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Radiotherapy has become much better targeted since the 1980s, improving both safety and efficacy. In breast cancer, radiotherapy to regional lymph nodes aims to reduce risks of recurrence and death. Its effects have been studied in randomised trials, some before the 1980s and some after. We aimed to assess the effects of regional node radiotherapy in these two eras.

Background: Vitamin C levels are decreased in arthritis patients and reduced levels following surgery may impair adequate healing.Aim: This study measured changes in vitamin C and inflammatory markers in patients undergoing total knee arthroplasty (TKA).Methods: Venous blood samples were collected from 10 patients during the preoperative to postoperative period. Vitamin C, interleukin-1β, interleukin-6 (IL-6), and C-reactive protein (CRP) levels were measured using various assays.Results: No significant changes in vitamin C levels were measured. However, all participants had suboptimal preoperative vitamin C levels and 90% had suboptimal levels postoperatively. IL-6 and CRP levels significantly increased during the immediate postoerative period.Conclusion: There was a rise in inflammation following TKA while vitamin C levels did not significantly change during this short study period. Of note, every patient had suboptimal vitamin C levels prior to surgery and 90% continued with suboptimal levels two days postoperatively.

Fluid resuscitation plays a prominent role in stabilizing trauma patients with hemorrhagic shock yet there remains uncertainty with regard to optimal administration time, volume, and fluid composition (e.g., whole blood, component, colloids) leading to complications such as trauma‐induced coagulopathies (TIC), acidosis, and poor oxygen transport. Synthetic fluids in combination with antioxidants (e.g., vitamin C) may resolve some of these problems.

Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy.

Adiponectin is a circulating cytokine with important cardioprotective effects. Plasma adiponectin levels are significantly reduced in patients with insulin resistance and type II diabetes mellitus and cardiovascular disease. Although adiponectin is primarily synthesized by adipocytes, new studies reveal that adiponectin is secreted by other cell types, including cardiomyocytes. Control of adiponectin gene expression in heart and microvasculature is poorly understood. We investigated the regulation of adiponectin expression by the transcription factor hypoxia inducible factor-1 (HIF-1) and its role in attenuating cardiac reperfusion injury. HIF-1 regulation of adiponectin was examined by isolating and characterizing the murine adiponectin promoter. HIF-1-dependent activation of the murine adiponectin promoter was verified via electrophoretic mobility shift assays, transient transfection assays, and QPCR. We show for the first time that HIF-1 activation via an siRNA-mediated prolyl 4-hydroxylase-2 gene silencing strategy induced adiponectin mRNA expression in murine microvascular endothelium in vitro (17-fold), intact hearts (22-fold, wild type; 5-fold, obese/diabetic) and white adipose tissue (37-fold, wild-type; 9.6-fold, obese/diabetic). HIF-1-induced adiponectin expression was associated with improved myocardial viability in obese/diabetic mice (32% increase) and preservation of left ventricular function (36% increase in rate pressure product). Our studies suggest that local production of adiponectin by cardiomyocytes/microvascular endothelial cells may regulate cardiac function and indicate a novel strategy for protecting diabetic hearts from ischemia/reperfusion injury.

Hydrolysis of intracellular cholesteryl esters (CEs) represents the first step in the removal of cholesterol from lipid-laden foam cells associated with atherosclerotic lesions. Neutral cholesteryl ester hydrolase (CEH) catalyzes this reaction, and we recently cloned the cDNA for the human macrophage CEH and demonstrated increased mobilization of intracellular CE droplets by CEH overexpression. The present study was undertaken to test the hypothesis that for CE hydrolysis, CEH must become associated with the surface of the cytoplasmic lipid droplets. Our data show the redistribution of CEH from cytosol to lipid droplets upon lipid loading of human THP-1 macrophages. Depletion of triacylglycerol (TG) by incubation with the acyl-CoA synthetase inhibitor Triacsin D had no effect on CEH association with the lipid droplets, suggesting that CEH associates with mixed (CE + TG) as well as TG-depleted CE droplets. However, CEH had 2.5-fold higher activity when mixed droplets were used as substrate in an in vitro assay, consistent with the reported higher cholesterol efflux from cells containing mixed isotropic droplets. Perilipin as well as adipophilin, two lipid droplet-associated proteins, were also present on the lipid droplets in THP-1 macrophages. In conclusion, CEH associates with its intracellular substrate (lipid droplets) and hydrolyzes CE more efficiently from mixed droplets.

The authors attempted to resolve the dilemma posed by the lack of unanimity concerning the optimal immunohistochemical (IHC) method for determining and scoring estrogen receptor (ER) and progesterone receptor (PR).Sections for IHC were prepared from paraffin embedded tumor samples from 402 patients with lymph node positive breast carcinoma who had biochemical receptor values (obtained with the dextran‐coated charcoal [DCC] method) and who were enrolled in a prospective, randomized trial (National Surgical Adjuvant Breast and Bowel Project protocol B‐09). IHC receptors were scored independently by two observers according to percent, intensity, and any‐or‐none algorithms. Results from these evaluations and from two computer‐assisted evaluations, DCC, and common pathologic characteristics were analyzed for optimum splits for positive reactions in univariate and multivariate analyses using a tree‐structured model. Concordance, sensitivity, and specificity were determined between the DCC method and all other methods.Interobserver agreement and concordance between the DCC method and the other methods and among the methods were high. Univariate analyses revealed that a positive ER score obtained with all methods was related significantly to overall survival (OS) at 5 years and at 10 years. Results related to PR scores and disease‐free survival and recurrence‐free survival were less consistent. In multivariate analysis, it also was found that all methods for scoring ER predicted a better prognosis for OS in patients with an unfavorable lymph node status at 5 years and 10 years. Patients in a favorable lymph node status group were discriminated further by nuclear grade.All IHC methods for scoring ER appeared valid as prognostic indicators of OS in patients with positive lymph nodes. The any‐or‐none IHC method, by virtue of its simplicity, represents an appropriate choice for practical use. Cancer 2005. © 2004 American Cancer Society.

Purpose. NSABP Protocol B-23 compared two chemotherapy regimens:(1) cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); and (2) doxorubicin and cyclophosphamide (AC) in terms of relapse-free survival, event-free survival, and overall survival in node-negative and estrogen receptor-negative breast cancer patients. There are no previous data regarding the comparison of quality of life (QOL) between the two regimens in this population of breast cancer patients. QOL information was considered especially relevant given the possibility that the two chemotherapy regimens would prove equivalent in terms of clinical outcome. Patients and methods. One hundred and sixty patients participated in the NSABP B-23 QOL study. Patients in B-23 were randomly assigned to one of four arms: CMF plus 5 years of tamoxifen (TAM), CMF, plus placebo, AC plus TAM, or AC plus placebo. The questionnaires included the Functional Assessment of Cancer Therapy (FACT-B); the vitality scale, comparative health item and general health item from the Medical Outcomes Study 36-item Short Form Health Status Survey (MOS SF-36), a symptom checklist and additional items regarding overall QOL; and return to normal activity. Statistical comparisons between treatment arms were performed with area under the curve analyses, repeated measures analyses, and Fisher exact tests. Results. Overall QOL as measured by the FACT-B did not significantly differ between chemotherapy treatment arms. However, the pattern of vitality over time during treatment differed between chemotherapy groups. The AC group vitality scores dropped more sharply during treatment and returned to baseline levels more quickly after treatment. Patients in the CMF arm were bothered by bladder problems and diarrhea significantly more often than were patients in the AC arm. Otherwise, no significant differences were found between AC and CMF for any of the QOL outcomes in terms of (1) overall QOL during the first 9 months after randomization, (2) the average QOL during treatment, or (3) the rate of recovery to baseline levels of QOL 1 year after randomization. Conclusion. Overall QOL is equivalent between the two chemotherapy regimens, with some differences in symptoms and in patterns of vitality over time.

The current report represents a 12-year clinicopathologic update of an earlier 5-year analysis of 180 patients with lobular carcinoma in situ (LCIS) who were treated with local excision and subsequent surveillance only. Nineteen pathologic characteristics of LCIS were assessed as potential predictors of invasive and noninvasive ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR) as well as mortality. Overall, only 26 IBTRs (14.4%) and 14 CBTRs (7.8%) were observed. Nine IBTRs (5.0% of the total cohort) and 10 CBTRs (5.6% of the total cohort) were invasive carcinomas. Eight of 9 IBTRs (88.9%) and 6 of 8 invasive CBTRs (75%) that had histologic sections available for review were of the lobular invasive type. Ninety-six percent of all IBTRs and 100% of invasive IBTRs occurred within the same site as the index LCIS. The numbers of invasive IBTRs were comparable within and after 5 years (5 invasive IBTRs vs. 4 IBTRs). Recurrences of invasive CBTR occurred later than recurrences of invasive IBTR, with 70% of invasive CBTRs recognized after 5 years compared with 44% of invasive IBTRs. It was found that Grade 2–3 LCIS was significantly predictive for invasive IBTR when combined with the number of recurrences of ductal carcinoma in situ (DCIS) alone or with LCIS. Only 2 patients in the cohort (1.1%) succumbed to breast carcinoma; 1 patient had a prior invasive IBTR, and the other patient had an invasive CBTR. The reasons for the lower frequency of invasive recurrences and the higher proportions of the lobular invasive phenotype than noted by others are discussed along with the impact of the findings on the nomenclature, precursor nature, and treatment of LCIS. LCIS is a more indolent form of in situ breast carcinoma than DCIS, with which it shares other features of its natural history, particularly very low mortality rates. There is no compelling reason to surgically treat LCIS other than conservatively. The values of other adjuvant modalities in the management of LCIS are discussed. The authors acknowledge that their findings are based on relatively few events and, even at 12 years, may be regarded as ‘preliminary’. Nonetheless, their findings may reflect the true biologic nature of LCIS. Cancer 2004;100:238–44. © 2003 American Cancer Society.

BACKGROUNDIn the current study, the authors compared the incidence of subsequent primary lung carcinoma in patients with breast carcinoma who received radiotherapy as part of their treatment and in those patients who did not. The patients were participants in two large National Surgical Adjuvant Breast and Bowel Project NSABP breast carcinoma trials, B04 and B06, which prospectively randomized women to either undergo surgery alone or to undergo surgery and postoperative radiotherapy.METHODSThe NSABP trial B04 1971–1974 randomized patients to undergo radical mastectomy versus total simple mastectomy and radiotherapy to the chest wall, axilla, and supraclavicular and internal mammary lymph node areas. For patients with a clinically uninvolved axilla, there was a third randomization arm: total mastectomy without radiotherapy. The B06 trial 1976–1984 randomized patients between those undergoing total mastectomy versus lumpectomy versus those undergoing lumpectomy and breast irradiation, with all patients undergoing an axillary lymph node dissection. The records of all patients who developed a recurrence in the lung or a new primary lung tumor were reviewed to determine the incidence and laterality of confirmed and probable primary lung carcinoma.RESULTSFor the 1665 evaluable patients on the NSABP B04 trial mean followup of 21.4 years, there was a total of 23 subsequent confirmed and probable ipsilateral or contralateral primary lung carcinomas. In those patients who had received comprehensive postmastectomy radiotherapy, there was a statistically significant increase in the incidence of these new primary tumors P 0.029. With regard to the development of confirmed new primary ipsilateral lung carcinoma alone, the incidence was statistically significantly increased P 0.013 in those patients who had received radiotherapy as part of their treatment, and when confirmed and probable ipsilateral lung carcinomas were analyzed, there was a strong trend toward a statistically significant increase in those patients who had received radiotherapy P 0.066. For the 1850 evaluable patients on the NSABP trial B06 mean followup of 19.0 years, there was a total of 30 second primary lung carcinomas but no increase in either ipsilateral or contralateral primary tumors of the lung in those patients who had received radiotherapy.CONCLUSIONSExtensive postmastectomy irradiation of the chest wall and regional lymphatic node areas, with consequent exposure of a greater volume of lung to higher doses as administered in the NSABP B04 trial compared with postlumpectomy breast irradiation in the NSABP B06 trial, was associated with an increased incidence of subsequent primary lung tumors, both ipsilateral and contralateral. Cancer 2003;98:1362–8. © 2003 American Cancer Society.DOI 10.1002cncr.11655

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. 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. 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). 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. Cancer 2002;95:681–95. © 2002 American Cancer Society. DOI 10.1002/cncr.10741

This paper is concerned with meteorological processes that may have an influence on the occurrence of episodes of high pollution involving chimney plumes. It reviews meteorological mechanisms that could lead to or maintain high concentrations at distances beyond the range normally considered in dispersion models (distances greater than 30 km). Fundamental parameters of the atmospheric boundary layer are shown to largely determine short‐range and long‐range dispersion, but their values are usually not well known in specific cases. A simple estimate is provided of the magnitude of the maximum hourly average concentrations during a long‐range fumigation episode from a tall stack. Copyright © 2002 Royal Meteorological Society

This paper is concerned with meteorological processes that may have an influence on the occurrence of episodes of high pollution involving chimney plumes. It reviews meteorological mechanisms that could lead to or maintain high concentrations at distances beyond the range normally considered in dispersion models (distances greater than 30 km). Fundamental parameters of the atmospheric boundary layer are shown to largely determine short-range and long-range dispersion, but their values are usually not well known in specific cases. A simple estimate is provided of the magnitude of the maximum hourly average concentrations during a long-range fumigation episode from a tall stack.

The benefit of using adjuvant tamoxifen to treat breast cancer has been firmly established for patients with estrogen receptor (ER)-positive tumors, regardless of age, lymph node status, or menopausal status. Uncertainty remains, however, regarding the optimal duration of tamoxifen therapy. We reviewed the findings of randomized clinical trials that directly compared alternative treatment durations. Trials comparing short-term adjuvant treatment with tamoxifen (i.e., 1–3 years) with treatments having durations of about 5 years consistently have demonstrated additional benefits stemming from the longer therapy. Trials testing 5 years of treatment with longer durations have, in the aggregate, suggested no additional benefit for the patient. Nevertheless, the number of recurrences reported to date in these trials is not large, and the results of the individual trials are heterogeneous. Furthermore, as a result of tamoxifens “carryover” effect, duration trials require considerable follow-up before definitive results can be established. Until more definitive data become available, adjuvant treatment with tamoxifen should be limited to 5 years outside the clinical trials setting. Continued accrual of ER-positive patients to ongoing tamoxifen duration trials, including the Adjuvant Tamoxifen Treatment Offer More (aTTom) and Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trials, is appropriate. Alternatively, patients who remain disease free after 5 years of tamoxifen therapy should be encouraged to participate in trials testing crossover to other hormonal interventions, including selective ER modulators or aromatase inhibitors.

Before 1989, credible information about the treatment of breast cancer was derived mainly from randomized clinical trials that enrolled women with either metastatic (stage IV); locally advanced (stage III); or primary, operable, axillary lymph node-positive (stage II) disease. This report provides information from six recent National Surgical Adjuvant Breast and Bowel Project (NSABP) trials involving lymph node-negative (stage I) patients. Findings from NSABP B-13 demonstrated, through 14 years of follow-up, improvements in disease-free survival (DFS) and overall survival from methotrexate and fluorouracil (MF), regardless of age, in women with estrogen receptor (ER)-negative tumors. Results from NSABP B-19, which was conducted with similar patients, demonstrated, through 8 years, a greater overall DFS and survival advantage with cyclophosphamide and MF (CMF) than that observed with MF. Findings from NSABP B-23, in which patients similar to those in B-13 and B-19 were randomly assigned to receive CMF plus placebo, CMF plus tamoxifen (TAM), doxorubicin (Adriamycin) and cyclophosphamide (AC) plus placebo, or AC plus TAM, demonstrated no difference in relapse-free survival (RFS) or overall survival among the four groups through 5 years, either for all patients or relative to age. NSABP B-14, which was carried out in women with ER-positive tumors, compared the outcomes of those who received either placebo or TAM. Through 14 years, superior DFS and overall survival advantages, as well as a reduction in contralateral breast cancer, were observed with TAM. No additional benefit resulted from TAM administration beyond 5 years. Findings from NSABP B-20, a second study conducted in patients with ER-positive tumors, showed, after 8 years, both a DFS and an overall survival advantage from TAM plus either MF or CMF over that achieved with TAM alone. A recent meta-analysis in women with negative lymph nodes and either ER-negative or ER-positive tumors of less than or equal to 1 cm in size was conducted using patients from five NSABP trials. After 8 years, the RFS in women with ER-negative tumors was greater in the group treated with surgery and chemotherapy than in those who underwent surgery alone. In women with ER-positive tumors, RFS and overall survival advantages were observed from the addition of chemotherapy to TAM when that treatment regimen was compared with TAM alone. In addition, evidence has been presented from NSABP B-21, a trial evaluating radiation therapy (XRT) and/or TAM for the prevention of ipsilateral breast tumor recurrence (IBTR) after lumpectomy in women with tumors less than or equal to 1 cm. Findings have shown that XRT is superior to TAM and that XRT + TAM is superior to XRT alone for preventing IBTR. The findings demonstrate that chemotherapy and/or hormonal therapy is effective for the management of women with negative axillary lymph nodes and either ER-negative or ER-positive tumors. Because it also has been proven effective in women with tumors less than or equal to 1 cm, such therapy might also be considered in the treatment of that patient population.

National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was initiated in 1988 to determine whether four cycles of doxorubicin/cyclophosphamide given preoperatively improve survival and disease-free survival (DFS) when compared with the same chemotherapy given postoperatively. Secondary aims included the evaluation of preoperative chemotherapy in downstaging the primary breast tumor and involved axillary lymph nodes, the comparison of lumpectomy rates and rates of ipsilateral breast tumor recurrence (IBTR) in the two treatment groups, and the assessment of the correlation between primary tumor response and outcome. Initially published findings were based on a follow-up of 5 years; this report updates results through 9 years of follow-up. There continue to be no statistically significant overall differences in survival or DFS between the two treatment groups. Survival at 9 years is 70% in the postoperative group and 69% in the preoperative group (P = .80). DFS is 53% in postoperative patients and 55% in preoperative patients (P = .50). A statistically significant correlation persists between primary tumor response and outcome, and this correlation has become statistically stronger with longer follow-up. Patients assigned to preoperative chemotherapy received notably more lumpectomies than postoperative patients, especially among patients with tumors greater than 5 cm at study entry. Although the rate of IBTR was slightly higher in the preoperative group (10.7% versus 7.6%), this difference was not statistically significant. Marginally statistically significant treatment-by-age interactions appear to be emerging for survival and DFS, suggesting that younger patients may benefit from preoperative therapy, whereas the reverse may be true for older patients.

The role of activator protein-1 (AP-1) in tumor necrosis factor-α (TNF-α)-induced interleukin-8 (IL-8) gene expression was evaluated. We showed that TNF-α activates AP-1 in the transformed endothelial cell line ECV304 by transient transfections of IL-8 promoter construct pGL-3BF2. Mutation of either the AP-1 site or the NF-IL-6 site on the IL-8 promoter suppressed the TNF-α-induced activation, suggesting cooperation between these transcription factors and transcription factor NF-κB. Overexpression of dominant negative mutants of c-Jun suppressed AP-1-driven transcription of the IL-8 promoter following stimulation by TNF-α, suggesting that cooperative interaction between AP-1 and NF-κB is essential for IL-8 transcription in the presence of TNF-α. We also showed that nitric oxide (NO), in the form of an exogenous NO donor, suppressed the level of activation of the AP-1 subunit, c-Jun, by down-regulation of c-Jun NH2terminal kinase. This down-regulation could be the putative mechanism of action for NO-mediated inhibition of IL-8 secretion in activated endothelium. These observations suggest for the first time that NO has broad suppressive activities on various proinflammatory effectors in activated endothelium.

Interleukin-8 (IL-8), a chemokine secreted by cells at injury sites, has recently been recognized as involved in the pathogenesis of Crohn's disease. However, the pathogenesis of enhanced spontaneous transcription of IL-8 by the bowel in patients with Crohn's disease is undefined. Although IL-8 is secreted primarily by neutrophils, macrophages, and endothelial and epithelial cells, we observed the involvement of mesenchymal cells in the inflammatory process. A smooth muscle cell line isolated from the ileum of a patient with Crohn's disease (CDISM) and maintained in culture exhibited spontaneous transcription and secretion of IL-8 when compared with intestinal smooth muscle cells obtained from a normal subject (NHISM). Furthermore, IL-8 transcription from CDISM cells was associated with remarkable spontaneous activation of the oxidant-sensitive transcription factor NF-κB, as assessed by transient transfection assays with an IL-8 promoter reporter construct, Western blot analysis, and electrophoretic mobility shift assays (EMSA). Finally, we report here that CDISM cells exhibit significantly altered redox balance. The antioxidant pyrrolidine dithiocarbamate (PDTC) restored the redox equilibrium by mechanisms that inhibit binding of NF-κB to its cognate site on the IL-8 promoter. These findings suggest that restoration of the redox balance could hold promise for therapeutic intervention in Crohn's disease.

This report updated previous findings, at the 15-year mark, of the National Surgical Breast and Bowel Project (NSAPB) Protocol B-06 with respect to the treatment of invasive breast carcinoma and the effects of pathologic features and the effects of some clinical features on its natural history. Thirty-one pathologic and 6 clinical features that were observed in a pathologic subset of 1039 evaluable patients were assessed as to their value in predicting survival, in predicting ipsilateral breast tumor recurrence (IBTR), and in predicting the necessity for local breast irradiation after lumpectomy. The patients had been randomly assigned to treatment by lumpectomy without local irradiation or to treatment by lumpectomy with local irradiation of the breast. A traditional and another statistical method were used for this purpose. Multivariate analyses revealed that the presence of IBTR, race, histologic tumor type, nodal status, nuclear grade, and blood vessel invasion affected survival independently. Treatment, patient age, nuclear grade, presence of intraductal carcinoma, and a lymphocytic tumor infiltrate were features that predicted IBTR by multivariate analyses. Irradiation reduced IBTR from 36% to 12% in the analyzed cohort. A test of interaction failed to reveal any pathologic or clinical feature that might have allowed for the omission of local irradiation of the breast after lumpectomy. In addition to the influence of pathologic and clinical features on patient survival and IBTR, the site, histopathologic features, and time of occurrence of the latter allowed for insights into some important biologic considerations concerning invasive breast carcinoma. Cancer 2001;91:1679–87. © 2001 American Cancer Society.

This report is an 8-year update of the authors' previous findings from National Surgical Adjuvant Breast Project (NSABP) Protocol B-17, which relates to the influence of pathologic characteristics on the natural history and treatment of intraductal carcinoma (DCIS). Nine pathologic features observed in a pathologic subset of 623 of 814 evaluable women enrolled in this randomized clinical trial were assessed for their role in the prediction of second ipsilateral breast tumors (IBT), other events, and selection of breast irradiation (XRT) following lumpectomy. The frequency of subsequent IBT was reduced from 31% to 13% (P = 0.0001) by XRT. The average annual hazard rates for IBT were reduced by XRT for all pathologic features examined. Four characteristics were individually noted to be significantly related to IBT, but only moderate-to-marked and absent-to-slight comedo necrosis were found to be independent high and low risk predictors, respectively, for such an event in patients of both treatment groups. XRT effected a 7% absolute reduction at 8 years in the low risk group. Despite a relatively high incidence (≈40%) of IBT consisting of invasive cancer, mortality due to breast carcinoma after DCIS for the entire cohort was found to be only 1.6% at 8 years. The degree of comedo necrosis in patients with DCIS appears to be sufficient for discriminating between high and low risks for IBT following lumpectomy for DCIS. Although margin status, unlike in our previous report, was found to have only a slight or borderline influence on the frequency of IBT at 8 years, excision of DCIS with free margins is advised. The low risk group exhibits a statistically significant reduction of IBT from XRT. The decision to forgo XRT in the treatment of this singular subset of patients would appear to depend on clinical considerations and the input of informed patients rather than being standard practice. [See editorial on pages 375–7, this issue.] Cancer 1999;86:429–38. © 1999 American Cancer Society.

Tumor necrosis factor (TNF) may be a major endogenous mediator of sepsis-induced acute organ injury. We proposed that treatment of septic pigs with the combined agents ibuprofen, a cycloox-ygenase inhibitor, and histamine receptor antagonists, cimetidine (H2antagonist) and diphenhydramine (H1antagonist) would result in lower circulating levels of TNF and decreased parameters of sepsis-induced injury in these animals. To test this, plasma TNF activity, cardiac index, systemic and pulmonary arterial pressures, arterial Po2and bronchoalveolar lavage protein content were monitored for 300 min in four groups of anesthetized pigs: saline-infused control pigs (n = 4); pigs infused for 60 min with Pseudomonas aeruginosa(5 x 1088organisms/mL, .3 mL/20 kg/min) (n = 5) and pigs infused for 60 min with P. aeruginosaplus ibuprofen (12.5 mg/kg) alone (n = 4) or ibuprofen plus cimetidine (150 mg) and diphenhydramine (30 mg/kg) at 0 and 120 min (CID, n = 4). Within 60 min, pigs infused with P. aeruginosaexhibited increased plasma TNF activity (>8-fold increase in ng/mL TNF; L929 cytolysis assay) and showed alterations in all hemodynamic and pulmonary parameters. Ibuprofen or CID administration in the septic pigs decreased peak TNF activity by 4.6 and 10.2 ng/mL, respectively, and CID treatment was correlated with better attenuation of certain sepsis-induced alterations. These results show that CID treatment attenuates sepsis-induced injury and that this is correlated with reduced plasma TNF activity in a porcine model of sepsis-induced acute organ injury.

This report presents an overview of findings from 2 interrelated studies carried out during the past 15 years by the National Surgical Adjuvant Breast and Bowel Project to determine the efficacy of alternative local and regional treatments of primary breast cancer. Findings from the first clinical trial, begun in 1971 involving 1,665 women, indicate that after 10 years of follow-up there are no significant differences in disease-free survival, distant disease-free survival, or survival among patients treated by radical mastectomy or total mastectomy with and without radiation. The findings also indicate that radiation of internal mammary nodes in patients with inner quadrant lesions does not improve survival and that results obtained at 5 years accurately predict the outcome through 10 years. The second clinical trial, implemented in 1976 and accruing 1,843 women, demonstrates that after 5 years, treatment by segmental mastectomy (lumpectomy) with or without radiation results in disease-free, distant disease-free, and overall survival at least equivalent to, and in certain aspects better than, that achieved after total breast removal. Whereas 92% of those treated with radiation remained free of breast tumor at 5 years, when breast radiation was not employed, 72% (p<0.001) were without tumor reoccurrence. In positive-node patients, 98% of those radiated remained tumor free, whereas only 64% of those receiving no radiation were free of tumor although both groups received chemotherapy.

Recently, the first results were disclosed from a trial carried out by the National Surgical Adjuvant Breast and Bowel Project (NSABP) to evaluate the efficacy of breast conservation. These observations indicate that lumpectomy and axillary dissection plus radiation can be employed instead of total mastectomy for the treatment of a large proportion of women with primary breast cancer. The present report describes the technique of operation (lumpectomy), how the pathological examination of the resected specimen is carried out, and the manner in which radiation therapy is administered to the operated breast. The methodologies are those utilized in more than 1,200 women who for almost a decade have been participants in the NSABP study. It is emphasized that the outcome of patients exposed to breast preservation relates to the expertise of the surgeon, pathologist, and radiation and medical oncologists. The orchestration of care that will result in a satisfactory cosmesis and control of disease in the breast is more complex than is necessary for carrying out a mastectomy. Above all it is emphasized that, although the Halstedian concept for cancer surgery has been displaced, that change does not provide the imprimatur for haphazard surgery.

Data are presented from a prospective clinical trial in which 1,891 patients with histologically confirmed stage II breast cancer were randomized to receive adjuvant therapy consisting of 1-phenylalanine mustard and 5-fluorouracil (PF) with and without tamoxifen (T). The findings indicate that the benefit previously noted for the addition of tamoxifen at 2 and 3 years' mean follow-up is still apparent at 4 years. Although the tamoxifen-containing regimen prolongs disease-free survival and survival, this effect is not uniform and is dependent on patient age and tumor receptor content. Only those patients ? 50 years of age demonstrated a benefit from the addition of tamoxifen to chemotherapy. The benefit was influenced by the degree of quantitative tumor receptor content. Patients ? 49 years of age failed to demonstrate a prolongation in disease-free survival with tamoxifen even when the tumor estrogen receptor content was ?100 fmol. Not only was there no benefit attributable to tamoxifen in patients ?49 years, if the tumor progesterone receptors were <10 fmol there was a significant diminution in disease-free survival and survival. The results continue to indicate that the response to PFT therapy is heterogeneous in that only specific patient subsets demonstrate a salutary effect. Whether this phenomenon of heterogeneity is unique to the PFT combination or is an intrinsic biological property of stage II breast cancer remains to be ascertained.

Since 1972 the National Surgical Adjuvant Breast and Bowel Project (NSABP) has completed 5 adjuvant chemotherapy protocols into which over 3,500 histologically nodepositive patients have been entered; data for this review are derived predominantly from the first 3 studies. Each study was performed sequentially with the intent of identifying patient subsets responding to 1, 2, or 3 chemotherapeutic agents. Comparison of disease-free survival in patients receiving l-phenylalanine mustard (L-PAM) or placebo after 10 years of follow-up disclosed that L-PAM was beneficial in patients up to 49 years of age, but not in women ?50 years. Further analysis indicated that the subset of patients ?49 years with 1–3 positive nodes sustained the greatest increment in disease-free survival with single-agent L-PAM. The addition of 5-fluorouracil (5-FU) to L-PAM was superior to L-PAM alone in patients ?50 years of age, particularly those with ?4 positive nodes. This effect became attenuated after 6 years of follow-up. The 3-drug regimen of L-PAM, 5-FU, and methotrexate failed to provide a benefit over and above that achieved by the L-PAM-5-FU combination in all subsets examined. Two further NSABP protocols are described in which the addition of Adriamycin® to L-PAM and 5-FU is addressed. The rationale for the current generation of NSABP adjuvant chemotherapy trials using short intensive Adriamycin® and cyclophosphamide regimens is discussed. The results continue to underscore the heterogeneous response to chemotherapy demonstrated by patient subsets characterized on the basis of age and nodal status.

During the past 15 to 20 years, there have resulted revolutionary changes in the local/regional management of primary breast cancer. Why have those changes come about? Has science played a role or have they been entirely related to the experiences of a few who have “tampered with tradition” for some nebulous reason? This report traces the pathway of change from Halsted's time to the present and attempts to point out wherever possible the relation of these changes to science and/or to “anecdotalism.” It traces the origins of the Halstedian hypothesis of cancer management, the reasons for its perpetuation, and the clinical challenges to it which were really not challenges at all. A description of laboratory and clinical research in the 1960's which led to an alternative hypothesis is presented, as is a description of how clinical trials tested the alternative hypothesis. The results of those trials, recently reported, lend support to a concept of surgery for cancer which embodies biological principles rather than the mechanistic and anatomical principles of the past. A brief discussion is provided relative to how cancer surgery interrelates with other modalities and the article concludes with the author's concept of a surgical oncologist.

In recent years, a trend has developed toward more conservative surgery for early breast cancer, often in combination with axillary dissection or sampling and with radiotherapy. Here, three prominent breast cancer surgeons discuss the proper role of these procedures and several areas of contention concerning them.

Summary The total number of mast cells and the number of such cells observed within and at the periphery of invasive breast cancers from 424 patients enrolled in protocol 4 of the National Surgical Adjuvant Breast Project were correlated with 38 other pathologic and 6 clinical features. High total mast cell counts as well as those within and at the periphery of the cancers were found to be significantly (p=.05) associated with a patient age less than 50 years and the degree of tumor lymphoid cell reaction. The latter has also been found to be related to young age and other pathologic characteristics related to mast cell content. This suggests that the mast cells may simply represent another cell type of this reactive change. No differences in 10 year disease-free survival were detected in patients without mast cells and those exhibiting varying numbers of such cells. This information indicates that identifiable mast cells do not represent a prognostic pathologic discriminant in patients with breast cancer. However, this does not unequivocally exclude a role of mast cell secretory products, since only intact and not degranulated or disrupted forms of these cells can be counted.

Summary A considerable fraction of first metastases in breast cancer patients are found in the skeletal system. Consequently, to improve the probability of detecting bone lesions, protocols of the National Surgical Adjuvant Breast and Bowel Project (NSABP) have required radionuclide scans every six months for the first three postoperative years and yearly thereafter. The present study was conducted to evaluate the worth of 7984 bone scans performed prior to documentation of first treatment failure on 2 697 stage II (positive node) patients entered into NSABP clinical trial B-09. At the time of evaluation, there were 779 patients with a treatment failure, 163 (20.9%) of whom had their recurrence limited to bone. At most, 52 (0.6%) of the total number of screening scans were efficacious in detecting lesions in asymptomatic patients. As a result of this minimal benefit from routine scans, it was recommended that they be conducted less frequently. In presently ongoing NSABP studies, asymptomatic patients having tumors with positive axillary nodes receive scans at yearly intervals for the first three years. Future NSABP trials will require follow-up bone scans only as indicated by symptoms.

A disparity in breast carcinoma survival between African-American and white women has been noted over the past several decades. A major factor implicated in this disparity is stage of disease at diagnosis. In this study, survival and related endpoints were examined among African-American women and white women with lymph node negative breast carcinoma who participated in two randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP). Patients from two studies, one conducted among patients with estrogen receptor (ER) negative tumors and the other among patients with ER positive tumors, were included. Study goals were to determine whether African-Americans and whites had comparable outcomes, accounting for ER status and differences in patient characteristics at diagnosis, and to determine whether treatment response was similar for African-Americans and whites. Five-year survival rates were 83% for African-Americans and 85% for whites among ER negative patients, and 93% for African-Americans and 92% for whites among ER positive patients. Rates of disease free survival (DFS) (i.e., time to disease recurrence, second primary cancer, or death) were 71% for African-Americans and 74% for whites at 5 years among ER negative patients, and 81% for African-Americans and 80% for whites among ER positive patients. African-Americans tended to have less favorable baseline prognostic characteristics. Adjusted relative risk (RR) estimates indicated similar prognosis for African-Americans compared with whites for mortality (African-American/white RR = 1.02 with 95% confidence interval [CI], 0.66-1.56 among ER negative patients; RR = 1.14 with 95% CI, 0.84-1.54 among ER positive patients) and DFS (RR = 0.98 with 95% CI, 0.70-1.37 for ER negative patients; RR = 0.96 with 95% CI, 0.75-1.22 for ER positive patients). Estimated percent reductions in DFS events for patients receiving adjuvant therapy were 32% for ER negative African-Americans, 36% for ER negative whites, 20% for ER positive African-Americans, and 39% for ER positive whites. African-American and white patients with localized breast carcinoma had similar outcomes and benefited equally from systemic therapy. These results suggest that early detection and appropriate therapy among African-American patients could result in a reduction in the current disparity in breast carcinoma mortality between African-Americans and whites. Cancer 1997; 80:80-90. ©; 1997 American Cancer Society.

Beginning in 1958, the first clinical trial of the National Surgical Adjuvant Breast Project compared a brief postoperative course of low dose triethylenethiophosphoramide (TSPA) with no adjuvant therapy or placebo in 826 patients who underwent radical mastectomy for breast cancer. After 5 years, one subset of patients made up of premenopausal women with 4 or more positive axillary lymph nodes had a significantly higher survival rate and longer disease free interval following TSPA therapy than after placebo therapy. After 10 years, these significant differences in survival and incidence of treatment failure between the TSPA-treated patients and the controls persisted.

From August 1971 to August 1974, almost 1700 patients with clinically curable breast cancer in 34 institutions in the United States and Canada were entered into the National Surgical Adjuvant Breast Project (NSABP) trial comparing the results of total (simple) mastectomy with those of radical mastectomy. Patients with clinically negative axillary nodes in the total mastectomy group were further randomized to receive postoperative regional radiotherapy or no radiotherapy, but the latter patients underwent an axillary dissection if clinically positive axillary nodes developed after operation. Patients with clinically positive axillary nodes in the total mastectomy group automatically received postoperative regional radiotherapy. After a follow-up period of 2 to 5 years, there are no significant differences in the results of the various types of treatment in either the groups of patients with clinically negative axillary nodes or those with clinically positive axillary nodes.

OBJECTIVE: To determine the effects of pretreatment and posttreatment with pentoxifylline in a porcine model of gram-negative sepsis. DESIGN: Nonrandomized controlled trial. STUDY SUBJECTS: Young Yorkshire swine. INTERVENTIONS: Six groups of ventilated swine were studied for 5 hours. Group 1 swine (control, n=8) received saline solution only. Group 2 swine (sepsis, n=8) received a 1-hour infusion of Pseudomonas aeruginosa. Groups 3, 4, and 5 swine received the P aeruginosa infusion and a 20 mg/kg bolus followed by a 6 mg/kg per hour infusion of pentoxifylline. Group 3 swine (n=6) received pentoxifylline prior to the onset of sepsis; group 4 swine (n=6) received pentoxifylline at 1 hour and group 5 swine (n=4) at 2 hours after the onset of the P aeruginosa infusion. Group 6 swine (control pentoxifylline, n=3) received pentoxifylline only. OUTCOME MEASURES: Hemodynamic variables, neutrophil counts and CD18 expression, tumor necrosis factor activity, and arterial blood gases were measured hourly. Bronchoalveolar lavage was performed at 0 and 5 hours to measure neutrophil and protein content. RESULTS: All variables remained unchanged in the control and control pentoxifylline groups. Both pretreatment and posttreatment with pentoxifylline significantly attenuated lung injury and improved arterial Pao2. The cardiac index was significantly improved by administration of pentoxifylline in groups 3 and 4. Administration of pentoxifylline to group 5 animals in established septic shock caused uncontrolled, fatal systemic hypotension in two of the four animals. Plasma tumor necrosis factor activity, blood polymorphonuclear leukocyte counts, and CD18 expression were unaffected by the administration of pentoxifylline. CONCLUSIONS: Pentoxifylline protects against pulmonary and systemic hemodynamic derangements in fulminant sepsis and protects against pulmonary dysfunction. Pentoxifylline has a "therapeutic window" when given in established sepsis; if administration is delayed until overt septic shock occurs, it may then have deleterious effects.(Arch Surg. 1994;129:1144-1152)

OBJECTIVE: To ascertain the effect of delayed tumor necrosis factor α (TNF-α) on the evolution of systemic and pulmonary injury after the onset of sepsis. DESIGN: Prospective controlled trial. INTERVENTION: Anesthetized swine were made septic with a 1-hour infusion of live Pseudomonas aeruginosa, following which a treatment group received an infusion of anti—TNF-α monoclonal antibody (5mg/kg). Control animals received 0.9% saline. RESULTS: Delayed anti—TNF-α treatment had no effect on septic pulmonary hypertension or decline in cardiac output. Late recovery in systemic arterial hypotension was associated with a reversal of arterial acidosis (P&lt;.05 by τ test and analysis of variance with Tukey's Studentized Range Test) compared with unprotected septic animals. Septic animals had a significant increase in mean (±SEM) plasma lactate levels at 5 hours compared with baseline values (3.8±0.7 vs 2±0.4, P&lt;.05), but remained unchanged from baseline following anti—TNF-α treatment (1.5±0.1 vs 1.6±0.2, not significant). Characteristic septic neutropenia was dramatically reversed by anti—TNF-α treatment and was associated with downregulation (P&lt;.05 by τ test and analysis of variance) of polymorphonuclear neutrophil (PMN) leukocyte CD18 adhesion receptors and reduction (P&lt;.05 by τ test and analysis of variance) in lung PMN sequestration measured by myeloperoxidase activity. The mean (±SEM) decrease in bronchoalveolar lavage protein indicated an attenuated permeability injury in anti—TNF-α animals (septic animals at 5 hours compared with baseline value, 1044 ±270 vs 149 ±28 μg/mL; control animals at 5 hours compared with baseline value, 217±83 vs 129±19 μg/mL; P&lt;.05 by τ test and analysis of variance). CONCLUSIONS: These data show that delayed anti—TNF-α treatment reversed metabolic acidosis associated with sepsis. Furthermore, anti—TNF-α treatment reversed septic neutropenia, reduced PMN sequestration, and was associated with attenuated lung injury in a model of fulminant sepsis. This supports evidence of PMN-mediated tissue injury in sepsis and suggests mechanisms for potential therapeutic benefit of anti—TNF-α treatment in clinical practice.(Arch Surg. 1994;129:80-89)

Activation of the kallikrein-kinin system in sepsis has long been recognized, but its role, beneficial or pathologic, has not been defined. Recently, however, specific bradykinin (BK) antagonists have become available and this study investigated the effects of a BK antagonist, NPC17731 (Scios-Nova) on systemic and pulmonary hemodynamics in a model of gram-negative sepsis. Anesthetized swine were studied for 5 h receiving a 1-h infusion of saline (controls, group 1, N = 8) or live Pseudomonas aeruginosa (septic, group 2, N = 8). Group 3 (treatment, N = 6) received NPC17731 (5 mg/kg initial bolus followed by 1 mg/kg hourly) just prior to the onset of sepsis. Group 2 animals showed a rapid decrease in systemic arterial pressure (SAP) from 30 min onward, and sustained significant hypotension from 2 h onward. In group 3, SAP fell similarly until 2 h then progressively rose, returning to baseline levels by 5 h. In contrast, cardiac index fell progressively from 3 h onward in groups 2 and 3. Systemic vascular resistance index (SVRI)fell significantly by 2 h in group 2 animals, recovering to baseline by 5 h. Group 3 showed a similar initial fall followed by a rebound increase in SVRI, which, at 5 h was significantly raised above the other groups. Group 2 developed significant, persistent pulmonary artery hypertension which was not reduced by NPC17731. The data imply a significant role for bradykinin in the pathogenesis of hypotension in septic shock in this model. Septic shock was reversed by a BK antagonist which increased peripheral resistance without affecting cardiac output. However, NPC17731 exerted no effect on the pulmonary circulation. BK antagonists my play a beneficial role in the armamentarium against septic shock.

A stochastic model wiuh exponential components is used to describe our data collected from a phase III cancer clinical trial. Criteria which guarantee that disease-free survival (DFS) can be used as a surrogate for overall survival are explored under this model. We examine several colorectal adjuvant clinical trials and find that these conditions are not satisfied. The relationship between the hazard ratio of DFS for an active treatment versus a control treatment and the cumulative hazard ratio of survival for the same two treatments is then explored. An almost linear relationship is found such that a hazard ratio for DFS of less than a threshold R corresponds to a non-null treatment effect on survival The threshold value R is determined for our colorectal adjuvant trial data. Based on this relationship, a one-sided test of equal hazard rate of survival is equivalent to a test of hazard ratio of DFS small than R This approach assumes that recurrence information is unbiasedly and accurately assessed; an assumpion which is sometimes difficult to ensure for multicenter clinical trials, particularly for interim analyses.

PURPOSE: National Surgical Adjuvant Breast and Bowel Project Protocol R-03 was designed to determine the worth of preoperative chemotherapy and radiation therapy in the management of operable rectal cancer. METHODS: Thus far, 116 patients of an eventual 900 with primary operable rectal cancer have been randomized to receive multimodality therapy to begin preoperatively (59 patients) or identical therapy beginning after curative surgery (57). All patients received seven cycles of 5-fluorouracil (FU)/leucovorin (LV) chemotherapy. Cycles 1 and 4 through 7 used a high-dose weekly FU regimen. In Cycles 2 and 3, FU and low-dose LV chemotherapy was given during the first and fifth week of radiation therapy (5,040 cGy). The preoperative arm (Group 1) received the first three cycles of chemotherapy and all radiation therapy before surgery. The postoperative arm (Group 2) received all radiation and chemotherapy after surgery. Primary study end points included disease-free survival and survival. Secondary end points included local recurrence, primary tumor response to combination therapy, tumor downstaging, and sphincter preservation. RESULTS: Overall treatment-related toxicity was similar in both groups. Although seven preoperative patients had events after randomization that precluded surgery, eight events occurred during an equivalent follow-up period in the postoperative group. No patient was deemed inoperable because of progressive local disease. Sphincter-saving surgery was intended in 31 percent of Group 1 patients and 33 percent of Group 2 patients at the time of randomization. Such surgery was actually performed in 50 percent of the preoperatively treated patients and 33 percent of the postoperatively treated patients. The use of protective colostomy in patients undergoing sphincter-sparing surgery and the development of perioperative complications in all surgical patients were similar in both groups. There was evidence of tumor downstaging in evaluable patients under-going preoperative therapy, with 8 percent of Group 1 patients having had a pathologic complete response. CONCLUSION: These data do suggest that the preoperative chemotherapy and radiation therapy regimen used are, at least, as safe and tolerable as standard postoperative treatment. There is presently a trend to tumor downstaging and sphincter preservation in the preoperative arm. Whether this arm will have greater or lesser survival and long-term toxicity awaits the completion of this relevant study.

This article considers the role of adjuvant therapy in primary breast cancer, utilizing data from randomized prospective clinical trials as illustrative examples. The ongoing efforts targeted toward addressing some of the unresolved issues are underscored.

The highlights of findings obtained from trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) are presented. The findings and conclusions regarding the present status of adjuvant therapy are summarized as provisional guidelines for the use of adjuvant therapy.

The effect of spirogermanium (SG) on hematopoietic stem cells, tumor burden, and survival times was investigated in C3H mice with transplanted mammary carcinoma. Compared to normal mice, the number of hematopoietic stem cells, or colony-forming units per spleen (CFU-S), was lower in the marrow of tumor-bearing mice. Spirogermanium at 15 and 30 mg/kg was not toxic to the normal hematopoietic cells in the marrow of either normal or tumor-bearing mice. In contrast to animals treated with cyclophosphamide, SG did not decrease the tumor growth rate or prolong the survival times of tumor-bearing C3H mice. Doses of 35–40 mg/kg SG did not prolong the survival times or decrease the tumor burden of AKR/J mice with a long-passaged lymphoma. These studies demonstrate that SG has minimal inhibitory effects to the marrow of normal mice and may promote the maintenance of normal marrow cells in tumor-bearing animals. However, in two different transplanted tumor cell lines, SG did not inhibit tumor growth or prolong host survival time.