Prognostic significance of Cytokeratin 20-positive lymph node vascular endothelial growth factor A mRNA and chromodomain helicase DNA binding protein 4 in pN0 colorectal cancer patients.

BACKGROUND: Cytokeratin 20-positive cells in lymph nodes from pN0 colorectal cancer (CRC) patients were detected previously by us. The aims of this study were to investigate which tumor metastasis-related genes were involved and their potential clinical significance. RESULTS: Fourteen of 84 (17%) genes were differentially expressed by at least 2-fold. Among them, 10 genes were up-regulated whereas 4 genes were down-regulated. Those differential expressed genes were validated in the second cohort of specimens. Follow-up analysis for 60 months showed that patients with lymph node vascular endothelial growth factor A (VEGF-A) mRNA and chromodomain helicase DNA binding protein 4 (CHD4) mRNA expression higher than the median copies had significantly shorter time to recurrence than those with lower than the median copies. Multivariate analysis showed that VEGF-A mRNA, CHD4 mRNA and lymphatic vessel involvement were independent prognostic factors for disease recurrence. CONCLUSIONS: VEGF-A mRNA and CHD4 mRNA were up-regulated in CK20-positive pN0 lymph nodes and they may have prognostic significance in pN0 CRC patients. METHODS: Two cohorts of lymph node specimens from pN0 CRC patients of each with and without CK20-positive cells were recruited. In the first cohort, tumor metastasis genes were profiled using gene expression arrays. Differential expressed genes were validated in the second cohort. Moreover, their prognostic significance was examined by following-up the second cohort of patients with CK20-positive cells for 60 months and all histopathological findings were correlated to recurrence.

Hong Kong consensus recommendations on the management of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is particularly prevalent in Hong Kong because of the high prevalence of chronic hepatitis B (CHB) infection; HCC is the fourth commonest cancer in men and the seventh commonest in women, and it is the third leading cause of cancer death in Hong Kong. The full spectrum of treatment modalities for HCC is available locally; however, there is currently no local consensus document detailing how these modalities should be used. SUMMARY: In a series of meetings held between May and October 2013, a multidisciplinary group of Hong Kong clinicians - liver surgeons, medical oncologists, clinical oncologists, hepatologists, and interventional radiologists - convened to formulate local recommendations on HCC management. These recommendations consolidate the most current evidence pertaining to HCC treatment modalities, together with the latest thinking of practicing clinicians engaged in HCC management, and give detailed guidance on how to deploy these modalities effectively for patients in various disease stages. KEY MESSAGES: Distinct from other regional guidelines, these recommendations provide guidance on the use of antiviral therapy to reduce the incidence of HCC in CHB patients with cirrhosis and to reduce recurrence of CHB-related HCC.

Improvement in institutional protocols leads to decreased mortality in patients with haemodynamically unstable pelvic fractures.

BACKGROUND: The mortality rate in patients with haemodynamically unstable pelvic fractures is as high as 40-60%. In recent years, angioembolisation and pelvic packing have been introduced as part of a multimodality treatment for these patients. Protocol-driven management has been shown to improve outcomes. PATIENTS AND METHODS: This is a Level III retrospective cohort study of patients suffering from unstable pelvic fractures from 1 January 1996 to 30 September 2011. The aim of the study was to review our results, particularly in terms of mortality through the evolution of three phases of treatment protocols: preangiography, angiography and pelvic packing. RESULTS: The overall 30-day mortality rate for all patients was 47.2%, with a rate of 63.5% in the preangiography phase, 42.1% in the angiography phase and 30.6% in the pelvic packing phase. Multivariate logistic regression analysis identified the use of retroperitoneal packing as a significant independent predictive factor for 24 h mortality. CONCLUSIONS: Our results showed an improvement in patient survival with sequential protocols over the study period, during which we incorporated a multidisciplinary approach to managing these complicated pelvic fractures. The results strongly suggest that retroperitoneal packing should be highly recommended for bleeding subsequent to pelvic fracture, in addition to other modalities of treatment.

Survival benefit of radioembolization for inoperable hepatocellular carcinoma using yttrium-90 microspheres.

BACKGROUND AND AIM: Transarterial radioembolization with yttrium-90 microspheres is one treatment option for inoperable hepatocellular carcinoma. We compared the survival in a cohort of patients receiving radioembolization or no radioembolization. METHODS: The data of 46 patients referred for radioembolization was retrospectively reviewed. The patient, tumor characteristics, and the survival were compared in the two groups. The independent predictors for survival were studied with multivariate analysis. The side-effects and the complication of radioembolization-induced liver disease was recorded. RESULTS: Thirty patients received radioembolization; 16 patients did not. The two groups did not differ in the mean age, Child-Pugh classes, Barcelona Clinic of Liver Cancer (BCLC) stages, tumor types, sum of diameter of the two biggest tumors, and extent of portal vein invasion. Those with BCLC stage C tumor, with portal vein thrombus, or with less than three nodules had significantly longer survival after radioembolization. There was a trend of longer survival in patients with Child-Pugh A liver function, or with BCLC stage B tumor after radioembolization. The median survival was more than 31.9 months, 14.5 months, and 5.2 months in patients with BCLC stage A, B, and C tumors. The independent predictors for longer survival were Child-Pugh class, tumor diameter sum, BCLC stage, and receiving radioembolization. Grade 2 irradiation-induced gastritis occurred in three patients (10%). Radioembolization-induced liver disease occurred in four patients (13%). CONCLUSIONS: Radioembolization may prolong survival for patients with inoperable hepatocellular carcinoma. Radioembolization-induced liver disease occurred and should be further studied.

Trauma survival prediction in Asian population: a modification of TRISS to improve accuracy.

UNLABELLED: The probability of survival (PS) in blunt trauma as calculated by Trauma and Injury Severity Score (TRISS) has been an indispensable tool in trauma audit. The aim of this study is to explore the predictive performance of the latest updated TRISS model by investigating the Age variable recategorisations and application of local Injury Severity Score (ISS) and Revised Trauma Score (RTS) coefficients in a logistic model using a level I trauma centre database involving Asian population. METHODS: Prospectively and consecutively collected 5684 trauma patients' data over a 10-year period at a regional level I trauma centre were reviewed. Four modified TRISS (mTRISS) models using Age coefficient from reclassifications of the Age variable according to their correlation with survival by logistic regression on the local dataset were acquired. RTS and ISS coefficients were derived from the local dataset and then applied to the mTRISS models. mTRISS models were compared with the existing Major Trauma Outcome Study (MTOS)-derived TRISS (eTRISS) model. Model 1=Age effect taken as linear; Model 2=Age classified into two groups (0-54, 55+); Model 3=Age classified into four groups (0-15, 16-54, 55-79, 80+) and Model 4=Age classified into two groups (0-69, 70+). Performance measures including sensitivity, specificity, accuracy and area under the Receiver Operating Characteristic (ROC) curve were used to assess the various models. The cross-validation procedure consisted of comparing the P(S) obtained from mTRISS Models 1 and 2 with the P(S) obtained from the MTOS derived from eTRISS. RESULTS: A 5147 blunt trauma patients' dataset was reviewed. Model 1, where Age was taken as a scale variable, demonstrated a substantial improvement in the survival prediction with 91.6% accuracy in blunt injuries as compared with 89.2% in the MTOS-derived TRISS. The 95% CI for ROC derived from mTRISS Model 1 was (0.923, 0.940), when compared with the hypothesised ROC value 0.886 obtained from eTRISS, it clearly indicated a significant improvement in predicting survival at 5% level. Furthermore, ROCs have shown clearly the superiority of Model 1 over Model 2, and of Model 2 over MTOS-derived TRISS. The recategorisation of the Age variable (Models 3 and 4) also demonstrated improved performance, but their strength was not as intense as in Model 1. Overall, the results point to the adoption of Model 1 as the best model for PS. Cross-validation analysis has further assured the validity of these findings. CONCLUSIONS: The present study has demonstrated that (1) having the Age variable being dichotomised (cut-off at 55 years) as in the eTRISS, but with the application of a local dataset-derived coefficients give better TRISS survival prediction in Asian blunt trauma patients; (2) improved performance are found with certain recategorisation of the Age variable and (3) the accuracy can further be enhanced if the Age effect is taken to be linear, with the application of local dataset-derived coefficients.

Clinical significance of frizzled homolog 3 protein in colorectal cancer patients.

Frizzled homolog 3 receptor was up-regulated in several gastrointestinal cancers such as esophageal and gastric cancers. Moreover, frizzled homolog 3 has recently reported to be expressed in colorectal adenoma specimens. In the present study, we investigated the clinical significance of frizzled homolog 3 protein in colorectal cancer patients. Using immunocytochemical staining, frizzled homolog 3 expression was examined in 186 colorectal cancer specimens, 79 colorectal adenoma specimens, 133 colorectal polyp specimens, 127 colorectal cancer specimens with lymph node and/or distant metastasis, 310 specimens of various non-colorectal cancer metastatic carcinomas and 40 specimens with simultaneous occurrence of colorectal cancer, colorectal adenoma and colorectal polyp. Statistical analysis was used to correlate frizzled homolog 3 protein expression to the clinicohistopathological factors, recurrence/metastasis and survival after follow-up for 42 months in colorectal cancer patients. Frizzled homolog 3 protein was expressed in 100% colorectal cancer specimens, 89% colorectal adenoma specimens, 75% colorectal polyp specimens and 69% normal colorectal epithelial tissues. Moreover, frizzled homolog 3 immunocytochemical scores were highly correlated with colorectal cancer progression. Furthermore, frizzled homolog 3 was expressed in a comparatively lower percentage of metastatic hepatocellular carcinoma and metastatic renal clear cell carcinoma with focal and very weak staining than other metastatic tumor types. On the other hand, the frizzled homolog 3 immunocytochemical scores of colorectal adenomas with synchronous colorectal carcinomas were significantly higher than those of pure colorectal adenomas. Statistical analysis showed that frizzled homolog 3 immunocytochemical scores were associated with Dukes stage and lymph node status. Finally, stratified groups of colorectal cancer patients had significant differences in their recurrence/metastasis and survival. In conclusion, the present large-scale study has clearly showed that frizzled homolog 3 protein can generate clinically important information for colorectal cancer patients.

Endovascular management of aortoduodenal fistula arising from recurrent mycotic aneurysm in an aortic stump.

BACKGROUND: We present a case of successful endovascular exclusion of an aortoduodenal fistula using an endovascular graft iliac plug. This treatment modality of aortoduodenal fistula arising from a recurrent mycotic aortic aneurysm stump has not yet been described in the literature. CASE REPORT: An 80-year-old man underwent emergency repair of a ruptured infrarenal mycotic aortic aneurysm with an axillobifemoral vascular bypass. Four months after the operation, a pseudoaneurysm arising from the aortic stump invaded the third part of the duodenum, forming an aortoduodenal fistula. An endovascular graft iliac plug and a chimney stent were used to achieve endovascular exclusion of the aortoduodenal fistula. CONCLUSION: The management of aortoduodenal fistula arising from recurrent mycotic aortic aneurysm stump with an endovascular graft iliac plug is successful, especially in patients with a previous history of abdominal aortic surgeries. This procedure reduces the mortality and morbidity associated with open surgery. Further validation with a greater number of cases and longer follow-up times would be required to prove that this is a viable definitive treatment modality.

Retroperitoneal pelvic packing in the management of hemodynamically unstable pelvic fractures: a level I trauma center experience.

BACKGROUND: Our objective is to evaluate the mortality and outcomes of hemodynamically unstable patients with pelvic fractures treated with a protocol that directs the patient to either early pelvic angiography or early retroperitoneal pelvic packing. METHOD: This is a retrospective review of prospectively collected database at a local trauma center. Hemodynamically unstable pelvic fracture patients received treatment according to our hospital protocol during two different time periods. Before June 2008, these patients underwent early angiography (ANGIO group, n=13), and from June 2008 onward, these patients underwent early pelvic packing and subsequent angiography if there was continued hemorrhage from the pelvis (PACKING group, n=11). The mechanism of injury, physiologic parameters, blood transfusion requirements, time to intervention, trauma scores, and mortality were recorded. RESULTS: Mean time to intervention in the ANGIO group was longer than that in the PACKING group, although this was not statistically significant (139.5 minutes vs. 78.8 minutes, respectively, p=0.248). Mortality in the ANGIO group was higher than that in the PACKING group; however, this was also not significant (69.2% vs. 36.3%, p=0.107). After univariate analysis, factors associated with mortality included systolic blood pressure, Glasgow Coma Score, Injury Severity Score, Revised Trauma Score, Trauma and Injury Severity Score, pH, and base excess. In the PACKING group, one patient died of uncontrolled hemorrhage from a liver laceration. In the ANGIO group, three patients died of uncontrolled hemorrhage from the pelvic fracture. CONCLUSION: Early experience in our institution suggests that early pelvic packing with subsequent angiography if needed is as good as angiography with embolization in treating patients with hemodynamically unstable pelvic fractures.

Oesophago-gastro-duodenoscopy for foreign body ingestion: is it necessary for everyone?

OBJECTIVE: To identify the possible predictive factors for positive identification of a foreign body by oesophago-gastro-duodenoscopy (OGD). METHODS: A series of 343 patients who underwent OGD in 2008 at Queen Elizabeth Hospital, Hong Kong were studied retrospectively. RESULTS: Foreign bodies were identified and removed by OGD in 80 patients (23.3%). The most common type of ingested foreign body was fishbone (259 patients; 80%). Foreign bodies were mostly found at or above the level of the cricopharyngeus (70.4%). The most common site of foreign body impaction was at the valleculae (30.9%). Neck X-ray showed low sensitivity of 17.1% and high specificity of 91.5% in detecting ingested foreign bodies. Univariate analysis showed that early presentation, emergency admission, male sex, positive X-ray findings, and old age were associated with positive OGD findings. In multivariate analysis, only male sex, old age and early presentation were shown to be independent predictive factors. CONCLUSION: Patients with predictive factors for positive endoscopic results, including male sex, old age and early presentation, were justified for OGD, during which identification and removal of the foreign bodies were carried out. As for the low risk group, a more conservative approach, for example with the use of computed tomography as a diagnostic tool, could help to reduce the number of negative endoscopies.

Radiofrequency ablation for hepatocellular carcinoma: a survival analysis of 117 patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world especially in Asia. Radiofrequency ablation is now commonly use as either first line or in combination with other treatment modality for patients with HCC. It is the objective of this article to report our experience in a tertiary referral hospital. METHODS: Patients who diagnosed with HCC and underwent RFA in Queen Elizabeth Hospital during the period from May 2002 to February 2009 were included and analyzed. RESULTS: During this period, 138 sessions of RFA were performed in 117 consecutive patients with HCC. The calculated rate of primary (single attempt) successful ablation during this entire period was 89.2%. The in-hospital/30-day mortality rate was zero, and morbidity was 24.1%. Hospital stays were significantly longer in the open group (4.4 days versus 8.9 days, P = 0.000). Median follow-up in this study was 21 months. 11 (9.4%), 10 (8.5%) and 49 (41.0%) patients developed local tumor progression (LTP), systemic recurrence and Intrahepatic distant recurrence (IDR), respectively. The mean and median times to recurrence were 15.4 and 11 months, respectively. Most patients (91%) with LTP developed in the first 24 months. Disease-free survival was 65% at 1 year, 40% at 3 years and 25% at 5 years. Overall survival at 1, 3 and 5 years was 85, 66 and 40%, respectively. Alpha fetoprotein, aFP > 1,000 ng/ml and multiple tumor ablation predicted increased risk of recurrence. CONCLUSION: Radiofrequecy ablation is useful tool in treating patients with HCC with high successful rate. However, intrahepatic recurrence is common and a well designed post ablation follow up protocol based on a sound knowledge of recurrence pattern is vital.

Surgical management of pancreatic necrosis: towards lesser and later.

BACKGROUND/PURPOSE: Our aim was to determine the overall success rate and survival rate with respect to the timing of intervention in the management of pancreatic necrosis. The use of minimally invasive pancreatic necrosectomy was also examined. METHODS: This was a retrospective study carried out in a tertiary referral hospital. The subjects were all patients who suffered from acute pancreatic necrosis with emergency interventions from January 2001 to December 2007. For outcome measures, special emphasis was placed on the overall success rate and survival rate with respect to the timing of intervention. The success rate of percutaneous pancreatic necrosectomy (PCPN) was examined. RESULTS: A total of 26 patients with pancreatic necrosis were studied. The overall mortality rate was 26.9% and the rate was significantly higher in those patients who had earlier intervention (before 6 weeks). Eleven patients had PCPN. There were 2 failures due to PCPN in the early phase; 2 had partial success, while the procedure was completely successful to remove all the necrotic tissues in the other 7 patients. CONCLUSIONS: With a multidisciplinary approach, particularly with sophisticated intensive care, most patients with pancreatic necrosis can survive the initial phase. Open surgery should be limited to simple drainage and laparostomy to relieve the abdominal tension. Active intervention preferably should be delayed until the necrosis has become walled off, when a variety of minimally invasive maneuvers, notably percutaneous necrosectomy, can be offered to remove the debris. The surgical management of pancreatic necrosis should change towards a strategy of "lesser and later".

Survival after transarterial embolization for spontaneous ruptured hepatocellular carcinoma.

OBJECTIVES: To examine the survival of patients with spontaneous ruptured hepatocellular carcinoma treated with transarterial embolization (TAE). METHODS AND MATERIALS: Patients diagnosed with spontaneous ruptured hepatocellular carcinoma treated with TAE were retrospectively studied. Hospital records were reviewed and data were collected and analyzed from the years 2000-2006. A total of 62 patients who had been diagnosed with spontaneous ruptured hepatocellular carcinoma were managed in our hospital during this period. RESULTS: All 62 patients (who had been diagnosed with ruptured hepatocellular carcinoma and were managed in our hospital) patients were treated with TAE, with a success rate of 91% (57/62). Early mortality (within 30 days after rupture) was 38%. Factors that were associated with early mortality were old age, low hemoglobin at presentation, elevated bilirubin at presentation, prolonged prothrombin time at presentation (INR > 1.3), low albumin level at presentation, and unsuccessful embolization. A low albumin level was the only independent risk factor for early mortality. The overall median survival time was 39 days. Surgical resections were possible in seven patients. Their cumulative survival was significantly longer (P = 0.002) than that of patients managed with non-operative treatment after embolization. CONCLUSION: Transarterial embolization (TAE) can achieve good hemostasis, though low albumin level, which reflects poor liver reserve, may predict early mortality. Portal vein thrombosis should not be regarded as an absolute contraindication for TAE. Staged surgical resection after embolization is safe and produces a good survival outcome.

Clinical significance of cytokeratin 20-positive circulating tumor cells detected by a refined immunomagnetic enrichment assay in colorectal cancer patients.

PURPOSE: Current immunomagnetic enrichment method can only detect general epithelial antigens of circulating tumor cells (CTC). Further characterization of the CTCs to provide specific information on the tumor type is not possible. We attempted to overcome this drawback by developing the methodology for using a gastrointestinal-specific anti-cytokeratin (CK) 20 antibody to detect CTCs in colorectal cancer patients' blood. EXPERIMENTAL DESIGN: The protocol was validated using a colorectal cancer SW480 cell line. The clinical significance of findings in colorectal cancer was investigated by detecting CK20-positive CTCs (pCTC) in patients with colorectal cancer, other common cancers, colorectal adenoma, benign colorectal diseases, and normal subjects. Moreover, the malignant nature of CK20 pCTCs was examined by comparing chromosome 17 aberration patterns with those from the corresponding primary tumors. RESULTS: The assay successfully showed CK20-positive SW480 cells. When applied in patient samples, the detection rates were 62% (132 colorectal cancer patients; median number = 11 CTCs), 0% (120 patients with other common cancers), 6% (50 colorectal adenoma patients), 0% (120 patients with benign colorectal diseases), and 0% (40 normal subjects). Furthermore, statistical analysis showed that CK20 pCTC numbers were associated with tumor-node-metastasis stage and lymph node status. Using the median CK20 pCTC numbers as the cutoff points, stratified groups of colorectal cancer patients had significant differences in their recurrence, metastasis, and survival. Finally, chromosome 17 aneusomy in 90% of colorectal cancer patients with CK20 pCTCs matched with those from the primary tumors. CONCLUSIONS: Detection of CK20 pCTCs using the new protocol could generate clinically important information for colorectal cancer patients.

IgG4-related sclerosing lymphoplasmacytic pancreatitis and cholangitis mimicking carcinoma of pancreas and Klatskin tumour.

BACKGROUND: Autoimmune sclerosing pancreatitis is a well-known disease entity for years, particularly recognizing the difficulty in distinguishing it from malignancy. Immunohistochemical study showed that immunoglobulin IgG4 staining was positive in plasma cells of some autoimmune pancreatitis or cholangitis. The term 'autoimmune sclerosing pancreatocholangitis' was used as it was believed that they belonged to a range of disease involving both pancreas and biliary tree. It may also be part of a systemic fibro-inflammatory disease. PATIENTS AND METHODS: All the patients suffering from immunoglobulin G4 (IgG4)-related pancreatitis and cholangitis from May 2003 to September 2006 in Queen Elizabeth Hospital, Hong Kong were retrospectively studied. RESULTS: A total of five patients with clinical diagnosis of IgG4-related autoimmune pancreatitis or cholangitis were analysed. All presented with jaundice or abdominal pain, mimicking carcinoma. Two patients had major resection, two patients were diagnosed by intraoperative biopsy and one was based on serum IgG4 level. CONCLUSION: With the growing awareness of this relatively recently characterized clinical entity and its similar presentation to pancreatic carcinoma or bile duct cholangiocarcinoma, it is important for autoimmune sclerosing pancreatocholangitis to be included in the differential diagnosis of pancreaticobiliary disease. The management strategy has shown to be modified--from major resection to intraoperative biopsy and to the assay of serum IgG4 level without the necessity of histology confirmation.

Liver resection for intrahepatic stones.

HYPOTHESIS: Long-term outcome is good for a selected group of patients with hepatolithiasis treated with liver resection. Liver resection should also be offered to patients with complex hepatolithiasis such as bilateral stones or those with strictures. DESIGN: Retrospective study. SETTING: Regional hospital. PATIENTS: A total of 174 patients with hepatolithiasis (201 procedures) treated between January 1, 1989, and September 30, 2003. INTERVENTIONS: Liver resection (52 procedures) or removal of stones primarily by percutaneous choledochoscopy (149 procedures). MAIN OUTCOME MEASURE: Recurrence of cholangitis. RESULTS: Most patients in the liver resection group had stones localized to the left side. The overall success rate in this group was 98.0% (49 of 50 patients, excluding 2 patients found to have cholangiocarcinoma). The chance of biliary sepsis at 5 years after resection was 13.3%. The overall success rate of stone removal primarily by percutaneous choledochoscopy was 70.5%. The bilaterality of stones, the presence of stricture, and the presence of atrophy were found to be significant risk factors for a poor long-term outcome after stone removal alone. The chance of biliary sepsis at 5 years was 26.4% and 43.2% for those without and with stricture, respectively. CONCLUSIONS: The long-term outcome after liver resection for hepatolithiasis was excellent for a selected group of patients. Poor outcomes were recorded for patients whose intrahepatic stones were removed primarily by percutaneous choledochoscopy, especially those with strictures. The indication for liver resection for hepatolithiasis should be extended to patients with strictures and those with bilateral stones. A combination of different treatment modalities is necessary to improve the outcome of these patients.

Percutaneous drainage and necrosectomy in the management of pancreatic necrosis.

BACKGROUND: The degree of necrosis and presence of infection are the crucial determinants of the outcome in patients with pancreatic necrosis. In patients with sterile necrosis, the necrotic material can persist and subsequently results in sepsis. Some of these patients will ultimately require an operation to remove the necrotic material. Percutaneous necrosectomy has been introduced to remove this residual debris in a minimally invasive way. METHODS: We retrospectively reviewed all patients with pancreatic necrosis who had percutaneous drainage (PCD) performed. Percutaneous pancreatic necrosectomy (PCPN) was done for those patients whose necrotic cavity failed to resolve. RESULTS: Percutaneous drainage was performed in eight patients, four with evidence of infection by the positive culture in the aspirate. In three of them, the necrotic cavity completely resolved after drainage. Percutaneous necrosectomy was performed in another three patients through the tract placed by the radiologist and another one through a sinus tract after an operation. The necrotic cavity in three of them completely resolved after percutaneous necrosectomy. CONCLUSION: Those patients who had 'organized necrosis' after the acute episode of pancreatitis could receive benefit from percutaneous necrosectomy. The persistent symptoms could be alleviated after the removal of the residual necrotic material. It could also be useful after an open surgery to remove any residual devitalized tissue.