Protein leak from normal vasculature due to human malignant ascites.

Malignant ascites is an accumulation of protein rich fluid (a filtrate of whole blood) in the peritoneal cavity of patients with abdominal malignancies. The normal peritoneal microvasculature of the cremaster muscle of rats, with the nerve and blood supply intact, was visualized before and after exposure of the tissue to human malignant ascites fluid and to human plasma. In vivo fluorescent microscopy was used to quantitate leakage of fluorescent-tagged albumin. Exposure of the abluminal side of the vasculature to malignant ascitic fluid and plasma causes significant protein leakage from the small veins to the interstitial space. This suggests that the continued production of malignant ascites may be caused by a positive feedback system, which is related to factors present in a normal plasma filtrate. These factors can induce leakage of protein by an effect on the abluminal side of the normal peritoneal microvasculature.

Human malignant ascites and histamine-induced protein leakage from the normal microcirculation.

The accumulation of malignant ascites is a significant cause of morbidity and mortality in patients with intraabdominal malignancies. However, the cause of malignant ascites is unknown. In this study, we used the rat cremaster muscle preparation to determine if and how malignant ascites could produce protein leakage from normal blood vessels which would lead to fluid accumulation in the peritoneal cavity. The rat cremaster muscle, with nerves and blood vessels to the animal intact, was prepared for microscopic observations of the microcirculation. Serum albumin was tagged to fluorescein isothiocyanate and injected into the rat. Fluorescent microscopy was used to quantitate leakage of the tagged albumin into the interstitial tissue. Malignant ascites was collected from a patient with metastatic breast cancer. The ascites fluid was placed on the cremaster muscle and it induced protein leakage from the normal blood vessels of this tissue. Protein leakage was partially blocked by diphenhydramine (10(-4) M) and by mast cell depletion with compound 48/80. There was a high level of C3a in the malignant ascites solution but C3a did not increase during the exposure period. These data suggest that activated complement in malignant ascites may release histamine from mast cells to cause protein leakage of the normal vasculature. The movement of protein into the peritoneal cavity would be followed by water, thus increasing the volume of the ascites and exacerbating the clinical condition.

Soft tissue sarcoma and non-Hodgkin's lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington.

A population-based case-control study was conducted in western Washington State to evaluate the relationship between occupational exposure of men aged 20-79 to phenoxyacetic acid herbicides and chlorinated phenols and the risks of developing soft tissue sarcoma (STS) and non-Hodgkin's lymphoma (NHL). Occupational histories and other data were obtained by personal interviews for 128 STS cases and 576 NHL cases, diagnosed between 1981 and 1984, and for 694 randomly selected controls without cancer. Among the study subjects with any past occupational exposure to phenoxyherbicides, the estimated relative risk and 95% confidence interval of developing STS was 0.80 (0.5-1.2), and of developing NHL, 1.07 (0.8-1.4). Risk estimates of developing STS and NHL associated with past chlorophenol exposure were 0.99 (0.7-1.5) and 0.99 (0.8-1.2), respectively. No increasing risk of either cancer was associated with overall duration or intensity of chemical exposure or with exposure to any specific phenoxyherbicide per se. However, estimated risks of NHL were elevated among men who had been farmers, 1.33 (1.03-1.7), forestry herbicide applicators, 4.80 (1.2-19.4), and for those potentially exposed to phenoxyherbicides in any occupation for 15 years or more during the period prior to 15 years before cancer diagnosis, 1.71 (1.04-2.8). Increased risks of NHL were also observed among those with occupational exposure to organochlorine insecticides, such as DDT [1.82 (1.04-3.2)] and organic solvents [1.35 (1.06-1.7)], and to other chemicals typically encountered in the agricultural, forestry, or wood products industries. These results demonstrate small but significantly increased risks of developing NHL in association with some occupational activities where phenoxyherbicides have been used in combination with other types of chemicals, particularly for prolonged periods. They do not demonstrate a positive association between increased cancer risks and exposure to any specific phenoxyherbicide product alone. Moreover, these findings provide no evidence of increased risks of developing NHL associated with chlorinated phenol exposure or of developing STS associated with exposure to either class of chemical.

Mechanisms of malignant ascites production.

The accumulation of malignant ascites is determined primarily by the obstruction of diaphragmatic lymphatics with tumor inhibiting the outflow of peritoneal fluid. An abnormal increase in peritoneal fluid production has been shown to contribute to ascites formation by a marked neovascularization of the parietal peritoneum. Cell-free malignant ascitic fluid obtained from rats with intra-abdominal Walker 256 carcinoma when infused into the peritoneal cavities of normal animals causes an increase in edema formation and an increase in the permeability of protein from normal omental vessels. Protamine sulfate, a known inhibitor of angiogenesis when infused into the peritoneal cavity along with cell free malignant ascitic fluid, significantly reduces the leak of protein from the intravascular space when compared to ascites alone. Persistent permeability changes continue to exist even after the inhibition of vessel proliferation. These results indicate that angiogenesis is responsible for a major portion of the increase in permeability caused by malignant ascitic fluids. Other tumor-induced factors may be present which alter vascular permeability by other mechanisms which remain to be elucidated.

Malignant tumors of the liver.

HCC occurs infrequently in Western countries, with recent increases being reported in California and parts of Europe. Southeast Asia, Japan, and South Africa continue to have a high incidence of this tumor with HBV, cirrhosis, and the ingestion of aflatoxins being identified as probable risk factors. Although the majority of patients present with abdominal pain or mass indicative of extensive tumor, asymptomatic, small HCCs are being detected with increasing frequency. Early detection in high-risk individuals is best accomplished by screening with serum AFP determinations and liver ultrasonography. CT and arteriography are valuable preoperatively in defining anatomy and determining resectability. Five-year survival following resection for cure of HCC ranges from 20 to 40 per cent, with improved survival reported for small asymptomatic tumors. Resection of metastatic liver tumors from colorectal primaries results in 48 per cent 2-year and 24 per cent 5-year survivals, with an additional 5 per cent dying of recurrent cancer after 5 years. Although patients with simultaneous and metachronous metastases do equally well after resection, the presence of four or more individual deposits adversely affects survival. Hepatic artery ligation or embolization can produce a significant palliative reduction in total tumor mass in patients with unresectable liver metastases. Regional chemotherapy using implantable hepatic artery drug infusion pumps is promising, with reports of prolonged survival compared with historical controls. Regional hyperthermia, laser vaporization of tumor, and cryosurgical techniques may prove to have useful roles in the selective treatment of liver cancer in the future. Orthotopic liver transplantation has been successful primarily in those in whom the malignancy is found incidentally in the chronically diseased liver.

Malignant ascites. Clinical and experimental observations.

Malignant ascites formation is a grave prognostic sign, but palliative efforts seem justified in some patients. Lack of knowledge concerning the natural history of this process hinders the choice of therapeutic options. Over 5 years, 107 patients with untreated malignant ascites were reviewed to define their survival. Pancreas (20), ovary (18), and colon (18) were the most frequent tumors, with 52% of patients presenting with ascites at the time of the initial cancer diagnosis. Cytology evaluation of the ascitic fluid was positive for tumor cells in 57% of cases and a high protein content was noted in 65%. Mean survival of the entire series was only 20 weeks from the time of diagnosis of ascites, with tumors of ovarian and lymphatic origin having better mean survivals of 32 and 58 weeks, respectively. Patients with high ascitic protein levels fared better than those with low levels. In an effort to explain this correlation of elevated protein levels and a favorable survival rate, a hypothesis was proposed that certain tumors secrete a factor, which alters vascular permeability and causes fluid accumulation in the absence of lymphatic obstruction. In an experimental rat model of malignant ascites, the intraperitoneal infusion of cell-free malignant ascitic fluid caused an increase in edema formation and a significant increase in capillary permeability to protein in the omentum. This demonstrated change in the leak of protein explains the formation of ascites by some tumors in the absence of tumor obstruction of the draining lymphatics of the peritoneal cavity and suggests another important mechanism in the genesis of malignant ascites.

Differential macromolecular leakage from the vasculature of tumors.

Tumor-induced neovascularization is essential for invasion, metastases, and exponential growth of solid tumors. The authors studied the differences in macromolecular leakage from the neovasculature of a fast-growing, early-metastasizing tumor, the Walker 256 carcinosarcoma, and a slow-growing, nonmetastasizing tumor, a rat chondrosarcoma. A 1-mm3 piece of the Walker 256 carcinoma or the chondrosarcoma was implanted in the cremaster muscle of rats. Five days after surgery the cremaster muscle with the implanted tumor was placed in a special bath containing Krebs solution such that the circulation and nerves from the animal to the cremaster were intact. Fluorescein isothiocyanate-labeled rat serum albumin (FITC-RSA) was injected (intra-arterially) into each rat to permit visualization of the vasculature by fluorescent microscopy. A closed-circuit television system was used to quantitate macromolecular leakage as a change in interstitial fluorescent intensity. Data are given as a relative fluorescent intensity (mean +/- standard error of the mean) in an area of the cremaster with tumor-induced neovascularization. These studies demonstrated that the vasculature induced by rapidly growing Walker 256 carcinosarcoma leak albumin freely when compared with the vasculature induced by the slow-growing chondrosarcoma. Furthermore, there was a significant increase in fluorescent intensity (albumin leakage) in the Walker tumor from 1 minute (24 +/- 3.0) to 30 minutes (49 +/- 5.6). In the normal cremaster area there was a significantly lower fluorescent intensity in the interstitium and a very slight increase with time (4 +/- 1.5 at 1 minute vs. 7 +/- 1.4 at 30 minutes). One interpretation of these data is that the mechanisms responsible for protein leakage from the vasculature of the Walker tumor may be involved in the fast growth and metastases of this tumor as compared with slower-growing tumors such as the chondrosarcoma.

Geometry, growth rates, and duration of cancer and carcinoma in situ of the breast before detection by screening.

The purpose of this study is to report the time elapsing between the moment a breast cancer reaches threshold size that would permit detection and the size at actual detection defined as sojourn time (STt) using data from the Breast Cancer Detection and Demonstration Project (Louisville data and reported composite data from 27 centers) by dividing prevalence rates by incidence rates. The number of cellular generations (n) required to produce cancers of different volumes was calculated at threshold (nt), at detection (nd), and the difference between the two (nd - nt). By dividing the difference (nd - nt) into STt, the average actual or net tumor volume doubling time (DTact) in this interval have been estimated. The STt value for carcinoma in situ was 557 and for cancer it was 538. At ages 35-39, STt ranged from 365-456 days, by ages 70-74, 942-1383 days. The average DTact similarly varied with age, carcinoma in situ, cancer with negative axillary nodes, and cancer with positive axillary nodes over a range of 28-732 days (95% confidence). The estimated DTact in the predetectable period was manyfold less than the DTact measured for mammographically visible cancers, in keeping with the predictions of decelerating growth. Models of the cytokinetic and clinical behavior of breast cancer are discussed.

Prevention of carcinomatosis and bloody malignant ascites in the rat by an inhibitor of angiogenesis.

It has previously been shown that protamine sulfate is an angiogenesis inhibitor. Regional infusion of protamine into the peritoneal cavity is now reported to prevent the growth of intraperitoneal vascularized tumor masses in rats. Walker 256 carcinoma was implanted directly into the liver or into the peritoneal cavity of rats. Hepatic implants grew in the liver with metastases to the wound and mesentery. Injected tumor cells grew as solid tumor masses in the mesentery. Bloody ascites developed after 7 days. Animals received an intraperitoneal infusion of protamine or saline. Protamine significantly inhibited growth of solid tumors in the mesentery (P less than 0.001). Histology showed tumor cells growing only in monolayer but without vascularization. Ascites was not bloody. In saline-treated animals large vascularized tumors grew in the peritoneal cavity and ascites became bloody.

The association of pathologic and mammographic characteristics of primary human breast cancers with "slow" and "fast" growth rates and with axillary lymph node metastases.

This article reports statistically significant associations existing between the clinical, mammographic and histopathologically classified properties of mammary cancers occurring in the population of 10,120 women screened in the BCDDP at the University of Louisville over a 5-year period and the propensity to grow "fast" and "slow" and metastasize or not metastasize to the axillary lymph nodes. Fast cancers, divided into two defined subsets as "fast 1" and "fast 2," are those surfacing in the intervals between mammograms. The faster cancers exhibited a significant absence of calcification, were discovered in younger patients and resulted in a shorter 5-year cumulative survival rate (fast 1 = 74 +/- 9% to slow = 94 +/- 4%). In addition to growth rates, another index of virulence in small cancers is the early appearance of metastases in the axillary lymph nodes. The absence of microscopic calcifications and the presence of lymphatic invasion around the primary cancer site were significantly associated with the presence of axillary metastases. Other factors associated with the occurrence of axillary metastases were a higher mitotic index, poor cellular differentiation and a larger size of cancer at diagnosis. The author's results confirm that interval surfacing cancers are biologically different and are not comparable to cancers discovered by scheduled screens. Cancers that metastasize to lymph nodes while very small have properties in common with these interval surfacing and, presumably, faster growing cancers.

Acute carcinoma of the breast.

The timely discovery of curable carcinoma through screening and early treatment is compromised by the existence of acute carcinoma with adverse properties. The existence of an acute carcinoma must be considered in planning and promoting any public health program for the control of carcinoma of the breast. These carcinomas will surface under any contemporarily available screening or detection program through no physician or patient error. These carcinomas have identifiable properties, and their occurrence should not be the basis of a malpractice suit, since their evolution is not presently preventable. The available data on actual doubling times obviously provide truncated distributions, since they contain no data on the faster subsets of carcinomas that surface in the intervals between screenings too quickly to permit measurement of size and calculation of DT (act).

Tumor growth, doubling times, and the inability of the radiologist to diagnose certain cancers.

In the absence of prevention, the control of breast cancer demands that it be discovered as soon as possible after it reaches threshold size, but before it disseminates. This optimal detection time is known as the "cancer control window." The actual doubling time of a cancer is a major determinant of the length of time available for effective discovery. Data are presented showing the enormous variance possible for this interval, ranging from very short times to extremely long times. With refined mammographic techniques and conscientious, aggressive mammographers, this threshold size continues to shrink and now approaches 2 mm. Many factors, however, continue to influence effective detection in this size range including cancer type, breast parenchymal density, proper applications of examination techniques, and the duration of the cancer control window for different cancers. Our own experience and review of the literature indicate that a certain percentage of cancers will be missed in the symptomatic and screened populations. With some adjustments of technique and interpretation and careful attention to them, many of these overlooked cancers can be recognized. However, data support the presence of a subset of acute breast cancers below threshold size at examination but that can grow to clinically detectable and symptomatic size within weeks to months of the breast evaluation showing no abnormality. These cancers will surface under any contemporarily available screening or detection program through no physician error. Under optimal conditions, this group of cancers can neither be prevented nor recognized and account for the inability of the radiologist to diagnose some breast cancers.