Cooperative Subtype Switch of Thyroid Hormone Receptor and Nuclear Receptor Corepressor Related Epithelial–Mesenchymal Transition in Papillary Thyroid Cancer

Background and Objectives@#Although thyroid hormones affect human cancer progression, the regulatory mechanism of thyroid hormone receptors in carcinogenesis has not been elucidated. This study aimed to evaluate the expression pattern of the thyroid hormone receptor (TR) and its corepressors, and to investigate the clinical and biological functions of TR. @*Materials and Methods@#Transcriptomic and clinical data for thyroid cancer were downloaded from The Cancer Genome Atlas. Paraffin-embedded tissue sections from patients who underwent thyroidectomy were used for immunohistochemistry. BCPAP cells were treated with T3 to investigate the thyroid hormone target genes. Thyroid hormone receptor alpha (THRA) and Thyroid hormone receptor beta (THRB) were knocked down by transient siRNA transfection. @*Results@#THRA and THRB expression was lower in thyroid cancer tissues than in normal tissues. However, strong focal staining of TRβ was observed in the invasive front. High THRB expression was associated with high Silencing Mediator for Retinoid or Thyroid hormone receptor (SMRT) expression, older age, a high MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) score, more aggressive histological subtypes, more frequent extra-thyroidal extension, and advanced TNM stage. THRB expression was positively correlated with Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A), L1 Cell Adhesion Molecule (L1CAM), and Lysyl Oxidase (LOX) expression. Thyroid hormone-induced HIF1A, L1CAM, and LOX upregulation was abolished by siTHRB but not siTHRA in BCPAP cells. High SMRT and high THRB groups (SMRT/THRB) presented more aggressive clinical features and showed an upregulation of HIF1A, L1CAM, and LOX, as well as of epithelial-mesenchymal transition (EMT)-related genes, causing changes in the tumor microenvironment. @*Conclusion@#Cooperative subtype switching from NCOR1/THRA to SMRT/THRB was thus related to aggressive clinical and molecular features, possibly related to EMT and EMT-related tumor microenvironment.

Liver X Receptor β Related to Tumor Progression and Ribosome Gene Expression in Papillary Thyroid Cancer

Background@#Intracellular lipid deposition has been reported in thyroid glands in obese animal and human. To understand the regulatory mechanism of lipid metabolism in thyroid cancer, we investigated the expression status of liver X receptor (LXR) and analyzed its clinicopathological characteristics and molecular biological features. @*Methods@#Expression status of LXR and its transcriptional targets in human cancers were analyzed using The Cancer Genome Atlas (TCGA). The gene-sets related to high LXRβ expression was investigated by gene set enrichment analysis (GSEA) using Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways and gene ontology biologic process. Quantitative reverse transcription polymerase chain reaction was performed in thyroid cancer samples using our validation cohort. @*Results@#In contrast to low expression of LXRα, LXRβ was highly expressed in thyroid cancer compared to the other types of human cancers. High LXRβ expression was correlated with the expression of LXRβ transcriptional targets genes, such as apolipoprotein C1 (APOC1), APOC2, apolipoprotein E (APOE), ATP binding cassette subfamily G member 8 (ABCG8), sterol regulatory elementbinding protein 1c (SREBP1c), and SPOT14. Furthermore, High LXRβ expression group indicated poor clinicopathological characteristics and aggressive molecular biological features independently from the drive mutation status. Mechanistically, high LXRβ expression was coordinately related to ribosome-related gene sets. @*Conclusion@#The mechanistic link between LXRβ and ribosomal activity will be addressed to develop new diagnostic and therapeutic targets in thyroid cancers.

Multiple Human Papillomavirus Infection Is Associated with High-Risk Infection in Male Genital Warts in Ulsan, Korea

Further understanding of male human papillomavirus (HPV) infection is necessary to prevent infection in men, as well as transmission to women. In our current study, we investigated patterns of HPV infection and genotype distributions in male genital warts using the Anyplex II HPV28 Detection kit. We reviewed the medical records of 80 male patients who presented to 5 neighborhood clinics in Ulsan, Korea, for the treatment of genital warts between April 2014 and January 2015. All patients underwent HPV genotyping. The prevalence and characteristics of HPV infection were analyzed, and the patterns of HPV infection according to age were assessed. Among the study patients, 13 (16.3%) were negative for HPV infection, 46 (57.3%) were infected with low-risk HPV, and 21 (26.3%) were infected with high-risk HPV. Patients with multiple HPV infection were more likely to have high-risk HPV infection (P = 0.001). The prevalence of HPV infection was much higher in samples obtained by tissue excision due to a definite lesion (P = 0.001). There were no differences in high-risk HPV infection (P = 0.459), multiple HPV infection (P = 0.185), and recurrence at diagnosis (P = 0.178) according to age. HPV-6 and HPV-11 were the most common type overall (39.7% and 13.8%, respectively). HPV-16 and HPV-18 were the most common high-risk infections (both 3.4%). HPV infection is not only commonly encountered in male genital warts, but is also accompanied by high-risk HPV and multiple infections.

Antioxidant effects and mechanism of thiopental and propofol on the rabbit abdominal aortic endothelial dependent vasorelaxation against reactive oxygen species / 대한마취과학회지

No abstract available.

Evaluation of Intralesional Injection Therapy for Pediatric Lymphangiomas Classified with MRI

Pediatric lymphangioma can occur at any site. However the neck is the most common site. There are two treatment modalities (surgical excision and intralesional injection) for lymphangiomas. But, the treatment guide line for lymphangioma has not been established, yet. The aim of this study is to establish the treatment guide line based on our experience with lymphangiomas. Medical records of 82 cases of lymphangioma were reviewed retrospectively. On MRI (magnetic resonance image) findings, lymphangiomas were divided into 4 groups by the proportion of the cyst bigger than 2 cm in diameter of the tumor; group A-proportion of cyst occupies more than 75%, group B-proportion of the cyst 50~75%, group C-25~50%, and D in less than 25%. All patients were treated with OK-432 intralesional injection as the initial treatment. The effective response rates of OK-432 in group A & B were 88.2% and 88.8%, respectively. Group C response was 38.0% and D only 20.0%. Twenty-three patients received surgical excision. The result of surgical excision was generally satisfactory. Surgical site infection occurred in 1 case and postoperative bleeding in 1 case. Theses results indicate that intralesional injection of OK-432 could be the first line therapy in group A & B. In group C, OK-432 would be better as the first line therapy than surgery. For the group D, surgical excision should be the first line of treatment.

Respiratory failure due to myotonic dystrophy combined with peripartum cardiomyopathy: A case report / 대한마취과학회지

Myotonic dystrophy is an autosomal-dominant inherited neuromuscular disorder that's characterized by slowly progressive muscular dystrophy, muscle weakness and myotonia. The clinical features may vary from just cataracts to involvement of multiple organ systems such as various muscles, the heart, lung and intestine. Its most common complication is postoperative respiratory failure. We encountered a patient who developed sudden unexpected peripartum cardiomyopathy (PPCM) and respiratory failure due to presumed myotonic dystrophy after cesarean section. We report here on our clinical experience with this malady and we include a brief review of the medical literature on myotonic dystrophy.

Comparison with hemodynamic changes of laparoscopic surgery by body position

BACKGROUND: The authors evaluated the hemodynamic effects of body position measured by esophageal Doppler monitor (EDM) during laparoscopic cholecystectomy or gynecologic laparoscopic surgery. METHODS: Fifty patients scheduled to undergo laparoscopic cholecystectomy (Group C) or gynecologic laparoscopic surgery (Group G), were divided into two groups. Pneumoperitoneum was instituted by CO2 gas and the intraperitoneal pressure was kept under 12 mmHg. Hemodynamic parameters at critical points were measured by the use of EDM: before skin incision (T1), 5, 10 and 15 min after changing position (T2, T3 and T4), and 5 min after CO2 exsufflation (T5). RESULTS: MAP (mean arterial pressure) was significantly higher in Group G when compared with Group C 10 min after changing position (T3) (P< 0.05). CO (cardiac output) was significantly decreased in Group G when compared with Group C 10 min after changing position (T3) (P< 0.05). And there were not significant differences in HR (heart rate) between two groups. PV (peak velocity) was significantly decreased in Group G when compared with Group C 10 min after changing position (T3) (P< 0.05). And there were not significant differences in FTc (corrected flow time) between two groups. But FTc in Group C was restored after CO2 exsufflation, FTc in Group G was not restored after CO2 exsufflation. CONCLUSIONS: Changing position in the gynecologic laparoscopic surgery group can elevate MAP and decrease CO. Therefore, careful caution is required in patients with cardiovascular disease who are undergoing gynecologic laparoscopic surgery.

Anesthetic Management of a Patient with Complete Tracheal Transection by Blunt Trauma: A case report / 대한마취과학회지

Tracheobronchial rupture due to blunt chest trauma is an uncommon injury and the clinical presentations are variable. Recently, the incidence of tracheobronchial injuries has increased with the increase in traffic accidents and mechanization.The early diagnosis and primary repair of tracheobronchial rupture not only restores normal lung function, but also avoids the difficulties and complications associated with delayed diagnosis and repair.We report our clinical experience in anesthetic management of a patient with complete tracheal transection suffering from progressive dyspnea, subcutaneous emphysema in the neck and anterior chest wall, and bilateral tension pneumothorax.The literature regarding accidental tracheal injuries will be reviewed.

Sequelae Associated with Spinal Anesthesia in a Undiagnosed Tethered Cord Syndrome Patient: A case report / 대한마취과학회지

Tethered cord syndrome is a form of spinal dysraphism, with a low-lying conus frequently associated with an intraspinal lipoma, diastematomyelia or fibrous band. The clinical manifestations include spine abnormalities, such as spina bifida, or various neurological symptoms involving the lower extremities and sphincters. Herein, our experience of a 42-year-old female tethered cord syndrome patient, with deficit, paresthesia and incontinence following spinal anesthesia for anti-incontinence surgery, is reported with a brief review of literature.

Utility of Esophageal Doppler and the Hemodynamic Effect of Nicardipine during a Laparoscopic Cholecystectomy / 대한마취과학회지

BACKGROUND: We performed this study to investigate the hemodynamic effect of nicardipine using an esophageal Doppler monitor (EDM) during a laparoscopic cholecystectomy. METHODS: Forty patients scheduled to undergo a laparoscopic cholecystectomy, were divided into two groups; the control group (Group C) and the nicardipine group (Group N). Pneumoperitoneum was initiated by CO2 gas and the intraperitoneal pressure was kept under 12 mmHg. Hemodynamic parameters at critical points were measured by the use of EDM: before skin incision (T1), 5, 10 and 15 min after the initiation of pneumoperitoneum (T2, T3 and T4), and 5 min after deflation (T5). RESULTS: The mean arterial pressure (MAP) was significantly lower in the Group N patients when compared to the Group C patients 5, 10 and 15 min after the initiation of pneumoperitoneum (T2, T3 and T4), and 5 min after deflation (T5)(P < 0.05). There was no significant differences in heart rate (HR) between patients in the two groups. The cardiac output (CO) was significantly increased in the Group N patients when compared to the Group C patients 5 min after the initiation of pneumoperitoneum (T2)(P < 0.05). The peak velocity (PV) was significantly increased in the Group N patients when compared to the Group C patients 5 and 10 min after the initiation of pneumoperitoneum (T2 and T3)(P < 0.05). The corrected flow time (FTC) was significantly increased in the Group N patients when compared to the Group C patients 5 min after the initiation of pneumoperitoneum (T2)(P < 0.05). CONCLUSIONS: We conclude that nicardipine continuous infusion with 0.5-2.0microgram/kg/min is effective in attenuating the hemodynamic change after pneumoperitoneum during a laparoscopic cholecystectomy.

Liver Transplantation for a Cirrhotic Patient with Situs Inversus

Situs inversus refers to a mirror image of the viscera, while situs solitus is defined as the normal anatomical situation. Several cases of successful liver transplantation for situs inversus recipients have been reported, and modifications of the standard surgical techniques were used. We report here on a case of cadaveric liver transplantation in an end-stage liver disease patient with situs inversus. The donor liver was rotated clockwise 90 degrees to the left with the right lobe lying in the left upper quadrant and the left lobe pointing down into the left iliac fossa. The donor's suprahepatic vena cava was oversewn and the infrahepatic vena cava anastomosed end to side to the recipient's inferior vena cava. The postoperative course was good until the postoperative 26th day, when rupture of a hepatic artery pseudoaneurysm occurred. An emergency laparotomy was done and the hepatic artery was ligated. Despite the hepatic artery ligation, the liver function recovered quite well. But sudden intracranial hemorrhage developed on the postoperative 28th day and sadly, the patient expired on the postoperative 30th day. Complete preoperative evaluation of the recipient is essential for the operative planning, and careful donor selection should be attempted to obtain a smaller graft to allow maximum flexibility for placing the donor liver. The use of a reduced-sized graft should be considered in the case for which a smaller graft is not available. In conclusion, adult situs inversus is no longer a contraindication for a liver transplant, although technical difficulties do exist for this procedure.

Correction of Syndactyly using Pentagonal Flap with Minimal Skin Graft

PURPOSE: The key of treatment in syndactyly is to separate the fused digits safely, and to create a normal web space with enough cutaneous coverage. Despite many techniques have described the correction of syndactyly, skin graft still remains the annoying one. We designed the pentagonal flap from hand dorsum to reconstruct the web space reliably and try to minimize the need for skin graft. METHODS: Between July 2003 and August 2005, six cases of syndactyly were corrected at UCLA Medical Center and Hallym University Sacred Heart Hospital using dorsal pentagonal flap for web space reconstruction and straight incisions for the sides of digits to minimize the need for skin graft. The proximal edge of the pentagonal flap was designed in V shape to allow for easy closure of the donor site after advancement. The pentagonal flap was advanced volarly with the underlying dermofat tissues to form a digital web. In some cases, skin defects were unavoidable and covered with full thickness skin graft from the inguinal area. RESULTS: Syndactyly were seen in 4 cases of Apert syndrome, 1 postburn scar webbing with PIP joint contracture and 1 recurrence after the incomplete reconstruction. In all Apert syndrome, straight line incision was used along the sides of the fingers and skin graft was needed. But, in 2 cases of incomplete type, we could save the need for skin graft only for the correction of syndactyly. We could get a good looking web space without any complications such as flap or graft loss. CONCLUSION: As a modification of Sherif's V-Y dorsal metacarpal flap, we believe pentagonal flap could be one of the easiest and safest way to reconstruct the web space of syndactyly in functional and cosmetic standpoint.

Correction of Syndactyly using Pentagonal Flap with Minimal Skin Graft

PURPOSE: The key of treatment in syndactyly is to separate the fused digits safely, and to create a normal web space with enough cutaneous coverage. Despite many techniques have described the correction of syndactyly, skin graft still remains the annoying one. We designed the pentagonal flap from hand dorsum to reconstruct the web space reliably and try to minimize the need for skin graft. METHODS: Between July 2003 and August 2005, six cases of syndactyly were corrected at UCLA Medical Center and Hallym University Sacred Heart Hospital using dorsal pentagonal flap for web space reconstruction and straight incisions for the sides of digits to minimize the need for skin graft. The proximal edge of the pentagonal flap was designed in V shape to allow for easy closure of the donor site after advancement. The pentagonal flap was advanced volarly with the underlying dermofat tissues to form a digital web. In some cases, skin defects were unavoidable and covered with full thickness skin graft from the inguinal area. RESULTS: Syndactyly were seen in 4 cases of Apert syndrome, 1 postburn scar webbing with PIP joint contracture and 1 recurrence after the incomplete reconstruction. In all Apert syndrome, straight line incision was used along the sides of the fingers and skin graft was needed. But, in 2 cases of incomplete type, we could save the need for skin graft only for the correction of syndactyly. We could get a good looking web space without any complications such as flap or graft loss. CONCLUSION: As a modification of Sherif's V-Y dorsal metacarpal flap, we believe pentagonal flap could be one of the easiest and safest way to reconstruct the web space of syndactyly in functional and cosmetic standpoint.

The Effect of Fish Consumption on Blood Mercury Levels of Pregnant Women

In the present study, we examined the relationship between average fish consumption, as well as the type of fish consumed and levels of mercury in the blood of pregnant women. We also performed follow-up studies to determine if blood mercury levels were decreased after counseling and prenatal education. To examine these potential relationships, pregnant women were divided into two groups: a study group was educated to restrict fish intake, whereas a control group did not receive any prenatal education regarding fish consumption. We measured blood mercury level and performed follow-up studies during the third trimester to examine any differences between the two groups. Out of the 63 pregnant women who participated in our study, we performed follow- up studies with 19 pregnant women from the study group and 12 pregnant women from control group. The average initial blood mercury level of both groups was 2.94 microgram/L, with a range of 0.14 to 10.75 microgram/L. Blood mercury level in the group who ate fish more than four times per month was significantly higher than that of the group who did not consume fish (p = 0.02). In follow-up studies, blood mercury levels were decreased in the study group but slightly increased in the control group (p = 0.014). The maternal blood mercury level in late pregnancy was positively correlated with mercury levels of cord blood (r = 0.58, p = 0.047), which was almost twice the level found in maternal blood. Pregnant women who consume a large amount of fish may have high blood mercury levels. Further, cord blood mercury levels were much higher than that of maternal blood. Because the level of fish intake appears to influence blood mercury level, preconceptual education might be necessary in order decrease fish consumption.

Clinical Experiences of Fetal Ovarian Cyst: Diagnosis and Consequence

Ovarian cysts are the most frequent, prenatally diagnosed intra-abdominal cysts. Fetal ovarian cyst often presents complication such as torsion and seems to be an indication for surgical intervention. In this study, we reviewed pre- and post-natal medical records and ultrasonography of 17 fetuses that were diagnosed with ovarian cysts. In a total of 17 cases, postnatal surgery was performed in 7 infants. Of these cases, four cases of ovarian cyst torsion were confirmed. In the remaining 10 fetuses, one case regressed completely during pregnancy, and the other nine cases including two complex cysts resolve spontaneously after birth. Postnatal symptomatic cysts or cysts with a diameter greater than 5 cm that do not regress or enlarge should be treated, but uncomplicated asymptomatic cysts less than 5 cm in diameter should only be observed and reassessed by serial ultrasonography. If they regress spon-taneously, no surgical intervention is necessary independent of their sonographic findings.

A Case of Forehead Reconstruction with Remnant Forehead Flap Unit

Acquired defects involving exposed bone on the forehead is challenging to reconstruct. Skin expansion provides an ideal thin flap for forehead aesthetic unit, but it takes long time and high cost, and many patients are dissatisfied at their figures. Free flap can provide enough tissue immediately, but it takes long time and has the risk of mismatches of color and texture. This report details our experiences with two patients who had soft tissue defect on their forehead that was covered with remnant forehead flap unit. This method uses one-unit-forehead island flap based on supratrochlear and supraorbital vessel. We obtained satisfactory results in terms of aesthetic and functional consideration.

Intubating Conditions and Hemodynamic Changes during Tracheal Intubation with Propofol Followed by Remifentanil without the Use of Muscle Relaxant / 대한마취과학회지

BACKGROUND: Studies have shown that tracheal intubation can be facilitated safely and effectively after induction of anesthesia with hypnotic and opioid without employing any muscle relaxants. Remifentanil is a new, ultra-short acting, selective mu-receptor agonist. The goal of our present study was to evaluate the appropriate induction dose of remifentanil with propofol for tracheal intubation without employing any muscle relaxants. METHODS: We have assessed intubating conditions in three groups of 45 ASA I or II Patients. Each group received intravenous dosage of 2 mg/kg of propofol with remifentanil 1microgram/kg (Group I), 2microgram/kg (Group II) or 3microgram/kg (Group III), respectively. No muscle relaxant was administered. Intubating conditions were assessed based on jaw relaxation, vocal cord position, vocal cord movement, airway reaction, and movement of limbs. Intubating conditions, mean arterial blood pressure and heart rate were measured just before induction (T00, baseline), before intubation (T0), 1 minute after intubation (T1), 2 minutes after intubation (T2) and 3 minutes after intubation (T3). RESULTS: Intubating conditions were clinically acceptable in 26.7, 86.7 and 93.3% of patients, after 1, 2 or 3microgram/kg administration of remifentanil, respectively. Clinically acceptable intubating conditions were significantly more in Group II and III when compared with Group I (P<0.05). Both HR (heart rate) and MAP (mean arterial pressure) were significantly lower in Group III when compared with Group I before intubation (T0), 1 minute after intubation (T1), 2 minutes after intubation (T2) and 3 minutes after intubation (T3) (P<0.05). CONCLUSIONS: We conclude that 2-3microgram/kg of remifentanil may reliably provide 'good' to 'excellent' conditions for tracheal intubation when administered after administration of 2 mg/kg propofol. The conditions for intubation were significantly better in patients receiving 2 mg/kg of propofol followed by 2-3microgram/kg of remifentanil than those receiving 1microgram/kg of remifentanil.

Rapid prenatal diagnosis for chromosomal aneuploidy using cDNA microarray-based comparative genomic hybridization / 대한산부인과학회지

OBJECTIVE: Prenatal cytogenetic diagnosis is limited to metaphase karyotype analysis of cultured cells obtained by amniocentesis or chorionic villus sampling. Moreover, genome wide analysis cannot be performed by FISH analysis using specific probe. Array comparative genomic hybridization (CGH) offers a number of advantages over conventional cytogenetic analysis and FISH. Microarray CGH can be highly comprehensive, amenable to very high resolution, sensitive and fast. The objective of this study was to determine the clinical use of cDNA microarray CGH for detection of fetal aneuploidy. METHODS: 21 amniotic fluid samples and 6 chorionic villi samples were obtained from 27 pregnant women in 9-19 gestational weeks. Genomic DNA was extracted from each sample and amplified. For cDNA microarray CGH analysis, test DNA sample and reference DNA sample were labeled with Cy3-dUTP and Cy5-dUTP, respectively. Each sample of labeled test and reference DNA was hybridized to microarray. The result was analysed with axon scanner and compared with cytogenetic analysis and FISH. RESULTS: In 27 cases, 3 cases with trisomy 21 and 1 case with trisomy 18 had increased hybridization signals on chromosome 21 and chromosome 18. One case with 45,X had decreased signals on chromosome X. One case with 46,X,i(Xq) had decreased signal on short arm of chromosome X and increased signal on long arm. And one case with 47,XYY had two fold increased signal on Y chromosome. cDNA microarray based CGH correctly identified fetal aneuploidy in all of the 7 cases with aneuploid fetuses. CONCLUSION: Prenatal genetic diagnosis by cDNA microarray-based CGH is an useful, innovative, rapid and accurate method. It is promising technique allowing rapid screening for whole chromosomal changes including aneuploidy, and may augment standard karyotyping techniques for prenatal genetic diagnosis by providing additional molecular information. This method may aid the discovery and description of minor genetic aberration, potentially enhancing future prenatal genetic diagnostic application.

Cerebral Infarction in IgG Multiple Myeloma with Hyperviscosity

Cerebral infarction is an uncommon complication in multiple myeloma with hyperviscosity. Serum hyperviscosity may cause a variety of clinical manifestations including bleeding from mucosal membranes, congestive heart failure, retinopathy, and various neurologic deficits. These manifestations have been attributed to the presence of large quantities of asymmetrical molecules of high molecular weight in the serum. We recently experienced a case of multiple myeloma with acute cerebral infarction, which caused by hyperviscosity, as an initial manifestation in IgG multiple myeloma, and reviewed the relevant literature of myeloma presenting with the stroke. A 68-yr-old woman abruptly developed hypesthesia and monoplegia in the left leg. The stroke confirmed by the brain MRI and MR angiography, which revealed acute infarction at the right anterior cerebral artery territory. On admission, routine blood tests showed a slight decrease in hemoglobin and a marked increase in erythrocyte sedimentation rate. Peripheral blood smear, serum protein electrophoresis, serum visocity, and bone marrow aspiration showed that she had IgG multiple myeloma with hyperviscosity. She was treated by chemotherapy with cyclophosphamide and discharged with the improved clinical condition.

Living Donor Liver Transplantation in a Child with Unresectable Hepatoblastoma / 대한이식학회지

Hepatoblastoma is the most common primary malignant liver tumor encountered during childhood. Complete surgical resection is the most important factor in predicting which children would achieve cure. Some chemotherapy regimens are effective in reducing tumor size, often rendering initially unresectable lesions amenable to complete surgical resection, and dramatically improving disease-free survival. Liver transplantation provides an additional treatment option for patients whose tumor remains unresectable even after preoperative chemotherapy. We report a case of unresectable hepatoblastoma in a child who underwent living related liver transplantation with pre and post-operative chemotherapy.