Search PubMed⌕ Search

Biomedical subjects

F Casale

Publications and source records attributed to F Casale.

At least 19 recordsLinked to original sources
PubMed2006

Determination of a potent non-competitive AMPA receptor antagonist in rat brain.

N-acetyl-1-(p-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivative (PS3Ac) has been determined in brain tissues by high performance liquid chromatography (HPLC) coupled with a diode array detection. In a previous paper we presented a validation method for detecting PS3Ac and its metabolites in plasma samples after intraperitoneal administration to Wistar rats. In the present paper, we report the results of the determination of PS3Ac and its N-deacetyl (PS3) and O-demethyl (PS3OH) metabolites, in the brain after extraction based on a polymeric matrix with a high hydrophilic-lipophilic balance, using Oasis cartridges. The chromatographic separation was performed in an octadecylsilica stationary phase at 25 degrees C using a mixture of 10 mM potassium dihydrogen orthophosphate (pH 2.24) and acetonitrile in ratio of 30:70 (v/v) as mobile phase, with a flow rate of 0.8 ml/min. The method exhibited a large linear range from 0.05 to 2 microg/ml for all studied compounds (n=6). In the within-day assay (n=4), the accuracy ranged from 87.5% determined with 0.05 microg/ml of PS3 to 110.1% determined with 0.2 microg/ml of PS3OH. In the between-day assay the coefficient of variation ranged from 2.4 determined with 0.05 microg/ml of PS3 to 9.7 determined with 0.2 microg/ml of PS3OH. The extraction efficiency ranged from 77.8% for PS3OH at 0.2 microg/ml to 94.3 for PS3Ac at 0.5 microg/ml. The limit of detection for all the tetrahydroisoquinoline derivatives ranged around 50 ng/ml. The method proved to be highly sensitive and specific to determinate PS3Ac and its metabolites and has been successfully applied to value their concentrations in brain matrix over the time.

Animals↗
PubMed2004

Determination of disodium clodronate in human plasma and urine using gas-chromatography-nitrogen-phosphorous detections: validation and application in pharmacokinetic study.

We present a specific method for the determination of disodium clodronate in human plasma and urine using a gas-chromatographic system with nitrogen phosphorus detector (NPD). The compound was extracted from plasma and urine samples by an anion-exchange resin and derivatizated with bistrimethylsilyltrifluoroacetamide (BSTFA). Sodium bromobisphosphonate was used as internal standard. The calibration curves were linear in both plasma and urine, with a regression coefficient r > 0.9975 in plasma and r > 0.9977 in urine. The limit of quantitation was 0.3 microg/ml in plasma and 0.5 microg/ml in urine. The method was validated by intra-day assays at three concentration levels. During the study we carried out inter-day assays to confirm the feasibility of the method. The precision in plasma at 0.5, 15, and 45 microg/ml was 12.4, 0.2, and 6.5% (n = 40), respectively; in urine at 0.8, 8, and 40 microg/ml it was 8.6, 6.4, and 9.3% (n = 40), respectively. The method was accurate and reproducible, and was successfully applied to determine the pharmacokinetic parameters of clodronate in healthy volunteers after intravenous infusion and intramuscular injection of 200 mg of the compound. The Cmax after intravenous infusion and intramuscular injection was 16.1 and 12.8 microg/ml, respectively. AUC(0-48 h) after infusion administration and intramuscular injection was 44.2 +/- 18.0 and 47.5 +/- 12.4 h microg/ml, respectively. The elimination half-life in both administrations was 6.31 +/- 2.7 h.

Area Under Curve↗
PubMed2004

P-glycoprotein 170 expression and function as an adverse independent prognostic factor in childhood acute lymphoblastic leukemia.

Little is known about the prognostic role of multidrug resistance (MDR) in newly diagnosed childhood acute lymphoblastic leukemia (ALL). P-glycoprotein 170 (MDR1), a cellular drug efflux pump, is thought to be one of the major causes of MDR. The aim of this retrospective study was to evaluate in 85 children with ALL the impact of the MDR1 product of the mdr-1 gene on the achievement of complete remission (CR) and outcome. MDR1 protein expression was performed by immunocytochemistry (ICC), and flow cytometry (FC). MDR1 functional activity was performed by a rhodamine (Rhd)-123 efflux test with or without verapamil. All patients enrolled in our study were treated with AIEOP ALL 91-95 protocols. At diagnosis, 40 patients (47%) expressed MDR1 protein at significant levels, and 45 (53%) were MDR1 negative. Forty-three of the latter patients were also negative for MDR1 function, while 34/40 (85%) patients MDR1 positive preserved the function. Rhd-123 efflux was inhibited by the MDR modulator verapamil in 12/40 (30%) patients. After induction treatment, CR was achieved in 77/85 children (90.6%). All patients who did not achieve CR were MDR1 positive. Twenty-nine patients relapsed, 17 (58.6%) of whom were MDR1 positive. The 10-year overall survival (OS) rate, and disease-free survival (DFS) for MDR1 negative patients compared to MDR1 positive patients were 75.7% versus 54.8%, and 67.5% versus 46%, respectively. The 10-year event-free survival (EFS) rate was significantly higher (67.5% versus 36.8%) in the MDR1 negative group compared with the MDR1 positive population (p=0.001). Multivariate analysis showed that only EFS was independent of age, WBC count, immunophenotype, FAB subtype and prednisone response (p=0.019). Our results, derived from a monocentric study, demonstrate that MDR1 expression in childhood ALL is an independent adverse prognostic factor on outcome, and could be a useful biological marker of response in these patients. Moreover, MDR1 function was also a predictor of response, but only in univariate analysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

[Advances in diagnosis and therapy of breast cancer between the 20th and the 21st centuries].

During the last two decades several new data have been acquired about tumor biology and therapy. Breast cancer is one of the more common cancers occurring, determining life threatening and depression in affected females. By the way a great interest has been developed during the time attempting to reach the earliest diagnosis and the more conservative treatment. However, breast cancer is now considered as a disease which meet the interests of several specialists (oncologists, surgeons, radiologists, and so), all dedicated to reduce the consequences of such pathology. The aim of this review is the resume of the progresses made in the last century about breast cancer knowledge.

Breast Neoplasms↗
PubMed2003

Determination of the in vivo effects of prednisone on Bcl-2 family protein expression in childhood acute lymphoblastic leukemia.

Glucocorticoid resistance is often associated with treatment failure in children with acute lymphoblastic leukaemia (ALL) but the underlying molecular mechanisms are still unclear. In 30 consecutive children with ALL treated with prednisone we determined changes in the expression of Bcl-2, Bax and Bcl-xl proteins in leukemic lymphoblasts and related these to clinical features and rate of prednisone-induced apoptosis. The apoptotic index increased after prednisone therapy in 24 of the 30 patients. At diagnosis, we detected expression of Bcl-2 and Bcl-xl protein in 28 samples, while Bax expression protein was detected in 21 of the 30 patients. Prednisone treatment induced a decrease in Bcl-2 and Bcl-xl levels in 17 and 16 of the 28 patients, respectively, while Bax protein increased in 14 of the 21 patients. Twenty of the 30 patients studied were considered to be good prednisone responders, whereas 10 were poor responders. We observed a statistically significant decrease only for Bcl-xl protein expression in T phenotype ALL, in the poor responder group and in patients with >20000/mm(3) white cell count (WBC) at diagnosis. These data suggest a role of Bcl-xl in the mechanisms of protection of leukemic cells from apoptosis induced by glucocorticoids (GCs).

Adolescent↗
PubMed2002

Simultaneous HPLC determination of 5-fluorouracil and its metabolites in plasma of cancer patients.

5-Fluorouracil (5-Fu) is a commonly used anticancer agent for treatment of solid tumours. Certain studies have reported conflicting results between individual plasma concentration levels and toxicity or therapeutic effects. For this reasons some authors proposed to evaluate the plasma levels of 5-Fu metabolites 5-fluorouridine, 5-fluoro-2'-deoxyuridine and 5-fluoro-5,6-dihydro-uracil. The aim of the present work is to develop and validate a new HPLC method simultaneously determining 5-fluorouracil and its three metabolites, to be used to study the plasma levels, therapeutic effects and toxicity in cancer patients. The analytes were separated on a 4.6 x 250 mm ODS1 (5 micro m) not end-capped column, operating at room temperature. Elution was performed under isocratic conditions, employing a 1.5 mM K(3)PO(4) mobile phase (pH 5). 5-Bromo-5,6-dihydro-uracil was used as internal standard. The limits of quantitation were 0.5 micro g/mL for 5-fluorouracil, 1 micro g/mL for 5-fluoro-5,6-dihydro-uracil, 3 micro g/mL for 5-fluoro-2'-deoxyuridine and 5-fluorouridine; the stability, recovery, linearity, accuracy and specificity of the compounds were evaluated according to the criteria widely accepted. Using this method we measured plasma samples of 18 cancer patients treated with folinic acid (100 mg/m(2)) by intravenous administration, followed by an i.v. bolus of 5-Fu (400 mg/m(2)). The concentration levels of 5-fluorouracil and for 5-fluoro-5,6-dihydro-uracil were detectable in all the subjects while 5-fluorouridine and 5-fluoro-2'-deoxyuridine were present only in eight patients.

Antimetabolites, Antineoplastic↗
PubMed2002

Localized unresectable neuroblastoma: results of treatment based on clinical prognostic factors.

BACKGROUND: We previously reported that stage 3 neuroblastoma comprises (i) a low-risk group including all infants (age 0-11 months) as well as older children with non-abdominal primaries, and (ii) a high-risk group made up of children >1 year of age with abdominal primaries. Aggressive chemotherapy was effective only in the latter group. PATIENTS AND TREATMENT: On this basis, in 1990 we designed a new protocol by which all low-risk patients received standard-dose chemotherapy, while the high-risk ones received very aggressive chemotherapy. RESULTS: Between November 1990 and December 1997 a total of 95 eligible and evaluable children were enrolled: 47 were low-risk (35 infants and 12>1 year of age at diagnosis and having non-abdominal primaries), and 48 were high-risk (being >1 year of age and having abdominal primaries). Of the 47 low-risk patients, five relapsed and four subsequently died. The 5-year overall survival (OS) was 91%. Of the 48 patients in the high-risk group, 22 relapsed or progressed, 18 of whom died from their disease and two from toxicity, and one was lost to follow-up. The 5-year OS was 60%. Univariate analysis showed that age, site of primary, risk-group, urine vanillylmandelic excretion, plasma levels of lactate dehydrogenase, ferritin and neurone-specific enolase, and MYCN status correlated with outcome. However, multivariate analysis showed that only MYCN status retained prognostic value. CONCLUSIONS: In low-risk stage 3 neuroblastoma, standard-dose chemotherapy is associated with an excellent chance of being cured. Aggressive chemotherapy is effective for high-risk patients, but results are still unsatisfactory. MYCN gene amplification is a prognostic indicator for most, but not all, treatment failures.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Effect of protracted high-dose L-asparaginase given as a second exposure in a Berlin-Frankfurt-Münster-based treatment: results of the randomized 9102 intermediate-risk childhood acute lymphoblastic leukemia study--a report from the Associazione Italiana Ematologia Oncologia Pediatrica.

PURPOSE: To assess in a randomized study the therapeutic effect of the addition of high-dose L-asparaginase (HD ASP) in the context of a Berlin-Frankfurt-Münster (BFM)-based chemotherapy regimen for intermediate risk (IR) childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: From March 1991 to April 1995, a total of 705 patients, with 59% of the cohort of patients fewer than 15 years old, with newly diagnosed non-B ALL, enrolled onto the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-91 study, were assigned to the IR group. Patients in remission at the beginning of the reinduction phase were randomized either to the standard treatment (SD ASP arm) or the experimental treatment (HD ASP arm; weekly intramuscular administration of HD ASP 25,000 IU/m(2) repeated for a total of 20 weeks). Most of the patients (90%) were treated with Erwinia chrysanthemi L-asparaginase product. RESULTS: Among the 610 patients randomized to the SD ASP arm (n = 322) or to the HD ASP arm (n = 288), relapse occurred at a median time of 24 months after randomization in 76 (24%) and in 64 children (22%), respectively. Most of the relapses occurred in the marrow (100 isolated, 21 combined). There was no significant difference between the disease-free survival in the two treatment arms (P =.64), with estimated values at 7 years from randomization of 72.4% (SE 3.1) v 75.7% (SE 2.6) in the SD ASP and HD ASP arms, respectively. CONCLUSION: No advantage was observed for IR ALL children treated with BFM-based intensive chemotherapy who received protracted E chrysanthemi HD ASP during reinduction and the early continuation phase.

Adolescent↗
PubMed2001

Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases.

PURPOSE: To report on the treatment of patients with newly diagnosed neuroblastoma presenting with spinal cord compression (SCC). PATIENTS AND METHODS: Of 1,462 children with neuroblastoma registered between 1979 and 1998, 76 (5.2%) presented with signs/symptoms of SCC, including motor deficit in 75 patients (mild in 43, moderate in 22, severe [ie, paraplegia] in 10), pain in 47, sphincteric deficit in 30, and sensory loss in 11. Treatment of SCC consisted of radiotherapy in 11 patients, laminectomy in 32, and chemotherapy in 33. Laminectomy was more frequently performed in cases with favorable disease stages and in those with severe motor deficit, whereas chemotherapy was preferred in patients with advanced disease. RESULTS: Thirty-three patients achieved full neurologic recovery, 14 improved, 22 remained stable, and eight worsened, including three who become paraplegic. None of the 10 patients with grade 3 motor deficit, eight of whom were treated by laminectomy, recovered or improved. In the other 66 patients, the neurologic response to treatment was comparable for the three therapeutic modalities. All 11 patients treated by radiotherapy and 26 of 32 patients treated by laminectomy, but only two of 33 treated by chemotherapy, received additional therapy for SCC. Fifty-four of 76 patients are alive at time of the analysis, with follow-up of 4 to 209 months (median, 139 months). Twenty-six (44%) of 54 survivors have late sequelae, mainly scoliosis and sphincteric deficit. CONCLUSION: Radiotherapy, laminectomy, and chemotherapy showed comparable ability to relieve or improve SCC. However, patients treated with chemotherapy usually did not require additional therapy, whereas patients treated either with radiotherapy or laminectomy commonly did. No patient presenting with (or developing) severe motor deficit recovered or improved. Sequelae were documented in 44% of surviving patients.

Adolescent↗
PubMed2001

Left ventricular systolic and diastolic function after anthracycline chemotherapy in childhood.

BACKGROUND: In childhood, late cardiotoxicity is characterized by inappropriately thin wall and consequent increased end-systolic wall stress, but the associations of impaired left ventricular geometry and function occurring under these circumstances need further investigation. HYPOTHESIS: The purpose of this study was to assess anthracycline late effects on the relationships occurring between increased end-systolic stress (ESS) and changes in both M-mode systolic measurements (i.e., endocardial and midwall fractional shortening) and Doppler diastolic indices in the pediatric age. METHODS: The population consisted of 101 children treated with anthracyclines for at least 12 months and 91 healthy children. Using M-mode echocardiography, end-systolic wall stress was calculated as index of afterload, and endocardial and midwall fractional shortening as systolic indices. Doppler transmitral measurements were made as diastolic indices. RESULTS: Patients treated with anthracyclines showed significantly lower relative wall thickness and left ventricular mass index, greater end-systolic wall stress, reduced endocardial and midwall fractional shortening and peak E/A ratio, prolonged deceleration, and isovolumic relaxation times. Direct relationships were found between end-systolic wall stress and both endocardial and midwall shortening. The use of midwall shortening in the relation showed a greater, but not significant increase (from 3 to 6%) in the proportion of patients with depressed systolic function than did endocardial shortening. In the anthracycline group, end-systolic wall stress was also inversely related to relative wall thickness and directly to isovolumic relaxation time. CONCLUSIONS: In childhood, reduced myocardial thickness and increased afterload explain much of systolic and diastolic dysfunction of late anthracycline toxicity. Midwall fractional shortening does not seem to add useful information for identifying subsets of children more prone to the development of heart failure.

Adolescent↗
PubMed2001

Recent advances in the prevention of anthracycline cardiotoxicity in childhood.

The prevention of anthracycline cardiotoxicity is particularly important in children who can be expected to survive for decades after cancer chemotherapy with these agents. The rapid increase in clinical toxicity at doses greater than 550 mg/m(2) of doxorubicin (DOX) has made this dose the limiting one in order to avoid DOX-induced cardiac failure. However, arbitrary dose limitation is inadequate because of variability of individual tolerance. Decreasing myocardial concentrations of anthracyclines (ANT) and their metabolites and schedule modification of administration can reduce anthracycline cardiotoxicity. Anthracycline structural analogues such as epirubicin, idarubicin and mitoxantrone have been used in clinical practice. In addition, the liposomal ANT, which can be incorporated into a variety of liposomal preparations, are a new class of agents that may permit more specific organ targeting of ANT, thereby producing less cardiac toxicity. Much interest has focused on the administration of ANT in conjunction with another agent that will selectively attenuate the cardiotoxicity. As is known, the ANT chelate iron and the DOX-iron complex catalyzes the formation of extremely reactive hydroxyl radicals. Many agents, such as dexrazoxane (DEX), able to remove iron from DOX, have been investigated as anthracycline cardioprotectors. Clinical trials of DEX have been conducted in children and significant short-term cardioprotection with no evidence of interference with antitumor activity has been demonstrated. Whether long-term cardiac toxicity will also be avoided in surviving patients has not yet been determined.

Anthracyclines↗
PubMed2000

Pleuropulmonary blastoma: management and prognosis of 11 cases.

BACKGROUND: Pleuropulmonary blastoma (PPB) is a rare and aggressive malignant tumor that affects children and adults. This neoplasm is histologically characterized by primitive blastema and a malignant mesenchymal stroma that often demonstrates multidirectional differentiation. Despite the introduction of multimodal therapy, the prognosis of patients with PPB remains poor. METHODS: In the current study the authors reported on PPB cases from a national retrospective search performed in 18 Italian Associations for Pediatric Hematology and Oncology centers. Clinical data, surgical notes, pathologic findings, and summaries of chemotherapy and radiotherapy were obtained from reports and correlated with outcome by standard statistical methods. RESULTS: The series included 11 patients (7 boys and 4 girls) with a median age of 32 months. Respiratory distress was the most common clinical symptom. In three patients the PPB developed from other primary dysplastic diseases: cystic adenomatoid malformation in one case and congenital lung cysts in the other two cases. Five patients experienced disease recurrences (local recurrence in three patients and distant metastasis in two patients, within the central nervous system and an intraocular location, respectively). Patients with a type 2 histologic pattern and/or pleural involvement were found to have a worse outcome compared with patients without such features. Event free survival at 2 years from the time of diagnosis was 45% for all patients. Overall survival at 2 years was 72% for all patients. CONCLUSIONS: PPB is an aggressive neoplasm of early childhood and to the authors' knowledge no adequate therapy has been defined to date for patients with PPB. After making the diagnosis, the main goal of therapy should be radical surgery, even in patients with microscopic residual disease. Because the response to chemotherapy is poor, the authors' experience suggests that chemotherapy should be given with local radiotherapy in the majority of patients.

Child↗
PubMed2000

Plasma erythropoietin concentrations in patients receiving intensive platinum or nonplatinum chemotherapy.

AIMS: Platinum chemotherapy has been shown to have potent antineoplastic activity against various tumours, especially testicular, bladder, ovarian, head and neck cancers. This activity is accompanied by side-effects of nephrotoxicity and cumulative myelosuppression, the latter frequently presenting as severe anaemia. Cisplatin and carboplatin nephrotoxicity might lower erythropoietin (Epo) secretion and, by this mechanism, contribute to the anaemia that follows therapy with this chemotherapeutic agent. The aim of the present work is to study the plasma immunoerythropoietin and haemoglobin levels of cancer patients treated with platinum or 5-fluorouracil-based chemotherapy. METHODS: Plasma was obtained from 25 patients who were about to receive chemotherapy for advanced malignancy: 15 treated with cisplatin or carboplatin and 10 with nonplatinum drugs. Blood was collected on the first day (before drug administration) and around day 15 of every chemotherapy course. Complete blood count, creatinine and immunoreactive Epo levels were also measured in 22 healthy volunteers. RESULTS: An increase in Epo levels occurred following every course of 5-FU or platinum based chemotherapy in patients with steady concentrations of creatinine and decreased levels of haemoglobin (Hb). In particular, we observed an increase after about 15 days of the chemotherapy treatment and the Epo levels declined toward normal just before the following course. This phenomenon was evident in every course. CONCLUSIONS: Our results suggest that chemotherapy administration, using the current standards of hydration and forced diuresis, slightly lowered Hb levels but did not depress Epo production, both in 5-FU and in platinum treated subjects.

Adult↗
PubMed1999

Dual or single hepatitis B and C virus infections in childhood cancer survivors: long-term follow-up and effect of interferon treatment.

We conducted a long-term prospective study of 89 cancer survivor children who had acquired hepatitis B virus (HBV) and/or hepatitis C virus (HCV) during treatment for neoplasia, the aim being to evaluate the natural history of the diseases and the effect of interferon (IFN) treatment. Patients were followed up for a median period of 13 years (range, 8 to 20); 46 were infected by HBV, 11 by HCV, and 32 coinfected by HBV and HCV. A spontaneous clearance of hepatitis B surface antigen (HBsAg) occurred more frequently in coinfected patients (19%) than in the HBV-infected (2%; P =.004), with an annual seroconversion rate of 2.1% and 0.2%, respectively (P =.008). Loss of hepatitis Be antigen (HBeAg) occurred in 44% of coinfected and in 28% of HBV-infected patients. Clearance of serum HCV-RNA was observed in 34% and 9%, respectively, of coinfected and HCV-infected patients. Seventeen HBV-infected, 4 HCV-infected, and 16 coinfected patients received alpha-IFN treatment. In the HBV group, 6 patients (35%) cleared serum HBV DNA and seroconverted to anti-HBe; in the HCV-group, none cleared HCV-RNA. In the coinfected group, 1 patient cleared both HBV DNA and HCV-RNA, 6 patients cleared serum HCV-RNA alone, and 1 only HBV DNA and HBeAg. Overall, the diseases showed a mild histological course with no evidence of liver cirrhosis. A reciprocal interference on viral replication between HBV and HCV may occur in coinfected patients. Treatment seems to be effective for selected cases and is justified in view of the uncertain prognosis of the disease in these patients.

Adolescent↗
PubMed1997

MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children.

PURPOSE: To evaluate the prognostic role of MYCN oncogene amplification in children with neuroblastoma. PATIENTS AND METHODS: Of 694 children (age, 0 to 15 years) with previously untreated neuroblastoma, 295 (42%) were evaluated at diagnosis for MYCN gene amplification. RESULTS: Clinical characteristics and survival results of 295 patients studied and 399 not studied for MYCN were comparable. In 48 of 295 patients studied for MYCN (16%), the gene was amplified (> or = three gene copies). Amplification was more frequent in children older than 1 year, with abdominal tumor (18% v 7%), advanced disease, normal vanillylmandelic (VMA) urinary excretion, and high lactate dehydrogenase (LDH), ferritin, and neuron-specific enolase (NSE) serum levels. In patients studied for MYCN, the 5-year overall survival (OS) rate was higher for children aged less than 1 year (90% v 44%), with extraabdominal tumor, stage 1 or 2 versus 3 versus 4, and normal NSE, LDH, and ferritin serum levels. Patients with amplified MYCN had a worse OS (odds ratio [OR], 3.38; confidence interval [CI], 2.22 to 5.16). This association held after adjustment for other characteristics. The impact of MYCN amplification was greater in patients with favorable characteristics, in particular age (OR, 10.28 for infants; 2.08 for older children) and stage (OR, 35.3 for stage 1 to 2; 8.41 for stage 3; 1.76 for stage 4). However, of 29 children with stage 4s, all three with amplified MYCN survive. In a multivariate analysis, the prognostic role of MYCN amplification, age, and stage was confirmed, but the size of the effect of MYCN was dependent on age and stage. CONCLUSION: MYCN amplification is associated with a worse prognosis in children with neuroblastoma at all ages and stages except 4s. This association is most pronounced in children with otherwise favorable prognostic indicators, and in these children should be considered as an indication for more intensive intervention.

Adolescent↗