Racial disparities in non-recommendation of adjuvant chemotherapy in stage II-III ovarian cancer.

OBJECTIVES: To identify patient factors associated with not receiving a recommendation for adjuvant chemotherapy after primary surgery for ovarian cancer. METHODS: This retrospective cohort study used the National Cancer Database (NCDB) data from 2004 to 2015 to identify patients with stage II-III ovarian cancer who underwent primary surgery. Multivariate logistic regression analyses evaluated factors associated with notation in the NCDB that "chemotherapy was not recommended/administered because it was contraindicated due to patient risk factors (i.e., comorbid conditions, advanced age)." Survival data were assessed via Kaplan-Meier analyses. RESULTS: Of the 48,245 patients who met the inclusion criteria, 522 (1.08%) did not receive adjuvant chemotherapy because it was determined to be contraindicated. In multivariate analyses, independent predictors for not receiving a recommendation for adjuvant chemotherapy were age ≥ 70 years old (adjusted odds ratio, aOR = 2.43, p < 0.0001), non-zero Charlson-Deyo comorbidity scores (score 1, aOR = 1.41, p = 0.002; score ≥ 2, aOR = 2.57, p < 0.0001), and Black race (aOR = 2.12, p < 0.0001). For Black patients, recommendation against adjuvant chemotherapy occurred at a younger median age (64.5 years vs. 72 years) and was associated with lower 5-year survival (25.9% vs. 40.3%, p < 0.0001). CONCLUSIONS: Patients with ovarian cancer who underwent surgery but did not receive chemotherapy "because it was contraindicated due to patient risk factors" were older and had higher comorbidity scores. Even after controlling for these differences, Black patients were disproportionately not recommended for chemotherapy, which was associated with worse survival. Determining eligibility for adjuvant chemotherapy requires an individualized approach, and the possible influence of racial bias on risk estimation should be further investigated.

Pediatric solid tumor genomics and developmental pliancy.

Pediatric solid tumors are remarkably diverse in their cellular origins, developmental timing and clinical features. Over the last 5 years, there have been significant advances in our understanding of the genetic lesions that contribute to the initiation and progression of pediatric solid tumors. To date, over 1000 pediatric solid tumors have been analyzed by Next-Generation Sequencing. These genomic data provide the foundation to launch new research efforts to address one of the fundamental questions in cancer biology-why are some cells more susceptible to malignant transformation by particular genetic lesions at discrete developmental stages than others? Because of their developmental, molecular, cellular and genetic diversity, pediatric solid tumors provide an ideal platform to begin to answer this question. In this review, we highlight the diversity of pediatric solid tumors and provide a new framework for studying the cellular and developmental origins of pediatric cancer. We also introduce a new unifying concept called cellular pliancy as a possible explanation for susceptibility to cancer and the developmental origins of pediatric solid tumors.

Monoallelic but not biallelic loss of Dicer1 promotes tumorigenesis in vivo.

Human tumors are characterized by widespread reduction in microRNA (miRNA) expression, although it is unclear how such changes come about and whether they have an etiological role in the disease. Importantly, miRNA knockdown has been shown to enhance the tumorigenic potential of human lung adenocarcinoma cells. A defect in miRNA processing is one possible mechanism for global downregulation. To explore this possibility in more detail in vivo, we have manipulated Dicer1 gene dosage in a mouse model of retinoblastoma. We show that although monoallelic loss of Dicer1 does not affect normal retinal development, it dramatically accelerates tumor formation on a retinoblastoma-sensitized background. Importantly, these tumors retain one wild-type Dicer1 allele and exhibit only a partial decrease in miRNA processing. Accordingly, in silico analysis of human cancer genome data reveals frequent hemizygous, but not homozygous, deletions of DICER1. Strikingly, complete loss of Dicer1 function in mice did not accelerate retinoblastoma formation. miRNA profiling of these tumors identified members of the let-7 and miR-34 families as candidate tumor suppressors in retinoblastoma. We conclude that Dicer1 functions as a haploinsufficient tumor suppressor. This finding has implications for cancer etiology and cancer therapy.

Mouse models of childhood cancer of the nervous system.

Targeted cancer treatments rely on understanding signalling cascades, genetic changes, and compensatory programmes activated during tumorigenesis. Increasingly, pathologists are required to interpret molecular profiles of tumour specimens to target new treatments. This is challenging because cancer is a heterogeneous disease-tumours change over time in individual patients and genetic lesions leading from preneoplasia to malignancy can differ substantially between patients. For childhood tumours of the nervous system, the challenge is even greater, because tumours arise from progenitor cells in a developmental context different from that of the adult, and the cells of origin, neural progenitor cells, show considerable temporal and spatial heterogeneity during development. Thus, the underlying mechanisms regulating normal development of the nervous system also need to be understood. Many important advances have come from model mouse genetic systems. This review will describe several mouse models of childhood tumours of the nervous system, emphasising how understanding the normal developmental processes, combined with mouse models of cancer and the molecular pathology of the human diseases, can provide the information needed to treat cancer more effectively.

p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations.

In the developing vertebrate retina, progenitor cell proliferation must be precisely regulated to ensure appropriate formation of the mature tissue. Cyclin kinase inhibitors have been implicated as important regulators of proliferation during development by blocking the activity of cyclin-cyclin-dependent kinase complexes. We have found that the p27(Kip1) cyclin kinase inhibitor regulates progenitor cell proliferation throughout retinal histogenesis. p27(Kip1) is upregulated during the late G(2)/early G(1) phase of the cell cycle in retinal progenitor cells, where it interacts with the major retinal D-type cyclin-cyclin D1. Mice deficient for p27(Kip1) exhibited an increase in the proportion of mitotic cells throughout development as well as extensive apoptosis, particularly during the later stages of retinal histogenesis. Retroviral-mediated overexpression of p27(Kip1) in mitotic retinal progenitor cells led to premature cell cycle exit yet had no dramatic effects on Müller glial or bipolar cell fate specification as seen with the Xenopus cyclin kinase inhibitor, p27(Xic1). Consistent with the overexpression of p27(Kip1), mice lacking one or both alleles of p27(Kip1) maintained the same relative ratios of each major retinal cell type as their wild-type littermates. During the embryonic stages of development, when both p27(Kip1) and p57(Kip2) are expressed in retinal progenitor cells, they were found in distinct populations, demonstrating directly that different retinal progenitor cells are heterogeneous with respect to their expression of cell cycle regulators.

Regulating proliferation during retinal development.

Recent studies have shown that components of the cell-cycle machinery can have diverse and unexpected roles in the retina. Cyclin-kinase inhibitors, for example, have been implicated as regulators of cell-fate decisions during histogenesis and reactive gliosis in the adult tissue after injury. Also, various mechanisms have been identified that can compensate for extra rounds of cell division when the normal timing of the cell-cycle exit is perturbed. Surprisingly, distinct components of the cell-cycle machinery seem to be used during different stages of development, and different organisms might rely on distinct pathways. Such detailed studies on the regulation of proliferation in complex multicellular tissues during development have not only advanced our knowledge of the ways in which proliferation is controlled, but might also help us to understand the degenerative disorders that are associated with gliosis and some types of tumorigenesis.

Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo.

During gastrulation in the mouse, mesoderm is induced and patterned by secreted signaling molecules, giving rise first to primitive erythroblasts and vascular endothelial cells. We have demonstrated previously that development of these lineages requires a signal(s) secreted from the adjacent primitive endoderm. We now show that Indian hedgehog (Ihh) is a primitive endoderm-secreted signal that alone is sufficient to induce formation of hematopoietic and endothelial cells. Strikingly, as seen with primitive endoderm, Ihh can respecify prospective neural ectoderm (anterior epiblast) along hematopoietic and endothelial (posterior) lineages. Downstream targets of the hedgehog signaling pathway (the genes encoding patched, smoothened and Gli1) are upregulated in anterior epiblasts cultured in the presence of Ihh protein, as is Bmp4, which may mediate the effects of Ihh. Blocking Ihh function in primitive endoderm inhibits activation of hematopoiesis and vasculogenesis in the adjacent epiblast, suggesting that Ihh is an endogenous signal that plays a key role in the development of the earliest hemato-vascular system. To our knowledge, these are the earliest functions for a hedgehog protein in post-implantation development in the mouse embryo.

The p57Kip2 cyclin kinase inhibitor is expressed by a restricted set of amacrine cells in the rodent retina.

Amacrine cells in the vertebrate retina can be grouped according to morphology into distinct types, which are organized into characteristic mosaics. Each type is believed to perform a unique role in visual signal processing. Neurotransmitters and calcium binding proteins have served as important markers for amacrine cell populations, yet many types remain to be characterized at the molecular level. We have found that a cyclin kinase inhibitor, p57Kip2, is expressed in a restricted group of amacrine cells in the inner nuclear layer (INL) and ganglion cell layer (GCL) of the rodent retina. Whole-mount antibody staining revealed that the p57Kip2 amacrine cells are evenly distributed across the retina with a density of 1654 +/- 63 cells/mm(2) in the INL and 994 +/- 26 cells/mm(2) in the GCL. These amacrine cells accumulate the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) but do not accumulate high levels of glycine. In addition, p57Kip2 immunoreactivity does not colocalize with any of the previously identified amacrine cell markers including calbindin, calretinin, parvalbumin, choline acetyltransferase, and tyrosine hydroxylase. To determine whether the p57Kip2 population of amacrine cells is organized into a regular or a random mosaic, nearest neighbor analysis was performed for both the INL and GCL populations. Results from this analysis demonstrated that the p57Kip2-immunoreactive amacrine cells are randomly organized and therefore they are likely to constitute two or more distinct populations. This new molecular marker will serve as a useful tool for future studies on the development and function of amacrine cells in the vertebrate retina.

Control of Müller glial cell proliferation and activation following retinal injury.

Müller glial cells are the major support cell for neurons in the vertebrate retina. Following neuronal damage, Müller cells undergo reactive gliosis, which is characterized by proliferation and changes in gene expression. We have found that downregulation of the tumor supressor protein p27Kip1 and re-entry into the cell cycle occurs within the first 24 hours after retinal injury. Shortly thereafter, Müller glial cells upregulate genes typical of gliosis and then downregulate cyclin D3, in concert with an exit from mitosis. Mice lacking p27Kip1 showed a constitutive form of reactive gliosis, which leads to retinal dysplasia and vascular abnormalities reminiscent of diabetic retinopathy. We conclude that p27Kip1 regulates Müller glial cell proliferation during reactive gliosis.

p57(Kip2) regulates progenitor cell proliferation and amacrine interneuron development in the mouse retina.

A precise balance between proliferation and differentiation must be maintained during retinal development to obtain the correct proportion of each of the seven cell types found in the adult tissue. Cyclin kinase inhibitors can regulate cell cycle exit coincident with induction of differentiation programs during development. We have found that the p57(Kip2) cyclin kinase inhibitor is upregulated during G(1)/G(0) in a subset of retinal progenitor cells exiting the cell cycle between embryonic day 14.5 and 16.5 of mouse development. Retroviral mediated overexpression of p57(Kip2) in embryonic retinal progenitor cells led to premature cell cycle exit. Retinae from mice lacking p57(Kip2) exhibited inappropriate S-phase entry and apoptotic nuclei were found in the region where p57(Kip2) is normally expressed. Apoptosis precisely compensated for the inappropriate proliferation in the p57(Kip2)-deficient retinae to preserve the correct proportion of the major retinal cell types. Postnatally, p57(Kip2) was found to be expressed in a novel subpopulation of amacrine interneurons. At this stage, p57(Kip2 )did not regulate proliferation. However, perhaps reflecting its role during this late stage of development, animals lacking p57(Kip2) showed an alteration in amacrine subpopulations. p57(Kip2) is the first gene to be implicated as a regulator of amacrine subtype/subpopulation development. Consequently, we propose that p57(Kip2) has two roles during retinal development, acting first as a cyclin kinase inhibitor in mitotic progenitor cells, and then playing a distinct role in neuronal differentiation.

The HMG domain protein SSRP1/PREIIBF is involved in activation of the human embryonic beta-like globin gene.

The human embryonic beta-like globin (epsilon-globin) gene is expressed in primitive erythroid cells of the yolk sac during the first few weeks of development. We have previously shown that developmental stage-specific expression of the epsilon-globin gene is mediated by multiple positive and negative regulatory elements upstream of the start of transcription. Of particular interest is one positive regulatory element, PRE II, that works together with other elements (PRE I and PRE V) to confer developmental stage- and/or tissue-specific expression on a minimal promoter. An approximately 85- to 90-kDa PRE II binding factor (PREIIBF) was identified in the nuclei of erythroid cells and shown to bind specifically to a novel 19-bp region within PRE II; binding of this protein to PRE II resulted in bending of the target DNA and was required for promoter activation. In this report, we present the cDNA expression cloning of PREIIBF. The cDNA encodes a previously identified member of the HMG domain family of DNA binding proteins termed SSRP1. By a number of biochemical and immunological criteria, recombinant SSRP1 appears to be identical to the PREII binding factor from erythroid nuclei. A hallmark of HMG domain proteins is their ability to bend their target DNAs; therefore, as we speculated previously, DNA bending by SSRP1/PREIIBF may contribute to the mechanism by which PRE II synergizes with other regulatory elements located upstream and downstream. In contrast with reports from other investigators, we demonstrate that SSRP1 binds DNA with clear sequence specificity. Moreover, we show that SSRP1/PREIIBF lacks a classical activation domain but that binding by this protein to PRE II is required for activation of a minimal promoter in stable erythroid cell lines. These studies provide the first evidence that SSRP1 plays a role in transcriptional regulation. SSRP1/PREIIBF may serve an architectural function by helping to coordinate the assembly of a multiprotein complex required for stage-specific regulation of the human epsilon-globin gene.

Nurses' job satisfaction, absenteeism, and turnover after implementing a special care unit practice model.

The purpose of the study was to compare job satisfaction, absenteeism, and turnover between nurses working in a nurse-managed special care unit (SCU) and those working in traditional intensive care units (ICU). A case management practice model with a shared governance management model and minimal technology was implemented in the SCU while contrasting features of a primary nursing practice model with a bureaucratic management model and high technology already in place in the traditional ICU. Individual nurses' perceptions of and their preferences for the SCU practice model also were examined related to job satisfaction. Using analysis of covariance, greater satisfaction with a lower absenteeism rate was found in nurses working in the SCU. Nurses' perceptions and preferences for the SCU practice model were closely related to their job satisfaction and growth satisfaction. The findings suggest that individual perception and preference should be taken into account before implementing autonomy, authority, and responsibility at the organizational level to lead to the desired nurse outcomes in a given working environment.

Outcomes of long-term ventilator patients: a descriptive study.

BACKGROUND: Long-term ICU patients who require prolonged mechanical ventilation are a growing segment of the in-hospital population. Despite recognition that this population is costly to care for no systematic research has been done on the characteristics, outcomes, and disposition of these patients after they leave the hospital. OBJECTIVE: To describe clinical and sociodemographic characteristics and outcomes of ICU patients who require long-term (5 days or more) mechanical ventilation while in the hospital. METHODS: A prospective, longitudinal descriptive design was used to study 57 ICU patients who required 5 days or more of continuous mechanical ventilation while in the hospital. Clinical and sociodemographic data were collected at the time of enrollment. Patients were followed up for up to 6 months after discharge from the hospital to ascertain disposition and morality. RESULTS: On average, patients had a hospital stay of almost 6 weeks and required mechanical ventilation for approximately 4 weeks; 43.9% of the patients died in the hospital. None of the patients discharged from the hospital were able to return home initially without assistance. By 6 months after discharge, more than 50% of the original sample and died, 9% resided in an institution, and 33% were living at home. CONCLUSIONS: A large percentage of ICU patients who require 5 days or more of mechanical ventilation die in the hospital, and many of those who live spend considerable time in an extended-care facility before they are discharged to their homes. These likely outcomes of patients who require long-term ventilation should be discussed with patients and their families to assist them in making informed decisions.

Procedures used in withdrawal of mechanical ventilation.

OBJECTIVE: The purpose of this study was to describe ways in which withdrawal of mechanical ventilation is carried out in one institution, patient responses to the various methods of withdrawal, and nurses' perceptions of the methods and morality of ventilator withdrawal. METHOD: A retrospective descriptive study was used with a convenience sample of adult patients who underwent terminal weaning at University Hospitals of Cleveland. Demographic and clinical data, and descriptions of the exact method of ventilator withdrawal were collected from the medical records of these patients. The nurse caring for the patient was interviewed about his or her perceptions, within 7 days of the withdrawal. RESULTS: Data were obtained on 42 subjects. There were no differences in mental status, ventilatory status, age, or duration of survival between the patients who had support removed gradually and those from whom it was abruptly removed. Morphine was administered to 88% of the sample during withdrawal. Survival duration was unrelated to morphine dosage, but did correlate with ventilatory status at the time of withdrawal. Every nurse interviewed reported that he or she believed the act of withdrawal for that patient was morally correct, although only 85% were completely comfortable with carrying out the procedure. CONCLUSIONS: These results provide a foundation for preliminary recommendations about the most humane form of ventilator withdrawal and the appropriate use of narcotics and sedatives during withdrawal.

Do-not-resuscitate practices in the chronically critically ill.

OBJECTIVES: To determine the frequency of do-not-resuscitate (DNR) orders in the chronically critically ill; to identify the differences in clinical and demographic characteristics of chronically critically ill patients who have DNR orders and those who do not; to identify the differences in the cost of care between patients with and without DNR orders; and to identify the differences in DNR practices between an experimental special care unit and the traditional intensive care unit (ICU). DESIGN: Randomized, prospective design with a block randomization scheme. SUBJECTS: Two hundred twenty patients who met the following eligibility criteria for enrollment in a parent study of the special care unit: an ICU stay of at least 5 days, an absence of pulmonary artery monitoring, an absence of frequent titration of intravenous vasopressors, an Acute Physiology and Chronic Health Evaluation II score of less than 18, and a Therapeutic Intervention Scoring System score of less than 39. SETTING: A large, urban academic medical center. MEASURES: Clinical and demographic variables describing the study populations, mental status, and timing of DNR orders, mortality rates, and cost of hospitalization. RESULTS: There was no difference in the frequency of DNR orders between the special care unit versus the intensive care unit--although patients in the special care unit had a longer interval between hospital admission and initiation of the DNR order. DNR patients differed from non-DNR in that they were older, less likely to be married, and had a higher Acute Physiology and Chronic Health Evaluation II score on admission to the study. The mortality rate in the DNR group was 71% versus 6% in the non-DNR group. There was no difference in total costs. DNR patients were also more likely to have an impaired mental status on admission, and more likely to have deterioration in mental status by the time of discharge than the non-DNR patients.

Survival experience of chronically critically ill patients.

Intensive care unit (ICU) patients were randomly assigned to either a traditional ICU or a special care unit (SCU) for chronically critically ill patients. The SCU used a low-technology, family-oriented environment, nursing case management, no physician house staff, and a shared governance model. In comparison, the ICU used high technology, limited family visiting, primary care nursing, and a bureaucratic management model. The survival experience of chronically critically ill patients in the two environments during hospitalization, as well as after hospital discharge, was examined. Using survival analytic techniques, the 1-year cumulative mortality for all patients in the study was found to be 59.9%. Risk of death was significantly lower after discharge than during hospitalization. Similar mortality experiences were found for SCU and ICU patients. Thus, the high-technology ICU environment did not produce better outcomes than the SCU environment.

A DNA-bending protein interacts with an essential upstream regulatory element of the human embryonic beta-like globin gene.

The mammalian beta-like globin gene family has served as an important model system for analysis of tissue- and developmental state-specific gene regulation. Although the activities of a number of regulatory proteins have been implicated in the erythroid cell-specific transcription of globin genes, the mechanisms that restrict their expression to discrete stages of development are less well understood. We have previously identified a novel regulatory element (PRE II) upstream from the human embryonic beta-like globin gene (epsilon) that synergizes with other sequences to confer tissue- and stage-specific expression on a minimal epsilon-globin gene promoter in cultured embryonic erythroid cells. Binding of an erythroid nuclear protein (PRE II-binding factor [PRE-IIBF]) to the PRE II control element is required for promoter activation. Here we report on some of the biochemical properties of PREIIBF, including the characterization of its specificity and affinity for DNA. The embryonic and adult forms of PREIIBF recognize their cognate sequences with identical specificities, supporting our earlier conclusion that they are very similar proteins. PREIIBF binds DNA as a single polypeptide with an Mr of approximately 80,000 to 85,000 and introduces a bend into the target DNA molecule. These results suggest a mechanism by which PREIIBF may contribute to the regulation of the embryonic beta-like globin gene within the context of a complex locus.

Patient outcomes for the chronically critically ill: special care unit versus intensive care unit.

The purpose of this study was to compare the effects of a low-technology environment of care and a nurse case management case delivery system (special care unit, SCU) with the traditional high-technology environment (ICU) and primary nursing care delivery system on the patient outcomes of length of stay, mortality, readmission, complications, satisfaction, and cost. A sample of 220 chronically critically ill patients were randomly assigned to either the SCU (n = 145) or the ICU (n = 75). Few significant differences were found between the two groups in length of stay, mortality, or complications. However, the findings showed significant cost savings in the SCU group in the charges accrued during the study period and in the charges and costs to produce a survivor. The average total cost of delivering care was $5,000 less per patient in the SCU than in the traditional ICU. In addition, the cost to produce a survivor was $19,000 less in the SCU. Results from this 4-year clinical trial demonstrate that nurse case managers in a SCU setting can produce patient outcomes equal to or better than those in the traditional ICU care environment for long-term critically ill patients.

The cost-effectiveness of a special care unit to care for the chronically critically ill.

To assess the relative value of healthcare programs, technologic innovations, and clinical decisions, policymakers are searching for ways to evaluate cost-effectiveness. What constitutes cost-effectiveness and how should it be measured? The authors discuss ways in which the cost-effectiveness of clinical programs can be measured and describes various methods of assessing both costs and effectiveness. Comparison of the cost-effectiveness of a nurse managed special care unit with that of traditional intensive care units illustrates some of these methods.

A novel developmental regulatory motif required for stage-specific activation of the epsilon-globin gene and nuclear factor binding in embryonic erythroid cells.

Members of the human beta-globin gene family are expressed at discrete stages of development and therefore provide an important model system for examining mechanisms of temporal gene regulation. We have previously shown that expression of the embryonic beta-like globin gene (epsilon) is mediated by a complex array of positive and negative upstream control elements. Correct developmental stage- and tissue-specific gene expression is conferred by synergistic interactions between a positive regulatory element (termed epsilon-PRE II) which is active only in embryonic erythroid cells and at least two other regulatory domains upstream of the epsilon-globin gene promoter. A nuclear factor highly enriched in cultured embryonic erythroid cells and in mouse embryonic yolk sac binds to a novel, evolutionarily conserved sequence within epsilon-PRE II. We show here that binding of this factor to the conserved element within epsilon-PRE II is critical for transcriptional activity. Point mutations that interfere with protein binding to epsilon-PRE II abolish transcriptional activation of the constitutive epsilon-globin promoter. Adult erythroid nuclei (from cultured cells or adult mouse liver) also contain a factor that binds to this region, but the complex formed migrates more rapidly during nondenaturing electrophoresis, suggesting either that distinct proteins bind to epsilon-PRE II or that a single protein is differentially modified in these cells in a way that modulates its activity. Several lines of evidence suggest that the binding factors in embryonic and adult erythroid cells are distinguished by posttranscriptional differences.