Clinical studies with angiogenesis inhibitors: biological rationale and challenges for their evaluation.
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Angiogenesis Inducing Agents↗
Biomedical subjects
G Gasparini
Publications and source records attributed to G Gasparini.
Clinical significance of cyclin D1 expression in patients with node-positive breast carcinoma treated with adjuvant therapy.
BACKGROUND: Experimental and clinical studies suggest that cyclin D1 is involved in transformation and tumour progression. However, there is little and contradictory data on the clinical significance of cyclin D1 in human invasive breast carcinoma. PATIENTS AND METHODS: We investigated whether the determination of cyclin D1 has prognostic value in a series of 180 patients with node-positive breast carcinoma and treated with adjuvant therapy with a median follow-up exceeding 6 years. We assessed cyclin D1 expression using the CDS-6 monoclonal antibody and a highly sensitive immunohistochemical technique. RESULTS: We found that most of the evaluable tumours (117 of 167; 70.1%) presented nuclear cyclin D1 staining and that its expression was significantly associated with both the hormone receptors (P = 0.009 and P = 0.005 for ER and PgR, respectively). Furthermore, 29 (17%) of 167 tumours had a weak (15 cases) or strong (9 cases) cytoplasmic cyclin D1 staining. In a subgroup of cases we also studied the amplification of the cyclin D1 gene and a moderate agreement between cyclin D1 nuclear overexpression assessed immunohistochemically and the gene amplification was found. In univariate analysis, cyclin D1 nuclear positivity was significantly associated with improved 6-year relapse-free survival (RFS) (P = 0.004), but not with overall survival (OS) (P = 0.12). The results of the Cox multivariate analysis (final model) indicate that cyclin D1 expression (P = 0.0049) as well as the number of involved nodes (P < 0.001) and tumour size (P = 0.036) are significant prognostic indicators for RFS. Only the number of involved nodes retained significance (P < 0.001) for OS in our series. The joint assessment of the variables considered in the final model of the multivariate analyses had a moderate prognostic capability as determined using the Harrell c statistic (c = 0.66 and 0.64 for RFS and OS, respectively). CONCLUSIONS: The patients with node-positive breast cancer who have a higher likelihood of gaining benefit from adjuvant therapy are those with tumours with cyclin D1 nuclear expression, small size and less than 3 metastatic nodes. Further studies are needed to verify the prognostic value of cyclin D1 in relation to different adjuvant treatments and to deepen the biological pathways that regulate its activation/ suppression in human breast carcinoma.
Adult↗
Spindle cells isolated from Kaposi's sarcoma-like lesions of BKV/tat-transgenic mice co-express markers of different cell types.
OBJECTIVE: To characterize murine spindle cells isolated from Kaposi's sarcoma-like skin lesions developed in BK virus (BKV)/tat-transgenic mice. METHODS: Kaposi's sarcoma-like spindle cells isolated from the lesions were propagated in vitro, and their phenotype was investigated using a panel of antibodies against various cell markers and angiogenic factors. Immunofluorescence and Western blot techniques were used. RESULTS: We observed co-expression of antigens specific for endothelial, smooth muscle and antigen-presenting cells, suggesting that cells from the TTB cell line represent poorly differentiated vascular precursors. Since TTB cells were derived from highly vascularized skin lesions, it is noteworthy that they synthesize a complex mixture of angiogenic factors, including fibroblast growth factor-2, vascular endothelial growth factor, placental growth factor, and hepatocyte growth factor. Due to their role in invasiveness and angiogenesis, we also observed the expression of urokinase plasminogen activator (uPA), uPA receptor, and plasminogen activator inhibitor-type 1 by TTB cells. CONCLUSIONS: Our results suggest that TTB cells share several features with human Kaposi's sarcoma spindle cells and can be a useful in vitro system to study the molecular mechanisms involved in Kaposi's sarcoma pathogenesis. Moreover, they synthesize a complex mixture of angiogenic factors and are growth-inhibited by the anti-angiogenic drug AGM-1470.
Animals↗
Amicrobial pustular dermatosis of cutaneous folds associated with autoimmune disorders: a new entity?
BACKGROUND: An unclassified amicrobial pustular dermatosis particularly affecting the main cutaneous folds, external auditory canals and scalp and coexisting with systemic lupus erythematosus has been recently described. OBJECTIVE: We studied 3 young females bearing such cutaneous manifestations in association with subacute cutaneous lupus erythematosus, celiac disease and various serum autoantibodies, respectively, in order to further characterize this possibly new entity. METHODS: Various routine and immunological laboratory tests, histopathologic and direct immunofluorescence examinations and in vitro studies of neutrophil function were performed in each patient. RESULTS: We reported our findings and compared our cases with the few others appearing in the literature. We documented an impaired neutrophil chemotaxis in 2 subjects, but neutrophil dysfunction does not seem to be one of the verifying criteria. CONCLUSIONS: All of these cases may represent a distinctive form in the clinicopathological spectrum of neutrophilic dermatoses (ND) because of the typical distribution and the close link with different autoimmune disorders. Cimetidine in combination with ascorbic acid can be indicated as an effective and safe alternative to the classic medications of ND, although the action of both drugs remains unexplained.
Adult↗
Microvascular count and prognosis in colorectal cancer.
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Colorectal Neoplasms↗
Skin ultrastructure after calcipotriol treatment: a transmission electron microscopic and freeze-fracture study on psoriatic patients.
Electron microscopic details in psoriatic skin during calcipotriol application are reported. Ten psoriatic patients (PASI score 3-14) were punch-biopsied on typical lesions before treatment and 2, 4 and 8 weeks after it. Two patients dropped out after 1 month because of lack of clinical response. Skin blocks were processed routinely for transmission electron microscopy and freeze-fracture techniques. The first modifications were the disappearance of fine intercellular granular material and the restoration of the granular layer. After 4 weeks desmosomes appeared in greater amounts than at baseline. Horny layer lipid vacuoles and remnants of nuclei as well as multilayering of the basal lamina were only focally observed. Dilatation of dermal capillaries was still seen even after 8 weeks. Freeze-fracture confirmed the data about the desmosomes and revealed a marked decrease of the gap junctions. Calcipotriol basically seems to act similarly to other antipsoriatic agents, though faster. The persistence of microvasculature dilatation could imply the need for long-term therapy.
Adult↗
Determination of angiogenesis adds information to estrogen receptor status in predicting the efficacy of adjuvant tamoxifen in node-positive breast cancer patients.
There is experimental and clinical evidence that angiogenesis is involved in breast cancer progression and metastasis. To investigate whether the determination of angiogenesis adds prognostic information to the estrogen receptor (ER) status, we studied a series of 178 node-positive breast cancer patients, with a median follow-up time exceeding 5 years, treated with adjuvant tamoxifen (TAM). We assessed angiogenesis by the quantification of the intratumoral microvessel density and the determination of the Chalkley score using light microscopy. Microvessels were immunostained using the anti-CD31 antibody. The other features studied were ER status and the conventional clinicopathological prognostic indicators. Results were pooled from two collaborating Centers using Chalkley counts to convert intratumoral microvessel density to a common quantification system. We found that Chalkley score was not associated with any other feature studied. In univariate analysis, Chalkley score was significantly predictive of both relapse-free survival (RFS) and overall survival (OS; P < 0. 00001 and P = 0.00004, respectively). Likewise, ER status, the number of metastatic axillary nodes, histological grading, and tumor size were significantly predictive for RFS and OS. Cox multivariate analysis showed that Chalkley score was the strongest significant independent predictor of outcome. For RFS, ER status, the number of metastatic nodes, and histological grading also retained significance. For OS, the number of metastatic nodes, tumor size, and histological grading were independent prognostic factors. The joint assessment of the above variables had a satisfactory prognostic capability, as found using the Harrel statistics (c = 0. 77). These results suggest the validity of using Chalkley counts to assess and compare angiogenesis for prognostic purposes between different Centers. We found that angiogenesis adds significant prognostic information to ER status in predicting the outcome of breast cancer patients treated with adjuvant TAM. In fact, irrespective of the ER status, the patients with highly angiogenic tumors had a poor outcome, even if treated with TAM. For these patients, the inhibition of angiogenesis with specific angioinhibitory drugs may be a promising new therapeutic strategy.
Breast Neoplasms↗
Re: Tumor angiogenesis as a prognostic assay for invasive ductal breast carcinoma.
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Breast Neoplasms↗
Value of head-up tilt testing potentiated with sublingual nitroglycerin to assess the origin of unexplained syncope.
This study was undertaken to assess the value of sublingual nitroglycerin administration during upright tilt as a simple practical test for the diagnosis of vasovagal syncope. To this purpose, 235 patients with syncope of unknown origin and no evidence of organic heart disease (110 men, mean age 52 +/- 20 years) and 35 asymptomatic control subjects underwent head-up tilt testing with nitroglycerin challenge. Patients and subjects were tilted at 60 degrees for 45 + 20 minutes; the initial 45 minutes were without medication and the final 20 minutes after 300 micrograms of sublingual nitroglycerin. During the drug-free phase of the test, 59 patients (25%) and no controls had a positive response. After drug administration, a positive response (syncope in association with sudden hypotension and bradycardia) occurred in 60 patients (26%) and in 2 controls (6%), whereas an exaggerated or false-positive response (minor or different symptoms in association with slowly increasing hypotension alone) was observed in 33 patients (14%) and in 5 controls (14%). We conclude that the sublingual nitroglycerin head-up tilt test is a useful tool to unmask the vasovagal origin of unexplained syncope in patients without organic heart disease. The addition of nitroglycerin to upright tilt allows the positive rate of passive tilting to be doubled (51% vs 25%) while maintaining a high specificity (94% vs 100%).
Administration, Sublingual↗
67-kDa laminin-receptor expression adds prognostic information to intra-tumoral microvessel density in node-negative breast cancer.
Experimental studies have shown that the 67-kDa laminin receptor (LRec) is an important molecule for the interaction of tumour cells with the extracellular matrix, and that it plays a role in the early steps of angiogenesis and in tumour invasion and metastasis. We performed a multi-parametric study in 171 node-negative breast cancers, followed for a median time of 6 years, to verify whether determination of the LRec provides prognostic information in addition to intra-tumoral microvessel density (IMD), a measure of tumour angiogenesis, and to other biological and conventional indicators. A positive association between LRec expression and high neovascularization was found, although it did not reach significance. LRec was not associated either with other biological markers (oestrogen receptor, progesterone receptor and p53 expression) or to the conventional prognostic features [menopausal status, tumour size, histological types, grading and peri-tumoral lymphatic vessel invasion (PLVI)]. In univariate analysis, IMD, p53, PgR, PLVI, grading and tumour size were significant prognostic indicators of relapse-free survival (RFS). LRec expression approached significance when considered as a dichotomous variable, after having selected the optimum cutoff of 10% to distinguish high-risk from low-risk patients. For overall survival (OS), tumour size and IMD (continuous variable) were significant prognostic factors, and p53 approached significance. In multivariate analysis for RFS, the joint variable LRec and vascularization was the strongest independent prognostic factor, followed by PgR, PLVI and p53. For OS, tumour size was the only independent prognostic indicator in this series.
Adult↗
Biological and clinical role of angiogenesis in breast cancer.
Angiogenesis, the process leading to the formation of new blood vessels, plays a central role in tumor progression of solid neoplasia. The switch from the avascular to the vascular phase is generally accompanied by rapid primary tumor growth and local invasiveness. Furthermore, angiogenesis is also necessary both at the beginning and at the end of the development of distant metastasis and is implicated in the phenomenon of dormant micrometastases. The angiogenic activity of both the primary tumor and its metastases is the result of the net balance between angiogenic peptides and natural inhibitors, and it is regulated by multiple biochemical and genetic mechanisms. In normal tissues of the adult, unlike invasive cancers, the angiogenic inhibitory pathway predominates. Several experimental and clinico-pathologic studies have confirmed that angiogenesis is specifically involved in transformation and progression of human breast cancer. In particular, clinicopathologic studies have found that the degree of vascularization of primary invasive human breast cancer is heterogeneous and correlates with the prognosis of patients. A number of antiangiogenic agents have been recently discovered, and some are under early clinical evaluation. Thus, angiogenic activity of the tumors represents a potentially novel anticancer therapeutic target. This issue of Breast Cancer Research and Treatment reports on the most relevant basic biological aspects of angiogenesis, on its clinical role in breast cancer prognosis, and on the implications of inhibition of angiogenesis for future novel anticancer therapeutic approaches.
Adult↗
Novel methods for the determination of the angiogenic activity of human tumors.
At present the most used method to quantify tumor angiogenesis in human solid tumors is the count of intratumoral microvessels in the primary lesion. This method requires the use of specific markers to vascular endothelium and of immunohistochemical procedures to visualize microvessels. Several studies have found that intratumoral microvessel density (IMD) determined in the primary tumor is significantly associated with metastasis and prognosis in some solid neoplasia, particularly in operable breast carcinoma. The subjective evaluation of IMD made by two observers at the microscope is rapid and of low cost, but presents some difficulties, mainly the identification of the most vascularized area ("hot-spot") within each tumor. This method can be improved upon to attain a better reproducibility among different pathologists. For example, the use of a multiparametric computerized image analysis system (CIAS) seems to be a promising tool to improve accuracy, feasibility and reproducibility of microvessel counts, although there are still some open technical problems to completely automate its use. Angiogenic activity is the result of a balance between angiogenic stimuli and angio-inhibition. Therefore the determination of angiogenic peptides and/or natural angiogenesis inhibitors in the tumor tissue, serum, or urine of cancer patients seems to be a promising alternative to microvessel counting. At present it is possible to determine the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and transforming growth factor beta using immunohistochemical methods. Serum and urine levels of bFGF can be assessed using an immunoenzymatic assay. Methods used to assess the expression and levels of urokinase-type plasminogen activator (uPA) or plasminogen activator inhibitor-1 (PAI-1) have also been developed, and correlate with angiogenic activity and prognosis of patients with breast cancer. Finally, some investigational methods to assess angiogenesis in vivo are presented and discussed. Angiogenesis is a very complex phenomenon. Thus it seems reasonable to hypothesize that its assessment by using concurrently several of the available methods may provide more valid, accurate, and comprehensive information on the angiogenic activity of each single tumor. For a reliable and reproducible assessment of angiogenesis for all of the assays, validation procedures and quality control protocols are mandatory.
Breast Neoplasms↗
Prognostic value of intratumoral microvessel density, a measure of tumor angiogenesis, in node-negative breast carcinoma--results of a multiparametric study.
In the present study we update previous results on the prognostic value of intratumoral microvessel density (IMD), determined immunocytochemically using the monoclonal antibody CD-31 and a standard streptavidin-immunoperoxidase technique, published in the J Clin Oncol 12:454-466, 1994. This study was undertaken in those 211 node-negative breast cancer (NNBC) cases of that series of which we had pathological material available to determine all the prognostic indicators. The median period of follow-up has been extended to 78 and 80 months for relapse-free survival (RFS) and overall survival (OS), respectively, and new biological indicators (i.e. Ki-67 labeling and 67 kDa laminin receptor expression) were included in the analysis. The main results obtained are: i) a confirmation that IMD is not associated with the other biological markers studied, i.e. expression of p53 protein, c-erbB-2 protein, 67 kDa laminin receptor, and cell kinetics; IMD was weakly associated only with histological grade (p = 0.053); ii) IMD remains a highly significant prognostic factor for RFS and OS (p < 0.0001 and p = 0.018, respectively) in univariate analysis; iii) in multivariate analysis on RFS, IMD (likelihood ratio test (LRT) = 30.16; p < 0.0001), 67 kDa laminin receptor (LRT = 9.80; p = 0.0017), the IMD/67 kDa laminin receptor interaction (LRT = 8.62; p = 0.0033), tumor size (LRT = 8.56; p = 0.0034), and p53 protein (LRT = 4.96; p = 0.025) are significant and independent prognostic indicators. For OS, only tumor size (LRT = 8.34; p = 0.0038), menopausal status (LRT = 5.16; p = 0.023), p53 protein (LRT = 4.37; p = 0.036), and IMD (LRT = 4.05; p = 0.044) retain a significant and independent prognostic value. The results of this study confirm the prognostic importance on RFS of the variables previously tested, but not of peritumoral lymphatic vessel invasion. A novel finding is that 67 kDa laminin receptor and the IMD/67 kDa laminin receptor interaction are also significant and independent variables. For OS, the results confirm that both IMD and tumor size are significant and independent variables. With prolonged follow-up the novel finding that emerges is the prognostic importance of menopausal status and p53 protein. This new information could be useful for a more accurate selection of high-risk NNBC patients who require careful follow-up and may benefit from adjuvant therapy.
Analysis of Variance↗
Italian multicenter clinical experience with endocardial defibrillation: acute and long-term results in 307 patients. The Italian Endotak Investigator Group.
This study presents the acute and long-term results of 307 patients (267 men, mean age 57.5 years, 205 suffering from coronary artery disease, mean left ventricular ejection fraction 33.3%) with malignant ventricular tachyarrhythmias who underwent attempted transvenous ICD implantation with the CPI Endotak lead system in 37 Italian centers. Transvenous ICD implantation was ultimately accomplished in 306 (99.7%) patients. These included 19 subjects with high (< 10 J below output energy of implanted device) defibrillation threshold (DFT) at implant. One hundred sixty-four patients (53%) were implanted with the endocardial lead alone, while 142 also received an SQ patch or SQ array. The mean DFT (not always step-down DFT) at implant was 16.9 +/- 5.7 joules; 15.3 +/- 5.2 joules with biphasic shock and 19.6 +/- 5.4 joules with monophasic shock; P < 0.0001. A significantly higher percentage of patients tested with a biphasic shock could be implanted with adequate safety margin and without an additional SQ patch or SQ array (98% and 81%, respectively). No perioperative deaths occurred. During the mean follow-up of 14.5 +/- 10.2 months, 140 patients (52%) received at least one appropriate shock. An inappropriate shock was observed in 26% of episodes. The 1- and 3-year actuarial incidence of sudden death was 2% and 4%, respectively, and that of total death was 10% and 20%, respectively. A pocket infection requiring ICD explantation occurred in 4 patients (1.4%) and an endocardial lead dislodgment in 11 patients (3.6%). Two patients (0.3%) showed a sensing pin disconnection and six patients (2.3%) had a lead insulation break. The results of this Italian multicenter trial indicate that the CPI Endotak lead system is a simple, safe, and reliable system for endocardial defibrillation. When compared to epicardial leads, it clearly reduces the perioperative mortality and morbidity, while maintaining a similar efficacy in preventing sudden death and terminating ventricular arrhythmias.
Actuarial Analysis↗
Tuberculosis verrucosa cutis which remained undiagnosed for forty-three years.
An unusual case of tuberculosis verrucosa cutis of the left lower limb in a 65-year-old woman is reported. The disease, arising on the plantar aspect of the foot in 1950, was correctly diagnosed by culture of Mycobacterium tuberculosis complex from a skin biopsy only in 1993. A spectacular improvement of the cutaneous lesions was achieved using combined therapy with isoniazide, rifampicin, ethambutol and pyrazinamide.
Aged↗
Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool.
PURPOSE: To review prognostic and therapeutic applications of angiogenesis research in breast carcinoma. METHODS: We reviewed the (1) biologic role of angiogenesis, particularly in transformation, progression, and metastasis of breast cancer; (2) methods to detect angiogenic activity in human pathology; (3) clinical studies relating clinical outcome of patients with breast cancer to the assessment of angiogenesis; (4) predictive value of angiogenesis for response to anticancer therapies; and (5) pharmacologic characteristics of current antiangiogenic drugs. RESULTS: There is mounting evidence that angiogenesis plays a relevant role in the biologic aggressiveness of breast cancer. Using either immunohistochemical or biochemical methods, several studies have shown a worse prognosis for those patients with tumors with high angiogenic activity. In some studies angiogenesis has an independent prognostic value. The most promising angiogenic inhibitors are under early-phase clinical evaluation in patients with tumors resistant to conventional therapies. Novel therapeutic strategies for breast cancer patients are presented and discussed. CONCLUSION: The majority of the retrospective studies show that angiogenesis is an important new prognostic indicator in early-stage breast carcinoma. This marker should be evaluated in prospective controlled clinical trials to demonstrate whether adjuvant therapies may improve the prognosis of those patients at high risk, eg, those with highly vascularized tumors. Since invasive breast carcinoma has a well defined stromal vascular component and produces angiogenic factors, it seems reasonable to postulate that this tumor may be one of the most responsive to angiogenesis inhibitors given alone or in combination with conventional anticancer treatments.
Breast Neoplasms↗
Microradiographic anatomy of the explanted rat colon.
The colon of 32 healthy Sprague-Dawley rats was studied microradiographically. The colonic arterial distribution of 18 rats was examined after injecting barium sulfate into the isolated aorta. The mucosal surface in 9 rats was studied using double-contrast technique after colon explantation. In 5 animals arterial and mucosal studies were carried out simultaneously. The radiographic thickness of the colonic wall was measured using a comparative microscope. The specimens were observed, photographed and examined histologically. Unlike the cecum and distal colon which, when insufflated, do not have mucosal folds, the proximal colon exhibits folds in an oblique direction corresponding to that of the arteries, and the colonic wall in this region is thicker. Comparison between arterial and mucosal microradiographic anatomy and wall thickness enables the proposition of a simple nontopographic division of the rat colon into cecum, proximal colon and distal colon.
Animals↗