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1.
Crit Rev Oncol Hematol ; 132: 66-75, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30447928

ABSTRACT

BACKGROUND: Previous studies found divergent effects of aspirin use on prostate cancer incidence, potentially due to studies with short durations of aspirin use and insufficient adjustment for screening. METHODS: A systematic review on the association between aspirin use ≥3 years and incident prostate cancer was performed in accordance with the PRISMA and MOOSE criteria. RESULTS: In the cohort studies, aspirin use for at least 3 years was associated with a lower incidence rate of prostate cancer (Odds ratio (OR) 0.88, 95% CI 0.80-0.97). No protective association was established for the case-control studies (OR 0.92, 95% CI 0.68-1.23). Subgroup analysis of advanced and aggressive cancers showed a protective association (OR 0.82, 95% CI 0.71-0.94 and OR 0.75, 95% CI 0.61-0.97). CONCLUSION: This synthesis of observational studies suggests a potential protective association between long term aspirin use and incident prostate cancer. The current literature is highly heterogenous and suffers from inconsistent aspirin dose definition and measurement.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Aspirin/administration & dosage , Prostatic Neoplasms/epidemiology , Humans , Incidence , Male , Prognosis , Prostatic Neoplasms/drug therapy , Time Factors
2.
Crit Rev Oncol Hematol ; 116: 99-105, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28693804

ABSTRACT

Merkel cell carcinoma (MCC) is a highly malignant skin cancer characterized by early metastases and poor survival. Although MCC is a rare malignancy, its incidence is rapidly increasing in the U.S. and Europe. The discovery of the Merkel cell polyomavirus (MCPyV) has enormously impacted our understanding of its etiopathogenesis and biology. MCCs are characterized by trilinear differentiation, comprising the expression of neuroendocrine, epithelial and B-lymphoid lineage markers. To date, it is generally accepted that the initial assumption of MCC originating from Merkel cells (MCs) is unlikely. This is owed to their post-mitotic character, absence of MCPyV in MCs and discrepant protein expression pattern in comparison to MCC. Evidence from mouse models suggests that epidermal/dermal stem cells might be of cellular origin in MCC. The recently formulated hypothesis of MCC originating from early B-cells is based on morphology, the consistent expression of early B-cell lineage markers and the finding of clonal immunoglobulin chain rearrangement in MCC cells. In this review we elaborate on the cellular ancestry of MCC, the identification of which could pave the way for novel and more effective therapeutic regimens.


Subject(s)
B-Lymphocytes/pathology , Carcinoma, Merkel Cell/pathology , Cell Lineage , Skin Neoplasms/pathology , Animals , Humans
3.
Hautarzt ; 68(3): 204-210, 2017 Mar.
Article in German | MEDLINE | ID: mdl-28194491

ABSTRACT

Merkel cell carcinoma (MCC) is a relatively rare but highly malignant non-melanoma skin cancer of the elderly and immunosuppressed patients. The discovery of the Merkel cell polyomavirus (MCPyV) in 2008 significantly impacted the understanding of the etiopathogenesis of MCC. MCPyV is clonally integrated into the MCC genome and approximately 80% of MCC are MCPyV-positive. Recent results of clinical trials using blockade of the PD-1 immune modulatory pathway are promising for the future treatment of MCC. Despite this major progress of the past few years, the cellular origin of MCC still remains obscure. Based on histomorphology, gene expression profiling, and molecular analyses, we have recently hypothesized that MCC originates from pre­/pro-B cells. Here we review putative cells of MCC, including Merkel cells, (epi­)dermal stem cells, and pro­/pre-B cells. In the present work, the focus is on the concept of pre­/pro-B cells as the cellular origin of MCC, which might also impact the understanding of other human small cell malignancies of unknown cellular origin, such as small cell carcinomas of the lung and other anatomical locations. In addition, this concept might pave the way for novel treatment options, especially for advanced MCC.


Subject(s)
B-Lymphocytes/virology , Carcinoma, Merkel Cell/pathology , Carcinoma, Merkel Cell/virology , Cell Transformation, Neoplastic/pathology , Merkel cell polyomavirus/isolation & purification , Skin Neoplasms/pathology , Skin Neoplasms/virology , B-Lymphocytes/pathology , Evidence-Based Medicine , Humans , Models, Biological , Tumor Cells, Cultured
4.
Pediatrics ; 102(1 Pt 1): 44-52, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9651412

ABSTRACT

OBJECTIVE: To evaluate the impact of newborn screening for cystic fibrosis (CF) on the reproductive knowledge and behavior of CF families and to determine if heterozygote detection with the immunoreactive trypsinogen (IRT) method in conjunction with DNA analysis (IRT/DNA) influences knowledge and attitudes about reproduction in false-positive families. METHODS: The Wisconsin CF Neonatal Screening Project investigated 650 340 infants from 1985 to 1994 in a comprehensive randomized controlled trial to study both benefits and risks of newborn screening and to determine if early diagnosis would improve the prognosis of children with CF. Assessments of reproductive knowledge, attitudes, and behaviors of 135 families of children diagnosed as having CF in both the early treatment group and control groups were made 3 months after diagnosis using a questionnaire which was completed by 100 families. The same questionnaire was administered 1 year later to evaluate retention of information. It was completed by 71 families. A follow-up assessment tool was also administered in 1994 and responses obtained from 73 families. Knowledge, attitudes, and behavior among false-positive families were also assessed at the time of the sweat test in 206 families who experienced IRT screening and 109 families tested with the IRT/DNA method. Follow-up assessments were completed 1 year later in 106 IRT families and 63 IRT/DNA families. RESULTS: In families with a CF child, 95% initially understood that there was a 1 in 4 risk in subsequent pregnancies, and there was good retention of this information 1 year later. At the 1994 assessment, 52% of families had not yet conceived more children, but 74% of these already had children. In the couples in whom CF was diagnosed in the first child, 70% (95% confidence interval = 54% to 85%) conceived more children. There were 43 subsequent pregnancies in 31 families. Prenatal diagnosis was used by 26% of the families (8/31) for 21% of the pregnancies (9/43). There were 3 pregnancies with CF detected, all of which were carried to term. In the false-positive groups, >95% of families initially understood that their child definitely did not have CF. There was no difference between false-positive IRT and IRT/DNA groups, and the information was retained at 1 year. Follow-up assessment 1 year after negative sweat tests revealed that 7% of the IRT and 10% of the IRT/DNA families still thought about the results often or constantly. When asked whether the experience of screening affected feelings about having more children, an affirmative response was obtained in 4% of IRT families but in 17% of IRT/DNA families. One year later, more than half of the false-positive IRT/DNA families did not understand that they were at increased risk of having a child with CF. CONCLUSIONS: We conclude that CF neonatal screening does not have a significant impact on the reproductive behavior of most families and that prenatal diagnosis is not used by the majority of CF families. IRT/DNA testing experiences seem to affect attitudes about having more children, and some parents are confused about the implications of the results, even with genetic counseling. However, persistent concerns about the sweat test result are limited. Questions raised by this study confirm the need for more research regarding the process of genetic counseling and its impact on reproductive attitudes and behavior in the newborn screening setting.


Subject(s)
Cystic Fibrosis/prevention & control , Genetic Counseling , Genetic Testing , Health Knowledge, Attitudes, Practice , Neonatal Screening , Cystic Fibrosis/genetics , False Positive Reactions , Female , Follow-Up Studies , Genetic Carrier Screening , Humans , Infant , Infant, Newborn , Male , Pregnancy , Wisconsin
5.
J Clin Exp Neuropsychol ; 20(4): 483-95, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9892052

ABSTRACT

We present the most extensive neuropsychological and language assessment yet reported of patients diagnosed with Floating-Harbor Syndrome (FHS), a rare genetic condition characterized by dysmorphid figures, short stature, and speech-onset delay. This is also the second reported occurrence of both a mother and daughter with FHS. Whereas the child demonstrated gross deficits in verbal expression, speech and language problems were largely ameliorated in the mother. Neuropsychological assessment also revealed a strikingly similar pattern of cognitive problems additional to language dysfunction, including difficulties with attention, mathematical, and visuospatial abilities. A mood disorder continued to be quite disabling for the mother.


Subject(s)
Face/abnormalities , Growth Disorders/psychology , Language Development Disorders/psychology , Adult , Affect/physiology , Attention/physiology , Cognition/physiology , Female , Humans , Infant , Infant, Newborn , Language Tests , Neuropsychological Tests , Perception/physiology , Personality/physiology , Pregnancy , Psychomotor Performance/physiology , Speech , Syndrome
6.
Neurology ; 47(1): 94-7, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8710132

ABSTRACT

OBJECTIVE: We sought to demonstrate that isolated episodes of vertigo can be the only manifestation of vertebrobasilar ischemia. BACKGROUND: Isolated persistent vertigo is classically ascribed to labyrinthine disorders and is only rarely considered to reflect vertebrobasilar ischemia. METHODS: We retrospectively analyzed all of the records of the Saint Louis University Stroke Registry between January 1, 1992 and September 1, 1993. We set out to identify those patients discharged with a diagnosis of transient ischemic attack (TIA) in the vertebrobasilar system. We reviewed their clinical records and the results of their diagnostic studies. RESULTS: We screened 600 admissions and found 29 patients with vertebrobasilar circulation TIAs. Of these, five men and one woman had episodic vertigo for at least 4 weeks as their only presenting symptom. All six patients had one of two abnormal patterns on magnetic resonance angiography (MRA): focal basilar stenosis or widespread vertebrobasilar slow flow. In three patients, the MRA findings were confirmed by cerebral angiography. Five patients were treated with warfarin and one with aspirin. Two patients developed brainstem infarctions, one of them fatal. CONCLUSIONS: Isolated vertigo can be the only manifestation of vertebrobasilar ischemia. Its frequency may be underestimated in clinical practice. Noninvasive testing is helpful both for diagnosis and follow-up.


Subject(s)
Basilar Artery , Brain Ischemia/complications , Vertebral Artery , Vertigo/etiology , Aged , Aged, 80 and over , Brain Ischemia/diagnosis , Female , Humans , Magnetic Resonance Angiography , Male , Middle Aged
7.
Hum Genet ; 97(5): 642-9, 1996 May.
Article in English | MEDLINE | ID: mdl-8655146

ABSTRACT

Autosomal dominant Charcot-Marie-Tooth type-1A neuropathy (CMT1A) is a demyelinating peripheral nerve disorder that is commonly associated with a submicroscopic tandem DNA duplication of a 1.5-Mb region of 17p11.2p12 that contains the peripheral myelin gene PMP22. Clinical features of CMT1A include progressive distal muscle atrophy and weakness, foot and hand deformities, gait abnormalities, absent reflexes, and the completely penetrant electrophysiologic phenotype of symmetric reductions in motor nerve conduction velocities (NCVs). Molecular and fluorescense in situ hybridization (FISH) analyses were performed to determine the duplication status of the PMP22 gene in four patients with rare cytogenetic duplications of 17p. Neuropathologic features of CMT1A were seen in two of these four patients, in addition to the complex phenotype asociated with 17p partial trisomy. Our findings show that the CMT1A phenotype of reduced NCV is specifically associated with PMP22 gene duplications, thus providing further support for the PMP22 gene dosage mechanism for CMT1A.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Chromosomes, Human, Pair 17 , Multigene Family , Myelin Proteins/genetics , Trisomy , Blotting, Southern , Charcot-Marie-Tooth Disease/pathology , Charcot-Marie-Tooth Disease/physiopathology , Child, Preschool , Chromosome Banding , Chromosome Mapping , Electrophysiology , Female , Genes, Dominant , Humans , In Situ Hybridization, Fluorescence , Male , Motor Neurons/physiology , Neural Conduction , Pedigree , Phenotype , Sural Nerve/physiopathology
8.
Stroke ; 25(10): 1920-3, 1994 Oct.
Article in English | MEDLINE | ID: mdl-8091434

ABSTRACT

BACKGROUND AND PURPOSE: Significant delays often occur during the treatment of patients with acute stroke. Some of those delays occur in the hospital. We attempted to shorten inhospital treatment intervals by creating a rapid-response system, similar to that available for cardiac arrest, that would allow the stroke team to be available within a few minutes to care for stroke victims. METHODS: We connected all beepers (pocket pagers) of stroke team members to a common access number and instructed the emergency staff to activate that number immediately upon arrival of a stroke victim. We monitored the response time and treatment interval for patients who were treated after this system was activated (Code Stroke patients) during the first 3 months of its availability and compared the results to those of patients seen for similar reasons during the study period but without the use of Code Stroke (control patients). RESULTS: A total of 12 Code Stroke patients were available for analysis, representing 12% of all patients (n = 98) seen in the emergency department for ischemic stroke during the study period. The remaining 86 patients constituted the control group. The mean time to evaluation of a Code Stroke patient by a stroke team member was 4.8 minutes (range, 2 to 7 minutes), and the mean time to treatment institution was 30 minutes (range, 10 to 120 minutes). There were significant differences between the consultation intervals in the two groups (P < .05). There was only a trend of a difference between treatment institution intervals (P = .06). CONCLUSIONS: It is possible to shorten inhospital treatment delays by instituting rapid-response systems within individual institutions.


Subject(s)
Cerebrovascular Disorders/therapy , Emergency Service, Hospital , Hospital Communication Systems , Adolescent , Adult , Aged , Aged, 80 and over , Brain Ischemia/diagnosis , Brain Ischemia/therapy , Cerebrovascular Disorders/diagnosis , Child , Emergency Medical Services , Emergency Service, Hospital/organization & administration , Female , Hospital Communication Systems/organization & administration , Humans , Male , Medical Staff, Hospital , Middle Aged , Nursing Staff, Hospital , Patient Care Team , Referral and Consultation , Retrospective Studies , Time Factors
9.
J Stroke Cerebrovasc Dis ; 4(3): 169-73, 1994.
Article in English | MEDLINE | ID: mdl-26486055

ABSTRACT

The evaluation of victims of ischemic stroke has evolved over the last few years, primarily as a result of the introduction of innovative, sensitive, and informative diagnostic procedures. The role of the neurologist appears to have been redefined as one in which the identification of the presumptive cause and mechanism of the stroke is one of the primary responsibilities. We compared the etiologic stroke subtypes of patients entered into the Saint Louis University Stroke Registry for the period January to June, 1986 (Group A), with analogous data collected in patients entered from January to June, 1992 (Group B). Group A included 57 patients whose stroke subtype distribution was as follows: 19% due to athero-thromboembolism, 18% cardiogenic, 5% lacunar, and 4% due to other causes. In addition, 54% of patients had strokes of unknown etiology. Group B comprised 137 patients with the following etiologic distribution: 35% cardiogenic, 26% atherothrombolic, 3% lacunar, and 6% from other causes. Only 29% had strokes of unknown etiology. The apparent increase in the proportion of cardiogenic strokes may be related to wider utilization of transesophageal echocardiography. There was also a significant drop in the proportion of strokes of unknown etiology. Finally, in comparison with other stroke registries, our data suggest that many small strokes may also result from cardiogenic embolism. These apparent changes in the proportion of stroke subtypes should be considered when patients are being evaluated for risk stratification.

10.
Stroke ; 24(9): 1352-9, 1993 Sep.
Article in English | MEDLINE | ID: mdl-8362430

ABSTRACT

BACKGROUND AND PURPOSE: Numerous studies have demonstrated an association between acute cardiac events, cerebrovascular accidents, and cocaine use. The underlying mechanisms leading to these complications have not been well defined. Using various in vitro model systems, it has been reported that cocaine, up to or greater than an order of magnitude of the lethal dose, causes either inhibitory or proaggregatory effects on platelet function. METHODS: To address these reported discrepancies, we examined the effect of cocaine and its carrier on the activation and aggregation of human platelets in vitro. RESULTS: We found that cocaine inhibited platelet aggregation when platelets were challenged with ADP, collagen, or arachidonic acid. This inhibition was due to a direct effect on fibrinogen binding to the activated platelet. Cocaine also caused the dissociation of preformed platelet aggregates. At these same concentrations, cocaine did not inhibit agonist-mediated increases in cytosolic calcium or inhibit platelet shape change, suggesting that its effect on platelet aggregation was a selective process and not due to a total destruction of platelet function. Interestingly, the organization of the cytoskeleton of activated platelets, a secondary event critical to cell receptor clustering and clot retraction, was disrupted by cocaine treatment. In addition, alterations in platelet protein electrophoretic patterns were observed on preincubation of platelets with cocaine. CONCLUSIONS: We conclude that cocaine may have a direct inhibitory effect on the ability of platelets to participate in thrombus formation. The contribution of this effect as an underlying mechanism of sudden death in cocaine abusers is unknown.


Subject(s)
Cocaine/adverse effects , Platelet Aggregation/drug effects , Adenosine Diphosphate/pharmacology , Arachidonic Acid/pharmacology , Calcium/metabolism , Cocaine/pharmacology , Collagen , Hematologic Diseases/chemically induced , Humans , Platelet Aggregation Inhibitors/pharmacology
11.
Stroke ; 22(9): 1203-5, 1991 Sep.
Article in English | MEDLINE | ID: mdl-1926265

ABSTRACT

Ischemic stroke temporally related to cocaine abuse has become increasingly common in young adults. Despite this relation, however, the pathogenesis of infarction in many of these patients remains obscure. I report the case of a 39-year-old man who developed occlusion of the frontopolar branches of the left middle cerebral artery 1 hour after intravenous cocaine use. Eleven days later he developed occlusion of the superior division of the right middle cerebral artery. In this case the mechanism of infarction was clearly cardiogenic embolization. Chest radiograph and echocardiogram revealed dilated cardiomyopathy with left ventricular thrombi. No cause other than cocaine abuse was found for his cardiomyopathy. This is the second reported case of cocaine-related cardiomyopathy presenting as embolic stroke and associated with intracavitary thrombus. Such an association may be more common than previously thought. Thorough cardiac evaluation in all patients with ischemic stroke related to cocaine abuse is appropriate.


Subject(s)
Cardiomyopathy, Dilated/complications , Cerebrovascular Disorders/etiology , Cocaine , Intracranial Embolism and Thrombosis/etiology , Substance-Related Disorders/complications , Adult , Cardiomyopathy, Dilated/chemically induced , Cardiomyopathy, Dilated/diagnosis , Cerebral Infarction/diagnostic imaging , Cerebrovascular Disorders/diagnostic imaging , Echocardiography , Humans , Intracranial Embolism and Thrombosis/diagnostic imaging , Male , Recurrence , Tomography, X-Ray Computed
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