Biomedical subjects

Timothy G Lesnick

Publications and source records attributed to Timothy G Lesnick.

At least 19 recordsLinked to original sources

PubMed2006

Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease.

CONTEXT: Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking. OBJECTIVE: To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset. DESIGN, SETTING, AND PARTICIPANTS: We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally. MAIN OUTCOME MEASURES: Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. RESULTS: Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55). CONCLUSION: This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.

Adult↗

PubMed2006

Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome patients undergoing gonadotropin therapy for in vitro fertilization.

CONTEXT: Polycystic ovary syndrome (PCOS) is a reproductive disorder of ovarian hyperandrogenism and insulin resistance characterized by abnormal luteinization of small follicles. After exposure to GnRH analog/FSH stimulation for in vitro fertilization (IVF), however, it is unclear whether such PCOS follicles remain abnormally luteinized during the resumption of oocyte maturation in vivo. OBJECTIVE: The aim of this study was to determine whether PCOS follicles exposed to GnRH analog/FSH stimulation for IVF show abnormal luteinization. DESIGN: This study was a prospective cohort. SETTING: The setting was an institutional practice. PATIENTS: Eleven PCOS and 30 normoandrogenic ovulatory women were included. INTERVENTION(S): All subjects received GnRH analog/FSH therapy after basal serum hormone determinations. MAIN OUTCOME MEASURE(S): Follicle fluid aspirated at oocyte retrieval from the first follicle of each ovary was assayed for gonadotropins, steroids, insulin, and glucose. LH receptor mRNA expression was determined in granulosa cells of the same follicle. RESULTS: In PCOS patients with basal hyperandrogenemia and hyperinsulinemia, total oocyte number was increased and follicle diameter was decreased, despite normal maximal serum estradiol levels. Within PCOS follicles, progesterone levels were reduced (P < 0.01), despite comparable bioactive LH and insulin levels and granulosa cell LH receptor mRNA expression; estradiol levels were normal, despite diminished FSH availability (P < 0.004). Elevated androstenedione (P < 0.01), testosterone (P < 0.001), and glucose (P < 0.01) levels also occurred. In PCOS follicles containing mature oocytes, however, elevated androgen levels were accompanied by both normal progesterone concentrations and a normal inverse relationship between glucose depletion and lactate accumulation. CONCLUSION: Hyperandrogenic follicles with mature oocytes from PCOS women receiving GnRH analog/recombinant human FSH therapy for IVF show sufficient glucose utilization for normal luteinization.

Adult↗

PubMed2006

Efficacy of systematic lymphadenectomy and adjuvant radiotherapy in node-positive endometrial cancer patients.

OBJECTIVE: To assess the efficacy of systematic lymphadenectomy and adjuvant radiotherapy in minimizing pelvic sidewall and para-aortic failures. METHODS: Between January 1984 and December 2001, a total of 146 patients with stage III and IV endometrial cancer and lymph node metastases were treated at our institution. Adequate pelvic lymphadenectomy was defined as the removal of more than 10 pelvic lymph nodes, and adequate para-aortic lymphadenectomy was defined as removal of 5 or more para-aortic lymph nodes. The 24 patients who received adjuvant chemotherapy were excluded. We assessed the ability of adequate pelvic and para-aortic lymphadenectomy, together with radiotherapy, to prevent pelvic and para-aortic recurrences. RESULTS: Of the 122 patients studied, 94 (77%) had adequate pelvic lymphadenectomy and 47 (39%) had adequate para-aortic lymphadenectomy. Pelvic radiotherapy was administered to 78% and para-aortic radiotherapy to 29% of patients. Median follow-up of censored patients was 56 months. Twenty-five percent of patients had pelvic sidewall failure at 5 years. Pelvic sidewall failures at 5 years occurred in 57% of patients who had inadequate node dissection and/or no radiotherapy, compared with 10% for those having both adequate lymphadenectomy and radiotherapy (P < 0.001). After risk factor assessment in a regression model, only treatment with adequate lymphadenectomy and radiotherapy was a significant independent predictor of pelvic control (P = 0.03). The performance of definitive pelvic lymphadenectomy may have increased treatment-related morbidity in the subgroup of patients who had postoperative radiotherapy. For the 41 patients with positive para-aortic lymph nodes, the 5-year para-aortic failure rate was 34% after adequate lymphadenectomy but without adjuvant para-aortic radiotherapy. Likewise, 69% failed in the para-aortic area when adjuvant para-aortic radiotherapy was administered to patients not having adequate para-aortic lymphadenectomy; however, none of the 11 patients failed in the para-aortic area after adequate lymphadenectomy and para-aortic radiotherapy (P = 0.08). CONCLUSIONS: Adequate (pelvic and para-aortic) lymphadenectomy and adjuvant radiotherapy appear complementary in reducing failures in both the pelvis and para-aortic areas in patients with node-positive endometrial cancer.

Aged↗

PubMed2006

Reliability of self-reported ancestry among siblings: implications for genetic association studies.

This study investigated the reliability of self-reported ancestry by comparing the interview responses of probands and their siblings. A total of 546 sibling pairs were ascertained in a family-based study of susceptibility genes for Parkinson's disease and asked to identify maternal and paternal countries of origin. Probands were recruited prospectively from the Department of Neurology of the Mayo Clinic in Rochester, Minnesota, from June 1, 1996, through May 31, 2005. Probands resided within Minnesota or one of the four surrounding states (Wisconsin, Iowa, South Dakota, North Dakota). Only 49 percent of these sibling pairs, primarily Caucasian, agreed completely on the countries of origin of both parents. The agreement increased to 68 percent when named countries were postcoded into six population genetic clusters (as previously defined by microsatellite markers). Self-reported ancestry may not be a reliable method to reduce the possible impact of population stratification in genetic association studies of outbred populations, such as in the United States.

Adult↗

PubMed2006

Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study.

BACKGROUND: Using the recent Consensus Panel recommendations, we sought to describe the incidence of transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) in critically ill patients. STUDY DESIGN AND METHODS: Consecutive patients at four intensive care units (ICUs) who did not require respiratory support at the time of transfusion were identified with custom electronic surveillance system that prospectively tracks the time of transfusion and onset of respiratory support. Respiratory failure was defined as the onset of noninvasive or invasive ventilator support within 6 hours of transfusion. Experts blinded to specific transfusion factors categorized the cases of pulmonary edema as permeability edema (suspected or possible TRALI) or hydrostatic edema (TACO) according to predefined algorithm. In a nested case-control design, transfusion variables and lung injury risk factors were compared between the TRALI cases and controls matched by age, sex, and admission diagnosis. RESULTS: There were 8902 units transfused in 1351 patients of whom 94 required new respiratory support within 6 hours of transfusion. Among 49 patients with confirmed acute pulmonary edema, experts identified 7 cases with suspected TRALI, 17 patients with possible TRALI, and 25 cases with TACO. The incidence of suspected TRALI was 1 in 1271 units transfused; possible TRALI, 1 in 534 per unit transfused; and TACO, 1 in 356 per unit transfused. When adjusted for sepsis and fluid balance in a stepwise conditional logistic regression analysis, patients who developed acute lung injury (suspected or possible TRALI) received larger amount of plasma (odds ratio 3.4, 95% confidence interval 1.2-10.2, for each liter infused; p = 0.023). CONCLUSION: In the ICU, pulmonary edema frequently occurs after blood transfusion. The association between infusion of plasma and the development of suspected or possible TRALI may have important implications with regards to etiology and prevention of this syndrome.

Aged↗

PubMed2005

The Aging Game: improving medical students' attitudes toward caring for the elderly.

OBJECTIVES: The objective of this study was to evaluate the effectiveness of a modified aging game to enhance medical students' attitudes toward caring for elderly patients, enhance empathy for elderly patients, and improve general attitudes toward the elderly. DESIGN: Preintervention and postintervention study PARTICIPANTS AND SETTING: All 84 students from 2 first-year medical school classes INTERVENTION: The aging game takes place over a period of 3 hours with a group of 10 to 12 students and 5 to 6 facilitators, and includes experiential learning about polypharmacy, medication cost, loss of functional status, semi-independent living, and living in a long-term care facility. MEASUREMENTS: Scores obtained through a modified Maxwell and Sullivan questionnaire, and the Aging Semantic Differential (ASD). RESULTS: There was a statistically significant improvement in 6 of the 8 attitudes toward caring for elderly and a statistically significant increase in empathy towards elderly patients following the aging game. There was a statistically significant change on 23 out of 32 ASD questions. There was no evidence of differences in the scores from pre-course to post-course by gender age group, interest in Family/Internal Medicine, or prior geriatric experience. Following the game, 77 (93%) of the students said they would take the course if not mandatory (P = .0001). A majority stated the aging game added significantly (61.5%) or moderately (37.3%) to their knowledge and skills in patient care for the elderly. CONCLUSION: A simulation experience like the aging game is an effective method of increasing the empathy and attitudes toward caring for the elderly early in the medical school curriculum. Longitudinal assessment of the effect of the aging game in maintaining the positive effect on empathy and attitudes toward caring for the elderly and especially in clinical practice needs to be done.

Activities of Daily Living↗

PubMed2005

High-resolution whole-genome association study of Parkinson disease.

We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70 x 10(-5)). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07 x 10(-6); P=2.96 x 10(-5)) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility.

Adult↗

PubMed2005

Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's Disease.

Potential roles for variants in the human BDNF gene in human brain disorders are supported by findings that include: (a) influences that this trophic factor can exert on important neurons, brain regions, and neurotransmitter systems, (b) changes in BDNF expression that follow altered neuronal activity and drug treatments, and (c) linkages or associations between genetic markers in or near BDNF and human traits and disorders that include depression, schizophrenia, addictions, and Parkinson's disease. We now report assembly of more than 70 kb of BDNF genomic sequence, delineation of 7 noncoding and 1 coding human BDNF exons, elucidation of BDNF transcripts that are initiated at several alternative promoters, identification of BDNF mRNA splicing patterns, elucidation of novel sequences that could contribute to activity-dependent BDNF mRNA transcription, targeting and/or translation, elucidation of tissue-specific and brain-region-specific use of the alternative human BDNF promoters and splicing patterns, identification of single nucleotide polymorphism (SNP), and simple sequence length polymorphism (SSLP) BDNF genomic variants and identification of patterns of restricted haplotype diversity at the BDNF locus. We also identified type 2 BDNF-locus transcripts that are coded by a novel gene that is overlapped with type 1 BDNF gene and transcribed in reverse orientation with several alternative splicing isoforms. Association studies of BDNF variants reveal no associations with Parkinson's disease. Comparisons between substance abusers and controls reveal modest associations. These findings increase interest in this diverse human gene.

Alternative Splicing↗

PubMed2005

UCHL1 is associated with Parkinson's disease: a case-unaffected sibling and case-unrelated control study.

To avoid the possible confounding effect of population stratification, we employed a discordant sibling study design and a liberalization of the sibling transmission disequilibrium test to confirm the association of the S18Y variant of the ubiquitin carboxi-terminal hydrolase L1 (UCHL1) gene with Parkinson's disease (PD). The study included 497 case-control pairs (427 case-unaffected sibling pairs and 70 case-unrelated control pairs). Analyses confirmed a significant inverse association of the UCHL1 S18Y polymorphism with PD overall (OR=0.18, 95% CI=0.05-0.64, p=0.002, recessive model) and in several strata.

Aryl Hydrocarbon Hydroxylases↗

PubMed2005

Interaction of alpha-synuclein and tau genotypes in Parkinson's disease.

To determine whether the microtubule-associated protein tau (MAPT) and alpha-synuclein (SNCA) genes interact to confer Parkinson's disease (PD) susceptibility, we conducted a study of 557 case-control pairs. There was an increased risk of PD for persons with either SNCA 261/261 or MAPT H1/H1 genotypes as compared with persons with neither (odds ratio, 1.96; 95% confidence interval, 1.34-2.86; p = 0.0003). However, the combined effect of the two genotypes was the same as for either of the genotypes alone (separate and equal). These findings are consistent with in vitro experiments that revealed tau-mediated fibrillization of alpha-synuclein protein at low concentrations (dose threshold effect).

Adult↗

PubMed2005

Improved performance and student satisfaction after implementation of a problem-based preclinical obstetrics and gynecology curriculum.

OBJECTIVE: This study was undertaken to assess student performance and satisfaction as a preclinical obstetrics and gynecology course changed from a didactic to a problem-based format. STUDY DESIGN: We prospectively compared examination scores and course evaluations given to 162 second-year medical students over 4 years: 2 years before and 2 years after the curricular change, to assess student performance and satisfaction with learning. We used analysis of variance for the analysis of student performance and likelihood-ratio test for analysis of student satisfaction. RESULTS: Mean examination scores increased from 79.1% to 84% after implementation of the problem-based curriculum (P < .0001). The data showed statistically significant improvement in satisfaction with course content, learning objectives, learning resources, instructional methods, and course examinations. CONCLUSION: Students' satisfaction and performance in a preclinical obstetrics and gynecology course improved significantly when problem-based learning methods were introduced.

Curriculum↗

PubMed2005

Diminished intrafollicular estradiol levels in in vitro fertilization cycles from women with reduced ovarian response to recombinant human follicle-stimulating hormone.

OBJECTIVE: To correlate serum and intrafollicular E(2) levels in women receiving GnRH agonist and recombinant human (h)FSH for IVF. DESIGN: Prospective study. SETTING: Academic IVF center. PATIENT(S): Twenty-three nonhirsute ovulatory women. INTERVENTION(S): In vitro fertilization cycles were classified as high- or low-normal response, according to whether the amount of recombinant hFSH administered was below or above, respectively, the mean recombinant hFSH given to all women combined. Serum bioactive LH and immunoreactive FSH were measured during pituitary desensitization preceding recombinant hFSH and repeated at oocyte retrieval. The first mature follicle aspirated from either ovary had a mean diameter >15 mm. MAIN OUTCOME MEASURE(S): Serum and follicular fluid (FF) insulin, bioactive LH, immunoreactive FSH, and steroid levels. RESULT(S): Basal serum gonadotropin levels were comparable between female groups. Serum immunoreactive FSH levels, but not bioactive LH levels, at oocyte retrieval were greater in cycles of low-normal vs. high-normal response, whereas maximum serum E2 levels and total oocyte counts were similar between both groups. Despite elevated FF immunoreactive FSH levels, FF E2 was decreased in low-normal response cycles. Intrafollicular T and P also were decreased and increased, respectively, in cycles of low-normal response, although FF bioactive LH levels were comparable in both groups. CONCLUSION(S): Intrafollicular E2 is decreased in cycles of reduced ovarian responsiveness to GnRH agonist and recombinant hFSH and is not predicted by maximal serum E2 or number of oocytes retrieved.

Adult↗

PubMed2005

Endometrial cancer: can nodal status be predicted with curettage?

OBJECTIVE: To determine whether histologic or molecular markers assessed in pretreatment curettage specimens predict nodal metastasis in endometrial cancer. METHODS: Phenotypic and molecular variables (ploidy, proliferating cell nuclear antigen, MIB-1, p53, HER-2/neu, and bcl-2) were analyzed in preoperative specimens from 82 patients with endometrial cancer who had lymph nodes dissected. These 82 patients had been selected from a total population of 283 patients with endometrial cancer, using a case-cohort design. Weighted logistic regressions were then used to determine significant predictors of positive lymph nodes, and results were estimated for the total population of 283 patients. RESULTS: Of the overall population, 12% of patients were estimated to have positive lymph nodes. Histologic subtype, p53, and bcl-2 each were significantly correlated (P <0.05) with lymph node status. With application of stepwise logistic regression, p53 was the only independent predictor of lymph node status. In addition, a statistical model predictive of positive lymph nodes was generated which incorporated the risk factors p53, bcl-2, and histologic subtype. CONCLUSION: In pretreatment curettage specimens, the presence of unfavorable levels of p53 or bcl-2 or of nonendometrioid histologic features, or combinations of those, significantly predicted lymph node status, thus facilitating the preoperative identification of patients at risk of lymph node metastases.

Adult↗

PubMed2005

Predictors of vaginal relapse in stage I endometrial cancer.

OBJECTIVE: To identify factors predictive of vaginal relapse in stage I endometrial cancer, thereby potentially facilitating the selection of patients who may benefit from vaginal brachytherapy. METHODS: The study population included 632 patients with stage I endometrial cancer managed with hysterectomy at our institution between 1984 and 1996. Median follow-up was 73 months; 122 patients (19%) received adjuvant radiotherapy. RESULTS: Overall, 2.9% of the stage I cohort developed vaginal relapse at 5 years. Vaginal relapse was observed in 1.7% of patients who received radiotherapy and in 3.0% of those whose treatment did not include radiotherapy (P = 0.36). Cox regression analysis (including radiotherapy) identified only grade 3 differentiation (hazard ratio = 3.83, P = 0.007) as an independent predictor of vaginal relapse. Patients with a low-grade tumor had a 5-year vaginal relapse rate of 2%, compared with 7% for those with a grade 3 tumor. When only patients who did not receive adjuvant radiotherapy were considered, both grade 3 tumor and lymphovascular invasion were significant predictors of vaginal relapse (P < 0.05). When neither variable was present, 2% of patients experienced vaginal relapse at 5 years, compared with 11% when either 1 was present (P < 0.001). Depth of myometrial invasion was not a significant predictor of vaginal recurrence. CONCLUSION: Histologic grade 3 tumor and lymphovascular invasion were the cogent predictors of vaginal relapse in our population. The cost and morbidity of vaginal brachytherapy should be balanced against the potential risk of vaginal relapse in this group of patients.

Cohort Studies↗

PubMed2004

Needle tip control and its effect in reducing intraoperative complications during tension-free vaginal tape placement.

Tactile needle tip control was used to aid perforation during standard tension-free vaginal tape (TVT) placement to treat urinary incontinence. The success and complications of this novel method were compared retrospectively with the reported results of the standard technique. One hundred nine patients had TVT placement between 1998 and 2001, with follow-up continuing into 2002. Preoperatively, the severity of urinary incontinence was assessed objectively. Postoperatively, TVT effectiveness was assessed subjectively by standardized questionnaire, completed by 78 of the 109 patients (72%). Objective 2-year rates for continence or improvement and most complication rates were similar to previously reported results. Needle tip control was helpful in lowering the occurrence of bladder perforation. Longer postoperative recovery times associated with postoperative dysuria or obstruction did not decrease patient satisfaction if the patient experienced a marked improvement in leakage.

Humans↗

PubMed2004

The natural history of recurrent optic neuritis.

BACKGROUND: Optic neuritis (ON) may occur in isolation or may herald multiple sclerosis (MS) or neuromyelitis optica (NMO). Occasionally, ON may recur many times without intervening evidence of dissemination in space. OBJECTIVE: To define the clinical course and prognosis of patients with recurrent ON. DESIGN: Retrospective medical record review and telephone follow-up survey. SETTING: Clinic-based practice in a large tertiary referral institution. MAIN OUTCOME MEASURES: Survival analysis of conversion to MS and NMO and final visual impairment. We studied the association of clinical and demographic factors, the presence of brain lesions on magnetic resonance images, and the use of corticosteroid treatment at the time of the first ON occurrence with conversion to MS and NMO. RESULTS: We identified 1274 patients with ON between 1994 and 2000 and selected 72 (5.7%) with recurrent ON without intervening symptoms of a disseminated demyelinating condition for further analysis. The 5-year conversion rate to NMO was 12.5% and to MS, 14.4%. Among 5 patients with 2 or more lesions consistent with MS on brain magnetic resonance images, 2 (40.0%) converted to MS and none to NMO, while among 11 patients without such lesions, none converted to MS and 2 (18.2%) converted to NMO (P =.16). Conversion to MS occurred in 7 (19.4%) of 36 individuals treated for their first ON episode with corticosteroids vs 4 (44.4%) of 9 untreated individuals (P =.19). There was no difference in the conversion rate to MS between those treated with intravenous steroids (4 [16.7%] of 24) vs oral steroids (3 [25.0%] of 12) (P =.33). Conversion to NMO occurred earlier than conversion to MS (2.3 +/- 1.6 vs 5.3 +/- 4.3 years, respectively; P =.01). Women tended to convert to NMO more frequently than men (female-male ratio for NMO converters, 7:1; MS converters, 2:1; nonconverters, 2:1; P =.56), as did those with a higher annual frequency of ON episodes (NMO converters, 2.0 +/- 1.3; MS converters, 1.0 +/- 1.0; nonconverters, 0.6 +/- 0.5; P =.04). The number of ON events in the first 2 years following the first ON episode was higher in the NMO group (NMO converters, 2.4 +/- 0.9; MS converters, 1.9 +/- 1.1; nonconverters, 1.7 +/- 0.7; P =.04). The final visual impairment was greatest in the NMO group (P =.02). CONCLUSIONS: Patients with rapid succession of severe ON events are more likely to develop a generalized demyelinating disease. Patients with NMO had a worse visual outcome.

Administration, Oral↗

PubMed2004

UCHL1 is a Parkinson's disease susceptibility gene.

The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73-0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57-0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis-generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease-modifying therapies.

Adult↗

PubMed2004

High-risk endometrial cancer subgroups: candidates for target-based adjuvant therapy.

OBJECTIVE: To identify patients with endometrial cancer at risk for hematogenous, lymphatic, or peritoneal recurrence (or combinations of them) who might potentially benefit from target-based therapies. METHODS: During a 13-year period, 915 patients had endometrial cancer managed with hysterectomy and standard adjuvant therapy. On the basis of our previous regression analyses, depth of myometrial invasion predicted the risk for hematogenous recurrence; positive lymph nodes and cervical stromal invasion predicted lymphatic recurrence; stage IV disease or combination of nonendometrioid histology, cervical stromal invasion, positive lymph nodes, and positive peritoneal cytology was predictive of peritoneal recurrence. Median follow-up was 66 months. RESULTS: Applying the above criteria to the population of 915 patients, 24% were considered at risk for hematogenous recurrence, 18% for lymphatic recurrence, and 16% for peritoneal recurrence. The respective relapse rates at 5 years were 28% for patients who were at risk for hematogenous recurrence, 31% for lymphatic recurrence, and 42% for peritoneal recurrence. This contrasted with less than a 5% recurrence rate in the corresponding subgroups not at risk for relapse (P < 0.001). Collectively, of the 915 patients, 324 (35%) were considered at risk for recurrence in one or more of the above three sites. Overall, 89% of all recurrences were identified in this at-risk group. Importantly, 46% of the patients considered at risk subsequently had recurrence in one or more of the three sites, compared with only 2% of patients not at risk for relapse (P < 0.001). CONCLUSION: Patients at risk for relapse had a 46% probability of experiencing recurrence within 5 years despite management with standard therapy. New target-based algorithms for the 35% of endometrial cancer patients deemed at risk should be incorporated in the development of future prospective multimodality clinical trials predicated on site(s) of recurrence.

Adult↗