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PubMed1991

Factors associated with slow progression in Huntington's disease.

The rate of disease progression was assessed for 42 persons affected by Huntington's disease who had been neurologically examined at least six times and followed up for at least 3 years. Disease progression was assessed by a disability rating scale administered at each examination. Slow progression was associated with older age at onset of disease and with heavier weight (body mass index) at the first examination. Men tended to have a slower disease progression than did women, and this was particularly evident among men inheriting Huntington's disease from affected mothers. Neither the butyrophenone haloperidol nor the tricyclic antidepressant imipramine were related to rate of progression. Assessments of depression, hostility, and tobacco use were also unrelated to rate of progression. Clinical trials in Huntington's disease should consider these factors when designing therapeutic studies.

Adolescent↗

PubMed1976

Alpha 1-antitrypsin activity of perilymph. Occurrence during progression of otospongiosis.

Previous studies by the Adams method demonstrated a strong correlation between hydrolytic enzyme activity of perilymph and progression of bone conduction loss two years preceding stapedectomy. Alpha 1-Antitrypsin was chosen since its activity can be very precisely measured by a radical immunodiffusion technique and since it is one of the enzymes identified in perilymph of patients with active otospongiosis. Samples of 3 mul to 5 mul of perilymph removed during 103 stapedectomies and samples of known alpha 1-trypsin activity were placed on slides coated with alpha 1-antitrypsin serum. The zone of diffusion was stained and measured after 38 hours of incubation. Antitrypsin values were lowest in 24 cases, two with no preoperative bone conduction progression, three with moderate progression of 10 to 15 dB, and 19 with rapid progression of more than 20 dB. They were highest in 36 cases with no progression, and in one case with moderate progression. This study confirms previous reports on the enzymatic activity in otospongiotic disease.

Humans↗

PubMed1997

Tumor angiogenesis correlates with progression after radical prostatectomy but not with pathologic stage in Gleason sum 5 to 7 adenocarcinoma of the prostate.

BACKGROUND: Prior studies have suggested that tumor angiogenesis (microvessel density [MVD]) may be of prognostic significance in patients with prostate carcinoma. METHODS: The authors examined the relationship of MVD in intermediate grade prostate carcinomas with stage at radical prostatectomy (RP) and progression after RP. For the former group, 109 RP specimens with Gleason sums of 6 and 7 were studied: 34 organ-confined tumors, 37 with capsular penetration, 21 with seminal vesicle involvement, and 17 with pelvic lymph node metastasis. For the latter group, 87 RP specimens were studied that had a Gleason sum of 5 to 7 for which the patients underwent follow-up of at least 7 years or until progression. Thirty-seven patients (43%) progressed at a mean of 3.5 years (range, 1-8 years). Representative sections of each tumor were stained for CD31 and "hot spot" microvessels were quantitated in a 3.14-mm2 area. RESULTS: In the first arm, there was no relationship between MVD and stage at RP. In the second arm, the mean MVD in tumors that progressed was significantly higher than in nonprogressors (43.0 +/- 26.1 vs. 29.0 +/- 13.1; P < 0.0001 by Wilcoxon-Gehan statistic). MVD and Gleason sum were independent statistically significant predictors of progression (MVD, P < 0.0001; Gleason sum, P < 0.0001 by Cox proportional hazards model). CONCLUSIONS: MVD is an independent significant predictor of progression after RP for tumors with a Gleason sum of 5 to 7. Because these comprise the majority of RP specimens, it is this group for which discrimination of biologic potential is most needed. Angiogenesis may be useful in the prognostic stratification of patients beyond that possible using stage and grade alone.

Adenocarcinoma↗

PubMed1991

Determination of growth fraction in advanced prostate cancer by Ki-67 immunostaining and its relationship to the time to tumor progression after hormonal therapy.

Reliable predictors of response for prostate cancer patients undergoing hormonal therapy are lacking. This study investigates the possibility that tumor proliferation rates might predict tumor behavior for these patients. The growth fraction of metastatic prostate cancer biopsy specimens obtained before androgen withdrawal therapy was evaluated by Ki-67 antibody immunohistochemical study to determine whether a higher tumor growth fraction was associated with a shorter time to tumor progression after therapy. The percentage of Ki-67-positive malignant epithelial nuclei in the primary tumors of 17 patients ranged from 1.7% to 7.5% (median, 2.5%). When patients were divided into two response groups according to the median time to progression, poor responders (time to progression less than 20 months) and good responders (greater than or equal to 20 months) had similar growth fractions (3.5 +/- 0.5% versus 3.1 +/- 0.6% Ki-67-positive nuclei, respectively). However, when patients were divided into two groups based on the median growth fraction, patients with a high growth fraction (greater than 2.5% Ki-67-positive nuclei) tended to have a shorter time to progression (median, 10 months) than patients with a low (less than 2.5%) growth fraction (median time to progression, 25 months), although statistical significance was not reached. Despite this interesting trend, Ki-67 immunostaining was not accurate to predict the time to progression in individual patients undergoing hormonal therapy. Reliable prediction of growth rates may require measurement of both cell proliferation and cell death rates.

Aged↗

PubMed1994

Neuroendocrine differentiation in prostatic adenocarcinoma and its relationship to tumor progression.

BACKGROUND: Neuroendocrine differentiation has been demonstrated by immunohistochemical preparations in many cases of acinar type prostatic adenocarcinoma (CAP). Some studies have suggested that this differentiation may indicate an adverse prognosis. METHODS: Tissue samples from 38 consecutive patients with clinical Stage II (AJCC) CAP who underwent radical retropubic prostatectomy (RRP) were studied after preparations were made with antichromogranin (ChA) and neuron-specific enolase (NSE). All patients were followed for at least 4 years post-RRP or until disease progression was documented by rising serum prostate specific antigen concentration, X-ray evidence of recurrence, or a positive tissue biopsy. RESULTS: Nine of the 38 RRP specimens (24%) were positive for NSE, and 11 (29%) were positive for ChA. Neither of these neuroendocrine markers showed a significant correlation with tumor progression. Neuroendocrine differentiation in needle biopsy specimens from these same patients (when available) did not correlate with tumor progression either. Of the patients with tumor progression, 9 of 11 (82%) had pathologic Stage III disease after RRP; of those with no progression of CAP, only 7 of 27 (26%) had pathologic Stage III disease. CONCLUSIONS: Neuroendocrine differentiation, as demonstrated by NSE and ChA preparations, was not helpful in predicting tumor progression of CAP.

Biomarkers, Tumor↗

PubMed2001

X-irradiation--induced changes in the progression of type B spermatogonia and preleptotene spermatocytes.

In response to induced DNA damage, proliferating cells arrest in their cell cycle or go into apoptosis. Ionizing radiation is known to induce degeneration of mammalian male germ cells. The effects on cell-cycle progression, however, have not been thoroughly studied due to lack of methods for identifying effects on a particular cell-cycle phase of a specific germ cell type. In this study, we have utilized the technique for isolation of defined segments of seminiferous tubules to examine the cell-cycle progression of irradiated rat mitotic (type B spermatogonia) and meiotic (preleptotene spermatocytes) G1/S cells. Cells irradiated as type B spermatogonia in mitotic S phase showed a small delay in progression through meiosis. Thus, it seems that transient arrest in the progression can occur in the otherwise strictly regulated progression of germ cells in the seminiferous epithelium. Contrary to the arrest observed in type B spermatogonia and in previous studies on somatic cells, X-irradiation did not result in a G1 delay in meiotic cells. This lack of arrest occurred despite the presence of unrepaired DNA damage that was measured when the cells had progressed through the two meiotic divisions.

Animals↗

PubMed1999

Magnetic resonance imaging-determined synovial membrane volume as a marker of disease activity and a predictor of progressive joint destruction in the wrists of patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the synovial membrane volume, determined by magnetic resonance imaging (MRI), as a marker of joint disease activity and a predictor of progressive joint destruction in rheumatoid arthritis (RA). METHODS: Twenty-six patients with RA, randomized to receive disease-modifying antirheumatic drug (DMARD) therapy alone (11 patients) or DMARDs in combination with oral prednisolone (15 patients), were followed up for 1 year with contrast-enhanced MRI of the dominant wrist (months 0, 3, 6, and 12), conventional radiography (months 0 and 12), and clinical and biochemical examinations. Bone erosion (by MRI and radiography) and synovial membrane volumes (by MRI) were assessed. RESULTS: Significant synovial membrane volume reductions were observed after 3 and 6 months in the DMARD + prednisolone group, and after 6 and 12 months in the DMARD-alone group (P < 0.01-0.02, by Wilcoxon-Pratt analysis). The rate of erosive progression on MRI was highly correlated with baseline scores and, particularly, with area under the curve (AUC) values of synovial membrane volume (Spearman's sigma = 0.69, P < 0.001), but not with baseline or AUC values of local or global clinical or biochemical parameters, or with prednisolone treatment. In none of 5 wrists with baseline volumes <5 cm3, but in 8 of 10 wrists with baseline volumes > or =10 cm3, erosive progression was found by MRI and/or radiography, indicating a predictive value of synovial membrane volumes. MRI was more sensitive than radiography for the detection of progressive bone destruction (22 versus 12 new bone erosions). CONCLUSION: MRI-determined synovial membrane volumes are closely related to the rate of progressive joint destruction. Quantitative MRI assessment of synovitis may prove valuable as a marker of joint disease activity and a predictor of progressive joint destruction in RA.

Administration, Oral↗

PubMed2000

A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores.

OBJECTIVE: To evaluate radiographic progression and the relationship of radiologic scores obtained by the Genant and Larsen methods in a clinical trial of recombinant human interleukin-1 receptor antagonist (IL-1Ra). METHODS: Patients with rheumatoid arthritis (RA) were randomized into 4 groups: placebo (n = 121) or IL-1Ra at a daily dosage of 30 mg (n = 119), 75 mg (n = 116), or 150 mg (n = 116). Hand radiographs obtained at baseline, 24 weeks, and 48 weeks were scored using both methods. RESULTS: At 24 weeks, by the Genant method, there was significant reduction in the score for progression of joint space narrowing (JSN) and the total score (a combination of erosion and JSN) in all treatment groups. Least-squares mean changes in the Genant erosion score from baseline to 24 weeks were significantly reduced after treatment with IL-1Ra at 30 mg/day and for all IL-1Ra treatment groups combined. The changes corresponded to a reduction of 38% in erosion, 58% in JSN, and 47% in total score. Patients treated with IL-1Ra at 75 mg/day had a significant reduction in the Larsen erosive joint count (LEJC), and all IL-1RA-treated groups combined showed a 45% reduction. Correlations (r) between the Genant total and Larsen scores were 0.84 at baseline, 0.83 at week 24, and 0.83 at week 48 (P < 0.0001); correlations between the Genant erosion score and the LEJC were 0.83 (P < 0.0001) at all visits; correlations between the Genant total and the Larsen scores were 0.32 and 0.49 (P < 0.0001) for progression from baseline to week 24 and from baseline to week 48, respectively; correlations between the Genant erosion score and the LEJC were 0.36 and 0.41 (P < 0.0001) for progression to weeks 24 and 48, respectively. CONCLUSION: IL-1Ra reduced radiologic progression of RA. Scores by the 2 methods correlated strongly for each individual time point, but much less strongly for assessments of disease progression.

Adult↗

PubMed2002

The relationship of bone density and fracture to incident and progressive radiographic osteoarthritis of the knee: the Chingford Study.

OBJECTIVE: Investigators performing cross-sectional studies have reported small increases in bone mineral density (BMD) in subjects with osteoarthritis (OA). This study was undertaken to examine the association of bone mass with incident and progressive disease and to determine whether prior fractures influence the development of OA. METHODS: Eight hundred thirty women had repeat knee radiographs 48 months from baseline. All radiographs were graded on the presence or absence of osteophytes and joint space narrowing (JSN). Incident knee OA was defined as new disease in the 715 women without knee OA at baseline. Progression was a change of at least one grade in the 115 women with baseline knee OA. All women underwent bone densitometry of the lumbar spine and hip. Rates of subsequent incident OA were compared between fracture groups. RESULTS: The 95 women with incident knee osteophytes had significantly higher baseline spine BMD (1.01 gm/cm2 versus 0.95 gm/cm2, or 6.3%; P = 0.002) and significantly higher hip BMD (0.79 gm/cm2 versus 0.76 gm/cm2, or 3.9%; P = 0.02) than those without incident disease. For the 33 women whose osteophytes progressed, no difference was seen compared with nonprogressors in spine BMD, but hip BMD was modestly reduced (-2.5%). The 81 women who had incident JSN had nonsignificantly higher baseline spine BMD (3.0%), while no difference was seen for the 30 women whose JSN had progressed. For hip BMD, a nonsignificant increase was seen in those with incident JSN (1.3%), and a nonsignificant reduction was seen in those whose JSN progressed (-2.7%). One hundred forty-five women sustained peripheral fractures, mainly in the distal forearm (27.6%) and vertebrae (28.3%). Women with a peripheral fracture had a reduced risk of subsequently developing incident knee OA (odds ratio [OR] 0.30, 95% confidence interval [95% CI] 0.11-0.84). Although numbers were smaller, nonsignificant reductions in rates of incident OA were seen for those with distal forearm (OR 0.40, 95% CI 0.11-1.49) and vertebral (OR 0.20, 95% CI 0.07-1.61) fractures. CONCLUSION: These results confirm that for women who develop incident knee OA, defined by osteophytes, BMD is higher and of a magnitude similar to that shown in cross-sectional studies. Low BMD at the hip appears weakly related to progression. Women with previous fractures have less chance of developing OA, independent of BMD status. Although the mechanism for this action is unclear, these results suggest a possible common role of bone turnover and repair in the early manifestations of OA.

Bone Density↗

PubMed1983

Antithrombin III progressive function: a biochemical analysis.

Antithrombin III (AT III) was isolated by two procedures using polyethylene glycol-400 (PEG) precipitation as the first stage. The PEG supernatant (PEG-sup) was applied to a heparin-affinity chromatographic system and AT III-heparin cofactor (AT III-HCF) was isolated. The PEG precipitate (PEG-ppt) was separated by a Sephacryl S-200 column. Fractions were collected and those demonstrating maximum AT III antigen and progressive thrombin inhibition were pooled and reapplied to the washed Sephacryl S-200 column. Fractions were again collected and assayed via specific antisera for AT III, alpha 1-antitrypsin (alpha 1 AG), alpha 2-macroglobulin (alpha 2 M), and alpha 1-acid glycoprotein (alpha 1 AT). AT III antigen (AT III AGN) and progressive function were confined primarily to one peak containing virtually no alpha 2 M, a low level of alpha 1 AT, and moderate quantities of alpha 1 AG. The PEG-sup, PEG-ppt, AT III-HCF, and the fraction obtained after two passes across Sephacryl S-200 (S#2) were similar in that they showed reactivity with specific AT III antisera and demonstrated heparin cofactor activity. They differed, however, in that the PEG-sup and AT III-HCF demonstrated considerably reduced progressive antithrombin function assessed over 30 min. This function was present in the PEG-ppt and S#2 fractions and this progressive activity was potentiated by EDTA. AT III two-dimensional immunoelectrophoresis (2-DIE) in the presence of heparin of both the Sephacryl and heparin-affinity purified components were very different, with the Sephacryl-purified AT III AGN showing both a fast peak and a very prominent slow-moving hump. The AT III heparin affinity fraction showed primarily a fast component. Dilution of the S#2 and PEG-ppt fractions resulted in considerable loss of the progressive activity and also the slow-moving component on 2-DIE. On the basis of these observations, it is postulated that AT III purified by PEG precipitation is in an aggregated form and that aggregate formation and dissolution is associated with AT III progressive activity.

Antithrombin III↗

PubMed1995

Urinary myelin basic protein-like material as a correlate of the progression of multiple sclerosis.

In the multicenter, randomized, placebo-controlled trial of alternate-day injections of recombinant interferon beta-1b in relapsing-remitting multiple sclerosis (MS), urine specimens were collected periodically from all patients (n = 64) in two of the clinical test sites over the 2 years of the study. Urine specimens were also collected over two consecutive 24-hour periods from 43 patients from a third center. Urine samples were assayed for their content of myelin basic protein-like material (MBPLM), the level of which was correlated with clinical changes, cranial magnetic resonance imaging results, and the development of progressive disease. Concordant changes in creatinine values affected some of the relationships of MBPLM. The level of urinary MBPLM correlated with a chronic progressive course and with the number of lesions and the total lesion area on cranial magnetic resonance images. A rise in the level of urinary MBPLM appeared to antedate the clinical transition from a relapsing-remitting to a chronic progressive course. By chance, the randomized entry of patients led to significant differences in urinary MBPLM levels among the three treatment groups, thus precluding correlation studies of treatment effects. However, the patient group from which 24-hour specimens were collected showed that the patients with relapsing-remitting MS changing to a chronic progressive course, and more specifically, those patients with chronic progressive MS receiving placebo, had the highest values of urinary MBPLM. These findings indicate that urinary MBPLM may offer an objective test and possibly serve as a surrogate marker for detecting or predicting the failure of remission or the transition to a progressive phase of MS.

Analysis of Variance↗

PubMed1993

Marital status and the progression of functional disability in patients with rheumatoid arthritis.

OBJECTIVE: To determine if marital status is associated with differences in rates of progression of functional disability in patients with rheumatoid arthritis (RA). METHODS: A community cohort of 282 persons with RA was followed prospectively for up to 9.5 years. The progression of functional disability over time was determined using the Health Assessment Questionnaire Disability Index, which was completed by study participants every 6 months. RESULTS: At study entry, the Disability Index was 1.1 +/- 0.8 (mean +/- 1 SD) (possible range 0-3) among the 188 married participants and 1.3 +/- 0.9 among the 94 unmarried participants. Over time, the rate of progression of functional disability was generally higher among unmarried participants. However, the extent of this difference varied somewhat over the disease course, with rates of progression higher among unmarried than among married participants during years 5-7 and years 17-29 of RA. Overall estimated rates of progression, adjusted for the effects of other sociodemographic factors, were 0.03 Disability Index units per year in unmarried participants and 0.01 Disability Index units per year in married participants (P < 0.0001). CONCLUSION: Marriage, possibly reflecting the influence of social support, is associated with a lower rate of progression of functional disability in persons with RA.

Adult↗

PubMed1990

1,2-Dioctanoylglycerol accelerates or retards mitotic progression in Tradescantia stamen hair cells as a function of the time of its addition.

We have treated living, intact stamen hair cells from the spiderwort plant, Tradescantia virginiana, with 0.5 microgram/ml or 60 micrograms/ml 1,2-dioctanoylglycerol, a potent and permeant activator of protein kinase C, and have observed the rates of progression of mitosis from prophase through anaphase. We have found that in addition to the concentration used, the time of initial treatment with 1,2-dioctanoylglycerol defines the response by the cells. The cells rapidly undergo nuclear envelope breakdown when this diglyceride is added in very late prophase, 0 to approximately 8 min prior to the time of normal nuclear envelope breakdown. Anaphase onset occurs 28 min after nuclear envelope breakdown, rather than after the 33 min interval observed in untreated cells. Rapid progression through metaphase is also observed if cells are treated with 0.5 microgram/ml 1,2-dioctanoylglycerol during prometaphase, up to 15 min after nuclear envelope breakdown. The addition of 0.5 microgram/ml 1,2-dioctanoylglycerol in late metaphase, approximately 26 min after nuclear envelope breakdown, results in sister chromatid separation slightly ahead of its normal time, 33 min after nuclear envelope breakdown, and in precocious cell plate vesicle aggregation, 3-5 min earlier than that observed in untreated cells. Treatment of cells with 60 micrograms/ml of 1,2-dioctanoylglycerol at any point during the interval from 0 to approximately 5 min prior to nuclear envelope breakdown results in precocious entry into anaphase. If cells are treated with either 0.5 microgram/ml or 60 micrograms/ml 1,2-dioctanoylglycerol earlier than 20 min before nuclear envelope breakdown, they do not enter mitosis, but instead revert to interphase without dividing. When 1,2-dioctanoylglycerol is added at other times during mitosis, the rate of subsequent mitotic progression is dramatically slowed; the cells require greater than 55 min to progress from nuclear envelope breakdown to anaphase onset, though once in anaphase, the cells progress onward to cytokinesis at normal rates. Treatments o of cells with 1,3-dioctanoylglycerol at any point during prophase, prometaphase, or metaphase are without effect on the rate of subsequent mitotic progression. The shifts in response by cells treated at specific times with 1,2-dioctanoylglycerol during mid- and late metaphase may be indicative of the existence of one or more regulatory switch points (i.e., checkpoints) just prior to anaphase onset.

Anaphase↗

PubMed2004

Second-line treatment with carboplatin for recurrent or progressive oligodendroglial tumors after PCV (procarbazine, lomustine, and vincristine) chemotherapy: a phase II study.

BACKGROUND: The efficacy of second-line chemotherapy for patients with recurrent or progressive oligodendroglial tumors is limited. In the current study, the authors investigated the use of carboplatin as a second-line chemotherapeutic agent against these types of tumors. METHODS: Twenty-three patients with recurrent or progressive oligodendrogliomas or oligoastrocytomas after first-line PCV (procarbazine, lomustine, and vincristine) chemotherapy were enrolled in a single-institution Phase II study of second-line carboplatin chemotherapy. All patients had undergone surgery, and most also had undergone conventional radiotherapy. Carboplatin was administered at a dose of 560 mg/m2 intravenously every 4 weeks. Responses were evaluated according to conventional criteria, based on magnetic resonance imaging (MRI) findings. RESULTS: Three of 23 patients (13%) had partial responses, with neurologic improvement. Twelve patients (52%) had stable disease; in 2 of these 12 patients, a minor response was seen on MRI. Eight patients (35%) had progressive disease. The median time to tumor progression was 3 months for all patients and 9 months for patients who experienced responses to treatment. Progression-free survival rates at 6 and 12 months were 34.8% and 8.7%, respectively. Among the salvage treatment plans followed after carboplatin chemotherapy were supportive care alone, radiotherapy, third-line chemotherapy, and reoperation. The median survival duration from the start of carboplatin administration was 16 months. Myelotoxicity was severe, with Grade 3 or 4 thrombocytopenia in 60% of patients and Grade 3 or 4 neutropenia in 48% of patients. CONCLUSIONS: When administered according to a monthly schedule, carboplatin exhibited modest activity in adult patients with recurrent or progressive oligodendroglioma or oligoastrocytoma who experienced treatment failure after PCV chemotherapy; the current treatment regimen also was associated with severe toxicity. Further improvement of second-line chemotherapy for the patient group examined in the current study is necessary.

Adult↗

PubMed2004

Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors.

Hepatocyte nuclear factors (HNF) play a critical role in development of the liver. Their roles during liver tumorigenesis and progression of hepatocellular carcinomas (HCC) are, however, poorly understood. To address the role of HNFs in tumor progression, we generated a new experimental model in which a highly differentiated slow-growing transplantable mouse HCC (sgHCC) rapidly gives rise in vivo to a highly invasive fast-growing dedifferentiated variant (fgHCC). This in vivo model has allowed us to investigate the fundamental mechanisms underlying HCC progression. A complete loss of cell polarity, a decrease in cell-cell and cell-extracellular matrix (ECM) adhesion, elevation of telomerase activity, and extinction of liver-specific gene expression accompanies tumor progression. Moreover, cells isolated from fgHCCs acquired the ability to proliferate rapidly in culture. These alterations were coupled with a reduced expression of several liver transcription factors including HNF4, a factor essential for hepatocyte differentiation. Forced re-expression of HNF4alpha1 in cultured fgHCC cells reversed the progressive phenotype and induced fgHCC cells to re-establish an epithelium and reform cell-ECM contacts. Moreover, fgHCC cells that expressed HNF4alpha1 also re-established expression of the profile of liver transcription factors and hepatic genes that are associated with a differentiated hepatocyte phenotype. Importantly, re-expression of HNF4alpha1 in fgHCC reduced the proliferation rate in vitro and diminished tumor formation in congenic recipient mice. In conclusion, loss of HNF4 expression is an important determinant of HCC progression. Forced expression of this factor can promote reversion of tumors toward a less invasive highly differentiated slow-growing phenotype.

Animals↗

PubMed1998

Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity.

In hepatitis C virus (HCV) patients with persistently normal alanine transaminase (ALT), the progression rate of fibrosis is unknown. The aims of this study were: 1) to compare HCV patients with normal ALT (group I) with HCV patients with elevated ALT (group II) matched on independent factors associated with fibrosis; and 2) to assess the progression rate of fibrosis. One hundred two HCV patients were included in each group. Histological lesions were staged using the METAVIR score. We defined fibrosis progression per year as the ratio of the fibrosis stage in METAVIR units to the duration of infection. In group I, ALT values were normal, and lower than in group II (25 vs. 127 IU/L; P < .0001). HCV RNA was present less frequently in group I (66% vs. 97%; P < .0001). There were no significant differences for viremia and genotypes. Histological activities were lower in group I (0.6 vs. 1.38; P < .0001). The stage of fibrosis was lower in group I (0.95 vs. 1.8; P < .001). The median progression rate of fibrosis was lower in group I (0.05 vs. 0.13; P < .001). In group I, after exclusion of negative HCV-RNA patients, the median progression rate of positives remained lower (0.05 vs. 0.13; P < .001). In group I, all cirrhotic patients (n = 3) were heavy drinkers. HCV patients with normal ALT showed weaker histological activity and lower fibrosis scores, and the progression rate of fibrosis was twice as slow as in HCV patients with elevated ALT. In these patients, severe fibrosis was associated with high alcohol consumption.

Adolescent↗

PubMed1976

Inflammatory cells in solid murine neoplasms. II. Cell types found throughout the course of Moloney sarcoma regression or progression.

Regressing and progressing Moloney sarcomas, induced in BALB/c mice by the injection of cultured sarcoma cells (MSC)1, were sampled for histologic analysis and then disaggregated using mixtures of trypsin, collagenase and DNAse or collagenase and DNAse alone. The types of inflammatory cells (IC) found in resultant cell suspensions were determined 6, 11, 14 and 18 days post inoculation. Inflammatory infiltrates were composed almost exclusively of three cell types; neutrophils, T lymphocytes and macrophages. The extent to which each was found in tumors was related to the time post inoculation. Neutrophils were part of an early acute inflammatory response seen in both developing regressing and progressing sarcomas. The onset of regression was associated histologically with the appearance within tumors of a mononuclear inflammatory infiltrate. T lymphocytes and macrophages were the principal constituents. A higher percentage of T lymphocytes was recovered at all sampling times from regressing, compared to progressing, sarcomas. During development of the mononuclear inflammatory infiltrate there were relatively more large T cells in regressing, than in progressing tumors, and the percentage of macrophages was higher. Thereafter, the proportion of macrophages in the recovered cell population was approximately the same for both types of tumor. Such equality was more apparent than real, however, since IC were restricted to the peripheries of progressing sarcomas after the acute inflammatory phase, but continued to be found throughout regressing neoplasms. The effective ratio of macrophages and T lymphocytes to tumor cells therefore was much lower in progressing sarcomas than was suggested by percentage figures. The data presented support the concept that T lymphocytes are instrumental in causing the regression of Moloney sarcomas, possibly through interactions with macrophages.

Animals↗

PubMed1988

Inflammatory cell infiltrates in human melanoma at different stages of tumor progression.

Progression of human melanoma is associated with changes in antigenic phenotypes of tumor cells. To establish whether inflammatory infiltrates in progressing melanoma also change, we studied 146 cutaneous melanomas at different stages of progression. Monoclonal antibodies (MAbs) against lymphocyte and macrophage subpopulations, interleukin-2 receptor (IL-2 R), immune interferon (IFN-gamma), and the IFN-gamma-inducible, progression-associated melanoma antigens HLA-DR and gp89 were applied in situ. During the course of melanoma progression, decreased amounts of peritumoral T cells, IL-2 R-expressing lymphocytes and dermal T6+ dendritic cells were found, while increased numbers of intratumoral T cells, inflammatory (27E10+) and mature (25F9+) macrophages were associated with local progression of primary melanomas. In metastases, most infiltrate components except 25F9+ macrophages were rare. Positive correlations were observed between: (1) dermal T6+ cells and IL-2 R+ lymphocytes, and (2) presence of IFN-gamma in the infiltrate and HLA-DR and gp89 antigens on tumor cells. In all stages, HLA-DR expression on tumor cells was correlated with: (1) a shift towards T8+ lymphocytes in the infiltrates and (2) a loss of IL-2 R expression. Our data suggest mutual influences between melanoma cells and mononuclear cell infiltrates in situ.

HLA-DR Antigens↗