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Esophageal cancer.

Accurate pretherapy staging for esophageal cancer is important for stage-directed therapy. Precise staging is also essential for quality control and ensuring the validity of clinical trials. Endoscopic ultrasound is currently the best technique in local regional staging. Various investigators have attempted to overcome the problems of nontraversable lesions and restaging after neoadjuvant therapy. Positron emission tomography scan was shown to be especially useful in identifying distant metastases. Its more widespread use is likely to impact on treatment strategies. Surgical resection remains the mainstay of treatment of esophageal cancer. Improvement in immediate postoperative morbidity, mortality, and long-term survival was shown by various reports to relate to experience and volume. The concept of three-field dissection was further defined by illustrating the importance of lymphadenectomy around the recurrent laryngeal nerves. Multimodality treatments continue to receive attention. Several studies have established the patterns of practice in the United States in treating esophageal cancer. Chemoradiation programs are gaining a more important role and are widely used, although their exact roles are uncertain. Closely related to this area of research is the search of molecular markers of favorable response to such therapies. Concerning palliative treatment for esophageal cancer, self-expanding metallic stents have a definite role in patients with malignant dysphagia. Their results and complications are reviewed. Lastly, quality-of-life issues have assumed more importance in studies in oncology. Prospective quality-of-life data should be evaluated in future studies on different treatment methods for this deadly disease.

Journal Article↗

The evolving role of androgen deprivation therapy in the management of prostate cancer.

Androgen deprivation therapy (ADT) plays a central role in the management of prostate cancer. ADT is the mainstay of treatment for metastatic disease; the most common method is gonadal suppression via luteinizing hormone release hormone (LH) agonists, with or without antiandrogens. Antiandrogen monotherapy remains investigational, as is the appropriate role of 5alphareductase inhibition for prostate cancer. Intermittent ADT offers the promise of improved quality of life and reduced cost without a decrease found to date in oncologic efficacy. A growing menu of options exists for secondary androgen deprivation after disease progression on primary therapy: these include high-dose antiandrogens, estrogens, and adrenal androgen suppressants. ADT is being used with increasing frequency as primary monotherapy in patients with localized disease, but only small, nonrandomized studies of highly selected patients have been reported to date. Neoadjuvant ADT (NADT) has been demonstrated in prospective, multi-institutional trials to improve outcomes for patients with high-risk or locally advanced disease undergoing external-beam radiotherapy. Trials for patients with lower-risk, localized disease are still ongoing. Neoadjuvant therapy does not improve outcomes for patients with localized disease opting for radical prostatectomy (RP) and has not been well studied in association with brachytherapy. The side effects of ADT can be managed increasingly successfully; in particular, the introduction of zoledronate may reduce the impact of ADT-associated osteoporosis. Finally, contemporary practice pattern data suggest that use of ADT is increasing across patient risk groups, both in contexts where such therapy is well supported by current evidence and in others where it is not.

Algorithms↗

Problems in neoadjuvant chemoradiotherapy preceding surgery for advanced squamous cell carcinoma of the thoracic esophagus.

The adverse effect of neoadjuvant chemoradiotherapy on the postoperative course in esophageal cancer was studied in 9 patients undergoing neoadjuvant chemoradiotherapy preceding surgery for thoracic esophageal carcinoma possibly involving adjacent organs (neoadjuvant group), and 13 patients undergoing surgery without neoadjuvant therapy for same disease (control group). The two groups were compared for volume of intraoperative hemorrhage, surgical duration, frequency of postoperative morbidity, and for postoperative changes in blood platelet counts, and serum thrombopoietin and interleukin-6 levels. Mean intraoperative blood loss was 1121 g (580-1,662 g) in the neoadjuvant group and 546.5 g (274.7-778.3 g) in controls group (Student's T test: p < 0.01). No significant difference was seen found between the two groups in the degree of postoperative deterioration in cardiopulmonary function or in interleukin-6 levels. Blood platelet counts decreased in both groups until postoperative day 7, but recovery on postoperative day 14 was significantly depressed in the neoadjuvant group compared to controls. Serum thrombopoietin levels were higher in the neoadjuvant group than in controls (Mann-Whitney U-test: p < 0.05). We found that neoadjuvant chemoradiotherapy induces latent postoperative myelosuppression and may lead to intractable infection.

Aged↗

Predictors of pathological stage before neoadjuvant androgen withdrawal therapy and radical prostatectomy. The Canadian Urologic Oncology Group.

PURPOSE: This prospective randomized trial was used to compare predictive factors for organ confined margin negative status after radical prostatectomy with and without a 3-month course of neoadjuvant androgen withdrawal therapy. MATERIALS AND METHODS: A total of 213 patients with localized adenocarcinoma of the prostate were randomized to radical prostatectomy with or without a 3-month course of 300 mg. neoadjuvant cyproterone acetate daily. Multivariate logistic regression analysis was used to determine significant predictors of organ confined margin negative status after radical prostatectomy in both groups. Parameters evaluated included baseline prostate specific antigen (PSA 4 or less, 4.1 to 10, greater than 10 ng./ml.), clinical stage (T2c versus T2b or less), biopsy Gleason score and percentage of surface area of biopsies involved with cancer. The multivariate analysis was repeated with PSA density and the natural logarithm of PSA to optimize the model. RESULTS: In the radical prostatectomy alone arm a model incorporating only PSA density was the best predictor of organ confined margin negative status. In the neoadjuvant androgen withdrawal therapy arm a model incorporating biopsy Gleason score, PSA density and clinical stage was the best predictor. CONCLUSIONS: The conventional predictors of pathology at radical prostatectomy, biopsy Gleason score, PSA density and clinical stage retain significance as predictors in patients treated with a 3-month course of neoadjuvant androgen withdrawal therapy before radical prostatectomy.

Adenocarcinoma↗

Phase II trial of concurrent paclitaxel, carboplatin, and external-beam radiation followed by surgical resection in locally advanced non-small-cell lung cancer, protocol 99-444.

PURPOSE: We conducted a phase II study to evaluate the utility and outcomes of concurrent weekly low-dose chemotherapy with concurrent radiation in an effort to "downstage" patients with locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eighteen patients with pathologically confirmed stage IIIA (T1-3 N2 or T3 N1) and 3 patients with stage IIB (T3 N0) NSCLC were enrolled. Seventeen of 18 patients with stage IIIA cancer had N2 disease. A chemotherapy/radiation schedule consisted of paclitaxel 50 mg/m(2 )and carboplatin administered at an area under the curve of 2 weekly for 5 weeks along with chest irradiation of 45 Gy. Patients with regressed or stable disease upon restaging were considered surgical candidates. Patients deemed inoperable were given additional radiation therapy. RESULTS: Twenty-one patients were enrolled from April 2000 to March 2004. Data from 21 patients were available for evaluation at the time of analysis. Grade 3/4 constitutional and pulmonary toxicity was <or= 10%. Grade 3/4 lymphopenia was noted in 9.5% of patients. One treatment-related death from postoperative acute respiratory distress syndrome occurred. Seventeen of 21 patients completed neoadjuvant therapy and 15 patients underwent resection. Four of 15 patients had a complete histopathologic response at the time of resection. Follow-up data were available on 20 patients. Overall, the median progression-free survival was 14.1 months. The median overall survival was 26.1 months. Six of 20 patients remain relapse free (range, 19.3-70.8 months). CONCLUSION: Neoadjuvant low-dose weekly chemotherapy given concurrently with conventional chest irradiation might improve outcomes in patients with stage IIB and IIIA NSCLC with acceptable toxicity.

Adult↗

Advances in the treatment of sarcomas of the extremity. Current status of limb salvage.

Nonamputative limb salvage is possible for many patients with malignant skeletal or soft tissue sarcomas. Significant advances in pathology, radiology, chemotherapy, radiation therapy, and surgical and biomechanical techniques have contributed to a better understanding of these diseases, and have provided the necessary techniques to achieve local tumor control without amputation. Integration of diagnostic and treatment modalities has reduced local recurrence and improved overall patient survival. Preoperative (neoadjuvant) therapy permits assessment of the treatment effect and appears to significantly improve selection of effective postoperative adjuvant therapy. As overall patient survival has improved, efforts to increase local tumor control and to evaluate long-term functional stability of the salvaged extremity are now possible.

Amputation, Surgical↗

Salvage chemotherapy for oligodendroglioma.

The authors present their experience with salvage chemotherapy for oligodendroglioma, an uncommon brain tumor that responds predictably to PCV (procarbazine, lomustine (CCNU), and vincristine) when given as initial therapy. The authors reviewed the records of patients with oligodendrogliomas who received a second, third, or fourth cytotoxic regimen prescribed to combat tumor recurrence documented by computerized tomography or magnetic resonance imaging following an initial chemotherapy program. Initial regimens were prescribed at various time points: as neoadjuvant therapy prior to radiotherapy, as adjuvant therapy in conjunction with radiotherapy, or at recurrence following radiotherapy. Response criteria were based on measurable changes in tumor size following published guidelines. Twenty-three patients (14 men and nine women) aged 25 to 58 years (median 36 years) received 33 salvage regimens. When non-PCV chemotherapy had been the prior regimen, seven (88%) of eight patients responded to salvage chemotherapy, all seven (100%) responding to PCV. Administration of PCV was effective after regimens of carmustine and CCNU but was ineffective after prior administration of PCV. When PCV had been given any time previously, only four (19%) of 21 patients responded to salvage chemotherapy; however, four (40%) of 10 patients who received etoposide (VP-16)/cisplatin (CDDP) responded. Despite the small number of patients, two noteworthy trends emerge from these data: first, PCV is a highly effective salvage treatment when used at tumor recurrence following non-PCV chemotherapy regimens, and second, the synergistic combination of VP-16 and CDDP may exert substantial anti-oligodendroglioma activity, and it warrants further evaluation.

Adult↗

Antiangiogenic tetrathiomolybdate enhances the efficacy of doxorubicin against breast carcinoma.

Constitutive activation of nuclear factor kappaB is implicated to be a critical survival mechanism used by carcinoma cells to escape apoptosis. Tetrathiomolybdate (TM), a novel copper chelator, exhibits potent antiangiogenic properties, in part, through suppression of the nuclear factor kappaB signaling cascade. In this study, we determined whether TM enhances doxorubicin-induced apoptosis in SUM149 inflammatory breast carcinoma cells. Apoptosis was not observed in these cells after TM treatment. Moreover, SUM149 cells were relatively resistant to doxorubicin-induced apoptosis ranging from 9.9 +/- 2.9% to 21.5 +/- 2.0% apoptotic cells for 0.1 to 2.5 micro M doxorubicin treatment. A greater-than-additive increase (33.8 +/- 4.6%, 57.5 +/- 5.2%, or 83.7 +/- 1.0% apoptosis with TM and 0.1, 0.5, or 2.5 micro M doxorubicin, respectively) in apoptosis was observed in cells treated with the combination therapy of TM and doxorubicin. In SUM149 xenografts, TM and doxorubicin significantly retarded tumor growth in comparison with either agent administered alone (P < 0.03). Tumor cell apoptosis in the combination therapy-treated mice was 113.3 +/- 20% greater than that in TM-treated mice and 52.4 +/- 14.3% greater than that in doxorubicin-treated mice. These results suggest that TM may enhance the rate of pathological complete response when used in combination with an anthracycline in neoadjuvant therapy of breast carcinoma.

Adenosine Triphosphatases↗

Neoadjuvant or adjuvant therapy for resectable gastric cancer? A practice guideline.

OBJECTIVE: To make recommendations on the use of neoadjuvant or adjuvant therapy in addition to surgery in patients with resectable gastric cancer (T1-4, N1-2, M0). OPTIONS: Neoadjuvant or adjuvant treatments compared with "curative" surgery alone. OUTCOMES: Overall survival, disease-free survival, and adverse effects. EVIDENCE: The MEDLINE, CANCERLIT and Cochrane Library databases and relevant conference proceedings were searched to identify randomized trials. VALUES: Evidence was selected and reviewed by one member of the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI) Gastrointestinal Cancer Disease Site Group and methodologists. A systematic review of the published literature was combined with a consensus process around the interpretation of the evidence in the context of conventional practice, to develop an evidence-based practice guideline. This report has been reviewed and approved by the Gastrointestinal Cancer Disease Site Group, comprising medical oncologists, radiation oncologists, surgeons, a pathologist and 2 community representatives. BENEFITS, HARMS AND COSTS: When compared with surgery alone, at 3 years adjuvant chemoradiotherapy has been shown to increase overall survival by 9% (50% v. 41%, p = 0.005) and to improve relapse-free survival from 31% to 48% (p = 0.001). At 5 years, it has been shown to increase overall survival by 11.6% (40% v. 28.4%) and to improve relapse-free survival from 25% to 38% (p < 0.001). Treatment has been associated with toxic deaths in 1% of patients. The most frequent adverse effects (> grade 3 [Southwest Oncology Group toxicity scale] are hematologic (54%), gastrointestinal (33%), influenza-like (9%), infectious (6%) and neurologic (4%). The radiation fields used can possibly damage the left kidney, resulting in hypertension and other renal problems. Furthermore, this therapy could increase the demand on radiation resources. Physicians and patients should understand the tradeoffs between survival benefit and toxicity and cost before making treatment decisions. RECOMMENDATIONS: After surgical resection, patients whose tumours have penetrated the muscularis propria or involve regional lymph nodes should be considered for adjuvant combined chemoradiotherapy. The current standard protocol consists of 1 cycle of 5-fluorouracil (5-FU) (425 mg/m2 daily) and leucovorin (20 mg/m2 daily) administered daily for 5 days, followed 1 month later by 45 Gy (1.8 Gy/d) of radiation given with 5-FU (400 mg/m2 daily) and leucovorin (20 mg/m2 daily) on days 1 through 4 and the last 3 days of radiation. One month after completion of radiation, 2 cycles of 5-FU (425 mg/m2 daily) and leucovorin (20 mg/m2 daily) in a daily regimen for 5 days are given at monthly intervals. There is no evidence on which to make a recommendation for patients with node-negative tumours that have not penetrated the muscularis propria. For patients unable to undergo radiation, adjuvant chemotherapy alone may be of benefit, particularly for those with lymph-node metastases. The optimal regimen remains to be defined. There is insufficient evidence from randomized trials to recommend neoadjuvant chemotherapy, or neoadjuvant or adjuvant radiotherapy or immunotherapy, either alone or in combination, outside a clinical trial. VALIDATION: A draft version of this document was circulated to 166 clinicians using a 21-item feedback questionnaire. Ninety-nine (63%) returned the questionnaire, and 74 of these indicated that the guideline was relevant to their clinical practice and completed the survey. Of the 74 clinicians, 52 (70%) agreed that the document should be approved as a practice guideline. SPONSORS: The CCOPGI is supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Chemotherapy, Adjuvant↗

Neoadjuvant cisplatin, methotrexate and vinblastine for muscle-invasive bladder cancer: long-term followup.

A total of 26 patients with locally advanced bladder cancer received chemotherapy consisting of cisplatin, methotrexate and vinblastine. Radical cystectomy was performed in 24 of 26 patients (92%) receiving neoadjuvant therapy, with a pathological complete response in 6 (23%) and pathological partial response in 1 (4%) for an overall response rate of 35% (95% confidence limits 17 to 56%). The overall median survival time is currently undefined. Of the patients 15 (58%) are alive with a median followup of 48.6 months. Response rates from this neoadjuvant chemotherapy appear to be similar to those reported with methotrexate, vinblastine, doxorubicin and cisplatin, and may represent a therapeutically equivalent regimen but neither may be curative in the majority of the patients.

Adult↗

M-VAC or MVC for the treatment of advanced transitional cell carcinoma: metastatic, induction, and adjuvant.

The cisplatin-based combination chemotherapy regimens of M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) or MVC (methotrexate, vincristine, cisplatin) were given to 25 patients with metastatic urothelial carcinoma, 13 with locally advanced bladder cancer, and 10 as adjuvant therapy after radical surgery. Toxicity was significant with two deaths. Forty-eight percent of the patients with metastatic disease had a complete (20%) or partial (28%) response. Survival was only improved if a CR was achieved. Nine of 13 patients given M-VAC/MVC as neoadjuvant therapy underwent cystectomy and six are free of disease (mean 31 months). Three of the four patients who did not have radical surgery are also free of disease. These regimens appear to be superior to cisplatin alone. In the overall response evaluation, however, toxicity is greater.

Antineoplastic Combined Chemotherapy Protocols↗

The chemotherapy of head and neck cancer.

Studies of combination therapy [with agents such as cisplatin, 5-fluorouracil (5-FU) and methotrexate] have shown some improvements in response rate; however, no obvious survival advantage over monotherapy in the treatment of patients with metastatic or advanced locoregional cancer of the head and neck have been observed. In the neoadjuvant setting, chemotherapy is helpful in preserving the larynx and hypopharynx but has no proven impact (positive or negative) on survival. New treatment options are needed to improve survival in head and neck cancer. Among the new options for chemotherapy in metastatic/recurrent disease is docetaxel. With monotherapy, response rates of 23-42% are seen, and, when used in combination with cisplatin and 5-FU, response rates of 52-100% have been reported in phase I/II trials. A phase III trial of the addition of docetaxel to standard neoadjuvant therapy with cisplatin and 5-FU is now underway.

Antineoplastic Agents↗

[Function preserving surgery of limb sarcomas: history and improvements].

In the seventies, limb-sparing surgery and radiation therapy appeared capable of successfully treating the great majority of adult patients with soft tissue sarcomas of the extremities. No survival benefit could be demonstrated in the patients selected for amputation. Microscopically positive surgical margins are related to a greater risk of local recurrence, whereas overall survival is compromised by high grade and large tumor size. Presurgery multidisciplinary discussion, management in reference center and management within cancer network independently predict conformity to the clinical practice guidelines. Reoperation should be a planned part of definitive management whenever the initial surgical procedure was done without a histologic diagnosis or was not planned to be a wide excision. Soft tissue flap reconstruction facilitates therapy for patients with locally advanced tumors so that patients with larger tumors can undergo resection, limiting complications and limb sacrifice. Vascular reconstruction is a feasible option in case of involvement of major vessels. Isolated limb perfusion (ILP) with TNF and chemotherapy is an efficient limb-sparing neoadjuvant therapy for locally advanced limb soft tissue sarcomas. Efficacy and safety of low-dose TNFalpha could greatly facilitate ILP procedures in the near future.

Arm↗

Cancer of the esophagus: the Wayne State University experience.

The rationale for the preoperative therapy for cancer of the esophagus is described. The first trial with infusion FUra mitomycin-c and radiation performed at Wayne State University (WSU) is described. The dramatic responses were duplicated when cisplatin was substituted for mitomycin. Moreover, survival was improved over the mitomycin-c trial. These neoadjuvant trials led to a third WSU clinical trial in which the neoadjuvant therapy became the definitive therapy.

Antineoplastic Combined Chemotherapy Protocols↗

[Strategy for multimodal therapy of soft tissue sarcomas of the trunk and extremities].

The aim of surgical therapy for soft tissue sarcoma is local tumor control with the best possible functional result. Only small, superficial, well-differentiated or strictly intracompartmental lesions should be treated by surgery alone. In all other cases, especially for recurrent lesions, multimodality treatment strategies should be applied. For locally advanced lesions, neoadjuvant therapy can achieve tumor response. Aside from systemic chemotherapy and preoperative radiation therapy, isolated limb perfusion with tumor necrosis factor and melphalan can aid local control, and thus enable limb-sparing resection. The application of adjuvant systemc chemotherapy must be further investigated in prospective trials before a general recommendation can be given. If the patient has distant metastases, decisions regarding treatment of the local lesion must take into account quality-of-life aspects. Should complete resection not be possible, multimodality strategies may be able to control the tumor for a longer period.

Chemotherapy, Adjuvant↗

The effect of micronized estradiol on bone turnover and calciotropic hormones in older men receiving hormonal suppression therapy for prostate cancer.

To examine the effect of estradiol (E(2)) without the confounding effect of hypothalamic-pituitary feedback, we studied men with prostate cancer in whom gonadotropin secretion was suppressed by LH-releasing hormone agonists (LHRH-A). Fourteen men over 65 yr of age and receiving established LHRH-A treatment (EST group) without bony metastases and 12 men who received LHRH-A as neoadjuvant therapy for locally advanced prostate cancer (NEO group) were randomized (double blind) to receive either 1 mg/d micronized E(2) (n = 12) or placebo (PL; n = 13) for 9 wk. E(2), estrone, testosterone, SHBG, PTH, and 25-hydroxy- and 1,25-dihydroxyvitamin D levels as well as markers of bone resorption [N- and C-telopeptide cross-links (NTX and CTX) and deoxypyridinoline] and bone formation (bone-specific alkaline phosphatase, osteocalcin, and N-terminal type I collagen) were measured before LHRH-A in the NEO group, before [baseline (BL)] and after 9 wk of E(2) or PL in all patients, and 6 wk after E(2) treatment in the EST group. In the NEO group, hormone levels fell 3 wk after the initial LHRH-A injection, and deoxypyridinoline increased significantly (P = 0.006). At BL, the EST group had higher bone turnover due to the longer duration of LHRH-A treatment. With E(2) treatment, E(2) levels rose into the normal male range, and two resorption markers decreased significantly from BL by 33% for NTX (P < 0.001) and 28% for CTX (P = 0.009). Bone formation markers did not change. PTH increased by 43% from BL (P < 0.01) in the E(2) group and decreased 16% from BL in the PL group (P < 0.01). Ionized calcium did not change in the E(2) group, but increased in the PL group by 2.3% (P < 0.01). NTX and CTX increased 6 wk after E(2) withdrawal in the EST group. We conclude that E(2) inhibits bone resorption in hypogonadal men through a direct skeletal effect that is independent of PTH. Low dose estrogen may be an option for the prevention and/or treatment of bone loss in this population.

Alkaline Phosphatase↗

[Recent trends in pathological diagnosis of breast cancer].

Recently, the significance of pathological evaluation in the field of diagnosis and treatment of breast cancer has become larger and many kinds of pathological examinations have been adopted. In the present review, the up-to-date information concerning to new pathological examinations, necessary for appropriate diagnosis and therapy of breast cancer, are demonstrated. In the field of pathological diagnosis, the DIN classification and USC/VNPI system are demonstrated. In addition, intra-operative examination of sentinel lymph node, post-operative evaluation of margin status of breast-conserving surgery specimen and definition of pathological effect in neoadjuvant therapy, are routinely performed. Furthermore, examinations of hormone receptor status, HER-2 over-expression and lymphatic vessel invasion are thought to be necessary for determination of indication in adjuvant therapy.

Breast Neoplasms↗

Response prediction by FDG-PET after neoadjuvant radiochemotherapy and combined regional hyperthermia of rectal cancer: correlation with endorectal ultrasound and histopathology.

Accurate response assessment after neoadjuvant therapy is essential in patients with rectal cancer. The aim of this study was to assess the value of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting response of locally advanced rectal cancer to preoperative multimodal treatment. Twenty-two consecutive patients with locally advanced (uT3/4) primary rectal cancer were entered in this prospective pilot study. FDG-PET was performed before and after neoadjuvant radiochemotherapy (RCT) with combined regional hyperthermia (RHT). Treatment consisted of external-beam radiotherapy (45 Gy), chemotherapy (folinic acid and 5-fluorouracil) and regional pelvic hyperthermia followed by curative tumour resection 6-8 weeks later. Semi-quantitative measurements (SUV) of tumour FDG uptake were made before and 2-4 weeks after completion of neoadjuvant treatment. Two patients who did not receive post-therapeutic restaging by FDG-PET were excluded from the analysis. Results were correlated with findings on endorectal ultrasound (EUS, n=17 patients) and histopathology. Histopathological evaluation of the resected tumour revealed complete response in one patient, partial response in 12 and stable disease in seven. SUV reduction in tumours was significantly greater in responders than in non-responders [60% (+/-15%) vs 30% (+/-18%), P=0.003, CI=95%). Using a minimum post-therapeutic SUV reduction of 36% to define response, FDG-PET revealed a sensitivity of 100% (EUS: 33%) and a specificity of 86% (EUS: 80%) in response prediction; the corresponding positive and negative predictive values were 93% (EUS: 80%) and 100% (EUS: 33%), respectively. FDG-PET results were statistically significant (P<0.001, CI=95%). FDG-PET has great potential in the assessment of tumour response to neoadjuvant RCT in combination with RHT and is superior to EUS for this purpose.

Adolescent↗