Assessment of pathological status of lower pelvic nodes to tailor surgery in not squamous early cervical carcinoma.
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Carcinoma, Squamous Cell↗
Biomedical subjects
M Distefano
Publications and source records attributed to M Distefano.
Color Doppler velocimetry and three-dimensional color power angiography of cervical carcinoma.
OBJECTIVES: To investigate the blood flow within invasive cervical carcinoma by transvaginal two-dimensional (2D) color spectral Doppler and three-dimensional (3D) color power angiography and to correlate these parameters with the clinicopathological characteristics. METHODS: Seventy-four patients with invasive cervical carcinoma were enrolled for the analysis. Squamous cell carcinoma serum antigen levels (SCC) were obtained for all the patients. Sections of all malignant tissues were analyzed for tumor expression of cyclooxygenase-2 (COX-2). All patients underwent color and spectral Doppler examination and 44 patients had 3D color power angiography. Color spectral Doppler parameters (color score, lowest resistance index (RI), highest peak systolic velocity (PSV)) and 3D color power angiography indices (relative color, average color, flow measure) of FIGO I/II cervical cancers were compared with those obtained in a control group of 24 patients with a normal uterine cervix. Pulsed Doppler parameters and the 3D vascular indices were compared with clinicopathological parameters, SCC serum antigen levels and tumor COX-2 expression. RESULTS: At color Doppler analysis 72 patients (97%) showed intralesional detectable vessels. Color spectral Doppler and 3D-derived parameters were significantly different in FIGO I/II cervical cancers compared with those in women with a normal cervix. A significantly higher color score (P = 0.0008), lower RI (P = 0.032) and higher PSV (P = 0.004) were associated with a tumor diameter > or =4 cm compared with smaller tumors. The highest PSV was significantly higher in patients with FIGO stage III/IV compared with FIGO stage I/II (P = 0.0069). There was a direct correlation between PSV and SCC (r = +0.44, P = 0.003). The median relative color was significantly higher in patients with a higher color score (P = 0.0006). No statistically significant correlations were found between 3D color power angiography parameters and the clinicopathological characteristics or between the 3D vascular parameters and biological factors. CONCLUSIONS: Alterations of 3D ultrasound-derived vascular indices were found in patients with cervical cancer compared with those with a normal cervix. Moreover, some vascular indices proved to be associated with tumor size. The assessment of a possible clinical role of 2D and 3D ultrasound-derived vascular indices in cervical cancer deserves further investigation.
Adult↗
Is there a place for a less extensive radical surgery in locally advanced cervical cancer patients?
OBJECTIVE: The aim of this study was to assess the association among the pathological status of different lymph node groups and parametrium in a single institutional population of 103 locally advanced cervical cancer (LACC) cases who underwent surgery after a neoadjuvant approach. A series of 29 early cervical cancer patients was also included in the analysis. METHODS: Eighty-two LACC patients with documented clinical response to neoadjuvant treatment and 29 early stage cases underwent radical surgery. The operative technique consisted of a type II-V radical hysterectomy and systematic pelvic lymphadenectomy (median number of lymph nodes removed 46; range 5-140). Sixty-four cases were submitted to para-aortic lymphadenectomy up to the level of the inferior mesenteric artery (median number of lymph nodes removed 13; range 1-37). RESULTS: Two subgroups of lymph nodes were defined: lower pelvic lymph nodes (LPN), including obturator and external iliac nodes, and upper pelvic nodes (UPN) including common iliac, presacral, and internal iliac nodes. Metastatic UPN involvement showed a strict association with LPN involvement: in LACC cases, 6 of 7 (86%) positive UPN cases had tumor disease at the LPN level. The single positive UPN case with negative LPN was intraoperatively identified by palpation and frozen section. Similarly, in early cervical cancer patients, 100% of positive UPN cases showed metastatic involvement at the LPN level. Sixty-three of 70 (90%) LACC patients with negative histological parametrium had negative LPN. Among 12 cases with metastatic involvement of parametrium, 5 cases (41.7%) had positive LPN. In early stage cervical cancer, 23 of 27 (85%) cases with negative parametrium showed no lymph nodal involvement. Intraoperative palpation of the parametrium could identify all cases with parametrial involvement not predicted by LPN status. CONCLUSIONS: These data offer the basis for tailoring the extent of radical surgery in LACC patients, through the selection of those lymph node stations likely to provide reliable information on the pathological status of UPN and parametrium.
Adult↗
A new method to evaluate in vitro myelotoxicity of antitumour agents in the first steps of drug development.
Research focused on the development of new anticancer agents has been based mainly on the assessment of the antitumour activity. This yields a large number of newly developed drugs endowed with good antitumour properties, but heavy side-effects on myelopoiesis. In this work, we validate a new method potentially useful to assess myelotoxic effect of newly developed agents. The proposed technique uses peripheral blood CD34+ cells as source of haematopoietic progenitors. These cells are grown in liquid culture in the presence of cytokines able to induce differentiation versus the three main lineages. Doxorubicin, carboplatin and topotecan served as reference drugs to investigate the accuracy of the technique. The three drugs mimick the effects reported in vivo. Doxorubicin and carboplatin produce a specific effect toward erythropoietic and thrombopoietic lineages, respectively, and topotecan a three-lineage toxicity. An advantage of the technique is the possibility to further investigate myelotoxicity. Here, we assessed differentiation markers in CD34+ cells to evaluate if the three drug treatments can affect the process of differentiation. Data show that the drug treatments were unable to modulate the expression of the selected differentiation markers in the surviving population. We propose this method as an innovative tool to score the myelotoxic effect of compounds in the first steps of drug development to further develop those compounds with the best ratio between activity and myelotoxic effects. Moreover, the fact that the method is performed in liquid phase allows its optimisation in a conventional "high throughput system".
Antigens, CD34↗
Biliocutaneous fistula following biliary stent migration.
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Biliary Fistula↗
In vitro evaluation of newly developed chalcone analogues in human cancer cells.
PURPOSE: Among flavonoids, chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. We studied a panel of newly developed chalcone analogues (S1-S10) using MDA-MB 231 and MCF-7 ADRr breast cancer cells and the T-leukemic Jurkat cell line. Quercetin was used as the reference compound. METHODS: Antiproliferative activity was evaluated by cell counts performed after 72 h of exposure to the drugs. DNA analysis and redox activity were evaluated using flow cytometry. Apoptosis was assessed by morphological analysis, using YOYO-1 as DNA dye; p-glycoprotein function was ascertained by quantitating the efflux of rhodamine 123. RESULTS: All cells were sensitive to chalcone analogues yielding IC50 in micromolar concentrations with the following order regardless of the multidrug resistance (MDR) status: S1 > S2 > quercetin. S1 and S2, the most active compounds, were selected to evaluate their effect on the cell cycle, apoptosis, redox activity, and modulation of the p-glycoprotein function. No significant perturbation in cell cycle was seen with concentration up to 1 microM after 24 h. After 72 h a slight increase in G2/M block and DNA fragmentation occurred at 10 microM. Morphological analysis of apoptosis showed that chalcone analogues induced apoptosis to a higher extent than quercetin. Redox analysis demonstrated that all substances were able to increase intracellular thiol levels, which returned to baseline value after 24 h for all drugs except quercetin. Production of reactive oxygen species was essentially unaffected by all compounds. Finally, in MDR-positive MCF-7 ADRr cells chalcone analogues were unable to modulate p-glycoprotein function while quercetin was able to. CONCLUSIONS: Newly developed S1 and S2 chalcones have a different but higher antitumor activity than quercetin and could be considered as potential new anticancer drugs.
ATP Binding Cassette Transporter, Subfamily B↗
Anti-tumour activity of a panel of taxanes toward a cellular model of human cervical cancer.
Using a model of human cervical cancer (ME-180 cells), the anti-tumour activity of paclitaxel was compared to that of docetaxel and IDN5109, a newly developed taxane. The growth inhibition effect of taxanes was assessed after 3 days of exposure. DNA analysis, the taxane-dependent modulation of the expression of the alpha and beta subunits of tubulin and DNA fragmentation were assessed by flow cytometry. The presence of apoptosis was confirmed by morphological analysis using a laser scan cytometer. For the evaluation of "in vivo" anti-tumour activity, taxanes were administered to nude mice intravenously once daily, according to a q3/4d x 4 schedule. Docetaxel, IDN5109 and paclitaxel obtained "in vitro" IC(50) values of 0.86, 1.4 and 2.4 nM, respectively. DNA analysis demonstrated a transient block at the G(2)/M phase of the cell cycle only after 12 h of culture in the presence of taxanes and an increase of nuclear fragmentation suggestive for apoptosis after additional 12 and 60 h of exposure. Morphological analysis confirmed the presence of apoptosis. Taxanes induced a down-modulation of the alpha subunit of tubulin in the G(0/1) phase of the cell cycle, and an overexpression of the beta subunit in the G(2)/M phase. A strong anti-tumour activity was obtained "in vivo" for nude mice xenografted using ME-180 cells (T/C=0% for all drugs). These data indicate that the three taxanes are strongly active both "in vitro" and "in vivo" toward ME-180 cells. Clinical studies are now needed to ascertain if the higher anti-tumour activity observed "in vitro" using docetaxel and IDN5109 yields a better clinical response in advanced cervical carcinoma with respect to paclitaxel.
Animals↗
Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors.
Taxanes antitumour agents such as paclitaxel and docetaxel represent a successful family of chemotherapeutic drugs. Unfortunately, acquired and innate resistance represents a clinical problem for these drugs. We investigated, on a panel of 7 human cancer cell lines, the growth inhibition effect of 3 newly developed taxanes (SB-T-1213, SB-T-1250 and SB-T-101187) with modification at the C10 and C3' positions of the taxane framework. These positions have been previously characterized as critical to make taxanes highly active against cells overexpressing the efflux pump P-glycoprotein (P-gp). Paclitaxel and docetaxel were used as reference compounds. Results unambiguously indicate the exceptional activity of the novel taxanes toward P-gp positive cells (up to >400 fold higher potency than that of paclitaxel). SB-T-1213 and SB-T-1250 are also substantially more active than the reference compounds against P-gp negative cells. To better understand the mechanisms underlying the enhanced activity of the newly developed taxanes, we performed cell cycle and apoptosis analysis. This study demonstrates that the striking growth inhibition effect exhibited by the novel taxanes is ascribed to their increased ability in inducing apoptosis and G(2)/M cell cycle block. SB-T-1213 and SB-T-1250 are also more active than reference compounds in inducing intracellular accumulation of the beta-tubulin subunits. Finally, it is revealed that these novel taxanes have ability to inhibit the function of the P-gp efflux pump on the basis of the Rhodamine 123 assay. These findings strongly suggest that SB-T-1213, SB-T-1250 and SB-T-101187 represent a new tool to overcome innate or acquired P-gp mediated taxane-resistance.
ATP Binding Cassette Transporter, Subfamily B↗
Antagonistic effect of the combination gemcitabine/topotecan in ovarian cancer cells.
The in vitro interaction between the new antimetabolite gemcitabine (GEM) and topotecan (TPT) was analyzed in A2780 ovarian cancer cells. The growth inhibitory effect was assessed after 3 days of drug exposure. GEM and TPT obtained in vitro IC50 values of 2.1 +/- 0.9 and 33.7 +/- 10.2 nM, respectively. The interaction between GEM and TPT was evaluated by exposing cancer cells at increasing doses of GEM (0.1, 1, and 10 nM) and TPT (1, 10, 100, and 1000 nM). Analysis of data about the interaction between GEM and TPT was performed by applying the isobole method. An antagonistic effect was noticed when GEM was combined with TPT in the tested concentration range. DNA analysis was also performed and showed an augmentation of cells blocked in the G2/M phase during TPT exposure, while an increase of blocked cells in the G0/1, phase was observed after GEM treatment. This latter effect was predominant when the two drugs were used in combination. We also investigated the effect of sequential exposure to drugs, pretreating A2780 cells for 24 h with TPT and then for 48 h with GEM, and, conversely, pretreating A2780 cells with GEM for 24 h and thereafter with TPT for 48 h. Both these combined sequential treatments showed an antagonist effect of the drugs' combination. Long-term growth inhibition effect was established by clonogenic assay performed after 10 days of culture after drug treatment. Also these data confirmed the antagonistic effect between GEM and TPT in A2780 ovarian cancer cells.
Antimetabolites, Antineoplastic↗
[Quaternary ammonium salts in gynecology and obstetrics].
We have summarized chemical, physical, and microbiological characteristics of Quaternary Ammonium Salts: particularly, benzalchromium chloride and didecyl-dimethyl-ammonium chloride characteristics were analyzed. These compounds may act as antimicrobial agents in different way: 1) they are surface-active agents and will denature protein or cause dissociation of an enzyme from its prosthetic group; 2) they may alter the cell permeability of bacteria and yeasts; 3) they may stimulate the glycolysis reaction and 4) may inhibit oxidation of lactate. These latest activities may play a role in maintenance of physiologic microbial ecology of vagina or in the re-establishment of the vaginal ecosystem after vaginitis or vaginosis. We have also summarized the physiologic variation of vaginal ecosystem during the different phases of women's life and the microbiology of vagina during vaginitis and vaginosis. The results of more recent studies about the therapeutic role of quaternary ammonium compounds in vulvo-vaginal infections an in vaginosis are synthetically reported. We concluded that quarternary ammonium compounds are efficacious, handy and safe, in obstetrics and gynecology. A very good compliance and low costs of these compounds suggest that they may be used alone as well in association with specific antimicrobial agents in the treatment of most of gynecological infections, and particularly in bacterial vaginosis.
Anti-Infective Agents, Local↗
Sequence of metabolic changes during X-ray-induced apoptosis.
A cell population undergoing apoptosis usually contains varying proportions of cells in the diverse stages of the process, from very early continuously through to secondary necrosis. This heterogeneity acts as a confounding factor in metabolic studies if a general population is investigated. Using fluorescent probes and multiparameter flow cytometry, we report on metabolic changes occurring during X-ray-induced apoptosis in human peripheral blood lymphocytes and relate the observed alterations to cells at various phases of the process assessed by monitoring the progressive loss of selective plasma membrane permeability. Data show that alterations of mitochondria cardiolipin and a reduction of plasma membrane potential are rather early events as they commence in cells which still possess an impermeable plasma membrane. Conversely, mitochondrial transmembrane potential is impaired only when plasma membrane permeability starts to be altered, that is, in relatively later apoptotic cells, thereby reflecting the complexity of mitochondria demise during apoptosis. The prooxidant/antioxidant balance is altered in cells in early apoptosis with a correlated increase of prooxidants and depletion of thiols, the latter indicative for the progressive impairment of this detoxifying mechanism. The imbalance in prooxidant/antioxidant remained evident through apoptosis suggesting that oxidative damage starts early and then continues, eventually leading to cellular disruption. Assessing cell transit through the apoptotic process and coupling the observed metabolic changes to selected stages of the process enables one to improve the understanding of the temporary sequence of biochemical phenomena occurring in a given model.
Antioxidants↗
Reproductive effects of dietary soy in female Wistar rats.
This study was designed to assess the effects of administration of dietary soy on reproductive function and fertility of female Wistar rats. Four groups, each of 20 females, were used. Control animals were fed a standard cereal-based diet for rats. Treated animals were fed a standard diet supplemented with 0.7%, 1.2% or 2.4% of a soy extract. Treatment started at weaning and continued until day 7 post-partum (day of sacrifice). Growth depression was seen in the 2.4% soy group. Vaginal opening occurred earlier in females receiving soy supplemented feed when compared with controls. Analysis of vaginal smears revealed that all animals were cycling, although an increase in the mean duration of each cycle was seen in the 2.4% soy group. Uterine effects were observed in high-dose females and included increases in weight, oedema, endothelial hyperplasia and leucocytic infiltration. Vaginal modifications (i.e. inflammation, hyperkeratosis and dyskeratosis) and alterations in the distribution of follicular size in the ovaries were also observed among treated animals. These data suggest that long-term exposure to high doses of phytoestrogens can produce significant agonistic actions in several oestrogen-dependent tissues and parameters, even though in this model no clear influence on reproductive processes was observed.
Animals↗
Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines.
Recent data have demonstrated that the anti-oestrogen tamoxifen (TAM) is able to facilitate apoptosis in cancer cells not expressing oestrogen receptor (ER). In an attempt to identify the biochemical pathway for this phenomenon, we investigated the role of TAM as an oxidative stress agent. In two ER-negative human cancer cell lines, namely T-leukaemic Jurkat and ovarian A2780 cancer cells, we have demonstrated that TAM is able to generate oxidative stress, thereby causing thiol depletion and activation of the transcriptional factor NF-kappaB. As described for other oxidative agents, TAM was able to induce either cell proliferation or apoptosis depending on the dose. When used at the lowest dose tested (0.1 microM), a slight proliferative effect of TAM was noticed in terms of cell counts and DNA synthesis rate, whereas at higher doses (10 microM) a consistent occurrence of apoptosis was detected. Importantly, the induction of apoptosis by TAM is not linked to down-regulation or functional inactivation by phosphorylation of the antiapoptotic bcl-2 protein.
Antineoplastic Agents, Hormonal↗
Biological evaluation on different human cancer cell lines of novel colchicine analogs.
Three new 7-0-substituted deacetamidothiocolchicine derivatives have been evaluated for their antitumor activity against various human tumor cell lines, some of which express the multidrug resistance (MDR) phenotype, for their impact on the cell cycle and their binding to tubulin. Colchicine and thiocolchicine were used as reference compounds. Thiocolchicine was the most active agent on MDR-negative cells in terms of growth inhibition, whereas for multidrug-resistant cells, thiocolchicone was the most active compound (IC50 = 14 nM). As indicated by statistical analysis, a perfect agreement for the potency order (IC50 values) of the compounds between all the MDR-negative cancer cells (k = 1.00), a poor agreement between MDR-positive and MDR-negative cancer lines, and a moderate agreement (k = 0.50) between the two resistant cancer cells MCF-7 ADRr and CEM VBL were observed. To gain further insight into the mechanism of the antitumor activity of colchicinoids, the most active compounds, colchicone and thiocolchicone, were selected to evaluate their effect on cell cycle, apoptosis, and tubulin interaction. The highest recruitment activity into the G21/M phase of the cell cycle was detected in thiocolchicone-treated breast cancer cells. Interestingly, after 72 h of culture, when the cell cycle block subsided, a consistent amount of DNA fragmentation, a hallmark of apoptosis, was evident. Morphological analysis of MCF-7 ADRr cells confirmed this hypothesis and revealed that thiocolchicone was able to induce apoptosis in this MDR-bearing model. We also demonstrated, using flow cytometry, that thiocolchicone interacts with alpha- and beta-tubulin, thereby affecting the expression of both subunits.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Cytotoxic effects toward human hematopoietic progenitor cells and tumor cell lines of paclitaxel, docetaxel, and newly developed analogues IDN5109, IDN5111, and IDN5127.
The growth inhibitory effect of paclitaxel, docetaxel, and newly developed taxanes IDN5109, IDN5111, and IDN5127 was assessed on peripheral blood (PB) CD34+ maintained in liquid culture and on three human cancer cell lines (MDA-MB231, MCF-7 ADRr, CEM VBLr). Concomitantly, DNA analysis was also performed. For unfractionated peripheral blood progenitor cells (PBPC) toxicity was also assessed by clonogenic assay. The cytotoxic effects induced by taxanes toward PBPC as measured by clonogenic assay were correlated with those found for multidrug resistance (MDR)-positive cell lines (IDN5109 > IDN5111 > IDN5127 > docetaxel > paclitaxel). We established a therapeutic index (TI) between the antitumor activity in MDR-positive cells and the toxicity toward PBPC. Paclitaxel and IDN5109, as determined by TI, showed the best value in MDR-negative and MDR-positive cells, respectively. The ranking of the cytotoxic effects observed in PB CD34+ was not correlated with that obtained in clonogenic assay and in cancer cells (IDN5127 > IDN5109 > docetaxel > IDN5111). Remarkably, in DNA analysis docetaxel induced the maximal cell cycle blocking activity. Newly developed taxanes IDN5109 and IDN5111 are endowed of a profile of anticancer activity in MDR-bearing cells and toxicity toward hematopoietic progenitors better than that of docetaxel. However, mechanism(s) underlying toxicity toward hematopoietic progenitors could be, at least in part, different from that of docetaxel and likely dependent on the interaction with P-glycoprotein function in PB CD34+ cells.
Antigens, CD34↗
Epidermal growth factor receptor (EGFR) is not related to the prognosis of cervical cancer.
We analyzed the prognostic significance of epidermal growth factor receptor (EGFR) in a large prospective series of 90 cervical cancer patients observed for a long follow-up period. EGFR levels ranged from 0 to 52.1 fmol/mg protein, with a median value of 6.0 fmol/mg protein. Patients with an advanced stage of disease expressed lower EGFR levels than those with an early stage of disease (median values were 7.8 fmol/mg protein for patients with stage I-II and 4.2 fmol/mg protein for patients with stage III-IV, P = 0.013). There was no correlation between EGFR expression and other clinicopathological parameters analyzed. No significant relationship was shown between EGFR positivity and overall survival. No significant relationship between EGFR status and disease-free survival was observed. Cox univariate regression analysis using EGFR as a continuous variable showed that EGFR levels are not associated with the risk of disease recurrence after treatment or death (P-value not significant). Our data didn't seem to indicate a prognostic role of EGFR in cervical cancer.
Adult↗
Antiproliferative activity of colchicine analogues on MDR-positive and MDR-negative human cancer cell lines.
In this study the in vitro antitumor activity of a series of 20 colchicine analogues was tested and compared with colchicine and thiocolchicine on three different human cancer cell lines, two of which express the multidrug-resistance (MDR) phenotype. At concentrations from 1 nM to 100 microM, all compounds tested inhibited cancer cell proliferation. The IC50 values indicate that the three fluorinated analogues were the most active compounds, with a similar decreasing order of potency (IDN 5005 > IDN 5079 > IDN 5080) on the two MDR-expressing cell lines, whereas thiocolchicine was the most effective compound on the MDR-negative MDA-MB 231 cells. A strong correlation (r = 0.94; P = 0.004) was found between IC50 values obtained using the two MDR-positive cell lines. Conversely, IC50 values obtained in MDA-MB 231 cells did not show a significant correlation with MDR-positive cell lines, thereby suggesting some difference in the antiproliferative mechanism(s) of colchicine analogues. Cell cycle analysis of the most active analogues in breast cancer cells showed a relationship between cell cycle blocking activity and growth inhibition. The most active agents on the MDR-positive MCF7 ADRr cell line, after 24 h of culture, in terms of cell cycle blocking activity were the three fluorinated analogues. Interestingly, after 72 h, when the cell cycle block subsided, a consistent amount of DNA fragmentation was evident. The extent of cell cycle block, measured as the G2/G1 ratio, was significantly correlated with the apoptosis rate expressed as a percentage of DNA fragmentation on both cell lines, thereby suggesting that a large number of blocked cells underwent the apoptotic pathway.
Antineoplastic Agents↗
[Therapy of bacterial vaginosis. Prospective clinical study ot the efficacy and tolerability of quaternary ammonium salts vs. clindamycin].
BACKGROUND: To evaluate the efficacy and safety of intravaginal quaternary ammonium antimicrobial compounds (SQA) versus clindamycin 2% intravaginal cream (CL) in the treatment of bacterial vaginosis (VB). MATERIALS AND METHODS: One hundred-thirty-three patients affected by VB were enrolled in the study from January 1995 to October 1997. Patients were classified according to Amsel's criteria and/or to the indications of the Scandinavian Society of Bacterial Vaginosis. Twenty-three patients were initially excluded from the study, and 110 patients were randomized in two groups, SQA versus CL. Patients were reevaluated after 3 weeks, 3 months and 6 months from the end of therapy. The safety of treatment was also investigated. RESULTS: Of 110 patients, 59 were treated with SQA and 51 with CL. One hundred (90.9%) patients completed the therapy and were subjected to the first control after 3 weeks from the end of therapy. A significant reduction of most of the symptoms and all signs of VB was observed in the group treated with SQA. Similarly, a significant reduction of most of the symptoms (vaginal and urinary in particular) and all signs of VB was observed in the group treated with CL. The percentage of response was 86.7% for SQA group and 87.2% for CL group. Moreover, after 3 months from the end of therapy, 47.2% and 50% of the patients treated with SQA and CL, respectively, recurred, and after 6 months 78.5% and 75% of the patients recurred, respectively. CONCLUSIONS: SQA treatment conferred 86.7% of response after 3 weeks from the end of therapy, with poor side effects and a good compliance in good keeping with the results obtained with CL treatment.
Adolescent↗