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C A Hoefnagel

Publications and source records attributed to C A Hoefnagel.

At least 19 recordsLinked to original sources
PubMed2000

Targeting of meta-iodobenzylguanidine to SK-N-SH human neuroblastoma xenografts: tissue distribution, metabolism and therapeutic efficacy.

The clinical results of [(131)I]meta-iodobenzylguanidine (MIBG)-targeted radiotherapy in neuroblastoma patients is highly variable. To assess the therapeutic potential of [(131)I]MIBG, we used the SK-N-SH human neuroblastoma, xenografted in nude mice. The model was first characterized for basic parameters of MIBG handling in the host species. This demonstrated the presence of both strain- and nu/nu mutation-related differences in [(131)I]MIBG biodistribution. Fecal and urinary clearance rates of [(131)I]MIBG in mice roughly resemble those in humans, but mice metabolize MIBG more extensively. In both species, enzymatic deiodination in vivo was not an important metabolic route. Therapy with increasing [(131)I]MIBG doses (25-92 MBq) given as single i.v. injections resulted in proportionally increasing specific growth delay values (tumor regrowth delay/doubling time) of 1 to 5. Using gamma-camera scintigraphy for non-invasive dosimetry, the corresponding calculated absorbed tumor radiation doses ranged from 2 to 11 Gy. We also compared the therapeutic effects of a single [(131)I]MIBG administration with those resulting from a more protracted exposure by fractionating the dose in 2 to 6 injections or with high dose rate external-beam irradiation. No therapeutic advantage of a fractionated schedule was observed, and 5.5 Gy delivered by low dose-rate [(131)I]MIBG endo-irradiation was equi-effective with 5.0 Gy X-rays. The SK-N-SH neuroblastoma xenograft model thus appears suitable to evaluate possible treatment improvements to reach full potential of MIBG radiotherapy.

3-Iodobenzylguanidine↗
PubMed2000

Sentinel node biopsy for melanoma in the head and neck region.

BACKGROUND: Lymphatic drainage in the head and neck region is known to be particularly complex. This study explores the value of sentinel node biopsy for melanoma in the head and neck region. METHODS: Thirty consecutive patients with clinically localized cutaneous melanoma in the head and neck region were included. Sentinel node biopsy was performed with blue dye and a gamma probe after preoperative lymphoscintigraphy. Average follow-up was 23 months (range, 1-48). RESULTS: In 27 of 30 patients, a sentinel node was identified (90%). Only 53% of sentinel nodes were both blue and radioactive. A sentinel node was tumor-positive in 8 patients. The sentinel node was false-negative in two cases. Sensitivity of the procedure was 80% (8 of 10). CONCLUSIONS: Sentinel node biopsy in the head and neck region is a technically demanding procedure. Although it may help determine whether a neck dissection is necessary in certain patients, further investigation is required before this technique can be recommended for the standard management of cutaneous head and neck melanoma.

Adult↗
PubMed2000

Reliability of lymphoscintigraphy in indicating the number of sentinel nodes in melanoma patients.

BACKGROUND: This study was undertaken to establish the reliability of lymphoscintigraphy in indicating the number of sentinel nodes in patients with melanoma. METHODS: Lymphoscintigraphy was performed with dynamic imaging after injection of 60 MBq 99mTc-nanocolloid (1.6 mCi) and static imaging after 2 hours in 200 patients with clinically localized primary melanoma of the skin. The following day, sentinel nodes were retrieved with the blue dye technique and a gamma detection probe (Neoprobe 1000/1500). The discrepancies between the number of sentinel nodes indicated by lymphoscintigraphy and the actual number of sentinel nodes as established by the surgeon were evaluated. RESULTS: Lymphoscintigraphy showed drainage to 393 sentinel nodes in 255 lymphatic fields in 199 patients. In 48 lymphatic fields (19%) in 46 patients (23%), the number of sentinel nodes was different from the number that was visualized with scintigraphy. Additional sentinel nodes were found by the surgeon because a lymphatic vessel was not seen on the lymphoscintigraphy (43%), because a sentinel node was not visualized separately from other hot nodes or vessels or the injection site (36%), or because a sentinel node was blue and not hot (4%). Fewer sentinel nodes were found than suggested by scintigraphy because a lymphangioma was mistaken for a sentinel node (4%) or because a single elongated node was depicted as two hot spots (6%). CONCLUSIONS: Although lymphoscintigraphy is indispensable for lymphatic mapping, the predicted number of sentinel nodes is accurate in only 81% of lymph node fields. The limited discriminating power of the gamma camera is an important cause of discrepancies.

Adolescent↗
PubMed2000

Reliability of sentinel lymph node biopsy for staging melanoma.

BACKGROUND: The aim of this study was to evaluate the reliability of sentinel lymph node biopsy for staging melanoma. METHODS: Two hundred consecutive patients with a cutaneous melanoma of at least 1. 0 mm Breslow thickness, without palpable regional lymph nodes, were included from 1993 in a prospective cohort study in a single tertiary care hospital. One day after lymphoscintigraphy, sentinel node biopsy was performed, guided by a gamma probe and patent blue dye. Lymph node dissection was performed only if metastasis was found in a sentinel node. Median follow-up was 32 (range 3-61) months. No patient was lost to follow-up. RESULTS: A sentinel node was removed in 199 of 200 patients (mean 2.2 nodes per patient). Forty-eight patients (24 per cent) had metastasis in a sentinel node. Fifteen patients developed recurrence after removal of a tumour-negative sentinel node; six relapsed in the previously mapped basin (false-negative rate 11 per cent (six of 54)). The overall survival at 3 years was 93 per cent if the sentinel node was negative and 67 per cent if it was positive. Sentinel node status and Breslow thickness were strong predictors of recurrence and survival. Minor complications were seen in 18 patients. CONCLUSION: The sentinel node status was a strong prognostic factor, even with a false-negative rate of 11 per cent. Published in abstract form as Eur J Nucl Med 1999; 26(Suppl): S57

Adolescent↗
PubMed2000

Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure.

PURPOSE: We evaluated the so-called dynamic sentinel node procedure in patients with penile cancer. This new staging technique consists of excisional biopsy of the first lymph node onto which a tumor drains the so-called sentinel node, based on individual mapping of lymphatic drainage. MATERIALS AND METHODS: From 1994 to 1998, 55 consecutive patients with stage T2 or greater bilateral or unilateral node negative squamous cell carcinoma of the penis were prospectively entered in this study. Tumor stage was T2N0 in 42, T2N1 in 4 and T3N0 in 9 cases. To locate the sentinel node each patient underwent lymphoscintigraphy with 99mtechnetium nanocolloid injected intradermally around the tumor. The following day the sentinel node was identified intraoperatively using patent blue dye injected intradermally around the tumor and a gamma detection probe. Regional lymph node dissection was restricted to patients with a tumor positive sentinel node only. RESULTS: Scintigraphy revealed 125 sentinel nodes in 107 inguinal regions, including no sentinel node in 2 patients, 1 or more unilateral nodes in 10 and bilateral drainage in 43. At surgery 108 sentinel nodes were removed. In 8 patients with 2 or more sentinel nodes on lymphoscintigraphy only 1 was noted intraoperatively and in 9 an additional sentinel node was removed, which was not identified by scintigraphy. All nodes were identified with the gamma detection probe. In 1 patient a wound abscess developed. Regional lymph node dissection was performed in 11 patients with sentinel node metastasis. Median followup was 22 months (range 4.1 to 61). In 1 patient lymph node metastasis was noted at followup despite prior excision of a tumor-free sentinel node. CONCLUSIONS: The dynamic sentinel node procedure is a promising staging technique to detect early metastatic dissemination of penile cancer based on individual mapping of lymphatic drainage, and enables identification of patients with clinically node negative disease requiring regional lymph node dissection.

Adult↗
PubMed2000

Evaluation of mammary lymphoscintigraphy by a single intratumoral injection for sentinel node identification.

UNLABELLED: The aim of this study was to evaluate the findings of mammary lymphoscintigraphy by a single intratumoral injection in 150 patients with breast carcinoma: 100 patients (group A) investigated in the validation phase of the study and 50 (group B) studied after the tracer dose was optimized. METHODS: Immediately after injection of 99mTc-nanocolloid using a 25-gauge needle and a 0.2-mL volume, simultaneous anterior and lateral images were acquired with a dual-head gamma camera during 20 min followed by sequential static anterior and prone lateral breast images after 30 min and after 2 and 4 h. 57Co-assisted skin marking defined the sentinel node location for subsequent gamma probe, blue dye-guided sentinel node biopsy. RESULTS: In group A (mean dose, 61.6 MBq; range, 42-88 MBq) scintigraphy revealed lymph nodes in 83 patients (83%), with an increase in the rate of visualization from 72% for the first 40 patients to 90% for the last 60; patient age (P = 0.01) and administered tracer dose (P = 0.04) were found to be significant factors for visualization, with optimal results obtained from doses higher than 65 MBq. Lymph nodes were visible in 34 patients (41%) during the first 30 min after injection, whereas in 49 patients appearance occurred at 2-4 h. A total of 97 lymphatic basins were visualized (80 axillary, 3 clavicular, 14 internal mammary). In group B (mean dose, 90.8 MBq; range, 68-124 MBq), the visualization rate was 94%, with early lymph node appearance in 27 patients (57%) and a total of 53 basins (45 axillary, 8 internal mammary). In combination with intraoperative blue dye mapping and y probing, the identification rate increased to 90% in group A and 98% in group B. Prone lateral images contributed to identification of intramammary lymph nodes in a total of 14 patients and axillary nodes close to the injection site in 8 other patients. CONCLUSION: Mammary lymphoscintigraphy by single intratumoral injection is a valid method for lymphatic mapping and identification of both axillary and nonaxillary sentinel nodes. Lymph node visualization appears to be improved with higher tracer doses. The compactness of the injection site enables high-quality additional lateral images that can depict intramammary or axillary lymph nodes adjacent to the injection site.

Adult↗
PubMed1999

Radionuclide therapy.

Nuclear medicine therapy uses unsealed radioactive sources for the selective delivery of radiation to tumours or target organs. For benign disorders such as thyrotoxicosis and arthritis radionuclide therapy provides an alternative to surgery or medical treatment. In cancer treatment, it often combines the advantage of target selectivity (like brachytherapy or external beam radiotherapy) with that of being systemic, as with chemotherapy, and it may be used as part of a therapeutic strategy with curative intent or for disease control and palliation. Toxicity is generally limited to the haematopoietic tissue and few side-effects are observed. When cure is feasible, the long-term consequences of radionuclide therapy (eg, fertility disorders and leukaemia or other secondary cancers) do compare favourably with the risks associated with and accepted for chemotherapy and radiotherapy.

Arthritis↗
PubMed1999

Lymphoscintigraphy in oncology: a rediscovered challenge.

The validation of the sentinel node concept in oncology has led to the rediscovery of lymphoscintigraphy. By combining preoperative lymphatic mapping with intraoperative probe detection this nuclear medicine procedure is being increasingly used to identify and detect the sentinel node in melanoma, breast cancer, and in other malignancies such as penile cancer and vulvar cancer. In the past lymphoscintigraphy has been widely applied for various indications in oncology, and in the case of the internal mammary lymph-node chain its current use in breast cancer remains essential to adjust irradiation treatment to the individual findings of each patient. In another diagnostic area, lymphoscintigraphy is also useful to document altered drainage patterns after surgery and/or radiotherapy; its use in breast cancer patients with upper limb oedema after axillary lymph-node dissection or in melanoma patients with lower-extremity oedema after groin dissection can provide information for physiotherapy or reconstructive surgery. Finally, the renewed interest in lymphoscintigraphy in oncology has led not only to the rediscovery of findings from old literature reports, but also to a discussion about methodological aspects such as tracer characteristics, image acquisition or administration routes, as well as to discussion on the study of migration patterns of radiolabelled colloid particles in the context of cancer dissemination. All this makes the need for standardized guidelines for lymphoscintigraphy mandatory.

Breast Neoplasms↗
PubMed1999

[Contribution of nuclear medicine to lymphatic mapping and sentinel node identification in oncology].

An overview of the current applications of nuclear medicine for lymphatic mapping and sentinel node identification is given. The validation of the sentinel node concept in oncology has led to the rediscovery of lymphoscintigraphy. By combining preoperative lymphatic mapping with intraoperative gamma probe detection this nuclear medicine procedure is increasingly used to identify and detect the sentinel node in melanoma, breast cancer, and in other malignancies such as penile cancer and vulvar cancer. In melanoma, the adequate combination of dynamic and static gamma camera images enables lymph node visualization with identification of the sentinel node in more than 97% of the cases. The variability in drainage in areas such as trunk, head and neck makes lymphoscintigraphy indispensable in protocols of sentinel node biopsy. The reproducibility of lymphoscintigraphy for sentinel node detection varies from 85% to 88% and the method appears to have a high interobserver agreement. In contrast to the procedure of lymphoscintigraphy for melanoma, for which the only dilemma remaining is probably the choice of the tracer, in breast cancer there has not yet been reached a consensus for many topics such as tracer characteristics, injection volume, and principally the site of administration. Lymphoscintigraphy by subdermal tracer administration is able to detect axillary lymph nodes in 98% of the cases but the method is accompanied by a low visualization incidence (2%) of drainage outside the lower axilla such as the internal mammary chain. This latter aspect appears to occur in 16% to 35% in the series using peri- or intratumoural administration with an axillary rate of visualization of 75% to 98%. Although peritumoural administration is predominantly associated with late lymph node detection, the early appearance observed after subdermal and intratumoural tracer injection justifies the obtention of early gamma camera images. The strategies of identification of the sentinel node depend strongly on the results of lymphoscintigraphy. In melanoma, the rapid lymphatic drainage and the visualization of afferent lymphatic vessels enables sentinel node identification by lymphoscintigraphy in almost the totality of the cases and intraoperative probe detection may subsequently be performed. In breast cancer, the slower drainage pattern may hamper image interpretation and diagnostic conclusion. Considering the first appearing node and the visualization of an afferent lymphatic vessel as the major criteria to identify the sentinel node, scintigraphy may be considered conclusive in approximately 75% of the cases, and not conclusive in about a fourth part of the cases in which 2 or more lymph nodes appear simultaneously without lymph vessel delineation. When lymphoscintigraphy is not conclusive, additional lymphatic mapping with blue dye is recommended to definitively identify the sentinel node. The use of nuclear medicine techniques for the sentinel node procedure will become an important part of clinical work in the nuclear medicine and surgical oncology practice of the next years. Principally mammary lymphoscintigraphy demands from the nuclear medicine community and allied disciplines a prompt standardization of the technique to solving some controversial aspects such as tracer requirements, administration route and interpretation criteria.

Biopsy↗
PubMed1999

Correlative 201Tl SPECT, MRI and ex vivo 201Tl uptake in detecting and characterizing cervical lymphadenopathy in head and neck squamous cell carcinoma.

UNLABELLED: The value of SPECT with 201Tl chloride, in combination with MRI (particularly short inversion-time inversion recovery [STIR] sequences that suppress fat signals) to detect and characterize cervical lymphadenopathies (nodes > or = 1 cm), and ex vivo lymph node 201Tl uptake were studied in patients with squamous cell carcinoma of the head and neck. METHODS: Preoperative SPECT and MRI, displayed in similar planes, were compared with the histologic findings in 15 neck dissection specimens from 12 patients with squamous cell carcinoma of the head and neck (9 with unilateral and 3 with bilateral neck dissection). Results were evaluated topographically with regard to the lymph node compartments (levels) of the neck. In addition, in 8 of these patients, the 201Tl activity of dissected lymph nodes of 10 neck sides was measured immediately after surgery in a gamma counter and expressed as percentage of the injected dose per gram tissue (%ID/g). RESULTS: Sixty-two lymph node levels were evaluated histologically. The high sensitivity of MRI (92% versus 71% for 201Tl SPECT), which correctly detected lymph node involvement in 22 of 24 levels, and the high specificity of 201Tl SPECT (92% versus 71% for MRI), which correctly characterized as negative 35 of 38 lymph node levels without metastasis on histology, led to a combined 201Tl SPECT/MRI accuracy of 92%. 201Tl SPECT was particularly effective in excluding involvement in 9 tumor-free neck levels with pathologically enlarged lymph nodes on MRI but failed to confirm involvement in 5 other tumor-positive levels. Mean 201Tl uptake in 53 lymph nodes with confirmed histologic involvement was significantly higher than uptake in 145 tumor-free lymph nodes (0.0043+/-0.0022 %ID/g versus 0.0023+/-0.0014 %ID/g, P = 0.0001), muscle and fat tissue but clearly lower than salivary gland uptake. CONCLUSION: Although 201Tl SPECT is not sensitive enough to be used as an independent imaging modality for staging of the neck, its correlative application with MRI appears to be an accurate method for the assessment of regional spread in head and neck squamous cell carcinoma. The ability of 201Tl SPECT to characterize neck lymphadenopathies detected by MRI appears to be based on the difference in 201Tl concentration found in lymph nodes with and without tumor involvement.

Adult↗
PubMed1999

Radioimmunotherapy in medullary thyroid cancer using bispecific antibody and iodine 131-labeled bivalent hapten: preliminary results of a phase I/II clinical trial.

The toxicity and therapeutic efficacy of escalating doses of anti-carcinoembryonic antigen x anti-N alpha-(diethylenetriamine-N,N,N',N''-tetraacetic acid)-In bispecific monoclonal antibody (F6-734) and iodine 131-labeled bivalent hapten were determined in a Phase I/II trial. A total of 26 patients with recurrences of medullary thyroid cancer documented by imaging and a rise in serum thyrocalcitonin were enrolled. Twenty to 50 mg of F6-734 and 40-100 mCi of 131I-hapten were injected 4 days apart. Quantitative scintigraphy was performed after the second injection for dosimetry estimations in eight cases. Clinical, biological, and morphological follow-up was carried out for 1 year after treatment. The mean percentage of injected activity per gram of tumor at the time of maximum uptake was 0.08% (range, 0.003-0.26%). The tumor biological half-life ranged from 3 to 95 days, and tumor doses ranged from 2.91 to 184 cGy/mCi. The estimated tumor-to-nontumor dose ratios were 43.8 x 53.4, 29.6 x 35.3, 10.9 x 13.6, and 8.4 x 10.0 for total body, red marrow, liver, and kidney, respectively. Grade III/IV hematological toxicity was observed in seven patients, most of them with bone metastases. Among the 17 evaluable patients, 4 pain reliefs, 5 minor tumor responses, and 4 biological responses with decrease of thyrocalcitonin were observed. Nine patients developed human anti-mouse antibody. Dose-limiting toxicity was hematological, and maximum tolerated activity was 48 mCi/m2 in this group of patients, most of whom had suspected bone marrow involvement. The therapeutic responses observed in patients mainly with a small tumor burden are encouraging for the performance of a Phase II trial with minimal residual disease.

Adolescent↗
PubMed1999

Nuclear medicine therapy of neuroblastoma.

Specific targeting of radionuclides to neuroblastoma, a neural crest tumour occurring predominantly in young children and associated with a relatively poor prognosis, may be achieved via the metabolic route (MIBG), receptor binding (peptides) or immunological approach (antibodies). The clinical role of 131I-MIBG therapy and radioimmunotherapy in neuroblastoma is discussed. In recurrent or progressive metastatic disease after conventional treatment modalities have failed, 131I-MIBG therapy, with an overall objective response rate of 35%, is probably the best palliative treatment, as the invasiveness and toxicity of this therapy compare favourably with that of chemotherapy, immunotherapy and external beam radiotherapy. In patients presenting with inoperable stage III and IV neuroblastoma, 131I-MIBG therapy at diagnosis is at least as effective as combination chemotherapy but is associated with much less toxicity. In patients with recurrent disease 131I-MIBG therapy in combination with hyperbaric oxygen therapy proved feasible and encouraging effects on survival have been observed. Attempts to intensify the treatment in relapsed patients by combination of 131I-MIBG therapy with high dose chemotherapy and/or total body irradiation have met with considerable toxicity. Developments in MIBG therapy aiming at improving the therapeutic index are mentioned. Early results of radioimmunotherapy using 131I-UJ13A or 131I-3F8 monoclonal antibodies have shown moderate objective response and considerable side effects in patients with stage IV neuroblastoma, who had relapsed or failed conventional therapy. New developments in radioimmunotherapy of neuroblastoma include the use of chimaeric antibodies, the enhancement of tumour uptake by modulation of antigen expression or by increasing the tumour perfusion/vascularity/permeability, the use of other labels and multistep targeting techniques, e.g. using bispecific monoclonal antibodies.

3-Iodobenzylguanidine↗
PubMed1998

Radionuclide cancer therapy.

Therapeutic nuclear medicine is rapidly developing as an additional treatment modality in oncology. Its unique characteristics are the systemic, yet selective delivery of radiation doses in target tissues, its non-invasiveness, the relative lack of immediate and late side effects, and the advantage that uptake and retention in the tumor can be pre-assessed by tracer studies. Many different tumor seeking radiopharmaceuticals are being used for therapy by different routes and a variety of targeting mechanisms. The current clinical role of radionuclide therapy is briefly reviewed, as well as more general aspects and considerations, such as mechanisms for tumor targeting, the choice of radionuclide labels, radiopharmacy, drug delivery, radiation protection, dosimetry and toxicity.

Drug Carriers↗
PubMed1998

Role of nuclear medicine in melanoma.

Melanoma is a malignant tumour of the melanocytes presenting characteristic metabolic and biological features, which remains a difficult and important issue in oncology. As a functional modality, nuclear medicine offers a variety of possibilities to assist in the clinical management of this disease. A brief survey of currently available techniques is presented for the diagnosis, staging and follow up, either by organ imaging or by using a great spectrum of tumour-seeking radiopharmaceuticals. The role of lymphoscintigraphy in melanoma is emphasized, as well as the supportive role of nuclear medicine in the surgical theater, enabling selective lymph node dissection by the sentinel node procedure and high dose regional chemotherapy by isolated limb perfusion. Although hardly used for metastatic melanoma so far, with all its tumour-seeking approaches nuclear medicine holds a therapeutic potential for this disease as well.

Humans↗
PubMed1997

Renal excretion of iodine-131 labelled meta-iodobenzylguanidine and metabolites after therapeutic doses in patients suffering from different neural crest-derived tumours.

Iodine-131 labelled meta-iodobenzylguanidine ([131I]MIBG) is used for diagnostic scintigraphy and radionuclide therapy of neural crest-derived tumours. After administration of therapeutic doses of [131I]MIBG (3.1-7.5 GBq) to 17 patients (n=32 courses), aged 2-73 years, 56%+/-10%, 73%+/-11%, 80%+/-10% and 83%+/-10% of the dose was cumulatively excreted as total radioactivity in urine at t=24 h, 48 h, 72 h and 96 h, respectively. Except for two adult patients, who showed excretion of 14%-18% of [131I]meta-iodohippuric acid ([131I]MIHA), the cumulatively excreted radioactivity consisted of >85% [131I]MIBG, with 6% of the dose excreted as free [131I]iodide, 4% as [131I]MIHA and 2.5% as an unknown iodine-131 labelled metabolite. Cumulative renal excretion rates of total radioactivity and of [131I]MIBG appeared to be higher in neuroblastoma and phaeochromocytoma patients than in carcinoid patients. Based on the excretion of small amounts of [131I]meta-iodobenzoic acid in two patients, a possible metabolic pathway for [131I]MIBG is suggested. The degree of metabolism was not related to the extent of liver uptake of radioactivity.

3-Iodobenzylguanidine↗
PubMed1997

Localizing the sentinel node in cutaneous melanoma: gamma probe detection versus blue dye.

BACKGROUND: Sentinel node (SN) biopsy can be used to select patients with melanoma for therapeutic lymphadenectomy. We investigated the value of two methods to locate the SN: patent blue dye (PBD) and gamma probe detection of 99mTc-nanocolloid. METHODS: One hundred ten patients with cutaneous melanoma were studied. Lymphoscintigraphy with 99mTc-nanocolloid was performed to determine the position of the SN. Before operation, PBD was injected at the same site as the radiopharmaceutical. When a blue node was identified intraoperatively, its radioactivity level was measured with the probe. In the absence of blue coloration, the probe was used to trace the SN. RESULTS: Scintigrams visualized a total of 219 SNs in 141 basins. Eight SNs were not explored. One SN was not found. The remaining 210 and 27 additional intraoperatively identified SNs were excised. From the total of 237 removed SNs, 200 (84%) were found using PBD only. All 37 nodes that were not found with the PBD were localized with the probe so that the probe combined with PBD identified 99.5% of all SNs. In 23 patients the SN contained tumor. In three patients the SN was false-negative for metastasis. CONCLUSION: The gamma probe together with PBD can identify more SNs (99.5%) than lymphatic mapping with PBD alone (84%).

Adolescent↗