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[Effectiveness of preoperative transcatheter arterial embolization for improved survival rates in patients with hepatocellular carcinomas (sandwich therapy using ethiodized oil, cisplatin and gelatin sponge].

The effect of hepatic transcatheter arterial embolization (TAE) therapy was evaluated in 153 patients with hepatocellular carcinomas who underwent radical hepatectomy. They were divided into 3 groups. Group A (n = 56) received preoperative TAE using ethiodized oil, cisplatin and gelatin sponge (sandwich therapy). Group B (n = 29) received preoperative TAE using adriamycin + gelatin sponge, ethiodized oil + adriamycin + gelatin sponge or adriamycin + degradable starch microsphere. Group C (n = 68) did not receive TAE preoperatively. The 3-year disease-free survival rates in Group A, B, and C were 56%, 34% and 32%, respectively. The rate was significantly higher in Group A than Group C (p less than 0.05). The 1-year disease-free survival rates after partial hepatectomy were 89% in Group A (n = 22), 53% in Group B (n = 15) and 67% in Group C (n = 22). The 3-year survival rate of these patients in Group A was significantly higher (95%), compared to Group C (70%) (p less than 0.05). Preoperative TAE using ethiodized oil, cisplatin and gelatin sponge (sandwich therapy) was considered a useful therapy for improvement of disease-free survival rates or survival rates after hepatectomy in patients with hepatocellular carcinomas.

Aged↗

Hepatic artery embolotherapy of hepatic metastases from carcinoid tumors: value of using a mixture of cyanoacrylate and ethiodized oil.

OBJECTIVE: Transcatheter embolization of the hepatic arterial supply is a well-known palliative treatment of tumor deposits in the liver. We performed a prospective study to evaluate the use of a mixture of N-butyl-2-cyanoacrylate and ethiodized oil with which a permanent vascular occlusion can be obtained, as an embolizing agent for transcatheter hepatic artery embolization for treatment of carcinoid hepatic metastases. SUBJECTS AND METHODS: Six patients had clinical symptoms from hormonal release by carcinoid hepatic metastases as well as elevated levels of 5-hydroxyindole acetic acid (5-HIAA) in the urine. Unilobar sequential transcatheter embolization of both the hepatic artery and the segmental hepatic arteries of both lobes of the liver was performed with a mixture of N-butyl-2-cyanoacrylate and ethiodized oil. CT and CT arterial portography (CTAP) were done to assess hepatic metastases and were used to monitor follow-up. Each patient had three CTAP studies; the third CTAP, performed 3 months after complete arterial devascularization, was compared with the first CTAP to evaluate tumor size. CT studies were performed routinely every 3 months thereafter and were compared with the initial CT scan to evaluate further tumor regression or progression. Tumor decrease and biochemical and symptomatic response rates were defined according to World Health Organization criteria. All complications and side effects of the treatment were documented. RESULTS: All patients showed complete symptomatic relief after embolization. The previously elevated levels of 5-HIAA in the urine returned to normal in three patients and in the other three patients were reduced by a mean of 89% of preembolization values. A decrease in tumor size by more than 50% was demonstrable in one patient; in five patients, hepatic lesions decreased in size by 25-50%. No new sites of metastatic liver disease were demonstrable in any patient during follow-up. No deaths or serious complications were directly attributable to the embolization procedure. All patients are alive after 12, 17, 18, 19, 19, and 19 months (mean, 17.3 months), respectively, with permanent relief of symptoms so far. CONCLUSION: Transcatheter embolization of both the hepatic artery and the segmental hepatic arteries with a mixture of N-butyl-2-cyanoacrylate and ethiodized oil provided excellent palliation in patients with carcinoid hepatic metastases. Complete and long-lasting relief of symptoms, a significant decrease or normalization of levels of 5-HIAA in the urine, and a reduction of metastatic tumor in the liver seem most likely to be the effect of sustained ischemia obtained with this permanent embolizing agent.

Carcinoid Tumor↗

Ethiodized oil emulsion enhanced computerized tomography in the preoperative assessment of metastases to the liver from the colon and rectum.

Selective reticuloendothelial (RE) cell uptake of ethiodized oil emulsion 13 (EOE-13), an emulsion of Ethiodol (ethiodized oil) roentgenographic contrast material in a phosphate buffer, permits detection of small metastatic lesions of the liver and spleen through enhancement of roentgenographic density differences on computerized tomography (CT) between tissues containing and not containing RE cells. To determine the efficacy of this contrast material in the assessment of patients with metastatic disease of the liver, routine CT and emulsion enhanced tomography (EOE) were performed in a series of 15 patients prior to surgical exploration for treatment of carcinoma of the colon and rectum. All patients were suspected of harboring hepatic metastasis on the basis of clinical examination, liver function tests or radionuclide scans. EOE consistently demonstrated the nature and location of hepatic defects. Surgical exploration failed to locate one metastasis that was judged to be real because of progressive enlargement on EOE and CT over a period of two years. CT scans detected metastases in three patients subsequently shown to have normal livers and failed to detect disease in one patient subsequently shown to have metastases. EOE contrast material provides a more sensitive and accurate picture of metastatic liver involvement from carcinoma of the colon and rectum than is available on routine CT. The information provided by the results of this test can be useful in preoperative planning when treatment of disease of the liver is considerable feasible.

Adenocarcinoma↗

Effect of glacial acetic acid and ethiodized oil concentration on embolization with N-butyl 2-cyanoacrylate: an in vivo investigation.

BACKGROUND AND PURPOSE: Precise control of the polymerization dynamics of cyanoacrylate mixtures used in the embolization of cerebral arteriovenous malformations is required to achieve a safe and permanent obliteration of the lesion. In this study, in vivo embolization using mixtures of Histoacryl, Lipiodol Ultra-Fluid, and glacial acetic acid (GAA) was investigated. The present study investigated whether increased ethiodized oil concentration or the addition of GAA increased rate of embolization. METHODS: Using embolic mixtures containing Histoacryl (N-butyl 2-cyanoacrylate [NBCA]), the embolization process in the femoral and subclavian arteries of the rabbit was examined. Various embolic agents composed of ethiodized oil and N-BCA mixtures, either with or without the addition of minute quantities of GAA, were injected. Blood flow through the aforementioned arteries was measured during embolization. The transient decay of blood flow to zero was modeled, and an optimized model parameter, termed the time elapsed to flow arrest (TEFA) factor, was compared with the experimental data related to the embolization process. RESULTS: The TEFA factor was independent of the variation of the ethiodized oil concentration in the mixture (P >.05). In contradistinction, the addition of GAA significantly increased the TEFA factor (P <.05). Moreover, a linear relation between the TEFA factor and the quantity of GAA in the mixture was discerned. CONCLUSION: Predictable control of the embolization process with N-BCA in vivo is attained by varying the amount of GAA in the embolic mixture.

Acetic Acid↗

Ethiodized oil emulsions in hepatic microcirculation: in vivo microscopy in animal models.

RATIONALE AND OBJECTIVES: The authors' purpose was to define the stability and drug-carrying and drug-releasing capacity of ethiodized oil emulsions in the hepatic circulation. METHODS: Emulsions prepared in various ratios of a nonionic contrast material containing doxorubicin to ethiodized oil were injected into the hepatic arteries of normal and tumor-bearing livers in rats or mice. In vivo microscopy was used to observe the dynamic distribution of the emulsions in the hepatic circulation. RESULTS: A solution of less water mixed with more oil formed water-in-oil (w/o) phase emulsions, whereas oil with more water formed oil-in-water (o/w) emulsions. The oil in the emulsions carried the water in the blood circulation. The w/o emulsions exhibited significantly higher carriage capacity and longer release time for the drug solution than did the o/w emulsions (P < .01). CONCLUSION: The delivery of w/o emulsions is superior to that of o/w emulsions. Further studies about preparation methods and delivery capability of emulsions in the liver are warranted.

Animals↗

Chemoembolization for hepatocellular carcinoma: epinephrine followed by a doxorubicin-ethiodized oil emulsion and gelatin sponge powder.

PURPOSE: This study evaluates chemoembolization (CE) of the liver with minimal vasoconstriction followed by selective intraarterial delivery of an emulsion of iopamidol, doxorubicin, and ethiodized oil and temporary occlusion of hepatic artery with gelatin sponge powder in patients with hepatocellular carcinoma. PATIENTS AND METHODS: Since 1988, 30 patients with nonresectable hepatocellular carcinoma underwent CE with the above protocol. Intraarterial epinephrine (0.5-1 microgram diluted in 10 mL of saline) was rapidly injected directly into the proper hepatic artery or selectively into the right or left hepatic arteries and was followed by 40-60 mg of doxorubicin dissolved in 10 mL of iopamidol and emulsified in 20 mL of ethiodized oil. The chemoembolic mixture was injected at the rate of arterial flow. Liver function and clotting parameters were monitored three times a day until there was a downward trend toward preembolic levels. Computed tomography (CT) was performed immediately after embolization and at 1-3-month intervals. Embolization was repeated when CT demonstrated recurrent or progressive disease. RESULTS: Disease recurred or progressed in 11 patients at 2-17 months after embolization. CE was repeated in four patients; one individual underwent three embolizations. Re-embolization was performed up to 14 months after initial embolization (median, 10 months). Five patients (16.7%) died within 1 month of embolization. Ten patients died at 3-33 months after CE. Two of these patients died of cirrhosis at 6 and 14 months, without evidence of recurrent tumor. Fifteen patients remain alive 5-28 months after CE. Kaplan-Meier estimation of probability of survival curves demonstrates a median survival of 14 months. Sixty-one percent of patients were alive at 1 year and 36% at 2 years after the procedure. CONCLUSION: CE with use of the above technique is effective for palliating inoperable hepatocellular carcinoma. It causes a significant prolongation of survival over the expected 18-24 weeks in untreated patients; this may occur because high doses of chemotherapeutic agents are delivered and come in contact with the tumor for a longer period, followed by ischemia brought about by temporary arterial occlusion.

Adult↗

Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intraarterial infusion of a mixture of cisplatin and ethiodized oil.

The therapeutic effectiveness of transcatheter arterial embolization (TAE) with intraarterial infusion of cisplatin/ethiodized oil mixture in treatment of resectable and unresectable hepatocellular carcinoma was compared with TAE with intraarterial infusion of doxorubicin mixed with and without ethiodized oil. The series included 97 patients with unresectable hepatocellular carcinoma and 40 patients with resectable hepatocellular carcinoma. With TAE using doxorubicin infusion, a partial response of the tumor was seen in only 11%, and the 2-yr survival was calculated to be only 5%. Histologic examination of the specimens obtained by hepatectomy also showed that this treatment was relatively ineffective in daughter tumor and portal tumor thrombi. In contrast, TAE with infusion of cisplatin/ethiodized oil mixture significantly increased the rate of partial response (38%), and significantly prolonged the 2-yr survival (45%). Histologically this treatment gave severe necrosis in daughter tumors (69%) and tumor thrombi (78%) as well as main tumor (75%). This treatment was significantly better than TAE with doxorubicin and ethiodized oil infusion in terms of the tumor regression and histologic responses of main tumor and portal vein tumor thrombi, but not in terms of the 2-yr survival. However, 2 patients (8%) died within 4 wk of the latter treatment, whereas no deaths were reported after the former treatment. Therefore, TAE combined with intraarterial infusion of cisplatin/ethiodized oil mixture may be a safe and useful treatment modality for hepatocellular carcinoma.

Carcinoma, Hepatocellular↗

CT detection of hepatic metastases with Ethiodized Oil Emulsion 13.

The use of an experimental liposoluble contrast agent-Ethiodized Oil Emulsion 13 (EOE 13)--is described in hepatic computed tomography (CT) of 23 oncologic patients. Without exception, all the hepatic metastases were better delineated in the EOE 13 enhanced scans. The postcontrast scans also detected an increased number of lesions but not all were malignant. There is no specificity to the increased lesion detection. Various splenic abnormalities were detected. Very few minor side effects and no major side effects were caused by the contrast media. We feel that with time, hepatic specific agents such as EOE 13 will become the contrast media of choice in hepatic CT examinations. Also, CT with hepatic specific agents may become the preoperative examination of choice in candidates for partial hepatectomy.

Adult↗

Formulation and evaluation of ethiodized oil emulsion for intravenous hepatography.

A study was conducted to prepare and evaluate an ethiodized oil emulsion for intravenous administration that would selectively opacify the liver. Several formulations with differing globule size were prepared and compared for their in vivo activity (degree of liver opacification obtained) and stability. Results of studies conducted in rabbits and monkeys revealed that the oil globules that concentrate most in liver were 2.0--3.0 micrometer in diameter. The formulation of choice was stable for 6 months at refrigeration temperature (2--6 degree). In monkeys, this formulation produced an improved diagnostic image of the liver using computerized tomography at a dose of 0.2 ml/kg. The potential use of such emulsions in diagnostic radiology is briefly discussed.

Animals↗

[Evaluation of preoperative chemoembolization using ethiodized oil, cisplatin and gelatin sponge (sandwich therapy) for hepatocellular carcinoma].

The significance of preoperative chemoembolization using ethiodized oil, cisplatin and gelatin sponge (Sandwich therapy) for resectable hepatocellular carcinoma (HCC) was evaluated. One hundred and thirteen patients with solitary and less than 10 cm sized HCC who underwent radical hepatic resection were chosen for this study. Fifty-three patients received Sandwich therapy before surgery (Group A), and the remaining 60 patients under-went surgery without any preoperative treatments (Group B). Any background factors between two groups were not significantly different. The anticancer effects of this therapy were evaluated by histologic examination in 31 patients who had preoperative Sandwich therapy. In 22 of 31 patients (71%), the main nodules were completely necrotic. The ratios of patients with complete necrosis in daughter nodules were 7/12 (58%), in portal vein tumor emboli, 7/10 (70%), in intracapsular invasions, 11/21 (52%), in extracapsular invasions, 4/11 (36%). The 4-year disease-free survival rates in Group A and Group B were 56% and 27% respectively, and the rate of the former was significantly higher than that of the latter (p less than 0.05). The 4-year survival rates in Group A and Group B were 83% and 53% respectively. The rate of Group A was also significantly higher than that of Group B (p less than 0.01). We concluded that preoperative Sandwich therapy was very significant to obtain successful long-term disease-free survival and survival in regard to relatively early stage HCC.

Carcinoma, Hepatocellular↗

Ethiodized oil emulsion 13 in computed tomography of hepatoma.

Six patients with biopsy-proven hepatoma were prospectively evaluated both by conventional computed tomography (CT) and by scans using ethiodized oil emulsion 13 (EOE 13) as a contrast agent. EOE 13 infusion resulted in marked improvement in the demonstration of the neoplasm in all cases and allowed more accurate definition of tumor extent than was possible with standard scanning techniques. In two cases EOE 13 enhancement was essential for complete radiographic depiction of tumor location, size, and extent. EOE 13 also proved to be of considerable value in assessment of therapeutic response in three patients, permitting more objective determination of tumor growth or regression. EOE 13--enhanced CT scanning provides a valuable means of staging patients presenting with hepatoma and is a reliable, accurate means of radiographic follow-up.

Adult↗

Improved detection of focal lesions with computerized tomographic examination of the liver using ethiodized oil emulsion (EOE-13) liver contrast.

A prospective study of computerized tomography (CT) of the liver using a liver contrast agent compared to conventional CT was undertaken. CT scanning without contrast agents (NC-CT), CT with water-soluble contrast (WSC-CT), and CT with ethiodized oil emulsion (EOE-CT) were performed on patients with possible or probable hepatic metastases. The findings on these three examinations were compared to the objective findings at surgery in 53 patients. Accuracy of these examinations was 80.7% for NC-CT, 77.1% for WSC-CT, and 84.9% for EOE-CT. The true-positive percentage for 129 hepatic lesions was 40.6% for the NC-CT, 33.6% for WSC-CT, and 76.7% for the EOE-CT. Eighty-three percent (44/53) of 1- to 2-cm liver lesions were detected by EOE-CT, whereas only 26.4% (14/53) lesions of this size were detected by the NC-CT and 20.4% (10/49) shown by WSC-CT. The likelihood that a lesion seen by CT scan was malignant was 84.6% for NC-CT, 89.4% for WSC-CT, and 81.8% for EOE-CT. The EOE contrast agent improves the sensitivity of liver CT for detecting hepatic metastases. The improvement occurs with lesions 1 cm and greater in diameter, but is particularly striking for lesions of 1 to 2 cm in diameter.

Ethiodized Oil↗

Biodistribution study of Ethiodized Oil Emulsion 13 for computed tomography of the liver and spleen.

Biodistribution studies were conducted with a new intravenous lipoid contrast material currently undergoing clinical trials in four hospitals. The contrast material selectively opacifies the liver and spleen for computed tomographic examination. The experiments were performed on rats with 125I-labeled ethiodized oil emulsion. The study showed that the liver accumulates nearly 80% of the injected iodine within 15 min of the injection and retains a high concentration over 3 h. The second highest concentration was found in the spleen. More than 99% of the iodine is eliminated from the liver and spleen within 48 h, primarily through the kidneys.

Animals↗

A new approach to chemoembolization therapy for hepatoma using ethiodized oil, cisplatin, and gelatin sponge.

This article reports on a new approach to hepatic arterial chemoembolization therapy using ethiodized oil (Lipiodol, Ultra Fluide), cisplatin, and gelatin sponge (Gelfoam, Upjohn, Kalamazoo, MI) for hepatocellular carcinoma (HCC). The anticancer effects of this therapy on 20 patients who underwent subsequent hepatic resection were evaluated mainly by histologic examination. All main tumors were reduced in size following this therapy. It is notable that in 65% of the patients the tumor size was reduced to less than 50% of that before therapy. All the values of serum alpha-fetoprotein (AFP) in the patients who exhibited pretreatment levels exceeding 100 ng/ml dropped by more than 50%, and in 55% of them it fell below 20 ng/ml. The concentration of platinum in the tumor tissue was significantly higher than that in the nontumorous tissue. In 15 of 20 patients (75%), the main nodules were completely necrotic. Thirteen of the patients had daughter nodules and/or small intrahepatic metastases (Group A); nine had tumor emboli in the portal (hepatic) vein (Group B); 17 had intracapsular invasions (Group C); and ten had extracapsular invasions (Group D). The ratios of patients with completely necrotic cancer cells in Group A were nine of 13 (69%); in Group B, seven of nine (78%), in Group C, 11/17 (65%); and in Group D, four of 10 (40%). In eight of the 20 patients (40%) no viable cancer cells were recognized at any foci. Lesions other than those with extracapsular invasion could be considerably eliminated with this form of therapy. It is expected that this method will become the therapy of choice not only for palliative treatment but also for preoperative treatment.

Adult↗

Targeting of different ethiodized oil-doxorubicin mixtures to hypovascular hepatic metastases with intraarterial and intraportal injections.

PURPOSE: The distribution of different ethiodized oil-doxorubicin mixtures within and around hypovascular liver metastases in athymic nude mice was compared following either intraarterial or intraportal injections. MATERIALS AND METHODS: Six different mixtures of doxorubicin and ethiodized oil in water-soluble contrast material, shaken for 5, 10, 15, and 30 minutes, respectively, were prepared and the size of the oil droplets in the mixtures evaluated. Intraarterial and intraportal injections of mixtures shaken for 10 and 15 minutes were performed in mice bearing hypovascular hepatic colorectal metastases. In vivo video microscopy was used to evaluate microvascular flow and the biodistribution and the size of the oil droplets within and around the tumors. RESULTS: Oil droplets smaller than 20 microns in diameter were taken up by tumor nodules. There was no significant difference in oil droplet accumulation within the tumor between intraarterial and intraportal injections. Oil droplets larger than 20 microns occluded small and medium portal branches. The optimum combination was 0.1 mL of ethiodized oil in 2 mL of diatrizoate sodium meglumine (Renografin-76) shaken for 15 minutes at 800 rpm, which formed droplets smaller than 20 microns (92%). CONCLUSION: Avascular regions of hepatic metastases may be embolized with ethiodized oil-anticancer drug mixtures containing oil droplets smaller than 20 microns. Since these droplets penetrate to the tumor interstitium with either intraarterial or intraportal injections, chemoembolization via the arterial route seems preferable for treatment of unresectable hypovascular hepatic metastases since it is easier to perform. The conclusions drawn from this study are limited to the animal model for experimental hypovascular hepatic metastases.

Animals↗

In vitro stability of tris-acryl gelatin microspheres in a multipharmaceutical chemoembolization solution.

PURPOSE: To evaluate the in vitro stability of tris-acryl gelatin microspheres (TAGMs) in a multipharmaceutical solution as a preliminary step before planned hepatic chemoembolization with TAGMs. MATERIALS AND METHODS: Half-cm(3) aliquots of 100-300- micro m and 300-500- micro m TAGMs were suspended in 1 mL of normal saline solution (NSS), 1 mL of ethiodized oil, or 1 mL of a standard chemoembolization solution (cisplatin 100 mg, doxorubicin 50 mg, mitomycin 10 mg, ethiodized oil 3 mL, and iodixanol 5 mL). Mixtures were incubated at 37 degrees C for 24 hours and were then examined visually and with use of light microscopy. Solutions containing ethiodized oil required centrifugation for separation. Determination of average sphere diameter after 24-hour chemoembolization incubation was performed after washing in ethanol, washing in acetone, and rinsing in 0.9% aqueous sodium chloride solution. RESULTS: TAGMs in NSS had no gross degradation, were intact on light microscopy, and had no visually perceptible change in average diameter. TAGMs in ethiodized oil alone appeared to dissolve into a cloudy solution; however, centrifugation separated spheres from ethiodized oil as a layer, which was intact on light microscopy. Spheres incubated in the chemoembolization solution were not grossly visible as a result of the deep red color of doxorubicin (which stained the spheres), but were easily seen after centrifugation. There were similar numbers of spheres per field on microscopy with a minimal (but significant) increase in analyzed diameter. CONCLUSION: TAGMs are stable in a standard chemoembolization solution and may be suitable as a substitute for PVA particles in hepatic chemoembolization.

Centrifugation, Density Gradient↗

In vivo and in vitro analysis of the effectiveness of doxorubicin combined with temporary arterial occlusion in liver tumors.

PURPOSE: The authors evaluated the effects of daunomycin (daunorubicin)--an analogue of doxorubicin--ethiodized oil, and arterial occlusion on an in vitro hepatoma analogue and on in vivo rat liver tumors. MATERIALS AND METHODS: A human Sk hepatoma cell monolayer sandwich system was used to determine uptake of 3H-daunomycin under normoxic/hypoxic conditions with use of autoradiography. Fluorescence microscopy was used to evaluate the biodistribution of doxorubicin in cell cultures (human Sk hepatoma and colon carcinoma). Microvascular flow adjacent to and within liver tumors and the intrahepatic effects of doxorubicin and ethiodized oil were studied with in vivo video microscopy on exteriorized rat livers containing peripheral hepatomas. RESULTS: Increased uptake of 3H-daunomycin by hepatoma cells occurred under hypoxic conditions. Intrahepatic arterial administration of ethiodized oil caused temporary occlusion of peripheral sinusoids following passage through arterioportal anastomoses. Tumors received portal venous and neovascular blood supply and ethiodized oil occluded but did not enter the narrow neovasculature perfusing the tumors. CONCLUSION: Hypoxia increases uptake of 3H-daunomycin by human Sk hepatoma and colon carcinoma cell cultures. Selective hepatic arterial occlusion (and perhaps the resultant hypoxia) may facilitate increased uptake of doxorubicin analogues into liver tumors. Hepatomas receive both arterial and portal venous blood supply, and ethiodized oil reaches the tumor via arterioportal anastomoses that perfuse the tumor periphery.

Animals↗

Respiratory distress syndrome from lymphangiography contrast medium.

Adult respiratory distress syndrome (ARDS) has been reported as a rare complication of lymphangiography with ethiodized oil. We report 2 patients who developed otherwise unexplained pulmonary edema after lymphangiography, and describe an animal model of pulmonary injury after an injection of ethiodized oil. We injected 0.25 ml/kg of body weight intravenously into 45 rabbits, and followed arterial blood gases and/or killed the rabbits randomly at various intervals for morphologic lung examination by light and electron microscopy. Within 24 h after injection, there was moderate hypoxemia from oil embolization, but only minimal lung edema. However, by 2 to 4 days after injections, hypoxemia was most severe and was accompanied by extensive alveolar and interstitial inflammation, hemorrhage, and edema. After 4 days, there was gradual blood gas and morphologic recovery, with complete restoration of normal anatomy by 6 wk. Our data showed that in rabbits, ethiodized oil can reproducibly cause delayed, severe pulmonary injury, thus supporting the clinical reports that ARDS may occur several days after lymphangiography.

Adult↗