Combined analysis of albumin in situ hybridisation and C reactive protein immunohistochemistry for the diagnosis of intrahepatic cholangiocarcinoma: towards a molecular classification paradigm.

AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a diagnosis of exclusion that can pose a challenge to the pathologist despite thorough clinical workup. Although several immunohistochemical markers have been proposed for iCCA, none of them reached clinical practice. We here assessed the combined usage of two promising diagnostic approaches, albumin in situ hybridisation (Alb-ISH) and C reactive protein (CRP) immunohistochemistry, for distinguishing iCCA from other adenocarcinoma primaries. METHODS: We conducted Alb-ISH and CRP immunohistochemistry in a large European iCCA cohort (n=153) and compared the results with a spectrum of other glandular adenocarcinomas of different origin (n=885). In addition, we correlated expression patterns with clinicopathological information and mutation data. RESULTS: Alb-ISH was highly specific for iCCA (specificity 98.8%) with almost complete negativity in perihilar CCA and only rare positives among other adenocarcinomas (sensitivity 69.5%). CRP identified the vast majority of iCCA cases (sensitivity 84.1%) at a lower specificity of 86.4%. Strikingly, the combination of CRP and Alb-ISH boosted the diagnostic sensitivity to 88.0% while retaining a considerable specificity of 86.1%. Alb-ISH significantly correlated with CRP expression, specific tumour morphologies and small or large duct iCCA subtypes. Neither Alb-ISH nor CRP was associated with iCCA patient survival. 16 of 17 recurrent mutations in either IDH1, IDH2 and FGFR2 affected Alb-ISH positive cases, while the only KRAS mutation corresponded to an Alb-ISH negative case. CONCLUSIONS: In conclusion, we propose a sequential diagnostic approach for iCCA, integrating CRP immunohistochemistry and Alb-ISH. This may improve the accuracy of CCA classification and pave the way towards a molecular-guided CCA classification.

Machine learning for optimized individual survival prediction in resectable upper gastrointestinal cancer.

PURPOSE: Surgical oncologists are frequently confronted with the question of expected long-term prognosis. The aim of this study was to apply machine learning algorithms to optimize survival prediction after oncological resection of gastroesophageal cancers. METHODS: Eligible patients underwent oncological resection of gastric or distal esophageal cancer between 2001 and 2020 at Heidelberg University Hospital, Department of General Surgery. Machine learning methods such as multi-task logistic regression and survival forests were compared with usual algorithms to establish an individual estimation. RESULTS: The study included 117 variables with a total of 1360 patients. The overall missingness was 1.3%. Out of eight machine learning algorithms, the random survival forest (RSF) performed best with a concordance index of 0.736 and an integrated Brier score of 0.166. The RSF demonstrated a mean area under the curve (AUC) of 0.814 over a time period of 10 years after diagnosis. The most important long-term outcome predictor was lymph node ratio with a mean AUC of 0.730. A numeric risk score was calculated by the RSF for each patient and three risk groups were defined accordingly. Median survival time was 18.8 months in the high-risk group, 44.6 months in the medium-risk group and above 10 years in the low-risk group. CONCLUSION: The results of this study suggest that RSF is most appropriate to accurately answer the question of long-term prognosis. Furthermore, we could establish a compact risk score model with 20 input parameters and thus provide a clinical tool to improve prediction of oncological outcome after upper gastrointestinal surgery.

Prognostic relevance of the revised R status definition in pancreatic cancer: meta-analysis.

BACKGROUND: The prognostic impact of margin status is reported with conflicting results after pancreatic cancer resection. While some studies validated an uninvolved resection margin (R0) 1 mm or more of tumour clearance, others have failed to show benefit. This systematic review and meta-analysis aimed to investigate the effects of margin definitions on median overall survival (OS). METHODS: MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies reporting associations between resection margins and OS between 2010 and 2021. Data regarding margin status (R0 circumferential resection margin (CRM) negative (CRM-), R0 CRM positive (CRM+), R0 direct, and R1 and OS were extracted. Hazard ratios (HRs) were pooled with a random-effects model. The risk of bias was evaluated with the Quality in Prognosis Studies (QUIPS) tool. RESULTS: The full texts of 774 studies were screened. In total, 21 studies compromising 6056 patients were included in the final synthesis. In total, 188 (24 per cent) studies were excluded due to missing margin definitions. The R0 (CRM+) rate was 50 per cent (95 per cent confidence interval (c.i.) 0.40 to 0.61) and the R0 (CRM-) rate was 38 per cent (95 per cent c.i. 0.29 to 0.47). R0 (CRM-) resection was independently associated with improved OS compared to combined R1 and R0 (CRM+; HR 1.36, 95 per cent c.i. 1.23 to 1.56). CONCLUSION: The revised R status was confirmed as an independent prognosticator compared to combined R0 (CRM+) and R1. The limited number of studies, non-standardized pathology protocols, and the varying number of margins assessed hamper comparability.

Microbial Load in Septic and Aseptic Procedure Rooms.

BACKGROUND: Highly effective measures to prevent surgical wound infections have been established over the last two decades. We studied whether the strict separation of septic and aseptic procedure rooms is still necessary. METHODS: In an exploratory, prospective observational study, the microbial concentration in an operating room without a room ventilating system (RVS) was analyzed during 16 septic and 14 aseptic operations with the aid of an air sampler (50 cm and 1 m from the operative field) and sedimentation plates (1 m from the operative field, and contact culture on the walls). The means and standard deviations of the microbial loads were compared with the aid of GEE models (generalized estimation equations). RESULTS: In the comparison of septic and aseptic operations, no relevant differences were found with respect to the overall microbial concentration in the room air (401.7 ± 176.3 versus 388.2 ± 178.3 CFU/m3; p = 0.692 [CFU, colony-forming units]) or sedimentation 1 m from the operative field (45.3 ± 22.0 versus 48.7 ± 18.5 CFU/m2/min; p = 0.603) and on the walls (35.7 ± 43.7 versus 29.0 ± 49.4 CFU/m2/min; p = 0.685). The only relevant differences between the microbial spectra associated with the two types of procedure were a small amount of sedimentation of Escherichia coli and Enterococcus faecalis in septic operations, and of staphylococcus aureus and pseudomonas stutzeri in aseptic operations, up to 30 minutes after the end of the procedure. CONCLUSION: These data do not suggest that septic and aseptic procedure rooms need to be separated. In interpreting the findings, one should recall that the study was not planned as an equivalence or non-inferiority study. Wherever patient safety is concerned, high-level safety concepts should only be demoted to lower levels if new and convincing evidence becomes available.

Decision Making in Necrotizing Pancreatitis.

The management of acute necrotizing pancreatitis (ANP) has undergone a change of paradigms during the last 2 decades with a decreasing impact of surgical interventions. Modern ANP management is done conservatively as long as possible and therapeutic approaches aim at volume resuscitation, pain management and early enteral nutrition. The diagnostic gold standard of contrast-enhanced CT scan helps to evaluate the extent of necrosis of the pancreas, which correlates with the risk of tissue infection. The crucial point for decision making is the proven existence of infected pancreatic necrosis. This can be achieved by diagnostic needle aspiration of the necrotic material and staining to prove bacterial and/or fungal infection. In case of infected necrosis - besides calculated antimicrobial treatment - an interventional or surgical approach is required to prevent systemic septic progression of the disease. As the first step, percutaneous interventional drainage and spilling of the necrosis are preferable. In case of insufficient clearing of the infectious focus, a step-up approach must be considered, which implies a retroperitoneoscopic or transabdominal minimally invasive necrosectomy and drain placement. Postoperatively, a continuous lavage should be performed using these drains. In case of further deterioration of the patient or development of associated intra-abdominal complications (e.g. bowel perforation or uncontrolled bleeding), an open surgical intervention must always be regarded as a salvage therapy and this offers the possibility to control complications and perform a further necrosectomy and extensive lavage for focus control. However, associated morbidity (e.g. pancreatic fistula, fluid collections, pseudocysts) is about 50-60% and mortality up to 20%. In summary, ANP is managed primarily by a conservative therapy. In case of infected necrosis, interventional and minimally invasive approaches are the therapy of choice. Open surgery should be considered for patients deteriorating despite other measures and should be postponed as long as possible.

CD44v10, osteopontin and lymphoma growth retardation by a CD44v10-specific antibody.

Blockade of CD44 is considered a therapeutic option for the elimination of leukemia-initiating cells. However, the application of anti-panCD44 can be burdened by severe side effects. We determined whether these side effects could be avoided by replacing anti-panCD44 with CD44 variant isoform (CD44v)-specific antibodies in CD44v-positive hematological malignancies using the EL4 thymoma and CD44v10-transfected EL4 (EL4-v10) as models. Subcutaneous growth of EL4 and EL4-v10 was equally well inhibited by the anti-panCD44 and anti-CD44v10 antibodies, respectively. Ex vivo analysis indicated that natural killer cytotoxicity and antibody-dependent cellular cytotoxicity were the main effector mechanisms. Under local inflammation, the efficacy of anti-CD44v10 prolonged the survival time twofold compared with untreated, EL4-v10 tumor-bearing mice, and this was due to inflammation-induced expression of osteopontin (OPN). A high level of OPN in EL4-v10 tumors supported leukocyte recruitment and tumor-infiltrating T-cell activation. Taken together, in hematological malignancies expressing CD44v, anti-panCD44 can be replaced by CD44v-specific antibodies without a loss in efficacy. Furthermore, CD44v10-specific antibodies appear particularly advantageous in cutaneous leukemia therapy, as CD44v10 binding of OPN drives leukocyte recruitment and activation.

[A young man with chronic diarrhea and epigastric pain]. / Junger Mann mit chronischer Diarrhö und Oberbauchschmerzen.

CASE REPORT: A 26-year-old man was admitted to hospital with a 6-month history of diarrhea and abdominal pain. Before admission, upper and lower gastrointestinal endoscopy had shown a mild erosive duodenitis and the patient was started on a proton pump inhibitor. Physical examination and laboratory tests on admission were not constructive. In addition, repeated gastrointestinal endoscopy, cross-sectional imaging and neuroendocrine markers did not point to a specific etiology. Therefore, as a provocation test, the proton pump inhibitor therapy was discontinued. Discontinuation resulted in a progression of the patient's symptoms and an endoscopic detection of duodenal ulcers. Except for the normal serum gastrin levels, this constellation was suggestive of a gastrinoma, so that further investigations were initiated. Subsequently, the diagnosis could be confirmed and the gastrinoma located. After successful pancreaticoduodenectomy, the patient was symptom-free. CONCLUSION: As part of a systematic investigation on chronic diarrhea, the work-up for neuroendocrine causes can play an important role. In this context, it should be kept in mind that some gastrinoma patients present without an elevation of serum gastrin levels. Regardless of a negative gastrin test, a typical symptom constellation should therefore prompt further investigations.

Expression of cytokeratin-20 in pancreatic cancer: an indicator of poor outcome after R0 resection.

BACKGROUND: After complete removal of the neoplasm (R0 resection), approximately 80% of pancreatic cancer patients will die of the disease within 5 years. The expression panel of cytokeratins (CK) is linked closely with cell differentiation. The aim of the study was to investigate the expression of CK-20 in pancreatic cancer tissue and to correlate CK-20 expression with survival in R0-resected pancreatic cancer patients. METHODS: Tissue samples of 63 patients with pancreatic cancer were subjected to CK-20 reverse-transcription polymerase chain reaction. Thirty-four of 63 patients underwent R0 resection and were followed-up for survival statistics. From these 34 patients, 26 (76%) neoplasms were CK-20 positive and 8 (24%) samples were CK-20 negative. The mean follow-up period for the entire group was 17 months (range, 4-36 mo), the follow-up period in censored patients was 23 months (range, 10-36 mo). RESULTS: In the R0-resected group, 3 of 8 (38%) patients with CK-20-negative neoplasms, and 16 of 26 (62%) patients with CK-20-positive neoplasms (P = .15) died of recurrent disease. The median survival time of patients with CK-20-positive neoplasms was 13 months (range, 4-36), the median survival in R0-resected patients with CK-20-negative neoplasm was 26 months (range, 13-35; P = .06). The survival difference observed in patients with CK-20-negative neoplasms could not be attributed to intergroup variations in tumor stage or tumor grade. CONCLUSIONS: A majority of primary ductal pancreatic adenocarcinomas express CK-20. This seems to be associated with poorer survival in R0-resected patients. Our data suggest that ductal pancreatic adenocarcinomas negative for CK-20 constitute a subgroup of patients showing a more favorable disease outcome. The expression of CK-20 in resected pancreatic cancer may be of interest as a prognostic parameter.

Acute retinopathy following pancreatic head resection for chronic pancreatitis: a rare, severe complication.

CONTEXT: Chronic pancreatitis is a pancreatic disorder affecting endocrine and exocrine pancreatic functions with a variety of mainly abdominal symptoms. CASE REPORT: We report the rare complication of acute retinopathy with visual loss following pancreatic head resection due to chronic pancreatitis. CONCLUSIONS: Acute retinal dysfunction is a rare severe complication of acute and chronic pancreatitis. Early recognition and therapy are of utmost importance in restoring normal visual acuity and avoiding irreversible damage.