Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus minimally invasive esophagectomy for resectable esophageal adenocarcinoma, a randomized controlled trial (ROBOT-2 trial).

BACKGROUND: For patients with esophageal adenocarcinoma or cancer of the gastroesophageal junction, radical esophagectomy with 2-field lymphadenectomy is the cornerstone of the multimodality treatment with curative intent. Both conventional minimally invasive esophagectomy (MIE) and robot assisted minimally invasive esophagectomy (RAMIE) were shown to be superior compared to open transthoracic esophagectomy considering postoperative complications. However, no randomized comparison exists between MIE and RAMIE in the Western World for patients with esophageal adenocarcinoma. METHODS: This is an investigator-initiated and investigator-driven multicenter randomized controlled parallel-group superiority trial. All adult patients (age ≥ 18 and ≤ 90 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 218) with resectable esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction are randomized to either RAMIE (n = 109) or MIE (n = 109). The primary outcome of this study is the total number of resected abdominal and mediastinal lymph nodes specified per lymph node station. CONCLUSION: This is the first randomized controlled trial designed to compare RAMIE to MIE as surgical treatment for resectable esophageal adenocarcinoma or adenocarcinoma of the gastroesophageal junction in the Western World. The hypothesis of the proposed study is that RAMIE will result in a higher abdominal and mediastinal lymph node yield specified per station compared to conventional MIE. Short-term results and the primary endpoint (total number of resected abdominal and mediastinal lymph nodes per lymph node station) will be analyzed and published after discharge of the last randomized patient within this trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04306458 . Registered 13th March 2020, https://clinicaltrials.gov/ct2/show/NCT04306458; Date of first enrolment 18.01.2021; Target sample size 218; Recruitment status: Recruiting; Protocol version 2; Issue date 10.03.2020; Rev. 02.02.2021; Authors ET, PCvdS, PPG.

Stringent adherence to a cytomegalovirus-prevention protocol is associated with reduced overall costs in the first 6 months after kidney transplantation.

BACKGROUND: We previously documented that a stringent implementation of a preemptive cytomegalovirus (CMV) prevention protocol reduced the number of CMV disease episodes after kidney transplantation, when compared with a routine preemptive protocol. The impact on overall costs was assessed. METHODS: Cost comparisons were made for inpatient and outpatient costs and overall costs, using costs provided by the financial department. Variables were analyzed using the Wilcoxon rank-sum test. A multivariable global linear model evaluated the effect of all co-variables on cost differences. In Cohort 1 (n = 84), 74% were followed with a standard CMV preemptive protocol, and 26% received prophylaxis. In Cohort 2 (n = 74), an intensified CMV surveillance protocol was applied in 74% of patients, and 26% were given prophylaxis. RESULTS: Overall, Cohort 1 had significantly higher treatment costs as compared with Cohort 2 (mean Swiss francs [CHF] 104,548 and CHF 76,983, respectively, P = 0.0005). Excluding patients who received prophylaxis reduced these costs to CHF 89,318 in Cohort 1 and CHF 73,652 in Cohort 2. Outcome between Cohort 1 and 2 was comparable. CONCLUSION: A stringent adherence to the CMV prevention protocol was associated with a significant reduction in overall costs. Whether this benefit is because of the demonstrated reduction in the rate of CMV disease needs to be assessed in a randomized trial.

Association of BK viremia with human leukocyte antigen mismatches and acute rejection, but not with type of calcineurin inhibitor.

INTRODUCTION: BK viremia and polyomavirus-associated nephropathy (PVN) represent a significant problem after kidney transplantation. Both are associated with intensified immunosuppression, but other risk factors and the impact of a screening program on outcome are incompletely understood. METHODS: Here, we report on the short- and long-term outcome of a cohort of patients, who were transplanted in 2006/2007 and included in a newly introduced systematic 3-monthly screening for BK viremia at the University Hospital Zurich. In patients testing positive for BK viremia, screening frequency was intensified and immunosuppression reduced. Patients with suspected PVN underwent transplant biopsy. RESULTS: Among 152 included patients, 49 (32%) tested positive for BK viremia, but only 8 developed biopsy-proven PVN. BK viremia had a significant impact on estimated glomerular filtration rate and proteinuria in the first 2 years. Acute rejection episodes and the number of human leukocyte antigen (HLA) mismatches were the strongest independent predictors of BK viremia in a multiple logistic model. In contrast, no particular immunosuppressive agent or regimen was associated with enhanced risk. CONCLUSION: Taken together, systematic BK viremia screening led to detection of a high percentage of viremic patients. With adjustment of immunosuppression, an excellent outcome was achieved. The independent association of HLA mismatches with BK viremia suggests impaired polyomavirus immunosurveillance in highly mismatched allografts.

A stringent preemptive protocol reduces cytomegalovirus disease in the first 6 months after kidney transplantation.

BACKGROUND: The optimal strategy to prevent cytomegalovirus (CMV) disease after kidney transplantation continues to be open to debate. The preemptive approach requires regular determination of CMV viremia and prompt initiation of therapy. METHODS: We retrospectively compared the incidence of CMV disease during two periods at our center: A first phase (P1, n = 84 kidney recipients), during which time the intensity of surveillance was determined by the responsible physician, was compared to a second phase (P2, n = 74), when a stringent protocol of CMV surveillance was required for all patients. The preemptive approach was applied for all CMV risk groups; prophylaxis was optional in the case of treatment for rejection or delayed graft function in the intermediate- and high-risk group. Follow-up was truncated at 6 months after transplant surgery. CMV syndrome was differentiated from asymptomatic replication by the presence of at least one systemic symptom, while diagnosis of CMV end-organ disease required histological confirmation. RESULTS: Immunosuppression was similar in the two periods. CMV prophylaxis was used equally (26 %) in both periods. The probability for asymptomatic viremia episodes was not different for patients in P1 and P2 regardless of the prevention strategy. For patients following the preemptive strategy, the probability for CMV disease was increased during P1 (p = 0.016), despite fewer PCR assays being performed in phase 2. Protocol violations were only observed during P1. CONCLUSIONS: The probability of CMV disease episodes (CMV syndrome and CMV end-organ disease) was substantially reduced using a very stringent protocol. This study highlights the crucial importance of a stringent protocol with optimal adherence by all caregivers if the preemptive strategy is to be successful.

Value of combined 6-[18F]fluorodihydroxyphenylalanine PET/CT for imaging of neuroendocrine tumours.

BACKGROUND: Accurate knowledge of tumour presence and location is essential to treat neuroendocrine tumours (NETs). Standard imaging has been hampered by low sensitivity and lack of spatial resolution. This study assessed prospectively the diagnostic value and impact of combined 6-[18F]fluorodihydroxyphenylalanine positron emission tomography-computed tomography (18F-DOPA-PET/CT) in the management of NET. METHODS: 18F-DOPA-PET/CT findings in 61 patients with suspected NET were compared with a composite reference standard including somatostatin receptor scintigraphy (SRS), magnetic resonance imaging, computed tomography, histological examination and clinical follow-up. The impact on clinical management was estimated by calculating the proportion of patients whose treatment changed as a result of 18F-DOPA-PET/CT findings. RESULTS: 18F-DOPA-PET/CT correctly identified 32 of 36 patients with NET. The sensitivity and specificity of 18F-DOPA-PET/CT for the detection of NET were 91 and 96 per cent respectively. Sensitivity using SRS was significantly lower (59 per cent), whereas the specificity was similar (86 per cent). In 16 (26 per cent) of the 61 patients the management was altered as a result of new findings on 18F-DOPA-PET/CT. CONCLUSION: 18F-DOPA-PET/CT yields a high sensitivity and specificity in the detection of NET. The clinical impact was highly relevant as changes in therapy were observed in more than a quarter of the patients.

[Surgery for diabetes type 2?]. / Metabole Chirurgie: Kann der Diabetes mellitus Typ 2 chirurgisch behandelt werden?

Diabetes mellitus type 2 is a chronic disease with increasing prevalence in western society. Obesity represents a well established risk factor for the development of diabetes mellitus type 2. Several studies on surgical procedures for the treatment of obesity have shown a postoperative reduction of obesity-related co-morbidities. Thus, diabetes mellitus type 2 was shown to resolve or improve in more than 75% of morbidly obese patients (BMI >35) after bariatric surgery. These insights paved the way for the advent of metabolic surgery - a novel field with the goal to improve glucose metabolism in patients with a BMI of less than 35. Encouraging results from mostly observational studies have sparked the interest in the surgical management of diabetes mellitus type 2.

[Intrahepatic sarcoma of the follicular dendritic cells]. / Intrahepatisches Sarkom der follikulär-dendritischen Zellen.

We report an intrahepatic sarcoma of the follicular dendritic cells in a 76-year-old woman with a medical history of a hyaline-vascular type of Castleman's disease. We discuss the clinico-pathological findings, the pathogenesis and the differential diagnosis of this rare tumour entity.

Perioperative morbidity affects long-term survival in patients following liver resection for colorectal metastases.

BACKGROUND: Hepatic resection is the treatment of choice in patients with colorectal liver metastases. Perioperative morbidity is associated with decreased long-term survival in several cancers. The aim of this study was to assess the impact of perioperative morbidity and other prognostic factors on the outcome of patients undergoing liver resection for colorectal metastases. METHODS: One hundred ninety seven patients undergoing liver resection with curative intent were investigated. The influence of prognostic factors, such as complications, tumor stage, margins, age, sex, number of lesions, transfusion, portal inflow obstruction, and era and type of resection, was assessed using univariate and multivariate analysis. Complications were graded using an objective surgical complication classification. RESULTS: The 5-year survival rate was 38%, with a median follow up of 4.5 years. The disease-free survival rate at 5 years was 23%. The perioperative morbidity and mortality rates were 30 and 2.5%, respectively. The median survival of patients with perioperative complications was 3.2 years, compared to 4.4 years in those patients without complications (p < 0.01). For patients with positive resection margins, the median survival was 2.1 years, compared 4.4 years in patients with a margin (p = 0.019). CONCLUSION: Perioperative morbidity and a positive resection margin had a negative impact on long-term survival in patients following liver resection for colorectal metastases.

Lost intrauterine devices during pregnancy: maternal and fetal outcome after ultrasound-guided extraction. An analysis of 82 cases.

OBJECTIVES: It is generally agreed that intrauterine devices (IUDs) with visible strings in pregnancy should be removed because of the increased risk of miscarriage, septic complications and premature delivery. The precise management of pregnancies in association with so-called 'lost IUDs', and especially the technique of their removal, has remained controversial. We present our experience of the management of intrauterine pregnancies with a lost IUD. METHODS: Ultrasound-guided extraction of a lost IUD was performed in 82 intrauterine pregnancies. The subsequent outcome of the pregnancies is described. RESULTS: There were no intra- or post-procedure maternal complications. Although the miscarriage rate in the first 3 weeks after the procedure was higher than that in normal pregnancy, the complication rate approached that of normal pregnancy as the pregnancies progressed. The total miscarriage rate of 22% was comparable to that following extraction of IUDs with visible filaments. The rate of live births was 77.0%. Delivery before 37 weeks occurred in 13.5% of cases. CONCLUSIONS: Ultrasound-guided extraction is a minimally invasive and inexpensive procedure that is associated with few postoperative complications. It has a high success rate and is associated with a moderate miscarriage rate and no maternal complications.

[Practical aspects of breast ultrasound]. / Praktische Mamma-Sonographie.

Breast ultrasound has become an important part of senological investigation and is considered as the most important complementary method to mammography. The strengths of ultrasound are the evaluation of the juvenile radiodense breast, peripherical breast lesions and the evaluation of mammary cysts. After the general examination of the mammary gland and its surroundings, breast lesions are evaluated based on the following criteria: shape and border of the tumor, structural breaks, tumor protuberances and posterior shadowing or enhancement, compressibility and shifting. The sensitivity of breast ultrasound in finding breast cancer is around 90%, its specifity 80% are lower in small tumors. That's why ultrasound must be combined with clinical findings and other imaging like mammogaphy and MRI to find a reliable diagnosis. A histological work up is indicated if not all the methods show benign findings.

[Ultrasound in pregnancy--practical aspects]. / Praktische Untersuchungstechnik: Schwangerschaftsultraschall.

According to the payments agreement of the health insurance law two screening-scans at 10-13 weeks and 20-23 weeks respectively are part of the low-risk pregnancy care. The first-trimestre-scan includes the determination of the gestational age, the anatomical integrity of the fetus and the chorionicity in case of monochorionic twins. The 20-23 week scan has to evaluate the fetal growth, fetal abnormalities and the placental site. Doppler sonography is reserved for high risk pregnancies, especially for hypertensive disorders and fetal growth retardation, for the evaluation of fetal anemia in case of blood group alloimmunisation and for the detection of the twin-twin-transfusion syndrome in monochorionic twins.

[Diagnosis of uterine vascular malformation using Doppler ultrasound]. / Diagnostik uteriner Gefässfehlbildung mittels Dopplersonographie.

We present the case of a 56-year-old woman, who was admitted to our clinic for diagnostic laparoscopy because of a cystic uterine tumour of uncertain dignity. In the patient's history three curettages due to recurrent acyclic premenopausal vaginal bleeding were reported without specific histological findings. The preceding MRI described the structure as a myoma. During preoperative diagnostics an arteriovenous malformation was suspected by transvaginal Doppler sonography. Consequently the procedure was changed and a laparotomy performed. The sonographic findings were confirmed during surgery and by histological examination. This case points out the important role of transvaginal sonography combined with colour-flow-mapping. By confirming the diagnosis preoperatively and changing the management a low-risk procedure could be ensured.

Umbilical cord edema associated with patent urachus.

Umbilical cord anomalies can often be detected prenatally by ultrasound, but a definitive prenatal diagnosis is not always possible. We present a case with increasing edema of the Wharton's jelly followed by the development of pseudocysts in the proximal umbilical cord due to a patent urachus. The first abnormal findings were detected by ultrasound in the 14th week of gestation. Differential diagnoses and their influence on surveillance and birth management are discussed.

The bifunctional rat pancreatic secretory trypsin inhibitor/monitor peptide provides protection against premature activation of pancreatic juice.

BACKGROUND: In the rat, two forms of the pancreatic secretory trypsin inhibitor, PSTI-I and PSTI-II, are secreted into pancreatic juice. It is assumed that their role is to protect the pancreas from premature activation of the protease-rich pancreatic juice. In the small intestine, PSTI-I, also called 'monitor peptide', is thought to have a different role: PSTI-I competes with protein for activated trypsin. In the presence of a protein-rich meal, free PSTI induces a release of cholecystokinine from the intestine. METHODS: To investigate whether its role as monitor peptide is compatible with the inhibitory, protective function in the pancreas, PSTI-I was chemically synthesized and then renatured. RESULTS: The peptide was almost completely trypsin resistant and exhibited a dose-dependent inhibitory activity to bovine and partially purified rat trypsin. Furthermore, experiments with trypsin- and endopeptidase-activated pancreatic juice demonstrated that its inhibitory capacity was sufficient to prevent premature activation. Binding studies of (125)I-labeled PSTI-I with the putative intestinal receptor using isolated membranes indicated the presence of high-affinity binding sites (k(d) = 5 x 10(-8)M). Binding of PSTI-I could be competed with excess PSTI-I or trypsin. In a biological assay system, injections of PSTI-I displayed monitor peptide activity by inducing a dose-dependent trypsinogen release from the pancreas. CONCLUSION: Our experiments support a dual function of PSTI-I: monitoring protein in the gut due to its 'moderate' affinity for trypsin and a protective role in the pancreas.

Split hand and foot malformation: ultrasound detection in the first trimester.

The split hand split foot malformation is a rare disorder inherited in an autosomal dominant pattern with variable expression. In our case it was detected early by ultrasound in the twelfth week of gestation. To our knowledge, this is the earliest finding by ultrasound of this malformation. The sonographic findings were bilateral split hands and split foot. No other associated malformation was observed. The pathological findings were consistent with the diagnosis of split hand split foot malformation. Prenatal diagnosis, the genetic background, and the differential diagnosis are discussed.

Increased secretion of the pancreatic secretory trypsin inhibitor (PSTI-I, monitor peptide) during development of chronic pancreatitis in the WBN/Kob rat.

BACKGROUND: Recent genetic investigations into cationic trypsinogen and pancreatic secretory trypsin inhibitor (PSTI) led to the conclusion that mutations in either gene can contribute to the development of (hereditary) chronic pancreatitis. Since genetic animal models are not available yet, we have studied the Wistar-Bonn/Kobori (WBN/Kob) rat, a model for chronic pancreatitis (CP). To explore the possibility that PSTI may be secreted at lower levels or contain a mutation in the WBN/Kob rat, we investigated the masses of PSTI-I and -II and asked whether the ratio of PSTI/trypsinogen is decreased in animals with CP. METHODS: We collected pancreatic juice from WBN/Kob and Wistar rats aged 6-36 weeks and measured PSTI-I (ELISA) and trypsin. RESULTS: PSTI-I and -II were identified in Wistar and WBN/Kob rats by mass spectrometry and N-terminal sequencing. Using a newly developed PSTI-I ELISA, we can show that the PSTI-I/trypsinogen ratio is not decreased but rather increased in WBN/Kob rats compared to healthy Wistar rats. No evidence for a PSTI mutation was found. CONCLUSION: Our data does not support the hypothesis that a dysbalance of PSTI/trypsinogen ratio is a causative factor for CP.

Coordinate regulation of secretory stress proteins (PSP/reg, PAP I, PAP II, and PAP III) in the rat exocrine pancreas during experimental acute pancreatitis.

BACKGROUND: Pancreatic stone protein (PSP/reg) is a constitutively secreted protein in pancreatic juice. Pancreatitis-associated protein (PAP) belongs to the same family of proteins. PAP is highly increased during acute pancreatitis, while no exact data exist regarding PSP/reg protein synthesis and secretion. Recently, an attempt to determine PSP/reg and PAP levels in sera of rats with acute pancreatitis showed a significant increase in PAP but failed to demonstrate changes in PSP/reg. Others reported that surgical manipulation of the pancreas, including sham controls, affected mRNA levels of PSP/reg. Neither report determined protein levels of PSP/reg. METHODS: Rats were treated intraperitoneally with a supramaximal dose of caerulein to induce pancreatitis, a physiological dose of caerulein, or a saline injection. Pancreata were analyzed for PAP and PSP/reg using ELISAs. RNA was extracted for Northern blot analysis of PAP I, II, and III and PSP/reg mRNA. RESULTS: Experimental induction of acute pancreatitis caused a coordinate increase in both PSP/reg and PAP. PAP showed an acute response and returned to low levels within 48 h while PSP/reg exhibited a more sustained response. Intraperitoneal application of a physiological dose of caerulein and even a saline injection caused an increase in PSP/reg. CONCLUSION: PSP/reg and PAP levels are increased through similar mechanisms by physiological and supramaximal doses of caerulein. However, PSP/reg regulation appears to sustain high levels while PAP levels are more transient. Since the regulation of this protein family is affected even under mild stress, we define them as secretory stress proteins.

Ellis-van Creveld syndrome: a generalized dysplasia of enchondral ossification.

We report a 25-week fetus with lethal Ellis-van Creveld syndrome who was diagnosed prenatally from the US detection of a narrow chest, postaxial polydactyly of the hands, short acro-/mesomelic limbs and a ventricular septal defect. The postnatal radiographic features of the skeleton confirmed the diagnosis. Literature review of the histopathology of the physeal growth plate is contradictory, varying between retardation of the hypertrophic chondrocytes without disorganization and marked disorganization of the proliferating chondrocytes. We investigated numerous sites of the enchondral ossification and observed retardation of the physeal growth plate in all sites and retardation with pronounced disorganization of the physeal growth plate in the upper mesomelic bone segments only. These data support the concept that Ellis-van Creveld syndrome is mainly a generalized disorder of the maturation of enchondral ossification.

Conformational changes of pancreatitis-associated protein (PAP) activated by trypsin lead to insoluble protein aggregates.

Pancreatitis-associated protein (PAP), a secretory acute-phase protein of the pancreatic acinar cell, is highly up-regulated early in acute pancreatitis. PAP expression returns to undetectable levels when the pancreas recovers. In the rat, three isoforms of PAP are known, all of which are upregulated during acute pancreatitis. Their functions remain obscure. Pancreatic stone protein (PSP/reg), which shows strong sequence homology to PAP, is secreted into pancreatic juice under physiologic and pathologic conditions. PSP/reg is highly susceptible to trypsin cleavage at its ARG11-ILE12 bond. Cleavage results in an N-terminal undecapeptide and a C-terminal peptide called pancreatic thread protein (PTP). PTP forms oligomeric fibrillar structures, which spontaneously sediment in vitro. PTP can be found in protein plugs or stones from patients with chronic pancreatitis. Rat PAP contains a trypsin cleavage site at the same position as PSP/reg. We hypothesize that PAP is susceptible to tryptic cleavage, and that the C-terminal cleavage product of PAP spontaneously precipitates at neutral pH. To test our hypothesis, we generated and purified recombinant PAP. Here we report the production of rat PAP I, II, and III in a yeast expression system using Pichia pastoris. We demonstrate in vitro the tryptic cleavage of rat PAP and the formation of a spontaneously precipitating peptide, which we call pancreatitis-associated thread protein (PATP). PATP displays pH-dependent solubility characteristics very similar to those of PTP.

A family of 16-kDa pancreatic secretory stress proteins form highly organized fibrillar structures upon tryptic activation.

A group of 16-kDa proteins, synthesized and secreted by rat pancreatic acinar cells and composed of pancreatic stone protein (PSP/reg) and isoforms of pancreatitis-associated protein (PAP), show structural homologies, including conserved amino acid sequences, cysteine residues, and highly sensitive N-terminal trypsin cleavage sites, as well as conserved functional responses in conditions of pancreatic stress. Trypsin activation of recombinant stress proteins or counterparts contained in rat pancreatic juice (PSP/reg, PAP I and PAP III) resulted in conversion of 16-kDa soluble proteins into 14-kDa soluble isoforms (pancreatic thread protein and pancreatitis-associated thread protein, respectively) that rapidly polymerize into insoluble sedimenting structures. Activated thread proteins show long lived resistance to a wide spectrum of proteases contained in pancreatic juice, including serine proteases and metalloproteinases. In contrast, PAP II, following activation with trypsin or pancreatic juice, does not form insoluble structures and is rapidly digested by pancreatic proteases. Scanning and transmission electron microscopy indicate that activated thread proteins polymerize into highly organized fibrillar structures with helical configurations. Through bundling, branching, and extension processes, these fibrillar structures form dense matrices that span large topological surfaces. These findings suggest that PSP/reg and PAP I and III isoforms consist of a family of highly regulated soluble secretory stress proteins, which, upon trypsin activation, convert into a family of insoluble helical thread proteins. Dense extracellular matrices, composed of helical thread proteins organized into higher ordered matrix structures, may serve physiological functions within luminal compartments in the exocrine pancreas.