Biomedical subjects

Mario Lise

Publications and source records attributed to Mario Lise.

At least 19 recordsLinked to original sources

PubMed2006

Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease.

BACKGROUND: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. PATIENTS AND METHODS: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement <or=50%, normal liver function, and previous failure of at least one conventional treatment. IHP was performed under hyperthermic conditions with melphalan (1.5 mg/kg body weight). Completeness of vascular isolation of the liver and drug distribution volumes of the perfusion circuit were assessed by a radiolabeled albumin-based method. Drug concentrations in perfusate and plasma were measured by means of high-performance liquid chromatography (HPLC). RESULTS: Twenty patients with unresectable liver metastases underwent IHP. No intraoperative mortality occurred. Treatment-related systemic toxicity was minimal and reversible. Three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Other six patients had significant (grade 3-4) but transitory hepatic toxicity. Complete and partial responses were observed in three and nine out of 17 evaluable patients, respectively (overall response rate = 70%). The pharmacokinetics study showed a 3% mean perfusate-to-plasma drug leakage (range 1-6%). Logistic regression analysis showed that drug concentration in the perfusate circuit, but not preoperative tests, significantly and independently correlated with hepatic toxicity (P = 0.028). CONCLUSIONS: Following melphalan-based IHP, objective tumor regression could be observed in a remarkable percentage of patients refractory to standard treatments. However, hepatic toxicity and related mortality were significant. Our findings suggest that drug dosage personalization based on the measurement of drug distribution volumes might minimize hepatic toxicity.

Adult↗

PubMed2006

Gene expression profile of primary gastric cancer: towards the prediction of lymph node status.

BACKGROUND: The identification of gastric tumors associated with a higher risk of lymph node metastasis could help surgeons select patients who may benefit from extended lymph node dissection. The aim of this study was to screen the genome in the search of primary gastric cancer gene expression profiles that might predict lymph node status. METHODS: The gene expression profile was evaluated in frozen tumor samples obtained from 32 patients with primary gastric adenocarcinomas. The array consisted of a duplicated spot panel of 5,541 human genes. To classify node-positive (N+) and node-negative (N-) cases, a logistic regression model was fitted optimizing the Akaike Information Criteria after a stepwise gene selection. The accuracy was evaluated by means of leave-one-out cross validation. RESULTS: All patients underwent radical gastrectomy and extended lymphadenectomy. Of all the cases, 21 were N+ and 11 demonstrated no lymph node involvement (N-). After quality filtering, the analysis of variance selected a set of 136 genes potentially correlated with nodal involvement (P value <.05). Of these 136 genes, 5 were differentially expressed (adjusted P value <.05). After a stepwise gene selection, only three genes (Bik, aurora kinase B, eIF5A2) were retained in the logistic model, which could correctly predict lymph node status in 30 of 32 cases. CONCLUSIONS: If our findings were confirmed, the identified gene pattern might be used to tailor the extent of lymph node dissection on a single patient basis.

Biomarkers, Tumor↗

PubMed2006

Support vector machine learning model for the prediction of sentinel node status in patients with cutaneous melanoma.

BACKGROUND: Currently, approximately 80% of melanoma patients undergoing sentinel node biopsy (SNB) have negative sentinel lymph nodes (SLNs), and no prediction system is reliable enough to be implemented in the clinical setting to reduce the number of SNB procedures. In this study, the predictive power of support vector machine (SVM)-based statistical analysis was tested. METHODS: The clinical records of 246 patients who underwent SNB at our institution were used for this analysis. The following clinicopathologic variables were considered: the patient's age and sex and the tumor's histological subtype, Breslow thickness, Clark level, ulceration, mitotic index, lymphocyte infiltration, regression, angiolymphatic invasion, microsatellitosis, and growth phase. The results of SVM-based prediction of SLN status were compared with those achieved with logistic regression. RESULTS: The SLN positivity rate was 22% (52 of 234). When the accuracy was > or = 80%, the negative predictive value, positive predictive value, specificity, and sensitivity were 98%, 54%, 94%, and 77% and 82%, 41%, 69%, and 93% by using SVM and logistic regression, respectively. Moreover, SVM and logistic regression were associated with a diagnostic error and an SNB percentage reduction of (1) 1% and 60% and (2) 15% and 73%, respectively. CONCLUSIONS: The results from this pilot study suggest that SVM-based prediction of SLN status might be evaluated as a prognostic method to avoid the SNB procedure in 60% of patients currently eligible, with a very low error rate. If validated in larger series, this strategy would lead to obvious advantages in terms of both patient quality of life and costs for the health care system.

Artificial Intelligence↗

PubMed2006

Multivariate analysis approach to the plasma protein profile of patients with advanced colorectal cancer.

The aim of the present study was to identify the pattern of plasma protein species of interest as markers of colorectal cancer (CRC). Using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS), the plasma protein profile was determined in nine stage IV CRC patients (study group) and nine clean-colon healthy subjects (control group). Multivariate analysis methods were employed to identify distinctive disease patterns at protein spectrum. In the study and control groups, cluster analysis (CA) on the complete MALDI-MS spectra plasma protein profile showed a distinction between CRC patients and healthy subjects, thus allowing the identification of the most discriminating ionic species. Principal component analysis (PCA) and linear discriminant analysis (LDA) yielded similar grouping results. LDA with leave-one-out cross validation achieved a correct classification rate of 89% in both the patients and the healthy subjects.

Adenocarcinoma↗

PubMed2006

5-fluorouracil and weekly oxaliplatin combined with radiotherapy for locally advanced rectal cancer: surgical complications and long-term results.

BACKGROUND: We undertook this study to evaluate early surgical complications and long-term results after preoperative radiotherapy and chemotherapy (RCT) using 5-fluorouracil (5-FU) and oxaliplatin (OXA) for rectal cancer. METHODS: Forty six TNM stage II-III rectal cancer patients were studied, who were given preoperative RT (50.4 Gy/28 fractions) combined with 5-FU (200-225 mg/m(2)/day by continuous venous infusion) and weekly OXA (25-60 mg/m(2)). Major complications and reoperations were recorded overall, whereas outcome analyses were performed only for patients who received the recommended regimen dosage. RESULTS: Forty three patients (M:F, 25:18; median age 59 years) were available for analysis. All patients received the planned RT dose. There were no postoperative deaths; seven patients had early major surgical complications, four requiring re-operation. One additional patient had a second surgical procedure due to a duodenal fistula complicating the resection of an aortic aneurysm performed concomitantly with rectal cancer surgery. At a median follow-up of 49 months, two of the 23 patients treated at the recommended doses developed recurrence (one local, and one local and distant), and two died of cancer progression. Following the Kaplan-Meier method, the estimated 5-year overall and disease-free survival rates were 92 and 89%, respectively. CONCLUSIONS: The preoperative RCT regimen used in the present study incurs a low rate of recurrence with an acceptable surgical morbidity.

Adult↗

PubMed2006

A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation.

OBJECTIVE: The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy. BASIC METHODS: Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data. MAIN RESULTS: Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype. CONCLUSIONS: Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy.

Adenocarcinoma↗

PubMed2005

Colorectal liver metastasis: towards the integration of conventional and molecularly targeted therapeutic approaches.

Radical surgery currently represents the only treatment with curative potential for patients with colorectal cancer (CRC) liver metastases. Unfortunately, only a minority of cases is eligible for hepatic resection and many patients still develop recurrent disease, which underscores the need for more effective adjuvant treatments. In case of unresectable disease, locoregional therapeutic strategies can obtain significant tumor regression/local disease control rates, but there is no definitive evidence of their effect on patients' survival. In regards to systemic chemotherapy, the conduction of randomized controlled trials has led to a substantial progress in terms of both tumor response and survival rates. Despite these results, most patients ultimately die of their disease due to hepatic and/or extra-hepatic cancer progression. Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of patients with metastatic CRC. The elucidation of CRC biology is paving the way to the development of molecularly targeted strategies, and results from controlled clinical trials have already demonstrated that some agents targeting tumor-specific molecules can significantly improve the therapeutic efficacy of conventional antineoplastic drugs. The dissection of the molecular mechanisms of CRC metastatization and tumor/host interactions will not only accelerate the development of more effective and less toxic anticancer strategies but also will allow for the personalization of the therapeutic regimen according to the molecular features of individual patients and their tumors. Only the broader clinical implementation of these novel molecular oncology findings and the optimal integration of conventional and molecularly targeted therapeutic approaches will enable clinicians to provide patients with a better chance of cure.

Antineoplastic Agents↗

PubMed2005

Kinase substrate protein microarray analysis of human colon cancer and hepatic metastasis.

BACKGROUND: Liver metastases represent the major determinant of survival in patients with colorectal cancer (CRC). In cases with unresectable liver disease, more effective agents are needed, since chemotherapy achieves median survival of only 15 months. Protein kinases coordinate complex functions that are often disregulated in cancer and are therefore considered important targets for molecular therapeutics. In this study, we investigated the phosphoproteomic status of different protein kinases in primary CRC and in liver metastases. METHODS: The status of 29 key endpoints was evaluated using reverse phase protein array on laser capture microdissected neoplastic cells from five primary CRCs without metastases, three patient-matched primary CRCs and synchronous liver metastases and five CRC metachronous liver metastases. RESULTS: Unsupervised hierarchical two-way clustering analysis showed an entirely different phosphoproteomic profile in primary CRCs compared to liver metastases. This difference was observed also in primary and metastatic patient-matched lesions. CONCLUSIONS: Our findings of different signaling pathways between primary and metastatic CRC suggest a possible microenvironment effect, and emphasize the need to perform molecular network analysis of metastatic tissue when molecular targeting is considered.

Cluster Analysis↗

PubMed2005

Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma.

Metastatic spread to the liver is the major contributor to mortality in patients with colorectal carcinoma (CRC). In order to seek for gene expression patterns associated with metastatic potential in primary CRC, we compared the transcriptional profiles of 10 radically resected primary CRCs from patients who did not develop distant metastases within a 5-year follow-up period with those of 10 primary/metastatic tumor pairs from patients with synchronous liver metastases. To focus selectively on neoplastic cells, the study was conducted on laser-microdissected bioptic tissues. Arrays of 7,864 human cDNAs were utilized. While a striking transcriptional similarity was observed between the primary tumors and their distant metastases, the nonmetastasizing primary tumors were clearly distinct from the primary/metastatic tumor pairs. Of 37 gene expression differences found between the 2 groups of primary tumors, 29 also distinguished nonmetastasizing tumors from metastases. The gene encoding for mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N-acetyl-glucosaminyl-transferase (GnT-IV) became significantly upregulated in primary/metastatic tumor pairs (p < 0.001). GnT-IV upregulation was confirmed by RT-PCR. These data support the existence of a specific transcriptional signature distinguishing primary colon adenocarcinomas with different metastatic potential, the further pursuit of which may lead to relevant clinical and therapeutic applications.

Adenocarcinoma↗

PubMed2005

Hyperthermic isolated perfusion with low-dose tumor necrosis factor alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcomas.

BACKGROUND: Tumor necrosis factor (TNF)-alpha-based hyperthermic isolated limb perfusion (HILP) is one of the most active available approaches for locally advanced soft tissue sarcomas (STS) of the limbs. The aim of this study was to investigate the anticancer activity of a novel drug regimen including doxorubicin (DXR) and low-dose TNF-alpha. METHODS: HILP with low-dose TNF-alpha (1 mg) and DXR (8.5 mg/L of limb volume) was given to 21 patients with limb-threatening STS: 14 had primary and 7 had recurrent STS, most of which were high grade (grade 1, n = 3; grade 2, n = 6; grade 3, n = 12). Resection of the tumor remnant was performed 6 to 8 weeks after HILP. TNF-alpha concentrations in plasma and perfusate were measured throughout perfusion. RESULTS: A major tumor response was observed at histology and clinical evaluation in 90% and 62% of patients, respectively. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 71% and 81% of cases, respectively. Fourteen patients had moderate regional toxicity, which was resolved in all cases. One patient had severe limb toxicity, which did not require amputation. Systemic side effects were minimal, and there were no postoperative deaths. The perfusate/plasma area under the curve ratio for TNF-alpha was 56. CONCLUSIONS: HILP with low-dose TNF-alpha and DXR seems to be an active neoadjuvant drug regimen against limb-threatening STS. This therapeutic approach can achieve high limb-sparing surgery rates with acceptable local and negligible systemic toxicity.

Adult↗

PubMed2005

Role of axillary sentinel lymph node biopsy in patients with pure ductal carcinoma in situ of the breast.

BACKGROUND: Sentinel lymph node (SLN) biopsy is an effective tool for axillary staging in patients with invasive breast cancer. This procedure has been recently proposed as part of the treatment for patients with ductal carcinoma in situ (DCIS), because cases of undetected invasive foci and nodal metastases occasionally occur. However, the indications for SLN biopsy in DCIS patients are controversial. The aim of the present study was therefore to assess the incidence of SLN metastases in a series of patients with a diagnosis of pure DCIS. METHODS: A retrospective evaluation was made of a series of 102 patients who underwent SLN biopsy, and had a final histologic diagnosis of pure DCIS. Patients with microinvasion were excluded from the analysis. The patients were operated on in five Institutions between 1999 and 2004. Subdermal or subareolar injection of 30-50 MBq of 99 m-Tc colloidal albumin was used for SLN identification. All sentinel nodes were evaluated with serial sectioning, haematoxylin and eosin staining, and immunohistochemical analysis for cytocheratin. RESULTS: Only one patient (0.98%) was SLN positive. The primary tumour was a small micropapillary intermediate-grade DCIS and the SLN harboured a micrometastasis. At pathologic revision of the specimen, no detectable focus of microinvasion was found. CONCLUSION: Our findings indicate that SLN metastases in pure DCIS are a very rare occurrence. SLN biopsy should not therefore be routinely performed in patients who undergo resection for DCIS. SLN mapping can be performed, as a second operation, in cases in which an invasive component is identified in the specimen. Only DCIS patients who require a mastectomy should have SLN biopsy performed at the time of breast operation, since in these cases subsequent node mapping is not feasible.

Adult↗

PubMed2005

Relationship between pathologic T-stage and nodal metastasis after preoperative chemoradiotherapy for locally advanced rectal cancer.

BACKGROUND: We investigated the relationship between pathologic T-stage and mesorectal metastases after preoperative chemoradiotherapy (CRT) for clinical stage II to III rectal carcinoma. METHODS: The records of consecutive patients with clinical stage II to III carcinoma of the mid or low rectum who underwent surgery after CRT were reviewed. Indications for preoperative CRT were cancer up to 11 cm from the anal verge, Eastern Cooperative Oncology Group performance status of 0 to 2, age 18 to 75 years, and clinical tumor-node-metastasis stage II or III. RESULTS: The study group consisted of 235 patients (148 men and 87 women; median age, 61 years). The pretreatment tumor-node-metastasis stage was as follows: I, n = 1; II, n = 96; and III, n = 138. Radiotherapy was delivered at a median dose of 50.4 Gy. A pathologic complete response on the rectal wall was found in 24% of patients, and nodal metastases were found in 20% of patients. According to the pT stage, the rate of node positivity was 2% for pT0, 15% for pT1, 17% for pT2, 38% for pT3, and 33% for pT4 cases. At multivariate analysis, the best model for predicting pathologic node involvement included young age, positive pretreatment N status, and pT status. On considering pT stage alone, the odds ratio was in the region of 10 for pT1/2 and >20 for pT3/4 patients. CONCLUSIONS: In patients with pT0 after preoperative CRT for clinical stage II to III mid or low rectal cancer, the risk of nodal metastases is very low. More conservative surgery (local excision) may be considered in these cases.

Adult↗

PubMed2005

Targeted therapy for colorectal cancer: mapping the way.

In spite of the significant advances in conventional therapeutic approaches to colorectal cancer (CRC), most patients ultimately die of their disease. Dissecting the molecular mechanisms underlying CRC progression will not only accelerate the development of novel cancer-selective drugs but will also enable the therapeutic regimen to be personalized according to the molecular features of individual patients and tumors. Here, we report on the novel insights into CRC biology that are paving the way to the development of molecular therapies and summarize the results from recent clinical trials demonstrating that agents targeting tumor-specific molecular derangements can significantly improve the therapeutic efficacy of conventional chemotherapy. Only a broader clinical implementation of these concepts will provide patients with CRC the best chance of a cure.

Angiogenesis Inhibitors↗

PubMed2005

DNA array-based gene profiling: from surgical specimen to the molecular portrait of cancer.

Cancer is a heterogeneous disease in most respects, including its cellularity, different genetic alterations, and diverse clinical behaviors. Traditional molecular analyses are reductionist, assessing only 1 or a few genes at a time, thus working with a biologic model too specific and limited to confront a process whose clinical outcome is likely to be governed by the combined influence of many genes. The potential of functional genomics is enormous, because for each experiment, thousands of relevant observations can be made simultaneously. Accordingly, DNA array, like other high-throughput technologies, might catalyze and ultimately accelerate the development of knowledge in tumor cell biology. Although in its infancy, the implementation of DNA array technology in cancer research has already provided investigators with novel data and intriguing new hypotheses on the molecular cascade leading to carcinogenesis, tumor aggressiveness, and sensitivity to antiblastic agents. Given the revolutionary implications that the use of this technology might have in the clinical management of patients with cancer, principles of DNA array-based tumor gene profiling need to be clearly understood for the data to be correctly interpreted and appreciated. In the present work, we discuss the technical features characterizing this powerful laboratory tool and review the applications so far described in the field of oncology.

Antineoplastic Agents↗

PubMed2005

Search for melanoma markers in plasma and serum samples.

Fourteen blood samples from patients with melanoma and eleven blood samples from healthy subjects were analyzed by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. The study was focussed on species of low molecular weight, in the range 800-5000 Da, present in plasma and sera. While for healthy subjects plasma samples lead to the production of a higher number of ionic species, for melanoma patients a high number of diagnostic ions, present with high frequency and with quite high relative abundance, are present in particular in serum samples and to a lesser extent also in plasma. Since plasma samples are obtained more easily in comparison to sera, it is possible to suggest that also plasma can be used for these studies.

Adult↗

PubMed2004

Prostate carcinoma and green tea: PSA-triggered basement membrane degradation and MMP-2 activation are inhibited by (-)epigallocatechin-3-gallate.

Prostate-specific antigen (PSA) is a serine-protease that, in addition to cleaving semenogelins in the seminal coagulum, is able to cleave extracellular matrix glycoproteins, thereby affecting cell migration and metastasis. We here report some new activities of PSA that deserve careful consideration in the cancer context: degradation of gelatin, degradation of type IV collagen in reconstituted basement membrane (Matrigel) and activation of progelatinase A (MMP-2), but not pro-MMP-9, in a cell-free system. Since consumption of green tea has been reported to lower the risk of prostate cancer, we investigated the effects of the major flavanol of green tea, (-)epigallocatechin-3-gallate (EGCG), on expression and activity of PSA by prostate carcinoma cells. In addition to restraint of PSA expression, EGCG was found to inhibit in a dose-dependent manner all the above PSA activities, at concentrations lower than the cytotoxic serine-protease inhibitor PMSF and close to levels measured in the serum following ingestion of green tea. The activity of PSA was suppressed also by the elastase released by the inflammatory leukocytes. These results highlight new PSA activities, suggest gelatin zymography as a new convenient assay for PSA, propose EGCG as natural inhibitor of prostate carcinoma aggressiveness, but also stimulate further investigation on the role of prostatic inflammation.

Antioxidants↗

PubMed2004

Induction of endothelial nitric oxide synthase expression by melanoma sensitizes endothelial cells to tumor necrosis factor-driven cytotoxicity.

PURPOSE: The cascade of molecular events leading to tumor necrosis factor (TNF)-mediated tumor regression is still incompletely elucidated. We investigated the role of endothelial nitric oxide synthase in determining the tumor-selective activity of TNF. EXPERIMENTAL DESIGN: Using quantitative real-time PCR, endothelial nitric oxide synthase gene levels were measured in melanoma metastases of the skin and normal skin biopsies obtained from 12 patients before undergoing TNF-based therapy. In vitro, the ability of melanoma cells supernatant to affect endothelial nitric oxide synthase transcription by endothelial cells and the influence of nitric oxide synthase inhibition on TNF cytotoxicity toward endothelial cells was evaluated. RESULTS: Endothelial nitric oxide synthase transcript abundance resulted significantly greater in tumor samples rather than in normal skin samples and in patients showing complete response to TNF-based treatment rather than in those showing partial/minimal response. In vitro, melanoma cells' supernatant induced endothelial nitric oxide synthase gene expression by endothelial cells. Nitric oxide synthase inhibition slowed endothelial cells proliferation and, if induced before TNF administration, decreased the cytokine-mediated cytotoxicity on endothelial cells. CONCLUSIONS: Taken together, these findings support the hypothesis that high expression of endothelial nitric oxide synthase in the tumor microenvironment might increase or be a marker for endothelial cells sensitivity to TNF. These observations may have important prognostic and/or therapeutic implications in the clinical setting.

Biopsy↗

PubMed2004

Molecular detection of circulating tumor cells is an independent prognostic factor in patients with high-risk cutaneous melanoma.

Detection of circulating tumor cells (CTCs) might improve current staging procedures by identifying a subgroup of patients with minimal residual disease and thus a higher risk of disease recurrence. Forty patients with > or =2-mm-thick cutaneous melanoma with or without lymph node metastasis were enrolled. After standard radical surgery and adjuvant therapy in case of lymph node metastasis, patients were followed up with routine physical and radiologic assessments as well as serial PCR-based analysis of CTCs using 2 melanoma markers (tyrosinase and Melan-A/Mart-1). After a median follow-up of 30 months, 18 patients had disease recurrence and 28 were PCR-positive before the disease became clinically evident. The sensitivity of the molecular test was 83%. Median time to PCR positivity and median PCR-to-relapse time were 12 and 8 months, respectively. At multivariate analysis, PCR positivity was an independent predictor of disease recurrence (hazard ratio=2.06, 95% CI 1.07-3.35; p=0.03). Among high-risk melanoma patients, serial PCR-based analysis of CTCs can identify a subgroup at higher risk of disease recurrence, with clinically significant advance. Therefore, CTC detection might be employed for the selection of patients for adjuvant treatment and during follow-up for early indication of therapeutic failure.

Adolescent↗