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This article summarizes key issues for future research on borderline ovarian tumors that emerged at a National Cancer Institute-sponsored Borderline Ovarian Tumor Workshop held in August 2003 in Bethesda, MD. Limitations in existing research and opportunities for future advances have been highlighted. The application of new molecular techniques in combination with improved study designs holds promise for elucidating the pathogenesis of these tumors and revealing the source of the extra-ovarian lesions ("implants") with which they are frequently associated. Clarification of the etiology of borderline tumors and the pathogenesis of their associated implants is critical for improving pathological diagnosis, revising the classification system of ovarian neoplasms, and developing optimal, evidence-based clinical management algorithms.

This article documents major points of agreement and disagreement among experts invited to participate in a Borderline Ovarian Tumor Workshop held in Bethesda, MD, on August 27-28, 2003. It is suggested that controversies related to the diagnosis and management of these tumors are often related to lack of data in the literature (small numbers of cases, unreported or unclear criteria for diagnosis and follow-up, insufficient length of follow-up, etc), and specific recommendations are made for further investigation and for reporting of data in future studies.

Matrix metalloproteinases are a highly regulated family of enzymes, that together can degrade most components of the extracellular matrix. These proteins are active in normal and pathological processes involving tissue remodeling; however, their sites of synthesis and specific roles are poorly understood. Using in situ hybridization, we determined cellular distributions of matrix metalloproteinases and tissue inhibitor of metalloproteinase-1, an inhibitor of matrix metalloproteinases, in endometrium during the reproductive cycle. The mRNAs for all the metalloproteinases were detected in menstrual endometrium, but with different tissue distributions. The mRNA for matrilysin was localized to epithelium, while the others were detected in stromal cells. Only the transcripts for the 72-kD gelatinase and tissue inhibitor of metalloproteinases-1 were detected throughout the cycle. Transcripts for stromelysin-2 and the 92-kD gelatinase were only detected in late secretory and menstrual endometrium, while those for matrilysin, the 72-kD gelatinase, and stromelysin-3 were also consistently detected in proliferative endometrium. These data indicate that matrix metalloproteinases are expressed in cell-type, tissue, and reproductive cycle-specific patterns, consistent with regulation by steroid hormones, and with specific roles in the complex tissue growth and remodeling processes occurring in the endometrium during the reproductive cycle.

OBJECTIVE: We 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. STUDY DESIGN: In situ and Northern nucleic acid hybridization and immunohistochemistry were used to detect and localize matrilysin ribonucleic acid and protein in normal endometrial tissue. RESULTS: Matrilysin 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. CONCLUSION: The expression of the matrilysin gene is regulated in endometrium during the reproductive cycle, implying an important role for matrilysin in endometrial physiologic characteristics.

Compared with the degree of investigation of stage-specific expression of tumor-associated glycoprotein-72 (TAG-72) in fundal endometrium, other regions of the female reproductive tract have not received comparable attention. Regional, cell-type-specific, and temporal differences in estrogen receptor and progesterone receptor distribution and concentration among these tissues should make such examination beneficial to our understanding of hormonal regulation of TAG-72 expression. The pattern of monoclonal antibody (MAb) B72.3 recognition in the cervix, uterus, oviduct, and ovary was examined by immunohistochemistry during both the proliferative and secretory intervals of the normal menstrual cycle. Intense immunoreactivity in fundal endometrium was limited to the secretory menstrual interval. Conversely, TAG-72 expression was generally weaker, sporadically distributed, and not stage specific in the lower uterine segment, endocervix, and cervix; no expression was detected in the oviduct or ovary. The disparity in both temporal and spatial distribution of TAG-72 expression throughout the female reproductive tract does not appear to be directly associated with the well-described changes in circulating estradiol or progesterone or the receptors for these steroids. Results suggest that regulation of TAG-72 expression may involve local paracrine/autocrine mechanisms, which in turn may be subject to hormonal influence.

“No species of fallibility is more important or less understood than fallibility in medical practice. The physician’s propensity for damaging error is widely denied, perhaps because it is so intensely feared. Patients who suffer at the hands of their physicians often seek compensation by invoking the procedures of malpractice claims, and physicians view such claims as perhaps the only outcomes more earnestly to be avoided than even the damaging errors from which they presumably arise. Malpractice insurance rates soar, physicians strike, legislatures intervene, and, in the end, health care suffers from the absence of a clear understanding of what medical error is, how it arises, to what extent it is avoidable, when it is culpable, and what relationship it should bear to compensation for harm.“’

As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GIST), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and thedevelop-ment of novel and effective therapy for GISTs using thereceptor tyrosine kinase in hibitor STI-571, these tumors have become the focus of considerable attention among pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a sourceof confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health (NIH) convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity indiagnosis and a proposed scheme for estimating metastatic riskin these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term benign for any GIST, at least at the present time.

Matrix metalloproteinases of the stromelysin family are expressed in the human endometrium as a consequence of cellular events during the menstrual cycle that require extracellular matrix remodeling. We have recently documented the presence of these enzymes in lesions of endometriosis, a benign disease that presents as persistent ectopic sites of endometrial tissue, usually within the peritoneal cavity. Endometriosis can develop after retrograde menstruation of endometrial tissue fragments, and establishment of ectopic sites within the peritoneal cavity requires breakdown of extracellular matrix. To examine whether matrix metalloproteinases might contribute to the steroid-dependent epidemiology and cellular pathophysiology of endometriosis, we have developed an experimental model of endometriosis using athymic nude mice as recipients of human endometrial tissue. Our results demonstrate that estrogen treatment of human endometrial tissue in organ culture maintains secretion of matrix metalloproteinases, and promotes establishment of ectopic peritoneal lesions when injected into recipient animals. In contrast, suppressing metalloproteinase secretion in vitro with progesterone treatment, or blocking enzyme activity with a natural inhibitor of metalloproteinases, inhibits the formation of ectopic lesions in this experimental model.

The hallmark of the menstrual cycle is extensive steroid-dependent tissue turnover. Estrogen mediates endometrial cell growth and structural remodeling, whereas progesterone suppresses estrogen-dependent proliferation and promotes cellular differentiation. In nonfertile cycles, tissue degradation and menstruation occur as a consequence of steroidal deprivation as the ovarian corpus luteum fails. Stromal-epithelial interactions are recognized as a necessary component in mediating steroid-induced endometrial turnover. Specific mRNAs for metalloproteinases of the stromelysin family are expressed during endometrial growth and menstrual breakdown but are absent in the progestin-dominated secretory phase. This expression pattern suggests involvement of stromelysins in remodeling the extracellular matrix of the endometrium during tissue growth and breakdown and implicates progesterone in the suppression of these enzymes. We examined the regulation of endometrial stromelysins in explant cultures and found no acute effect of estradiol on their expression, whereas progesterone was a potent inhibitor of stromelysin expression. Progesterone also suppressed stromelysin expression in cultures of isolated stromal cells, but epithelial cells were progesterone insensitive. Coculture of recombined stromal and epithelial cells restored steroidal suppression of the epithelial-specific metalloproteinase. Our data confirm that progesterone inhibits endometrial stromelysins and further demonstrate the necessity for a stromal-derived factor(s) as a mediator of steroid suppression of an epithelial metalloproteinase.

The Accreditation Council for Graduate Medical Education (ACGME) is requiring that all medical specialties adopt a new paradigm for residency education: competency-based residency education. Competency-based education includes not only the acquisition of knowledge and the demonstration of safe medical practice, but also competency in practice-based learning, practice improvement, interpersonal skills and communication, professionalism, and an awareness of pathology's role in a larger health care system. Implementation of this new training program will require new educational resources and the implementation of new faculty and resident skills and incentives.

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/mm 2 >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.

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 - 3.39 mm). A Cox multivariate analysis yielded a combination of four variables that best predicted bony or visceral metastases for these patients: 1) mitoses greater than 6/min 2 (p = 0.0007), 2) location other than the forearm of leg) p = 0.009, 3) ulceration width greater than 3 mm (p = 0.04), 4) microscopic satellites (p = 0.05). The overall prognostic model chi square was 32.40 with 4 degrees of freedom (p less than 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 greater than 6/mm 2 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 greater than 3 mm wide or microscopic satellites. The low risk group was defined as follows: 1) mitoses less than or equal to 6/mm 2 and a location on the leg or forearm, or 2) mitoses less than or equal to 6/mm 2 and the absence in histologic sections of the primary tumor of both microscopic satellites and ulceration greater then 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.

A genetic mutation in mice (W/Wv) causes an autosomal recessive disease characterized by hypoplastic anemia which lasts throughout life. Double- dominant W/Wv anemic mice were sublethally irradiated to facilitate repopulation of marrow with transplanted cells and were injected intravenously with suspensions of 5–10 million placental cells of 15 days gestation derived from normal, isogeneic donors. Red cell counts fell promptly after irradiation and then rose progressively over a period of weeks, reaching normal levels of the nonmutant. Mean corpuscular volume and hemoglobin electrophoresis patterns of red cells in recipient W/Wv mice resembled those of normal donor animals. The therapeutic effect lasted for the duration of the observation period, in some instances over 9 mo. W/Wv mice that were administered Hanks' solution or fetal blood, instead of placental transplants, remained anemic. Late gestation placentas (18 days) were also ineffective.

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, greater than 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 less than 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 greater than 3.0 mm, 39.5% (30/76). Primary melanomas greater than 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 less than 50 days after diagnosis may underestimate the prevalence of metastases.

Appropriate endometrial maturation is of paramount importance to achieve reproductive success. Practical and ethical considerations require that in vitro methods be available to evaluate regulation of human endometrial function. Additionally, tissue complexity requires separation of individual cell populations. This report describes an improved method for isolation of endometrial epithelial and stromal cells, using biopsy specimens as a tissue source. Separated cells were obtained using selective enzymatic digestion in conjunction with physical separation procedures. Isolated populations exhibited over 95% homogeneity, ascertained immunocytochemically. Using this system, isolated cells from normal endometrium can readily be obtained for in vitro studies. Within the defined conditions of a culture system, important areas of current concern in the endometrium such as ectopic endometrial growth and implantation can be addressed.

Monoclonal antibody (MAb) B72.3, reactive with a high molecular weight mucin-like glycoprotein [termed tumor-associated glycoprotein (TAG)-72], has been shown previously to react preferentially with adenocarcinomas of the ovary, breast, and colon versus a variety of normal human tissues using immunohistochemical and radioimmunoassay (RIA) techniques. We report here B72.3 reactivity with normal postovulatory endometria, in contrast to proliferative phase epithelia that were nonreactive. Both immunohistochemical and RIA techniques were used to evaluate this phenomenon. TAG-72 expression was also detected in 100% of endometrial adenocarcinomas (n = 32) examined. No MAb B72.3 reactivity was noted in resting, postmenopausal endometria; however, it was present in hyperplastic lesions and appeared to correlate with the severity of histologic abnormality. The utility of MAb B72.3 for screening, radiolocalization, or perhaps therapy of endometrial adenocarcinoma is also discussed.

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 presumed new radiological-pathological entity of atherosclerotic subintimal of the carotid artery is described. Subintimal hematomas were found in 12 of 50 (24%) carotid bifurcations during surgery for repeated transient ischemic attacks in a single hemispheric distribution; only 33% were associated with ulcerations. The typical angiographic appearance was a sharply marginated, rounded, eccentric filling defect located near the extracranial carotid bifurcation, although occasionally it may simulate a typical smooth or even ulcerated atherosclerotic plaque. Pathological mechanisms responsible for the hemorrhage into the atherosclerotic plaque resulting in the hematoma are discussed.

Fifteen variables 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 less than 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 x 100% (percentage of positive nodes) greater than or equal to 20%; or (2) a primary tumor thickness of greater than 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.

Fourteen variables were tested for their prognostic usefulness in 203 patients with clinical Stage I melanoma and primary tumor 0.76-169 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 less than 0.0001 Fisher's Exact Test). Of the 67 BANS patients, 51 had level II or level III lesions and five (10%0 died of melanoma. This compared with six deaths from melanoma in 16 patients (37.5%) with level IV BANS lesions (5/51 vs 6/16, p = 0.01 Fisher's 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.

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).

SummaryThe number and content of dilated splenic hilar lymph vessels were examined in patients with and without congestion of the spleen. Sections from 10 patients without congestion showed no dilated lymph vessels. Sections from 7 patients with congestion all showed an increased number of dilated lymph vessels many of which contained red blood cells. One other patient who died after portal decompression demonstrated normal lymph vessels.The results indicate that splenic hilar lymphatics enlarge as a result of splenic congestion and reflect an increase in splenic lymph formation. Absence of red blood cells in splenic lymph vessels under normal circumstances and their appearance in congested states supports the view that the intermediate circulation of the spleen is normally closed and that in congested states may be open.

Endotoxinemia was produced in rabbits by a continuous intravenous infusion of endotoxin (30 to 50 βg per kilogram per hour) for 8 to 14 hours. Disseminated intravascular coagulation occurred 6 to 14 hours after the onset of the infusion. Fibrin deposition was observed in decreasing order of frequency in kidney, liver, lung, and spleen. Approximately 50 per cent of the treated animals revealed focal glomerular necrosis. The extent of glomerular fibrin deposition was correlated to the occurrence of focal glomerular necrosis. In one group of animals allowed to survive lysis of glomerular fibrin deposition was demonstrated in kidney sections. Hemodynamic studies revealed a rise in central venous pressure during the experiment. The parameters of pH, pCO 2 , serum lactate, and base excess indicated a steady state of metabolic acidosis during the infusion. Renal function revealed a polyuric phase with disturbed medullary function preceding renal failure.

Summary Heterospecific antiplatelet sera were demonstrated to have a direct action on coagulation, as manifest by the inhibitory effect on thromboplastin generation. This effect is distinct from the previously demonstrated ability to agglutinate platelets and inhibit clot retraction. Platelet phospholipid represents the antigenic platelet constituent responsible for this phenomenon. This constituent is not unique to platelets, but is also present in red cells since erythrocyte phospholipid cross reacts with antiserum directed against platelet phospholipid. Brain cephalin, which contains another phospholipid active in thromboplastin generation, exhibited no cross reaction. Fibrinogen is another antigenic substance intricately associated with platelets. It was confirmed that the precipitin action with sonicated platelets is due to fibrinogen. A platelet protein constitutes a third antigenic constituent which was found to be responsible for the immunological specificity of platelets. Platelet agglutination and inhibition of clot retraction are the result of an immune reaction involving this platelet protein as the specific substrate. Resume Les serums anti-plaquettaires heterospecifiques ont une action directe sur la coagulation se manifestant par un effet inhibiteur de la thromboplastinogenese. Cet effet est different de celui deja demontre qui se manifeste par une tendance a agglutiner les plaquettes et a inhiber la retraction du caillot. Left phospholipides plaquettaires representent le constituent plaquettaire antigenique responsable de ce phenomene. Ce constituant n'est pas le seul apanage des plaquettes, mais il est aussi present sur les erythrocytes puisque les phospholipides erythrocytaires presentent une reaction croisee avec l'anti-serum anti-phospholipide plaquettaire. Avec la cephaline cerebrale, autre phospholipide active dans la thromboplastinogenese, on n'observe pas de reaction croisee. Le fibrinogene est une autre substance antigenique intimement associee aux plaquettes. II a ete confirme que la reaction de precipitation des plaquettes traitees par les ultra-sons est due au fibrinogene. Une proteine plaquettaire forme un troisieme constituant antigenique qui s'est avere comme etant responsable de la specificite immunologique des plaquettes. L'agglutination plaquettaire et l'inhibition de la retraction du caillot sont le resultat d'une reaction immunitaire component cette proteine plaquettaire comme substrat specifique. Zusammenfassung Heterospezifische Antiplattchenseren hemmen die Thromboplastinbildung und beeinflussen auf diese Weise die Blutgerinnung. Diese Wirkung ist verschieden von der Fahigkeit solcher Seren, Plattchen zu agglutinieren und Gerinnselretraktion zu hemmen. Bei dem an diesem Phanomen beteiligten Antigen handelt es sich um Plattchenphospholipid. Diese Substanz kommt nicht nur in Plattchen, sondern auch in Erythrozyten vor, was daraus zu ersehen ist, das Erythrozytenphospholipid mit Antiseren gegen Plattchenphospholipid Kreuzreaktionen zeigt. Mit Hirnkephalin, einem anderen an der Thromboplastinbildung beteiligten Phospholipid wurden hingegen keine Kreuzreaktionen beobachtet. Fibrinogen ist ein anderes Plattchenantigen. Es wurde bestatigt, das bei der Prazipitationsreaktion mit Ultraschall zertrummerten Plattchen Fibrinogen das Antigen darstellt. Ein Plattchenprotein bildet das dritte Antigen; es ist verantwortlich fur die immunologische Spezifitat der Plattchen. Bei der Plattchenagglutination, wie auch bei der Retraktionshemmung zufolge von Immunreaktionen bildet dieses Plattchenprotein das spezifische Substrat.

Summary1. Among each of 2 groups of guinea pigs immunized with 50 μg and 500 μg of picrylated thyroglobulin in Freund's adjuvant respectively, 57.2% (63 of 110 animals) developed thyroiditis 17 days following the initial dose of antigen. Delayed skin reactivity to intradermal thyroglobulin was observed in 72.7% of the animals. There was no significant difference in incidence of thyroiditis and delayed skin reactivity in the 2 groups of animals. However, circulating antithyroglobulin antibody as determined by passive hemagglutination, was found in 4.6% (2 of 43 animals) in the low antigen group and 30% (18 of 60 animals) in the high antigen group.

SummaryThe production of a myopathy and paralysis in mice inoculated with tissue culture passaged Coxsackie A-21 virus was directly related to the inoculum dose and extent of virus multiplication. The virus yield from paralyzed mice was usually about 1067 TCD50 or greater per mouse. Four strains of naturally occurring virus did not produce paralysis of suckling mice but virus multiplication occurred in mice with 2 of the 4 strains. Serial passage of Coxsackie A-21 virus in HEK cell cultures did not alter its virulence for suckling mice. The histopathologic changes associated with Coxsackie A-21 virus infection in mice were characterized by a waxy degeneration of the skeletal musculature which was generally confined to the lower extremities.

Murine IgG1 monoclonal antibody (MoAb) B72.3, reactive with a high molecular weight glycoprotein complex [designated tumor-associated glycoprotein-72 (TAG-72)] was shown, with the use of the avidin-biotin-complex-immunoperoxidase technique and surgically resected tissues, to be reactive with a variety of histologic tumor types. TAG-72 is expressed in at least 5% (and up to 100%) of the malignant epithelial cells in 77% (n = 52) of human primary cancers and 71% (n = 31) of metastatic ovarian cancers of the common "epithelia" histologic category. Of these, several histologic types, including serous and mucinous cystadenocarcinomas, undifferentiated carcinomas, and less common types of ovarian carcinoma, were all shown to express TAG-72. In contrast, normal ovarian tissues and 26 of 27 benign ovarian tumors of various histologic types failed to express similar levels of TAG-72. Of interest is the 1 benign tumor that demonstrated unusual glandular complexity, as well as 3 tumors designated as borderline malignancy, that contained elevated TAG-72 expression. MoAb B72.3 also was used successfully to detect ovarian carcinoma cells in 28 cytologic preparations of human serous effusions and peritoneal washings. The reactivity of MoAb B72.3 was shown to be distinct from that of MoAb OC125 and an anti-CEA MoAb B1.1. The potential applications of MoAb B72.3 in the study of human ovarian cancer cell populations, as well as in several aspects of the management of human ovarian cancer, are discussed.

Smears were made from tracheobronchial washings of patients undergoing general endotracheal anesthesia for surgery. Morphologically abnormal histiocytes were noticed in specimens obtained from subjects during hemorrhagic shock. These cells were overloaded with Papanicolaou stain (a greenish orange compound) which compressed the nucleus against the cell membrane. Cytochemical staining methods were undertaken to discover the composition of this substance. In secretions suctioned from ten patients in shock, large numbers of histiocytes were found to have ingested inorganic iron detectable by the Prussian blue method. Only two patients from a matched control group had smears in which this phenomenon was discovered. The maximum proportion of histiocytes containing Prussian blue granules was 40% for patients in shock and only 2% in normal controls. Histologic studies conducted on rats submitted to hemorrhagic shock were carried out to investigate this phenomenon. Iron-laden histiocytes were found in the kidneys, spleen, and lungs of both shocked and control animals. However, substantially more histiocytes containing Prussian blue positive granules were discovered in the lungs of rats in shock than in controls. It may, therefore, be that iron is deposited in the lungs in low flow states.