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John Bryant

Publications and source records attributed to John Bryant.

31 records · Page 2Linked to original sources
PubMed2003

Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience.

PURPOSE: We reviewed data from all adjuvant NSABP breast cancer trials that tested regimens containing both doxorubicin (A) and cyclophosphamide (C) to characterize the incidence of subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). MATERIALS AND METHODS: Six complete NSABP trials have investigated AC regimens (B-15, B-16, B-18, B-22, B-23, and B-25). Six distinct AC regimens have been tested and are distinguished by differences in cyclophosphamide intensity and cumulative dose and by the presence or absence of mandated prophylactic support with growth factor and ciprofloxacin. In all regimens, A was given at 60 mg/m(2) q 21 days x 4. C was given as follows: 600 mg/m(2) q 21 days x 4 ("standard AC"); 1,200 mg(2) q 21 days x 2; 1,200 mg/m(2) q 21 days x 4; 2,400 mg/m(2) q 21 days x 2; and 2,400 mg/m(2) q 21 days x 4. Occurrence of AML/MDS was summarized by incidence per 1,000 patient-years at risk and by cumulative incidence. Rates were compared across regimens, by age, and by treatment with or without breast radiotherapy. RESULTS: The incidence of AML/MDS was sharply elevated in the more intense regimens. In patients receiving two or four cycles of C at 2,400 mg/m(2) with granulocyte colony-stimulating factor (G-CSF) support, cumulative incidence of AML/MDS at 5 years was 1.01% (95% confidence interval [CI], 0.63% to 1.62%), compared with 0.21% (95% CI, 0.11% to 0.41%) for patients treated with standard AC. Patients who received breast radiotherapy experienced more secondary AML/MDS than those who did not (RR = 2.38, P=.006), and the data indicated that G-CSF does may possibly also be independently correlated with increased risk. CONCLUSION: AC regimens employing intensified doses of cyclophosphamide requiring G-CSF support were characterized by increased rates of subsequent AML/MDS, although the incidence of AML/MDS was small relative to that of breast cancer relapse. Breast radiotherapy appeared to be associated with an increased risk of AML/MDS.

Aged↗
PubMed2002

Recovery and separation of cell lysate proteins using hydrogels guided by aqueous two-phase extraction principles.

The addition of poly(ethylene glycol) and salts to clarified cell lysates of Thiosphaera pantotropha increases sorption of microbial proteins into dextran hydrogels, consistent with the thermodynamics of aqueous two-phase extraction. Addition of 12 wt% PEG-10,000 to the lysate increased total sorption of protein by the dextran gel from 5.2 mg/g dextran to 37 mg/g; addition of either 0.1 M potassium iodide or tetrabutylammonium fluoride along with PEG to the lysate increased protein sorption to more than 63 mg/g, a 12-fold increase. SDS-PAGE demonstrated that the type of salt added controls which proteins are absorbed by the gel. Previously demonstrated only with model solutions, these results suggest another approach to recovery and separation strategies for proteins produced by fermentation.

Absorption↗
PubMed2002

Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.

BACKGROUND: In 1976, we initiated a randomized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer. METHODS: A total of 1851 women for whom follow-up data were available and nodal status was known underwent randomly assigned treatment consisting of total mastectomy, lumpectomy alone, or lumpectomy and breast irradiation. Kaplan-Meier and cumulative-incidence estimates of the outcome were obtained. RESULTS: The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3 percent in the women who underwent lumpectomy and breast irradiation, as compared with 39.2 percent in the women who underwent lumpectomy without irradiation (P<0.001). No significant differences were observed among the three groups of women with respect to disease-free survival, distant-disease-free survival, or overall survival. The hazard ratio for death among the women who underwent lumpectomy alone, as compared with those who underwent total mastectomy, was 1.05 (95 percent confidence interval, 0.90 to 1.23; P=0.51). The hazard ratio for death among the women who underwent lumpectomy followed by breast irradiation, as compared with those who underwent total mastectomy, was 0.97 (95 percent confidence interval, 0.83 to 1.14; P=0.74). Among the lumpectomy-treated women whose surgical specimens had tumor-free margins, the hazard ratio for death among the women who underwent postoperative breast irradiation, as compared with those who did not, was 0.91 (95 percent confidence interval, 0.77 to 1.06; P=0.23). Radiation therapy was associated with a marginally significant decrease in deaths due to breast cancer. This decrease was partially offset by an increase in deaths from other causes. CONCLUSIONS: Lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained.

Breast Neoplasms↗
PubMed2002

Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.

PURPOSE: This trial was prompted by uncertainty about the need for breast irradiation after lumpectomy in node-negative women with invasive breast cancers of </= 1 cm, by speculation that tamoxifen (TAM) might be as or more effective than radiation therapy (XRT) in reducing the rate of ipsilateral breast tumor recurrence (IBTR) in such women, and by the thesis that both modalities might be more effective than either alone. PATIENTS AND METHODS: After lumpectomy, 1,009 women were randomly assigned to TAM (n = 336), XRT and placebo (n = 336), or XRT and TAM (n = 337). Rates of IBTR, distant recurrence, and contralateral breast cancer (CBC) were among the end points for analysis. Cumulative incidence of IBTR and of CBC was computed accounting for competing risks. Results with two-sided P values of.05 or less were statistically significant. RESULTS: XRT and placebo resulted in a 49% lower hazard rate of IBTR than did TAM alone; XRT and TAM resulted in a 63% lower rate than did XRT and placebo. When compared with TAM alone, XRT plus TAM resulted in an 81% reduction in hazard rate of IBTR. Cumulative incidence of IBTR through 8 years was 16.5% with TAM, 9.3% with XRT and placebo, and 2.8% with XRT and TAM. XRT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status. Distant treatment failures were infrequent and not significantly different among the groups (P =.28). When TAM-treated women were compared with those who received XRT and placebo, there was a significant reduction in CBC (hazard ratio, 0.45; 95% confidence interval, 0.21 to 0.95; P =.039). Survival in the three groups was 93%, 94%, and 93%, respectively (P =.93). CONCLUSION: In women with tumors </= 1 cm, IBTR occurs with enough frequency after lumpectomy to justify considering XRT, regardless of tumor ER status, and TAM plus XRT when tumors are ER positive.

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PubMed2002

Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation.

BACKGROUND: In women with breast cancer, the role of radical mastectomy, as compared with less extensive surgery, has been a matter of debate. We report 25-year findings of a randomized trial initiated in 1971 to determine whether less extensive surgery with or without radiation therapy was as effective as the Halsted radical mastectomy. METHODS: A total of 1079 women with clinically negative axillary nodes underwent radical mastectomy, total mastectomy without axillary dissection but with postoperative irradiation, or total mastectomy plus axillary dissection only if their nodes became positive. A total of 586 women with clinically positive axillary nodes either underwent radical mastectomy or underwent total mastectomy without axillary dissection but with postoperative irradiation. Kaplan-Meier and cumulative-incidence estimates of outcome were obtained. RESULTS: No significant differences were observed among the three groups of women with negative nodes or between the two groups of women with positive nodes with respect to disease-free survival, relapse-free survival, distant-disease-free survival, or overall survival. Among women with negative nodes, the hazard ratio for death among those who were treated with total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.08 (95 percent confidence interval, 0.91 to 1.28; P=0.38), and the hazard ratio for death among those who had total mastectomy without radiation as compared with those who underwent radical mastectomy was 1.03 (95 percent confidence interval, 0.87 to 1.23; P=0.72). Among women with positive nodes, the hazard ratio for death among those who underwent total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.06 (95 percent confidence interval, 0.89 to 1.27; P=0.49). CONCLUSIONS: The findings validate earlier results showing no advantage from radical mastectomy. Although differences of a few percentage points cannot be excluded, the findings fail to show a significant survival advantage from removing occult positive nodes at the time of initial surgery or from radiation therapy.

Breast Neoplasms↗
PubMed2002

Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18.

BACKGROUND: Examination was performed on pathologic material from patients enrolled in the National Surgical Adjuvant Breast Project (NSABP) protocol B-18, in which the clinical effects of preoperative (preop) and postoperative (postop) doxorubicin and cyclophosphamide (AC) were compared. METHODS: Of the total number of 1523 patients, 1234 patients (81%) were in the pathologically evaluable cohort. Six hundred twenty-six patients had been randomized prospectively to receive AC postop and 608 had been randomized to receive AC preop. Preentry diagnosis was made by fine-needle aspiration (FNA) and/or Tru-cut biopsy (TC). AC-induced and other pathologic changes were identified, and their relation to pathologic response and overall survival (OS) and disease-free survival (DFS) was determined. Frequencies of the number of lymph node metastases, their size, stromal reaction, and extracapsular extension (ECE) were compared in the two treatment groups, as was their correlation with OS and DFS. Survival estimates were based on 9 years of follow-up. RESULTS: Approximately 13% of primary breast carcinoma cases exhibited both a clinical complete response (cCR) and a pathologic complete response (absence of invasive tumor [pCR]) to preop AC. An additional 7% of patients exhibited a pCR in the absence of a cCR. A pCR occurred in 38% of those patients determined to have achieved a cCR. Poor nuclear grade of the tumor cells in the pre-entry FNA and/or TC specimens significantly predicted a pCR. Patients with the latter exhibited a better OS and DFS compared with those with a pathologic partial response (presence of sparse invasive tumor [pPR]) or no pathologic response (pNR). Epithelial alterations considered to be induced in tumors by preop AC were comprised of types 1 and 2 giant cells with meganuclei, apocrine metaplasia, and cytoplasmic vacuolation. They had a high degree of specificity (range, 86-99%) but a low sensitivity (range, 7-38%). All were predictive of a pPR and were found to be related adversely to OS and DFS. A fibrous stromal reaction noted in tumors or their putative sites in the preop group was found to have only modest degrees of specificity (63%) and sensitivity (74%). Moderate/marked sclerosis of basement membranes of the ductal and ductular elements of the terminal ductolobular unit (TDLU) was significantly more frequent in nontumor-bearing areas of breasts from patients in the preop treatment group compared with those in the postop treatment group (67% vs. 48%; P < 0.0001). The degrees of change in the TDLU in patients in the postop treatment group were found to be unrelated to age. Lymphatic tumor extension in the primary tumor, as well as a positive lymph node status, were less frequent in the preop treatment group compared with the postop treatment group. The OS and DFS were nearly identical in both treatment groups, being 69% and 55% and 70% and 53% in the preop and postop treatment groups, respectively, at 9 years. A fibrous stromal response to lymph node metastases was found to be significant for DFS but not OS. ECE was similar in both groups (55% vs. 48%; P = 0.12). Only 1% of ECE was found to be related to axillary failure in both treatment arms combined. There was no significant difference with regard to the parameters of survival for patients in the postop treatment group whose lymph nodes contained micrometastases (< 2.0 mm) or mini micrometastases (< 1.0 mm) (the latter detected immunohistochemically with anticytokeratin), and a true-negative lymph node status (not immunohistochemically converted to positive). Conversely, there was no apparent difference with regard to OS in preop treated patients with lymph node micrometastases, mini micrometastases, and macrometastases (P = 0.19). Those with mini micrometastases had a significantly worse OS compared with those with a true-negative lymph node status (P = 0.0007). DFS remained worse for patients in that treatment group with micrometastases and mini micrometastases compared with those with negative lymph nodes, although it was better than that for patients with macrometastases (P = 0.02). CONCLUSIONS: Poor nuclear grade of tumor cells in the preentry FNA or TC specimens in the preop group was predictive of a pCR. AC-induced meganuclear giant cells and apocrine changes and nuclear and histologic grades of the primary tumors also were found to be prognostically significant in patients in the preop treatment group, and the latter two variables were found to be significant for those patients in the postop treatment group. No evidence was found to support the need for axillary lymph node radiation for ECE of lymph node metastases. Extended pathologic or immunohistochemical procedures also appear to be unnecessary for the detection of lymph node mini micrometastases, at least when traditional postop chemotherapy is used. The adverse relation between such small metastases and OS and DFS after preop AC appears to be related to the timing of the chemotherapy administration rather than any pathobiologic reasons.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Real-world performance of HER2 testing--National Surgical Adjuvant Breast and Bowel Project experience.

Trastuzumab (Herceptin) provides clinical benefits for patients diagnosed with advanced breast cancers that have overexpressed the HER2 protein or have amplified the HER2 gene. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-31 is designed to test the advantage of adding Herceptin to the adjuvant chemotherapeutic regimen of doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) in the treatment of stage II breast cancer with HER2 overexpression or gene amplification. Eligibility is based on HER2 assay results submitted by the accruing institutions. We conducted a central review of the first 104 cases entered in this trial on the basis of immunohistochemistry (IHC) results. We found that 18% of the community-based assays, which were used to establish the eligibility of patients to participate in the B-31 study, could not be confirmed by HercepTest IHC or fluorescence in situ hybridization (FISH) by a central testing facility. This report provides a snapshot of the quality of HER2 assays performed in laboratories nationwide.

Antibodies, Monoclonal↗
PubMed2002

Multinational study of pneumococcal serotypes causing acute otitis media in children.

BACKGROUND: Streptococcus pneumoniae is a major cause of acute otitis media (AOM) in young children. More than 90 immunologically distinct pneumococcal serotypes have been identified, but limited information is available regarding their relative importance in AOM. METHODS: We analyzed nine existing datasets comprising pneumococcal isolates from middle ear fluid samples collected from 1994 through 2000 from 3,232 children with AOM from Finland, France, Greece, Israel, several East European countries, the US and Argentina. We examined the distribution of pneumococcal serotypes in relation to several demographic and epidemiologic variables, including gender, age, antibiotic resistance and source of culture material. RESULTS: The major serotypes identified included 19F and 23F, each comprising 13 to 25% of pneumococcal middle ear fluid isolates in most datasets; 14 and 6B, comprising 6 to 18%; whereas 6A, 19A and 9V each comprised 5 to 10%. Despite differences in location, study design and antibiotic susceptibility, each major serotype was prominent in most age groups of each dataset. Serotypes represented in the 7-valent pneumococcal conjugate vaccine (PCV-7, 4, 6B, 9V, 14, 18C, 19F, 23F) accounted for 60 to 70% of all pneumococcal isolates in the 6- to 59-month age range, but only 40 to 50% of isolates in children <6 or >/=60 months old. Serotype 3 and, in certain datasets, serotypes 1 and 5, were more important in the <6- and >/=60-month age groups. In each age group vaccine-related serotypes (mainly 6A and 19A) comprised an additional 10 to 15% of all pneumococcal isolates. Four serotypes (23F, 19F, 14 and 6B) accounted for 83% of all penicillin-resistant observations. CONCLUSIONS: This analysis of several geographically diverse datasets indicates that a limited number of serotypes, largely represented in PCV-7, accounted for the majority of episodes of pneumococcal AOM in children between 6 and 59 months of age. Certain serotypes appeared to be relatively more significant in children <6 months or >59 months of age.

Age Factors↗
PubMedDate not supplied

Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials.

BACKGROUND: Findings from the National Surgical Adjuvant Breast and Bowel Project B-14 and B-20 trials showed that tamoxifen benefited women with oestrogen-receptor-positive tumours and negative axillary nodes, and that chemotherapy plus tamoxifen was more effective than tamoxifen alone. We present long-term findings from those trials and relate them to age, menopausal status, and tumour oestrogen-receptor concentrations. We also discuss the extent of progress made in the treatment of such patients. METHODS: B-14 patients were randomly assigned to placebo (n=1453) or tamoxifen (n=1439); B-20 patients to tamoxifen (n=788) or cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT, n=789). Primary endpoints were recurrence-free survival and overall survival estimated according to patients' age, menopausal status, and tumour oestrogen-receptor concentration. Smoothed recurrence rates were used to measure patterns of recurrence as a continuous function of age. FINDINGS: Compared with placebo, tamoxifen benefited women in B-14 through 15 years, irrespective of age, menopausal status, or tumour oestrogen-receptor concentration (hazard ratio [HR] for recurrence-free survival 0.58, 95% CI 0.50-0.67, p<0.0001; HR for overall survival 0.80, 0.71-0.91, p=0.0008). In B-20, the benefit from CMFT over 12 years was greater than that from tamoxifen alone (HR for recurrence-free survival 0.52, 0.39-0.68, p<0.0001; HR for overall survival 0.78, 0.60-1.01, p=0.063). When CMFT was compared with placebo, there were reductions in treatment failure of about 65% in all age-groups. INTERPRETATION: Much benefit has been achieved in treatment of women with oestrogen-receptor-positive tumours and negative nodes. When planning systemic therapy for such patients of all ages, it should be understood that some have tumours with variable concentrations of oestrogen-receptors, a surrogate for other biomarkers associated with tumour growth and response to treatment. Older women tend to have higher tumour oestrogen-receptor concentrations and are more likely to benefit from tamoxifen than from chemotherapy; in younger women, the converse is true. Consequently, the notion that use of tamoxifen or chemotherapy should be based only on age is too restrictive.

Aged↗