Herbert Irving Comprehensive Cancer Center

BACKGROUND: Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer. METHODS: We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. RESULTS: Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. CONCLUSIONS: The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

fallen dramatically over the past 70 years Despite its recent decline, gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death worldwide In 2000, about 880 000 people were diagnosed with gastric cancer and approximately 650 000 died of the disease

Cancer cells contain multiple genetic and epigenetic abnormalities. Despite this complexity, their growth and survival can often be impaired by the inactivation of a single oncogene. This phenomenon, called "oncogene addiction," provides a rationale for molecular targeted therapy. The efficacy of this strategy requires novel methods, including integrative genomics and systems biology, to identify the state of oncogene addiction (i.e., the "Achilles heel") in specific cancers. Combination therapy may also be required to prevent the escape of cancers from a given state of oncogene addiction.

Sequencing studies from several model systems have suggested that diverse and abundant small RNAs may be derived from tRNA, but the function of these molecules remains undefined. Here, we demonstrate that one such tRNA-derived fragment, cloned from human mature B cells and designated CU1276, in fact possesses the functional characteristics of a microRNA, including a DICER1-dependent biogenesis, physical association with Argonaute proteins, and the ability to repress mRNA transcripts in a sequence-specific manner. Expression of CU1276 is abundant in normal germinal center B cells but absent in germinal center-derived lymphomas, suggesting a role in the pathogenesis of this disease. Furthermore, CU1276 represses endogenous RPA1, an essential gene involved in many aspects of DNA dynamics, and consequently, expression of this tRNA-derived microRNA in a lymphoma cell line suppresses proliferation and modulates the molecular response to DNA damage. These results establish that functionally active microRNAs can be derived from tRNA, thus defining a class of genetic entities with potentially important biological roles.

The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown. The full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains <20 clonally represented gene alterations/case, including predominantly nonsilent mutations, and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. Although most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%), as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance.

Splenic marginal zone lymphoma (SMZL) is a B cell malignancy of unknown pathogenesis, and thus an orphan of targeted therapies. By integrating whole-exome sequencing and copy-number analysis, we show that the SMZL exome carries at least 30 nonsilent gene alterations. Mutations in NOTCH2, a gene required for marginal-zone (MZ) B cell development, represent the most frequent lesion in SMZL, accounting for ∼20% of cases. All NOTCH2 mutations are predicted to cause impaired degradation of the NOTCH2 protein by eliminating the C-terminal PEST domain, which is required for proteasomal recruitment. Among indolent B cell lymphoproliferative disorders, NOTCH2 mutations are restricted to SMZL, thus representing a potential diagnostic marker for this lymphoma type. In addition to NOTCH2, other modulators or members of the NOTCH pathway are recurrently targeted by genetic lesions in SMZL; these include NOTCH1, SPEN, and DTX1. We also noted mutations in other signaling pathways normally involved in MZ B cell development, suggesting that deregulation of MZ B cell development pathways plays a role in the pathogenesis of ∼60% SMZL. These findings have direct implications for the treatment of SMZL patients, given the availability of drugs that can target NOTCH, NF-κB, and other pathways deregulated in this disease.

OBJECTIVE: To perform a population-based analysis comparing the performance of the 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) staging systems. METHODS: Women with endometrioid adenocarcinoma of the uterus treated between 1988 and 2006 and recorded in the Surveillance, Epidemiology, and End Results database were analyzed. Women were classified based on 1988 and 2009 FIGO staging systems. Major changes in the 2009 system include: 1) classification of patients with stage IA and IB tumors as stage IA; 2) elimination of stage IIA; and 3) stratification of stage IIIC into pelvic nodes only (IIIC1) or paraaortic nodal (IIIC2) involvement. Survival and use of adjuvant therapy were analyzed. RESULTS: A total of 81,902 women were identified. Based on the 1988 staging system, survival for stage IA was 90.7% (95% confidence interval [CI], 90-91%) compared with 88.9% (95% CI 88-89%) for IB tumors. In the 2009 system, survival was 89.6% (95% CI 89-90%) for stage IA and 77.6% (95% CI 76-79%) for stage IB. The survival for FIGO 1988 stage IIA was superior to stage IC, whereas in the 2009 system, survival for stage II was inferior to all stage I patients. The newly defined stage IIIC substages are prognostically different. Survival for stage IIIC1 was 57.0% (95% CI 54-60%) compared with 49.4% (95% CI 46-53%) for stage IIIC2. CONCLUSION: The 2009 FIGO staging system for uterine corpus cancer is highly prognostic. The reduction in stage I substages and the separation of stage III will further clarify important prognostic features. LEVEL OF EVIDENCE: III.

Alterations in DNA methylation patterns, both at specific loci and overall in the genome, have been associated with many different health outcomes. In cancer and other diseases, most of these changes have been observed at the tissue level. Data on whether DNA methylation changes in white blood cells (WBC) can serve as a useful biomarker for different health outcomes are much more limited, but rapidly emerging. Epidemiologic studies have reported associations between global WBC methylation and several different cancers including cancers of the colon, bladder, stomach, breast and head and neck, as well as schizophrenia and myelodysplastic syndrome. Evidence for WBC methylation at specific loci and disease risk is more limited, but increasing. Differences in WBC DNA methylation by selected risk factors including demographic (age, gender, race), environmental exposures (benzene, persistent organic pollutants, lead, arsenic, and air pollution), and other risk factors (cigarette smoke, alcohol drinking, body size, physical activity and diet) have been observed in epidemiologic studies though the patterns are far from consistent. Challenges in inferences from the existing data are primarily due to the cross-sectional and small size of most studies to date as well as the differences in results across assay type and source of DNA. Large, prospective studies will be needed to understand whether changes in risk factors are associated with changes in DNA methylation patterns, and if changes in DNA methylation patterns are associated with changes in disease endpoints.

Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ∼20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator is associated with ∼30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.

This Viewpoint proposes a framework for modifying cancer care in the midst of the COVID-19 pandemic that balances considerations about the time-sensitivity of patient need for visits and treatment, risk of infectious exposure, and hospital and staff capacity and stress.

The paradigm for the response to hypoxia is erythropoietin gene expression; activation of hypoxia-inducible factor-1 (HIF-1) results in erythropoietin production. Previously, we found that oxygen deprivation induced tissue factor, especially in mononuclear phagocytes, by an early growth response (Egr-1)-dependent pathway without involvement of HIF-1 (Yan, S.-F., Zou, Y.-S., Gao, Y., Zhai, C., Mackman, N., Lee, S., Milbrandt, J., Pinsky, D., Kisiel, W., and Stern, D. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 8298-8303). Now, we show that cultured monocytes subjected to hypoxia (pO2 approximately 12 torr) displayed increased Egr-1 expression because of de novo biosynthesis, with a approximately 10-fold increased rate of transcription. Transfection of monocytes with Egr-1 promoter-luciferase constructs localized elements responsible for hypoxia-enhanced expression to -424/-65, a region including EBS (ets binding site)-SRE (serum response element)-EBS and SRE-EBS-SRE sites. Further studies with each of these regions ligated to the basal thymidine kinase promoter and luciferase demonstrated that EBS sites in the element spanning -424/-375 were critical for hypoxia-enhanceable gene expression. These data suggested that an activated ets factor, such as Elk-1, in complex with serum response factor, was the likely proximal trigger of Egr-1 transcription. Indeed, hypoxia induced activation of Elk-1, and suppression of Elk-1 blocked up-regulation of Egr-1 transcription. The signaling cascade preceding Elk-1 activation in response to oxygen deprivation was traced to activation of protein kinase C-betaII, Raf, mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase and mitogen-activated protein kinases. Comparable hypoxia-mediated Egr-1 induction and activation were observed in cultured hepatoma-derived cells deficient in HIF-1beta and wild-type hepatoma cells, indicating that the HIF-1 and Egr-1 pathways are initiated independently in response to oxygen deprivation. We propose that activation of Egr-1 in response to hypoxia induces a different facet of the adaptive response than HIF-1, one component of which causes expression of tissue factor, resulting in fibrin deposition.

CONTEXT: Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes. OBJECTIVES: To determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses. MAIN OUTCOME MEASURE: Prevalence of pathogenic mutations in APC and MUTYH genes. RESULTS: Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%-87%]) and 2 of 119 (2% [95% CI, 0.2%-6%]), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% [95% CI, 54%-59%]) and 94 of 1338 (7% [95% CI, 6%-8%]) among those with 100 to 999 adenomas, 326 of 3253 (10% [95% CI, 9%-11%]) and 233 of 3253 (7% [95% CI, 6%-8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%-7%]) and 37 of 970 (4% [95% CI, 3%-5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses. CONCLUSIONS: Among patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation.

In 1982 we proposed the concept and a framework for implementing molecular cancer epidemiology. Here, we review progress during the past 17 years in validating and applying this approach to cancer prevention. There have been major advances, notably in the understanding of environment-susceptibility interactions in human cancer. However, a review of major findings to date reveals several urgent research needs to keep pace with the rapid evolution in knowledge of mechanisms in carcinogenesis. Although much valuable progress continues to be made in the study of carcinogens that cause direct DNA damage and are mutagenic, exogenous and endogenous carcinogens can also act by altering gene expression, cell proliferation and differentiation. The mechanisms include aberrant DNA methylation, oxidative damage, effects on metabolism of nitrogen oxide and nitrites, activation of receptors and transcription factors, cyclins and other cell cycle proteins. Sensitive, validated biomarkers are needed to detect these mechanisms in small numbers of cells, tissues or fluids. There is also increasing recognition that individual risk from carcinogen exposure varies as a function of both inherited and acquired factors. Recent advances in genomics, microassay technologies and informatics hold promise for rapid identification of polymorphic variants or changes in expression of genes influencing both response and susceptibility to carcinogens. Another emerging area of molecular epidemiology concerns the role of nutrition and specific dietary factors (including studies on antioxidants, energy metabolism, insulin and various growth factors) and the modulating effect of genetic polymorphisms. Finally, molecular epidemiology has enormous potential in cancer prevention through the early identification of 'at risk' populations and the rapid assessment of intervention efficacy. Its success in fully reaching this potential will depend on the application of validated biomarkers, with adherence to sound epidemiologic and ethical principles.

Autophagy is activated in response to a variety of cellular stresses including metabolic stress. While elegant genetic studies in yeast have identified the core autophagy machinery, the signaling pathways that regulate this process are less understood. AMPK is an energy sensing kinase and several studies have suggested that AMPK is required for autophagy. The biochemical connections between AMPK and autophagy, however, have not been elucidated. In this report, we identify a biochemical connection between a critical regulator of autophagy, ULK1, and the energy sensing kinase, AMPK. ULK1 forms a complex with AMPK, and AMPK activation results in ULK1 phosphorylation. Moreover, we demonstrate that the immediate effect of AMPK-dependent phosphorylation of ULK1 results in enhanced binding of the adaptor protein YWHAZ/14-3-3ζ; and this binding alters ULK1 phosphorylation in vitro. Finally, we provide evidence that both AMPK and ULK1 regulate localization of a critical component of the phagophore, ATG9, and that some of the AMPK phosphorylation sites on ULK1 are important for regulating ATG9 localization. Taken together these data identify an ULK1-AMPK signaling cassette involved in regulation of the autophagy machinery.

Germinal centers (GCs) are the sites where memory B cells and plasma cells producing high-affinity antibodies are generated during T cell-dependent immune responses. The molecular control of GC B cell maintenance and differentiation remains incompletely understood. Activation of the NF-κB signaling pathway has been implicated; however, the distinct roles of the individual NF-κB transcription factor subunits are unknown. We report that GC B cell-specific deletion of the NF-κB subunits c-REL or RELA, which are both activated by the canonical NF-κB pathway, abolished the generation of high-affinity B cells via different mechanisms acting at distinct stages during the GC reaction. c-REL deficiency led to the collapse of established GCs immediately after the formation of dark and light zones at day 7 of the GC reaction and was associated with the failure to activate a metabolic program that promotes cell growth. Conversely, RELA was dispensable for GC maintenance but essential for the development of GC-derived plasma cells due to impaired up-regulation of BLIMP1. These results indicate that activation of the canonical NF-κB pathway in GC B cells controls GC maintenance and differentiation through distinct transcription factor subunits. Our findings have implications for the role of NF-κB in GC lymphomagenesis.

BACKGROUND: Recently, many cancer patients have been using the Internet for information with which to make informed choices. We are not aware of any studies that investigate this Internet use among breast cancer patients or women. OBJECTIVE: We investigate the prevalence and predictors of Internet use for medical information among women with breast cancer. METHODS: We used a cross-sectional design and approached 251 women with breast cancer being treated at a university-based hospital. We successfully interviewed 188 (74.9%), through mailed self-report questionnaires. Medical information was obtained from the hospital tumor registry. We used t tests and chi-square tests to assess differences in Internet use for breast health issues and binary logistic regression to estimate the odds ratio (OR) for predictors of Internet use for breast health issues. RESULTS: In our sample, 41.5% of patients used the Internet for medical information. Internet users differed from nonusers on income level, educational level, and by race/ethnicity. After controlling for the other predictors, Internet users had a higher income (OR = 3.10; 95% CI = 1.09-8.85) and tended to be more educated (OR = 2.59; 95% CI = 0.87-7.74) than nonusers. There was also a suggestion that those of nonwhite ethnicity were less likely to use the Internet (OR = 0.39; 95% CI = 0.14-1.11). Increasing age, length of time since diagnosis, and breast cancer stage had no effect. CONCLUSIONS: A substantial proportion of breast cancer patients used the Internet as a source of information. Patients with higher income or education, and patients of white race/ethnicity are more likely to use the Internet for breast health issues.

The BCL6 proto-oncogene encodes a transcriptional repressor that is required for germinal center (GC) formation and whose deregulation by genomic lesions is implicated in the pathogenesis of GC-derived diffuse large B cell lymphoma (DLBCL) and, less frequently, follicular lymphoma (FL). The biological function of BCL6 is only partially understood because no more than a few genes have been functionally characterized as direct targets of BCL6 transrepression activity. Here we report that the anti-apoptotic proto-oncogene BCL2 is a direct target of BCL6 in GC B cells. BCL6 binds to the BCL2 promoter region by interacting with the transcriptional activator Miz1 and suppresses Miz1-induced activation of BCL2 expression. BCL6-mediated suppression of BCL2 is lost in FL and DLBCL, where the 2 proteins are pathologically coexpressed, because of BCL2 chromosomal translocations and other mechanisms, including Miz1 deregulation and somatic mutations in the BCL2 promoter region. These results identify an important function for BCL6 in facilitating apoptosis of GC B cells via suppression of BCL2, and suggest that blocking this pathway is critical for lymphomagenesis.

Given the proportion of American adults who smoke, even if health professionals only have a small effect on quit rates, the public health impact of this change could potentially be enormous. Yet, health care providers may differ in their cessation efficacy. The purpose of this study was to evaluate recent rigorous trials of smoking cessation counseling among physicians, nurses, dentists, and teams of providers: (1) to compare providers on the efficacy of cessation and (2)to determine which intervention and study characteristics explain variations in intervention effects. Thirty-seven randomized clinical trials or quasi-experiments (with control groups) of health care provider-delivered smoking cessation interventions, out of over 200 articles that were published between 1990 and 2004 were collected through searches of Medline, CINAHL, PSYCINFO, and dissertation abstracts, as well as hand searches. The outcome modeled was the mean difference between intervention and control groups in the cessation rates using Hedges g. The univariate results revealed that receiving advice from any health care professional produced increases in quit rates. Multivariate analyses of intervention effects on cessation revealed that physicians were most effective, followed by multiprovider teams, dentists, and nurses. The findings suggest that contact with a health care professional will increase cessation; however, additional training in tobacco control for nurses is warranted. Longer-term studies of smoking cessation, particularly among dentists, are necessary.

Studies on genetic-epigenetic interactions, including the mapping of methylation quantitative trait loci (mQTLs) and haplotype-dependent allele-specific DNA methylation (hap-ASM), have become a major focus in the post-genome-wide-association-study (GWAS) era. Such maps can nominate regulatory sequence variants that underlie GWAS signals for common diseases, ranging from neuropsychiatric disorders to cancers. Conversely, mQTLs need to be filtered out when searching for non-genetic effects in epigenome-wide association studies (EWAS). Sequence variants in CCCTC-binding factor (CTCF) and transcription factor binding sites have been mechanistically linked to mQTLs and hap-ASM. Identifying these sites can point to disease-associated transcriptional pathways, with implications for targeted treatment and prevention.

BACKGROUND: Surgical management of ovarian cancer consists of hysterectomy with bilateral oophorectomy. In young women, this results in the loss of reproductive function and estrogen deprivation. In the current study, the authors examined the safety of fertility-conserving surgery in premenopausal women with epithelial ovarian cancers. METHODS: Women aged<or=50 years with stage IA or IC epithelial ovarian cancer who were registered in the Surveillance, Epidemiology, and End Results database were examined. Patients who underwent bilateral oophorectomy were compared with those who underwent ovarian conservation. A second analysis examined uterine conservation versus hysterectomy. Multivariate Poisson regression models were developed to describe predictors of fertility preservation. Survival was examined using Cox proportional hazards models and the Kaplan-Meier method. RESULTS: In total, 1186 women, including 754 women (64%) who underwent bilateral oophorectomy and 432 women (36%) who underwent ovarian preservation, were identified. Younger age, later year of diagnosis, and residence in the eastern or western United States were associated with ovarian preservation (P<.05 for all). Women with endometrioid and clear cell histologies and stage IC disease were less likely to have ovarian conservation (P<.05). In a Cox model, ovarian preservation had no effect on survival (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.39-1.20). Young age, later year of diagnosis, residence in the eastern or western United States, single women, mucinous tumors, and patients with stage IA disease were more likely to have uterine preservation (P<.05 for all). In a multivariate model, uterine preservation had no effect on survival (HR, 0.87; 95% CI, 0.62-1.22). CONCLUSIONS: Ovarian and uterine-conserving surgery were safe in young women who had stage IA and IC epithelial ovarian cancer.