Immunohistochemical angiogenic biomarkers in hepatocellular carcinoma and cirrhosis: correlation with pathological features

OBJECTIVE To investigate immunohistochemical markers of angiogenesis and their association with pathological prognostic features in hepatocellular carcinoma and cirrhotic liver. METHODS Vascular endothelial growth factor, CD105, and cyclooxygenase-2 were immunohistochemically detected in 52 hepatocellular carcinoma tissue samples and 48 cirrhotic liver tissue samples. Semiquantitative measurements of vascular endothelial growth factor and cyclooxygenase-2 were evaluated considering the degree and intensity of immunostaining based on a 7-point final scoring scale. CD105 microvascular density (MVD-CD105) was measured using automated analysis. Morphological aspects evaluated in the hepatocellular carcinoma samples included size (≤2 and >2 cm), differentiation grade, and microvascular invasion. RESULTS The mean vascular endothelial growth factor immunoreactivity score was slightly higher in the hepatocellular carcinoma samples (4.83±1.35) than the cirrhotic liver (4.38±1.28) samples. There was a significant and direct correlation between these mean scores (rs=0.645, p=0.0001). Cyclooxygenase-2 was expressed in all the cirrhotic liver samples but was only found in 78% of the hepatocellular carcinoma samples. The mean cyclooxygenase-2 score was higher in the cirrhotic liver samples (4.85±1.38) than the hepatocellular carcinoma samples (2.58±1.68), but there was no correlation between the scores (rs=0.177, p=0.23). The mean CD105 percentage in the hepatocellular carcinoma samples (11.2%) was lower than that in the cirrhotic samples (16.9%). There was an inverse relationship in MVD-CD105 expression between the hepatocellular carcinoma and cirrhotic samples (rs=-0.78, p=0.67). There were no significant associations between vascular endothelial growth factor expression and morphological characteristics. Cyclooxygenase-2 and CD105 were associated with hepatocellular carcinoma differentiation grade (p=0.003 and p=0.05, respectively). CONCLUSION Vascular endothelial growth factor, cyclooxygenase-2, and MVD-CD105 were highly expressed in cirrhotic liver compared to hepatocellular carcinoma and might be involved in liver carcinogenesis. Additionally, cyclooxygenase-2 and CD105 might be involved in hepatocellular carcinoma differentiation grade.

Lesão renal aguda como complicação da ingestão excessiva de suco do fruto biri biri (Averrhoa bilimbi)

O fruto biri-biri pertence à família das Oxalidacae, espécie Averrhoa bilimbi. Este fruto tem um alto conteúdo de oxalato solúvel e é utilizado na culinária, na produção de picles, geleias, e como tratamento para algumas doenças como hipertensão, diabetes e hiperlipidemia. Assim como outros frutos ricos em oxalato, pode provocar lesão renal aguda. Relatamos o caso de um paciente de 50 anos, hipertenso, com função renal normal, que ingeriu uma grande quantidade de suco em jejum para tratamento de hipertensão. O paciente desenvolveu quadro de lesão renal aguda associado a dores lombares, soluços e diarreia. A lesão renal aguda era não oligúrica e teve uma evolução favorável em 10 dias sem necessidade de tratamento dialítico. A função renal retornou ao normal após esses 10 dias de seguimento.

80-kVp CT Using Iterative Reconstruction in Image Space Algorithm for the Detection of Hypervascular Hepatocellular Carcinoma: Phantom and Initial Clinical Experience

OBJECTIVE: To investigate whether the low-tube-voltage (80-kVp), intermediate-tube-current (340-mAs) MDCT using the Iterative Reconstruction in Image Space (IRIS) algorithm improves lesion-to-liver contrast at reduced radiation dosage while maintaining acceptable image noise in the detection of hepatocellular carcinomas (HCC) in thin (mean body mass index, 24 +/- 0.4 kg/m2) adults. SUBJECTS AND METHODS: A phantom simulating the liver with HCC was scanned at 50-400 mAs for 80, 100, 120 and 140-kVp. In addition, fifty patients with HCC who underwent multiphasic liver CT using dual-energy (80-kVp and 140-kVp) arterial scans were enrolled. Virtual 120-kVP scans (protocol A) and 80-kVp scans (protocol B) of the late arterial phase were reconstructed with filtered back-projection (FBP), while corresponding 80-kVp scans were reconstructed with IRIS (protocol C). Contrast-to-noise ratio (CNR) of HCCs and abdominal organs were assessed quantitatively, whereas lesion conspicuity, image noise, and overall image quality were assessed qualitatively. RESULTS: IRIS effectively reduced image noise, and yielded 29% higher CNR than the FBP at equivalent tube voltage and current in the phantom study. In the quantitative patient study, protocol C helped improve CNR by 51% and 172% than protocols A and B (p < 0.001), respectively, at equivalent radiation dosage. In the qualitative study, protocol C acquired the highest score for lesion conspicuity albeit with an inferior score to protocol A for overall image quality (p < 0.001). Mean effective dose was 2.63-mSv with protocol A and 1.12-mSv with protocols B and C. CONCLUSION: CT using the low-tube-voltage, intermediate-tube-current and IRIS help improve lesion-to-liver CNR of HCC in thin adults during the arterial phase at a lower radiation dose when compared with the standard technique using 120-kVp and FBP.

Transarterial chemoembolization for hepatocellular carcinoma: Significance of extrahepatic collateral supply.

Purpose: Transarterial chemoemblization (TACE) is the most common treatment modality for treating patients of large unresectable hepatocellular carcinoma (HCC). Extrahepatic collateral arterial supply (ECS) to these large tumors is not uncommon. This study was designed to assess the significance and outcome of TACE in patients of HCC with ECS. Materials and Methods: A total of 85 patients of HCC of Barcelona clinic liver cancer (BCLC) stage B/C who fulfilled the following inclusion criteria--Child's A/B cirrhosis, normal main portal vein and tumor bulk involvement less than 50% of the liver-were included. TACE was done using cisplatin 100 mg, doxorubicin 50 mg and 20 ml lipiodol followed by gelfoam embolization. Presence of extrahepatic supply to the tumor was looked for in suspected cases. When the collateral supply to the mass was documented, additional chemoembolization through the extrahepatic feeding collateral was attempted. If this was unsuccessful, then the treatment was completed by percutaneous acetic acid ablation (PAI). Results: Eight patients showed the presence of additional extrahepatic supply to the liver tumor. The sources included inferior phrenic artery, intercostals, internal mammary artery, omental arteries, gastroduodenal artery and branch of the superior mesenteric artery. Successful chemoembolization through these collaterals was achieved in five cases and complete response was noted on follow-up. In the remaining three cases, chemoembolization could not be done and PAI was performed subsequently. Conclusions: Hepatocellular carcinoma having extrahepatic collateral supply requires additional chemoembolization through the collateral to enhance the efficacy of TACE failing which an alternative locoregional therapy of percutaneous ablation may be resorted to.

Hepatocellular Carcinomas Smaller Than 4 cm Supplied by the Intercostal Artery: Can We Predict Which Intercostal Artery Supplies the Tumor?

OBJECTIVE: To predict which intercostal artery supplies a tumor by examining the spatial relationship between hepatocellular carcinoma (HCC) and the intercostal artery feeding the tumor on transverse computed tomography (CT) images. MATERIALS AND METHODS: Between January 2000 and September 2009, 46 intercostal arteries supplying HCCs smaller than 4 cm were noted in 44 patients, and CT scans and angiograms of these patients were retrospectively reviewed. The intercostal artery feeding the tumor was marked on the CT scan showing the center of the tumor. In addition, its spatial relationship with the tumor center was examined. The angle of the tumor location was measured on the transverse CT scan in the clockwise direction from the sagittal line on the virtual circle centered in the right hemithorax. Correlations between the angle of the tumor location and the level of the tumor-feeding intercostal artery were assessed with the Spearman rank coefficient. RESULTS: Of 46 intercostal arteries feeding HCC, 39 (85%) were the first ones observed from the tumor center in a counterclockwise direction on the transverse CT image containing the tumor center. The level of the tumor-feeding intercostal artery was significantly correlated with the angle of the tumor, as the posteriorly located tumor tends to be supplied by lower intercostal arteries, while the laterally located tumor by upper intercostal arteries (Spearman coefficient = -0.537; p < 0.001). CONCLUSION: We can predict the tumor feeder with an accuracy of 85% as the first intercostal artery encountered from the tumor center in a counterclockwise direction on a transverse CT image.

Hypoxia-inducible factor 1, hepatocellular carcinoma and angiogenesis / 대한간학회지

No abstract available.

Effects of the knockdown of hypoxia inducible factor-1alpha expression by adenovirus-mediated shRNA on angiogenesis and tumor growth in hepatocellular carcinoma cell lines / 대한간학회지

BACKGROUND/AIMS: Hypoxia-inducible factor-1alpha (HIF-1alpha) is a central transcriptional factor involved in the cellular responses related to various aspects of cancer biology, including proliferation, survival, and angiogenesis, and the metabolism of the extracellular matrix in hypoxia. This study evaluated whether adenovirus-mediated small hairpin RNA (shRNA) against HIF-1alpha (shHIF-1alpha) inhibits cell proliferation and angiogenesis in hepatocellular carcinoma (HCC) cell lines. METHODS: Knockdown of HIF-1alpha expression was constructed by adenovirus-mediated RNA interference tools, and HCC cell lines infected with shHIF-1alpha coding virus were cultured under a hypoxia condition (1% O2) for 24 hours. Following infection, the expression levels of HIF-1alpha, angiogenesis factors, and matrix metalloproteinase (MMP) were examined using Western blotting. Cell proliferation and angiogenesis were measured by a cell proliferation assay (MTT assay) and an angiogenesis-related assay (invasion and tube-formation assay), respectively. RESULTS: Adenovirus mediated inhibition of HIF-1alpha induced suppression of tumor growth in HCC cell lines. It also down-regulated the expression of angiogenesis factor and MMP proteins. Angiogenesis as well as mobility of vascular cells to tumor was suppressed by adenovirus-mediated shHIF-1alpha-infected groups in human umbilical vein endothelial cells (HUVECs). CONCLUSIONS: These data suggest that adenovirus-mediated inhibition of HIF-1alpha inhibits the invasion, tube formation, and cell growth in HUVECs and HCC cells.

Expression of Caveolin in Hepatocellular Carcinoma: Association with Unpaired Artery Formation and Radiologic Findings / 대한간학회지

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is becoming one of the common malignant tumors worldwide, and it is characterized by its high vascularity. Caveolin is the major structural protein in caveolae, which are small omega-shaped invaginations within the plasma membrane. Caveolin has been implicated in mitogenic signaling, oncogenesis and angiogenesis. The expression of caveolin-1 and -2 in HCC and its potential relationship with angiogenesis has not been examined. METHODS: Paraffin sections of 35 HCC specimens were immunostained with caveolin-1, caveolin-2, alpha-smooth muscle actin, and CD34 antibodies. In addition, the expression of caveolin-1 and -2 mRNA in HCC was examined. The relationship between the radiological findings and the number of unpaired arteries and microvessel density (MVD) was also investigated. RESULTS: Caveolin-1 and -2 were expressed in the sinusoidal endothelial cells in 20 out of 35, and 18 out of 35 HCC specimens, respectively. Caveolin-1 and -2 were also expressed in the smooth muscle cells of the unpaired arteries in 26 out of 35, and 18 out of 35 HCC specimens, respectively. Increased expression of caveolin-1 and -2 mRNA was detected in 26.7% and 33.3% of the tumor specimens, respectively, compared with the corresponding non-tumorous adjacent liver tissues. There was a significant correlation between expression of caveolin-1, -2 in the smooth muscle cells of unpaired arteries and the number of unpaired arteries. The number of unpaired arteries in HCCs was found to be associated with the degree of contrast enhancement in the arterial phase imaging. However, it did not correlate with the degree of MVD. CONCLUSIONS: These findings suggest that the expression of caveolin-1, -2 is associated with the formation of unpaired arteries in HCC. In addition, there is a correlation between the degree of contrast enhancement of the HCC in the arterial phase image and the number of unpaired arteries.

A New and Simple Practical Plane Dividing Hepatic Segment 2 and 3 of the Liver: Evaluation of Its Validity

OBJECTIVE: The conventional method of dividing hepatic segment 2 (S2) and 3 (S3) is subjective and CT interpretation is unclear. The purpose of our study was to test the validity of our hypothesis that the actual plane dividing S2 and S3 is a vertical plane of equal distance from the S2 and S3 portal veins in clinical situations. MATERIALS AND METHODS: We prospectively performed thin-section iodized-oil CT immediately after segmental chemoembolization of S2 or S3 in 27 consecutive patients and measured the angle of intersegmental plane on sagittal multiplanar reformation (MPR) images to verify its vertical nature. Our hypothetical plane dividing S2 and S3 is vertical and equidistant from the S2 and S3 portal veins (vertical method). To clinically validate this, we retrospectively collected 102 patients with small solitary hepatocellular carcinomas (HCC) on S2 or S3 the segmental location of which was confirmed angiographically. Two reviewers predicted the segmental location of each tumor at CT using the vertical method independently in blind trials. The agreement between CT interpretation and angiographic results was analyzed with Kappa values. We also compared the vertical method with the horizontal one. RESULTS: In MPR images, the average angle of the intersegmental plane was slanted 15 degrees anteriorly from the vertical plane. In predicting the segmental location of small HCC with the vertical method, the Kappa value between CT interpretation and angiographic result was 0.838 for reviewer 1 and 0.756 for reviewer 2. Inter-observer agreement was 0.918. The vertical method was superior to the horizontal method for localization of HCC in the left lobe (p < 0.0001 for reviewers 1 and 2). CONCLUSION: The proposed vertical plane equidistant from S2 and S3 portal vein is simple to use and useful for dividing S2 and S3 of the liver.

Tumor Response to Transcatheter Arterial Chemoembolization in Recurrent Hepatocellular Carcinoma after Living Donor Liver Transplantation

OBJECTIVE: To evaluate the tumor response and patient survival rate following transcatheter arterial chemoembolization (TACE) in recurrent hepatocellular carcinoma (r-HCC) after living donor liver transplantation (LDLT). MATERIALS AND METHODS: Twenty-eight patients with r-HCC underwent one or more cycles of TACE after LDLT (mean, 2.5 cycles). After a mixture of iodized oil and anti-cancer drugs was injected via the arteries feeding the tumors, these vessels were embolized with a gelatin sponge. Tumor response was determined by follow-up CT imaging on all patients four weeks after each TACE procedure. Patient survival was calculated using the Kaplan-Meier survival curve. RESULTS: After TACE, targeted tumor reduced in size by 25% or more in 19 of the 28 study patients (67.9%). However, intrahepatic recurrence or extrahepatic metastasis occurred in 21 of the 28 patients (75.0%) during the 3-month follow-up period and in 26 of the 28 patients (92.9%) during the 6-month period following TACE. Extrahepatic metastasis was noted in 18 of the 28 patients (64.3%). The 1-, 3- and 5-year survival rates following TACE were 47.9, 6.0 and 0%, respectively, with a mean survival of nine months in all patients. There were no significant complications related to TACE. CONCLUSION: TACE produces an effective tumor response for targeted r-HCC after LDLT. However, the survival rate of patients with r-HCC after LDLT is poor due to extrahepatic metastasis and intrahepatic recurrence.

A New Technique for Superselective Catheterization of Arteries: Preshaping of a Micro-Guide Wire into a Shepherd's Hook Form

OBJECTIVE: We wanted to introduce a new technique for superselective catheterization of arteries with preshaping of a micro-guide wire into a shepherd's hook form, and this is useful for superselection of small arteries branching at an acute angle from a large parent artery for the treatment of tumors and hemorrhages. MATERIALS AND METHODS: We developed a superselective catheterization technique by using preshaping of a micro-guide wire into a shepherd's hook form. We encountered six patients in our practice for whom we failed to catheterize the small tumor-feeding arteries that branched at an acute angle from wide parent arteries during chemoembolization of hepatocellular carcinoma; the parent arteries were the right inferior phrenic artery (n = 4) and the left gastric artery (n = 1) from the celiac axis with celiac stenosis due to compression by the median arcuate ligament and the proper hepatic artery from the gastroduodenal artery (n = 1) in a patient who had celiac axis occlusion with collateral circulation via the pancreaticoduodenal arcade from the superior mesenteric artery. In these consecutive six patients, we tested the usefulness of this new technique with employing preshaping of a micro-guide wire into a shepherd's hook form for superselective catheterization of targeted vessels. RESULTS: The target arteries were successfully catheterized and satisfactory transcatheter arterial chemoembolization was performed in all six patients. There were no significant complications such as arterial dissection. CONCLUSION: We developed a technique that is effective for superselection of vessels with preshaping of micro-guide wire into a shepherd's hook form, and we successfully applied it during chemoembolization of hepatocellular carcinoma. This technique can be useful for superselection of small arteries that branch from a large parent artery at acute angles for the treatment of tumors and hemorrhages.

Hemoperitoneum as a first manifestation of HCC with bleeding from ruptured aberrant vessel: a case report.

A young man presented with a history of abdominal pain and distension for 4 days. Diagnosis of spontaneous hemoperitoneum was made after clinical examination, abdominal USG and a diagnostic peritoneal tap. Emergency laparotomy revealed massive hemoperitoneum with extensive bilobar hepato-cellular carcinoma (HCC). A ruptured aberrant vessel communicating between the intercostal vessel and HCC in the liver had caused massive hemoperitoneum.

The Efficacy of Hepatic Arterial Infusion Therapy for Advanced Hepatocellular Carcinoma according to Extrahepatic Collateral Feeding Vessels / 대한간학회지

BACKGROUND/AIMS: Despite the poor response rate of 20-30%, hepatic arterial infusion therapy (HAIT) has been often tried for advanced hepatocellular carcinoma with portal vein tumor thrombosis or ineffective response to other treatments. The factors that predict treatment response to HAIT remain unclear. This study ascertained the response rate to HAIT based on the existence of extrahepatic collateral feeding vessels or anatomical variants. METHODS: Forty one patients received repeated HAIT using an implanted drug delivery system. Of the 41 patients, 18 patients were treated with 5-FU, epirubicin and mytomycin-C; 17 patients were treated with 5-FU and cisplatin; and 6 patients were treated with 5-FU, cisplatin and leucovorin. The patients were divided into two groups according to the existence of extrahepatic collateral feeding vessels or anatomical variants. RESULTS: Of the 41 patients, 10 patients (24.4%) showed a complete response (CR) or partial response (PR). Of 41 patients, 22 patients (group A) did not have extrahepatic collateral feeding vessel or an anatomical variant, but 19 patients (group B) did. In group A, 10 patients (45.5%) had a treatment response (CR+PR). However, only one patient (5.3%) had a treatment response (CR+PR) in group B. The response rate in group A was significantly higher than that in group B (45.5 vs. 5.3%; P=0.005). The median survival of group A was significantly longer than that of group B (10.8 vs 3.4 months, P=0.031). CONCLUSIONS: Hepatic arterial infusion therapy may be useful therapeutic option for patients with advanced HCC, especially in those that do not have extrahepatic collateral feeding vessel or anatomical variant.

The Role of Angiostatin, Vascular Endothelial Growth Factor, Matrix Metalloproteinase 9 and 12 in the Angiogenesis of Hepatocellular Carcinoma / 대한간학회지

BACKGROUND/AIMS: Tumor angiogenesis, a major requirement for tumor growth and metastasis, is regulated by pro- and anti-angiogenic factors. Hepatocellular carcinoma (HCC) has become a common malignant tumor worldwide. It is characterized by a high vascularity. METHODS: We studied the immunohistochemical expression of angiostatin, vascular endothelial cell growth factor (VEGF), matrix metalloproteinase (MMP)-9 and MMP-12, and the relationship between these results and the microvessel density (MVD) in 48 HCC specimens. To determine whether HCC cells express angiostatin per se, we examined the expression of angiostatin, MMP-9 and MMP-12 by Western blotting in four HCC cell lines. RESULTS: Expression of angiostatin and MMP-12 (but not MMP-9) were strongly correlated with decreased MVD in HCCs (P=0.006, P=0.038, respectively). VEGF positive tumors showed a significantly higher MVD than VEGF negative tumors (P=0.01). We divided the 48 cases into the following four groups: group A, angiostatin (+), MMP-9 or -12 (+), and VEGF (-); group B, angiostatin (-) and VEGF (-); group C, angiostatin (+), MMP-9 or -12 (+), and VEGF (+); group D, angiostatin (-) and VEGF (+). There was a significant correlation with MVD among these groups (P<0.001). Angiostatin was detected by Western blotting in 2 out of 4 HCC cell lines and was associated with plasminogen and MMP expression. CONCLUSIONS: These results indicate that angiogenesis in HCC is a complex process involving multiple factors including angiostatin, VEGF, and MMP. Our results suggest that angiostatin is generated by MMP-mediated proteolysis of plasminogen in HCC cells.

Spontaneous Intratumoral Hemorrhage into Hepatocellular Carcinoma During Transcatheter Arterial Embolization: A Case Report

Spontaneous extrahepatic rupture of hepatocellular carcinoma (HCC) is a rare but serious complication that occurs with an incidence of between 5 and 15% of patients with HCC. It is thought to be preceded by rapid expansion due to intratumoral bleed-ing. Extrahepatic rupture of HCC has been reported as a rare complication of tran-scatheter arterial embolization (TAE). Although there have been reports of extrahepatic rupture of HCC after TAE, but there is no report regarding intratumoral hemor-rhage into HCC during TAE. We report a unique case of intratumoral hemorrhage into HCC during TAE presumably triggered by TAE. Although a rare complication, intratumoral hemorrhage into HCC after TAE should be considered in any patient with TAE due to HCC.

Focal Hepatic Lesions: Contrast-Enhancement Patterns at Pulse-Inversion Harmonic US using a Microbubble Contrast Agent

OBJECTIVE: To analyze the contrast-enhancement patterns obtained at pulseinversion harmonic imaging (PIHI) of focal hepatic lesions, and to thus determine tumor vascularity and the acoustic emission effect. MATERIALS AND METHODS: We reviewed pulse-inversion images in 90 consecutive patients with focal hepatic lesions, namely hepatocellular carcinoma (HCC) (n=43), metastases (n=30), and hemangioma (n=17). Vascular and delayed phase images were obtained immediately and five minutes following the injection of a microbubble contrast agent. Tumoral vascularity at vascular phase imaging and the acoustic emission effect at delayed phase imaging were each classified as one of four patterns. RESULTS: Vascular phase images depicted internal vessels in 93% of HCCs, marginal vessels in 83% of metastases, and peripheral nodular enhancement in 71% of hemangiomas. Delayed phase images showed inhomogeneous enhancement in 86% of HCCs; hypoechoic, decreased enhancement in 93% of metastases; and hypoechoic and reversed echogenicity in 65% of hemangiomas. Vascular and delayed phase enhancement patterns were associated with a specificity of 91% or greater, and 92% or greater, respectively, and with positive predictive values of 71% or greater, and 85% or greater, respectively. CONCLUSION: Contrast-enhancement patterns depicting tumoral vascularity and the acoustic emission effect at PIHI can help differentiate focal hepatic lesions.

A Case of Nodular Hepatic Involvement of Multiple Myeloma Mimicking Hypervascular Hepatocellular Carcinoma / 대한간학회지

Nodular hepatic involvement of multiple myeloma is very rare. We report a case of nodular hepatic involvement of multiple myeloma, mimicking hypervascular hepatocellular carcinoma.

Hepatocellular Carcinoma; Treatment with a Rodioiodinated Fatty Acid Ester

It has been shown that iodinated fatty acid esters such as Ethiodol(*) or Lipiodol(**) are selectively retained in hypervascular hepatic tumors following intrahepatic arterial admininstration. Such agents have been utilized in the detection and treatment of hepatocellular carcinoma (HCC) along with anticancer drug emulsions. Radioildination of Lipiodol(1-131-Lipiodol) was achieved by using a simple exchange method and the agent was used in the treatment of HCC following intrahepatic arterial-injection via superselective catheterization of tumor feeding vessels. Forty patients with HCC (massive 18; multinodular 12; infiltrative 10) were treated in an attempt to deliver a high dose of internal radiation; a cumulative tumor dose of 12,000 rad(120 GY) or higher was aimed in single or multiple procedures. Following therapy, the patients were divided into 2 groups, responsive or nonresponsive. Patients classfied as massive type responded to this treatment best (72.3%) followed by multinodular type (33.3%) and infiltrative type(10.0%). According to the size of tumor there was an 80.0% response for tumors of less than 5cm in diameter, 60.0%, between 5 to 8cm and 9.0% larger than 10cm in diameter. The clinical results of this treatment modality appear to be quite promising in the management of HCC, especially in the less than 8cm sized massive type of HCC. Also this method was able to not only provide long term local control but also a good quality of life without complications.