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Biomedical subjects

K Hoekman

Publications and source records attributed to K Hoekman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Multiple cycles of high-dose doxorubicin and cyclophosphamide with G-CSF mobilized peripheral blood progenitor cell support in patients with metastatic breast cancer.

BACKGROUND: In a previous study we applied doxorubicin and cyclophosphamide in a dose-intensive regimen with GM-CSF to patients with metastatic breast cancer (MBC). That treatment failed to prolong the remission duration compared to conventional-dose chemotherapy. In the present study we escalated the dosages of the same agents to: 1) determine the maximum tolerated dosages (MTD) when given for three cycles with G-CSF mobilised peripheral blood progenitor cell (PBPC) reinfusion and 2) evaluate the antitumour effect of this regimen. PATIENTS AND METHODS: For mobilisation of PBPC, G-CSF 15 microg/kg/day was given subcutaneously (s.c.), and in subsequent cohorts leucapheresis was started on days 3, 4 or 6. The intention was to treat MBC patients with three cycles of doxorubicin and cyclophosphamide at a starting dose of doxorubicin 90 mg/m2 and cyclophosphamide 1000 mg/m2. Dosages were then escalated in subsequent cohorts of at least three patients. In case of dose-limiting mucositis, only the dose of cyclophosphamide was escalated in the next cohort. RESULTS: Twenty-one patients entered this protocol, of which 18 patients received high-dose chemotherapy. The mobilisation of PBPC using G-CSF only was sufficient for three cycles of high-dose chemotherapy in 10 of 21 (47%) patients. Mucositis precluded dose escalation of doxorubicin beyond 110 mg/m2. The MTD in this combination was 110 mg/m2 for doxorubicin, and 4 g/m2 for cyclophosphamide, with haemorrhagic cystitis being the dose-limiting toxicity. The overall response rate was 78% (95% confidence interval (95% CI): 57%-97%), with 22% (95% CI: 3%-41%) complete responses. CONCLUSION: The MTD of this three cycle high-dose regimen was doxorubicin 110 mg/m2 and cyclophosphamide 4 g/m2 with mucositis and cystitis being dose-limiting toxicities. Although the primary aim was not the evaluation of antitumour effect, this high-dose regimen does not appear to provide an improvement of treatment results in comparison with our previous study with the same drugs at moderately high-dosages without stem cell support.

Adult↗
PubMed1997

Experience with intraperitoneal cisplatin and etoposide and i.v. sodium thiosulphate protection in ovarian cancer patients with either pathologically complete response or minimal residual disease.

BACKGROUND: High-dose platinum-based regimens can produce responses in patients not responding to standard chemotherapy. As in many ovarian cancer patients the disease remains confined to the peritoneal cavity, intraperitoneal (i.p.) chemotherapy has been applied as an alternative approach to increase drug exposure. The delivery of cytotoxic agents to the peritoneal cavity can lead to high drug concentrations intraperitoneally with less systemic toxicity. This study aimed at evaluating the efficacy and toxicity of high-dose i.p. cisplatin plus etoposide and intravenous sodium thiosulphate protection in ovarian cancer. PATIENTS AND METHODS: Patients with either a pathologically complete response (pCR) after first-line treatment or with persistent disease after first-line platinum-based chemotherapy or abdominal recurrences were eligible. All intraabdominal lesions had to be < 2 cm at the start of i.p. treatment. The treatment consisted of etoposide 350 mg/m2 i.p. followed by cisplatin 200 mg/m2 i.p. with intravenous sodium thiosulphate (4 g/m2 bolus, followed by 12 g/m2 over six hours) protection. Four courses of i.p. treatment were administered in case of pCR and 6 courses otherwise, at four-weekly intervals. RESULTS: The study comprised 29 patients, six patients with pCR, 17 patients with persistent disease and six patients with abdominal recurrences. They received a total of 105 courses of treatment (65% of the scheduled number of courses). Twelve patients completed scheduled treatment, illustrating its feasibility. In 17 patients treatment had to be prematurely stopped because of inflow obstruction (seven patients), bowel perforation (two patients), renal toxicity (two patients), neurotoxicity (two patients), or malaise and vomiting (four patients). One patient with bowel perforation died of this complication. Severe nausea and vomiting occurred in 51% of cycles. Leukopenia and thrombopenia grade 3 and 4 occurred in 30% and 6% of cycles, respectively. Ototoxicity of cisplatin was measured by serial tone audiography in 23 patients: only eight patients (35%) showed significant audiographic changes, although none of them developed clinical hearing loss. Fifteen patients were evaluable for response: four pCR, five PR, two SD, four PD. The median duration of freedom from progression was 616 days and the median overall survival 1065 days from the start of treatment. CONCLUSIONS: High-dose i.p. treatment with cisplatin and etoposide can be associated with significant toxicities. Major clinical problems are nausea, vomiting, and the formation of intraabdominal adhesions. Intravenous sodium thiosulphate effectively reduces the systemic toxicity of high-dose cisplatin. The value of high-dose i.p. treatment is uncertain and its routine use cannot be recommended.

Adult↗
PubMed1997

Highly sensitive and specific detection of P-glycoprotein function for haematological and solid tumour cells using a novel nucleic acid stain.

Progress in our understanding of the contribution of P-glycoprotein (P-gp)-mediated resistance to chemotherapy failure in haematological as well as solid tumours has been hampered by the lack of highly sensitive, reliable methods for the detection of P-gp function in fresh human tumour cells. The present study identifies the novel nucleic acid stain SYTO16 as a highly sensitive and specific dye to assess P-gp function. The effect of P-gp is expressed here as the ratio of dye fluorescence (RF) from cells incubated with dye with or without 2 microM of the P-gp inhibitor PSC 833. Using flow cytometric analysis, an RF of 0.9 was found for SYTO16 in the KB3-1 (P-gp-) and 1.6 in KB8 (P-gp+) cells. Three types of patients' cells were studied: (1) in haematopoietic CD34+ cells, which are known to express P-gp, the RF was 6.0 for SYTO16 compared with 2.5 for rhodamine 123 and 1.3 for daunorubicin (mean of five individuals); (2) in acute myeloid leukaemia cells, the RF for SYTO16 was 1.0 in P-gp- and 4.5 in P-gp+ samples; (3) for the first time, we have quantitated P-gp function in fresh human solid tumour (sarcoma) cells. We found, in a P-gp+ leiomyosarcoma, an RF of 16 for SYTO16 and 2.7 for daunorubicin. This means that complete inhibition of P-gp function in these sarcoma cells would lead to an increase of daunorubicin accumulation with 170% compared with 30% in the CD34+ cells. Next, we showed that SYTO16 could be fixed in nuclei by 3.6% formaldehyde treatment, allowing quantification of the nuclear fluorescence on cytospins by laser scanning microscopy. In conclusion, SYTO16 proved to have a combination of favourable properties: it can be excited at 488 nm and has large fluorescence enhancement upon binding to nucleic acids, allowing the use of low, nontoxic (< 10 nM) concentrations. Because the RF for SYTO16 is much higher than for daunorubicin, it can be applied for the determination of P-gp function in relatively small numbers of low-P-gp-expressing tumour cells by laser scanning microscopy. Individual sarcomas were found to have high P-gp function compared with CD34+ cells. This assay may be used to select patients for P-gp modulation protocols.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Effects of chemotherapy on pathologic and biologic characteristics of locally advanced breast cancer.

In 42 patients with locally advanced breast cancer treated with neoadjuvant chemotherapy followed by surgery and radiation therapy, the effects of chemotherapy on tumor architecture, morphometric nuclear and nucleolar characteristics, DNA ploidy, proliferation index measured by mitotic activity index, expression of differentiation antigens, and microvessel density were studied. Pretreatment biopsy specimens were available to compare with mastectomy specimens for 24 patients, and subclavicular biopsy specimens taken before chemotherapy were available for 9 patients. In the remaining patients, fine-needle aspiration was performed before chemotherapy, and morphologic and biologic features of the tumors could be studied only after chemotherapy. In 23 patients, only microscopic tumor or no tumor was left after chemotherapy, and in these patients we observed a characteristic pattern of relatively cellular fibrous tissue with lymphocytic infiltrate, ironloaded macrophages, and, when present, scattered foci of tumor cells in between. We found a reduction in mitotic activity index and in global microvessel density over all the tumors as a group. There was, however, no consistent pattern of changes in nuclear and nucleolar morphometric characteristics, DNA ploidy, and expression of differentiation antigens, and no pathologic or biologic features were predictive for response to chemotherapy.

Adult↗
PubMed1997

Platelet: transporter of vascular endothelial growth factor.

In animal models, growth of tumors and their metastases is dependent on factors that stimulate vessel formation (angiogenesis). Most clinical studies confirm the importance of angiogenesis for cancer growth in patients. Recent studies on circulating angiogenic factors in patients have focused on serum vascular endothelial growth factor (VEGF) levels in a variety of cancer types. We measured serum VEGF concentrations and blood counts in 27 breast cancer patients during each of 6 cycles of chemotherapy with doxorubicin and cyclophosphamide supported by granulocyte macrophage colony-stimulating factor. Serum VEGF concentrations highly correlated with platelet counts during chemotherapy (r = 0.8; P < 0.01). In particular, during the first treatment cycle, after an initial episode of thrombocytopenia, a strong platelet rebound coincided closely with a serum VEGF peak (r = 0.9; P < 0.01). In addition, plasma VEGF concentrations from 15 other cancer patients and 30 healthy volunteers were 5- to 8-fold lower than their corresponding serum VEGF concentrations (P < 0.001). Activation of platelets increased the VEGF content 8-10 times. These findings demonstrate that VEGF is released by platelets during serum preparation. In this study, we found evidence for VEGF transport by platelets, indicating that serum VEGF concentrations reflect mainly platelet counts rather than tumor burden in cancer patients, as reported earlier. Platelets, known to be important for wound healing, have also been reported to contribute to metastasis formation and tumor growth in animal models. Indeed, tumors can be regarded as never-healing wounds. Our data suggest that platelets may have a stimulating role on angiogenesis-dependent tumor growth through their function as transporters of VEGF.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

A patient with adrenocortical carcinoma: characterization of its biological activity and drug resistance profile.

We describe a patient with a metastasized adrenocortical cancer who exhibited excessive production of both glucocorticoids and mineralocorticoids combined with suppressed androgen production. Unusual steroid metabolites found in the patient's urine have not been described previously in association with this tumor type. Investigation of the multidrug resistance phenotype in single-cell suspensions of the tumor revealed low expression of multidrug resistance protein but high expression of P-glycoprotein (Pgp) and lung resistance-related protein. Functional Pgp in these tumor cells was shown by the modulatory effect of PSC833 on daunorubicin accumulation. Mitotane, at a concentration achieved in this patient's plasma, completely reversed the Pgp-related resistance both in the Pgp-overexpressing KB8-5 cell line and in the patient's tumor cells. On the basis of these in vitro results, the patient was treated with a combination of multidrug resistance drugs (doxorubicin, vincristine, and etoposide) plus mitotane as a Pgp modulator. This treatment was ineffective, however. A chemosensitivity assay demonstrated that the tumor cells were highly resistant to the drugs used. The adrenocortical cancer cells expressed mutant p53, and no evidence for induction of apoptosis by these drugs was found.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

IL-1 beta does not cause neutrophil degranulation but does lead to IL-6, IL-8, and nitrite/nitrate release when used in patients with cancer.

The use of IL-1 in humans is associated with dose-limiting toxicity which resembles that of TNF-alpha or IL-2. Activation of neutrophils is thought to contribute to the toxicity caused by these two cytokines. We studied the effect of IL-1 in vivo on changes in neutrophil numbers and neutrophil degranulation as well as on the formation of neutrophil agonists, such as complement activation products, and on levels of TNF, IL-6, IL-8, and nitrite/nitrate (as a measure of nitric oxide production). Six patients with metastatic melanoma were treated with 3 ng/kg recombinant human IL-1 beta daily. One hour after the start of the 30-min IL-1 infusion, which caused mild cardiovascular toxicity, plasma levels of IL-6 reached a peak of 25 +/- 9 ng/L (mean +/- SEM), IL-8 reached a peak of 311 +/- 100 ng/L at 2 h, and nitrite/nitrate peaked after 10 h to 89 +/- 27 mumol/L. IL-1 did not induce significant changes in plasma levels of TNF or of the complement activation products C3a and C4b/c. Although IL-1 induced neutrophilia, levels of elastase and lactoferrin did not change. The failure of IL-1 to degranulate neutrophils was confirmed in an ex vivo model with whole blood culture in which doses of up to 100 microgram/L IL-1 beta or IL-1 alpha failed to induce significant elastase or lactoferrin release, whereas TNF, tested as a positive control, was able to do so. These results demonstrate that, unlike TNF, IL-1 does not cause neutrophil degranulation in man, despite its ability to cause neutrophilia and the rapid release of IL-6, IL-8, and nitrite/nitrate.

Adult↗
PubMed1996

Well-differentiated papillary mesothelioma of the peritoneum: a separate entity.

Three female patients with a diffuse well-differentiated papillary mesothelioma of the peritoneum are presented. They did not have a history of exposure to asbestos. The peritoneal biopsies were studied extensively, including electron microscopy, nuclear morphometry and DNA ploidy analysis. The results from these more sophisticated investigations confirmed the mesothelial origin and further characterised these lesions. One of the 3 patients has continuing elevated serum CA-125 levels, which increased transiently during and after pregnancy. All 3 patients have done well without therapy, 2 patients being alive and non-symptomatic 6 and 7 years after the initial diagnosis. It is important to distinguish this disorder from the malignant diseases of the peritoneum and the ovary. In view of the indolent course of this subtype of mesothelioma, avoidance of treatment is justified unless there is evidence of progressive disease.

Adult↗
PubMed1996

p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer.

Expression of both P-glycoprotein (P-gp) and mutant p53 have recently been reported to be associated with poor prognosis of breast cancer. The expression of P-gp is associated in vitro and in vivo with cross-resistance to several anti-cancer drugs. p53 plays a regulatory role in apoptosis, and mutant p53 has been suggested to be involved in drug resistance. Interestingly, in vitro experiments have shown that mutant p53 can activate the promoter of the MDR1 gene, which encodes P-gp. We investigated whether p53 and P-gp are simultaneously expressed in primary breast cancer cells and analysed the impact of the co-expression on patients prognosis. Immunohistochemistry was used to investigate P-gp expression (JSB-1, C219) and nuclear p53 accumulation (DO-7) in 20 operable chemotherapy untreated and 30 locally advanced breast cancers undergoing neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. Double immunostaining showed that P-gp expression and nuclear p53 accumulation often occur concomitantly in the same tumour cells. A correlation between p53 and P-gp expression was found in all 50 breast cancers (P = 0.003; Fisher's exact test). P-gp expression, nuclear p53 accumulation, and co-expression of p53 and P-gp were more frequently observed in locally advanced breast cancers than in operable breast cancers (P = 0.0004, P = 0.048; P = 0.002 respectively. Fisher's exact test). Co-expression of p53 and P-gp was the strongest prognostic factor for shorter survival by multivariate analysis (P = 0.004) in the group of locally advanced breast cancers (univariate analysis: P = 0.0007). Only 3 out of 13 samples sequentially taken before and after chemotherapy displayed a change in P-gp or p53 staining. In conclusion, nuclear p53 accumulation is often associated with P-gp expression in primary breast cancer, and simultaneous expression of p53 and P-gp is associated with shorter survival in locally advanced breast cancer patients. Co-expression of P-gp and mutant p53 belong to a series of molecular events resulting in a more aggressive phenotype, drug resistance and poor prognosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Continuous infusion or subcutaneous injection of granulocyte-macrophage colony-stimulating factor: increased efficacy and reduced toxicity when given subcutaneously.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a haematopoietic growth factor with a wide variety of applications in the clinic. In early phase I studies the continuous intravenous (c.i.) route of administration was often used. Later it was shown that subcutaneous (s.c.) administration was also effective. The optimal route of administration remains, however, poorly defined, and no studies have made a direct comparison between these two routes of administration. We treated patients with advanced breast cancer with moderately high-dose doxorubicin and cylophosphamide and GM-CSF. The first 14 patients received GM-CSF by c.i, while subsequently 47 patients received it s.c. Comparison between the two groups showed that c.i. GM-CSF was more toxic in several respects. There was a higher need for erythrocyte and platelet transfusions and a significant deterioration in the performance status. This study indicates that subcutaneous GM-CSF is the preferred route of administration. Randomised trials are, however, needed to confirm these conclusions.

Adult↗
PubMed1996

The role of nitric oxide in bacterial meningitis in children.

To investigate the role of nitric oxide (NO) in bacterial meningitis, concentrations in serum, cerebrospinal fluid (CSF), or both of the precursor (L-arginine) and degradation products of NO (nitrate, nitrite) and tumor necrosis factor (TNF)-alpha were measured in 35 patients and 30 controls. CSF nitrate levels were significantly elevated, mainly due to increased blood-brain barrier permeability, and are therefore not a good parameter for gauging endogenous NO production in the CSF compartment. CSF NO/nitrite levels were significantly elevated in patients. NO/nitrite levels decreased over time (26%/6 h; P < .001). CSF levels of NO/nitrite correlated with those of TNF-alpha (r = .55; P = .001) and glucose (r = -.43; P = .02). CSF levels of L-arginine were lower in patients than in controls (P < .001). Dexamethasone did not exert a significant effect on NO metabolism. In conclusion, enhanced NO production may contribute to anaerobic glycolysis and neurologic damage in bacterial meningitis.

Adolescent↗
PubMed1996

Dose-intensive chemotherapy with doxorubicin, cyclophosphamide and GM-CSF fails to improve survival of metastatic breast cancer patients.

BACKGROUND: A dose response relationship for doxorubicin and cyclophosphamide has been suggested. In a previous dose finding study we treated advanced breast cancer patients with escalating doses of doxorubicin and cyclophosphamide in combination with GM-CSF. The aim of this study is to further define the acute and cumulative toxicity of this treatment in relation to its antitumor activity. PATIENTS AND METHODS: Twenty-eight patients with metastatic breast cancer were treated with doxorubicin (90 mg/m2) and cyclophosphamide (1000 mg/m2) at 3-week intervals. Dose reductions of 10% were applied in the second and fourth cycles. On the second day GM-CSF was started at 250 mu g/m2 daily for 10 days. The intention was to give 6 cycles, but when a complete remission was reached earlier only one more cycle was given as consolidation. RESULTS: The median number of cycles was 5 (range 2-6). Twenty-three patients responded (82%, 95% CI 69%-97%), with 9 of them achieving a complete response (32%, 95% CI 14%-50%). For the 18 patients evaluable for time to progression and survival the median time to progression was 8 months and the median survival 14.5 months. Toxicity was substantial: grades 3 or 4 neutropenia occurred in 95% of cycles and grades 3-4 thrombocytopenia in 49% of cycles. Grade 3-4 mucositis was present in 13% of the cycles. Weakness and fatigue were always present and were cumulative. Four patients had a decline in the left ventricular ejection fraction (LVEF). These side effects were the reason for discontinuing therapy in 9 of the 28 patients (32%). CONCLUSION: This treatment has a high response rate in comparison with conventional-dose chemotherapy but does not prolong time to progression or survival. The toxicity makes this protocol unsuitable for use as palliative treatment.

Adult↗
PubMed1996

Incidence and prevention of nonhaematological toxicity of high-dose chemotherapy.

The introduction of the haematopoietic growth factors (HGFs), together with the evolution of techniques to harvest haematopoietic stem cells from the peripheral blood, have greatly facilitated the use of high-dose chemotherapy (HDC). While haematological toxicity of HDC is no longer dose-limiting, damage to other tissues has become more pronounced. In fact, nonhaematological toxicity (NHTOX) is now often dose-limiting in HDC regimens. NHTOX associated with HDC regimens depends on the type and dose of the drugs used, the physical condition and the characteristics of the patients treated and the given comedication. We describe the most important toxic effects of commonly used HDC programmes, such as nausea, vomiting, and mucositis, neutropaenic fever and sepsis, various major organ toxicities, catheter-associated problems and long-term complications. In addition, we discuss the possibilities of preventing these side-effects and what action to take if they occur.

Antineoplastic Agents↗
PubMed1995

[Favorable results of paclitaxel (Taxol) in patients with ovary carcinoma pretreated with platinum].

OBJECTIVE: To assess the anti-tumour and side effects of paclitaxel in patients with ovarian carcinoma, after prior treatment with al least one platinum-containing chemotherapy regimen. DESIGN: Phase II study. SETTING: Academic Hospital of the Free University, Amsterdam. METHOD: Fourteen of 55 patients with progressive ovarian carcinoma were treated with 135 mg/m2 and 41 with 175 mg/m2 paclitaxel. 9 patients by 24-hour and 46 by 3-hour intravenous infusion. RESULTS: In 9/55 (16%) patients an objective tumour response was obtained, which was complete in 1 patient. In 19/55 (35%) patients the disease stabilised. The serum CA 125 level was increased in 52 patients. In 33% of the patients the course of the serum CA 125 was an indication of the tumour response. The median duration of response was 8 months (range 4.1-13.1) and the median duration of survival was 11.3 months (range 0.3-28.2). Side effects of paclitaxel treatment were hair-loss, arthralgia and myalgia and neutropenia of short duration. In 76% of patients pre-existing neurosensory symptoms increased mildly or developed de novo. The neurotoxic effect appeared reversible in most instances after discontinuation of the paclitaxel treatment. CONCLUSION: In this rather unfavourable patient population, paclitaxel induced only 16% objective response. However, more than 50% of the patients did benefit from paclitaxel treatment, as a much larger group had long lasting disease stabilisation without symptoms or had reduction of symptoms. The treatment was well tolerated by most patients.

Adult↗
PubMed1995

Chemotherapy for gynecologic malignancies.

Platinum-based chemotherapy is still the cornerstone in the chemotherapeutic approach of ovarian cancer patients. Recent advances include the introduction of paclitaxel in first-line chemotherapy and the demonstrated importance of administering cisplatin intraperitoneally in patients with small-volume disease. DNA repair and apoptosis are increasingly recognized as important processes involved in resistance to chemotherapy. Tamoxifen use is associated with a higher risk of endometrial cancer, with duration and cumulative dose of tamoxifen as additional factors. Hormonal therapy continues to be an important component of treatment of patients with advanced or recurrent endometrial cancer. Combination chemotherapy induces higher response rates in such patients. However, any advantage towards an improved survival remains a controversial issue. Isotretinoin plus interferon alfa-2a for squamous cell carcinoma of the cervix is still a topic of interest. There is a great need for agents and interventions with more efficacy and more specificity for the biology of the different gynecologic malignancies.

Antineoplastic Agents↗
PubMed1994

[Primary high-dose chemotherapy with hematopoietic growth factors followed by surgery and radiotherapy in stage III breast carcinoma; a Phase II study in 15 patients].

OBJECTIVE: To establish if the prognosis of a stage III breast carcinoma is improved by primary high-dose chemotherapy in combination with haemopoietic growth factors, followed by radical surgery and radiotherapy. DESIGN: Phase II study. SETTING: University Hospital Free University, Amsterdam. METHOD: Fifteen patients with a locally advanced breast carcinoma (stages IIIA or IIIB) were treated every three weeks with doxorubicin 90 mg/sq.m. and cyclophosphamide 1000 mg/sq.m., followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) 250 micrograms/sq.m. from day 2 up to and including day 12. After 4-6 of these courses the treatment in principle was continued with a modified radical mastectomy, followed by radiotherapy. Median duration of follow-up was 18 months. RESULTS: All tumours were reduced by over 50%. 10/15 Patients went into clinical complete remission; in 6/9 of these, pathological examination revealed only microscopical tumour rests, in the other three the rest diameter was < or = 1 cm. The haematological toxicity was mild. Grade III-IV bone marrow suppression was followed by rapid return to normal of the numbers of neutrophil granulocytes and thrombocytes under the influence of GM-CSF. The non-haematological toxicity manifested itself with nausea and vomiting, stomatitis and mild side effects attributable to GM-CSF. CONCLUSION: It appears justified in the treatment of locally advanced breast carcinoma to start with chemotherapy. Dose escalation of efficacious chemotherapeutics resulted in a large number of complete remissions.

Adult↗