Biomedical subjects
M Pavone-Macaluso
Publications and source records attributed to M Pavone-Macaluso.
Local microwave hyperthermia and intravesical chemotherapy as bladder sparing treatment for select multifocal and unresectable superficial bladder tumors.
PURPOSE: The role of a combined regimen of local hyperthermia and topical chemotherapy in patients with multifocal and recurrent superficial bladder tumors not curable by transurethral resection was evaluated in a neoadjuvant organ sparing clinical study. MATERIALS AND METHODS: A total of 19 patients with multifocal, superficial grades 1 to 3 bladder tumors that recurred after intravesical chemoprophylaxis or immunoprophylaxis underwent local combined administration of microwave induced hyperthermia and intravesical chemotherapy as a debulking approach. Due to extensive superficial involvement of the bladder walls complete transurethral resection of all tumors seemed technically unfeasible in all cases and radical cystectomy was considered the treatment of choice. Endovesical hyperthermia at 42.5 to 46C was delivered using the SB-TS 101 system, based on a microwave transurethral applicator that irradiates the bladder filled with a circulating solution of mitomycin C. Patients underwent 8 weekly 1-hour sessions on an outpatient basis without anesthesia. When possible, after treatment patients underwent transurethral resection of residual tumors and all suspicious areas. RESULTS: After treatment transurethral resection appeared to be feasible and curative in 16 patients (84%). Histological study revealed complete and partial responses in 9 (47%) and 7 (37%) cases, respectively. Due to extensive residual tumors radical cystectomy was performed in 3 patients (16%). At a median 33-month followup 8 superficial transitional tumor recurrences were documented and easily eradicated by transurethral resection or laser therapy in patients in whom the bladder had been saved. CONCLUSIONS: Microwave induced hyperthermia combined with intravesical mitomycin C seems to be a feasible, safe and elective approach for conservative treatment of multifocal and recurrent superficial bladder tumors when other treatment strategies have failed.
The fate of patients with locally advanced bladder cancer treated conservatively with neoadjuvant chemotherapy, extensive transurethral resection and radiotherapy: 10-year experience.
PURPOSE: We assess the results of bladder preservation for infiltrating bladder cancer. The potential for neoadjuvant chemotherapy followed by extensive transurethral resection and radiotherapy was evaluated in 40 patients with T2-T4a G2-G3 bladder carcinoma. MATERIALS AND METHODS: From 1983 to 1995, 40 patients with bladder cancer underwent bladder sparing treatment, consisting of neoadjuvant chemotherapy, extensive transurethral resection and radiotherapy. Most patients had T3G3 cancer. A deep transurethral resection biopsy was performed before and after chemotherapy, and an extensive transurethral resection was repeated at the end of radiotherapy. Of the patients 30 received cisplatin and methotrexate and 10 also received vinblastine. Total dose of radiotherapy was 60 to 65 Gy. Recurrent superficial tumors were treated transurethrally. Radical cystectomy was considered for persistent or recurrent invasive disease. RESULTS: Complete response occurred in 19 patients (47.5%) after chemotherapy, and in 8 patients after transurethral resection and radiotherapy (67.5%). Within 10 years 8 responding patients (30%) had local recurrences and 3 underwent cystectomy. Of the patients 14 (35%) are alive, including 13 with no evidence of disease (mean survival 65 months), 5 died of unrelated disease and 21 (52.5%) died of distant metastases (mean survival 28 months). Of the 21 patients 14 had residual tumor after radiotherapy, 3 presented with distant metastases after vesical infiltrating recurrence and 4 had distant metastases in the absence of locoregional recurrence. In 22 patients (55%) the bladder was salvaged. Patients with complete response to chemotherapy had a low risk for recurrent infiltrating tumors and metastases. CONCLUSIONS: Complete tumor control was maintained at 5 years in more than 50% of the patients treated conservatively. Bladder salvage is feasible in select patients.
[Conservative treatment of locally advanced bladder carcinoma: neoadjuvant chemotherapy, TUR and radiotherapy. Results in 40 patients].
PURPOSE: to assess the results of bladder preservation in infiltrating bladder cancer. The potential for neoadjuvant chemotherapy followed by extensive TUR and radiotherapy was investigated in 40 patients with T2-T4a G2-G3 bladder carcinoma. MATERIALS AND METHODS: from 1983 to 1995, 40 patients were submitted to bladder-sparing treatment consisting of neoadjuvant chemotherapy, extensive, TUR and radiotherapy. Most patients had T3G3 cancer. Cystectomy was not performed due to patient" choice in 29 cases (72.5%), for severe pulmonary or cardiovascular disease in disease in 9 patients (22.5) and age over 80 in 2 (5%) patients. A deep TUR-biopsy was performed before and after chemotherapy and an extensive TUR was repeated at the end of radiotherapy. In the first 30 patients chemotherapy consisted of 2-4 cycles of 70 mg/m2 cisplatin on fay 1, and 40 mg/m2 methotrexate on days 8 and 15. In the last 10 patients chemotherapy consisted of 3 cycles of CMV (100 mg/m2 cisplatin on day 2, 30 mg/m2 of vinblastine on days 1 and 8). Total dose of radiotherapy was 60-65 Gy. Recurrent superficial tumors were treated transurethrally. Radical cystectomy, when feasible, was considered for persistent or recurrent invasive disease. RESULTS: after chemotherapy, a clinical objective response was obtained in 27 patients (67.5%), 19 (47.5%) of whom showed a complete response. Thirteen (32.5%) patients showed no response and 5 (12.5%) progressed during chemotherapy. After extensive TUR of any residual mass and radiotherapy, a complete response was achieved in 6 patients who initially showed a partial response and in other 2 patients and stable disease after chemotherapy. Altogether, 27 patients (67.5%) presented had local recurrences, 3 patients underwent cystectomy. Fourteen patients (35%) are alive and 13 NED (65 months mean survival). Five patients died of unrelated disease. Twenty-one patients (52.5%) died of distant metastases (mean survival 28 months). Four patients presented distant metastases after vesical infiltrating recurrence and 4 patients had distant metastases in the absence of loco-regional recurrence. Twenty-two patients (55%) maintained an intact bladder. Patients with complete response to chemotherapy showed a low risk for developing recurrent infiltrating tumors and metastases. CONCLUSIONS: A complete tumor was maintained at 5 years in over 50% of the patients conservatively treated. Bladder salvage is feasible in selected patients.
Adjuvant chemotherapy for superficial transitional cell bladder carcinoma: long-term results of a European Organization for Research and Treatment of Cancer randomized trial comparing doxorubicin, ethoglucid and transurethral resection alone.
PURPOSE: We compared the efficacy of transurethral resection alone or transurethral resection followed by bladder instillations of doxorubicin or ethoglucid for 1 year in patients with superficial bladder carcinoma, and followed them long term for the incidence of progression to muscle invasion. MATERIALS AND METHODS: A total of 443 patients with superficial transitional cell carcinoma of the bladder was randomized. After randomization of 206 patients the control arm was closed to patient entry based on the results of an interim analysis showing a significant difference in favor of those receiving adjuvant chemotherapy. RESULTS: Final analysis of treatment results for recurrence included 432 patients at a median followup of 3.4 years for time to first recurrence, 5 years for analysis of time to invasion (Category T2 disease or worse) and 10.7 years for duration of survival. Time to first recurrence was significantly prolonged by both drugs compared to transurethral resection alone (doxorubicin versus transurethral resection alone p < 0.001 and ethoglucid versus control p < 0.001). Recurrence rate per year was 0.30 for both adjuvant treatment arms and 0.68 for the resection only group. Progression to muscle invasion was rare (15.1% of cases) and not apparently different in the 3 treatment arms. Of the 423 patients death from any cause in 199 and from malignant disease in 59 was not correlated with treatment. However, there was a strong correlation between death from malignant disease, and T category and tumor grade. CONCLUSIONS: In regard to time to first recurrence and recurrence rate per year this study indicates that adjuvant chemotherapy with doxorubicin and ethoglucid using the indicated schedule is superior to transurethral resection alone. However, progression in stage or survival was not influenced by the treatment regimen.
Evaluation and follow-up of patients with N1-3 M0 or NXM1 prostate cancer in phase III trials.
OBJECTIVES: The aim of this discussion is to review the design and conduct of phase III trials in metastatic prostate cancer, to seek ways of improving their study design, accuracy, relevance to clinical practice, acceptability to patients, and ease of participation by clinicians. We also aim to try to set uniform definitions for the evaluation of the different endpoints used in clinical trials on metastasized prostate cancer. METHODS: The work was started by correspondence between the participants in the group for the year before the consensus meeting. Two comprehensive questionnaires were circulated and the answers were distributed to all the members of the group. The statements were finalized during the consensus meeting. RESULTS: There were some differing opinions concerning the methods of evaluation of endpoints for follow-up, such as time to tumor progression and time to treatment failure. After the consensus conference, there were no major disagreements within the group. CONCLUSIONS: The aim of phase III trials is to influence clinical management. To obtain a credible result they require a sound statistical basis with appropriate power and encompassing patients from small urologic practices as well as large or academic institutions. However, deviation from routine practice may affect the accrual rate, and the trial procedure should therefore be as similar as possible to routine management. Trials inevitably involve extra work and cost. Both should be kept to a minimum to encourage participation and hasten a timely conclusion. It is mandatory to create uniform ways of designing and evaluating clinical trials in prostate cancer.
Expression of different 17beta-hydroxysteroid dehydrogenase types and their activities in human prostate cancer cells.
The 17beta-hydroxysteroid dehydrogenase (17betaHSD) enzyme system governs important redox reactions at the C17 position of steroid hormones. Different 17betaHSD types (no. 1-4) have been identified to date in peripheral human tissues, such as placenta, testis, and breast. However, there is little information on their expression and activity in either normal or malignant prostate. In the present work, we have inspected pathways of 17beta-oxidation of either androgen or estrogen in human prostate cancer cells (LNCaP, DU145, and PC3) in relation to the expression of messenger RNAs (mRNAs) for 17betaHSD types 1-4. These cell systems feature distinct steroid receptor status and response to hormones. We report here that high expression levels of 17betaHSD4 were consistently observed in all three cell lines, whereas even greater amounts of 17betaHSD2 mRNA were detected solely in PC3 cells. Neither 17betaHSD1 nor 17betaHSD3 mRNAs could be detected in any cell line. From a metabolic standpoint, intact cell analysis showed a much lower extent of 17beta-oxidation of both androgen [testosterone (T)] and estrogen [estradiol (E2)] in LNCaP and DU145 cells compared to PC3 cells, where a greater precursor degradation and higher formation rates of oxidized derivatives (respectively, androstenedione and estrone) were observed. Using subcellular fractionation, we have been able to differentiate among 17betaHSD types 1-4 on the basis of their distinct substrate specificities and subcellular localization. This latter approach gave rise to equivalent results. PC3 cells, in fact, displayed a high level of microsomal activity with a low E2/T activity ratio and approximately equal apparent Km values for E2 and T, suggesting the presence of 17betaHSD2. Dehydrogenase specific activity with both E2 and T was also detected, although at lower levels, in LNCaP and DU145 cells. No evidence for reductase activity could be obtained in either the soluble or microsomal fraction of any cell line. As comparable expression levels of 17betaHSD4 were seen in the three cell lines, 17betaHSD2 is a likely candidate to account for the predominant oxidative activity in PC3 cells, whereas 17betaHSD4 may account for the lower extent of E2 oxidation seen in both LNCaP and DU145 cells. This is the first report on the expression of four different 17betaHSD types in human prostate cancer cells. It ought to be emphasized that for the first time, analysis of different 17betaHSD activities in either intact or fractionated cells harmonizes with the expression of relevant mRNAs species.
[The Urologic Cooperative Group of the EORTC. Structure, scope, research, results].
The European Organization for Research and Treatment of Cancer (EORTC) was founded in 1962. The first urological group was French-speaking and concentrated particularly on testicular tumours. Shortly after, an English-speaking group started its activities in Yorkshire, with main emphasis on prostate cancer, and a "bladder cancer group" attracted many urologists from Belgium and other European countries. In 1976 all these groups were fused into a one new urological group of which M. Pavone-Macaluso from Palermo, Italy, secretary of the French-speaking group, was chosen as secretary and then chairman of the unified group, whereas Ph. Smith from Leeds, UK, chairman of the English-speaking group, was elected as chairman and later as secretary of the new group. The two "founding fathers" celebrated the 10th and 20th anniversaries of the foundation of the group respectively in Leeds in 1986 and in Palermo in 1996. Later chairman were L. Denis, Belgium; F. Schröder, The Netherlands; D. Newling, UK; F. Debruyne, The Netherlands and R. Hall, UK. A. van der Meijden, The Netherlands, will take over in 1997. The present secretary is A.V. Bono from Varese, Italy. The present structure of the group consists of a variety of working parties (disease-orientated groups), with special interest in a given pathology (such as prostate cancer, superficial or advanced bladder cancer, etc.) and of other committees (chemotherapy, quality of life, quality control). All the activities are coordinated by a Data Centre in Brussels, that is responsible for the statistical support. In its 20 years of activity the group has made many contributions of significance which have coincided with a number of changes in the urological oncology and have obtained international recognition. The paper analyses in detail the most significant of the group's achievements in the various fields of urological oncology.
Steroid-growth factor interaction in human prostate cancer. 2. Effects of transforming growth factors on androgen metabolism of prostate cancer cells.
The ability of human prostate cancer cells to metabolize androgens was assessed through administration of physiological concentration (0.5-10 nM) of tritiated testosterone (T) as precursor and one-step analysis of both T degradation and products' formation by reverse-phase HPLC and on-line radioactive detection after either 24 h or 72 h incubation. Overall, different prostate cancer cells degraded T quite differently, favoring alternatively reductive or oxidative metabolic pathways. In particular, both LNCaP and DU145 cells retained high levels of unconverted T, with a limited production of androstenedione and its 17-keto derivatives and relatively high amounts of dihydrotestosterone (DHT) and 3 alpha-androstanediol (3 alpha-diol). In contrast, PC3 cells quickly degraded T and exhibited high formation rates of androstenedione and 17-keto metabolites, while neither dihydrotestosterone nor 3 alpha-diol were detected after short or longer incubation times. The effects of both TGF alpha (50 ng/mL) and TGF beta 1 (5 ng/mL) on rates and direction of T metabolism were also explored. In LNCaP cells TGF alpha induced a significant (P < 0.04) decrease of the reductive metabolism of T with a corresponding enhancement of the oxidative pathway (P < 0.002), while TGF beta 1 did not significantly affect T metabolism. On the other hand, both reductive and oxidative pathways were only partially influenced by either growth factor in DU145 and PC3 cells, although TGF alpha significantly raised 5 alpha-androstanedione formation and reduced androsterone production in DU145 cells. All the above evidence was confirmed at both 24 h and 72 h or using increasing doses of TGF alpha and TGF beta 1, a peak activity of 50 ng/mL and 5 ng/mL, respectively, being generally encountered. Overall, our data suggest that TGFs may have a role in the growth regulation of hormone-responsive prostate tumor cells through changes of the intracellular contents of biologically active androgen metabolites.
Genitourinary group phase II study of chemotherapy in stage T3-4 N0-X M0 transitional cell cancer of the bladder: prognostic factor analysis.
The aim of this study was to examine prognostic factors for survival of patients with invasive bladder cancer who had received neoadjuvant chemotherapy followed by further treatment. From 1986 to 1990, 149 eligible patients with T3-4 N0-X M0 bladder cancer were entered into a phase II trial of neoadjuvant chemotherapy, consisting of cisplatin and methotrexate. Patients received two or four courses of chemotherapy, depending on the absence or presence, respectively, of a major clinical response after two courses. 136 patients were evaluable for clinical response after two courses of chemotherapy, and 75 patients were evaluable for pathological response after two or four courses. A multivariate analysis, based on pretreatment variables and the post-treatment variables, clinical response and pathological response, showed that performance status, tumour size and clinical response after two courses of chemotherapy were the only independent prognostic factors for all eligible patients. A second multivariate analysis in the selected subgroup of patients, who underwent a cystectomy, showed that the G-cagetory and pathological response were the only independent prognostic factors. In conclusion, in this group of patients, the response to chemotherapy was a strong and independent prognostic factor in addition to other independent variables. However, it was not accurate or strong enough to allow an impact on the choice of locoregional therapy.
Results of conservative treatment (transurethral resection plus adjuvant intravesical chemotherapy) in patients with primary T1, G3 transitional cell carcinoma of the bladder.
OBJECTIVES: To evaluate a selected population of 50 consecutive patients with primary T1, G3 bladder transitional cell carcinoma in the absence of carcinoma in situ (Tis) treated with a bladder-sparing approach. METHODS: Between January 1983 and December 1992, all patients were treated by transurethral resection (TUR) plus adjuvant intravesical chemotherapy over 1 year. In most cases, doxorubicin, epirubicin, and mitomycin were used alone or in combination. RESULTS: At a mean follow-up period of 52 months (range, 18 to 126), 16 of 50 patients (32%) showed a recurrent superficial tumor. The recurrent lesion was of Stage T1 in 11 (22%) cases, but was a T1, G3 tumor only in 5 cases (10%). In 2 additional patients (4%) a Tis developed during the observation period after TUR. The mean interval between TUR and first recurrence was 14.6 months (range, 3 to 38). At a mean time of 17 months after the initial TUR, 3 patients (6%) underwent a radical cystectomy due to a progression in T category and 3 additional patients (6%) developed distant metastases at a mean time of 23 months after TUR. In brief, 84% of the patients are alive and tumor-free. Five patients (10%) died of bladder cancer with a mean follow-up of 52 months. CONCLUSIONS: If no concomitant Tis exist, a conservative approach is a legitimate option as an initial treatment of patients with primary T1, G3 bladder tumors.
Epidemiology, prevention and screening for prostate cancer.
Prostate cancer is a growing social problem. The economical impact is high and is likely to become greater in future years, not only because the number of patients diagnosed with prostatic neoplasias is increasing steadily, but also because of the promotion of screening programmes and the rise in the number of surgical procedures available. It can be concluded that, at the present stage, widespread implementation of screening cannot be recommended. The answer to the question of screening can only be provided by large randomised trials, comparing either screening versus no screening, or early versus delayed treatment in patients in whom early cancer is detected by screening.
Factors affecting recurrence and progression in superficial bladder tumours.
Prognostic factors in superficial bladder tumours are highly correlated with each other. In this study, their relative importance is examined and grouping of patients in three different prognostic groups suggested. 576 patients (from EORTC protocols 30790 and 30782) were analysed. They have been followed from 3 months to 8.6 years with a median of 4 years. 76 patients developed an invasive tumour (> or = T2); the shortest time to invasion was 12 weeks, the longest was 6.6 years. Time from invasion to death ranged from 3 weeks to 4.4 years with a median of 2 years. Prognostic factors contributing to recurrence, invasion and survival were investigated: age, sex, size of largest tumour, number of tumours, T-category, G-grade, time from diagnosis (years), prior recurrence rate/year, site of involvement. The relative importance of these factors was measured by performing a multivariate analysis based on Cox's proportional hazards regression model. Based on the most important prognostic factors and their association with invasion and death, an index was computed reflecting the risk of both invasion and death due to malignant disease, respectively. The index was used to assign patients to one of three prognostic groups. Three main factors determined patient's prognosis: tumour size, G-grade and prior recurrence rate/year. The model coefficients for invasion were 0.51 (recurrence rate < 1/year, 1-3/year, > 3/year), 84 (grade 1, 2, 3), 0.48 (size < 1.5, 1.5-3, > 3 cm) and for death due to malignant disease 0.89 (recurrence rate), 0.73 (grade) and 0.44 (size), respectively. Risk groups are suggested based on the index. Additional treatment in patients with superficial transitional cell carcinoma of the bladder may be decided depending on the risk group to which the patient belongs.
Is there a role for recombinant tumor necrosis factor alpha in the intravesical treatment of superficial bladder tumors?--a phase II study.
Clinical use of recombinant tumor necrosis factor-alpha is strongly limited by its severe toxicity, mainly cardiovascular, when systemically administered. Recent studies suggest that topical (intrapleural, intraperitoneal, intratumoral) administration is free of significant toxicity. Human recombinant tumor necrosis factor-alpha was administered intravesically, at a dose of 500 mg dissolved in 30 ml of phosphate buffer (pH 7.6-7.8) plus 0.25% human albumin, weekly for two months to 18 patients with papillary transitional cell carcinoma of the bladder. Of the 15 evaluable patients, four (26%) achieved a complete response. Systemic and local tolerability were excellent.
What are the risks of cystectomy and the advances in perioperative care?
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Androgen receptors and hormone sensitivity of a human prostatic cancer cell line (PC-3) are modulated by natural beta-interferon.
Androgen receptors are expressed at a low level in the cell line PC-3, which does not respond to either androgens or antiandrogens. If these cells are exposed to natural beta-interferon (beta-IFN) a reduction in cell growth and an increase in androgen receptors, evaluated by both biochemical and immunocytochemical techniques, occur. This increase seems not to be related to a selective block of PC-3 in any phase of the cell cycle. Pretreatment with beta-IFN determines in PC-3 cells a partial responsiveness to the androgen dihydrotestosterone as reflected by the increase in cell number. Moreover, the antiandrogen hydroxyflutamide shows agonistic properties by increasing the cell number of PC-3 cells pre-exposed to beta-IFN. When the antiandrogen is tested in combination with interferon, it produces a reduction in the beta-IFN-induced inhibition of cell growth. It is not known whether these unexpected effects are due to the increase in androgen receptors or to other mechanisms.
Steroid-growth factor interaction in human prostate cancer. 1. Short-term effects of transforming growth factors on growth of human prostate cancer cells.
In order to better define potential mechanisms of growth regulation in human prostate cancer cells, we have compared biological responses (such as short-term response to both transforming growth factor alpha and beta; TFG alpha and TFG beta) in relation to hormone sensitivity of LNCaP, DU145, and PC3 cells. Androgen receptor (AR) and epidermal growth factor receptor (EGF-R) content of each cell line was also investigated. In addition, expression of EGF, TGF alpha, and TGF beta was evaluated through immunofluorescent staining. Growth of androgen non-responsive PC3 cells was stimulated by TGF alpha (about 35%) and inhibited by TGF beta (more than 50%), with respect to controls, after 48 h exposure. Conversely, AR-positive, hormone-responsive LNCaP cells proved to be poorly sensitive, at least short-term, to either growth factor. Furthermore, high levels of both EGF-R and TGF alpha, and a fairly high amount of EGF, were found in DU145 cells and, to a lesser extent, in LNCaP cells; in contrast, PC3 cells exhibited low expression levels of both receptors (EGF-R) and ligands (EGF, TGF alpha), but displayed remarkable TGF beta binding and relatively high levels of endogenous TGF beta. Overall, these results suggest a differential sensitivity to TGF alpha and TGF beta by prostate cancer cells; TGF alpha response seems not to be proportional to the EGF-R content of individual cell lines.
Steroid receptors in prostate cancer tissues and cells: pathophysiology, problems in methodology, clinical value and controversial questions.
This paper reviews basic and clinical aspects of human prostate cancer, with special regard to steroid hormones and growth factors, their receptors and the use of these tools in clinical practice. Unlike other endocrine-related tumours, such as breast and endometrial cancer, human prostatic carcinoma has distinctive features that crucially hinder its definition in terms of both biological potential and clinical course. Failure of androgen receptors to represent helpful discriminants for both prognosis and treatment of prostate cancer patients may depend upon methodological pitfalls and/or the heterogeneous composition of most tumour tissues. The former involve either technical problems (tissue sampling and storage, assay procedures) or biochemical and biological points (heterogeneity and functional integrity of steroid binding sites, subcellular and tissue distribution of steroid receptors). The latter mostly concern the unique feature of both normal and diseased prostate gland to present regional diversities in hormone sensitivity and steroid receptor content. Another important area of interest resides in the potential role played by stromal-epithelial interaction in the regulation of growth and function of prostate epithelial cells. In this respect, continued growth of androgen-dependent prostate cancer cells is achieved through intricate pathways where mesenchymal steroid-induced polypeptide growth factors may act in a paracrine/autocrine fashion to mediate androgen action on tumor epithelial cells. In particular, epidermal growth factor (EGF) and transforming growth factor-a (TGFa) may serve as androgen intermediaries in the proliferative control of prostate epithelial cells, but may also be involved in androgen-independent autocrine epithelial cell growth. Clinical correlations of androgen receptors in human prostatic carcinoma have been insofal disappointing. Biochemical or histochemical assays have failed to satisfactorily predict prognosis and response to endocrine therapies of patients. This recalls problems in both methodologies and tissue suitability and points to the need of prolonged follow-up studies wherein special care is placed in sampling conditions, identification of high-affinity sites of steroid binding and selection of threshold values for receptor concentrations. Assay of the EGF receptors might provide additional contribution for a deeper inspection of the biological nature of prostate tumour tissues and help in selecting more appropriate individual-based therapeutic strategies.