William R. Welch

Bio: William R. Welch is an academic researcher from Brigham and Women's Hospital. The author has contributed to research in topics: Ovarian cancer & Serous fluid. The author has an hindex of 58, co-authored 159 publications receiving 15798 citations. Previous affiliations of William R. Welch include Memorial Hospital of South Bend & Duke University.

Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma.

Abstract: Background. Experimental evidence suggests that the growth of a tumor beyond a certain size requires angiogenesis, which may also permit metastasis. To investigate how tumor angiogenesis correlates with metastases in breast carcinoma, we counted microvessels (capillaries and venules) and graded the density of microvessels within the initial invasive carcinomas of 49 patients (30 with metastases and 19 without). Methods. Using light microscopy, we highlighted the vessels by staining their endothelial cells immunocyto-chemically for factor VIII. The microvessels were carefully counted (per 200×field), and their density was graded (1 to 4+), in the most active areas of neovascularization, without knowledge of the outcome in the patient, the presence or absence of metastases, or any other pertinent variable. Results. Both microvessel counts and density grades correlated with metastatic disease. The mean (±SD) count and grade in the patients with metastases were 101±49.3 and 2.95±1.00 vessels, respect...

Determinants of Ovarian Cancer Risk. II. Inferences Regarding Pathogenesis

Abstract: Entrapment of surface epithelium within the ovarian stroma was proposed as an initial event in the pathogenesis of cystadenocarcinoma of the ovary. Subsequent events, including differentiation, proliferation, and eventual malignant transformation of the entrapped epithelium, may occur as a consequence of stimulation by estrogen or estrogen precursors. These events were more likely when the steroid producing stroma itself had been stimulated by high gonadotropins. Animal experiments suggested that gonadotropin excess and stromal stimulation may result by disturbing normal feedback inhibition between ovary and pituitary or by destroying ovarian follicles. By analogy, in humans, a number of common chemicals and drugs may increase gonadotropins by enhancing estrogen degradation in the liver or by directly stimulating production by the pituitary. Elevated gonadotropins may also result via mechanisms that cause primary ovarian failure including pelvic irradiation, exposure to chemicals or metabolites toxic to follicles, or ovarian infections such as mumps.

Tissue distribution of a coelomic-epithelium-related antigen recognized by the monoclonal antibody OC125.

Abstract: OC125, a murine monoclonal antibody, recognizes an antigenic determinant (CA125) that is associated with greater than 80% of epithelial ovarian neoplasms of serous, endometrioid, clear cell, and undifferentiated types. In the present report, a sensitive biotin-avidin immunoperoxidase technique was used to determine reactivity of OC125 with normal adult and fetal tissues, as well as with neoplasms of nonovarian origin. In fetal tissues, the antibody reacted with amnion and with derivatives of the coelomic epithelium, i.e., the mullerian epithelium and the lining cells of the peritoneum, pleura, and pericardium. Among adult tissues, OC125 reacted with the epithelium of fallopian tubes, endometrium, and endocervix. The CA125 determinant was also detected on mesothelial cells in the adult pleura, pericardium, and peritoneum, particularly in areas of inflammation and adhesion. Curiously, the surface epithelium of normal fetal and adult ovaries, thought to be derived from coelomic epithelium, did not express the determinant, except in inclusion cysts, areas of metaplasia, and papillary excrescences. Of neoplastic tissues of nonovarian origin, OC125 reacted consistently only with adenocarcinomas of the endocervix, endometrium, and fallopian tube, and with mesotheliomas. Only seven of 64 nongynecological tumors tested reacted with OC125. Thus, OC125 detects a differentiation antigen shared by fetal coelomic epithelium and its derivatives in the fetus and the adult. Apparently, this antigen disappears early in the course of formation of the ovarian epithelium and is reexpressed in certain reactive and neoplastic lesions, a process that could be termed "molecular metaplasia."

Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas.

Abstract: Among the genes most commonly identified in gene expression profiles of epithelial ovarian carcinomas (EOC) is the gene for human epididymis protein 4 (HE4). To ascertain its clinical utility, we did a comprehensive assessment of HE4 protein expression in benign and malignant ovarian and nonovarian tissues by immunohistochemistry. In comparison with normal surface epithelium, which does not express HE4, we found that cortical inclusion cysts lined by metaplastic Mullerian epithelium abundantly express the protein. Its expression in tumors was restricted to certain histologic subtype: 93% of serous and 100% of endometrioid EOCs expressed HE4, whereas only 50% and 0% of clear cell carcinomas and mucinous tumors, respectively, were positive. Tissue microarrays revealed that the majority of nonovarian carcinomas do not express HE4, consistent with our observation that HE4 protein expression is highly restricted in normal tissue to the reproductive tracts and respiratory epithelium. HE4 is predicted to encode a secreted protein. Using reverse transcription-PCR, we identified ovarian cancer cell lines that endogenously overexpress HE4. Cultured medium from these cells revealed a secreted form of HE4 that is N-glycosylated. This observation is consistent with the recent report that HE4 circulates in the bloodstream of patients with EOC. Therefore, HE4 is a secreted glycoprotein that is overexpressed by serous and endometrioid EOCs. Its expression in cortical inclusion cysts suggests that formation of Mullerian epithelium is a prerequisite step in the development of some types of EOCs.

Ovarian sex cord tumor with annular tubules. Review of 74 cases including 27 with Peutz-Jeghers syndrome and four with adenoma malignum of the cervix†

Abstract: The sex cord tumor with annular tubules (SCTAT) is a distinctive ovarian neoplasm the predominant component of which has morphologic features intermediate between those of the granulosa cell tumor and those of the Sertoli cell tumor; focal differentiation into either granulosa cell or Sertoli cell tumor may occur. Of the 74 cases that form the basis of this investigation 27 were associated with the Peutz-Jeghers syndrome; these tumors were all benign and were typically multifocal, bilateral, very small or even microscopical in size and calcified. Twelve of the 27 patients had symptoms suggestive of hyperestrinism attributable to the SCTAT; menstrual irregularity had occurred in eleven cases and postmenopausal bleeding in one. Four of the 27 patients had "adenoma malignum" of the cervix and two of them died of it. The 47 tumors from patients without evidence of the Peutz-Jeghers syndrome were unilateral and usually large. Twenty-five of them were accompanied by symptoms suggestive of hyperestrinism, such as menstrual irregularity, postmenopausal bleeding or sexual precocity; seven were malignant and four of these were fatal.

Angiogenesis in cancer, vascular, rheumatoid and other disease

Abstract: Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.

Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.

Abstract: background The influence of excess body weight on the risk of death from cancer has not been fully characterized. methods In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. We examined the relation in men and women between the body-mass index in 1982 and the risk of death from all cancers and from cancers at individual sites, while controlling for other risk factors in multivariate proportional-hazards models. We calculated the proportion of all deaths from cancer that was attributable to overweight and obesity in the U.S. population on the basis of risk estimates from the current study and national estimates of the prevalence of overweight and obesity in the U.S. adult population. results The heaviest members of this cohort (those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of at least 40) had death rates from all cancers combined that were 52 percent higher (for men) and 62 percent higher (for women) than the rates in men and women of normal weight. For men, the relative risk of death was 1.52 (95 percent confidence interval, 1.13 to 2.05); for women, the relative risk was 1.62 (95 percent confidence interval, 1.40 to 1.87). In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney; the same was true for death due to non-Hodgkin’s lymphoma and multiple myeloma. Significant trends of increasing risk with higher body-mass-index values were observed for death from cancers of the stomach and prostate in men and for death from cancers of the breast, uterus, cervix, and ovary in women. On the basis of associations observed in this study, we estimate that current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women. conclusions Increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites.

Radiomics: Images Are More than Pictures, They Are Data.

Abstract: In the past decade, the field of medical image analysis has grown exponentially, with an increased number of pattern recognition tools and an increase in data set sizes. These advances have facilitated the development of processes for high-throughput extraction of quantitative features that result in the conversion of images into mineable data and the subsequent analysis of these data for decision support; this practice is termed radiomics. This is in contrast to the traditional practice of treating medical images as pictures intended solely for visual interpretation. Radiomic data contain first-, second-, and higher-order statistics. These data are combined with other patient data and are mined with sophisticated bioinformatics tools to develop models that may potentially improve diagnostic, prognostic, and predictive accuracy. Because radiomics analyses are intended to be conducted with standard of care images, it is conceivable that conversion of digital images to mineable data will eventually become routine practice. This report describes the process of radiomics, its challenges, and its potential power to facilitate better clinical decision making, particularly in the care of patients with cancer.

The biology of vascular endothelial growth factor

Abstract: The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult1 Neovascularization (angiogenesis) is also implicated in the pathogenesis of a number of disorders These include: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis1,2 A strong correlation has been noted between density of microvessels in primary breast cancers and their nodal metastases and patient survival3 Similarly, a correlation has been reported between vascularity and invasive behavior in several other tumors4–6