Safety of Laparoscopic Sentinel Basin Dissection in Patients with Gastric Cancer: an Analysis from the SENORITA Prospective Multicenter Quality Control Trial

PURPOSE: We investigated complications after laparoscopic sentinel basin dissection (SBD) for patients with gastric cancer who were enrolled in a quality control study, prior to the phase III trial of sentinel lymph node navigation surgery (SNNS). MATERIALS AND METHODS: We analyzed prospective data from a Korean multicenter prerequisite quality control trial of laparoscopic SBD for gastric cancer and assessed procedure-related and surgical complications. All complications were classified according to the Clavien-Dindo Classification (CDC) system and were compared with the results of the previously published SNNS trial. RESULTS: Among the 108 eligible patients who were enrolled in the quality control trial, 8 (7.4%) experienced complications during the early postoperative period. One patient with gastric resection-related duodenal stump leakage recovered after percutaneous drainage (grade IIIa in CDC). The other postoperative complications were mild and patients recovered with supportive care. No complications were directly related to the laparoscopic SBD procedure or tracer usage, and there were no mortalities. The laparoscopic SBD complication rates and patterns that were observed in this study were comparable to those of a previously reported trial. CONCLUSIONS: The results of our prospective, multicenter quality control trial demonstrate that laparoscopic SBD is a safe procedure during SNNS for gastric cancer.

Long-term results of oncoplastic breast surgery with latissimus dorsi flap reconstruction: a pilot study of the objective cosmetic results and patient reported outcome

PURPOSE: The goal of oncoplastic breast surgery is to restore the appearance of the breast and improve patient satisfaction. Thus, the assessment of cosmetic results and patient-reported outcomes (PROs) using appropriately constructed and validated instruments is essential. The aim of the present study was to assess the long-term objective cosmetic results and corresponding PROs after oncoplastic breast surgery. METHODS: Cosmetic results were assessed by the patients, a medical panel, and a computer program (BCCT.core). PROs were assessed using BREAST-Q, a questionnaire that measures the perception of patients having breast surgery. The cosmetic results and PROs were analyzed in patients who underwent quadrantectomy and partial breast reconstruction utilizing the latissimus dorsi flap. RESULTS: The mean duration of the follow-up period was 91.6 months (range, 33.3-171.0 months), and mean age of the patients was 51 years old (range, 33-72 years). The mean tumor size was 2.1 cm (range, 0.9-5.5 cm). There was fair agreement between the medical panel and BCCT.core score (K = 0.32, P < 0.001), and a statistically significant correlation between the BCCT.core score and medical panel cosmetic results was identified (r = 0.606, P < 0.001). A better BCCT.core result was related to a higher PRO of each BREAST-Q domain-satisfaction with breasts (R2 = 0.070, P = 0.039), satisfaction with outcome (R2 = 0.087, P = 0.021), psychosocial well-being (R2 = 0.085, P = 0.023), sexual well-being (R2 = 0.082, P = 0.029), and satisfaction with information (R2 = 0.064, P = 0.049). CONCLUSION: Our long-term results of oncoplastic surgery achieved a high level of patient satisfaction with good cosmetic results. The medical panel and BCCT.core results correlated well with the PROs of the patients using valid, reliable, and procedure-specific measures.

Case Series of Gastric Hepatoid Adenocarcinoma

Hepatoid adenocarcinoma of the stomach (HAS) is a rare form of gastric cancer that histologically resembles hepatocellular carcinoma and is characterized by large amounts of alpha fetoprotein in the serum. The prognosis of HAS is poor compared to that of primary gastric cancer with five-year survival rates of 9% and 44%, respectively. Here, we report five patients diagnosed with HAS. Our experience suggests that an advanced stage of HAS has an extremely poor prognosis, but early detection and radical surgery can help improve the prognosis of the disease.

Laparoscopic Treatment of Gangrene of Giant Meckel's Diverticulum Secondary to Axial Torsion

Meckel's diverticulum is a common congenital anomaly in the small bowel. Most cases of Meckel's diverticulum are asymptomatic and are found incidentally. We herein report on a case of a 21-year-old male patient who complained of lower abdominal pain and febrile sensation with incidentally diagnosed gangrenous change of Meckel's diverticulum due to axial torsion itself. A 21-year-old man presented to our institution with acute lower abdominal pain. No accurate focus on abdominal pain such as appendicitis or diverticulitis was observed on abdominal ultrasonography and abdominal CT scan. However, the physical examination of the patient revealed the symptom of localized peritonitis with fever. Finally, laparoscopic exploration was performed to determine the cause of acute abdominal pain. During the operation, we found gangrenous change of Meckel's diverticulum with axial torsion itself and laparoscopic Meckel's diverticulectomy was performed. The patient made an uneventful recovery and was discharged on the 6th postoperative day.

Changes in Fat Intake, Body Fat Composition and Intra-Abdominal Fat after Bariatric Surgery

Bariatric surgery is considered to be the effective treatment alternative conducted over the lifetime for reducing weight in patients with clinically morbid obesity. For many patients, the benefits of weight loss, including decreases in blood glucose, lipids, and blood pressure as well as increase in mobility, will outweigh the risks of surgical complications. But patients undergoing bariatric surgery have the least risk for long-term diet-related complications as reported in several studies. Thus, with an increasing number of severely obese patients undergoing bariatric surgery, the multidisciplinary healthcare system will need to be managed continuously. Many nutrition support specialists will need to become familiar with the metabolic consequences for the frequent monitoring of nutrition status of the patients. South Korea has a very short history with bariatric surgery, and relatively few studies have been conducted on bariatric surgery. Therefore, the objective of this report was to compare the nutrient intake, weight loss, body fat composition, and visceral fat before and after the bariatric surgery.

Perigastric Lymph Node Metastasis from Papillary Thyroid Carcinoma in a Patient with Early Gastric Cancer: The First Case Report

Distant metastasis from papillary thyroid carcinoma (PTC), particularly from papillary thyroid microcarcinoma, is rare. We present a case of perigastric lymph node metastasis from PTC in a patient with early gastric cancer and breast cancer. During post-surgical follow-up for breast cancer, a 56-year-old woman was diagnosed incidentally with early gastric cancer and synchronous left thyroid cancer. Therefore, laparoscopic distal gastrectomy with lymph node dissection and left thyroidectomy were performed. On the basis of the pathologic findings of the surgical specimens, the patient was diagnosed to have papillary thyroid microcarcinoma with perigastric lymph node metastasis and early gastric cancer with mucosal invasion. Finally, on the basis of immunohistochemical staining with galectin-3, the diagnosis of perigastric lymph node metastasis from PTC was made. When a patient has multiple primary malignancies with lymph node metastasis, careful pathologic examination of the surgical specimen is necessary; immunohistochemical staining may be helpful in determining the primary origin of lymph node metastasis.

Long-Term Outcomes of Proximal Gastrectomy versus Total Gastrectomy for Upper-Third Gastric Cancer

PURPOSE: There are two surgical procedures for proximal early gastric cancer (EGC): total gastrectomy (TG) and proximal gastrectomy (PG). This study aimed to compare the long-term outcomes of PG with those of TG. MATERIALS AND METHODS: Between January 2001 and December 2008, 170 patients were diagnosed with proximal EGC at Soonchunhyang University Cheonan Hospital, of which 64 patients underwent PG and 106 underwent TG. Clinicopathologic features, postoperative complications, blood chemistry data, changes in body weight, and oncological outcomes were analyzed and retrospectively compared between both groups. RESULTS: Tumor size was smaller and the number of retrieved lymph nodes was lower in the PG group. The postoperative complication rate was 10.9% in the TG group and 16.9% in the PG group. The incidence of Los Angeles grade C and D reflux esophagitis was significantly higher in the TG group. Hemoglobin level was higher and body weight loss was greater in the TG group at 2, 3, and 5 years postoperatively. The albumin levels at 3 and 5 years were lower in the TG group. There was no significant difference in the 5-year overall survival rates between the two groups (P=0.789). CONCLUSIONS: Postoperative complications and oncologic outcomes were observed to be similar between the two groups. The PG group showed better laboratory data and weight loss than did the TG group. Moreover, severe reflux esophagitis occurred less frequently in the PG group than in the TG group. PG can be considered as an effective surgical treatment for proximal EGC.

Long-Term Efficacy of Endoscopic Submucosal Dissection Compared with Surgery for Early Gastric Cancer: A Retrospective Cohort Study

BACKGROUND/AIMS: This study aimed to compare the outcomes of endoscopic submucosal dissection (ESD) and gastrectomy based on the two sets of indications for ESD, namely guideline criteria (GC) and expanded criteria (EC). METHODS: Between January 2004 and July 2007, 213 early gastric cancer (EGC) patients were enrolled in this study. Of these patients, 142 underwent ESD, and 71 underwent gastrectomy. We evaluated the clinical outcomes of these patients according to the criteria. RESULTS: The complication rates in the ESD and gastrectomy groups were 8.5% and 28.2%, respectively. The duration of hospital stay was significantly shorter in the ESD group than the gastrectomy group according to the GC and EC (p<0.001 and p<0.001, respectively). There was no recurrence in the ESD and gastrectomy groups according to the GC, and the recurrence rates in the ESD and gastrectomy groups were 4.7% and 0.0% according to the EC, respectively (p=0.279). The occurrence rates of metachronous cancer in the ESD and gastrectomy groups were 5.7% and 5.0% according to the GC (p=1.000) and 7.5% and 0.0% according to the EC (p=0.055), respectively. CONCLUSIONS: Based on safety, duration of hospital stay, and long-term outcomes, ESD may be an effective and safe first-line treatment for EGC according to the EC and GC.

Retroperitoneal Leiomyoma of the Uterus Mimicking Sarcoma in Perimenopausal Woman: Case Report

Leiomyomas are very common benign tumors in the uterus and it is rare condition to present the retroperitoneal leiomyoma. The author reported a 48-year-old female patient who presented right pelvic mass with urinary incontinence and lower abdominal discomfort. Based on the preoperative imaging, provisional diagnosis was mesenchymal sarcoma. In the intraoperative findings, huge mass abutting to the uterus was observed in retroperitoneal space beneath the right broad ligament. After the exposure the retroperitoneal space, we encountered the well-demarcated tumor measuring 8 x 6 cm in diameter and this tumor attached the right surface of the uterus with fibrotic tissue. Pathologic findings demonstrated retroperitoneal uterine leiomyoma.

Transvaginal Endoscopic Appendectomy

Since Kalloo and colleagues first reported the feasibility and safety of a peroral transgastric approach in the porcine model in 2004, various groups have reported more complex natural orifice transluminal endoscopic surgery (NOTES) procedures, such as the cholecystectomy, splenectomy and liver biopsy, in the porcine model. Natural orifice access to the abdominal cavity, such as transgastric, transvesical, transcolonic, and transvaginal, has been described. Although a novel, minimally invasive approach to the abdominal cavity is a peroral endoscopic transgastric approach, there are still some challenging issues, such as the risk of infection and leakage, and the method of gastric closure. Hybrid-NOTES is an ideal first step in humans. Human hybrid transvaginal access has been used for years by many surgeons for diagnostic and therapeutic purposes. Here, we report a transvaginal flexible endoscopic appendectomy, with a 5-mm umbilical port using ultrasonic scissors in a 74-year-old woman with acute appendicitis.

Factors Associated with Operation Time of Laparoscopic Wedge Resection for Gastric Submucosal Tumors / 대한내시경복강경외과학회지

PURPOSE: Laparoscopic gastric wedge resection (LWR) is being increasingly performed as a safe and effective treatment for gastric submucosal tumors (SMTs). However, there are few studies on the factors associated with operation time of LWR for gastric SMTs. The purpose of this study was to determine the factors associated with the operation time of LWR for gastric SMTs. METHODS: Between June 2001 and December 2008, 58 patients with gastric SMTs underwent LWR. We analyzed the clinicopathologic data, perioperative parameters and outcomes, and surgeon's experience retrospectively. We also analyzed the factors associated with the operation time of LWR for gastric SMTs. RESULTS: Among 58 patients that underwent LWR, exogastric wedge resection (n=48) was mainly performed. Transgastric wedge resection (n=8) took the longest amount of time. Intraoperative GFS (n=7) was frequently performed for smaller tumors. When the tumor was located at the cardia and fundus, more time was needed for LWR of the SMTs. There was no correlation of the operation time with the clinicopathologic data and surgeon's experience; however, the tumor location (axis) and the approach used for the resection of the stomach were statistically correlated with the operation time. CONCLUSION: The operation time of LWR for gastric SMTs was related to the tumor location (according to gastric axis) and the approach used for the resection of the stomach. If the tumor location was identified precisely and the proper approach for resection of the stomach was determined preoperatively, the operation time of LWR for gastric SMTs might be reduced.

Usefulness of Reoperation after Recurrence of Gastric Cancer

PURPOSE: Radical gastrectomy and lymph node dissection is the treatment of choice for gastric cancer but the efficacy of surgical treatment of recurrent gastric cancer has been debated. We evaluated the efficacy of surgical treatment for recurrent gastric cancer. METHODS: We collected the data on 108 recurrent gastric cancer patients who underwent radical gastrectomy and lymph node dissection for gastric cancer and analyzed the clinicopathologic data, the patterns of recurrence of gastric cancer, and the strategies of treatment for recurrent gastric cancer. RESULTS: The patterns of recurrence were 32 locoregional, 26 hematogenous, 24 peritoneal, and 26 mixed recurrences. The strategies of treatment for recurrent gastric cancer were the combination of surgical treatment and chemotherapy in 31 cases (28.7%), chemotherapy alone in 49 cases (45.4%), and conservative treatment in 28 cases (25.9%). The morbidity and mortality in reoperation group were 35.5% and 9.7%, respectively. The mean survival after recurrence was 25.4, 12.7, and 4.9 months in reoperation group, chemotherapy group and conservative treatment group, respectively. In multivariate analysis, the differentiation of primary tumor, patterns of recurrence, and the strategies of treatment for recurrent gastric cancer were related with survival after recurrence of gastric cancer. CONCLUSION: Our data suggested that the more aggressive and intensive treatment such as surgical treatment could improve the survival rate for recurrent gastric cancer. Therefore, if the patients' conditions are tolerable and there is resectability, surgical treatment may be an applicable strategy for recurrent gastric cancer in terms of long-term survival.

Ante situm Liver Resection under Total Vascular Exclusion and Venovenous Bypass with Hypothermic Perfusion for Treating a Recurrent Rectal Cancer Liver Metastasis

We present here a case of recurrent rectal cancer liver metastasis that was managed with ante situm liver resection under total vascular exclusion (TVE) and venovenous bypass with hypothermic perfusion. A 58-year-old man who suffered with rectal cancer liver metastasis was transferred to our hospital in January 2006. A left lateral sectionectomy had been previously performed. Recurrent lesion developed in segments I, IV and VIII one year after the first hepatectomy. The tumor was 5 cm in diameter and it involved the confluence of the hepatic veins and the retrohepatic vena cava. An incomplete tumor-free margin and massive bleeding were expected with performing a conventional liver resection, together with vena cava reconstruction. Therefore, we planned an ante situm liver resection under TVE and venovenous bypass with hypothermic perfusion. After adhesiolysis, hilar dissection was carried out. The inflow to the medial segment was interrupted, and then the liver and inferior vena cava (IVC) were mobilized fully. During controlling the bleeding of a short hepatic vein, we found adhesion of the hepatocaval portion. Therefore, TVE and venovenous bypass were performed along with suprahepatic IVC transection. The long conduit of V5 was preserved during hepatic parenchymal dissection, and the paracaval portion of the caudate lobe was readily detached from the IVC. The suprahepatic IVC was reconstructed after V5 reconstruction with using the saphenous vein. Portal vein anastomosis was then conducted. After reperfusion, an end-to-side anastomosis was performed between the saphenous vein graft and the IVC. Finally, a Roux-en-Y hepaticojejunostomy was carried out. The patient remains well without recurrence 12 months after the last operation.

Primary Squamous Cell Carcinoma of the Stomach that was Misdiagnosed as a Submucosal Tumor

Squamous cell carcinoma (SCC) of the stomach is relatively rare. We report a patient with a primary SCC of the stomach that was initially misdiagnosed as a submucosal tumor. The patient was a 64-year-old male who had a large submucosal tumor in the gastric fundus. Gastric endoscopy, endoscopic ultrasonography and abdominal computed tomography indicated a malignant submucosal tumor with multiple lymph node metastases. The patient underwent a total gastrectomy and a regional lymph node dissection. Histologically, the tumor was identified as a primary SCC of the stomach.

Expression and Function of ABC Transporters as Multidrug Resistance Mechansims in Colon Cancer Cells

PURPOSE: Multidrug resistance (MDR) is a phenomenon whereby tumor cells acquire resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs. The most widely implicated mechanism of MDR is that concerned with altered membrane transporters in tumor cells. P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast-cancer-resistance protein (BCRP) are well-known membrane transporters that pump out antitumor agents by using an ATP-dependent process, the so-called ATP-binding cassette (ABC) superfamily or transporter. This study was undertaken to test the prevalence of each ABC transporter and to determine which transporter has functional acitivity in various colon cancer cells. METHODS: Expressions of Pgp, MRP, and BCRP mRNA were determined in 9 colon-cancer cell lines by using an RT-PCR assay. The sensitivity to anticancer agents substrate for each ABC transporter in the colon cancer cells determined using an MTT assay. The accumulation of fluorescent compounds for functional detection of each ABC transporter was determined by using flow cytometry. RESULTS: Pgp mRNA was variably expressed in 6 of 9 colon cancer cells lines. MRP and BCRP mRNA were expressed in all the 9 cell lines. A smaller cytotoxic effect to paclitaxel and a smaller amount of rhodamine123 accumulation were observed in Colo 320HSR expressing the highest levels of Pgp than in SNU-C5 not expressing Pgp. These effects in Colo320HSR were reversed with the addition of various Pgp inhibitors, but such a reversal did not occur in SNU-C5. The cytotoxic effect to VP-16 was not related to the expression levels of MRP in Colo320HSR and SNU-C, but the amount of calcein-AM accumulation was reversed with addition of probenecid, MRP inhibitor. The cytotoxic effect and the drug accumulation of mitoxantrone were not related to the expression levels of BCRP. CONCLUSIONS: This study suggests that of the ABC transporters, primarily Pgp and MRP have functional activity in colon cancer cell lines.

Expression of the PTEN Gene Product in the Invasive Cancer of Breast and Its Relationship with Other Prognostic Factors

PURPOSE: The tumor suppressor gene PTEN is located on chromosome 10q23 and is mutated in a variety of sporadic cancers. The aim of this study is to understand the expression of the PTEN gene product in invasive breast cancer and its relationships with clinicopathologic factors of breast cancer. METHODS: The hospital records and pathologic findings of 57 patients who underwent breast operation due to invasive breast carcinoma between January 1996 and June 2002 were reviewed. We examined the relationships between PTEN expression and various clinicopathologic factors of breast cancer such as age, tumor size, lymph node metastasis, histologic grade, nuclear grade, stage and estrogen, and progesterone receptors. RESULTS: Among the 57 invasive breast cancers, 5 (8.8%) were immunohistochemically negative, and 14 (24.6%) had reduced expression of PTEN. Among clinicopathologic factors, age, tumor size, lymph node metastasis, stage, histologic grade, and estrogen receptor had no correlation with PTEN expression. Nuclear grade and positive progesterone receptor were significant correlated with decreased PTEN expression. However, these results are different from those of other reports showing that negative progesterone receptor was significantly correlated with the decrease of PTEN expression. CONCLUSION: According to other reports, PTEN expression does play some role as a prognostic factor for breast cancer, but the results of our study did not support this hypothesis. Further evaluation and study are required into the role of PTEN as a prognostic factor of breast cancer.

Expression of the PTEN Gene Product in the Invasive Cancer of Breast and Its Relationship with Other Prognostic Factors

PURPOSE: The tumor suppressor gene PTEN is located on chromosome 10q23 and is mutated in a variety of sporadic cancers. The aim of this study is to understand the expression of the PTEN gene product in invasive breast cancer and its relationships with clinicopathologic factors of breast cancer. METHODS: The hospital records and pathologic findings of 57 patients who underwent breast operation due to invasive breast carcinoma between January 1996 and June 2002 were reviewed. We examined the relationships between PTEN expression and various clinicopathologic factors of breast cancer such as age, tumor size, lymph node metastasis, histologic grade, nuclear grade, stage and estrogen, and progesterone receptors. RESULTS: Among the 57 invasive breast cancers, 5 (8.8%) were immunohistochemically negative, and 14 (24.6%) had reduced expression of PTEN. Among clinicopathologic factors, age, tumor size, lymph node metastasis, stage, histologic grade, and estrogen receptor had no correlation with PTEN expression. Nuclear grade and positive progesterone receptor were significant correlated with decreased PTEN expression. However, these results are different from those of other reports showing that negative progesterone receptor was significantly correlated with the decrease of PTEN expression. CONCLUSION: According to other reports, PTEN expression does play some role as a prognostic factor for breast cancer, but the results of our study did not support this hypothesis. Further evaluation and study are required into the role of PTEN as a prognostic factor of breast cancer.

Correlations of Atherosclerotic Risk Factors and Carotid Artery Intima-media Thickness in Healthy Subjects

PURPOSE: Atherosclerotic risk factors are highly associated with the progression and severity of cerebrovascular disease; the carotid artery intima-media thickness (IMT) correlates well with the known risk factors for atherosclerosis. The aims of this study are to evaluate the associations of the carotid artery IMT with the atherosclerotic risk factors and to determine the reference values of the carotid artery IMT in healthy subjects who were without cardiovascular symptoms. METHOD: Ultrasound high-resolution B-mode imaging of the carotid artery was performed in 273 subjects (168 men, 105 women). We investigated the mean carotid artery IMT and the correlation between the carotid artery IMT and the atherosclerotic risk factors. RESULT: The mean carotid artery IMT values were 0.70+/-0.25 mm in the common carotid artery, 0.61+/-0.15 mm in the internal carotid artery, 0.55+/-0.26 mm in the external carotid artery and 0.92+/-0.45 mm in the carotid bulb. The mean carotid artery IMT was significantly increased with increasing age (P<0.05), and particularly in males. Age, systolic and diastolic blood pressure, body mass index, total cholesterol and LDL cholesterol levels correlated with the mean carotid artery IMT. Especially, the presence of plaque (26 subjects) was correlated with the mean carotid artery IMT in the internal carotid artery (P<0.05) and bulb (P<0.01). CONCLUSION: This study revealed the correlation between the carotid artery IMT and the atherosclerotic risk factors; we also elucidated the reference values for the mean carotid artery IMT in healthy subjects who were without cardiovascular diseases and symptoms.

Brain Metastasis from Papillary Carcinoma of the Thyroid

Papillary thyroid carcinomas are the most common type of thyroid malignancy, and have more excellent prognosis compared to other types of thyroid malignancy, with rare occurrences of distant metastasis. The most frequent sites for distant metastases are the lungs and bones, but brain metastases are extremely rare, with a frequency of only 0.1~5% in reported series. Hence we report a patient with a papillary thyroid carcinoma metastasis to the right parietal lobe of brain, the lung, the left chest wall and right acetabulum, with a review of the literature.

The Effect of Renal Transplantation on Sexual Hormone of Female Recipients / 대한이식학회지

PURPOSE: Endocrine abnormalities are common feature of chronic renal failure. The purpose of this study is to understand women's hormonal changes in connection with renal transplantation and to verify improved quality of life of recipient by comparing level of sexual hormone between renal transplant recipients and dialyzed patients. METHODS: To evaluate the level of hormones before and after female renal transplantation, we measured FSH, LH, estradiol, progesterone and prolactin (PRL) in 10 renal transplant recipients (RTR), 10 chronic renal failure patients (CRF) undergoing dialysis (hemodialysis or peritoneal dialysis) and 10 healthy, regularly menstruating women (controls). RESULTS: All 30 females' mean age was 37.83 years. All 10 RTR were menstruating and mean age was 38.6 years and mean serum creatinine (sCr) level was 1.09 mg/dL. Of ten dialyzed patients (6 hemodialysis and 4 peritoneal dialysis), nine of ten dialyzed patients had menstrual disturbance and their mean age was 37.5 years and mean sCr level was 9.8 mg/dL. In RTR, serum PRL and LH level were reduced compared with CRF patients, but these hormones were increased compared with controls. In RTR, progesterone level was significantly lower compared with controls, whereas slightly decreased compared with CRF patients. Estradiol level in dialyzed patients was significantly higher compared with RTR or controls and in RTR was increased compared with controls. CONCLUSION: Following successful renal transplantation, uremic hormonal abnormalities were ameliorated. However, these hormonal changes are not always fully restored which can be attributed to renal insufficiency grade or result from the administered immunosuppressive treatment.