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Biomedical subjects

G Bolis

Publications and source records attributed to G Bolis.

At least 37 records · Page 2Linked to original sources

Determinants of risk of invasive cervical cancer in young women.

We analysed determinants of risk of cervical cancer in women aged less than 45 years using data from a case-control study conducted in Italy. Cases were 261 women aged < 45 years with histologically confirmed invasive cervical cancer. Controls were 257 women aged < 45 years, with acute, non-neoplastic conditions, judged to be unrelated to any of the known or suspected risk factors for cervical cancer. In comparison with women reporting one or no sexual partner, the multivariate odds ratio (OR) of cervical cancer was 2.4 (95% confidence interval, CI, 1.3-4.6), for women reporting two or more sexual partners, and, in comparison with women reporting their first intercourse at 17 years of age or before, the multivariate OR was 0.5 (95% CI 0.3-0.9) in women aged > or =23 years at first intercourse. The risk of cervical cancer was higher in parous women and increased with number of births (OR = 8.1 for three or more births). Among parous women the risk tended to increase with later age at last birth; in comparison with parous women reporting their last birth before age 25, the OR was 1.9 in those reporting their last birth at > or =35 years. No clear association emerged between oral contraceptive use, smoking, education, social class and risk of cervical cancer.

Acute Disease↗

Survival and prognostic factors of early ovarian cancer.

Survival and prognostic factors were analysed in 150 patients with histologically confirmed epithelial ovarian cancer stage IA-IIA. The relapse-free and overall survival rates were, respectively, 81% and 88% after 3 and 74% and 84% after 5 years. The analysis of various prognostic factors indicates as the main factor the grade differentiation of the tumour.

Adult↗

Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group.

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.

Antineoplastic Agents↗

Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel.

PURPOSE: Topotecan, a topoisomerase I inhibitor, was evaluated in a multicenter, phase II study of women with epithelial ovarian carcinoma who relapsed after one or two prior regimens that included platinum and paclitaxel. PATIENTS AND METHODS: Topotecan 1.5 mg/m2 daily was administered as a 30-minute infusion for 5 consecutive days on a 21-day cycle. Eligibility criteria included bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of 2 or less, and adequate bone marrow, liver, and renal function. Efficacy was assessed by independent radiologic review. RESULTS: One hundred thirty-nine patients were treated; 81% were platinum resistant. Sixty-two patients had received one prior regimen and 77 patients had received two prior regimens. Nine patients were not assessable for response; however, all patients were included in the response analysis. The overall response rate was 13.7%; 12.4% in platinum-resistant and 19.2% in platinum-sensitive patients. Stable disease lasted at least 8 weeks in 27.3% of the patients. The median duration of response and time to progression were 18.1 and 12.1 weeks, respectively. The median survival was 47.0 weeks. Grade 4 neutropenia occurred in 82% of the patients (34% of the courses) and thrombocytopenia in 30% of the patients (9% of the courses). Infectious complications occurred in 6% of the courses. Nonhematologic toxicities were mild. There were no drug-related toxic deaths. CONCLUSION: As a single agent, topotecan has modest activity in women with advanced epithelial ovarian carcinoma who have progressed or not responded after one or two prior regimens with platinum and paclitaxel. Further investigation of combination regimens is indicated in the primary therapy for ovarian cancer based on the mechanism of action and tolerability.

Adult↗

Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding.

A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-GR 43,694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold--Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazoli din-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46,470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 micrograms/kg i.v.) in the Bezold--Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.

Animals↗

Generation and phenotypic characterization of new human ovarian cancer cell lines with the identification of antigens potentially recognizable by HLA-restricted cytotoxic T cells.

This study describes a simple method for long-term establishment of human ovarian tumor lines and prediction of T-cell epitopes that could be potentially useful in the generation of tumor-specific cytotoxic T lymphocytes (CTLs). Nine ovarian tumor lines (INT.Ov) were generated from solid primary or metastatic tumors as well as from ascitic fluid. Notably all lines expressed HLA class I, intercellular adhesion molecule-1 (ICAM-1), polymorphic epithelial mucin (PEM) and cytokeratin (CK), but not HLA class II, B7.1 (CD80) or BAGE. While of the 9 lines tested 4 (INT.Ov1, 2, 5 and 6) expressed the folate receptor (FR-alpha) and 6 (INT.Ov1, 2, 5, 6, 7 and 9) expressed the epidermal growth factor receptor (EGFR); MAGE-1 and p185HER-2/neu were only found in 2 lines (INT.Ov1 and 2) and GAGE-1 expression in 1 line (INT.Ov2). The identification of class I MHC ligands and T-cell epitopes within protein antigens was achieved by applying several theoretical methods including: 1) similarity or homology searches to MHCPEP; 2) BIMAS and 3) artificial neural network-based predictions of proteins MAGE, GAGE, EGFR, p185HER-2/neu and FR-alpha expressed in INT.Ov lines. Because of the high frequency of expression of some of these proteins in ovarian cancer and the ability to determine HLA binding peptides efficiently, it is expected that after appropriate screening, a large cohort of ovarian cancer patients may become candidates to receive peptide-based vaccines.

Antigens, Neoplasm↗

Case-control study of oestrogen replacement therapy and risk of cervical cancer.

OBJECTIVE: To examine the relation between use of oestrogen replacement therapy and risk of cervical cancer. DESIGN: Case-control study. SETTING: Northern Italy. SUBJECTS: 645 women aged 40-75 years with cervical cancer admitted between 1981 and 1993 to university and general hospitals. The control group consisted of 749 women aged 40-75 years admitted to the same hospitals with acute conditions judged to be unrelated to any of the known or suspected risk factors for cervical cancer. MAIN OUTCOME MEASURES: Use of oestrogen replacement therapy and risk of cervical cancer. RESULTS: 40 cases versus 86 controls had ever used oestrogens, and the corresponding multivariate odds ratio was 0.5 (95% confidence interval 0.3 to 0.8). The odds ratios of cervical cancer decreased with duration of use, being 0.6 (0.4 to 1.1) for less than 12 months' use and 0.5 (0.2 to 1.0) for use for 12 months or more compared with never users. The protection tended to be somewhat stronger for women reporting first oestrogen use before age 50. The odds ratio was 0.9 (0.5 to 1.7) for women who had taken oestrogens within the past 10 years and 0.4 (0.2 to 0.7) for those who had taken them 10 or more years ago. CONCLUSION: These findings suggest that exogenous oestrogens do not increase the risk of cervical cancer and may decrease the risk.

Adenocarcinoma↗

NMR solution structure of a novel hirudin variant HM2, N-terminal 1-47 and N64-->V + G mutant.

The 64 amino acid hirudin-like peptide HM2 (Hirudinaria manillensis) is one of the agents known to specifically block the blood-clotting enzyme thrombin, and therefore is used as a potential pharmacological tool for the treatment of arterial and venous thrombosis. This peptide and its derivatives provide a new set of probes for studies aimed at elucidating the structural basis of the inhibition of alpha-thrombin. We used 581, 699, and 492 nmr-derived constraints respectively in a protocol employing simulated annealing, followed by restrained molecular dynamics and restrained energy minimization to derive the three-dimensional structures of HM2 and its mutants the HM2 (V + G) and the HM2 (1-47). HM2 consists of a well-defined core region of two double-stranded beta-sheet and a disordered C-terminus. These features are shared by other members of the hirudin family. The same type of folding has also been observed for recombinant hirudins whose structure has been determined in solution by nmr spectroscopy and in the structure of the complex hirudin-thrombin determined by x-ray diffraction. Molecular dynamics (MD) simulation methods were applied in the study of the structural and dynamic fluctuation properties of the hirudin derivatives solvated by 1625 and 1276 water molecules with periodic boundary conditions for HM2 and HM2 (1-47), respectively. Trajectories of 100 and 50 ps for the two unconstrained systems were generated at constant temperature and pressure. Analysis of the MD simulation shows that the structure of the peptide core is fairly rigid and stable in itself while the conformation of the C-terminal tail, which is involved in the inhibitory mechanism of thrombin, fluctuates and appears as a disordered region.

Amino Acid Sequence↗

A phase I-II trial of fixed-dose carboplatin and escalating paclitaxel in advanced ovarian cancer.

We conducted a phase I-II study with escalating paclitaxel doses plus carboplatin at a fixed dose for previously untreated patients with advanced ovarian cancer in order to define the maximum tolerated dose. Eligible for the study were women with a histologically confirmed diagnosis of ovarian cancer stage III-IV according to the FIGO classification. In the first phase of the study, 6 patients were allocated escalating paclitaxel doses with fixed-dose carboplatin in order to establish the maximum tolerated dose. The starting dose of paclitaxel was 150 mg/m2 given after carboplatin (300 mg/m2) every 4 weeks for a total of six courses. The paclitaxel dose step was 25 mg/m2 up to 250 mg/m2. The study then progressed to a phase II trial using the maximum tolerated paclitaxel dosage reached during the escalating dose phase. A total of 27 patients entered phase I and 23 phase II. Neurotoxicity was observed in 47 patients (94%; 29 grade 1, 17 grade 2, 1 grade 3, according to the WHO classification). The intensity of neurotoxicity tended to be dose related: out of the 15 patients who received < or = 200 mg paclitaxel, a total of 14 grade 1, but no grade 2 or 3 neurotoxicities, were observed. The frequency of grade 1, 2 and 3 neurotoxicity was 15, 17 and 1, respectively, in the 35 women who received > or = 225 paclitaxel +300 mg carboplatin. There was no clear relationship between median WBC and platelet nadir and dose level. Among other toxicities, alopecia was observed in all 50 cases, hypersensitivity in two (4%) and myalgia in 41 (82%; 34 grade 1 and 7 grade 2). These frequencies tended to increase with the dose, but the relationship was not statistically significant. The overall response rate was 78% (39/50) with a complete response rate of 62% (31/50). In conclusion, this study suggests that carboplatin and paclitaxel can be administered safely to patients with advanced ovarian carcinoma. The maximum dose reached was 250 mg/m2 paclitaxel and 300 mg/m2 for carboplatin, but from a clinical point of view the maximum paclitaxel dose we would consider safe is 225 mg/m2.

Adult↗

Ovarian cancer risk and history of selected medical conditions linked with female hormones.

To investigate the role of selected medical conditions on the risk of ovarian cancer, we analysed data from a case-control study. Cases were 971 women below the age of 75 years with histologically confirmed epithelial ovarian cancer, admitted to a network of hospitals including the major teaching and general hospitals in the greater Milan area. Controls were 2758 women admitted to the same network of hospitals for acute, non-gynaecological, non-hormone related, non-neoplastic conditions. Obesity/severe overweight were inversely associated with the risk of ovarian cancer (multivariate relative risk, RR, 0.66, 95% confidence interval, CI, 0.52-0.85). Hyperlipidaemia was also inversely related to ovarian cancer risk, (RR 0.64, 95% CI 0.45-0.89). No relationship emerged between ovarian cancer risk and diabetes (RR 0.80, 95% CI 0.54-1.19), hypertension (RR 0.85, 95% CI 0.68-1.06), thyroid diseases (RR 0.89, 95% CI 0.63-1.13) and cholelithiasis (RR 0.86, 95% CI 0.66-1.12). A decreased frequency of ovarian cancer was seen in women with a history of uterine leiomyomas (RR 0.66, 95% CI 0.47-0.92) and benign ovarian cysts (RR 0.69, 95% CI 0.41-1.13).

Adult↗

Phase II study of weekly 4'-epidoxorubicin in patients with metastatic adenocarcinoma of the cervix: an EORTC Gynaecological Cancer Cooperative Group study.

In this study 22 patients with metastatic adenocarcinoma of the cervix were treated with a weekly bolus injection of 4'-epidoxorubicin at a dose of 12 mg/m2. Seventeen patients had received prior radiotherapy, all patients were chemo-naive. Toxicity was generally absent or very mild. One patient had a complete response and 2 patients had a partial response, one was an unconfirmed partial response, giving a response rate of 14%. Six patients had stable disease. The median progression-free survival and overall survival was 2.8 months and 6.1 months, respectively. In conclusion, 4'-epidoxorubicin used at this dosage and schedule has minimal activity in metastatic adenocarcinoma of the cervix.

Adenocarcinoma↗

Experience with independent radiological review during a topotecan trial in ovarian cancer.

BACKGROUND: The results of phase II clinical trials are usually based on response of tumours to new oncolytic agents as evidenced by radiological imaging techniques. In this trial, all claimed responders were reviewed at a specially convened meeting by the peer group of study investigators and a radiologist, independent of the study institutions. PATIENTS AND METHODS: One hundred eleven patients with advanced epithelial ovarian cancer who had previously been treated with a platinum based regimen and had subsequently relapsed and who had measurable disease were treated with topotecan at a dose of 1.5 mg/m2/day i.v. on five consecutive days repeated every 21 days to assess efficacy and tolerability. Ninety-three were considered eligible for the study per protocol and lesions were assessed by either computerised tomography (CT) or ultrasound (US). At the meeting, scans from all 24 (25.8%) claimed responders were reviewed, lesions remeasured by the radiologist and a group discussion led to a final response classification. RESULTS: Ninety-two patients were found to be eligible for the study and 14 (15.2%) were confirmed as responders. Ten were rejected as responders, mainly because the lesion did not decrease in size by < or = 50%, but one patient failed to meet the entry criteria. Remeasurement of CT scans was more objective than US scans. Difficulties were encountered during review of some CT scan sequences because of non-uniform imaging parameters. CONCLUSIONS: Independent radiological review in conjunction with the peer review group in this trial enabled rigorous and consistent application of response criteria. This decreased the response rate from 25.8% to 15.2%, but this represents a more objective assessment. CT scanning is an objective technique for assessing response rates in phase II studies whereas US is subjective and dose not necessarily allow accurate lesion assessment on subsequent examinations, nor allows independent review at a later date. For these reasons it should not be used in such studies for accurate lesion assessment. Cross-sectional imaging techniques such as CT and magnetic resonance imaging (MRI) do allow accurate lesion assessment and independent review at a later date, but standard protocols need to be instituted, to allow consistency and a comparison to be made with subsequent studies using the same agent and a broad comparison to be made with other agents.

Antineoplastic Agents↗

Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer.

PURPOSE: To compare the efficacy of a treatment with cisplatin plus cyclophosphamide given for 5 months and a short treatment with cisplatin alone in advanced ovarian cancer, we conducted a multicenter randomized clinical trial. PATIENTS AND METHODS: Eligibility criteria were as follows: first diagnosis of histologically confirmed invasive epithelial ovarian cancer of International Federation of Gynecology and Obstetric (FIGO) stage III-IV, age younger than 75 years, and Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Within 28 days of cytoreductive surgery, eligible women were randomly assigned treatment with weekly cisplatin 50 mg/m2 for nine courses or cisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m2 every 21 days for six courses. RESULTS: A total of 607 women were entered onto the study. There was no difference in the response to treatment. Pathologic complete response (CR) was documented in 63 of the weekly cisplatin cases and 70 of the cisplatin plus cyclophosphamide group (chi 1(2) = 1.43; P = .23). The median follow-up time was 3 years. There were 151 and 148 deaths in the weekly cisplatin and cyclophosphamide plus cisplatin arms, respectively. Survival curves were similar in the two groups, with a 3-year percent survival estimate of 44.1 (SE = 3.4) in the weekly cisplatin and 44.6 (SE = 3.4) in the cisplatin plus cyclophosphamide group (log-rank test chi 1(2) = 0.004; P = .96). CONCLUSION: This study found that 2-month monochemotherapy treatment with cisplatin was as effective as 5-month polychemotherapy including cisplatin at a similar doses but different dose-intensity plus cyclophosphamide.

Adult↗

Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.

PURPOSE: Topotecan and paclitaxel were evaluated in a randomized, multicenter study of patients with advanced epithelial ovarian carcinoma who had progressed during or after one platinum-based regimen. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 112) or paclitaxel (175 mg/m2) infused over 3 hours every 21 days (n = 114). Patients had bidimensionally measurable disease and were assessed for efficacy and toxicity. RESULTS: Response rate was 23 of 112 (20.5%) in topotecan-treated patients and 15 of 114 (13.2%) in paclitaxel-treated patients (P = .138). Disease stabilization for at least 8 weeks was noted in 30% of patients with topotecan and 33% of patients with paclitaxel. Median durations of response to topotecan and paclitaxel were 32 and 20 weeks, respectively (P = .222) and median times to progression were 23 and 14 weeks, respectively (P = .002). Median survival was 61 weeks for topotecan and 43 weeks for paclitaxel (P = .515). Response rates for topotecan and paclitaxel were 13.3% versus 6.7% (P = .303) in resistant patients (not responded to prior platinum-based therapy or progressed within 6 months of an initial response) and 28.8% versus 20.0% (P = .213) in sensitive patients (progressed > 6 months after response). Neutropenia was significantly more frequent on the topotecan arm 79% versus paclitaxel arm 23% (P < .01). It was short-lasting and noncumulative in both arms. Nonhematologic toxicities were generally mild (grades 1 to 2) for both agents. CONCLUSION: Topotecan has efficacy at least equivalent to paclitaxel manifested by the higher response rate and significantly longer time to progression.

Adult↗

A phase I trial with fixed-dose carboplatin and escalating doses of paclitaxel in advanced ovarian cancer.

A dose-finding study involving 27 untreated patients with ovarian cancer was performed to define the maximum tolerated dose of a 3-hour infusion of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with a fixed dose of carboplatin. The median age of the study patients was 55 years (age range, 30 to 74 years), the median Eastern Cooperative Oncology Group performance status was 0 (range, 0 to 2), and residual tumor to first surgery was > or = 1 cm in 14 patients and less than 1 cm in 13 patients. All patients received carboplatin at a fixed dose of 300 mg/m2 over 1 hour. Paclitaxel was administered at five dose levels starting at 150 mg/m2 and increasing in 25-mg/m2 increments to 250 mg/m2. In the absence of toxicity, courses were repeated every 4 weeks for a total of six cycles. World Health Organization grade 1 hypersensitivity and cardiotoxicity were observed in 7.4% and 14.8% of patients, respectively. Moderate peripheral neuropathy was experienced by 29.6% of patients. Grades 3 and 4 neutropenia lasted less than 7 days; no patient required hospitalization for sepsis or febrile neutropenia, and no supportive treatment with granulocyte or granulocyte-macrophage colony-stimulating factor was needed. The maximum tolerated paclitaxel dose was not achieved.

Aged↗

Survival of women with advanced ovarian cancer and complete pathologic response at second-look laparotomy.

BACKGROUND: The purpose of the study was to analyze the determinants of long term survival in women with advanced ovarian cancer and negative second-look laparotomy. METHODS: A series of 140 advanced (Stage III-IV) ovarian cancer patients (median age, 54 years; range, 22-74 years) with negative second-look laparotomy after primary surgery and chemotherapy is included in the analysis. At first diagnosis, all patients were treated with radical or debulking surgery. After primary surgery, the patients were treated with a chemotherapy regimen based on cisplatin or carboplatin alone or in combination with other drugs. All second-look laparotomies were performed 6-8 months after first surgery. RESULTS: The overall survival rates were 76% at 3 years, 66% at 5 years, and 51% at 8 years. The corresponding rates for disease free survival were 57, 50, and 43%, respectively. Survival rates were better for women with a residual tumor 1 cm or less after primary surgery. The 5-year probability of survival was 78% in this group, compared with 55% in women with a residual tumor more than 1 cm (log rank test, P < 0.05). Survival rates for women with tumor Grade 3 tended to be worse than Grades 1-2, but the difference was only of borderline statistical significance. No relationship emerged between survival and age, histotype, and presence of ascites at diagnosis. Women with a residual tumor 1 cm or less and positive lymph nodes had a 66% 5-year probability of survival, compared with 85% for women with a residual tumor 1 cm or less and negative lymph nodes. This difference was significant (log rank test, P = 0.05). The 5-year survival probabilities were 47 and 58%, respectively, in women with a residual tumor more than 1 cm and positive or negative lymph nodes. CONCLUSIONS: This analysis shows a favorable long term survival rate for women with advanced ovarian cancer and complete pathologic response after debulking surgery and postoperative chemotherapy. It further suggests that lymph nodal status is a prognostic factor for women with minimal residual tumor after surgery.

Adult↗

Determinants of response to a cisplatin-based regimen as neoadjuvant chemotherapy in stage IB-IIB invasive cervical cancer.

The response rate and the determinants of response to a cisplatin-based regimen of neodjuvant chemotherapy (NACT) in women with a histologically confirmed first-diagnosis of invasive bulky stage IB-IIB cervical cancer are analyzed. A total of 79 cases were treated with cisplatin (40 mg/m2) each 7 days for seven courses. During the first, fourth, and seventh cycles, ifosfamide (3.5 g/m2) was given by infusion for 24 hr. At the end of the seven cycles, 51 had a partial response (64.5%) and 4 a complete pathological response (5.1%). The overall 24-month cumulative survival was 80%, being 93% in responders and 43% in nonresponders (log-rank test, P < 0.05). With respect to the 66 subjects for whom pretreatment status of pelvic lymph nodes was available, complete or partial response was obtained in 35 of 42 subjects with negative pelvic lymph nodes at computed tomography, but in only 13 of 24 with positive lymph nodes. The corresponding odds ratios of response was 0.2 for women with positive status in comparison with those with negative status (95% confidence interval, 0.1-0.4). With respect to the 66 women who underwent surgery after NACT, of the 24 women with pretreatment positive lymph nodal status, 15 had positive nodes at surgery, but in 9 cases the histological analysis of nodes showed negative findings. Positive nodes at surgery were observed in 2 of the 42 subjects with negative nodes before treatment.

Adult↗