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.     

Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40 , 59–74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51 , 789–808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.     

Measurements of acetabular cup position and pelvic spatial orientation after total hip arthroplasty using computed tomography/radiography matching.

This study presents a clinical validation of postoperative measurements of acetabular cup alignment following total hip arthroplasty (THA). The methodology was based on concurrent anatomic three-dimensional (3D) measurements of both the acetabular cup alignment and pelvic orientation, using an original CT/X-ray matching algorithm named Xalign. The subjects were 19 patients who had undergone bilateral THA using CT-based surgical navigation. All patients had postoperative pelvic CT scans and multiple antero-posterior (AP) pelvic X-rays. Using a proprietary software algorithm, the X-rays included in the study were matched with the corresponding postoperative CT scans. The goal of this method was to allow 3D anatomic pelvic and acetabular measurements on two-dimensional AP X-rays. The postoperative cup abduction, version and pelvic flexion angles were determined in three different ways: using CT images directly, applying the Xalign method, and finally by performing conventional (abduction only) measurements on AP pelvic X-rays. The cup orientation measured on CT images was taken as the ground truth. The Xalign measurement errors were defined as the difference between the CT cup values and those obtained by applying the matching method. The mean cup abduction error was 0.85 degrees +/- 1.3 degrees (+/- standard deviation) and the mean version error was 0.01 degrees +/- 1.99 degrees . Conventionally measured cup abduction ranged from 44 degrees to 62 degrees and correlated significantly (p = 0.001, r = -0.5) with pelvic flexion angle, proving the linear negative correlation between pelvic flexion and the error in conventional radiographic cup measurements. The Xalign method offered reasonable accuracy for cup orientation, and allowed cup and pelvic 3D anatomic measurements at different times.     

Evisceration Following Abdominal Stab Wounds: Analysis of 66 Cases

Background  Abdominal stab wounds with evisceration remain an indication for emergency laparotomy. The purpose of this study was validate a policy of mandatory laparotomy for organ evisceration and a policy of selective nonoperative management with serial physical abdominal examination for omentum evisceration. Methods  The charts of 379 patients with abdominal stab wounds who presented to our Level I trauma center over a 3-year (January 2005 to December 2007) period were retrospectively reviewed. Altogether, 66 (17.4%) patients with evisceration were identified and included in the study. Indications for mandatory laparotomy were peritonitis, hemodynamic instability, organ evisceration, and a high spinal cord or severe head injury with an abdominal stab wound. Further data gathered included the organ eviscerated, intraabdominal organs injured, and complications. Injury severity was categorized using the revised trauma score (RTS), injury severity score (ISS), and penetrating abdominal index (PATI). Results  Organ and omentum evisceration occurred in 35 (53%) and 31 (47%) patients, respectively. Organs eviscerated were as follows (number of patients): small bowel in 27 (40.9%), stomach in 2 (3%), colon in 1 (1.5%), small bowel and stomach in 2 (3%), and small bowel and colon in 3 (4.5%). The mean RTS, ISS, and PATI scores were 7.71, 13.74, and 8.26, respectively. Only two (5.7%) patients with organ evisceration underwent a negative laparotomy. In total, 23 patients with omentum evisceration (21 with peritonitis, 1 with a head injury, 1 who failed abdominal observation) underwent therapeutic laparotomy. Six patients with omentum evisceration were managed successfully nonoperatively. Two patients with left thoracoabdominal omentum evisceration underwent delayed laparoscopy, which revealed a diaphragm injury in one patient. Overall, 57 (86.4%) patients with evisceration had an intraabdominal injury that required repair. Conclusions  Evisceration should continue to prompt operative intervention. An exception can be made to a select few patients with omentum evisceration with benign abdominal findings.     

Early Prosthetic Valve Dysfunction Due to Bioprosthetic Valve Thrombosis: The Role of Echocardiography

Objectives

The purpose of this study was to review the institutional practice of surveillance transthoracic echocardiography (TTE) for diagnosing early prosthetic valve dysfunction (PVD).

Chronotropic response to exercise predicts angiographic severity in patients with suspected or stable coronary artery disease

Inappropriate chronotropic response to exercise has been observed to correlate with poor prognosis in patients with coronary disease, but the mechanism for this association is not well defined. We attempted to examine the association between chronotropic response to exercise and angiographic severity of coronary disease in patients with suspected or stable coronary artery disease. The chronotropic response, expressed as peak heart rate, chronotropic index (ratio of heart rate reserve and metabolic reserve utilized), or percent maximal heart rate achieved, was correlated with angiographic findings obtained within 180 days of the test. Significant coronary disease was defined as ≥1 stenosis of ≥50% in a major epicardial artery or its main branches; severe coronary disease was defined as ≥50% stenosis in all 3 epicardial arteries, or in the left main coronary trunk, or 2-vessel disease with ≥70% proximal left anterior descending artery stenosis. We observed that peak heart rate and percent maximal heart rate achieved were independent negative predictors of both significant and severe coronary disease by logistic regression. The chronotropic index predicted severe coronary disease only. All 3 parameters of chronotropic response exhibited a significant gradient of abnormality across the spectrum of coronary disease (p < 0.01 for all), expressed by the number of vessels involved and correlated with left anterior descending artery involvement (p < 0.05 for all). We conclude that chronotropic response to exercise predicts the presence and angiographic severity of coronary disease. This association is likely related to the proportion of left ventricular myocardium rendered ischemic during stress.     

Aortic rupture during reoperative bariatric surgery

Morbid obesity has become a very common problem worldwide, causing severe health-related consequences including cardiovascular or metabolic diseases, arthritis, sleep apnea, or an increased risk of cancer. Bariatric surgery was shown to be the only way to achieve sustainable weight loss and to decrease the frequency and severity of metabolic and cardiovascular comorbidities. The purpose of this article is to present a case of bariatric surgery complicated with lesion of the aorta with a lethal outcome.     

Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity

The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1). Here we report that inactivation of SEC63 induces an unfolded protein response (UPR) pathway that is protective against cyst formation. Specifically, using murine genetic models, we determined that SEC63 deficiency selectively activates the IRE1α-XBP1 branch of UPR and that SEC63 exists in a complex with PC1. Concomitant inactivation of both SEC63 and XBP1 exacerbated the polycystic kidney phenotype in mice by markedly suppressing cleavage at the G protein–coupled receptor proteolysis site (GPS) in PC1. Enforced expression of spliced XBP1 (XBP1s) enhanced GPS cleavage of PC1 in SEC63-deficient cells, and XBP1 overexpression in vivo ameliorated cystic disease in a murine model with reduced PC1 function that is unrelated to SEC63 inactivation. Collectively, the findings show that SEC63 function regulates IRE1α/XBP1 activation, SEC63 and XBP1 are required for GPS cleavage and maturation of PC1, and activation of XBP1 can protect against polycystic disease in the setting of impaired biogenesis of PC1.