Nhu D. Le

Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer

BACKGROUND Radiotherapy after mastectomy to treat early breast cancer has been known since the 1940s to reduce rates of local relapse. However, the routine use of postoperative radiotherapy began to decline in the 1980s because it failed to improve overall survival. We prospectively tested the efficacy of combining radiotherapy with chemotherapy. METHODS From 1978 through 1986, 318 premenopausal women with node-positive breast cancer were randomly assigned, after modified radical mastectomy, to receive chemotherapy plus radiotherapy or chemotherapy alone. Radiotherapy was given to the chest wall and locoregional lymph nodes between the fourth and fifth cycles of cyclophosphamide, methotrexate, and fluorouracil. RESULTS After 15 years of follow-up, the women assigned to chemotherapy plus radiotherapy had a 33 percent reduction in the rate of recurrence (relative risk, 0.67; 95 percent confidence interval, 0.50 to 0.90) and a 29 percent reduction in mortality from breast cancer (relative risk, 0.71; 95 percent confidence interval, 0.51 to 0.99), as compared with the women treated with chemotherapy alone. CONCLUSIONS Radiotherapy combined with chemotherapy after modified radical mastectomy decreases rates of locoregional and systemic relapse and reduces mortality from breast cancer.

Use of Allelic Loss to Predict Malignant Risk for Low-grade Oral Epithelial Dysplasia

One of the best approaches to identifying genetic changes critical to oral cancer progression is to compare progressing and nonprogressing oral premalignant lesions. However, such samples are rare, and they require long-term follow-up. The current study used the large archive network and clinical database in British Columbia to study loss of heterozygosity (LOH) in cases of early oral premalignancies, comparing those with a history of progression to carcinoma in situ or invasive cancer and those without a history of progression (referred to as nonprogressing cases). Each of 116 cases was analyzed for LOH at 19 microsatellite loci on seven chromosome arms (3p, 4q, 8p, 9p, 11q, 13q, and 17p). The progressing and nonprogressing cases showed dramatically different LOH patterns of multiple allelic losses. An essential step for progression seems to involve LOH at 3p and/or 9p because virtually all progressing cases showed such loss. However, LOH at 3p and/or 9p also occurred in nonprogressing cases. Individuals with LOH at 3p and/or 9p but at no other arms exhibit only a slight increase of 3.8-fold in relative risk for developing cancer. In contrast, individuals with additional losses (on 4q, 8p, 11q, or 17p), which appeared uncommon in nonprogressing cases, showed 33-fold increases in relative cancer risk. In conclusion, analysis of LOH at 3p and 9p could serve as an initial screening for cancer risk of early premalignancies. Follow-up investigation for additional losses would be essential for predicting cancer progression.

Quality of life and oral function following radiotherapy for head and neck cancer.

Multiple oral complaints occur following radiotherapy for oropharyngeal cancer, but the frequency and severity of symptoms of dysfunction and discomfort are not well understood. The purpose of this investigation was to assess the quality of life, oral function, and oral symptoms following radiotherapy.

Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma

Ovarian surface epithelial carcinomas are routinely subclassified by pathologists based on tumor cell type and grade. It is controversial whether cell type or grade is superior in predicting patient response to treatment or survival, in patients stratified by stage of disease. The aim of this study was to uniformly apply updated criteria for cell-type and grade assignment to a series of 575 cases of ovarian surface epithelial carcinoma. All patients were optimally surgically debulked, with no macroscopic residual disease after primary surgery. Slides from these cases were reviewed by a single pathologist, who was blinded to patient outcomes. In 50 cases, 2 additional pathologists reviewed the slides independently to determine interobserver variation in assessment of cell type and grade. The distribution of tumor stage was as follows: stage I--233 cases, stage II--246 cases, stage III--96 cases. The most common cell type encountered was serous carcinoma (229/575, 40%), followed by clear cell (149/575, 26%), endometrioid (139/575, 24%), and mucinous (36/575, 6%). Serous carcinomas were significantly more likely to present with advanced stage disease (76/229 [33.2%] were stage III, and 82% of all stage III tumors were serous), whereas all nonserous cell types were stage I or II at diagnosis in greater than 90% of cases. Both FIGO grade and Silverberg grade stratified patients into groups with significantly different risks of relapse and survival, but the Silverberg grading system was a more powerful prognosticator. In multivariate analysis, stage was the most powerful prognostic indicator (P < .0001), followed by tumor cell type (P = .015), but grade was not of independent significance. Interobserver variation in assignment of cell type was very good (kappa = 0.77) with moderate reproducibility in assignment of Silverberg grade (kappa = 0.40) and minimal reproducibility in assignment of FIGO grade (kappa = 0.27). Thus, in this series of cases of ovarian surface epithelial carcinomas with no macroscopic residual disease after primary debulking surgery, assignment of tumor cell type was both more reproducible and provided superior prognostic information compared with assignment of tumor grade. As tumor cell type also correlates with underlying molecular abnormalities and may predict response to chemotherapy, this suggests that tumor cell type could be used to guide treatment decisions for patients with ovarian surface epithelial carcinoma.

Carcinogenic and endocrine disrupting effects of cigarette smoke and risk of breast cancer

BACKGROUND Results of epidemiological studies, assessing the relation between smoking and breast cancer, have been inconclusive. Our aim was to assess the carcinogenic and possibly antioestrogenic effects of cigarette smoke on risk of breast cancer. METHODS We sent a questionnaire to 1431 women younger than age 75 years who had breast cancer and were listed on the population-based British Columbia cancer registry between June 1, 1988, and June 30, 1989. We also sent questionnaires to 1502 age-matched controls, randomly selected from the 1989 provincial voters list. We obtained information on all known and suspected risk factors for breast cancer, and on lifetime smoking, alcohol consumption, and occupational history. We assessed the effect of smoking separately for premenopausal and postmenopausal women, adjusting for confounding variables. FINDINGS 318 premenopausal women and 340 controls replied. Risk of breast cancer was significantly increased (adjusted odds ratio 1.69, 95% CI 1.13-2.51) in women who had been pregnant and who started to smoke within 5 years of menarche, and in nulliparous women who smoked 20 cigarettes daily or more (7.08, 1.63-30.8) and had smoked for 20 cumulative pack-years or more (7.48, 1.59-35.2). Postmenopausal women (700 breast cancer and 685 controls) whose body-mass index increased from age 18 to current and who started to smoke after a first fullterm pregnancy had a significantly reduced risk of breast cancer (0.49, 0.27-0.89). INTERPRETATION Our results suggest that cigarette smoke exerts a dual action on the breast, with different effects in premenopausal and postmenopausal women. Our observations reinforce the importance of smoking prevention, especially in early adolescence, and draw attention to the timing of exposure in relation to susceptibility and refractory windows in the design of studies to investigate associations between environmental carcinogens or putative endocrine disruptors and risk of breast cancer.

Toluidine Blue Staining Identifies High-Risk Primary Oral Premalignant Lesions with Poor Outcome

There is a pressing need for the development of visual aids that will facilitate the detection of oral premalignant lesions (OPLs) with a high-risk of progression. Preliminary data suggest that toluidine blue stain may be preferentially retained by OPLs with high-risk molecular clones. In this study, we monitored OPLs from 100 patients without any history of oral cancer for an average of 44 months in order to evaluate the association of toluidine blue status with clinicopathologic risk factors, molecular patterns (microsatellite analysis on seven chromosome arms: 3p, 9p, 4q, 8p, 11q, 13q, and 17p) and outcome. Toluidine blue-positive staining correlated with clinicopathologic risk factors and high-risk molecular risk patterns. Significantly, a >6-fold elevation in cancer risk was observed for toluidine blue-positive lesions, with positive retention of the dye present in 12 of the 15 lesions that later progressed to cancer (P = 0.0008). This association of toluidine blue status with risk factors and outcome was evident even when the analysis was restricted to OPLs with low-grade or no dysplasia. Our results suggest the potential use of toluidine blue in identifying high-risk OPLs.

Interpolation with uncertain spatial covariances: a Bayesian alternative to Kriging

In this paper a Bayesian alternative to Kriging is developed. The latter is an important tool in geostatistics. But aspects of environmetrics make it less suitable as a tool for interpolating spatial random fields which are observed successively over time. The theory presented here permits temporal (and spatial) modeling to be done in a convenient and flexible way. At the same time model misspecifications, if any, can be corrected by additional data if and when it becomes available, and past data may be used in a systematic way to fit model parameters. Finally, uncertainty about model parameters is represented in the (posterior) distributions, so unrealistically small credible regions for the interpolants are avoided. The theory is based on the multivariate normal and related distributions, but because of the hierarchical prior models adopted, the results would seem somewhat robust with respect to the choice of these distributions and associated hyperparameters.

A double-blind crossover trial of Oral Balance gel and Biotene toothpaste versus placebo in patients with xerostomia following radiation therapy.

Following therapeutic irradiation of the head and neck, patients with profound xerostomia have complaints associated with oral dryness, effects upon use of oral prosthesis, speech, and taste. In addition, xerostomia may lead to risk of oral infections and rampant demineralization of teeth. The use of topical Oral Balance gel and Biotene toothpaste (Laclede Professional Products, Gardena, CA) versus carboxymethylcellulose gel and commercial toothpaste applications was assessed in a 2-week double-blind, crossover design. The palliative effects of Oral Balance gel and Biotene toothpaste were superior to the effects of a placebo. No effect on oral colonization by Candida species and cariogenic oral microflora was seen with use of the topical agents.

Organochlorines and risk of non-Hodgkin lymphoma

Organochlorine chemicals and polychlorinated biphenyls (PCBs) have been suspected as possible risk factors for non‐Hodgkin lymphoma (NHL). We investigated PCBs and organochlorine pesticides and risk of NHL in a population‐based case–control study in British Columbia, Canada. Congeners of PCBs (including dioxinlike congeners) and pesticides or pesticide metabolites were measured in plasma of 422 pretreatment cases and 460 control subjects. This is so far the largest study to examine organochlorines in plasma to date. Several dioxin‐like PCB congeners were associated with increased risk of NHL, including dioxin‐like PCB nos. 118 and 156 with odds ratios (OR) for the highest versus lowest quartile between 1.6 and 1.8. Several non‐dioxin‐like congeners also showed significant associations. The PCB congener with the strongest association was no. 180 with an OR for the highest versus the lowest quartile of 1.83 (95% confidence interval = 1.18–2.84). Six pesticide analytes also showed a significant association with NHL; β‐hexachlorocyclohexane, p,p′‐DDE, hexachlorobenzene, mirex, oxychlordane and trans‐nonachlor. The strongest association was found for oxychlordane, a metabolite of the pesticide chlordane (highest vs. lowest quartile OR = 2.68, 95% confidence interval = 1.69–4.24). Our results provide further evidence that organochlorines contribute to NHL risk.

Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease subtypes.

Summary. The clinical and pathological features, including karyotype data and BCL2 protein expression pattern, of follicular lymphoma without a t(14;18)(q32;q21) have not been well defined. We have identified and conducted a detailed analysis of 50 cases with follicular lymphoma who lack the t(14;18). Fluorescent in situ hybridization (FISH) analysis was used to exclude cases with a cryptic IGH/BCL2 rearrangement. BCL2 protein expression level was assessed by immunohistochemistry. The karyotypes were assessed for recurrent sites of structural rearrangement, duplications and deletions on a band‐by‐band basis, and compared with a large cohort of cases with t(14;18). A distinct pattern of chromosomal alterations was identified in the cases without t(14;18). BCL2 protein overexpression was detected in 33% of 49 tested cases. In this minority, the karyotypes frequently showed increased copies of chromosome 18. The majority of cases (67%) did not show BCL2 overexpression and were characterized prominently by the presence of t(3;14)(q27;q32), implying a role for BCL6. Follicular lymphomas that lack a t(14;18) were segregated into two subgroups with distinct cytogenetic, phenotypic and possibly clinical features: one with BCL2 protein overexpression not related to an IGH/BCL2 rearrangement and a second without BCL2 overexpression. Objective identification of BCL2 expression level as well as BCL2 and BCL6 status by cytogenetic or FISH analysis has potential clinical utility and may yield insights into alternative genetic mechanisms associated with B‐cell lymphomas with a follicular growth pattern.