Fred Gorstein

Expression and localization of matrilysin, a matrix metalloproteinase, in human endometrium during the reproductive cycle

OBJECTIVEnWe studied the expression of a matrix metalloproteinase, matrilysin, in the human endometrium to determine whether metalloproteinase genes are expressed during the reproductive cycle. Matrix metalloproteinases are a tightly regulated family of enzymes that degrade components of the extracellular matrix and basement membrane; they play important roles in growth and development and in invasion and metastasis of tumors and thus are likely enzymes participating in the dynamic structural changes occurring in endometrium during the reproductive cycle.nnnSTUDY DESIGNnIn situ and Northern nucleic acid hybridization and immunohistochemistry were used to detect and localize matrilysin ribonucleic acid and protein in normal endometrial tissue.nnnRESULTSnMatrilysin protein and matrilysin messenger ribonucleic acid are abundant in proliferative, late secretory, and menstrual endometrial epithelium but are not detected in early or mid secretory endometrium.nnnCONCLUSIONnThe expression of the matrilysin gene is regulated in endometrium during the reproductive cycle, implying an important role for matrilysin in endometrial physiologic characteristics.

Malignant melanoma. Prognostic significance of "microscopic satellites" in the reticular dermis and subcutaneous fat.

A review of the microscope slides of the primary tumors for 596 patients with clinical Stage I melanoma revealed that primary lesions displayed two distinct patterns of invasion: 1) single cell invasion with direct extension of the main body of tumor into the reticular dermis or subcutaneous fat, and 2) invasion with microscope satellites (i.e. discrete tumor nests greater than 0.05 mm in diameter, that were separated from the main body of the tumor by normal reticular dermal collagen or subcutaneous fat). The five-year disease free survival rate for 95 patients with microscopic satellites was 36% +/- 6%. This is in contrast to a five-year disease free survival rate of 89% +/- 2% for 501 patients without these satellites (p = 4.3 x 10(-29), generalized Wilcoxon test). Microscopic satellites (present vs absent) was comparable to histologic ulceration in its additive prognostic effect of tumor thickness (Breslow).

Prognostic Factors for Patients with Clinical Stage I Melanoma of Intermediate Thickness (1.51–3.99 mm)* A Conceptual Model for Tumor Growth and Metastasis

Fourteen variables were tested for their ability to predict visceral or bony metastases in 177 patients with clinical Stage I melanoma of intermediate thickness (1.51–3.99 mm). A Cox multivariate analysis yielded a combination of four variables that best predicted bony or visceral metastases for these patients: 1) mitoses > 6/mm2 (p = 0.0007), 2) location other than the forearm or leg) p = 0.009), 3) ulceration width > 3 mm (p = 0.04), and 4) microscopic satellites (p = 0.05). The overall prognostic model chi square was 32.40 with 4° of freedom (p < 10-5). Combinations of the above variables were used to separate these patients into at least two risk groups. The high risk patients had at least a 35% or greater chance of developing visceral metastases within five years, while the low risk group had greater than an 85% chance of being disease free at five years. Criteria for the high risk group were as follows: 1) mitoses > 6/mm2 in at least one area of the tumor, irrespective of primary tumor location, or 2) a melanoma located at some site other than the forearm or leg and histologic evidence in the primary tumor of either ulceration > 3 mm wide or microscopic satellites. The low risk group was defined as follows: 1) mitoses ≤ 6/mm2 and a location on the leg or forearm, or 2) mitoses ≤ 6/mm2 and the absence in histologic sections of the primary tumor of both microscopic satellites and ulceration ≥ 3 mm wide. The number of patients in this series who did not undergo elective regional node dissection (N = 47) was probably too small to detect any benefit from this procedure. Based on survival rates from this and other studies, it is estimated that approximately 1500 patients with clinical Stage I melanoma of intermediate thickness in each arm of a randomized clinical trial would be needed to detect an increase in survival rates from elective regional node dissection.

Prognostic factors for melanoma patients with lesions 0.76 - 1.69 mm in thickness. An appraisal of "thin" level IV lesions.

Fourteen variables were tested for their prognostic usefulness in 203 patients with clinical Stage I melanoma and primary tumors 0.76–1.69 mm thick. Only two variables, primary tumor location and level of invasion, were useful in predicting death from melanoma for these patients. Of the 12 deaths from melanoma, 11 occurred in patients with primary tumors located on the upper back, posterior arm, posterior neck, and posterior scalp (= BANS). There has been only one death from melanoma in 136 patients with melanoma located at other sites (11/67 vs 1/136, p < 0.0001 Fishers Exact Test). Of the 67 BANS patients, 51 had level II or level III lesions and five (10%) died of melanoma. This compares with six deaths from melanoma in 16 patients (37.5%) with level IV BANS lesions (5/51 vs 6/16, p = 0.01 Fishers Exact Test). The relatively high incidence of both melanoma deaths and regional node metastases for the BANS group merits consideration for testing the efficacy of elective regional node dissection for these patients.

Ovarian pregnancy and the intrauterine device

Abstract Nine ovarian pregnancies among women with an intrauterine device (IUD) in situ are reviewed in this report. Five cases were discovered among 45 ectopic pregnancies reported in the Cooperative Statistical Program (CSP) of the Population Council, and four additional cases were obtained in response to a notice published in the American Journal of Obstetrics and Gynecology or by personal contacts. The ratio of one ovarian pregnancy to nine ectopic pregnancies among IUD wearers in the CSP is much higher than in the general population, where it is about 1:200. Estimation of the probable number of fertilized ova among women wearing IUDs suggests that the device reduces uterine implantation by about 99.5 per cent, tubal implantation by 95 per cent, and the incidence of ovarian pregnancy not at all. This finding could be explained by the production in the endometrium of an agent interfering with either fertilization or implantation and suggests direct chemical action, possibly by retrograde flow into the tubes.

Malignant melanoma patients with positive nodes and relatively good prognoses: Microstaging retains prognostic significance in clinical stage I melanoma patients with metastases to regional nodes

Fifteen yariables were tested for their value in predicting recurrent disease in 46 clinical Stage I melanoma patients with metastases to regional nodes. A stepwise proportional hazards general linear model (Cox multivariate analysis) separated these melanoma patients with regional node metastases into at least two risk groups. Twenty patients in the relatively low‐risk group had a five‐year disease‐free survival of 80% (in spite of having nodal metastases). This compares to a five‐year disease‐free survival of 17.5% for 26 patients in the high‐risk group (P < 0.001, Lee‐Desu Statistic). Criteria for the high‐risk group required that a patient have only one of the following two values: (1) The number of regional lymph nodes that contained tumor divided by the total number of nodes removed × 100% (percentage of positive nodes) ≥20%; or (2) a primary tumor thickness of >3.5 mm (regardless of node percentage). Conversely, patients in the low‐risk group had neither of the above features. The high‐risk group could further be stratified by the lymphocytic response at the base of the tumor. These findings have direct immediate application to the elective regional node dissection controversy and to adjuvant therapy studies containing these patients. Cancer 47:955–962, 1981.

“Microscopic satellites” are more highly associated with regional lymph node metastases than is primary melanoma thickness

A multivariate analysis was performed on 20 clinical and histologic variables from 327 Stage I prospectively studied melanoma patients who underwent elective regional lymph node dissection (ERLD). Primary tumor thickness, microscopic satellites, and the elapsed interval between diagnosis and ERLD, were selected as the combination of variables that were most highly associated with clinically occult regional lymph node metastases (P = 10−15, model chi‐square). Microscopic satellites were defined as tumor nests, >0.05 mm in diameter, in the reticular dermis, panniculus, or vessels beneath the principal invasive tumor mass but separated from it by normal tissue on the section in which the Breslow measurement was taken. The probability of finding nodal metastases for melanomas <0.75 mm thick was 0% (0/41 patients); for those 0.76–1.50 mm, 4% (4/108); 1.51–3.0 mm, 14% (14/102); and >3.0 mm, 39.5% (30/76). Primary melanomas >1.50 mm thick with microscopic satellites were more often associated with nodal metastases than those of similar thickness without satellites (30/57 (53%) versus 14/121 (12%), P = 0.01). Some satellites probably represent intraspecimen metastases, while others do not. Any predictive model for occult regional lymph node metastases based on data from ERLD done <50 days after diagnosis may underestimate the prevalence of metastases.

A prognostic model for clinical stage I melanoma of the upper extremity. The importance of anatomic subsites in predicting recurrent disease.

Thirteen variables were studied for their relative usefulness in predicting recurrent disease in 107 patients with clinical Stage I melanoma of the upper extremity. After a mean follow-up period of 54 months, the only patients who have had recurrent disease to date are those whose primary lesions were located either on the hand or posterior upper arm. The five-year, disease-free survival role for 44 patients with melanoma at these sites was 68%. None of 63 patients with melanoma located on the forearm of anterior upper arm have had recurrent disease (i.e., the five-year, disease-free survival rate was 100% (p = 0.00004), compared with the hand or posterior arm group). A Cox proportional hazards (multivariate) analysis demonstrated that two primary tumor histologic variables, thickness in millimeters and ulceration, interacted to produce the best prognostic model for those 44 patients with melanoma of the hand or posterior upper arm. Twenty-one

A multivariate analysis of prognostic factors for melanoma patients with lesions greater than or equal to 3.65 mm in thickness. The importance of revealing alternative Cox models.

Fourteen prognostic factors were examined in 79 patients with clinical Stage I melanoma greater than or equal to 3.65 mm in thickness. All nine patients with melanoma of the hands or feet died of melanoma. A Cox proportional hazards (multivariate) analysis of the remaining 70 patients showed that a combination of the following four variables best predicted bony or visceral metastases: 1) a nearly absent or minimal lymphocyte response at the base of the tumor, 2) histologic type other than superficial spreading melanoma, 3) location on the trunk, and 4) positive nodes or no initial node dissection. Ulceration and/or ulceration width were not useful in predicting outcome either singly or in combination with other variables. Patients with negative lymph nodes and primary tumors of the trunk, hands, and feet did not do better than patients with positive nodes at those sites. Conversely, non of 16 patients with negative lymph nodes and extremity melanomas (excluding the hands and feet) or head and neck melanomas developed visceral or bony metastases (i.e., five-year disease-free survival rate 100%).

A prognostic model for clinical stage I melanoma of the trunk: Location near the midline is not an independent risk factor for recurrent disease☆☆☆

Fifteen variables were studied for their usefulness in predicting recurrent disease in 254 patients with clinical stage I melanoma of the trunk. Thickness of the primary tumor correctly predicted outcome with an accuracy of 90 percent or greater in 176 patients with melanoma primaries with a thickness of less than 1.70 mm or 5.5 mm or greater. No other variables significantly increased predictive accuracy over these ranges of thickness. A Cox proportional hazards analysis of the remaining 78 patients with primary tumors 1.70 to 5.49 mm thick demonstrated that the following four variables functioned as independent risk factors for recurrent disease: (1) thickness of the primary tumor (p = 0.0005), (2) mitoses/mm2 greater than 6 (p = 0.006), (3) a nearly absent or minimal lymphocyte response at the base of the tumor (p = 0.009), and (4) location on the upper trunk (p = 0.03). Trunk lesions located near the midline did not have a worse prognosis than more lateral melanomas of similar thickness.