Biomedical subjects

James J Schlesselman

Publications and source records attributed to James J Schlesselman.

12 recordsLinked to original sources

PubMed2006

The emerging case-control study: lung cancer in relation to tobacco smoking.

Two influential case-control studies that clearly implicated cigarette smoking as a cause of lung cancer are reviewed in terms of their respective strengths and weaknesses. The findings from a U.S. study reported in 1950 by Wynder and Graham were strikingly similar to those arising from a U.K. study reported later that year by Doll and Hill. The methodological rigor of these investigations effectively ruled out alternatives to smoking as plausible explanations for the increased risk, although additional investigations in animals and man were needed to buttress the original results. The exceptionally high relative risk of lung cancer that was found has had far-reaching medical, social, and economic consequences.

Case-Control Studies↗

PubMed2005

Polymorphisms in the DNA methyltransferase 3b gene and prostate cancer risk.

Inactivation of tumor suppressor genes by promoter methylation is an important mechanism of tumorigenesis. Increased expression of DNA methyltransferases has been commonly observed in cancer. A C/T polymorphism in the DNA methyltransferase 3b (DNMT3b) promoter region results in increased activity and has recently been identified as a risk factor for lung cancer. In this study, we examined the C/T polymorphism of the DNMT3b gene in specimens from 81 patients with prostate cancer and 42 controls selected from patients with benign prostatic hypertrophy (BPH). Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. DNMT3b genotypes were determined by restriction-fragment-length-polymorphism polymerase chain reaction. The DNMT3b polymorphism frequencies in the prostate cancer and BPH specimens were, respectively, 20 and 26% for CC, 42 and 52% for CT, and 38 and 21% for TT. Although such differences fall within the realm of chance variation (P>0.05), the data suggest that the TT genotype may be associated with an increased risk of prostate cancer: the age-adjusted odds ratio (aOR) was 2.6 [95% confidence interval: 0.8-8.0]; the increase in odds ratio was seen in both blacks and whites (aOR=4.3 in blacks, and 2.0 in whites). The samples used in this study have previously been examined for methylation index (MI) based on the number of genes methylated, the range being 0 to 5. A trend toward an increase in MI was detected for the DNMT3b polymorphisms in prostate cancer patients but not for BPH subjects (mean MI 2.6, 2.9, 3.1 for CC, CT, and TT genotype in prostate cancer; 0.8, 0.8, 0.7 for CC, CT, and TT genotype in BPH subjects). These findings suggest that the DNMT3b polymorphisms may be associated with an increase in promoter methylation of tumor-suppressor genes related to the development of prostate cancer, and may thereby increase the risk of this disease.

Black or African American↗

PubMed2004

Allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the safety, immunogenicity, and clinical response to an allogeneic tumor vaccine for non-small-cell lung cancer, we conducted a phase I trial in patients with advanced metastatic disease. PATIENTS AND METHODS: We treated 19 patients with a vaccine based on an adenocarcinoma line (AD100) transfected with B7.1 (CD80) and HLA A1 or A2. Patients were vaccinated intradermally with 5 x 10(7) cells once every 2 weeks. Three vaccinations represented one course of treatment. If patients had complete response, partial response, or stable disease, they continued with the vaccinations for up to three courses (nine vaccinations). Immune response was assessed by a change between pre-study and postvaccination enzyme-linked immunospot frequency of purified CD8 T-cells secreting interferon-gamma in response to in vitro challenge with AD100. RESULTS: Four patients experienced serious adverse events that were unrelated to vaccine. Another four patients experienced only minimal skin erythema. All but one patient had a measurable CD8 response after three immunizations. The immune response of six surviving, clinically responding patients shows that CD8 titers continue to be elevated up to 150 weeks, even after cessation of vaccination. Overall, one patient had a partial response, and five had stable disease. Median survival for all patients is 18 months (90% CI, 7 to 23 months), with corresponding estimates of 1-year, 2-year, and 3-year survival of 52%, 30%, and 30%, respectively. HLA matching of vaccine, age, sex, race, and pathology did not bear a significant relation to response. CONCLUSION: Minimal toxicity and good survival in this small population suggest clinical benefit from vaccination.

Adenocarcinoma↗

PubMed2004

Safety concerns and health benefits associated with oral contraception.

Since the introduction of hormonal contraceptives in the 1960s, there have been a variety of both health benefits and safety concerns attributed to their use. In most instances, the noncontraceptive benefits of oral contraceptives (OCs) outweigh the potential cardiovascular risks. In fact, the probability of a patient experiencing a cardiovascular event while taking a low-dose OC is very low. However, smoking, hypertension, obesity, and diabetes are risk factors that must be taken into account when prescribing OCs. The neoplastic effects of hormonal contraceptives have been extensively studied, and recent meta-analyses indicate that there is a reduction in the risk of endometrial and ovarian cancer, a possible small increase in the risk for breast and cervical cancer, and an increased risk of liver cancer. Finally, many women will experience noncontraceptive health benefits with OCs that expand far beyond pregnancy prevention. Some of these benefits include reduction in menstrual-related symptoms, fewer ectopic pregnancies, a possible increase in bone density, and possible protection against pelvic inflammatory disease.

Contraceptives, Oral, Combined↗

PubMed2004

Methylation of multiple genes in prostate cancer and the relationship with clinicopathological features of disease.

Promoter methylation plays an important role in the inactivation of tumor suppressor genes during tumorigenesis. We examined the methylation status of glutathione s-transferase Pi1 (GSTP1), retinoic acid receptor beta (RARB), CD44, E-cadherin (ECAD), RAS association domain family protein 1A (RASSF1A) and endothelin B receptor (EDNRB) genes in 81 prostate cancer and 42 benign prostatic hyperpasia specimens. Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. Methylation-specific PCR (MSP) was carried out after bisulfite treatment of genomic DNA. Methylation frequencies in prostate cancer and benign prostatic hyperplasia were 72% and 5% for GSTP1, 40% and 0% for RARB, 72% and 38% for CD44, 61% and 14% for ECAD, 49% and 19% for RASSF1A and 72% and 62% for EDNRB, respectively. Methylation of GSTP1, RARB, CD44, ECAD and RASSF1A, but not of EDNRB was detected at a statistically higher frequency in prostate cancer than in the benign prostatic hypertrophy specimens. Methylation of RARB occurred more frequently in early onset (age <55 years) as compared to late onset disease (age >70 years) (odds ratio, 8.6; 95% CI, 1.4-51.4; P=0.02). Methylation of RARB also occurred more frequently in stage III as compared to stage II disease (odds ratio, 3.2; 95% CI, 1.1-8.8; P=0.03). A methylation index (MI) was calculated as the total number of genes methylated, excluding EDNRB. A trend toward higher MI was noted in stage III as compared to stage II disease, and in Gleason score 7 as compared to Gleason score 6 tumors. Our results suggest that the methylation of selected genes in prostate cancers correlates with clinicopathological features of poor prognosis.

Aged↗

PubMed2004

Polymorphisms in the methylenetetrahydrofolate reductase gene and prostate cancer risk.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, which is involved in the methylation of homocysteine to methionine. Genetic polymorphisms that decrease MTHFR activity result in an altered cancer risk depending on folic acid intake. In this study we examined the C677T and A1298C polymorphisms of the MTHFR gene in specimens from 81 patients with prostate cancer and 42 controls selected from patients with benign prostatic hypertrophy (BPH). Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. MTHFR genotypes were determined by restriction-fragment-length-polymorphism polymerase chain reaction. The MTHFR polymorphism frequencies in the prostate-cancer and BPH specimens were, respectively, 60% and 48% for 677CC, 31% and 48% for 677CT, 9% and 5% for 677TT, 36% and 43% for 1298AA, 53% and 40% for 1298AC, and 11% and 17% for 1298CC. Although such differences fall within the realm of chance variation (P>0.05), the data suggest that the 677CT genotype may be associated with a reduced risk of prostate cancer: the age-adjusted odds ratio (aOR) was 0.6 [95% confidence interval (CI): 0.3-1.4]; the odds-ratio reduction was similar in both blacks and whites (aOR=0.4 in blacks, and 0.6 in whites); and when polymorphisms at the 677 and 1298 loci were analyzed in conjunction, a lower frequency of the 677CT-1298AA genotype was observed in the patients with prostate cancer (aOR=0.3, 95% CI: 0.1-1.1). This particular genotype, moreover, was associated with lower Gleason score tumors (aOR=0.1 for Gleason-score 7 versus 6 tumors, 95% CI: 0.0-0.7) and earlier stage disease (aOR=0.3 for stage III versus II, 95% CI: 0.3-2.6). These findings suggest that polymorphisms of the MTHFR gene may alter the risk of developing prostate cancer.

Aged↗

PubMed2003

Induction of CD8 T-cell-Ifn-gamma response and positive clinical outcome after immunization with gene-modified allogeneic tumor cells in advanced non-small-cell lung carcinoma.

Large tumor burdens in advanced non-small-cell lung carcinoma (NSCLC) are thought to be immunosuppressive. To determine whether CD8-mediated immune responses could be elicited in stage IIIB/IV NSCLC patients, 14 subjects were immunized several times with allogeneic NSCLC cells transfected with CD80 (B7.1) and HLA-A1 or A2. Patients enrolled were matched or unmatched at the HLA A1 or A2 locus and their immune response compared. Immunization significantly increased the frequencies of interferon-gamma secreting CD8 T cells in all but one patient in response to ex vivo challenge with NSCLC cells. The CD8 response of matched and unmatched patients was not statistically different. NSCLC reactive CD8 cells did not react to K562. Clinically, five of 14 patients responded to immunization with stable disease or partial tumor regression. The study demonstrates that CD8 Ifn-gamma responses against nonimmunogenic or immunosuppressive tumors can be evoked by cellular vaccines even at advanced stages of disease. The positive clinical outcome suggests that nonimmunogenic tumors may be highly susceptible to immune effector cells generated by immunization.

Adult↗

PubMed2003

Evaluating systematic reviews and meta-analyses.

Systematic review and meta-analysis procedures make use of explicit methods to methodically search and critically appraise and synthesize the medical care research literature. The methods involve refining a clinical question, designing a search procedure to find eligible studies, and determining the validity of the eligible studies. Independent data extraction by two or more reviewers is preferred. Agreement between the reviewers with respect to relevance and validity should be measured. Meta-analysis procedures estimate an overall average effect from the individual study effects and determine whether these effects appear to measure the same relationship (that is, the studies are not heterogeneous). In the inverse variance method, which is most frequently applied, the overall effect is a weighted average of the individual study effects, where each weight is the inverse of the study variance. To evaluate a systematic review, first determine whether it addresses a question that is relevant to the patients, treatments, and outcomes that are usual in your clinical practice. Then assess the validity of the systematic review, which is reflected by quality of the individual studies, the rigor with which the systematic methods were applied, and the extent of heterogeneity. If the results of the systematic review are valid, then is the effect important enough to make a difference in your clinical practice? Applying the results to an individual patient involves the absolute treatment effect or the number needed to treat, and an awareness of the patient's specific level of risk and personal preferences.

Data Interpretation, Statistical↗

PubMed2002

Risk of positive margins and biochemical recurrence in relation to nerve-sparing radical prostatectomy.

PURPOSE: To assess the effect of nerve-sparing (NS) radical retropubic prostatectomy (RRP) on surgical margins and biochemical recurrence. PATIENTS AND METHODS: Location and incidence of positive surgical margins, recurrence, and time to recurrence were assessed in a consecutive series of 734 men who underwent RRP for localized prostate cancer from 1992 through February 2000. NS procedures were used in 33% (n = 240) of 734 patients studied. RESULTS: Surgical margins were positive for 24% (n = 58) and 31% (n = 152) of NS and non-NS patients, respectively (P =.06). No significant difference between the groups was found in location of positive margins (P =.92). Prostate-specific antigen level greater than 10 ng/mL, extraprostatic extension, tumor volume more than 20%, capsular penetration, Gleason score > or = 7, positive margins, and seminal vesicle invasion were associated with significantly increased risk of recurrence. However, NS patients were not at increased risk of recurrence compared with non-NS patients (hazard ratio, 0.96; 95% confidence interval, 0.53 to 1.72). The cumulative risk of recurrence within 3 and 5 years of surgery in NS patients was 9.7% and 14.4%, respectively, as compared with 17.1% and 21.1% for non-NS patients. CONCLUSION: In patients with localized prostate cancer, neither margin status nor biochemical-free survival within 5 years of surgery were altered by the nerve preservation technique. Given our experience, we recommend preservation of neurovascular bundles in these patients whenever the procedure is technically feasible.

Aged↗

PubMed2002

Perimenopausal use of reproductive hormones effects on breast and endometrial cancer.

The effect of reproductive hormone use in the form of oral contraception or HRT on endometrial cancer incidence is not caused by simply bias: the epidemiologic studies are consistent; the effect of ERT is large; the biologic rationale cited is a plausible mechanism; and the response to progestin in oral contraception or combined HRT tends to confirm the biologic mechanism. In contrast, it remains unclear whether changes in breast cancer incidence following use of oral contraception and HRT are caused by hormone exposure or to other factors: the results of epidemiologic studies are not entirely consistent, and the smaller relative effect on risk of breast cancer is susceptible to bias and other sources of error. Although the exact nature of the association between repro ductive hormone use and breast cancer incidence is not yet clear, breast cancer is a common neoplasm in older women. Prescribers and users should take this into account in weighing benefits to ensure that unnecessary risks are avoided.

Breast Neoplasms↗

PubMed2002

Family history of cancer, oral contraceptive use, and ovarian cancer risk.

OBJECTIVE: The purpose of this study was to determine whether women with a family history of ovarian cancer are at reduced risk of ovarian cancer from the use of oral contraceptives and to compare their risk with that of women with no family history of ovarian cancer. STUDY DESIGN: A population-based case-controlled study was conducted from May 1994 through July 1998 in which 767 women aged 20 to 69 years with a diagnosis of epithelial ovarian cancer were ascertained from 39 hospitals in 3 northeastern states. Personal interviews with the women and 1367 control subjects provided data that allowed us to estimate the relative risk of ovarian cancer in relation to a family history of cancer and total duration of oral contraception. RESULTS: Among the 33 case patients and 24 control subjects with a first-degree family history of ovarian cancer, risk of ovarian cancer declined with increasing duration of oral contraception (P =.01). Risk reduction from short-term use of oral contraceptives (< or = 48 months) did not differ significantly by family history (combined estimate of odds ratio, 0.72; 90% CI, 0.59%-0.87%). Risk reduction from long-term use of oral contraceptives (>48 months) was greater in women with a positive family history of ovarian cancer (odds ratio, 0.12) than in women with a negative family history of ovarian cancer (odds ratio, 0.51; test of interaction, P =.04; 692 case patients, 1279 control subjects). CONCLUSION: Four to 8 years of oral contraception may substantially reduce the risk of ovarian cancer by age 70 years in women with a family history of the disease, from approximately 4 women per 100 women who did not use oral contraceptives to only 2 women per 100 women who did use oral contraceptives.

Adult↗

PubMedDate not supplied

Phase II clinical trials in oncology: strengths and limitations of two-stage designs.

Two-stage designs are used widely in Phase II oncology clinical trials to reduce the number of patients placed on ineffective experimental therapies. They provide clear-cut rules for stopping early in the event that treatment is not succeeding as hoped and are relatively simple to implement. Such designs, however, can lead to situations in which patient accrual is continued in the face of a clearly inferior treatment. In situations where patients' response can be determined for many or most subjects before additional patients are enrolled, analyses using Bayesian methodology can lead to earlier termination of studies of ineffective treatments and better align the statistical assessment of treatment effect with the therapeutic objectives of study. These points are discussed in context of the role of Phase II clinical trials in the development of new treatments for cancer.

Bayes Theorem↗