Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets

Background

The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.

Methods

Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.

Results

The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.

Conclusions

Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.     

Stimulus and site specific induction of hiccups in the oesophagus of normal subjects

Background—Hiccups that are induced by a largemeal have been suggested to result from gastric overdistension. Therole of the oesophagus in precipitating hiccups has never been defined.
Aims—To determine the involvement of oesophagealmechanoreceptors in the hiccup reflex.
Methods—Ten normal healthy subjects wereprospectively evaluated at a university affiliated hospital. Controlledinflation of a polyethylene bag in the proximal and distal oesophaguswas carried out using slow ramp and rapid phasic distensions, by an electronic distension device.
Results—Hiccups were induced in four subjects onlyduring rapid phasic distensions and only in the proximal oesophagus.The mean (SEM) minimal volume threshold for the hiccup reflex was 32.5 (4.8) ml, which was above the perception threshold. Hiccups appearedduring inflation and resolved after deflation.
Conclusions—Sudden rapid stretch of themechanoreceptors in the proximal oesophagus can trigger the hiccupreflex in normal subjects. Only rapid distensions above a determinedvolume threshold will predictably induce hiccups in a given subject.This mechanism may play a role in the physiological induction of hiccups.

Keywords:hiccups; oesophageal mechanoreceptors; electronicdistension device; phasic distension; ramp distension; perceptionthresholds

     

Synthetic Cannabinoid Intoxication Presenting as Malignant Catatonia: a Case Report

International Journal of Mental Health and Addiction - The use of synthetic cannabinoids (SCs) has been steadily increasing in recent years and represents a new class of substances of abuse....     

A comparison of regional and general anesthesia in patients undergoing carotid endarterectomy

Purpose: The optimal anesthetic for use during carotid endarterectomy is controversial. Advocates of regional anesthesia suggest that it may reduce the incidence of perioperative complications in addition to decreasing operative time and hospital costs. To determine whether the anesthetic method correlated with the outcome of the operation, a retrospective review of 3975 carotid operations performed over a 32-year period was performed.Methods: The records of all patients who underwent carotid endarterectomy at our institution from 1962 to 1994 were retrospectively reviewed. Operations performed with the patient under regional anesthesia were compared with those performed with the patient under general anesthesia with respect to preoperative risk factors and perioperative complications.Results: Regional anesthesia was used in 3382 operations (85.1%). There were no significant differences in the age, gender ratio, or the rates of concomitant medical illnesses between the two patient populations. The frequency of perioperative stroke in the series was 2.2%; that of myocardial infarction, 1.7%; and that of perioperative death, 1.5%. There were no statistically significant differences in the frequency of perioperative stroke, myocardial infarction, or death on the basis of anesthetic technique. A trend toward higher frequencies of perioperative stroke (3.2% vs 2.0%) and perioperative death (2.0% vs 1.4%) in the general anesthesia group was noted. In examining operative indications, however, there was a significant increase in the percentage of patients receiving general anesthesia who had sustained preoperative strokes when compared with the regional anesthesia patients (36.1% vs 26.4%; p < 0.01). There was also a statistically significant higher frequency of contralateral total occlusion in the general anesthesia group (21.8% vs 15.4%; p = 0.001). The trend toward increased perioperative strokes in the general anesthesia group may be explicable either by the above differences in the patient populations or by actual differences based on anesthetic technique that favor regional anesthesia.Conclusions: In a retrospective review of a large series of carotid operations, regional anesthesia was shown to be applicable to the vast majority of patients with good clinical outcome. Although the advantages over general anesthesia are perhaps small, the versatility and safety of the technique is sufficient reason for vascular surgeons to include it in their armamentarium of surgical skills. Considering that carotid endarterectomy is a procedure in which complication rates are exceedingly low, a rigidly controlled, prospective randomized trial may be required to accurately assess these differences. (J Vasc Surg 1996;24;946-56.)     

Tumor size and operative risks of extended right-sided hepatic resection for hepatocellular carcinoma: implication for preoperative portal vein embolization

HYPOTHESIS: Major hepatic resection for hepatocellular carcinoma (HCC) is associated with high operative morbidity and mortality, especially in patients with underlying chronic liver disease. The present study evaluated the factors associated with increased operative risks in patients who underwent extended right-sided hepatic resection for HCC. DESIGN: Retrospective study. SETTING: Tertiary referral center. PATIENTS: A retrospective study was performed on 172 patients who underwent extended right-sided hepatic resection of more than 4 Couinaud segments for HCC during a 16-year period (January 1, 1989, to December 31, 2004) to evaluate the clinical factors associated with operative morbidity and mortality. MAIN OUTCOME MEASURE: Risk factors associated with hospital mortality and major operative morbidity. RESULTS: The overall major morbidity and hospital mortality rates were 14.0% and 8.1%, respectively. On multivariate analysis, small tumor size, conventional-approach hepatectomy, Child-Pugh grade B cirrhosis, and preexisting tumor rupture were the independent factors significantly associated with an increased risk of operative mortality. Discriminant analysis showed that a tumor size smaller than 10 cm significantly increased the risk of operative mortality compared with larger tumors (17.2% vs 3.5%; P = .046). CONCLUSIONS: Anterior approach is the preferred technique for extended right-sided hepatic resection for HCC. Increased risk of operative mortality was identified in patients who had a small tumor, which was associated with the resection of a large volume of functioning liver parenchyma. Preoperative portal vein embolization should be considered in this group of patients to enhance atrophy of the right lobe and hypertrophy of the future liver remnant to minimize the operative risk.     

Is Hepatic Resection for Large or Multinodular Hepatocellular Carcinoma Justified? Results From a Multi-Institutional Database

Background The role of surgical resection in patients with large or multinodular hepatocellular carcinoma (HCC) remains unclear. This study evaluated the long-term outcome of patients with hepatic resection for large (>5 cm in diameter) or multinodular (more than three nodules) HCC by using a multi-institutional database.Methods The perioperative and long-term outcomes of 404 patients with small HCC (<5 cm in diameter; group 1) were compared with those of 380 patients with large or multinodular HCC (group 2). The prognostic factors in the latter group were analyzed.Results The postoperative complication rate (27% vs. 23%; P = .16) and hospital mortality rate (2.4% vs. 2.7%; P = .82) were similar between groups. The overall survival rates were significantly higher in group 1 than group 2 (1 year, 88% vs. 74%; 3 years, 76% vs. 50%; 5 years, 58% vs. 39%; P < .001). Among patients in group 2, five independent prognostic factors were identified to be associated with a worse overall survival: namely, symptomatic disease, presence of cirrhosis, multinodular tumor, microvascular tumor invasion, and positive histological margin.Conclusions Hepatic resection can be safely performed in patients with large or multinodular HCC, with an overall 5-year survival rate of 39%. Symptomatic disease, the presence of cirrhosis, a multinodular tumor, microvascular invasion, and a positive histological margin are independently associated with a less favorable survival outcome.     

Abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases

OBJECTIVE: The aim of this study was to determine whether abdominal drainage is beneficial after elective hepatic resection in patients with underlying chronic liver diseases. SUMMARY BACKGROUND DATA: Traditionally, in patients with chronic liver diseases, an abdominal drainage catheter is routinely inserted after hepatic resection to drain ascitic fluid and to detect postoperative hemorrhage and bile leakage. However, the benefits of this surgical practice have not been evaluated prospectively. PATIENTS AND METHODS: Between January 1999 and March 2002, 104 patients who had underlying chronic liver diseases were prospectively randomized to have either closed suction abdominal drainage (drainage group, n = 52) or no drainage (nondrainage group, n = 52) after elective hepatic resection. The operative outcomes of the 2 groups of patients were compared. RESULTS: Fifty-seven (55%) patients had major hepatic resection with resection of 3 Coiunaud's segments or more. Sixty-nine (66%) patients had liver cirrhosis and 35 (34%) had chronic hepatitis. Demographic, surgical, and pathologic details were similar between both groups. The primary indication for hepatic resection was hepatocellular carcinoma (n = 100, 96%). There was no difference in hospital mortality between the 2 groups of patients (drainage group, 6% vs. nondrainage group, 2%; P = 0.618). However, there was a significantly higher overall operative morbidity in the drainage group (73% vs. 38%, P < 0.001). This was related to a significantly higher incidence of wound complications in the drainage group compared with the nondrainage group (62% vs. 21%, P < 0.001). In addition, a trend toward a higher incidence of septic complications in the drainage group was observed (33% vs. 17%, P = 0.07). The mean (+/- standard error of mean) postoperative hospital stay of the drainage group was 19.0 +/- 2.2 days, which was significantly longer than that of the nondrainage group (12.5 +/- 1.1 days, P = 0.005). With a median follow-up of 15 months, none of the 51 patients with hepatocellular carcinoma in the drainage group developed metastasis at the drain sites. On multivariate analysis, abdominal drainage, underlying liver cirrhosis, major hepatic resection, and intraoperative blood loss of >1.5L were independent and significant factors associated with postoperative morbidity. CONCLUSION: Routine abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases.     

Pancreaticoduodenectomy with En Bloc Portal Vein Resection for Pancreatic Carcinoma with Suspected Portal Vein Involvement

Pancreaticoduodenectomy combined with portal vein resection is increasingly accepted as a viable treatment option for pancreatic carcinoma with suspected involvement of the portal vein.However, its clinical benefit remains controversial. This study evaluated the outcomes of pancreaticoduodenectomy with portal vein resection for pancreatic carcinoma in a group of Chinese patients operated on by a specialized team in a center with a low case volume of pancreatic cancer. The perioperative and long-term outcomes of 12 patients with portal vein resection for suspected involvement of the portal vein and 38 patients who underwent pancreaticoduodenectomy without portal vein resection during the same period were compared. In the former group, eight patients underwent segmental resection, and four patients underwent wedge resection of the portal vein. There were no significant differences in operative blood loss (median 0.8 vs. 0.8 liter, p = 0.313), hospital mortality (0% vs. 2.6%, p = 1.000), or operative morbidity (41.7% vs. 42.1%, p = 0.979) between the two groups. Patients who required portal vein resection had higher frequencies of microscopic lymphatic permeation (58.3% vs. 18.4%, p = 0.023) and vascular invasion (50.0% vs. 15.8%, p = 0.025). Long-term survival was comparable between patients with portal vein resection and those without it (median 19.5 vs. 20.7 months, p = 0.769). These findings suggest that pancreaticoduodenectomy combined with portal vein resection can be performed safely by a specialized team in a center with a low case volume of pancreatic carcinoma and that it may offer survival benefit in patients with suspected portal vein involvement.     

Microdilution Technique for Antimicrobial Susceptibility Testing of Anaerobic Bacteria

A microdilution technique using commercially available media and materials was developed and used to determine the minimal inhibitory concentrations (MICs) of clindamycin, chloramphenicol, tetracycline, minocycline, ampicillin, carbenicillin, cephalothin, and gentamicin for 101 anaerobic isolates. Representative strains of Bacteroides, Clostridium, Fusobacterium, Peptococcus, and Peptostreptococcus were tested. The use of Schaedler broth at pH 7.2, an inoculum of 10(5) to 10(7) colony-forming units per ml, and incubation at 35 C in an anaerobic glove box with an atmosphere of 80% nitrogen, 10% hydrogen, and 10% carbon dioxide resulted in good growth and easily interpretable results. After 48 h of incubation, 97% of strains tested were inhibited by 3.1 mug or less of clindamycin per ml and 98% were inhibited by 12.5 mug or less of chloramphenicol per ml. Tetracycline and minocycline inhibited 81 and 88% of strains tested in concentrations of 1.6 mug or less per ml and 1.6 mug or less per ml, respectively. Ampicillin inhibited all strains other than B. fragilis in concentrations of 3.1 mug or less per ml. Excluding certain strains of Bacteroides and Clostridium, carbenicillin in concentrations of 12.5 mug or less per ml and cephalothin in concentrations of 6.2 mug or less per ml inhibited all strains tested. Gentamicin was inactive although some strains of anaerobic cocci and Bacteroides were inhibited by 3.1 mug or less per ml. After 18 to 24 h of incubation, eight of the 101 strains had not grown sufficiently for MICs to be determined; for the 93 strains which had grown sufficiently, 93% of 744 MICs were the same or one concentration lower than the 48-h MICs.