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Syoji Kuroki

Publications and source records attributed to Syoji Kuroki.

At least 19 recordsLinked to original sources
PubMed2006

Phyllodes tumor of the breast: correlation between MR findings and histologic grade.

PURPOSE: To retrospectively evaluate the magnetic resonance (MR) imaging findings of phyllodes tumor of the breast and to compare these findings with the histologic grade. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. The authors reviewed the MR findings in 30 female patients aged 16-73 years (mean, 40.2 years) with surgically confirmed phyllodes tumors. Analyzed MR findings included tumor shape, margin, internal enhancement, and size; signal intensity (SI) of tumor higher than that of normal breast tissue on T1-weighted images; SI of tumor lower than or equal to that of normal tissue on T2-weighted images; cyst wall appearance; kinetic curve assessment; and apparent diffusion coefficient (ADC). The MR findings and histologic grade were statistically analyzed to determine whether any correlations existed. Significant MR findings were compared with histopathologic findings. RESULTS: Nineteen benign, six intermediate (characterized by five to nine cell reproductions at 10 high-power fields, pushing or infiltrative margins, moderate stromal cellularity, and atypia and overgrowth), and five malignant phyllodes tumors were assessed. Irregular cyst wall (P = .003), tumor SI lower than or equal to normal tissue SI on T2-weighted images (P = .005), and low ADC (P = .001) correlated significantly with histologic grade. Tumor SI higher than normal tissue SI on T1-weighted images was more frequent in the malignant (in three of five tumors) and intermediate (in three of six tumors) groups than in the benign group (in two of 19 tumors); however, it was not a significant finding (P = .024). Tumor SI higher than normal tissue SI on T1-weighted images and irregular cyst wall corresponded histopathologically to hemorrhagic infarction and necrosis, respectively. Tumor SI lower than or equal to normal tissue SI on T2-weighted images and low ADC corresponded histopathologically to stromal hypercellularity. Other findings were not significant. CONCLUSION: Several MR findings can be used to help determine the histologic grade of phyllodes breast tumors.

Adolescent↗
PubMed2006

MR imaging features of pure mucinous carcinoma of the breast.

OBJECTIVE: To characterize MR imaging features of pure mucinous carcinoma of the breast. MATERIALS AND METHODS: MR images obtained from 16 women (age range, 29-81; mean age, 57 years) with pure mucinous carcinoma of the breast determined at surgery were reviewed. The MR findings used were shape, margin, internal mass enhancement, kinetic curve pattern on dynamic study, signal intensity on short time inversion recovery (STIR) T2-weighted images, and non-mass-like enhancement around the main tumor. Non-mass-like enhancement was compared with the presence of extensive intraductal component (EIC) on histopathological findings. RESULTS: Eleven tumors (69%) had lobular contour, and nine tumors (56%) had smooth margin. Eight tumors (50%) showed rim enhancement and six tumors (38%) showed heterogeneous enhancement. Fourteen tumors (88%) showed a persistent enhancing pattern on kinetic curve. Fifteen tumors exhibited homogenous strongly high signal intensity on STIR T2-weighted images. In six cases with EIC, five cases had non-mass-like enhancement around the main mass. CONCLUSIONS: MR findings such as lobular shape, rim or heterogeneous enhancement, persistent pattern on kinetic curve, and homogeneous strongly high signal intensity on STIR T2-weighted images may be useful in diagnosing pure mucinous carcinoma. Moreover, linear-ductal enhancement around main mass may indicate presence of EIC.

Adenocarcinoma, Mucinous↗
PubMed2006

Inhibition of inducible nitric oxide synthase prevents hepatic, but not pulmonary, injury following ischemia-reperfusion of rat liver.

The aim of this study was to investigate the contribution of inducible nitric oxide synthase (iNOS)-derived nitric oxide on the liver and lung injury following hepatic ischemia-reperfusion (I/R) using a novel and potent iNOS inhibitor, ONO-1714. Rats were subjected to 90 min of partial hepatic ischemia followed by 3, 6, 12, and 24 hr of reperfusion. Expression of iNOS mRNA peaked at 3 hr of reperfusion in the liver and lung. Plasma nitric oxide levels were increased fourfold at 24 hr of reperfusion and plasma ALT was increased, reaching a peak at 12 hr of reperfusion; both were significantly inhibited by ONO-1714. Histological examination revealed extensive liver damage, whereas this was not seen in the ONO-1714 group. Lung injury was not significantly changed in groups with versus without ONO-1714. Nitrotyrosine expression was seen in regions similar to those of the histological injuries of the liver, while this staining was absent in the ONO-1714 group. These data show that generation of peroxynitrite could be involved in the pathogenesis of liver injury but not lung injury after hepatic I/R. Inhibition of iNOS could be applied for attenuation of liver injury following hepatic I/R.

Amidines↗
PubMed2006

Hepatic ischemia/reperfusion injury is prevented by a novel matrix metalloproteinase inhibitor, ONO-4817.

BACKGROUND: Matrix metalloproteinases (MMPs) play an important role in inflammation and neoplastic invasion and metastasis. Little is known about the effects of MMP inhibitors on hepatic ischemia/reperfusion injury. The aim of this study is to examine the inhibitory effects of ONO-4817 (oral inhibitor of MMPs) in rats. METHODS: Hepatic ischemia/reperfusion was induced in male Wister rats by clamping the portal vein and hepatic artery. The animals were randomized into an ONO-4817 group (300 mg/kg body weight per/day) and a vehicle group by oral gavage of a test substance. Serum alanine aminotransferase, histologic changes, gelatinolytic activity, MMP-2 and MMP-9 activities, tissue inhibitor of metalloproteinase 2 (TIMP-2) messenger RNA (mRNA) levels, and mRNA and serum levels of tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) were measured in both groups. RESULTS: ONO-4817 prevented ischemia/reperfusion injury to the hepatocytes as shown by significant reductions of serum alanine aminotransferase and less severe histologic changes. Gelatinolytic activity was inhibited markedly in the liver of the ONO-4817 group as demonstrated by film in situ zymography. MMP-9 and MMP-2 activities also were inhibited in the ONO-4817 group as shown by gelatin zymography. TIMP-2 mRNA levels showed no significant differences between the 2 groups. TNFalpha mRNA showed no downregulation, but IL-1beta mRNA was downregulated in the liver of the ONO-4817 group 1 to 3 hours after reperfusion. Serum levels of TNFalpha and IL-1beta showed a significant decrease in the ONO-4817 group, compared with the vehicle group after reperfusion. CONCLUSIONS: Hepatic ischemia/reperfusion injury was improved by a novel MMP inhibitor, ONO-4817, not only by inhibition of gelatinolytic activity but also by a decrease in release of inflammatory cytokines.

Animals↗
PubMed2005

Enhanced efficacy of conditionally replicating herpes simplex virus (G207) combined with 5-fluorouracil and surgical resection in peritoneal cancer dissemination models.

BACKGROUND: The therapeutic efficacy of G207, a replication-competent herpes simplex virus, for malignancies is increased when combined with certain chemotherapies, but the mechanism is unclear and the interaction between G207 and surgical resection has not been extensively studied. The goals of the current study were to examine the performance of combination treatments for peritoneal disseminated cancers and to explore the mechanism of effective combinations. METHODS: Hamsters and SCID and BALB/c mice harboring peritoneal dissemination of gallbladder, gastric or colon cancer cells were treated with G207, 5-fluorouracil (5FU), or surgical resection alone, or G207 combined with 5FU or surgery. Animal survival, antiviral immunity, intratumoral ribonucleotide reductase activity, and viral spread were compared between the groups. RESULTS: The combination of G207 and 5FU prolonged the survival of hamsters bearing peritoneal dissemination of gallbladder cancer compared with the controls, G207 alone and 5FU alone. 5FU did not suppress the production of neutralizing antibodies against G207, but increased ribonucleotide reductase activity and viral spread in subcutaneous gallbladder tumors. The enhanced efficacy of the combination treatment was also observed in immunodeficient mice with disseminated gastric cancer. Although surgical resection did not significantly prolong animal survival or increase the intratumoral activity of ribonucleotide reductase, long-term survivors emerged from groups of animals treated with surgical resection and G207 for gallbladder and colon disseminated cancers. CONCLUSIONS: These results indicate that the increased activity of ribonucleotide reductase in tumors mediated by 5FU and the decreased tumor burden resulting from surgical resection may enhance the therapeutic efficacy of oncolytic herpes virus for peritoneal disseminated cancer.

Animals↗
PubMed2005

Intraoperative parathyroid hormone assay in patients with Graves' disease for prediction of postoperative tetany.

We measured intraoperative parathyroid hormone (IOPTH) levels before and after thyroidectomy in a large group of patients to test whether changes in IOPTH can predict postoperative tetany. Subjects were 111 consecutive patients (94 females and 17 males) with Graves' disease undergoing subtotal thyroidectomy. Blood samples for IOPTH assay were obtained after anesthesia (basal) and following skin closure (postoperative). Data were compared between patients who developed tetany (n = 9) and those who did not (n = 102). There was no significant difference in sex, age, period of antithyroid drug administration, or the weight of the thyroid between the two groups. The preoperative serum calcium level was significantly lower (p < 0.05) and the basal IOPTH significantly higher (p < 0.05) in the tetany group than in the non-tetany group. The IOPTH level was significantly lower (p < 0.005) and the average percent decrease in IOPTH levels was higher (p < 0.001) in the tetany group than in the non-tetany group. A decrease in IOPTH of more than 70% was shown to be 78% sensitive, 94% specific, and 93% accurate, and it has 78% positive predictive value and 94% negative predictive value for the development of tetany. Our study shows that a postoperative decrease of IOPTH level is the most predictive of postoperative tetany of the clinical risk factors investigated. We recommend IOPTH measurement as an adjunct to postoperative management of patients with Graves' disease to assist in preventing hypocalcemia and determining the earliest time for safe discharge.

Adolescent↗
PubMed2005

Significant clinical differences in primary hyperparathyroidism between patients with and those without concomitant thyroid disease.

PURPOSE: We evaluated the differences in diagnosis and treatment for primary hyperparathyroidism (pHPT) in patients with and those without concomitant thyroid disease. METHODS: One hundred and ten patients with pHPT underwent parathyroid localization and thyroid examination by ultrasonography (US) and sestamibi scintigraphy (MIBI). The clinical and biochemical findings, parathyroid localization, and operations performed were compared in 49 patients without thyroid disease and 61 patients with thyroid disease. RESULTS: Asymptomatic hypercalcemia was significantly more prevalent in patients with concomitant thyroid disease (88.5%) than in those without thyroid disease (49.0%) (P < 0.01). The mean serum calcium was significantly higher and the inorganic phosphate level was significantly lower in patients without concomitant thyroid disease than in those with concomitant thyroid disease (P < 0.05, P < 0.01, respectively). The pathologic parathyroid gland was identified significantly more often in patients without concomitant thyroid disease than in those with concomitant thyroid disease both by US and MIBI (P < 0.05). Unilateral exploration was performed more often in patients without thyroid disease than in those with thyroid disease (P < 0.01). CONCLUSION: Primary hyperparathyroidism was diagnosed at an earlier stage in patients with concomitant thyroid disease. Thyroid disease concomitant with pHPT influenced parathyroid localization as well as the indication for minimally invasive parathyroidectomy.

Adult↗
PubMed2005

Thyroid evaluation in patients with primary hyperparathyroidism.

We evaluated the efficacy of preoperative high-resolution ultrasonography (US) for diagnosing possible concomitant thyroid disease which affects the surgical management in patients with primary hyperparathyroidism (pHPT). One hundred and nine patients with sporadic pHPT underwent US with or without ultrasound-guided fine-needle aspiration biopsy (US-FNAB). Diagnosis of concomitant thyroid nodules by US and US-FNAB were compared with the histopathological findings. Of the 109 patients, 19 (17.4%) had malignant thyroid nodules, 26 (23.9%) had benign thyroid nodules alone, and 12 (11.0%) had diffuse goiter. The sensitivity, specificity, and accuracy of diagnosing 72 thyroid nodules were 91.3%, 91.8%, and 91.7% for US, 57.9%, 94.3%, and 81.5% for US-FNAB, and 95.7%, 91.8%, and 93.1% for combined US and US-FNAB, respectively. True positive/false negative ratio of US-FNAB diagnosis was significantly lower in nodules of 5-9 mm than nodules of 10 mm or more. Four unexpected thyroid cancers existed at a different site in 3 of the 39 patients with palpable thyroid disease. Five thyroid cancers were histopathologically confirmed in 5 (7.1%) of 70 patients without palpable thyroid disease. Eight (88.9%) of the 9 non-palpable thyroid cancers were accurately diagnosed by combined US and US-FNAB. Preoperative US is useful for evaluation of possible concomitant thyroid disease, especially for prediction of malignancy.

Adenoma↗
PubMed2004

Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer.

The Hedgehog (Hh) signaling pathway functions as an organizer in embryonic development. Genetic analysis has demonstrated a critical role for the Hh pathway in mammary gland morphogenesis. Disruption of Patched1, a component of the Hh pathway, results in abnormal growth of mammary duct. Recent studies have shown constitutive activation of the Hh pathway in various types of malignancies. However, it remains unclear whether this pathway is activated in human breast cancer. Here, we determined the expression of the components, including Sonic Hh, Patched1, and Gli1, of the Hh pathway by immunohistochemical staining in a series of 52 human breast carcinomas. All of 52 tumors display staining of high intensity for Gli1 when compared with adjacent normal tissue. The nuclear staining ratio of Gli1 correlates with expression of estrogen receptor and histologic type. Exposure to cyclopamine, a steroidal alkaloid that blocks the Hh pathway, suppresses expression of Gli1 and the growth of the Hh pathway-activated breast carcinoma cells. These data indicate that the Hh pathway is a new candidate for therapeutic target of breast cancer.

Adult↗
PubMed2004

Role of leukotrienes on hepatic ischemia/reperfusion injury in rats.

BACKGROUND: Leukotrienes (LT), composed of cysteinyl LT (cLT; LTC(4), LTD(4), and LTE(4)) and LTB(4), are potent lipid mediators enhancing the vascular permeability and recruitment of neutrophils, which are common features of hepatic ischemia/reperfusion (I/R) injury. The aim of this study was to investigate whether LT can mediate the liver and lung injuries following hepatic I/R. MATERIALS AND METHODS: Sprague-Dawley rats were subjected to 90 min of partial hepatic ischemia followed by 3, 12, and 24 h of reperfusion. In the hepatic and pulmonary tissues, LT content and the mRNA expression of LT-synthesis enzymes, 5-lypoxygenase (5-LO), LTC(4) synthase (LTC(4)-S), and LTA(4) hydrolase (LTA(4)-H) were measured. Tissue injuries were assessed by plasma ALT, histological examination, and wet-to-dry tissue weight ratios. RESULTS: The cLT content in the hepatic tissue after 12 and 24 h reperfusion was increased 4- to 5-fold compared to controls and this was accompanied by the enhancement of hepatic edema and plasma ALT elevation. There were no significant changes in the mRNA expression of LT-synthesis enzymes in both tissues. LTB(4) levels were not increased despite a significant neutrophil infiltration in both tissues. CONCLUSIONS: These data suggest that cLT are generated in the liver during the reperfusion period and may contribute to the development of hepatic edema and exert cytotoxicity. Factors other than LTB(4) may contribute to neutrophil infiltration.

Alanine Transaminase↗
PubMed2004

A case of breast cholesterol granuloma accompanied by cancer.

Cholesterol granuloma of the breast is a very rare benign disease with clinical and imaging features that are often indistinguishable from cancer preoperatively. We report a case of breast cholesterol granuloma accompanied by cancer. The patient was a 78-year-old woman who complained of a lump in her right breast. Mammography and ultrasonography showed a well-circumscribed mass. Fine needle aspiration cytology showed many cholesterol crystals and inflammatory cells without malignancy. With a diagnosis of cholesterol granuloma, tumor extirpation was performed. Histopathologic examination revealed cholesterol granuloma together with breast cancer, and additional partial mastectomy was subsequently performed. It is noted that breast cholesterol granuloma could be accompanied by cancer.

Aged↗
PubMed2004

Regulation of bile acid synthesis under reconstructed enterohepatic circulation in rats.

Cholesterol 7alpha-hydroxylase (CYP7A1) is regulated by bile acids through the farnesoid X receptor (FXR) mechanism in a negative feedback fashion. However, the fact that CYP7A1 is down-regulated by intraduodenal administration of bile acid, but not by intravenous administration may not be explained only by this mechanism. The aim of this study was to establish a new rat model with reconstructed or simulated enterohepatic circulation to examine if intravenous or portal administration of bile acid can regulate CYP7A1. Under biliary drainage, taurocholate (0 or 6 micromol/h/100g body weight) was administered continuously for 48h into the duodenum (ID-0/ID-6), femoral vein (IV-0/IV-6), or portal vein (IP-0/IP-6) to create a condition in which biliary bile acids were continuously lost, and a similar dose of taurocholate was supplied to the liver simultaneously. CYP7A1 activity and mRNA expression of the ID-0 group were significantly increased compared with the no treatment (NT) group. CYP7A1 activity and mRNA expression of the ID-6 group were suppressed significantly to 41 and 46% of those of the ID-0 group, respectively. In the IV-6 and IP-6 groups, however, enzyme activity and mRNA expression were decreased slightly, but the suppression was not statistically significant. The results suggested that portal as well as intravenous administration of bile acids cannot suppress bile acid synthesis as effectively as intraduodenal administration. It was concluded that an unidentified regulatory factor other than the nuclear receptors may be involved in bile acid synthesis in vivo.

Alanine Transaminase↗
PubMed2004

Pitavastatin, a potent hydroxymethylglutaryl coenzyme a reductase inhibitor, increases cholesterol 7 alpha-hydroxylase gene expression in HepG2 cells.

BACKGROUND: The effect of pitavastatin on the mRNA levels of apolipoprotein (apo) A-I, peroxisome proliferator-activated receptor alpha (PPARalpha), cholesterol 7alpha-hydroxylase (CYP7A1), and farnesoid X receptor (FXR) in HepG2 cells was examined to establish whether pitavastatin affects bile acid synthesis and if so, to determine a possible molecular mechanism. METHODS AND RESULTS: HepG2 cells were cultured in serum-free Dulbecco's modified Eagle medium for 18 h before drug treatment. Total RNA was extracted at set times and mRNA levels were quantified by reverse transcription-real time polymerase chain reaction. Pitavastatin at 0.1, 1, 5, and 10 micromol/L increased the mRNA levels of apo A-I, PPARalpha, CYP7A1, and FXR in a dose-dependent manner. The mRNA levels of apo A-I, PPAR alpha, CYP7A1, and FXR similarly increased with increasing doses of pitavastatin. Coincubation of mevalonate (4 mmol/L) with pitavastatin (5 micromol/L) reversed the inductive effects of pitavastatin on the mRNA levels of these genes, indicating that the inductive effects of pitavastatin were related to its inhibition of HMG-CoA reductase. CONCLUSIONS: Pitavastatin increased the mRNA levels of CYP7A1 in HepG2 cells, suggesting that increased conversion of cholesterol to bile acids may be the mechanism for its potent low-density lipoprotein cholesterol-lowering effects.

Apolipoprotein A-I↗
PubMed2003

Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer.

Constitutive activation of signal transducer and activator of transcription (Stat) proteins has been demonstrated in a wide variety of malignancies. In this study, we elucidated the significance of Janus kinase (JAK) and the downstream transcription factor Stat3 signals on malignant potentials of pancreatic cancer. Electrophoretic mobility shift assay and immunohistochemical analysis revealed that Stat3 was constitutively activated in subsets of human pancreatic cancer tissues and cell lines (Panc1, Kp4, AsPC-1, BxPC-3). A JAK-specific inhibitor, tyrphostin AG490, markedly inhibited Stat3 activation and expression of cyclin D1, bcl-xL and vascular endothelial growth factor mRNAs estimated by RT-PCR, as followed by growth arrest (6.3-21.3% vs controls; P<0.001) of pancreatic cancer cells. Inactivation of Stat3 by dominant-negative Stat3 adenovirus partly suppressed the growth of pancreatic cancer cells on day 4 post-inoculation (P<0.05) but not the expression of these mRNAs. These results indicate that activation of the JAK/Stat3 signaling pathway plays an important role in the progression of pancreatic cancer and that blockade of JAK/Stat3 signals may provide a novel therapeutic strategy for pancreatic cancer.

Cell Division↗
PubMed2002

Relation of biliary bile acid output to hepatic adenosine triphosphate level and biliary indocyanine green excretion in humans.

We have previously demonstrated that there are two subgroups of patients with different types of biliary bile acid output after relief of obstructive jaundice by percutaneous transhepatic biliary drainage (PTBD). The reason for two groups is not clear but is possibly the difference in hepatic reserve function. The aim of this study was to examine the relation of biliary bile acid output to the hepatic ATP level and biliary excretion rate of indocyanine green (ICG) in humans. Patients whose bile could be collected through a PTBD tube participated in this study. The mean serum total bilirubin concentration was 12.7 mg/dl at the time of PTBD, decreasing to 1.1 mg/dl before surgery. These patients underwent curative resection for cancer of the bile duct, duodenal papilla, or pancreatic head after the relief of hyperbilirubinemia. Bile was collected at 1-hour intervals for 5 hours after intravenous administration of ICG (0.5 mg/kg) within a few days before surgery, and a small liver tissue sample was obtained immediately after laparotomy without using ischemic procedures. The concentrations of total bile acid and ICG in bile, the bile flow rate, and the bile acid output and ICG excretion rate in bile over 5 hours were determined. ATP concentrations in liver tissue were determined by high performance liquid chromatography. Results of hepatic ATP levels were correlated with the bile acid output and ICG excretion rate into bile. Both the biliary bile acid output (micromoles per 5 hours) and ICG excretion rate (percent of injected dose of ICG) over 5 hours were significantly correlated with the hepatic ATP level (p = 0.0190 and p = 0.0084, respectively). Neither the bile flow rate nor the serum liver function tests were related to the hepatic ATP level. Significant correlation was found between the bile acid output and the ICG excretion rate (p = 0.0127). Biliary bile acid output reflects the hepatic ATP level. Determination of the biliary bile acid output and ICG excretion may provide useful parameters for evaluating the hepatic energy status, which is essential for organ viability.

Adenosine Triphosphate↗
PubMed2002

Is a bilateral modified radical neck dissection beneficial for patients with papillary thyroid cancer?

PURPOSE: We previously reported a poor prognosis in papillary thyroid carcinoma patients with recurrence in the contralateral cervical lymph nodes after thyroidectomy and ipsilateral modified radical neck dissection (MRND) with a curative intent. The aim of this study was to investigate whether bilateral MRND improved prognosis in patients at risk for contralateral nodal recurrence. METHODS: We retrospectively reviewed the cases of 86 patients with contralateral nodal metastasis who underwent a thyroidectomy with bilateral MRND (group 1) and the cases of 32 patients who suffered contralateral nodal recurrence after a thyroidectomy with ipsilateral MRND (group 2). RESULTS: Although tumor progression was considered similar in patients from groups 1 and 2, group 1 developed fewer distant metastases than group 2 (6.8% vs 31.1%), thus resulting in a lower cancer death rate (5.8% vs 28.1%). Group 1 had a better 10-year survival rate than of group 2 (97.1% vs 83.7%). CONCLUSION: Bilateral MRND during initial surgical management is thus considered to improve the prognosis of some papillary carcinoma patients at risk for recurrence in the contralateral cervical lymph nodes.

Adult↗
PubMed2002

Video-assisted thyroid lobectomy through a small wound in the submandibular area.

BACKGROUND: Endoscopic thyroidectomy has not gained wide acceptance because of the expertise required, the long operation time, the wide dissection, and the extra cost of specialized instruments. We developed a video-assisted hemithyroidectomy procedure that requires only one small incision at the upper neck. METHODS: Hemithyroidectomy was performed through a 25 to 30 mm transverse incision made in the upper lateral neck for the treatment of benign thyroid nodule. No gas or external lift dissection was needed. RESULTS: The mean age of 39 patients was 33.8 years. The tumor size ranged from 1.9 to 5.5 cm (mean 3.1 cm). All patients underwent total lobectomy without conversion to traditional cervicotomy. The mean operation time was 56 minutes (range 36 to 90). Follicular adenoma was the final pathologic diagnosis in 25 patients and adenomatous goiter in 14. Transient recurrent laryngeal nerve palsy was seen in 1 patient. CONCLUSIONS: Our technique is safe, minimally invasive, less time consuming, and cosmetically excellent.

Adolescent↗