John A. Greager

Steroid sex hormones regulate the release of tumor necrosis factor by macrophages

Generally, females have been found to have a heightened immune response and a concomitantly higher incidence of autoimmune diseases compared to males. We have used male rat peritoneal macrophages (M phi) to study the effect of female sex hormones on tumor necrosis factor (TNF) release. The amount of TNF released by macrophages (M phi) exposed to 10(-2) and 10(-3) ng/ml of 17 beta-estradiol (E2) (35.1 +/- 7.3 and 23.2 +/- 2.5 units/ml, respectively) was significantly (P < 0.05; n = 9) greater than that released by untreated M phi. Progesterone (P) also significantly (P < 0.05; n = 8) stimulated a maximal TNF release (24.4 +/- 2.8 units/ml TNF) at 10(-2) ng/ml. On the other hand, the amount of TNF released by M phi exposed to E2 or P at concentrations greater than 10(-1) or less than 10(-4) ng/ml was significantly (P < 0.05) reduced compared to untreated controls. In contrast, testosterone did not significantly affect TNF release at any concentration. Within the physiological range of E2 and P concentrations, TNF release from M phi is finely regulated and dramatically affected by relatively small changes in hormone concentrations.

Soft tissue sarcomas of the adult head and neck

From 1969 to 1983, 53 adult patients with head and neck soft tissue sarcomas were evaluated and treated by the Division of Surgical Oncology at the University of Illinois. The most common anatomic location was the neck (36%), and these patients had the highest 5‐year disease‐free survival rate (67%). Fibrosarcoma was the most common histologic type (26%); patients with aggressive fibromatosis had the longest mean survival time (93 months). The mean overall survival time was 58.7 months, and the disease‐free 2‐year, 5‐year, and 10‐year survival rates were 68%, 54%, and 28%, respectively. Wide excision was the treatment of choice, with adjuvant radiotherapy or chemotherapy, or both, used in selected patients. In all of the long‐term survivors, the tumors were either well‐differentiated or ≤5.0 cm in diameter. It is apparent that aggressive therapy of such tumors can provide good long‐term results.

Malignant schwannoma of the head and neck

From the Division of Surgical Oncology, University of Illinois College of Medicine at Chicago. Cook County Hospital, and Hektoen Institute for Medical Research, Chicago, Illinois. This work was supported in nart bv the Eleanor B. Pillsburv Fellowshi~Universitv of Illinois HospiLl, aid by the Living Institu~ for %&al Studies Gf the Departm&t of Surgery, University of Illinois College of Medicine at C&ago (KWR). Requests for reprints should be addressed to John A. Greager, II, MD, Division of Su&al Oncology, Cook County Hospital, Room 650, 1835 West Harrison Stmet. Chicago, Illinois 60612. Presented as a poster paper at the 37th Ammal Meeting of the Society of Head and Neck Surgeons, Kaanapali Beach, Hawaii, May l-4,1991. M alignant schwamomas of the head and neck region are rare tumors, for which accurate diagnosis and therapy is frequently delayed [I ,2]. In an attempt to define prognostic characteristics and optimal therapeutic strategies in these patients, we reviewed our 37year experience with this unusual tumor. Seventeen patients were treated for malignant schwannoma of the head and neck between 1953 and 1990 at the University of Illinois and Cook County Hospitals, Chicago, Illinois. There were 10 (59%) females and 7 (41%) males, who ranged in age from 14 to 88 years (mean: 41 years). Twelve (71%) were white, 3 (18%) black, and 2 (11%) Hispanic. A mass was the presenting symptom in nearly all patients, and by far the most common site was the neck. Seven patients had von Recklinghausen’s disease, and there were a variety of other associated conditions (Table I). Histologic diagnosis was based on light and electron microscopy. Tumors were staged according to the method approved by the Joint Commission of the American College of Surgeons [3]. There were seven patients with stage I disease, two with stage III, and eight with stage IV. Primary treatment consisted of surgical excision when feasible. Three patients received adjuvant chemo therapy and radiation. Local failure was treated with radiation and/or chemotherapy, and surgical re-excision was performed when possible. Survival curves were evaluated using the product-limit method, and the Wilcoxon rank-sum test. Survival rates were compared using Fisher’s exact teat, and mean survivals were compared using the independent sample ttest. The 2-, 5, and lo-year disease-free survivals were 47%, 35%, and 24%, respectively, with overall survivals of 651, 47%, and 29%, respectively. Patients with stage I tumors survived longer, on average, than those with more advanced disease (136 versus 60 months, p = 0.07). Patients with grade I tumors had the greatest survival advantage, 129 months compared with 37 months for those with more advanced disease (p = 0.02) (Figure 1, Left). Seven patients in this series had von Recklinghausen’s disease. Five patients who had stage IV disease died less than 2 years after diagnosis. The other two, who had stage I disease, have survived longer than 10 years free of disease (Figure 1, Right). Five of 17 patients (29%) underwent excisional biopsy (grossly negative margins at surgery) without wide excision. The average overall survival for this group was 74 months. Two died of other causes without evidence of disease. The others developed local recurrence, and two subsequently died of their disease. Seven of the 17 patients (42%) underwent wide exci-

Soft tissue sarcomas of the adult thoracic wall

Forty‐nine adult patients with soft tissue sarcomas of the thoracic wall have been treated by the Division of Surgical Oncology at the University of Illinois. Fibrosarcoma was the most common histologic type (20%). Patients with dermatofibrosarcoma protuberans had the longest mean overall survival time (150.8 months). The mean overall survival time for all patients was 98.2 months, and the disease‐free 2‐, 5‐, and 10‐year survival rates were 68%, 51%, and 34%, respectively. Wide excision was the treatment of choice; selected patients also received adjuvant radiotherapy, chemotherapy, or both. In all 10‐year survivors, the sarcomas were low grade and well differentiated, or were ≤5.0 cm in diameter. Aggressive treatment afforded these patients good long‐term results. Cancer 59:370–373, 1987.

Female Sex Hormones Modulate the Function of LPS-treated Macrophages

PROBLEM: To study the effects of estradiol (E2) or progesterone on macrophage function in the presence of lipopolysaccharide (LPS).
 METHOD OF STUDY: Male rat peritoneal macrophages were treated in vitro with 0.1 μg/mL of LPS and E2 or progesterone.
 RESULTS: At 10−2 ng/mL, E2 significantly (P<0.05; n=6) enhanced tumor necrosis factor (TNF) release by LPS‐treated macrophages. TNF release was significantly (P<0.05; n=6) inhibited by 102 ng/mL or 103 ng/mL of E2 and by progesterone at less than 10−3 ng/mL or greater than 10−1 ng/mL. E2 (10−4 and 10 ng/mL) and progesterone (10−6–10−4 ng/mL and 102 ng/mL) each significantly (P<0.05, n=8) enhanced H2O2 release by LPS‐treated macrophages. E2 (<10−2 and >10 ng/mL) and progesterone (10−7–104 ng/mL) each significantly inhibited (P<0.05; n=6) NO2− release by LPS‐treated macrophages.
 CONCLUSIONS: Exposure to LPS tended to diminish the effects of E2 and to enhance the effects of progesterone on the parameters determined here. Such LPS‐associated alterations in the dose–response profile of macrophages to female sex hormones may contribute to gender‐related differences in the immune response under normal and pathological conditions.

Merkel Cell Tumor of the Back Detected During Pregnancy

Merkel cell tumor is an unusual, aggressive malignancy of skin that has been considered to be derived from cutaneous Merkel cells. We are reporting a case of Merkel cell tumor overlying the left scapula with metastases to the thoracic spine and pleura. The tumor was found incidentally in a 23-year-old pregnant black woman. The tumor recurred locally 5 months after initial wide excision. Subsequently, a second wide excision of the recurrent tumor with ipsilateral axillary dissection was performed. The course of the disease was complicated by local recurrence and formation of distant metastases to pleura and spine. At the end-stage of the disease, the patient was found to have a cardiac murmur, and echocardiography revealed a mass in the anterior wall of the right ventricle that was suspicious for a metastatic lesion. The patient expired from extensive distant metastases 23 months after diagnosis.

Results of treatment of stage I-III breast cancer in black Americans: the Cook County Hospital experience, 1973-1987

Whether the prognosis for black women with breast cancer differs from that of nonblack women remains controversial. The treatment results of 526 black women who received definitive therapy for Stage I‐III breast cancer at Cook County Hospital, 1973 through 1987 are presented. The 5‐year and 10‐year projected survival rates for 272 node‐negative patients (83.9% and 76.6%, respectively) and for 72 node‐positive nonadjuvant treated patients (58.1% and 35.2%, respectively) are similar to those reported in the literature for nonblack patients. Adjuvant therapy improved the projected relapse‐free (P = 0.0744) and overall survival curves (P = 0.0448) for 182 node‐positive patients compared with nonadjuvant patients. The greatest benefit was seen for patients > 50 years of age with one to three positive nodes. The incidence of estrogen and progesterone receptors was found to be similar to those reported for nonblack patients. Once breast cancer has been diagnosed and appropriately treated, there appear to be few differences in the natural history of breast cancer between black and nonblack patients.

Breast cancer screening in an urban black population: a preliminary report

Breast cancer is a major cause of death among black women. At Cook County Hospital in Chicago, a hospital serving a predominantly black population, only 31% of breast cancers were localized at the time of diagnosis in the years 1980–1983. A survey of patient records in the largest primary care clinic in the hospital revealed that only 2% of eligible patients had received mammograms in 1982. A nurse‐run breast cancer detection program was begun in mid‐1983. Since that time the proportion of women who have received periodic breast examinations has increased from 26% to 46% (P < 0.001) and periodic mammograms have increased from 2% to 41% (P < 0.001). The proportion of women having received breast self‐examination teaching increased from 10% to 58% (P < 0.001). The proportion of localized breast cancer was significantly greater for those women whose cancer was diagnosed through the screening program (44 of 72, 61%) compared to other clinical areas (71 of 213, 33%) in the years 1984 through 1986 (P < 0.001). There has been a significant increase in the percentage of localized breast cancer at Cook County Hospital comparing 1980–1983 statistics (31%), before the Breast Cancer Detection Program was fully established, with 1984–1986 statistics (40%) (P < 0.02).

The extensor carpi radialis longus muscle flap for anterior elbow coverage

A muscle group resection for treatment of malignant fibrous histiocytoma of the distal arm exposed a 15 cm length of radial nerve. The soft tissue defect and radial nerve were covered with an extensor carpi radialis longus muscle island flap. The proximal dominant vascular pedicle enabled extensive mobilization and transposition of this muscle to cover the defect while preserving normal elbow, radial nerve, and hand function. Because of its ease of elevation, extensive arc of rotation, and its expendability, the extensor carpi radialis longus muscle flap should be considered as an option for reconstruction of defects about the elbow joint.

In vivo effects of recombinant interferon-γ : augmentation of endotoxin-induced necrosis of tumors and priming of macrophages for tumor necrosis factor-α production

Abstract Recombinant interferon-γ (rIFN-γ) is currently undergoing clinical trials in cancer patients. In this paper, we assessed the in vivo antitumor effects of this lymphokine in rodents. Recombinant murine IFN-γ or control medium was injected intraperitoneally for 5 days into mice with subcutaneous Meth A tumors. An injection of a suboptimal dose of endotoxin (2 μg) on the fifth treatment day caused significant necrosis of tumors in the IFN-γ-treated group while causing essentially no necrosis of tumors in the control group. Next, we examined macrophages isolated from rats treated for 9 days with either IFN-γ or saline. Endotoxin stimulated release of significantly higher amounts of TNF-α from macrophages from the IFN-γ-treated group compared to macrophages from the control group. A polyclonal antiserum against recombinant murine TNF-α abrogated all of the TNF cytotoxic activity from these rat macrophage supernatants, while control rabbit serum had no effect. These results provide strong evidence that rIFN-γ can prime macrophages in vivo for TNF-α synthesis.