) control IgG (IgG), (2) RT + IgG, (3) 9H10 monoclonal antibody against CTLA-4, (4) RT + 9H10. RT was delivered to the primary tumor by one or two fractions of 12 Gy. 9H10 and IgG were given i.p. thrice after RT. Results: Consistent with the fact that 4T1 is poorly immunogenic, 9H10 alone did not have any effect on primary tumor growth or survival. RT was able to delay the growth of the primary irradiated tumor, but in the absence of 9H10 survival was similar to that of control mice. In contrast, mice treated with RT + 9H10 had a statistically significant survival advantage. The increased survival correlated with inhibition of lung metastases formation and required CD8+ but not CD4+ T cells. Conclusions: The combination of local RT with CTLA-4 blockade is a promising new immunotherapeutic strategy against poorly immunogenic metastatic cancers.

Brain metastases: epidemiology and pathophysiology

Abstract: Metastases are the most common tumors of the central nervous system (CNS), but cancer databases are often incomplete leading to underestimation of the incidence of even symptomatic brain metastases. Brain imaging studies are not routinely performed on neurologically asymptomatic cancer patients and autopsy studies are outdated. Furthermore, while incidence rates for cancers are stable and mortality is decreasing due to earlier detection and better therapy, the incidence of brain metastases appears to be increasing. The pathophysiology of brain metastases is a complex multistage process, mediated by molecular mechanisms; from the primary organ, cancer cells must transform, grow and be transported to the CNS where they can lay dormant for various lengths of time before invading and growing further. Understanding the pathophysiology of brain metastases is of great importance, because it may lead to the development of more efficient therapies to combat brain tumor growth or to possibly make the CNS an undesirable environment for tumor progression.

Targeting the Cell Cycle: A New Approach to Cancer Therapy

Abstract: The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. Critical parts of the cell cycle machinery are the cyclin-dependent kinases (CDKs), which, when activated, provide a means for the cell to move from one phase of the cell cycle to the next. The CDKs are regulated positively by cyclins and regulated negatively by naturally occurring CDK inhibitors (CDKIs). Cancer represents a dysregulation of the cell cycle such that cells that overexpress cyclins or do not express the CDKIs continue to undergo unregulated cell growth. The cell cycle also serves to protect the cell from DNA damage. Thus, cell cycle arrest, in fact, represents a survival mechanism that provides the tumor cell the opportunity to repair its own damaged DNA. Thus, abrogation of cell cycle checkpoints, before DNA repair is complete, can activate the apoptotic cascade, leading to cell death. Now in clinical trials are a series of targeted agents that directly inhibit the CDKs, inhibit unrestricted cell growth, and induce growth arrest. Recent attention has also focused on these drugs as inhibitors of transcription. In addition, there are now agents that abrogate the cell cycle checkpoints at critical time points that make the tumor cell susceptible to apoptosis. An understanding of the cell cycle is critical to understanding how best to clinically develop these agents, both as single agents and in combination with chemotherapy.

Differential exoprotease activities confer tumor-specific serum peptidome patterns

Abstract: Recent studies have established distinctive serum polypeptide patterns through mass spectrometry (MS) that reportedly correlate with clinically relevant outcomes. Wider acceptance of these signatures as valid biomarkers for disease may follow sequence characterization of the components and elucidation of the mechanisms by which they are generated. Using a highly optimized peptide extraction and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) MS-based approach, we now show that a limited subset of serum peptides (a signature) provides accurate class discrimination between patients with 3 types of solid tumors and controls without cancer. Targeted sequence identification of 61 signature peptides revealed that they fall into several tight clusters and that most are generated by exopeptidase activities that confer cancer type-specific differences superimposed on the proteolytic events of the ex vivo coagulation and complement degradation pathways. This small but robust set of marker peptides then enabled highly accurate class prediction for an external validation set of prostate cancer samples. In sum, this study provides a direct link between peptide marker profiles of disease and differential protease activity, and the patterns we describe may have clinical utility as surrogate markers for detection and classification of cancer. Our findings also have important implications for future peptide biomarker discovery efforts.

Screening for psychologic distress in ambulatory cancer patients

Abstract: BACKGROUND Based on evidence that psychologic distress often goes unrecognized although it is common among cancer patients, clinical practice guidelines recommend routine screening for distress. For this study, the authors sought to determine whether the single-item Distress Thermometer (DT) compared favorably with longer measures currently used to screen for distress. METHODS Patients (n = 380) who were recruited from 5 sites completed the DT and identified the presence or absence of 34 problems using a standardized list. Participants also completed the 14-item Hospital Anxiety and Depression Scale (HADS) and an 18-item version of the Brief Symptom Inventory (BSI-18), both of which have established cutoff scores for identifying clinically significant distress. RESULTS Receiver operating characteristic (ROC) curve analyses of DT scores yielded area under the curve estimates relative to the HADS cutoff score (0.80) and the BSI-18 cutoff scores (0.78) indicative of good overall accuracy. ROC analyses also showed that a DT cutoff score of 4 had optimal sensitivity and specificity relative to both the HADS and BSI-18 cutoff scores. Additional analyses indicated that, compared with patients who had DT scores < 4, patients who had DT scores ≥ 4 were more likely to be women, have a poorer performance status, and report practical, family, emotional, and physical problems (P ≤ 0.05). CONCLUSIONS Findings confirm that the single-item DT compares favorably with longer measures used to screen for distress. A DT cutoff score of 4 yielded optimal sensitivity and specificity in a general cancer population relative to established cutoff scores on longer measures. The use of this cutoff score identified patients with a range of problems that were likely to reflect psychologic distress. Cancer 2005. © 2005 American Cancer Society.

Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors

Abstract: We used bioluminescence imaging to reveal patterns of metastasis formation by human breast cancer cells in immunodeficient mice. Individual cells from a population established in culture from the pleural effusion of a breast cancer patient showed distinct patterns of organ-specific metastasis. Single-cell progenies derived from this population exhibited markedly different abilities to metastasize to the bone, lung, or adrenal medulla, which suggests that metastases to different organs have different requirements. Transcriptomic profiling revealed that these different single-cell progenies similarly express a previously described “poor-prognosis” gene expression signature. Unsupervised classification using the transcriptomic data set supported the hypothesis that organ-specific metastasis by breast cancer cells is controlled by metastasis-specific genes that are separate from a general poor-prognosis gene expression signature. Furthermore, by using a gene expression signature associated with the ability of these cells to metastasize to bone, we were able to distinguish primary breast carcinomas that preferentially metastasized to bone from those that preferentially metastasized elsewhere. These results suggest that the bone-specific metastatic phenotypes and gene expression signature identified in a mouse model may be clinically relevant.

Merkel Cell Carcinoma: Prognosis and Treatment of Patients From a Single Institution

Abstract: Purpose Merkel cell carcinoma (MCC) is an uncommon cutaneous malignancy. Most reports consist of single-institution experiences of fewer than 30 patients. The natural history of MCC is poorly defined. Patients and Methods A review was performed of Memorial Sloan-Kettering Cancer Center's MCC database, identifying 251 patients who had been treated between 1970 and 2002. Patient, tumor, and treatment-related factors were analyzed for their association with recurrence and survival. Results The average follow-up for all patients was 40 months and 46 months for patients alive at last follow-up. The 5-year disease-specific survival rate was 64%. Disease stage was the only independent predictor of survival (stage I, 81%; stage II, 67%; stage III, 52%; stage IV, 11%; P = .001). Pathologic staging of the draining nodal basin was performed in 71 (40%) of 177 patients who presented with clinically negative nodes, and 16 of these patients (23%) were found to have node-positive disease. Pathologic nodal staging was as...