Value of routine intraoperative frozen sections of proximal bile duct margins in perihilar cholangiocarcinoma, a retrospective multicenter and matched case-control study.

BACKGROUND: Currently, the potential benefits of additional resection after positive proximal intraoperative frozen sections (IFS) in perihilar cholangiocarcinoma (pCCA) on residual disease and oncological outcome remain uncertain. Therefore, the aim of this study is to investigate the number of R0 resections after additional resection of a positive proximal IFS and the influence of additional resections on overall survival (OS) in patients with pCCA. MATERIALS AND METHODS: A retrospective, multicenter, matched case-control study was performed, including patients undergoing resection for pCCA between 2000 and 2019 at three tertiary centers. Primary outcome was the number of achieved 'additional' R0 resections. Secondary outcomes were OS, recurrence, severe morbidity and mortality. RESULTS: Forty-four out of 328 patients undergoing resection for pCCA had a positive proximal IFS. An additional resection was performed in 35 out of 44 (79.5%) patients, which was negative in 24 (68.6%) patients. Nevertheless, seven out of these 24 patients were eventually classified as R1 resection due to other positive resection margins. Therefore, 17 (48.6%) patients could be classified as "true" R0 resection after additional resection. Ninety-day mortality after R1 resections was high (25%) and strongly influenced OS. After correction for 90-day mortality, median OS after negative additional resection was 33 months (95%CI:29.5-36.5) compared to 30 months (95%CI:24.4-35.6) after initial R1 (P = 0.875) and 46 months (95%CI:32.7-59.3) after initial R0 (P = 0.348). CONCLUSION: There were only 17 patients (out of a total of 328 patients) that potentially benefitted from routine IFS. Additional resection for a positive IFS leading to R0 resection was not associated with improved long-term survival.

Expression of integrin ανß6 differentiates perihilar cholangiocarcinoma (PHC) from benign disease mimicking PHC.

BACKGROUND: Approximately 15% of patients undergoing resection for presumed perihilar cholangiocarcinoma (PHC) have benign disease at final pathological assessment. Molecular imaging targeting tumor-specific biomarkers could serve as a novel diagnostic tool to reduce these futile surgeries. Imaging agents have been developed, selectively binding integrin ανß6, a cell receptor upregulated in pancreatobiliary malignancies, for both (preoperative) PET and (intraoperative) fluorescent imaging. Here, expression of integrin ανß6 is evaluated in PHC, intrahepatic cholangiocarcinoma (ICC), hepatocellular carcinoma (HCC) and benign disease mimicking PHC using immunohistochemistry. MATERIALS & METHODS: Three tissue microarrays (TMA) including 103 PHC tumor cores and sixty tissue samples were selected from resection specimens of pathologically proven PHC (n = 20), ICC (n = 10), HCC (n = 10), metastatic PHC lymph nodes (n = 10) and benign disease (presumed PHC with benign disease at pathological assessment, n = 10). These samples were stained for integrin ανß6 and quantified using the H-score. RESULTS: Immunohistochemical staining for integrin ανß6 showed membranous expression in all twenty PHC whole mount slides (100%) and 93 out of 103 (92%) PHC tumor cores. Mean H-score of PHC samples was 195 ± 71, compared to a mean H-score of 126 ± 57 in benign samples (p = 0.013). In both benign and PHC samples, inflammatory infiltrates and pre-existent peribiliary glands showed integrin ανß6 expression. The mean H-score across ten ICC was 33 ± 53, which was significantly lower compared to PHC (p < 0.001) but too weak to consistently discriminate ICC from HCC (H-score 0)(p = 0.062). CONCLUSION: Integrin ανß6 is abundantly expressed in PHC and associated metastatic lymph nodes. Expression is significantly higher in PHC as compared to benign disease mimicking PHC, ICC and HCC, emphasizing its potential as a target for tumor-specific molecular imaging.

Molecular targets for diagnostic and intraoperative imaging of pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX treatment.

Neoadjuvant systemic treatment is increasingly being integrated in the standard treatment of pancreatic ductal adenocarcinoma (PDAC) patients to improve oncological outcomes. Current available imaging techniques remain unreliable in assessing response to therapies, as they cannot distinguish between (vital) tumor tissue and therapy induced fibrosis (TIF). Consequently, resections with tumor positive margins and subsequent early post-operative recurrences occur and patients eligible for potential radical resection could be missed. To optimize patient selection and monitor results of neoadjuvant treatment, PDAC-specific diagnostic and intraoperative molecular imaging methods are required. This study aims to evaluate molecular imaging targets for PDAC after neoadjuvant FOLFIRINOX treatment. Expression of integrin αvß6, carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5), mesothelin, prostate-specific membrane antigen (PSMA), urokinase-type plasminogen activator receptor, fibroblast activating receptor, integrin α5 subunit and epidermal growth factor receptor was evaluated using immunohistochemistry. Immunoreactivity was determined using the semiquantitative H-score. Resection specimens from patients after neoadjuvant FOLFIRINOX treatment containing PDAC (n = 32), tumor associated pancreatitis (TAP) and TIF (n = 15), normal pancreas parenchyma (NPP) (n = 32) and tumor positive (n = 24) and negative (n = 56) lymph nodes were included. Integrin αvß6, CEACAM5, mesothelin and PSMA stainings showed significantly higher expression in PDAC compared to TAP and NPP. No expression of αvß6, CEACAM5 and mesothelin was observed in TIF. Integrin αvß6 and CEACAM5 allow for accurate metastatic lymph node detection. Targeting integrin αvß6, CEA, mesothelin and PSMA has the potential to distinguish vital PDAC from fibrotic tissue after neoadjuvant FOLFIRINOX treatment. Integrin αvß6 and CEACAM5 detect primary tumors and tumor positive lymph nodes.

Effect of structured use of preoperative portal vein embolization on outcomes after liver resection of perihilar cholangiocarcinoma.

BACKGROUND: Portal vein embolization (PVE) is performed to reduce the risk of liver failure and subsequent mortality after major liver resection. Although a cut-off value of 2·7 per cent per min per m2 has been used with hepatobiliary scintigraphy (HBS) for future remnant liver function (FRLF), patients with perihilar cholangiocarcinoma (PHC) potentially benefit from an additional cut-off of 8·5 per cent/min (not corrected for body surface area). Since January 2016 a more liberal approach to PVE has been adopted, including this additional cut-off for HBS of 8·5 per cent/min. The aim of this study was to assess the effect of this approach on liver failure and mortality. METHODS: This was a single-centre retrospective study in which consecutive patients undergoing liver resection under suspicion of PHC in 2000-2015 were compared with patients treated in 2016-2019, after implementation of the more liberal approach. Primary outcomes were postoperative liver failure (International Study Group of Liver Surgery grade B/C) and 90-day mortality. RESULTS: Some 191 patients with PHC underwent liver resection. PVE was performed in 6·4 per cent (9 of 141) of the patients treated in 2000-2015 and in 32 per cent (16 of 50) of those treated in 2016-2019. The 90-day mortality rate decreased from 16·3 per cent (23 of 141) to 2 per cent (1 of 50) (P = 0·009), together with a decrease in the rate of liver failure from 19·9 per cent (28 of 141) to 4 per cent (2 of 50) (P = 0·008). In 2016-2019, 24 patients had a FRLF greater than 8·5 per cent/min and no liver failure or death occurred, suggesting that 8·5 per cent/min is a reliable cut-off for patients with suspected PHC. CONCLUSION: The major decrease in liver failure and mortality rates in recent years and the simultaneous increased use of PVE suggests an important role for PVE in reducing adverse outcomes after surgery for PHC.

ANTECEDENTES: La embolización de la vena porta (portal vein embolization, PVE) se realiza para reducir el riesgo de insuficiencia hepática y de mortalidad asociada después de una resección hepática mayor. Aunque con la gammagrafía hepato-biliar (hepato-biliary scintigraphy, HBS) se ha utilizado un punto de corte de 2,7%/min/m2 para la función hepática remanente futura (future remnant liver function, FRLF), los pacientes con colangiocarcinoma perihilar (perihilar cholangiocarcinoma, PHC) se beneficiarían potencialmente de un punto de corte adicional de 8,5%/min (no corregido para el área de superficie corporal). Desde enero de 2016, se adoptó un enfoque más liberal para la PVE, incluyendo este punto de corte adicional para la HBS de 8,5%/min. El objetivo de este estudio fue evaluar el efecto de este enfoque sobre la insuficiencia hepática y la mortalidad. MÉTODOS: Se trata de un estudio retrospectivo de un solo centro, en el que los pacientes consecutivos sometidos a resección hepática por sospecha de PHC entre 2000-2016 se compararon con los pacientes tratados entre 2016-2019, después de la implementación de un enfoque más liberal. Los objetivos primarios fueron la insuficiencia hepática postoperatoria (ISGLS grado B/C) y la mortalidad a los 90 días. RESULTADOS: Un total de 191 pacientes con PHC se sometieron a resección hepática. Se realizó PVE en el 6% (9/141) de los pacientes antes de 2016 y en el 32% (16/50) de los pacientes después de 2016. La mortalidad disminuyó del 16% (23/141) al 2% (1/50) (P = 0,009), junto con una disminución de la insuficiencia hepática del 20% (28/141) al 4% (2/50) (P = 0,008). Después de 2016, 20 pacientes tuvieron un FRLF > 8,5%/min y no se produjo insuficiencia hepática o mortalidad, lo que sugiere que el 8,5%/min es un punto de corte fiable para los pacientes con sospecha de PHC. CONCLUSIÓN: La disminución marcada de la insuficiencia hepática y de la mortalidad en los últimos años y el aumento simultáneo del uso de la PVE, sugiere que la PVE ha jugado un importante papel en el descenso de los resultados adversos después de la cirugía para el PHC.

Minimally invasive surgery for perihilar cholangiocarcinoma: a systematic review.

Minimally invasive surgery (MIS) is quickly becoming mainstream in hepato-pancreato-biliary surgery because of presumed advantages. Surgery for perihilar cholangiocarcinoma (PHC) is highly demanding which may hamper the feasibility and safety of MIS in this setting. This study aimed to systematically review the existing literature on MIS for PHC. A systematic literature review was performed according to the PRISMA statement. The PubMed and EMBASE databases were searched and all studies describing MIS in patients with PHC were included. Data extraction and risk of bias were assessed by two independent researchers. Overall, 21 studies reporting on a total of 142 MIS procedures for PHC were included. These included 82 laparoscopic, 59 robot-assisted and 1 hybrid procedure(s). Risk of bias was deemed substantial. Pooled conversion rate was 7/142 (4.9%), pooled morbidity 30/126 (23.8%), and pooled mortality rate 4/126 (3.2%). The only comparative study, comparing 10 robot-assisted procedures to 32 open procedures, reported a significant increased operative time and higher morbidity rate with MIS. The available evidence on MIS for PHC is limited and generally of poor quality. This systematic review shows that the implementation of MIS for patients with PHC is still in its infancy.

[Periacetabular osteotomy-what influence does age have on patient-relevant results? : A prospective 5­year investigation]. / Periazetabuläre Osteotomie ­ Welchen Einfluss hat das Alter auf patientenrelevante Ergebnisse? : Eine prospektive 5­Jahres-Untersuchung.

INTRODUCTION: Periacetabular osteotomy (PAO) is an effective procedure in treatment of symptomatic hip dysplasia. To achieve a good outcome a strict patient selection has to be applied. The aim of this study was to evaluate the influence of patient age at surgery on clinical outcome. METHODS: In a prospective study 86 patients (106 hips) underwent clinical and radiographic follow-up at a mean time of 5 years (2.5-8.5 years) after PAO. Patient-related outcome measurements (PROMs: EQ-5D, WOMAC, OHS, GTO) were applied preoperatively as well as postoperatively and the deformity correction as well as development of osteoarthritis were evaluated. In order to analyze the influence of patient age at surgery on clinical outcome, we subdivided the patient cohort into four different age groups (<20 years, 20-29 years, 30-39 years, >40 years). RESULTS: Of the patients 90% were very satisfied or satisfied with the results 5 years after surgery, and in all age groups PROMs significantly increased. Even though preoperative as well as postoperative algofunction declined in cohorts with increasing age, the overall benefit as measured in WOMAC and EQ-5D scores was equal in all age groups. Increasing age is associated with a progression in osteoarthritis as well as a higher conversion rate to total arthroplasty. DISCUSSION: Age is an important influencing factor on the long-term outcome after PAO. A certain age as cut off for indications could not be identified in this study. Even patients in the age groups 30-39 years and > 40 years showed PROM improvement and satisfaction with outcome at medium-term follow-up. The expected success rate has to be discussed preoperatively with the patient; however, as a higher conversion rate to hip arthroplasty as well as progressive osteoarthritis is associated with higher age, not only patient age alone but also morphological characteristics of the hip joint have to be taken into consideration.

Population pharmacokinetics of haloperidol in terminally ill adult patients.

PURPOSE: Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen. METHODS: Using non-linear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 87 samples from 28 terminally ill patients who received haloperidol either orally or subcutaneously. The covariates analysed were patient and disease characteristics as well as co-medication. RESULTS: The data were accurately described by a one-compartment model. The population mean estimates for oral bioavailability, clearance and volume of distribution for an average patient were 0.86 (IIV 55%), 29.3 L/h (IIV 43%) and 1260 L (IIV 70%), respectively. This resulted in an average terminal half-life of haloperidol of around 30 h. CONCLUSION: Our study showed that the pharmacokinetics of haloperidol could be adequately described by a one-compartment model. The pharmacokinetics in terminally ill patients was comparable to other patients. We were not able to explain the wide variability using covariates.

Pharmacokinetics of Polymersomes Composed of Poly(Butadiene-Ethylene Oxide); Healthy versus Tumor-Bearing Mice.

Vesicles composed of block copolymers (i.e., polymersomes) are one of the most versatile nano-carriers for medical purposes due to their tuneable physicochemical properties and the possibility to encapsulate simultaneously hydrophobic and hydrophilic substances, allowing, for instance, the combination of therapy and imaging. In cancer treatment, these vesicles need to remain long enough in the blood stream to be sufficiently taken up by tumors. Here, we have investigated the biodistribution and the pharmacokinetics of polymersomes, composed of poly(butadiene-b-ethylene oxide) having dimensions around 80 nm. The polymersomes have been radiolabeled with ¹¹¹In via the so-called active loading method achieving a loading efficiency of 92.9 ± 0.9% with radionuclide retention in mouse serum of more than 95% at 24 h. The optimized ¹¹¹In containing polymersomes have been intravenously administered in healthy and tumor bearing mice for pharmacokinetic determination using microSPECT (Single Photon Emission Computed Tomography). In healthy mice these polymersomes have been found to exhibit relatively long blood circulation (> 6 h), low liver uptake (6 ± 1.5%ID/g, 48 h p.i.) and elevated spleen uptake (188 ± 30%ID/g). The blood circulation in tumor bearing mice is dramatically reduced (< 1.5 h) most likely due to elevated splenic filtration, clearly indicating the importance of in vivo studies in diseased mice. Finally, the polymersomes have been injected subcutaneously in tumor bearing mice revealing retention of 77% in the mice, primarily accumulated at the site of injection, up to 48 hours after administration.

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol.

INTRODUCTION: A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. AREAS COVERED: This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). EXPERT OPINION: The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

A design for a picture archiving communication system central storage facility.

A Picture Archive and Communication System (PACS) as it is to be used in a Hospital will consist of a number of workstations, data acquisition stations and output stations, connected to a central storage facility. In this paper the architecture of the central storage facility is studied, and an implementation is proposed. Simulation studies have been performed on the proposed implementations, showing their feasibility. The simulation studies show that the central storage facility can store over 500 sets on a daily basis, while simultaneously handling the review and output activity associated with such a production. On the average, each set is assumed to consist of 3 images of 4 Mbyte each. Simulation results are presented for a number of alternative systems. Special attention is given to the implications of prefetching on the protocols to be used in the PACS system. It is shown that prefetching, in particular in combination with a pipelined system, can yield significant performance benefits. We believe that prefetching of images is a prerequisite for good system performance. The implementation assumes that a high-speed communication protocol is used to interconnect the PACS components. The paper will not go into details on the network considerations. The central storage facility is designed using a general purpose System/370 machine, with the peripherals commonly used for such machines. This implies that it can be realized with currently available equipment. Several alternative implementations using interconnected workstation based systems are suggested.

Central nervous system complications of Mycoplasma pneumoniae.

Three cases of central nervous system complications of Mycoplasma pneumoniae infections are reported. There were several atypical findings: the first patient presented with an acute disseminated encephalitis with normal cerebrospinal fluid and hypogammaglobulinaemia. The second patient presented with a left sixth nerve palsy followed six weeks later by choreoathetoid movements and an acute psychosis. The third patient presented with an acute encephalitis associated with acute renal failure secondary to rhabdomyolysis and was the only patient who did not completely recover; he was discharged akinetic and mute, but with normal renal function. The diagnosis of complications of Mycoplasma pneumoniae may be difficult. In two of the three cases a raised red blood cell volume secondary to a high titre of cold agglutinins rapidly led to the correct diagnosis.

Traumatic asphyxia: an unusual cause of traumatic coma and paraplegia. Case report.

An unusual case of traumatic asphyxia with cerebral and spinal cord symptoms is presented. A survey of the literature indicates that a primary cord lesion is very rare as a consequence of such a trauma. The possible pathogenetic mechanisms of these neurological manifestations are discussed.

Morel's laminar sclerosis.

A 49-year-old alcoholic woman was admitted for convulsions. She died after a 4-week clinical course characterized by a persistent coma with diffuse muscular hypertonia. Post-mortem examination of the brain demonstrated a spongy degeneration and gliosis of the cerebral cortex, limited to the 3rd and the 4th layers. No other pathological lesion of the central nervous system could be objectivated. This is the first reported case in which Morel's laminar sclerosis was the only manifestation of 'alcoholic encephalopathy'. Morel's syndrome should be considered as a pathological entity separate from the Marchiafava-Bignami disease.

Myopathy caused by polymyxin E: functional disorder of the cell membrane.

A myopathy caused by the activity of polymyxin E on the cell membrane was accompained by immunological manifestations. There were also disturbances of the central nervous system, contrasting with the absence of serious renal lesion.