Distinct lymph nodal sonographic characteristics in breast cancer patients at high risk for axillary metastases correlate with the final axillary stage.

The purpose of this study was to assess the clinical relevance, limitations and most common findings of axillary ultrasound and subsequent image-guided aspiration cytology in clinically node-negative breast cancer patients who are at high risk for axillary metastasis. Following institutional review board approval and Health Insurance Portability and Accountability Act (HIPAA) compliance, sonographic axillary surveys from 112 patients considered at high risk for axillary metastases were reviewed retrospectively for the following abnormal features: asymmetric cortical thickening/lobulations; loss or compression of the hyperechoic medullary region; absence of fatty hilum; abnormal lymph node shape; hypoechoic cortex; admixture of normal and abnormal appearing nodes; and increased peripheral blood flow. Patients with either normal or abnormal ultrasound exams, but negative cytology, underwent sentinel node mapping. Patients with abnormal ultrasound and positive cytology proceeded to complete axillary dissection. The number of positive nodes, the size of tumour deposits and the histological pattern of metastatic disease on the positive nodes were then correlated and compared with their corresponding sonographic abnormalities. Abnormalities related to the lymph node cortex were indicative of N1a disease. Features such as loss or compression of the hyperechoic medullary region, absence of fatty hilum, abnormal lymph node shape and increased peripheral blood flow were predictors of N2-3 disease. In conclusion, nodal sonographic characteristics of patients at high risk for metastases are useful predictors of tumour burden in the axilla. When combined with the results from aspiration cytology, these findings could modify the surgical approach to the axilla, eliminating the need for sentinel node mapping in a significant proportion of patients.

The critical role of axillary ultrasound and aspiration biopsy in the management of breast cancer patients with clinically negative axilla.

BACKGROUND: Sonographic evaluation of the axilla can predict node status in a significant proportion of clinically node-negative patients. This review focuses on the value of ultrasound followed by ultrasound-guided cytology in assessing the need for sentinel node mapping and conservative versus complete axillary dissections. DESIGN: Breast primaries from 168 sentinel node candidates were prospectively assessed for clinicopathologic variables associated with increased incidence of axillary metastases. Patients were classified accordingly, and those at a higher risk underwent ultrasound of their axillae, followed by aspiration biopsy if needed. Sentinel node mapping was performed in all low-risk patients, and in high-risk patients with normal axillary ultrasounds or negative cytology. Final axillary status was compared in terms of nodal stage, number of positive nodes, and size of metastasis. RESULTS: 112 patients were at high risk for nodal disease (67%), with a statistically significant lower probability for remaining node-negative and a statistical significantly higher risk for having more than one positive node. All patients with more than three positive nodes were detected by ultrasound-guided cytology. High-risk patients with final positive axillae missed by ultrasound or ultrasound guided cytology had tumor deposits measuring

Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23.

PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status. RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years. CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.

Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02.

BACKGROUND: The conviction that postoperative radiotherapy and chemotherapy represent an acceptable standard of care for patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the rectum evolved in the absence of data from clinical trials designed to determine whether the addition of radiotherapy results in improved disease-free survival and overall survival. This study was carried out to address this issue. An additional aim was to determine whether leucovorin (LV)-modulated 5-fluorouracil (5-FU) is superior to the combination of 5-FU, semustine, and vincristine (MOF) in men. PATIENTS AND METHODS: Eligible patients (n = 694) with Dukes' B or C carcinoma of the rectum were enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol R-02 from September 1987 through December 1992 and were followed. They were randomly assigned to receive either postoperative adjuvant chemotherapy alone (n = 348) or chemotherapy with postoperative radiotherapy (n = 346). All female patients (n = 287) received 5-FU plus LV chemotherapy; male patients received either MOF (n = 207) or 5-FU plus LV (n = 200). Primary analyses were carried out by use of a stratified log-rank statistic; P values are two-sided. RESULTS: The average time on study for surviving patients is 93 months as of September 30, 1998. Postoperative radiotherapy resulted in no beneficial effect on disease-free survival (P =.90) or overall survival (P =.89), regardless of which chemotherapy was utilized, although it reduced the cumulative incidence of locoregional relapse from 13% to 8% at 5-year follow-up (P =.02). Male patients who received 5-FU plus LV demonstrated a statistically significant benefit in disease-free survival at 5 years compared with those who received MOF (55% versus 47%; P =.009) but not in 5-year overall survival (65% versus 62%; P =.17). CONCLUSIONS: The addition of postoperative radiation therapy to chemotherapy in Dukes' B and C rectal cancer did not alter the subsequent incidence of distant disease, although there was a reduction in locoregional relapse when compared with chemotherapy alone.

Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25.

PURPOSE: In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results. PATIENTS AND METHODS: Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival. RESULTS: No significant difference was observed in DFS (P =.20), distant DFS (P =.31), or survival (P =.76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P =. 29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P =.71) and 3 (78% v 79%, respectively; P =.86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups. CONCLUSION: Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.

Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05.

BACKGROUND: National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 showed a benefit from leucovorin (LV)-modulated 5-fluorouracil (5-FU) adjuvant therapy (5-FU + LV) in patients with Dukes' stage B or C carcinoma of the colon. Preclinical and clinical phase I/II data suggested that interferon alfa-2a (IFN) enhanced the efficacy of 5-FU therapy. Accordingly, in NSABP protocol C-05, the addition of recombinant IFN to 5-FU + LV adjuvant therapy was evaluated. METHODS: Data are presented for 2176 patients with Dukes' stage B or C cancer entered onto protocol C-05 during the period from October 1991 through February 1994. Individuals with an Eastern Cooperative Oncology Group performance status of 0-2 (ranges from fully active to ambulatory and capable of self-care but unable to work), a life expectancy of at least 10 years, and curative resection were stratified by sex, disease stage, and number of involved lymph nodes and were randomly assigned to receive either 5-FU + LV or 5-FU + LV + IFN; the mean time on the study as of June 30, 1997, was 54 months. All statistical tests were two-sided. RESULTS: There was no statistically significant difference in either disease-free survival (5-FU + LV, 69%; 5-FU + LV + IFN, 70%) or overall survival (5-FU + LV, 80%; 5-FU + LV + IFN, 81%) at 4 years of follow-up. Toxic effects of grade 3 or higher were observed in 61.8% of subjects in the group treated with 5-FU + LV and in 72.1% of subjects in the group treated with 5-FU + LV + IFN; fewer patients in the latter group completed protocol-mandated 5-FU + LV therapy than in the former group (77.1% versus 88.5%). CONCLUSION: The addition of IFN to 5-FU + LV adjuvant therapy confers no statistically significant benefit, but it does increase toxicity.

The use of partially HLA-mismatched donors for allogeneic transplantation in patients with mucopolysaccharidosis-I.

Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling appears to improve survival and diminish some of the physiologic derangements seen in children with mucopolysaccharidosis (MPS)-I (Hurler Syndrome), an inherited metabolic storage disease resulting from the lack of alpha-L-iduronidase enzyme activity. Death is usually expected in the first decade of life. Unfortunately, most patients lack an HLA-matched sibling donor and alternative donors have been identified for transplant. This study reports on a five-year median follow-up (range: 985-2,355 days) in 11 Hurler Syndrome patients who underwent allogeneic BMT from partially mismatched related donors (PMRDs). The median age was 20 months (range: 11-44 months). The overall survival rate was 64% (95% CI 34-94%). The overall graft failure rate (36%) was higher than reported with matched sibling BMT. All patients with sustained engraftment experienced improvement in physical manifestations, such as corneal opacity, gum and tongue hypertrophy, hepatosplenomegaly and joint mobility. Skeletal abnormalities, such as dysostosis-multiplex, were stabilized but not reversed. Some patients have continued to show decline in neuropsychometric testing, while others appear to stabilize and one has demonstrated improvement. Until better methods for replacing enzyme activity are developed, BMT from a matched sibling of alternative donors can be considered a viable intervention for Hurler Syndrome patients to achieve partial improvement or stabilization from the deterioration caused by substrate storage, particularly in minimally affected patients early in life.

Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22.

PURPOSE: The National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a randomized trial (B-22) to determine if intensifying but maintaining the total dose of cyclophosphamide (Cytoxan, Bristol-Myers Squibb Oncology, Princeton, NJ) in a doxorubicin (Adriamycin, Pharmacia, Kalamazoo, MI)-cyclophosphamide combination (AC), or if intensifying and increasing the total dose of cyclophosphamide improves the outcome of women with primary breast cancer and positive axillary nodes. PATIENTS AND METHODS: Patients (N = 2,305) were randomized to receive either four courses of standard AC therapy (group 1); intensified therapy, in which the same total dose of cyclophosphamide was administered in two courses (group 2); or intensified and increased therapy, in which the total dose of cyclophosphamide was doubled (group 3). The dose and intensity of doxorubicin were similar in all groups. Disease-free survival (DFS) and overall survival were determined using life-table estimates. RESULTS: There was no significant difference in DFS (P = .30) or overall survival (P = .95) among the groups through 5 years. At 5 years, the DFS of women in group 1 was similar to that of women in group 2 (62% v 60%, respectively; P = .43) and to that of women in group 3 (62% v 64%, respectively; P = .59). The 5-year survival of women in group 1 was similar to that of women in group 2 (78% v 77%, respectively; P = .86) and to that of women in group 3 (78% v 77%, respectively; P = .82). Grade 4 toxicity increased in groups 2 and 3. Failure to note a difference in outcome among the groups was unrelated to either differences in amount and intensity of cyclophosphamide or to dose delays and intervals between courses of therapy. CONCLUSION: Intensifying or intensifying and increasing the total dose of cyclophosphamide failed to significantly improve either DFS or overall survival in any group. It was concluded that, outside of a clinical trial, dose-intensification of cyclophosphamide in an AC combination represents inappropriate therapy for women with primary breast cancer.

Treatment of leukemia with partially matched related bone marrow transplantation.

The results of partially matched related donor (PMRD) marrow transplantation for 82 patients with leukemia are reported, including 45 who received two antigen disparate grafts. Following intensive radiochemotherapy, patients received grafts which were partially depleted of T cells by the monoclonal antibody T10B9 and complement. Actuarial probability of engraftment was 86% (95% CI = 78-93%). The median day to engraftment was similar among recipients of grafts disparate at one, two or three antigen loci. The incidence of severe (grades III and IV) acute graft-versus-host disease and extensive chronic graft-versus-host disease was 13% and 6%, respectively. The probability of disease-free survival for the entire cohort of patients is 31% at 3 years. Age < or = 30 years, early or intermediate stage disease and a graft disparate at one or two loci predicted longer disease-free survival in multivariant analysis. Moreover, 47% of patients receiving PMRD grafts disparate at two loci who had both these favorable pretransplant characteristics were alive and free of disease 3 years after transplantation. We believe that the utilization of PMRDs, especially those with two antigen disparate grafts, can extend allogeneic transplantation to additional leukemic patients lacking a histocompatible donor, with acceptable results.

Long-term survival in advanced chronic myelogenous leukemia following bone marrow transplantation from haploidentical related donors.

From 1987 to 1991, 26 patients with CML and a median age of 31 years received allogeneic BMT from a partially mismatched related donor (PMRD) who shared at least one haplotype with the recipient. Nine patients were in accelerated phase (AP), and 11 patients were in blast crisis (BC) at the time of BMT. Patients were mismatched either in graft-versus-host or host-versus-graft directions for one antigen in 3 patients, two antigens in 14 patients, and three antigens in 9 patients. All patients were prepared with a regimen consisting of total body irradiation, etoposide, cytosine arabinoside, cyclophosphamide and methylprednisolone. All marrows were treated ex vivo with T10B91.A-31, a monoclonal antibody directed toward the alpha beta heterodimer of the CD3 receptor, and rabbit complement. Additional GVHD prophylaxis included either the anti-CD5 immunoconjugate XomaZyme-H65, cyclosporine, or both in combination with methylprednisolone. Eight patients did not have sustained engraftment. The 100-day survival was 42%. The incidence of > or = grade II acute GVHD was 29%. The incidence of chronic GVHD was 50% and was limited in all cases. The median survival at 4 years for all 26 patients was 27%. Seven patients (CP 1, AP 3, BC 3) remain in hematologic remission 1297-2241+ days after transplantation. AlloBMT from a PMRD may be considered for patients with advanced CML who lack a matched sibling or unrelated donor.

Allogeneic bone marrow transplantation with T cell-depleted partially matched related donors for advanced acute lymphoblastic leukemia in children and adults: a comparative matched cohort study.

Allogeneic BMT provides the best treatment currently available for long-term disease-free survival in patients with recurrent ALL. Historically, partially matched related donors provided the opportunity for treatment to a greater number of patients than matched related donors at the expense of decreased overall survival. In this study we compare the results in recurrent ALL patients transplanted with either HLA identical sibling bone marrow or partially matched related bone marrow. Thirty-two patients with relapsed ALL received partially matched bone marrows from a relative with one to three HLA, A, B and Dr antigen mismatches. Bone marrow was partially T cell-depleted with murine T10B9.1A-31 moAb. Sixteen patients with relapsed ALL received HLA-matched sibling bone marrows. All partially matched patients received additional GVHD prophylaxis with methylprednisolone in addition to anti-CD5 immunotoxin and/or CYA. All matched patients in addition to methylprednisolone received MTX and/or CYA. We observed no difference in disease-free survival between patients transplanted with partially matched bone marrow (median follow-up 1252 days, range 778-2035 days) vs those transplanted with HLA-matched bone marrow (median follow-up 1472 days, range 1165-2800 days; P = 0.48). Median survival for all patients is 38% (95% CI 24-52%) at 6 years. Patients transplanted in remission had a significant increase in disease-free survival when compared to those in relapse (P = 0.007). Our data suggest that partially matched BMTs from related donors are a comparable alternative to fully matched transplants in patients with ALL.

Lymphocyte infusion for delayed extramedullary relapse of acute leukemia following bone marrow transplantation.

We report a case of extramedullary relapse of acute myelogenous leukemia twelve years after allogeneic bone marrow transplantation. Due to the localized nature of the relapse, we were able to eliminate a majority of the tumor burden, utilizing local irradiation. Destined with eventual systemic leukemia relapse, further therapy utilizing donor lymphocytes was given at a time of minimal disease burden. The patient remains in a state of complete remission.

Combined in vitro and in vivo T lymphocyte depletion for the control of graft-versus-host disease following haploidentical marrow transplant.

Most patients requiring allogeneic bone marrow transplantation (BMT) lack a human leukocyte antigen genotypically identical sibling and require an alternative donor. This carries an increased risk of graft failure and acute graft-versus-host disease (GVHD). We sought to overcome these problems with transplants by using grafts obtained from the most readily available source: the haploidentical, partially mismatched, related donor. This study of 40 patients used a novel approach combining in vitro and in vivo T cell depletion with T lymphocyte targeted monoclonal antibodies (mAb) and intensified conditioning therapy, including fractionated total body irradiation before etoposide, cytoside arabinoside, cyclophosphamide, and methylprednisolone. Grafts were treated with T10B9.1A-31 mAb, directed against the alpha-beta heterodimer of the T cell receptor, and rabbit complement. In vivo depletion was attempted with an anti-CD5 mAb-Ricin A-chain (H65-RTA) immunotoxin (IT). Study patients were compared with a historical control group of 17 patients not given H65-RTA. Rates of engraftment were not significantly different (93% vs. 100%, P=0.12), although patients receiving IT engrafted more rapidly. The incidence of > grade I GVHD was significantly lower in the study group (36% vs. 100%, P=0.0001), as well as for severe grade III-IV GVHD (19% vs. 92%, P=0.0001). Five-year survival tended to be improved in the study group (40% vs. 18%, P=0.21). Transplant from haploidentical family members is indicated for patients without a matched sibling in whom allogeneic BMT offers the best opportunity to achieve cure.

Patients' knowledge of their caregivers' names. A teaching-hospital study.

In busy hospitals--particularly teaching hospitals--ensuring that patients know the names of those attending them is a task often given low priority. Yet such knowledge is a crucial element in establishing the high-priority patient-provider relationship, and certainly one within hospitals' control. In a university teaching hospital, the authors tested patients' knowledge of names before and after the use of an information sheet listing their particular caregivers.

Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant.

Lupus anticoagulant (LA), an antibody against anionic phospholipid with anticoagulant laboratory manifestations, is paradoxically associated with a high incidence of thrombosis. In the present study we analyzed the phospholipid- and platelet-dependent degradation of factor Va following clotting in plasma from 15 consecutive patients with LA to provide evidence for a distinct procoagulant effect of the antibody. After clotting with 25 micrograms phospholipid/mL, all samples containing LA showed markedly decreased rates of factor Va degradation (k = 0.01 to 0.14 min-1 v 0.27 to 0.35 min-1 in controls). Also with higher phospholipid concentrations (up to 100 micrograms/mL), as well as in the presence of platelets (5 to 33 x 10(7)/mL), significantly less of the procoagulant activity disappeared per unit of time in samples with LA than in controls. Plasma with LA was to a variable extent capable of decreasing or abolishing factor Va inhibition in normal plasma. Most importantly, exogenous activated protein C failed to correct the ineffective factor Va destruction despite adequate protein S levels. These data suggest that LA prevents the formation of the complex essential for rapid proteolysis of factor Va both on phospholipid and on the platelet membrane, thereby compromising the catalytic function of activated protein C. Our findings offer a new opportunity for a more comprehensive evaluation of patients with antiphospholipid antibody in defining the pathogenesis of thrombosis in this clinical condition.