Neoplastic progression and prognosis in melanoma

Most melanomas evolve through an initial stage known as radial growth phase (RGP), encompassing in situ and microinvasive malignancies in which the probability of cure approaches 100%. At the present time, despite a shift toward earlier recognition of melanoma, by the time of diagnosis roughly 70% of melanomas have evolved to a point, known as vertical growth phase (VGP) or tumorigenic melanoma, at which cure is not certain, and prognosis depends upon certain attributes of the neoplasm and the host. Attempts have been made to assemble these attributes into prognostic models to permit estimation of the probability of cure for individuals and for groups of patients. Attributes that have been identified as independent prognostic variables include thickness of the primary neoplasm, the numbers of mitotic figures, and the presence of tumor-infiltrating lymphocytes (TIL). Other biologically important prognostic variables are on the horizon, and some will likely be based on molecules (markers) expressed on neoplastic cells that show functional significance in mechanisms of metastasis.     

Hodgkin's lymphoma -- prognosis as related to histology, clinical stage and treatment

The rapid advances in modern chemotherapy and actinotherapy of Hodgkin's lymphoma and an improvement in its diagnosis have ushered in numerous novel procedures. This is a preliminary analysis of the results of treatment of 117 patients with actinotherapy, polychemotherapy, consisting of a chemotherapeutic four-combination as substitution for MOPP and a combined actino-chemotherapy. Actinotherapy was found more efficient in localized disorders of stages I and II, while polychemotherapy proved the more suitable when the disease was generalized -- stages III and IV. The analysis of our results has brought only partial support to the prognostic significance of the histological classification of Hodgkin's lymphoma according to Rye. No difference of statistical significance has been noted between the histological types of lymphocyte dominance, nodular sclerosis and mixed cellularity. Lymphocyte depletion alone showed a conspicuously worse prognosis than the other histological types.     

Genetic epidemiology of breast and ovarian cancers

Most civilian and military air traffic control facilities in the United States use rapid rotation shift schedules. These schedules have generally been chosen for social reasons. Safety concerns have been raised because the air traffic controllers (ATCs) often carry an acute sleep debt onto the night-shift where they have little active work to do as they sit in the dark at the nadir of their circadian rhythms. This paper reviews advancing and delaying rapid shiftwork schedules, ATC workload factors as they relate to error rates and safety, and potential countermeasures. Recent studies indicate that ATC performance declines on the night-shift and that ATCs may be falling asleep while on-duty. There is indirect evidence that ATC error rates are highest on the night-shift. There are only limited studies which have evaluated potential countermeasures. The operational significance of the problems associated with ATC shiftwork is not yet clear. Further study is needed.     

Tumour blood flow and partition coefficients: correlation with grade of cerebral gliomas using xenon-enhanced computed tomography

It is possible to underestimate the grade of nonenhancing cerebral tumours on conventional contrast-enhanced MRI or CT. Differentiation of high- and low-grade gliomas by measurement of the brain-blood partition coefficient lambda (T lambda) with Xe-enhanced CT (XeCT) has been reported. We assessed the practical applications of XeCT in suspected low-grade astrocytomas. We examined 15 patients with tumours which showed no contrast enhancement on conventional MRI and CT, using XeCT. Tumour blood flow (TBF) and T lambda were calculated. Fourteen patients underwent surgery, one patient had a biopsy. We recognized three histological groups. While T lambda differed significantly between them, TBF did not. Group 1 contained grade II-III astrocytomas and T lambda was 0.77; group 2 contained grade I-II astrocytomas with T lambda 1.14, and group 3 four oligodendrogliomas in which a T lambda of 1.50 was found.     

Pathological anatomy of breast cancers]

A simple method for the simultaneous separation and purification of peripheral blood mononuclear cells (PBMC) and polymorphonuclear neutrophil cells (PMNC) was developed for comparative and functional studies in the immune system of the dog. Purity and cell viability were > 95%, yields were similar to those obtained by other techniques but without red blood cell contamination. Differential blood cell count studies of the isolated cells in blood samples of beagle dogs and German shepherd dogs demonstrated that the 1.077/1.119 double density centrifugation is an effective method of acquiring both highly purified blood mononuclear cells and polymorphonuclear cells as separate entities from the same sample. The interface between plasma and 1.077 contained an average 97% blood mononuclear cells vs. 3% polymorphonuclear cells, and the interface between 1.077 and 1.119 an average 96% polymorphonuclear cells vs. 4% blood mononuclear cells. These data indicate that Histopaque 1.077/1.119 double density gradient allows the purification and physical separation of lymphocytes and phagocytes from a blood sample in the dog, enabling the investigator to examine both cell types from the same sample simultaneously.     

Association between coronary heart disease and cancers of the breast, prostate, and colon

Coronary heart disease (CHD) and cancers of the breast, prostate, and colon are more common in industrialized countries than in the developing world, and to some degree, these conditions appear to share risk factors. To investigate whether there is an association between these cancers and a prior history of CHD, a hospital-based case-control study was conducted at Columbia-Presbyterian Medical Center in New York. The study was based on 252 breast cancer cases, 256 colorectal cancer cases, and 322 benign surgical controls, all of whom underwent biopsy or surgery between January 1989 and December 1992, and on 319 prostate cancer cases and 189 benign prostatic hypertrophy controls diagnosed between January 1984 and December 1986 (prior to widespread use of prostate-specific antigen screening). Medical records were reviewed on each, focusing on the preoperative anesthesia and surgical clearances. No association was found between a history of CHD and breast or colorectal cancer, but an elevated risk was found for prostate cancer (odds ratio, 2.00; 95% confidence interval, 1.18-3.39), using unconditional logistic regression with adjustment for appropriate confounders. No association was found between cigarette smoking and any of the three cancers. Aspirin use was protective for colorectal cancer (odds ratio, 0.35; 95% confidence interval, 0.17-0.73) but had no association with breast or prostate cancer. The study suggests that individuals with CHD are at elevated risk for prostate cancer but not breast or colorectal cancer. Etiological risk factors associated with CHD should be investigated with regard to prostate cancer. Patients with CHD may represent a high-risk group for prostate cancer and potential future targets for prostate cancer screening interventions.     

Parity and prognosis in breast cancer

Analysis of five-year disease-free survival rates in 608 women with operable breast cancer revealed that the reproductive history is a significant prognostic determinant. Overall parous women had a significantly higher cumulative five-year disease-free survival rate (60%), compared to the nulliparous (46%) (z = 2.5, p = 0.012). Significant differences were also noted when gravidity in addition to parity was taken as the determinant. The corresponding disease-free survival rates were 61% and 50%, respectively (z = 1.98, p = 0.048). Five-year survival rates were influenced in a similar manner by these variables but the observed differences were less significant. The trend toward higher survival rates in parous and gravidae women were noted in all tumor stages but achieved statistical significance only in stage III. The findings indicate that parity and gravidity affect not only the risk of breast cancer development but also the subsequent course of the disease. Parity seems to be a strong risk and prognostic factor than gravidity.     

Immunosuppressive factors: role in cancer development and progression

The concept of the immunological surveillance against neoplastic cells was initially proposed by Erlich in 1909 and later elaborated by Burnet. This hypothesis states that the normal function of the immune system, in particular the cell-mediated immunity, is to recognize and destroy the transformed and proliferating tumor cells. The role of cell-mediated immunity during the first steps of tumorigenesis remains controversial. However, there is certain evidence about its importance in the progression and dissemination of cancer. The frequent immunosuppressed condition of cancer patients at tumor relapse or recurrence of secondary tumors is a clinical sign supporting this hypothesis, and many studies have demonstrated a defective immune response in patients diagnosed with advanced cancer. Several mechanisms of escape from the immune surveillance have been described, including the immunoselection of tumor antigen-negative variants, the downregulation of MHC class I expression, suppressive T cells, and the elaboration of immunosuppressive cytokines and other factors. Because of the technical difficulty of isolating the very small amounts from culture supernatants or body fluids, only a few of these substances have been characterized and studied with respect to their biological activity: transforming growth factor-beta (TGF-beta), the protein p15E, interleukin 10 (IL-10), prostaglandin E2 (PGE2), mucins, suppressive E-receptor (SER), immunosuppressive acidic protein (IAP), and adhesion molecules. The possibility of monitoring cancer patients by testing biochemical factors related to cancer growth led to a proposal to measure a number of these factors as tumor markers. Some of them, e.g. mucins, enjoy the consensus of the oncologic community, as for some indications they can help the clinician in the management of cancer patients. Except for the class of mucins, the other above-mentioned immunosuppressive factors have not found any clinical application in the laboratory routine because the information deriving from their measurement, although of speculative and scientific interest, has limited clinical value at present. Nevertheless, even if they have no impact on patient management, these substances do have a potential role to play in the study of cancer patients, and should be taken into account when developing new therapeutic strategies.     

Tumour progression and survival in patients with T1G3 bladder tumours: 15-year outcome

OBJECTIVE: To evaluate tumour progression and survival of patients with T1G3 bladder tumours who were followed for 15 years. PATIENTS AND METHODS: A subset of 48 patients with T1G3 bladder tumours was entered into a randomized trial of transurethral resection (TUR) or TUR plus bacille Calmette-Guèrin (BCG) therapy and followed for a minimum of 15 years. Thirty-nine (81%) patients received one or more courses of BCG. The endpoints of the study were stage progression (defined as muscle invasion of metastasis) and disease-specific survival. RESULTS: Of the 48 patients, 25 (52%) progressed and 15 (31%) died from the disease; 33 patients (69%) survived, including 24 (50%) with an intact bladder. The median progression-free survival time was 151 months. Tumour progression occurred in 35% of the patients within the first 5 years, in 16% after 5-10 years and in 12% of those followed for 10-15 years. Deaths from cancer occurred in 25% of the patients in the first 5 years and in 10% of patients at risk from 5 to 15 years. CONCLUSIONS: Patients with T1G3 bladder tumours who are treated conservatively are at life-long risk of having a muscle-invasive tumour and dying from bladder cancer.     

Systematic review and meta-analysis in anatomic pathology: the value of nuclear DNA content in predicting progression in low grade CIN, the significance of the histological subtype on prognosis in cervical carcinoma

Meta-analysis, though increasingly popular in clinical medicine, has not found acceptance in anatomic pathology. This paper argues that, in combination with a systematic review of the literature, meta-analysis may be usefully applied to pathological research and two examples drawn from gynaecological pathology (the value of nuclear DNA quantitation in predicting progression in low grade cervical intraepithelial neoplasia and the difference in prognosis between squamous cell carcinoma and adenocarcinoma of the cervix) are included to illustrate the methods used and to demonstrate some of the difficulties associated with these techniques.     

Estrogens, cathepsin D and metastasis in cancers of the breast and ovary: invasion or proliferation?

This short review presents the current stage of knowledge of our laboratory on the mechanism of action of cathepsin D and estrogens on tumor progression, mostly based on studies of human breast and ovarian cancer cell lines. Cathepsin D (cath-D) overexpression in breast cancer cells is associated with increased risk of metastasis in patients as confirmed by a recent meta-analysis of clinical studies on node negative breast cancer patients. Transfection of a human cDNA cath-D expression vector increases the metastatic potential of a rat tumor cells line when intravenously injected into nude mice. The mechanism of cath-D induced metastasis seems to require maturation of the pro-enzyme, mostly in large acidic compartments identified as phagosomes. Cath-D is mitogenic in different cell types, and different substrates (growth inhibitors, precursors of growth factor etc.) are proposed to mediate this activity. A mitogenic effect of the pro-enzyme on transmembrane receptor is not totally excluded. The mitogenic activity of estrogens in several estrogen receptor positive breast and ovarian cancer cell lines is well established in our and other laboratories. By contrast the role of estrogens during early steps of metastasis, involving cell invasion through the basement membrane and cell motility is more controversial. The motility of several estrogen receptor (ER) positive breast (MCF7, T47D) and ovarian (BG-1, SKOV3, PEO4) cancer cell lines were studied in our laboratory using a modified Boyden chamber assay. We observed, in all cases, estradiol-induced inhibition of cancer cell invasion and motility. A similar inhibitory effect of estradiol was found when the wild-type ER was stably transfected in the ER-negative MDA-MB231 cells and 3Y1-Ad12 cancer cells. The mechanism of this inhibitory effect is unknown. In ovarian cancer, however it may involve intermediary proteins such as fibulin-1, an extracellular matrix protein that strongly interacts with fibronectin and which is induced by estrogen and secreted by ovarian cancer cells. In breast cancer cells other estrogen regulated proteins may be involved. We conclude that estrogens in ER-positive breast and ovarian cancers have a dual effect, since they stimulate tumor growth but inhibit invasion and motility. This may be consistent with the good initial prognostic value of ER-positive breast cancers compared to ER negative breast cancers noted in several clinical studies, and with the better prognosis of breast cancer occurring after a prolonged treatment of menopause by estrogen as described by the collaborative group on hormonal factors in breast cancer.