Stuart D. Flynn

Prior medical conditions and medication use and risk of non-Hodgkin lymphoma in connecticut United States women

AbstractObjective: To further investigate the role of prior medical conditions and medication use in the etiology of non-Hodgkin lymphoma (NHL), we analyzed the data from a population-based case–control study of NHL in Connecticut women. Methods: A total of 601 histologically confirmed incident cases of NHL and 717 population-based controls were included in this study. In-person interviews were administered using standardized, structured questionnaires to collect information on medical conditions and medication use. Results: An increased risk was found among women who had a history of autoimmune disorders (such as rheumatoid arthritis, lupus erythematosus, Sjogrens syndrome, and multiple sclerosis), anemia, eczema, or psoriasis. An increased risk was also observed among women who had used steroidal anti-inflammatory drugs and tranquilizers. A reduced risk was found for women who had scarlet fever or who had used estrogen replacement therapy, aspirin, medications for non-insulin dependent diabetes, HMG-CoA reductase inhibitors, or beta-adrenergic blocking agents. Risk associated with past medical history appeared to vary based on NHL subtypes, but the results were based on small number of exposed subjects. Conclusion: A relationship between certain prior medical conditions and medication use and risk of NHL was observed in this study. Further studies are warranted to confirm our findings.

EVALUATION OF HER-2 NEU ONCOPROTEIN EXPRESSION AS A PROGNOSTIC INDICATOR OF LOCAL RECURRENCE IN CONSERVATIVELY TREATED BREAST CANCER: A CASE-CONTROL STUDY

PURPOSE The purpose of this study is to determine the prognostic significance of overexpression of the HER-2 neu oncoprotein with respect to local relapse following conservative surgery and radiation therapy (CS + RT). METHODS AND MATERIALS Twenty consecutive patients who sustained a local recurrence as the first and only site of failure following CS + RT comprised the case population base for this study. Only patients who received no adjuvant systemic chemotherapy or tamoxifen were selected for analysis. Following the identification of 20 consecutive local-relapse patients, the patient database was searched for 20 matching control patients who did not sustain a local relapse. Each control patient was matched to the index case with respect to age, menopausal status, follow-up, primary histology, axillary nodal status, and primary tumor size. Both index cases and the matched control group received full course radiation therapy, to a total dose of 64 Gy to the tumor bed. The paraffin-embedded blocks of the original primary tumor of the local-relapse cases and the primary tumor of 20 matched controls were processed for immunohistochemical staining of the HER-2 neu oncoprotein. Each slide was rated on the 3-point scale, 0 representing no stain, 1+ indicating light staining, and 2+ denoted heavy staining (overexpression). RESULTS Of the 20 index cases, with each of the matched controls, 16 were evaluable for analysis. The 4 cases that were eliminated had inadequate paraffin-embedded material in either the case or the match control for adequate staining. By design of the study, the index case group and control group had similar ages (52 years index vs. 51.4 control), follow-up (10.8 years index vs. 10.5 years control), and histologies. For the immunostaining, a value of 2+ was considered to denote high activity and overexpression, and 0 and 1+ were considered negative values. Using these criteria, a total of 9 of the 16 index cases (56%) exhibited overexpression of HER-2 neu oncoprotein, and only 3 of the 16 control cases (18%) demonstrated high immunoreactivity. The difference in immunostaining between the index and control cases was statistically significant by a Pierson chi-square analysis at the p = 0.03 level. CONCLUSIONS In this matched case-control study, overexpression of the HER-2 neu oncoprotein appears to have prognostic significance with respect to local relapse in the conservatively treated breast. The correlation of overexpression of HER-2 neu by multivariable analysis with other prognostic factors for local recurrence warrants further investigation. The clinical implications of the study are discussed.

Local recurrence versus new primary: Clinical analysis of 82 breast relapses and potential applications for genetic fingerprinting☆

PURPOSE The purpose of this study was to perform a detailed clinical pathological analysis of breast relapses in patients treated with conservative surgery and radiation therapy in an effort to classify those relapses as true local recurrences or second primary tumors, and to assess the prognostic and therapeutic implications of such a classification system. METHODS AND MATERIALS Of 990 patients treated with conservative surgery and radiation therapy at our facilities prior to December 1987, 82 patients have experienced a relapse in the conservatively treated breast as the primary site of failure. Patients were classified as having new primary tumors if they fulfilled any one of the following criteria: a) breast relapse occurring at a site distinctly removed from the original tumor; b) histology of the breast relapse compared with the original tumor consistent with a new primary; or c) DNA flow cytometry converting from an aneuploid primary to a diploid relapse. RESULTS As of 2/92, with a median follow-up of 5.4 years from the time of breast relapse, the overall 5-year survival rate following breast relapse was 55%. Forty-seven patients were classified as true recurrences and 33 patients were classified as new primaries. Patients classified as true recurrences had a shorter median time to breast relapse than patients classified as new primaries (3.16 years vs. 5.42 years, p < .05) and an inferior post breast recurrence survival rate compared to patients classified as new primaries (36% vs. 89%, p < .05). Residual disease outside of the recurrent tumor bed was also noted to be more frequent in patients classified as true recurrences compared to patients classified as new primaries (48% vs. 16%, p < .05). CONCLUSION Based on the clinical and pathological criteria outlined, it appears that a significant portion of patients experiencing a relapse in the conservatively treated breast may have new primary tumors as opposed to true local relapses. Distinction between a true recurrence and a new primary tumor may have significant prognostic implications. Uncertainties associated with the clinical and pathological criteria are presented and further investigations with genetic fingerprinting techniques to establish the clonality of breast relapses are presented and discussed.

Cigarette smoking and risk of non-Hodgkin lymphoma subtypes among women

Previous studies of the relationship between cigarette smoking and non-Hodgkin lymphoma (NHL) have yielded conflicting results, perhaps because most studies have evaluated the risk for all NHL subtypes combined. Data from a population-based case–control study conducted among women in Connecticut were used to evaluate the impact of cigarette smoking on the risk of NHL by histologic type, tumour grade, and immunologic type. A total of 601 histologically confirmed, incident cases of NHL and 718 population-based controls provided in-person interviews. A standardised, structured questionnaire was used to collect information on each subjects current smoking status, age at initiation, duration and intensity of smoking, and cumulative lifetime exposure to smoking. Our data suggest that cigarette smoking does not alter the risk of all NHL subtypes combined. However, increased risk of follicular lymphoma appears to be associated with increased intensity and duration of smoking, and cumulative lifetime exposure to smoking. Compared with nonsmokers, women with a cumulative lifetime exposure of 16–33 pack-years and 34 pack-years or greater experience 50% increased risk (OR=1.5, 95% CI 0.9–2.5) and 80% increased risk (OR=1.8, 95% CI 1.1–3.2), respectively, of follicular lymphoma (P for linear trend=0.05). Our study findings are consistent with several previous epidemiologic studies suggesting that cigarette smoking increases the risk of follicular lymphoma. This research highlights the importance of distinguishing between NHL subtypes in future research on the aetiology of NHL.

Mechanism of technetium 99m sestamibi parathyroid imaging and the possible role of p-glycoprotein

BACKGROUND Localization of parathyroid glands is critical in the treatment of recurrent or persistent hyperparathyroidism. Technetium sestamibi imaging may improve localization; however, the mechanism of visualization of parathyroid tissue remains unclear. On the basis of the chemical structure of sestamibi it has been suggested that p-glycoprotein is involved in the transport of sestamibi across cell membranes. This study was designed to examine sestamibi uptake and retention and p-glycoprotein expression in normal and abnormal parathyroid tissue. METHODS Thirty-two consecutive patients underwent 2-methoxy-isobutyl-isonitrile imaging immediately before parathyroid exploration. Tissue was obtained from normal and abnormal parathyroids and from the thyroid gland. Touch preparations gave rapid confirmation of tissue origin. Specimens were trimmed and weighed, and gamma-emission was counted. Percentage injected dose per gram of tissue was calculated. Immunohistochemistry was obtained with a battery of monoclonal antibodies to identify p-glycoprotein in parathyroid tissue submitted for permanent histologic examination. Slides were graded by a pathologist familiar with immunohistochemistry. RESULTS Abnormal parathyroid tissue had a higher mean retention of injected dose per gram than did normal thyroid and parathyroid tissue. Immunohistochemistry revealed that abnormal parathyroid tissue expresses less p-glycoprotein. CONCLUSIONS These results suggest that size is not the single determinant of parathyroid visualization and that p-glycoprotein expression may be involved in the mechanism of parathyroid imaging.

Alcohol use and risk of non-Hodgkin's lymphoma among Connecticut women (United States).

Objective: Incidence rates of non-Hodgkins lymphoma (NHL) have risen dramatically over the past several decades; however, the etiology of NHL remains largely unknown. Previous studies of the relationship between alcohol consumption and NHL have yielded conflicting results. Data from a population-based case–control study among women in Connecticut were analyzed to determine the potential impact of alcohol consumption on risk of NHL. Methods: The study included 601 histologically confirmed, incident cases of NHL and 718 population-based controls. In-person interviews were administered using standardized, structured questionnaires to collect data on history of consumption for beer, wine, and liquor. Results: When compared to non-drinkers, women who reported consumption of at least 12 drinks per year of any type of alcohol experienced slightly reduced risk of NHL (OR: 0.82; 95% CI: 0.65–1.04). Further stratification by alcohol type revealed that the inverse association was mainly limited to wine consumption (OR: 0.75; 95% CI: 0.59–0.96), with no clear association for beer or liquor consumption. Risk of NHL was further reduced with increasing duration of wine consumption (p for linear trend = 0.02). Consumption of wine for greater than 40 years was associated with approximately 40% reduction in risk (OR: 0.63; 95% CI: 0.44–0.91). Conclusion: Our results are consistent with several recent epidemiologic studies that have also suggested an inverse association between wine consumption and risk of NHL. The reduction in risk of NHL associated with increased duration of wine consumption warrants further investigation in other populations.

Functional assay for HER-2/neu demonstrates active signalling in a minority of HER-2/neu-overexpressing invasive human breast tumours

Overexpression of HER-2/neu in human breast carcinomas correlates with poor prognosis, although its strength as a prognostic indicator varies widely in different reports. Variability may be due to active signalling by HER-2/neu in a subset of the tumours in which it is overexpressed. To study this hypothesis, we have developed an activation state-specific anti-HER-2/neu monoclonal antibody. In this report, we use this antibody to analyse the signalling status of HER-2/neu in a large series of invasive breast carcinomas. Overexpression of HER-2/neu was detected in 9% of 223 cases. Of the cases demonstrating overexpression, active signalling by HER-2/neu was detected in only 35%. The clinicopathological characteristics of these cases are described. This functional assay is predicted to improve the utility of HER-2/ neu as a prognostic indicator.

Pulmonary meningiomas: A report of two cases☆

Two intraparenchymal lung tumors exhibiting the histopathologic and immunophenotypic characteristics of an intracranial meningioma are presented. The meningiomas presented as solitary asymptomatic nodules in elderly individuals. Both patients survived longer than 3 years following resection, and neither displayed clinical or radiographic evidence of a central nervous system tumor, suggesting that these are primary lung tumors. Review of the literature and discussion of other lesions in the differential diagnosis of this rare intrapulmonary neoplasm are presented.

Trifluoperazine as a modulator of multidrug resistance in refractory breast cancer

Abstract Overexpression of P-glycoprotein (P-gp) has been implicated as the mechanism of multidrug resistance (MDR) in a number of human cancers, including carcinoma of the breast. We conducted a clinical trial to determine whether the P-gp inhibitor, trifluoperazine, could sensitize patients with refractory breast cancer to vinblastine chemotherapy. Adult patients with histologically confirmed, refractory, advanced breast cancer were treated with vinblastine at a dose of 1.7 mg/m2 per day by continuous infusion for five consecutive days. Patients who did not respond after two cycles were subsequently treated with vinblastine plus trifluoperazine at a dose of 8 mg twice daily during the five days of chemotherapy. In patients from whom tumor samples were available, the expression of P-gp was determined by immunocytochemistry. Of 35 patients enrolled, 30 were evaluable, 2 of whom (7%) achieved a partial response to vinblastine alone. Among the 16 patients treated with vinblastine plus trifluoperazine there was one response (6%) which lasted 16 weeks. Tumor samples were available from 16 patients, and 14 (87%) were immunoreactive for P-gp. P-gp expression was detected both in the patient who responded to vinblastine plus trifloperazine and in one of the two patients who responded to vinblastine alone. Continuous-infusion vinblastine demonstrated limited activity in this study. Furthermore, trifluoperazine did not effectively reverse established resistance to vinblastine. This failure may be related the presence of multiple mechanisms of drug resistance in this heavily pretreated population, or because ineffective concentrations of the modulator were achieved in vivo. Future studies should evaluate more effective modulators, and attempt to reverse MDR earlier in the course of treatment, before other forms of resistance can develop.

Prognostic value of DNA flow cytometry in the locally recurrent, conservatively treated breast cancer patient.

PURPOSEThis study attempted to determine the prognostic value of DNA flow cytometry in the treatment of patients with locally recurrent, conservatively treated breast cancer.METHODS AND MATERIALSOf 433 patients with clinical stage I and II breast cancer treated with conservative surgery and radiotherapy at Yale-New Haven Hospital before January 1985, 50 patients experienced an ipsilateral breast relapse as a first site of treatment failure. Using standard flow-cytometric techniques, DNA ploidy, DNA index, and S-phase fraction (SPF) were measured for 38 of the 50 (76%) paraffin-embedded specimens available for analysis.RESULTSAt a median postrecurrence follow-up of 5.8 years, the 5-year and disease-free survival rates following ipsilateral breast treatment failure were 48% and 54%, respectively. Sixty-three percent of the recurrent tumors were DNA diploid and 37% were aneuploid. Both DNA ploidy and SPF were statistically significant prognostic indicators for 5-year survival and disease-free survival after ...