Progressive Phase Of Disease Research Articles

High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: A renewed role for adrenalectomy

Background. Stage IV hormone-sensitive breast cancer is often treated with aromatase inhibitors (anastrozole, letrozole, exemestane), which block the conversion of dehydroepiandrosterone (DHEA) to estrone and estradiol. This is intended to obviate the need for steroid replacement and antiquate adrenalectomy. Methods. Patients who underwent oophorectomy and were being treated with new aromatase inhibitor therapy received serial measurements of serum estrone, estradiol, and DHEA-sulfate (DHEA-S). Steroid values during responsive and progressive phases of disease were compared. In vitro, human breast cancer cell lines T-47D (estrogen-receptor and progesterone-receptor positive) and HCC 1937 (estrogen-receptor and progesterone-receptor negative) were treated with DHEA-S. Proliferation rates were measured by colorimetric assay. Results. Disease in 12 of the 19 patients progressed. DHEA-S was less than 89 μg/dL in patients during the responsive phase and more than or equal to 89 μg/dL during disease progression, with 1 exception (P <.0005). Estrone and estradiol remained suppressed. After disease progression, the condition of 9 patients stabilized with aminoglutethimide therapy (n = 8) or adrenalectomy (n = 1), and their DHEA-S levels were reduced to less than 89 μg/dL. In vitro, elevated DHEA-S induced cell proliferation in T-47D cells. Conclusions. DHEA-S levels more than or equal to 89 μg/dL predicted disease progression in states of low estrogen. Tissue culture results supported the role of DHEA-S as an estrogenic agent. Oophorectomies with either aminoglutethimide therapy or adrenalectomy were effective remedies for breast cancer progression due to high DHEA-S. (Surgery 2001;130:947-53.)

Interactions between hormone-mediated and vaccine-mediated immunotherapy for pulmonary tuberculosis in BALB/c mice.

Problems of logistics, compliance and drug resistance point to an urgent need for immunotherapeutic strategies capable of shortening the current 6-month chemotherapy regimens used to treat tuberculosis, or of supplementing ineffective therapy. In this study we sought to define the mechanism of action of two immunotherapies, both of which have previously been shown to prolong survival. Secondly, we wished to identify any clinically useful synergy between these therapies. In BALB/c mice infected via the trachea with Mycobacterium tuberculosis H37Rv there is an initial phase of partial resistance dominated by type 1 cytokines plus tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), followed by a phase of progressive disease. This progressive phase is accompanied by increasing expression of IL-4, and diminished expression of IL-1 and TNF-alpha. Animals in this late progressive phase of the disease (day 60) were treated with two injections (day 60 and day 90) of 0.1 or 1.0 mg of heat-killed Mycobacterium vaccae, or with 3beta, 17beta-androstenediol (AED; 25 microg subcutaneously three times/week), or with both therapies. We show here using four techniques in parallel (morphometry, immunohistochemistry with automated cell counting, semiquantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assays of cytokines in lung extracts) that treatment with M. vaccae causes a switch back towards a type 1 cytokine profile, restoration of expression of IL-1alpha and TNF-alpha, and a switch from pneumonia to granuloma. This is very similar to the changes previously seen after treatment with AED. However, there was no evidence for synergy between M. vaccae and AED.

Antigen and superantigen presentation in the human CNS

Although the central nervous system (CNS) is often considered a site of relative immune privilege, this compartment has also long been recognized as a susceptible target of immune mediated disorders. The recognition of the clinical entity post-vaccination or acute disseminated encephalomyelitis (ADEM) established the precedent that systemic immunization with neural tissue could result in an inflammatory demyelinating disorder affecting the CNS. Studies of the animal disorder experimental autoimmune encephalomyelitis (EAE), initially developed to model ADEM ( Rivers et al., 1933 Rivers T.M. Sprunt D.H. Berry G.P. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J. Exp. Med. 1933; 58 (Abstract): 39-53 Crossref PubMed Scopus (350) Google Scholar ), have now documented that such a disease process is initiated by antigen-specific T cells which are generated in the systemic compartment and then migrate to the CNS. Similar sequences of events are speculated to underlie the development of the human disease, multiple sclerosis (MS). The clinical and neuroimaging features of MS raise the further questions of what mechanisms account for the typical initial relapsing course of the disease, which then frequently acquires a superimposed progressive course. The initial relapsing disease course in MS is characterized by a high frequency of gadolinium enhancing lesions visualized by magnetic resonance (MR) imaging. The best available pathological data indicate that these magnetic resonance findings reflect an active lymphocyte dominated inflammatory response. In the chronic or progressive disease phase, lesions are dominated by macrophages and microglia. There is a relative paucity of lymphocytes. One does caution that there is likely heterogeneity of pathology in MS; such heterogeneity may correspond to distinct immunopathogenic mechanisms being operative in individual cases ( Lucchinetti et al., 1996 Lucchinetti C.F. Bruck W. Rodriguez M. Lassmann H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol. 1996; 6: 259-274 Crossref PubMed Scopus (676) Google Scholar , Lassmann et al., 1998 Lassmann H. Raine C.S. Antel J. Prineas J.W. Immunopathology of multiple sclerosis: report on an international meeting held at the Institute of Neurology of the University of Vienna. J. Neuroimmunol. 1998; 86: 213-217 Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar ). EAE and virus-induced immune mediated models, which more closely resemble the various clinical–pathological features of MS, continue to be developed.

Osteopontin in chronic puromycin aminonucleoside nephrosis.

Increased expression of osteopontin (OPN) associated with interstitial monocyte infiltration has been demonstrated in the early phase of a variety of experimental renal diseases. Whether these changes occur in the chronic phase of progressive glomerular disease is unknown. Chronic puromycin aminonucleoside nephrosis (PAN) was induced in 16 rats by the injection of a single bolus of PA into the internal jugular vein, which results in a triphasic disease characterized by minimal glomerular change and marked proteinuria, peaking at about 10 to 14 d and subsiding by 28 d, followed by a quiescent 4-wk period of no or minimal proteinuria and then the development of progressive focal glomerulosclerosis (FGS) and increasing proteinuria. Fifteen rats injected similarly with normal saline served as controls. At 11 d after injection, PA rats demonstrated significantly greater urinary protein excretion (P = 0.0107), cortical tubular OPN expression (P = 0.0086), and intraglomerular (P = 0.0009) and interstitial (P = 0.0212) monocyte infiltration than did the controls. At 42 d, no significant differences between the two groups with respect to the above parameters were detected. At 98 d, PA rats had FGS and showed a definite trend to increased proteinuria, cortical tubular OPN, and intraglomerular monocyte infiltration. Although the cortical interstitial monocyte count was not elevated in PA rats compared with controls, there were significantly more monocytes around OPN-positive cortical tubules than around OPN-negative ones (P = 0.0011). Cortical tubular OPN expression correlated well with urinary protein excretion (r = 0.932, P < 0.0001), cortical tubular proliferating cell nuclear antigen (r = 0.796, P < 0.0001), and intraglomerular monocyte count (r = 0.552, P = 0.0013). The results are consistent with a monocyte chemoattractant role for OPN and suggest that OPN is upregulated in the chronic phase of PAN and that this increase in expression is a result of glomerular events.

Evidence for a prolonged role of alpha 4 integrin throughout active experimental allergic encephalomyelitis.

The leukocyte integrin receptor, alpha 4 beta 1, and its endothelial cell ligand, vascular cell adhesion molecule 1, appear to be of critical importance in the leukocyte trafficking that accompanies CNS damage in experimental allergic encephalomyelitis (EAE). In this study, the persistence of the role for alpha 4 beta 1/VCAM-1 in EAE was established by observing antibody-mediated disease reversal up to 1 month following disease onset. Limited treatment with a monoclonal antibody against alpha 4 integrin, GG5/3, resulted in a significant decrease in both clinical and histopathologic signs. This was not observed in isotype control experiments. In the latter phase of progressive disease, widespread demyelination occurred in the animals that did not respond to 6 days of anti-alpha 4 treatment. These results demonstrate an essential role for alpha 4 beta 1 interactions throughout active EAE and illustrate the difference between reversible clinical deficits caused by edema and irreversible deficits associated with demyelination.

In multiple myeloma, clonotypic B lymphocytes are detectable among CD19+ peripheral blood cells expressing CD38, CD56, and monotypic Ig light chain [published erratum appears in Blood 1995 Jun 1;85(11):3365

Multiple myeloma (MM) is characterized by a plasma cell infiltrate of the bone marrow (BM). However, late-stage monotypic B cells have been detected in the blood. This work analyzes the effects of clinical treatment on late stage CD19+ B cells present in 752 blood samples from 152 MM patients. MM patients have 2 to 8 times as many circulating CD19+ cells as do normal donors. Analysis of the Ig heavy chain (IgH) gene rearrangements using polymerase chain reaction indicates that the CD19+ population includes cells sharing the same clonotypic CDR3 region as is detected in the BM plasma cells, for patients analyzed during chemotherapy or in relapse. They are also monotypic as defined by their cytoplasmic or surface expression of Ig kappa or lambda light chain. The light chain restriction is the same as that of the BM plasma cells. Individual patients observed over 1- to 2-year periods exhibit considerable variation in the number of B cells present in blood; this number does not correlate with the concentration of serum monoclonal Ig. The monoclonal blood CD19+ cells are not eliminated by any of the chemotherapy regimens analyzed and remain at high levels during transient remissions. Patients in the progressive phase of disease or in relapse have significantly higher numbers of B cells than do patients in transient remission or untreated patients. During periods when the quantity of blood B cells approaches normal, phenotypically their quality is highly abnormal, with physical and phenotypic heterogeneity. Most B cells express CD45R0, a high density of CD38, and CD56 characteristic of late-stage B or pre-plasma cells. CD38hi blood B cells had a cyclical presence. We conclude that monoclonal B cells in the blood of myeloma patient populations include drug-resistant reservoirs of clonotypic cells that may underlie relapse.

In Multiple Myeloma, Clonotypic B Lymphocytes Are Detectable Among CD19+ Peripheral Blood Cells Expressing CD38, CD56, and Monotypic Ig Light Chain

Multiple myeloma (MM) is characterized by a plasma cell infiltrate of the bone marrow (BM). However, late-stage monotypic B cells have been detected in the blood. This work analyzes the effects of clinical treatment on late stage CD19+ B cells present in 752 blood samples from 152 MM patients. MM patients have 2 to 8 times as many circulating CD19+ cells as do normal donors. Analysis of the Ig heavy chain (IgH) gene rearrangements using polymerase chain reaction indicates that the CD19+ population includes cells sharing the same clonotypic CDR3 region as is detected in the BM plasma cells, for patients analyzed during chemotherapy or in relapse. They are also monotypic as defined by their cytoplasmic or surface expression of Ig kappa or lambda light chain. The light chain restriction is the same as that of the BM plasma cells. Individual patients observed over 1- to 2-year periods exhibit considerable variation in the number of B cells present in blood; this number does not correlate with the concentration of serum monoclonal Ig. The monoclonal blood CD19+ cells are not eliminated by any of the chemotherapy regimens analyzed and remain at high levels during transient remissions. Patients in the progressive phase of disease or in relapse have significantly higher numbers of B cells than do patients in transient remission or untreated patients. During periods when the quantity of blood B cells approaches normal, phenotypically their quality is highly abnormal, with physical and phenotypic heterogeneity. Most B cells express CD45R0, a high density of CD38, and CD56 characteristic of late-stage B or pre-plasma cells. CD38hi blood B cells had a cyclical presence. We conclude that monoclonal B cells in the blood of myeloma patient populations include drug-resistant reservoirs of clonotypic cells that may underlie relapse.

PATTERNS OF BLOOD-BRAIN BARRIER BREAKDOWN IN INFLAMMATORY DEMYELINATION

The evolution of the changes in the blood-brain barrier (BBB) in chronic relapsing experimental allergic encephalomyelitis (CREAE), a model of immune-mediated demyelination, has been studied by magnetic resonance imaging (MRI); gadolinium-DTPA (Gd-DTPA) was used to detect BBB breakdown by both quantitative and qualitative techniques. Animals with acute EAE were examined for comparison. In animals with CREAE an approximately linear relationship was found between the mean number of lesions enhancing with Gd-DTPA seen per MRI slice and the severity of clinical disability at relapse. In addition, a direct relationship was seen between the duration of clinical relapse and the duration of enhancement with Gd-DTPA for lesions associated with the relapse. Lesions studied in animals having entered a progressive phase of disease showed the most sustained BBB breakdown. These observations suggest that BBB breakdown is important in the development of clinical signs in inflammatory demyelination. In CREAE, areas of focal enhancement with Gd-DTPA could usually be clearly defined at a time of clinical relapse. In slices free of focal lesions, no abnormal Gd-DTPA leakage could be detected using a quantitative method. In contrast, in acute EAE no focal lesions were visible, but significant leakage was detected by measurement. No change was found in T2 relaxation times in CREAE or acute EAE. The pattern of BBB breakdown in inflammatory demyelination evolves from a diffuse shortlived disturbance in acute EAE to a more focal and prolonged breakdown in animals with chronic relapsing and progressive disease. The broad similarities in the pattern of BBB breakdown seen in CREAE and multiple sclerosis support the hypothesis that the initial vascular changes in the human disease are due to inflammation which could be mediated immunologically.

Eosinophilia-Myalgia Syndrome Associated With L-Tryptophan Ingestion

Four patients fulfilling the case definition for eosinophilia-myalgia syndrome are described, including one whose disease began in 1986. Each displayed a variety of symptoms: one suffered principally from myalgia and recovered spontaneously on discontinuation of L-tryptophan therapy; one exhibited progressive sclerodermiform skin changes, neuropathy, and myopathy; a third had prominent neuromuscular disease and sclerodermiform skin changes; and the fourth experienced profound weight loss, an axonal polyneuropathy, and perivascular lymphoid infiltrates simulating a lymphoma. Evidence of T-cell activation was present in peripheral blood and affected tissues during the clinically active progressive phase of disease. Among other manifestations pleural effusion, cutaneous vasculitis, joint contractures, and bloody diarrhea were observed. A history of L-tryptophan ingestion should be sought in patients with myalgia, fatigue, or the above outlined symptoms.