Clinical correlations of steroid receptors and male breast cancer.

Estrogen receptors (ER) were present in tumor specimens from 29 of 34 cases of male breast cancer. There was a significant negative correlation of ER concentration with age. The quantity of ER tended to correlate directly with progesterone receptor levels, disease-free interval, and response duration among responders, but not to a statistically significant extent. In 13 patients for whom response data were available, no significant correlation was observed between ER levels and either frequency or duration of orchiectomy response. Among the six patients with tumor ER levels of less than 30 fmol per mg of protein, however, only two brief responses to orchiectomy occurred that were of little clinical benefit, while three of seven patients with higher ER responded more favorably. Thus, although this suggests that a relationship between low ER and unfavorable orchiectomy response may emerge as more patients are studied, currently available data do not justify basing therapeutic intervention on ER status of a biopsy in a manner analogous to that used for female breast cancer. Nine of 14 male breast cancer patients had positive progesterone receptor assays and several had androgen or glucocorticoid receptors. Tissue from only three of ten men with gynecomastia had measurable ER, and these were limited to the 4S component on sucrose gradients.

Effects of steroid hormones on phytohemagglutinin-stimulated human peripheral blood lymphocytes.

The interactions of steroid hormones and human peripheral blood lymphocytes (PBLs) have been investigated following glass-wool column separation of PBLs and incubation in a serum-free medium in the presence of phytohemagglutinin (PHA). Addition of hydrocortisone or progesterone above physiological concentrations resulted in inhibition of [14C]2-TdR incorporation. 17beta-Estradiol and 5alpha-dihydrotestosterone inhibited [14C]2-TdR incorporation only at steroid concentrations thousands of times higher than the physiological concentrations. The kinetics of hydrocortisone and progesterone inhibition appeared to be similar and suggested that events occurring early after PHA addition were most sensitive to steroid inhibition and that addition of steroid at 28 hr, at the end of the early prereplicative phase of the cell cycle, inhibited DNA synthesis only at very high concentrations. The PHA-induced increase in RNA synthesis could be prevented by hydrocortisone addition even if delayed for up to 4 hr; morphological transformation was similarly affected. These data, and other investigations showing that progesterone binds to a specific glucocorticoid receptor in PBLs suggest that the progesterone inhibition of macromolecular synthesis in human PBLs is exerted via a glucocorticoid-like mechanism, and that glucocorticoid sensitivity is greatest during the early phases of lymphocyte activation. These results also provide a rationale for the apparent in vivo immunosuppressive capability of progesterone.

Incompletely resected advanced squamous cell carcinoma of the head and neck: the effectiveness of adjuvant vs. salvage radiotherapy.

Between 1982 and 1988, 441 patients were treated at the Medical College of Virginia for AJC Stage III and IV squamous cell carcinoma of the head and neck. We report here on 84 patients whose tumors were incompletely resected based on histopathological margins of 1 mm or less. Of these 84 patients, 49 were treated with surgery alone and 35 received immediate postoperative irradiation to doses of 50-70 Gy. The two patient groups are comparable with respect to stage of disease, age, male/female and racial ratios. This retrospective analysis, based on follow-up of 24-110 months, gives actuarial locoregional tumor control and survival data. The local control and disease-free survival rates in the combined modality group are significantly superior at the p = 0.0006 and p = 0.0003 levels, respectively, relative to the group treated with surgery alone. Patients in the combined modality group also experienced a significantly improved adjusted and overall survival, p = 0.005 and p = 0.01, respectively. The administration of postoperative irradiation was not associated with an increased rate of complications. The benefit of radiotherapy on survival was only seen when given as postoperative treatment but was lost in patients treated for salvage after tumor recurrence.

Inhibition of human neuroblastoma by dopamine antagonists.

The effects of dopamine agonists and antagonists were investigated in human neuroblastoma (HNB) tissue culture cell lines and correlated with the presence of specific membrane-bound dopamine-binding activity ("receptor"). In four HNB cell lines the dopamine antagonists domperidone, pimozide, and spiroperidol inhibited macromolecular synthesis in vitro as indicated by decreased 3H-TdR and 14C-leu incorporation in a dose-response fashion with at least 50% inhibition noted at 10(-6)M concentration of each drug. Dopamine agonists showed no significant inhibition. Scatchard analysis of competitive dopamine-binding assays in all four HNB cell lines and in five of eight solid tumors obtained at surgery demonstrated high affinity, limited-capacity binding consistent with a single class of receptor sites with receptor concentrations (Rc) ranging from 8.8 to 26.7 pmol/gm wet weight of tissue with dissociation constants (KD) from 0.40 to 6.6 nmol/L, compared with a mean Rc of 28.1 +/- 5.2 pmol/gm wet weight of tissue and KD = 0.38 +/- 0.09 nmol/L in receptor-rich dog caudate nucleus, the normal dopamine-sensitive control. Survival was prolonged after inoculation of the SK-N-AS cell line into nude mice and subsequent domperidone administration by 50% (24 days after drug initiation versus 16 days in control mice). These data demonstrate inhibition of macromolecular synthesis in HNB by dopamine antagonists and suggest that dopamine receptor is associated with this inhibition. The determination of dopamine receptors may prove useful in the selection of dopamine antagonists as specific chemotherapy for patients with neuroblastoma.

Prognostic features of pediatric soft-tissue sarcomas.

Eight hundred ninety-two patients under 20 years of age with soft-tissue sarcomas histologically diagnosed between 1955 and 1971 (before the era of combined modality therapy) were reviewed to delineate important prognostic variables. Differing histologic findings, extent of disease at initial presentation, and site of the primary tumor correlated with prognosis; age, sex, and race did not affect survival significantly. Patients with fibrosarcomas, liposarcomas, and leiomyosarcomas had improved survival rates when compared with adults with the same histologic findings; patients with localized tumors and extremity primary sites had the best prognosis. Patients with rhabdomyosarcomas, disseminated disease, or retroperitoneal primary sites had the worst prognosis. These data suggest that some childhood sarcomas are not as aggressive as adult sarcomas or childhood rhabdomyosarcomas. Therefore they may not require the adjuvant therapy shown to be beneficial in childhood rhabdomyosarcomas.

Estrogen receptors in primary breast cancer.

Estrogen receptor (ER) activity was assayed in 132 patients undergoing mastectomy for primary breast cancer and in 75 patients whose initial treatment for metastatic cancer was endocrine manipulation. Estrogen receptor status correlated with response to endocrine therapy. Among patients whose ER activity was assayed in the primary tumor, ER-positive patients had an improved disease-free survival (independent of stage or nodal or menopausal status) after mastectomy when compared with ER-negative patients (P less than .05). The ER-positive and ER-negative patients receiving adjuvant chemotherapy had similar disease-free survivals. These data confirm that patients with ER-positive primary tumors have a better prognosis than patients with ER-negative primary tumors. Although adjuvant chemotherapy improves the prognosis in patients with histologically positive lymph nodes in both ER-positive and ER-negative patients, the disease-free survivals in ER-negative patients may improve to a greater extent than in ER-positive patients.

Epidermal growth factor receptor expression in squamous cell carcinoma of the hypopharynx.

Expression of the epidermal growth factor receptor (EGFR) has been demonstrated in normal and malignant squamous epithelia. Its presence has been suggested to be important in the pathophysiology and prognosis of epithelial cancers. Archival tumour specimens from 57 patients with squamous cell carcinoma of the hypopharynx were studied using OM-11-951, a new murine anti-EGFR monoclonal antibody which recognizes the receptor on deparaffinized tissue. By visual inspection, 28 (49%) tumours were EGFR negative; 29 (51%) tumours were EGFR positive. While patients whose tumours were EGFR positive were younger, there was no significant correlation with other clinical or pathological variables (including grade and stage). Patients whose tumours were EGFR negative had a median survival of 21 (95% CI 4.3-37.7) months compared with a median survival of 17 (95% CI 11.4-22) months for patients whose tumours were EGFR positive. The difference was not statistically significant. A multiple regression analysis did not demonstrate EGFR status to be important in predicting survival. These data cast doubt on the prognostic significance of EGFR expression in this neoplasm.

Reconstruction after mediastinal tracheostomy.

Mediastinal tracheostomy has been associated with high morbidity and mortality, often due to skin necrosis, with resultant exposure of the great vessels and subsequent hemorrhage. During a 4 year period, 11 patients underwent mediastinal tracheostomy. Reconstruction included the use of a pectoralis major musculocutaneous flap to provide well-vascularized skin for anastomosis to the superior portion of the tracheostoma in nine patients. Whenever possible (eight patients), the trachea was transposed below the innominate artery to allow for slightly more mobility of the trachea and to remove the cartilaginous portion of the trachea from the artery. Among the eight elective operations reported herein, there were no postoperative deaths and only two minor wound-related complications. Among three patients who underwent emergency mediastinal tracheostomy, two patients died, one with an aneurysm of the innominate artery that ruptured several weeks postoperatively and the other with respiratory instability who could not be weaned from the respirator. These results suggest that use of the pectoralis major musculocutaneous flap and tracheal transposition decreases the risk of skin necrosis and resultant major vessel rupture. We advocate this approach in the reconstruction of the patient who requires mediastinal tracheostomy.

Closure of craniofacial defects after cancer resection.

Resection of malignancies of the upper face and skull base may result in complex bone and soft tissue defects. To better define the optimal management of these defects, we conducted a retrospective review of 75 consecutive patients who underwent closure of 76 craniofacial defects after malignant tumor excision from 1966 to 1990. Wound complications requiring further surgery occurred in 30% of the defects (23 of 76). Wound complications at anterior, temporal, or combined sites were correlated with each method of reconstruction (scalp flap or split thickness skin graft, pedicled myocutaneous flap, and free flap). The presence of a large combined defect involving both frontal and temporal areas was the only significant risk factor for development of a wound complication requiring secondary surgery. These data suggest that anterior or temporal craniofacial defects may be closed with either scalp flaps and split thickness skin grafts or pedicled myocutaneous flaps with reasonable wound complication rates of 16% to 22%. Large combined defects have high wound complication rates (90%) when local tissue is used; therefore, other methods of closure such as free tissue transfer should be strongly considered in these patients.

Management of locoregional recurrent oropharyngeal carcinoma.

Sixty-seven patients with recurrent locoregional squamous cell epithelioma of the oropharynx were reviewed to determine the curative potential of secondary therapy for recurrent carcinoma. Of the 37 patients in whom recurrent carcinoma developed after radical surgery, only 11 percent (4 of 37) had a 2 year disease-free survival following secondary treatment. Recurrence developed in 30 patients after radiation therapy. Surgical resection of the recurrent carcinoma was possible in 13 of the patients, 38 percent (5 of 13) of whom were free of disease for a minimum of 2 years. Though treatment results in patients with recurrent oropharyngeal carcinoma are discouraging, secondary therapy in selected patients can yield 2 year disease survival in over a third of cases. Favorable prognostic factors included the development of recurrent carcinoma following radiation therapy and a tumor initially classified as stage I or II, irrespective of the initial mode of therapy.

Pancreatic and periampullary carcinoma. Experience with 200 patients over a 12 year period.

The operative management of 200 patients with pancreatic and periampullary cancer was reviewed. Patients with metastatic disease and biliary obstruction are best treated by the nonoperative techniques of biopsy and internal biliary drainage if technically feasible. For patients who undergo exploration and are found to be candidates for a bypass procedure, both biliary and gastroduodenal bypass should be performed. Lymph node involvement and age of the patient were found to be significant variables in determining the candidates suitable for curative resection. A definite incidence of multicentricity was found in patients undergoing total pancreatectomy for ductal carcinoma of the pancreas; however, significant problems with diabetic management arose from this procedure. The primary site of the lesion as well as the intelligence and socioeconomic background of the patient should dictate the type of resection employed. Pancreatoduodenectomy (Whipple procedure) is recommended for periampullary cancers other than pancreatic carcinoma, while total pancreatectomy may be appropriate in selected patients. However, there has been no evidence thus far in this early trial with total pancreatectomy that more complete resection of the pancreas leads to longer survival.

The pectoralis major myocutaneous flap in head and neck reconstruction. Analysis of complications.

Sixty-seven patients underwent 73 pectoralis major myocutaneous flap procedures for the immediate reconstruction of defects after resection of head and neck cancers. Thirty-six patients experienced a total of 50 complications for an overall complication rate of 54 percent. There were 3 instances of total flap necrosis, 9 of partial flap necrosis, 12 orocutaneous fistulas, 9 suture line separations, 8 neck wound complications, 1 donor site complication, and 8 mandibular replacement complications. Most complications were minor and did not require a second procedure for correction; however, 36 percent did require a second operation. Eight of 10 patients in whom a metal appliance was placed to restore mandibular continuity required the removal of that appliance due to either flap necrosis, fistula formation, or exposure. Based on our experience, we conclude that attention to flap design, operative technique, and post-operative management were useful in reducing the incidence of complications. We also conclude that a metal appliance was an unsatisfactory means of restoring mandibular continuity when utilized beneath a pectoralis major myocutaneous flap. Although the overall incidence of complications was high, the actual incidence of flaps failing to accomplish their intended purpose and requiring secondary repair was acceptable. The pectoralis major myocutaneous flap was reliable in the reconstruction of defects in the head and neck region.

Postoperative radiotherapy improves survival in squamous cell carcinoma of the hypopharynx.

BACKGROUND: Postoperative radiation is considered to be "standard of care" therapy for advanced, resectable squamous cell carcinoma of the head and neck. This approach has been supported by retrospective data but has not been validated in randomized clinical trials. PATIENTS AND METHODS: The present analysis examined the clinical course of 110 patients with squamous cell cancer of the hypopharynx treated with surgery alone (n = 65) and postoperative radiotherapy alone (n = 45) between 1966 and 1990. Staging of patients was performed using the 1988 American Joint Committee on Cancer criteria. Cox regression analyses identified clinical and pathologic factors that were significant for disease-free and overall survival. Crude and adjusted cancer-specific survival rates were calculated. RESULTS: The postoperative radiotherapy group presented with more advanced disease than the surgery alone group (stage III and IV combined, 96% versus 77%, P = 0.015). Crude 5-year cancer-specific survival probabilities were 43% for the postoperative therapy group and 27% for the surgery alone group (P = NS). Adjusted 5-year survival rates, correcting for differences in significant prognostic variables between groups, were 18% and 48%, respectively, for the surgery and postoperative radiotherapy groups (P = 0.029). CONCLUSIONS: The addition of postoperative radiotherapy was associated with improved disease-free and adjusted overall cancer-specific survival in patients with advanced hypopharyngeal squamous cancer. The potential survival benefit of postoperative radiotherapy should be addressed in a randomized clinical trial.

The potential of hormone receptors in the treatment of various cancers.

Breast cancer, prostate cancer, endometrial cancer, and lymphocytic leukemias may possess steroid hormone receptors that can predict a high probability of response to the appropriate hormone when the receptor is present. The presence or absence of receptor may also be an important prognostic variable and may aid in the selection of patients for appropriate adjuvant therapy. Although putative receptors have been described in many other tumors, their clinical significance is questionable because these tumors generally do not respond to hormonal therapy. In the future, steroid receptors may enable us to target drugs, radioisotopes, or other molecules to tumors by linking these drugs to steroid hormones.

Experience with the Hickman catheter: unusual complications and suggestions for their prevention.

With the expanding clinical use of the Hickman catheter, new complications have emerged. This report describes two such complications: one in an adult with postplacement malposition and a second in a child with a ballooning double-lumen catheter. The risk of postplacement malposition can be reduced by placing the catheter's tunnel as medial as possible; the risk of material malfunction can be reduced by careful quality control and careful surgical technique.

A retrospective epidemiologic study of pediatric fibrosarcomas.

One hundred eighty-two patients with histologically diagnosed fibrosarcoma below the age of 19 yr reported to the End Results Section of the National Cancer Institute before 1971 were analyzed. Race, sex, and age did not significantly affect prognosis. Site of the primary lesion and extent of disease at diagnosis did significantly affect prognosis. Overall 3-yr survival was 80%, and this remained constant over the next 5 yr. Survival of patients with upper extremity lesions exceeded 90%, whereas those with retroperitoneal primary sites had 17% survival. Patients with localized disease at diagnosis had 5-yr survival of 90%, but those with disseminated disease had a median survival of 6 mo, and 22% 1-yr and 5-yr survival.

Principles in the management of pediatric intestinal leiomyosarcomas.

Primary intestinal leiomyosarcomas in children are unusual tumors with little known about their natural history. Two patients (aged 9 and 10 years) with leiomyosarcoma of the jejunum treated at our institution are reported and added to the 20 other patients reported in the literature. The first patient had a grade 1 leiomyosarcoma completely resected, received no additional therapy, and remains alive with no evidence of disease 14 years later. The second patient presented with a perforated grade 2 leiomyosarcoma which was incompletely resected; he received combination chemotherapy with an initial good response, but eventually died from sarcomatosis 7 years after initial diagnosis. The 22 cases of pediatric intestinal leiomyosarcoma presented more commonly with obstruction or perforation, were able to be completely resected more often, and appear to have a better prognosis than in adults. Thus, intestinal leiomyosarcomas in children appear to have a natural history different from that of the same tumor arising in adults.

Malignant fibrous histiocytomas in children.

The natural history of malignant fibrous histiocytomas in children has not been well delineated. During a 6-year period, we have treated six patients less than 18 years of age. The sites of origin included the retroperitoneum in 2 patients, neck in 2 patients, and extremities in 2 patients. Surgical treatment consisted of wide local excision in 5 patients and amputation in 12; radiation and/or chemotherapy were administered to 2 patients following resection of all tumor. All children remain free of local recurrence or distant metastases with a median follow-up in excess of 4 years. These data suggest that malignant fibrous histiocytomas in children may have a better prognosis than in adults.

Management of congenital microgastria with a jejunal reservoir pouch.

A 3-mo-old female presented with growth retardation, vomiting, reflux esophagitis, recurrent aspiration pneumonias, and was found to have megaesophagus and microgastria. After the failure of conservative therapy a double-lumen jejunal (Hunt-Lawrence) pouch with distal Roux-en-Y anastomosis was anastomosed to the stomach to increase the gastric reservoir. One year later, there has been progressive weight gain, the megaesophagus and gastroesophageal reflux have lessened significantly, pneumonia has not recurred, and the tracheobronchitis and esophagitis have resolved. This suggests that the gastroesophageal reflux and megaesophagus were due to an inadequate reservoir with a secondary gastric overflow as the esophagus dilated to enlarge the reservoir capacity of the upper gastrointestinal tract. Utilization of a jejunal pouch increased the size of the gastric reservoir, allowed resolution of the secondary esophageal changes, and permitted normal growth to proceed.

Soft tissue sarcomas.

Soft tissue sarcomas in infants and children differ from those in adults in clinical presentation, histology, and response to therapy. For rhabdomyosarcoma, the most common sarcoma in children, each primary site has special characteristics that affect both treatment programs and survival rates. Some results are so good, from the standpoint of survival data, that studies are now in progress to evaluate means of reducing treatment morbidity. Other ongoing studies focus on improved protocols for metastatic or recurrent rhabdomyosarcoma. Results thus far in the IRS trials have proven the value of cooperative clinical trials in the management of patients with this disease.