Pathologic features associated with nonsentinel lymph node metastases in patients with metastatic breast carcinoma in a sentinel lymph node.

BACKGROUND: To the authors' knowledge it has not yet been determined which patients with primary breast carcinoma and an axillary sentinel lymph node (SN) metastasis have additional metastases in nonsentinel lymph nodes. METHODS: Pathologic features of the primary breast carcinoma and its SN metastasis were examined in 194 patients and correlated with the tumor status of the non-SNs in the same axillary basin. Two-level cytokeratin immunohistochemistry was applied to the SNs and to non-SNs of cases that were negative by standard hematoxylin and eosin examination. RESULTS: Lymph node staging based on SN findings, size of the primary tumor, and presence of peritumoral lymphatic vascular invasion (LVI) were associated with non-SN metastasis. The majority (63%) of the 101 patients with SN macrometastases had non-SN metastases. Extranodal hilar tissue invasion in conjunction with SN involvement also was strongly associated with non-SN metastasis (P = 0.0001) but was present in only 65% of patients (35 of 54 patients) with non-SN macrometastases. Approximately 26% of patients (24 of 93 patients) with SN micrometastases (

Sequential multi-agent chemotherapy and whole abdominal irradiation for stage III ovarian carcinoma.

Modern therapy for stage III ovarian carcinoma patients usually involves one or more laparotomies with maximal resection of tumor, and intensive multi-agent chemotherapy. However, with long-term follow-up only 10-15% of patients remain free of disease. In the hope of improving outcome, we have treated 17 women with sequential multimodality therapy, including initial surgical resection (if possible), cyclophosphamide-adriamycin +/- cis-platinum, second-look surgery, and whole abdominal irradiation. Seven patients are currently alive without disease, with median follow-up of 52 months since initiation of radiation and 60 months since initiation of chemotherapy. Disease-free survival correlated with residual tumor at the start of radiotherapy: none (4/4); microscopic, less than or equal to 5 mm (3/4); greater than 5 mm or no surgery (0/9). Survival also correlated with tumor grade: grade 1 (2/2); grade 2 (2/3); grade 3 (3/11). Hematological tolerance of radiotherapy was dependent upon the number of chemotherapy cycles: ten of 11 patients receiving less than or equal to eight cycles completed radiotherapy without excessive delay, compared with only one of five receiving greater than eight cycles. There were no treatment-related deaths and only one patient required laparotomy for bowel obstruction. We conclude that intensive multimodal treatment may be tolerated moderately well if the amount of chemotherapy is limited, and that further studies are justified.

[Reconstruction of the cervical esophagus by the free transfer of a jejunal loop. An experimental study in dogs]. / Reconstruction de l'oesophage cervical par transplant libre d'anse jéjunale. Etude expérimentale chez le chien.

A study was performed in twenty dogs in order to evaluate the chronic effects of free jejunal transfer and possible subsequent radiation therapy. Ten dogs were sacrificed within one week after surgery, three survived twelve to twenty days, and seven survived longer than six weeks with only one completing a full course of radiation equivalent to 6,000 rads to the jejunal flap. Fistulization was the most frequent complication in short-term and intermediate survivors. Inanition due to a functional rather than anatomic stenosis and dysmotility was observed in the long-term survivors. Interval oesophagoscopy and biopsy was of no additional value in evaluating flap survival. The jejunum of the animal receiving radiation showed a greater submucosal inflammatory response when compared to the other animals. Attempts at intraoperative cooling of the jejunal segment did not increase bowel survival or diminish the rate of fistulization.

Severity of illness and the teaching hospital.

In the current environment of cost containment pressures on health care providers, teaching hospitals are facing increased financial risks that could jeopardize their special role in the health care delivery system. One of these risks is that the Medicare prospective payment system does not adequately account for severity of illness. Whether teaching hospitals treat a case mix of patients with more severe illness than do nonteaching hospitals was tested in the study reported here using two severity measures, Horn's severity of illness index and Gonnella's "disease staging." Teaching hospitals were found to treat a significantly greater proportion of severely ill patients than community hospitals, especially when measured by the severity of illness index. Differences in case mix of severity of illness among hospitals can have a significant impact on patient care costs, which may not be adequately met by a reimbursement system based on diagnosis related groups. Hospital managers can use severity of illness measures to assess the resource needs of patients and the practice patterns of physicians. If severity of illness measures help describe the special burden of treatment that teaching hospitals bear, they should be used to establish the case for adequate financial support.

Intraductal carcinoma of the breast: results of treatment with excisional biopsy and irradiation.

Between 1976 and 1983, 40 women with intraductal carcinoma of the breast without invasion underwent excisional biopsy and irradiation as an alternative to mastectomy. The median age was 53 years (range, 28 to 77 years) and the median follow-up time since initiation of radiation was 44 months (range, 14 to 97 months). Twenty-seven patients presented with a palpable mass; in 13 patients the tumor was detected only by mammography. A limited axillary dissection was performed in 13 patients, and all lymph nodes removed were negative. Treatment was administered to the breast and adjacent chest wall to a dose of 4,600 to 5,000 rad, with 26 patients also receiving a boost dose of 1,000 to 2,000 rad to the site of the primary. Four patients have developed a recurrence in the treated breast, at 17, 19, 35, and 63 months after the beginning of radiation therapy. The 5-year actuarial rate of local recurrence is 10%. Three of the recurrences were in those four patients who presented with a nipple discharge and a central primary. In two cases, the recurrence consisted of only intraductal carcinoma; in the other two, both intraductal and invasive cancer were found. All four patients with recurrence underwent mastectomy and are well without evidence of distant metastases at 1, 12, 15, and 15 months since mastectomy. Cosmetic results were excellent. No patient has developed distant metastases. Since the number of patients treated is small and the period of follow-up is short, one must be cautious in the interpretation of these results. Nonetheless, the treatment of intraductal carcinoma of the breast by excision and irradiation appears to give acceptable local control and excellent survival when suitable precautions of patient selection and evaluation are taken.

A pilot study of women's attitudes towards breast-conserving surgery with primary radiation therapy for breast cancer.

Breast-conserving surgery ("lumpectomy") with primary radiation therapy is gaining acceptance as an alternative to mastectomy for breast cancer. Currently, little is known about the specific immediate and long-range biopsychosocial effects of breast-conserving therapy as compared to more traditional mastectomy procedures. Physicians' speculations about the women who chose breast-conserving treatment as opposed to mastectomy seem to have been influenced by the scientific debate concerning the efficacy of this procedure. This study is a preliminary investigation of the attitudes and experiences of women receiving breast-saving therapy for carcinoma of the breast.

Cosmetic results following primary radiation therapy for early breast cancer.

In order to assess the cosmetic results of treatment, the results in 239 patients with early breast cancer treated by primary radiation treatment without adjuvant chemotherapy were reviewed. Four patients had bilateral cancers, making a total of 243 breasts available for analysis. Follow-up ranged from 24 to 78 months with a median of 33 months. The parameters measured were breast edema, retraction, telangiectasia, arm edema, and the overall cosmetic appearance. The cosmetic results declined over the first 3 years after treatment, but then stabilized. At 5 years, the overall cosmetic results were judged by physicians as excellent in 77%, good in 9%, fair in 9%, and poor in 5%. A fair or poor cosmetic result was highly correlated with the development of moderate or severe breast retraction. Telangiectasia was uncommonly the only cause of a fair or poor cosmetic result. Breast and arm edema were rarely noted to be significant, but were more common in patients who underwent axillary dissection. In 210 cases, a supplementary boost dose of radiation was delivered to the primary tumor area, and in 33 cases a boost was not used. This boost consisted of an interstitial iridium-192 implant in 204 cases and either high-energy photons or electrons in the remainder. At 4 years, no patient treated without a boost had a fair or poor result compared with 22% who received a boost (P = 0.13). The conclusion is that, in general, primary radiation treatment provides highly satisfactory cosmetic results for patients with early breast cancer.

Anti-B1 monoclonal antibody and complement treatment in autologous bone-marrow transplantation for relapsed B-cell non-Hodgkin's lymphoma.

Eight patients with relapsed B-cell non-Hodgkin's lymphoma were treated with intensive chemoradiotherapy and reconstituted with autologous bone marrow rendered free of tumour cells by the B-cell-specific monoclonal antibody anti-B1 and complement. Before the autologous marrow transplantation patients were induced with chemotherapy, radiotherapy, or both, into a minimum disease state with less than 5% bone-marrow involvement with tumour. All patients treated achieved a complete clinical response and had stable haematological engraftment by 8 weeks. No significant acute or chronic toxic effects have occurred. B cells could be detected by 2 months after transplantation and normal immunoglobulin levels were achieved by 6 months. Six of eight patients are disease free in unmaintained remission more than 20, 19, 10, 8, 5, and 3 months after transplantation.

Functional organization of the hematopoietic stem cell compartment: implications for cancer and its therapy.

Recent discoveries indicate that hematopoietic stem cells have limits on their proliferative capacity and are unable to divide indefinitely. There is great heterogeneity within the compartment as to the extent of this proliferative limitation. At any given time it appears that hematopoiesis is maintained by the progeny of only a few stem cells. When these are exhausted the progeny from other stem cells take their place. The observations of proliferative limitation, heterogeneity, and clonal succession must be incorporated into any model of stem cell organization. These new discoveries and the models incorporating them have important clinical implications. They may explain the inability of normal tissues to develop drug resistance and they also offer a mechanism by which cell renewal systems decrease the development of malignancies. In the selection of chemotherapeutic agents not only the effectiveness of the drug upon the tumor must be considered, but also how specific agents affect the stem cell compartment. These data have important implications in the use of bone marrow transplantation for both malignant and nonmalignant disease.

An evaluation of long-term survival and treatment complications in children with Hodgkin's disease.

Between April 1969 and July 1977, 83 patients, 16 years or younger, with pathologically staged IA-IIIB Hodgkin's disease were seen and treated at the Joint Center for Radiation Therapy. The five-year actuarial relapse-free and overall survivals were 82 and 95%, respectively, with a median follow-up from diagnosis of 65 months. Relapse occurred in 6/50 Stage IA-IIA, 2/9 Stage IIB, 4/9 Stage IIIA, and 3/15 Stage IIIB patients. Of patients who relapsed, 11/15 are currently disease-free following retreatment with chemotherapy. Nine patients with Stage IV disease were also evaluated. Four of seven patients initially treated with chemotherapy remain free of disease. Forty-two patients in this study were treated with mantle and para-aortic irradiation alone, thus avoiding the risk of sterility associated with pelvic irradiation or MOPP chemotherapy while retaining a high probability for long-term disease-free survival. Complications of radiation therapy included growth retardation and thyroid function abnormalities in some patients. Standing height measurements were normal regardless of age at initial treatment, however, 16 of 23 patients 3-12 years old at initial treatment had sitting heights measuring more than one standard deviation below the mean. Intraclavicular distances were shortened in some patients and examples are shown. Thyroid stimulating hormone levels were elevated in 21 of 37 patients evaluated. Radiation therapy, without adjuvant chemotherapy remains an important treatment approach for children with early stage Hodgkin's disease.

Axillary sampling in the definitive treatment of breast cancer by radiation therapy and lumpectomy.

Between January, 1967 and July, 1980, 176 women who were referred to the Joint Center for Radiation Therapy (JCRT) for definitive breast irradiation underwent low axillary dissection. A typical operative technique is described. The dissection stops short of the axillary vein although the vein is usually visualized. One hundred thirty-two axillae were thought to be N0 or N1a. Forty-six axillae were felt to be N1b. Seventeen percent of the T1 N0 patients had pathologically positive nodes. Twenty-seven percent of the T2 N0 patients had positive nodes. When 5 or less nodes were removed at axillary sampling the incidence of nodal involvement was very low. There were no differences in nodal positivity when comparing upper quadrant to lower or central lesions. Lateral lesions appeared to have higher positivity rates compared with either medial or central lesions. Ninety-four percent of axillae with N1b lesions were pathologically confirmed. The complication rate for this procedure was low. There were 5 transient non-surgical complications and 1 cellulitis resulting in a frozen shoulder, which required corrective surgery. There were no cases of moderate or severe arm edema. Axillary sampling is compared to axillary dissection as a diagnostic procedure. Axillary sampling may underestimate the true pathologic positive rate, but diagnostic accuracy appears excellent if level 1 and 2 nodes are sampled.

Pool size of pluripotential hematopoietic stem cells increased in continuous bone marrow culture by Friend spleen focus-forming virus.

Continuous mouse bone marrow cultures were infected with Friend murine leukemia virus. Production of nonadherent (NA) and adherent cells, granulocyte-macrophage colony-forming unit(s) of progenitor cells (GM-CFUc), pluripotential hematopoietic stem cells (CFUs), the self-renewal potential (Rs) of CFUs, and generation of factor-dependent (FD) multipotential and committed permanent stem cell cloned lines were measured. Uninfected marrow cultures from C57BL/6J, C57BL/6JUt, B6.S, C3H/HeJ, (C57BL/6J x DBA/2J)F1, CD- 1 Swiss, or N:NIH(S) mice generated NA cells, GM-CFUc, and CFUs for 20-41 weeks; cultures infected with Rauscher or other helper viruses generated them for 35-45 weeks. GM-CFUc and CFUs production in SFFV-positive cultures persisted for over 65 weeks and exceeded control levels by twentyfold to fiftyfold. The Rs of CFUs in SFFV-positive cultures was not detectably increased above control cultures. Multipotential (erythroid-neutrophil-mast cell-basophil-eosinophil) permanent FD cell clones were derived from control and SFFV-positive cultures. Thus SFFV amplifies the stem cell pool in vitro without detectably increasing the Rs capacity of CFUs.

Reversible brachial plexopathy following primary radiation therapy for breast cancer.

Reversible brachial plexopathy has occurred in very low incidence in patients with breast carcinoma treated definitively with radiation therapy. Of 565 patients treated between January 1968 and December 1979 with moderate doses of supervoltage radiation therapy (average axillary dose of 5000 rad in 5 weeks), eight patients (1.4%) developed the characteristic symptoms at a median time of 4.5 months after radiation therapy. This syndrome consists of paresthesias in all patients, with weakness and pain less commonly seen. The symptom complex differs from other previously described brachial plexus syndromes, including paralytic brachial neuritis, radiation-induced injury, and carcinoma. A possible relationship to adjuvant chemotherapy exists, though the etiology is not well-understood. The cases described demonstrate temporal clustering. Resolution is always seen.

Differential effects of cytotoxic agents on hematopoietic progenitors.

In order to predict the effect of chemotherapeutic agents on the hematopoietic progenitor compartment, it is necessary to have a hypothesis concerning the dynamics of the cells within the compartment. By viewing this compartment as a continuum of cells with varying self-renewal capacity, one can assess the significance of the stem cell damage incurred following a single drug dose. Vinblastine, 5-fluorouracil, cyclophosphamide, busulfan, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were investigated. The acute toxicity of the drug-exposed marrow was studied by the colony-forming units-spleen (CFU-S) and agar diffusion chamber assay. Busulfan and BCNU were found to kill CFU-S preferentially. By following CFU-S recovery for 14 days post drug, different recovery patterns are noted. Busulfan and BCNU produce prolonged depression in CFU-S, whereas cyclophosphamide and 5-fluorouracil show relatively rapid recovery. If one determines the Rs (a measure of proliferative capacity) after drug, busulfan and, to a lesser extent, BCNU produce a prolonged depression without return to normal even 650 days post drug. No such depression is noted with the other drugs. The data from the recovery curves and Rs support the notion of stem cells being heterogeneous with regard to self-renewal capacity. The agar diffusion chamber and CFU-S acute survival curves would not have predicted which drugs cause significant proliferative damage. Only with the use of CFU-S recovery and ratio of CFU-S can prolonged marrow damage be ascertained.

A regulatory mechanism for the number of pluripotential haemopoietic progenitor cells in mice.

Large changes in the pattern of regeneration of haemopoietic progenitor cells (CFU-S) are reported as a result of simply altering the time interval between administration of certain cytotoxic agents and whole-body irradiation. These results suggest a negative feedback control for the number of CFU-S, which has an appreciable time delay. A high inverse correlation between the number of maturing granulocytic cells (with ring-shaped nuclei) at the time of irradiation and the subsequent regeneration of CFU-S is consistent with these cells producing some substance that controls the number but not the proliferation rate of the CFU-S. The possibility is considered that this mechanism is an important control in the biological regulation of haemopoiesis.

Evidence for structured variation in self-renewal capacity within long-term bone marrow cultures.

Bone marrow pluripotent stem cells (CFUs) demonstrate capacity for both proliferation and differentiation. The proliferative capacity of CFUs has been measured by serial transplantability and by the Rs, a measurement of CFU production in a single 14-day transfer. In the present study, the self-renewal capacity fo both adherent and nonadherent CFUs from long-term bone marrow cultures was measured. Culture conditions were established such that nonadherent cells were derived from the adherent cell layer. Both adherent and non-adherent cells produced spleen colonies, demonstrating that significant proliferative potential was present in both locations; however, at all times in culture, the CFUs within the adherent stromal cell layer had a significantly greater self-renewal capacity than did the nonadherent CFUs. During the initial establishment of the cultures, the self-renewal capacity of the adherent CFUs decreased as the total number of CFUs per flask increased. After 3 weeks in culture, the self-renewal potential of the adherent CFUs stabilized and was maintained. These results suggest two different mechanisms of stem cell proliferation. In order to increase the most primitive stem cell pool size, there was initial proliferation of early stem cells with a concomitant decrease in self renewal capacity. Once this pool was established, the self-renewal capacity of the adherent CFUs maintained for 13 weeks in culture suggests that CFU production and cell maintenance were achieved by clonal succession.