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ABSTRACT: : Lumican, a member of the small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. The lumican expression correlates with pathological conditions and the growth and metastasis of various malignancies. In cutaneous neoplasms, the lumican expression is lower in advanced-stage malignant melanomas that invade the dermis than in early-stage melanomas. Furthermore, we have recently reported that the expression pattern of lumican is different from that of actinic keratosis and the Bowen disease. Lumican is positive in the poroid cells of intraepidermal sweat ducts; therefore, we examined the expression patterns of lumican in acanthotic-type seborrheic keratosis and Pinkus-type poroma followed by clonal-type seborrheic keratosis and hidroacanthoma simplex. The neoplastic cells of acanthotic-type seborrheic keratosis exhibited positive immunostaining in only 1 of 31 cases (3.23%), whereas the poroid cells of Pinkus-type poroma exhibited positive immunoreactivity in 26 of 28 patients (92.8%). In the hidroacanthoma simplex cases, lumican was expressed in poroid cells forming intraepidermal nests in 22 of 28 patients (78.6%), whereas the neoplastic cells in most cases of clonal-type seborrheic keratosis were negative for lumican. In some seborrheic keratosis cases that were positive for lumican in neoplastic cells, lumican was observed in squamoid cells but not in basaloid cells. Therefore, it is necessary to evaluate the immunoreactivity of lumican in seborrheic keratosis and in basaloid cells. These findings suggest that lumican is a potent differential diagnostic marker that distinguishes hidroacanthoma simplex from clonal-type seborrheic keratosis.
The American Journal of dermatopathology 05/2013; · 1.30 Impact Factor
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ABSTRACT: Nestin, a class VI intermediate filament protein, was originally described as a neural stem cell/progenitor cell marker. Expression of nestin has been reported to be associated with the migration and metastasis of various types of tumor. In the present study, we examined the expression of nestin in malignant melanomas and nevi. Immunohistochemically, nestin was detected in all compound nevi, but not in the majority of junctional nevi. Nestin was expressed at particularly high levels in nevi with neurotization. In melanoma, nestin was expressed in all T3 and T4 cases, but only in half of the cases of T2 or less severe disease. These results indicate that the expression levels of nestin in melanoma are associated with advanced disease. In conclusion, nestin was expressed in advanced melanoma tissues and neurotized nevi. Nestin may be an important marker of melanocytic neoplasms. Further studies are required to elucidate the regulatory mechanisms of nestin expression and to examine the possibility of nestin-targeted therapy for malignant melanomas.
Oncology Reports 04/2013; 29(4):1595-9. · 1.84 Impact Factor
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Journal of Investigative Dermatology 02/2013; · 6.31 Impact Factor
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ABSTRACT: Cancer stem cells (CSCs) play pivotal roles in cancer growth, invasion, metastasis and recurrence. Several proteins have been reported as CSC markers for pancreatic ductal adenocarcinoma (PDAC). In the present study, we examined the correlation between pancreatic intraepithelial neoplasias (PanINs) and CSC markers including CD24, CD44, CD133, CXCR4, ESA and nestin using immunohistochemical analysis. Furthermore, we examined the roles and clinical significance of these CSC markers in PDAC. CD24-, CD44-, CXCR4-, ESA- and nestin-positive cells were detected in the following tissues, listed in order of increasing percentage: normal ducts < low-grade PanINs < high-grade PanINs < PDACs. CD133 did not increase according to the malignancy grade. In PDAC, cells positive for each of the following CSC markers were detected, listed according to increasing percentage: nestin < CD133 < CD44 < CD24 < CXCR4 < ESA. CXCR4 and ESA expression correlated with well-differentiated PDAC. Venous invasion was positively associated with CD133 and inversely associated with ESA. CSC marker expression levels detected in PDAC cell lines using flow cytometry showed lowest expression of CD133 and highest of CD44, differing from the results obtained using immunohistochemistry. In two PDAC subtypes, adenosquamous carcinoma and anaplastic carcinoma, ESA was expressed more abundantly in adenocarcinoma components, whereas CD44 and nestin showed high expression in anaplastic components. Together, these results suggest that most CSC markers correlate with pancreatic carcinogenesis through the PanIN-to-PDAC sequence. Each CSC marker was related in a different manner with proliferation, differentiation, invasiveness or tissue type of PDAC.
International Journal of Oncology 07/2012; · 2.40 Impact Factor
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ABSTRACT: Glioblastomas are associated with high mortality due to their aggressive growth and invasiveness. Interactions and functional cross-talk between tumor cells and their microenvironments are mediated by cell surface receptors that are responsible for cell-cell and cell-extracellular matrix adhesion. Central nervous tissues contain plenty of the glycosaminoglycan hyaluronan, and glioma cells express the major cell surface hyaluronan receptor, CD44. In this study, we analyzed the expression and roles of CD44 in human brain tissues. Normal brain tissues showed no or weak CD44 expression, while reactive astrocytes and astrocytoma cells expressed CD44 at variable levels. Immunohistochemically, a higher percentage and intensity of CD44-positive tumor cells were detected in high-grade astrocytomas compared with low-grade astrocytomas. Glioblastoma cells that express CD44 were localized in perivascular and perinecrotic lesions. The human glioma cell lines A172 and KG-1-C expressed CD44 mRNA and protein. Administration of monoclonal anti-human-CD44 antibody inhibited the migration of A172 cells, which are glioblastoma-derived, but did not affect cell growth. In conclusion, CD44 expression levels correlated with the histopathological grade of gliomas, and monoclonal anti-CD44 antibody inhibited the migration of glioblastoma cells. These findings suggest that CD44 is a potential therapeutic target of glioblastomas.
Pathology International 07/2012; 62(7):463-70. · 1.62 Impact Factor
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ABSTRACT: Gastric schwannoma is a rare tumor that accounts for only 0.2 % of all gastric tumors. We report a case of gastric schwannoma that underwent computed tomography (CT), magnetic resonance imaging (MRI), and [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and its histological confirmation was acquired. Gastric schwannoma showed high intensity on T2-weighted and diffusion-weighted MRI and high maximum standardized uptake on [(18)F]-FDG-PET. Lymphadenopathy close to the tumor was also found. Although diffusion-weighted MRI, [(18)F]-FDG-PET, and the presence of lymphadenopathy could suggest malignant tumors, the detail interpretation of the other CT and MRI findings may give a clue for the diagnosis of gastric schwannoma.
Japanese journal of radiology 06/2012; 30(7):602-5. · 0.65 Impact Factor
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ABSTRACT: Nestin expression reportedly correlates with aggressive growth, metastasis, poor prognosis and presence of cancer stem cells (CSCs) in various tumors. In this study, we determined the expression and role of nestin in cervical intraepithelial neoplasia (CIN) and cervical cancer. We performed immunohistochemical and in situ hybridization analyses of nestin in 26 cases for each stage of CIN and 55 cervical cancer tissue samples. To examine the role of nestin in cervical cancer cells, we stably transfected expression vectors containing nestin cDNA into ME-180 cells. We studied the effects of increased nestin expression on cell proliferation, cell motility, invasion as well as sphere and soft agar formation. Nestin was not localized in the squamous epithelium in normal cervical tissues, but it was weakly expressed in the basal squamous epithelium of CIN 1. In CIN 2, nestin was localized to the basal to lower 2/3 of the squamous epithelium, whereas in CIN 3, it was localized to the majority of the squamous epithelium. Nestin was detected in all cases of invasive cervical cancer. Nestin mRNA was expressed in both ME-180 and CaSki cells. Growth rate, cell motility and invasion ability of stably nestin-transfected ME-180 cells were not different from empty vector-transfected ME-180 (mock cells). However, the nestin-transfected ME-180 cells formed more colonies and spheres compared to the mock cells. These findings suggest that nestin plays important roles in carcinogenesis and tumor formation of cervical cancer cells. Nestin may closely correlate with regulation of CSCs.
International Journal of Oncology 05/2012; 41(2):441-8. · 2.40 Impact Factor
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ABSTRACT: An unusual case of a hepatobiliary cystadenoma caused severe abdominal pain and obstructive jaundice by rapid enlargement
in a woman aged 73 years. Magnetic resonance imaging revealed a 12 cm cystic lesion in the left medial segment of the liver
and dilatation of the intrahepatic bile ducts. The abdominal pain was worse 4 days later, when magnetic resonance imaging
demonstrated enlargement of the cystic lesion, to 14 cm in diameter. Laboratory tests on admission revealed serum alkaline
phosphatase, 1342 IU/L; gamma glutamic transpeptidase, 672 IU/L; total serum bilirubin, 7.4 mg/dL; direct bilirubin, 5.8 mg/dL;
and carbohydrate antigen 19-9, 37U/mL. Serosanguineous fluid was obtained by emergency percutaneous transhepatic drainage
of the cyst, which resolved the patient's abdominal pain. Culture and cytologic examination of the fluid were nondiagnostic.
The discharged fluid through dramage tube turned brown, and the total serum bilirubin concentration gradually decreased. Cystography
and endoscopic retrograde cholangiography demonstrated communication between the cyst and the intrahepatic bile ducts on the
left side of the liver. The cyst was removed by left hepatectomy 14 days after it had been drained. Pathologic examination
of the resected specimen confirmed the presence of a hepatobiliary cystadenoma. Although hepatobiliary cystadenoma is a rare
benign cystic tumor of the liver, it can become malignant and should thus be excised.
Journal of Medical Ultrasonics 04/2012; 30(4):257-262. · 0.33 Impact Factor
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ABSTRACT: In pancreatic ductal adenocarcinoma (PDAC), the fibroblast growth factor receptor 1 (FGFR-1) IIIb isoform correlates with the inhibition of cancer cell proliferation, migration, and invasion, whereas FGFR-1 IIIc enhances cancer cell proliferation. The FGFR-2 IIIb isoform is expressed in PDAC, and its expression correlates with increased venous invasion. We examined the role of FGFR-2 IIIc in PDAC. FGFR-2 IIIc was expressed in all six pancreatic cancer cell lines examined and was highest in PANC-1 cells. FGFR-2 IIIc was abundant in the cancer cells from 83 of 117 PDAC cases, which correlated with decreased duration to development of liver metastasis after surgery. FGFR-2 IIIc-transfected cells exhibited increased proliferation in vitro and formed larger subcutaneous and orthotopic tumors, the latter producing more liver metastases. Moreover, FGF-2 exerted a more rapid stimulatory effect on the levels of phosphorylated extracellular signal-regulated kinase (p-ERK) in FGFR-2 IIIc stably transfected PANC-1 cells, compared with control cells. FGFR-2 IIIc-transfected cells also formed more spheres and contained more side population cells. Suppression of FGFR-2 IIIc expression inhibited the proliferation of PANC-1 cells, whereas an anti-FGFR-2 IIIc antibody inhibited the proliferation and migration of PANC-1 cells. Thus, high FGFR-2 IIIc levels in PDAC contribute to disease aggressiveness and confer to pancreatic cancer cells features suggestive of cancer stem cells, indicating that FGFR-2 IIIc may be a novel and important therapeutic target in PDAC.
American Journal Of Pathology 03/2012; 180(5):1928-41. · 4.89 Impact Factor
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ABSTRACT: Keratinocyte growth factor (KGF), also known as fibroblast growth factor-7, is mainly synthesized by mesenchymal cells. KGF modulates proliferation, differentiation, migration and adhesion to extracellular matrices of epithelial cells that specifically express the KGF receptor (KGFR). We previously reported that KGF is expressed in cancer cells and adjacent stromal fibroblasts in human pancreatic cancer tissues. Furthermore, KGF is thought to stimulate the growth of certain pancreatic cancer cell lines. The aim of the present study was to examine whether the mitogen-activated protein kinase (MAPK) pathway contributes to exogenous KGF-induced pancreatic cancer cell growth. Recombinant human KGF (rhKGF) was administered to MIA PaCa-2 cells, which expressed KGFR and negligible levels of KGF. Cell growth rates in MIA PaCa-2 cells were significantly increased in a dose-dependent manner following the addition of rhKGF. In the MAPK pathway, phosphorylation of extracellular signal-regulated kinase (ERK) in MIA PaCa-2 cells was increased in a dose-dependent manner, and phosphorylation of p38 was slightly increased following the administration of 100 ng/ml rhKGF. In contrast, JNK was not phosphorylated following the addition of rhKGF in MIA PaCa-2 cells. U0126, a specific inhibitor of ERK activation, decreased the rhKGF-induced phosphorylation of ERK and the growth rates of MIA PaCa-2 cells. These findings indicated that phosphorylation of the ERK signaling pathway plays a significant role in exogenous KGF-induced pancreatic cancer cell growth.
Oncology letters 02/2012; 3(2):307-310. · 0.11 Impact Factor
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ABSTRACT: Lumican expression in the stromal tissues of pancreatic ductal adenocarcinoma (PDAC) correlates with tumor invasion, and tends to correlate with poor prognosis. We used gene transfection techniques to examine the biological roles of lumican secreted from PDAC cells. Lumican-transfected PANC-1 cells secreted a 70-kDa lumican protein and had an active ERK pathway. Transfection stimulated PANC-1 cell growth, increased cell adhesion to laminin, inhibited cell invasion, and decreased active matrix metalloproteinase-9. Down-regulation of lumican using siRNA resulted in opposite cell behavior. Thus, the 70-kDa lumican secreted by PDAC cells plays important roles in cell growth and invasion.
Cancer letters 01/2012; 320(1):31-9. · 4.86 Impact Factor
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ABSTRACT: The class VI intermediate filament protein, nestin is reported to be a progenitor cell marker in various tissues. In the present study, we analyzed the expression and roles of nestin in angiogenesis of pancreatic ductal adenocarcinomas, and determined whether nestin is a potential target for inhibiting tumor angiogenesis using a gene silencing strategy. Nestin expression was detected only in small vessels, whereas CD34, CD31 and factor VIII were also expressed in large-sized blood vessels in PDAC. The number of nestin-positive vessels was approximately 20% the number of CD34-positive vessels, and the average dimension of nestin-positive vessels was approximately 75% that of CD34-positive vessels. The PCNA labeling indices of nestin-positive vessels were higher than those of CD34-positive vessels and nestin-negative vessels. Reducing nestin expression by use of siRNA targeting nestin transcripts inhibited growth of the vascular endothelial cell lines, but there was no difference in cell motility. In xenograft models, administration of siRNA targeting mouse-nestin suppressed subcutaneous human pancreatic cancer cell growth in nude mice. In conclusion, nestin was expressed in small proliferating blood vessels in pancreatic cancer tissues and may be a useful marker of angiogenesis in pancreatic ductal adenocarcinoma tissues. Furthermore, nestin is a potential novel therapeutic target in pancreatic cancers to inhibit tumor angiogenesis.
International Journal of Oncology 01/2012; 40(5):1345-57. · 2.40 Impact Factor
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Journal of Nippon Medical School 01/2012; 79(6):392-3.
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ABSTRACT: The annual incidence of pancreatic carcinoma has been increasing worldwide, and the overall 5-year survival rate has remained at approximately 5%. We re-evaluated 30 autopsy cases histologically diagnosed as pancreatic carcinoma from 1994 through 2010 at Nippon Medical School Hospital. The mean patient age was 69.5 years, with no significant differences between male and female patients. The location of the primary tumor was most often the head of the pancreas (46.7%), followed by the body (36.7%) and tail (16.7%). All patients had advanced-stage pancreatic carcinoma at diagnosis, which limited the therapeutic options. Surgical resection, radiation, and surgical resection with chemotherapy were each performed for a single patient, and chemotherapy was performed for 5 patients. The other patients received only symptomatic therapy. The mean survival time from the first medical examination to death was short (5.5 months; range, 1-40 months). The cases were classified into 28 ductal adenocarcinomas, 1 acinar cell carcinoma, and 1 intraductal papillary mucinous neoplasm (IPMN) with an associated invasive carcinoma. Death in most cases was directly related to the pancreatic carcinoma, including cachexia, carcinomatous peritonitis and pleuritis, hepatic failure and ileus due to metastasis, and malignancy-related disorders, such as coagulation disorders and immunodeficiency. The most frequent site of metastasis was the lymph nodes, followed by the liver, peritoneum, spleen, lung and/or pleura, small intestine, adrenal gland, kidney, omentum, diaphragm, and bone. We classified the autopsy cases as showing distant metastasis or local infiltration. All cases with local infiltration were located in the pancreatic head, but no difference was seen in other clinicopathological features between cases with local infiltration and cases with distant metastasis. Thus, the autopsies revealed an extremely poor prognosis for pancreatic carcinoma due to the tumor itself and malignancy-related disorders. The progression pattern (i.e., local infiltration or distant metastasis) may correlate with the location of the primary tumor.
Journal of Nippon Medical School 01/2012; 79(6):459-67.
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ABSTRACT: To compare the antitumor efficacy and safety of transcatheter arterial chemoembolization (TACE) by epirubicin suspension (epirubicin suspension: epirubicin-iodized oil mixture without solution) to that by epirubicin emulsion (epirubicin emulsion: epirubicin-iodized oil mixture with solution), the efficacy of treatment by administration of either an epirubicin suspension or emulsion was examined in an animal model. Changes in plasma epirubicin concentration were compared over 24 h immediately after treatment, and enhanced ultrasonographic and histopathological analysis subsequently conducted 7 days after treatment to determine the growth ratio and proportion of viable tumor cells. The growth ratio and proportion of viable tumor cells were found to be significantly lower in the suspension group than in the emulsion group while the plasma epirubicin concentration was found to be significantly higher in the suspension group than in the emulsion group. These results indicate that administration of an epirubicin suspension is a superior form of TACE compared to that of administration of an epirubicin emulsion.
TheScientificWorldJOURNAL 01/2012; 2012:961986. · 1.66 Impact Factor
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ABSTRACT: Sarcoidosis is a multisystem disorder of unknown etiology that involves multiple organs. Computed tomography is the first-line imaging modality for diagnosing sarcoidosis because of its capacity to detect hilar lymphadenopathy and pulmonary lesions. Magnetic resonance (MR) imaging provides good soft tissue contrast that is useful for detecting sarcoidosis in some body parts, including skeletal muscle. Signal intensity on pre- and postcontrast T(1)- and T(2)-weighted imaging may reflect disease activity and the pathological appearance of sarcoidosis. In this review, we demonstrate these conventional MR imaging findings of hepatosplenic and muscular sarcoidosis and describe the usefulness of diffusion-weighted imaging for detecting sarcoidosis.
Magnetic Resonance in Medical Sciences 01/2012; 11(2):83-9. · 0.97 Impact Factor
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ABSTRACT: Dedifferentiated liposarcoma of the mesentery is an extremely rare tumor. A 71-year-old man with a 2-month history of abdominal distention was admitted to our department for evaluation and treatment of an abdominal mass. Computed tomography and magnetic resonance imaging revealed an 11 × 9 cm mass lesion with fat density in the upper right abdominal cavity, displacing the ascending and transverse colon ventrally. Abdominal angiography showed small feeding vessels of the tumor from the ileocolic artery and the middle colic artery. On basis of these findings, liposarcoma arising from the mesocolon ascendens was diagnosed, and complete removal of the tumor and central pancreatectomy (partial resection of the body of the pancreas) were performed. The histopathological diagnosis was dedifferentiated liposarcoma, and the patient is free from recurrence 6 months after surgery. The treatment strategy for abdominal dedifferentiated liposarcoma is surgical resection with a wide surgical margin.
Journal of Nippon Medical School 01/2012; 79(5):385-90.
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ABSTRACT: Aim: To evaluate the antitumor effects and hepatotoxicity of transcatheter arterial chemoembolization (TACE) with cisplatin-iodized oil suspension and emulsion in a rabbit tumor model. Methods: Transcatheter arterial chemoembolization was performed on 12 rabbits with hepatic VX2 tumors using a cisplatin suspension (1 mg/kg cisplatin and 0.1 mL/kg iodized oil, n = 6) or emulsion (1 mg/kg cisplatin, 0.1 mL/kg of iodized oil, and 0.1 mL/kg saline solution, n = 6). Time series changes in plasma platinum concentration were compared over 24 h. All rabbits were killed at 7 days after TACE, and the growth ratio and residual viable proportion of tumors were calculated on the basis of ultrasonographic and histopathological findings. Hepatotoxicity was also evaluated. Differences between the two groups were statistically assessed with the Mann-Whitney U-test. The animal care committee of our institute approved this study. Results: Plasma platinum concentrations were significantly higher in the suspension group than in the emulsion group at 0.5-24 h after TACE (P < 0.05). Growth ratios (-24.6 ± 9.98% vs. 21.4 ± 8.87%, respectively; P = 0.004) and residual viable proportions of tumors (25.8 ± 5.02% vs. 51.1 ± 11.4%, respectively; P = 0.009) were significantly lower in the suspension group than in the emulsion group. Hepatotoxicity was transient in all rabbits. Conclusion: Cisplatin-iodized oil suspensions facilitated the slow release of cisplatin at the tumor border. A suspension is preferable to an emulsion for drug delivery and the antitumor effect during the treatment of VX2 liver tumors with TACE.
Hepatology Research 12/2011; 42(5):473-81. · 2.20 Impact Factor
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ABSTRACT: Keratinocyte growth factor (KGF), also known as fibroblast growth factor-7, and KGF receptor (KGFR) play important roles in the growth of epithelial cells and are overexpressed in a variety of malignant epithelial tumors, including pancreatic ductal adenocarcinoma (PDAC). We previously reported that co-expression of KGF and KGFR in PDAC is associated with venous invasion, enhanced vascular endothelial growth factor A expression and poor prognosis. Matrix metalloproteinase-9 (MMP-9) is known to participate in the degradation of type IV collagen, which is a primary component of extracellular matrices in the vascular basement membrane. In the present study, we examined the expression and roles of KGF, KGFR and MMP-9 in human PDAC cell lines and tissues. Quantitative real-time polymerase chain reaction analysis demonstrated the expression of MMP-9 mRNA in all eight PDAC cell lines. KGF, KGFR and MMP-9 were, respectively, expressed in 27 (43%), 23 (37%) and 35 (56%) of 63 patients. Each expression of KGF, KGFR or MMP-9 correlated positively with venous invasion. Furthermore, expression of KGF or MMP-9 correlated positively with liver metastasis. KGF-positive cases exhibited shorter survival than KGF-negative cases, while KGFR and MMP-9 expression were unrelated to prognosis. Administration of recombinant human KGF increased MMP-9 expression in PDAC cells, while transient transfection with short hairpin RNAs targeting KGF transcripts reduced MMP-9 expression in PDAC cells. Moreover, recombinant human KGF significantly enhanced migration and invasion of PDAC cells. These findings suggest that KGF and KGFR promote venous invasion via MMP-9 in PDAC, and closely correlate with liver metastasis. The KGF/KGFR pathway may be a critical therapeutic target for PDAC metastasis.
International Journal of Oncology 12/2011; 40(4):1040-8. · 2.40 Impact Factor
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ABSTRACT: Numerous reports have been published on skin rejuvenation by the so-called fractional laser device that delivers a laser beam in a dot form over a grid pattern.
In this study, we characterized the effects of a fractional CO(2) laser on atrophic acne scars at the clinical and ultrastructural levels.
Seven healthy adult Japanese volunteers (aged 32-46 years, mean 37.6, five men and two women of Fitzpatrick skin type III) were recruited for this study. A fractional CO(2) laser device, SmartXide DOT (DEKA, Florence, Italy), was used with irradiation parameters set as follows: output power 10 W, pulse width 600 μs, dot spacing 800 μm, and stack 2 (irradiation output power 0.91 J/cm(2) ). A clinical examination and punch biopsy of each subject was performed before and just after the irradiation, and also at week 3 after three irradiation sessions. The biopsy specimens were stained with toluidine blue and were examined ultrastructurally.
Clinical improvement of the atrophic acne scars was observed at week 3 after the third irradiation session in all cases compared with the condition before treatment. Histologically, outgrowths of many degenerated elastic fibers were observed as irregular rod-shaped masses in the superficial dermis prior to the treatment in the region of the acne scars. At week 3 after the third irradiation, the degenerated elastic fibers were no longer observed, and the elastic fibers were elaunin-like.
The fractional CO(2) laser is considered to be very effective for treating atrophic acne scars.
Journal of Cosmetic Dermatology 12/2011; 10(4):294-300. · 0.98 Impact Factor
