Maribavir for treatment of cytomegalovirus infection in a liver-transplanted patient.

Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for therapy-refractory CMV infection or when other treatment options cannot be used. The patient in this case report was a CMV-infected liver transplant recipient, who developed a severe erythema and high CMV DNA during valganciclovir therapy. Toxic epidermal necrolysis was suspected. The patient was treated with maribavir, and both CMV DNA and the skin normalised. This case illustrates that maribavir is a useful alternative to other antiviral drugs for CMV infection.

Prevalence of hyperthyroidism and hypothyroidism in liver transplant recipients and associated risk factors.

The prevalence of hyperthyroidism and hypothyroidism and associated risk factors are unknown in liver transplant recipients. We aimed to determine the prevalence of hyperthyroidism and hypothyroidism and associated risk factors in liver transplant recipients and to compare it with controls from the general population. As part of the Danish Comorbidity in Liver Transplant Recipients (DACOLT) Study, all Danish liver transplant recipients over the age of 20 were invited for measurements of concentrations of thyrotropin and thyroid hormones. The prevalence of hyperthyroidism and hypothyroidism was compared to age- and sex-matched controls from the Copenhagen General Population Study. Using logistic regression adjusted for age, sex, smoking, and body-mass index, we investigated potential risk factors. We recruited 489 liver transplant recipients and 1808 controls. Among liver transplant recipients, 14 (2.9%) had hyperthyroidism compared with 21 (1.2%) of controls (adjusted odds ratio [aOR] 2.24, 95% confidence interval [CI] 1.05-4.75, P = 0.04), while 42 (5.7%) had hypothyroidism compared with 139 (7.7%) of controls (aOR 0.68, 95% CI 0.43-1.08, P = 0.10). Female sex, and autoimmune hepatitis and primary sclerosing cholangitis as causes of transplantation were associated with hyperthyroidism after adjustments. Age, female sex, and autoimmune liver diseases as cause of transplantation were associated with hypothyroidism after adjustments. DACOLT is registered in ClinicalTrials.gov (NCT04777032).

Perioperative factors associated with survival following surgery for pancreatic cancer - a nationwide analysis of 473 cases from Denmark.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers worldwide, with an overall 5-year survival rate of only 5%. The effect of perioperative treatment factors including duration of surgery, blood transfusions as well as choice of anesthesia and analgesia techniques on overall survival (OS) following pancreatic resections for PDAC, is currently not well known. We hypothesized that these perioperative factors might be associated with OS after pancreatic resections for PDAC. METHODS: This is a retrospective study from a nationwide cohort of patients who underwent surgery for PDAC in Denmark from 2011 to 2020. Kaplan-Meier 1, 2 and 5-year survival estimates were 73%, 49% and 22%, respectively. Data were obtained by joining the national Danish Pancreatic Cancer Database (DPCD) and the Danish Anaesthesia Database (DAD). Associations between the primary endpoint (OS) and perioperative factors including duration of surgery, type of anesthesia (intravenous, inhalation or mixed), use of epidural analgesia and perioperative blood transfusions were assessed using Hazard Ratios (HRs). These were calculated by Cox regression, controlling for relevant confounders identified through an assessment of the current literature. These included demographics, comorbidities, perioperative information, pre and postoperative chemotherapy, tumor staging and free resection margins. RESULTS: Overall, data from 473 resected PDAC patients were available. Multivariate Cox regression indicated that perioperative blood transfusions were associated with shorter OS (HR 2.53, p = 0.005), with survival estimates of 8.8% in transfused vs. 28.0% in non-transfused patients at 72 months after surgery. No statistically significant associations were identified for the duration of surgery or anesthesia/analgesia techniques. CONCLUSION: In this study, the use of perioperative blood transfusions was associated with shorter OS.

Impact of para aortic lymph node removal on survival following resection for pancreatic adenocarcinoma.

INTRODUCTION: For PDAC patients undergoing resection, it remains unclear whether metastases to the paraaortic lymph nodes (PALN+) have any prognostic significance and whether metastases should lead to the operation not being carried out. Our hypothesis is that PALN + status would be associated with short overall survival (OS) compared with PALN-, but longer OS compared with patients undergoing surgical exploration only (EXP). METHODS: Patients with registered PALN removal from the nationwide Danish Pancreatic Cancer Database (DPCD) from May 1st 2011 to December 31st 2020 were assessed. A cohort of PDAC patients who only had explorative laparotomy due to non-resectable tumors were also included (EXP group). Survival analysis between groups were performed with cox-regression in a multivariate approach including relevant confounders. RESULTS: A total of 1758 patients were assessed, including 424 (24.1%) patients who only underwent explorative surgery leaving 1334 (75.8%) patients for further assessment. Of these 158 patients (11.8%) had selective PALN removal, of whom 19 patients (12.0%) had PALN+. Survival analyses indicated that explorative surgery was associated with significantly shorter OS compared with resection and PALN + status (Hazard Ratio 2.36, p < 0.001). No difference between PALN + and PALN- status could be demonstrated in resected patients after controlling for confounders. CONCLUSION: PALN + status in patients undergoing resection offer improved survival compared with EXP. PALN + should not be seen as a contraindication for curative intended resection.

Robotic Distal Pancreatectomy: A Novel Standard of Care? Benchmark Values for Surgical Outcomes From 16 International Expert Centers.

BACKGROUND AND OBJECTIVE: Robotic distal pancreatectomy (DP) is an emerging attractive approach, but its role compared with laparoscopic or open surgery remains unclear. Benchmark values are novel and objective tools for such comparisons. The aim of this study was to identify benchmark cutoffs for many outcome parameters for DP with or without splenectomy beyond the learning curve. METHODS: This study analyzed outcomes from international expert centers from patients undergoing robotic DP for malignant or benign lesions. After excluding the first 10 cases in each center to reduce the effect of the learning curve, consecutive patients were included from the start of robotic DP up to June 2020. Benchmark patients had no significant comorbidities. Benchmark cutoff values were derived from the 75th or the 25th percentile of the median values of all benchmark centers. Benchmark values were compared with a laparoscopic control group from 4 high-volume centers and published open DP landmark series. RESULTS: Sixteen centers contributed 755 cases, whereof 345 benchmark patients (46%) were included the analysis. Benchmark cutoffs included: operation time ≤300 minutes, conversion rate ≤3%, clinically relevant postoperative pancreatic fistula ≤32%, 3 months major complication rate ≤26.7%, and lymph node retrieval ≥9. The comprehensive complication index at 3 months was ≤8.7 without deterioration thereafter. Compared with robotic DP, laparoscopy had significantly higher conversion rates (5×) and overall complications, while open DP was associated with more blood loss and longer hospital stay. CONCLUSION: This first benchmark study demonstrates that robotic DP provides superior postoperative outcomes compared with laparoscopic and open DP. Robotic DP may be expected to become the approach of choice in minimally invasive DP.

Relieving the bile ducts prior to pancreatoduodenectomy - A retrospective cohort study.

Introduction: Obstructive jaundice is a common problem in pancreatic and periampullary tumors, but preoperative biliary drainage in patients with hyperbilirubinemia is still controversial. This study aimed to assess the risk of complications after preoperative drainage of biliary obstruction in patients who underwent pancreaticoduodenectomy. Method: A retrospective cohort study of all patients who underwent pancreaticoduodenectomy from January 1st, 2015 to September 30th, 2021. Patients who had preoperative bile duct drainage were compared to patients without intervention. Type of interventions, complications, and outcomes after surgery were compared using univariate and multivariate analysis. Results: Of 722 patients who underwent pancreatoduodenectomy, 389 patients had preoperative drainage of the bile ducts by ERC or PTC. There was an incidence of 27% drainage-related complications, all categorized as minor (Clavien-Dindo <3) and mainly related to PTC-aided drainage. After pancreaticoduodenectomy, 23% of patients who had a preoperative biliary drain, had minor complications. Patients without biliary drainage had a higher risk of a complicated postoperative course (p = 0.001) and had a higher 30-day (p = 0.002) and 90-day mortality (p = 0.025). Conclusion: Our study found preoperative bile duct drainage to be a safe procedure without severe complications. Patients undergoing preoperative bile duct drainage had fewer post-pancreatoduodenectomy complications and lower mortality.

Trends in underlying causes of death in solid organ transplant recipients between 2010 and 2020: Using the CLASS method for determining specific causes of death.

Monitoring specific underlying causes of death in solid organ transplant (SOT) recipients is important in order to identify emerging trends and health challenges. This retrospective cohort study includes all SOT recipients transplanted at Rigshospitalet between January 1st, 2010 and December 31st, 2019. The underlying cause of death was determined using the newly developed Classification of Death Causes after Transplantation (CLASS) method. Cox regression analyses assessed risk factors for all-cause and cause-specific mortality. Of the 1774 SOT recipients included, 299 patients died during a total of 7511 person-years of follow-up (PYFU) with cancer (N = 57, 19%), graft rejection (N = 55, 18%) and infections (N = 52, 17%) being the most frequent causes of death. We observed a lower risk of all-cause death with increasing transplant calendar year (HR 0.91, 95% CI 0.86-0.96 per 1-year increase), alongside death from graft rejection (HR 0.84 per year, 95% CI 0.74-0.95) and death from infections (HR 0.86 per year, 95% CI 0.77-0.97). Further, there was a trend towards lower cumulative incidence of death from cardiovascular disease, graft failure and cancer in more recent years, while death from other organ specific and non-organ specific causes did not decrease. All-cause mortality among SOT recipients has decreased over the past decade, mainly due to a decrease in graft rejection- and infection-related deaths. Conversely, deaths from a broad range of other causes have remained unchanged, suggesting that cause of death among SOT recipients is increasingly diverse and warrants a multidisciplinary effort and attention in the future.

Pancreatic surgery during the COVID-19 pandemic 2020-2021: an observational cohort study from a third level referral center.

BACKGROUND: During the COVID pandemic there has been limited access to elective surgery including oncologic surgery in several countries world-wide. The aim of this study was to investigate if there was any lockdown effect on pancreatic surgery with special focus on malignant pancreatic and periampullary tumours. METHODS: Patients who underwent pancreatic surgery during the two Danish lockdown periods from 11. March 2020 and the following 12 months were compared with patients who were operated the preceding 3 years. Data on patients' characteristics, waiting time, operations, and clinical outcomes were evaluated. RESULTS: During lockdown and the previous three years the annual number of resections were 242, 232, 253, and 254, respectively (p = 0.851). Although the numbers were not significantly different, there were fluctuations in operations and waiting time during the lockdown. During the second outbreak of COVID October 2020 to March 2021 the overall median waiting time increased to 33 days (quartiles 26;39) compared to 23 (17;33) days during the first outbreak from March to May 2020 (p = 0.019). The same difference was seen for patients with malignant tumours, 30 (23;36) vs. 22 (18;30) months (p = 0.001). However, the fluctuations and waiting time during lockdown was like the preceding three years. Neither 30- nor 90-days mortality, length of stay, number of extended operations, and complications and tumour stage were significantly different from previous years. CONCLUSIONS: There were significant fluctuations in waiting time for operations during the lockdown, but these variations were not different from the preceding three years, wherefore other explanations than an impact from COVID are conceivable.

Long-Term Outcomes of Venous Resections in Pancreatic Ductal Adenocarcinoma Patients: A Nationwide Cohort Study.

To investigate whether pancreatic resections (PR) for pancreatic ductal adenocarcinoma (PDAC) is associated with worse survival when resection of the superior mesenteric vein/portal vein (SMV/PV) is required. Background: PR for PDAC with resection of the superior mesenteric vein/portal vein (SMV/PV, PR+V resection) may be associated with inferior overall survival (OS) compared with PR without the need for SMV/PV resection (PR-V). We hypothesized that PR+V results in lower OS compared with PR-V. Method: Retrospective study using data from the nationwide Danish Pancreatic Cancer Database from 2011 to 2020. Data on patients who underwent PR for PDAC were extracted. A group of PR patients found nonresectable on exploratory laparotomy (EXP) was also included. OS was assessed using Kaplan-Meier and Cox proportional hazards models adjusting for confounders (age, sex, R-resection level, chemotherapy, comorbidities, histology T and N classification, procedure subtype as well as tumor distance to the SMV/PV). Results: Overall, 2403 patients were identified. Six hundred two underwent exploration only (EXP group), whereas 412 underwent pancreatic resection with (PR+V group) and 1389 (PR-V) without SMV/PV resection. Five-year OS for the PR+V group was lower (20% vs 30%) compared with PR-V, although multivariate Cox proportional hazards modeling could not associate PR+V status with OS (Hazard ratio 1.11, P = 0.408). Conclusion: When correcting for confounders, PR+V was not associated with lower OS compared with PR-V.

The Danish comorbidity in liver transplant recipients study (DACOLT): a non-interventional prospective observational cohort study.

BACKGROUND: Liver transplantation is the only curative treatment for patients with end-stage liver disease. Short-term survival has improved due to improved surgical techniques and greater efficacy of immunosuppressive drugs. However, long-term survival has not improved to the same extent as the short-term survival, and the 10-year survival after liver transplantation is 60%. In addition to liver- and transplant-related causes, comorbidities such as cardiovascular, pulmonary, renal, and metabolic diseases have emerged as leading causes of morbidity and mortality in liver transplant recipients. The objective of this study is to assess the burden of comorbidities and identify both liver- and transplant-related risk factors as well as traditional risk factors that contribute to the pathogenesis of comorbidity in liver transplant recipients. METHODS/DESIGN: The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study is an observational, longitudinal study. We aim to include all adult liver transplant recipients in Denmark (n = approx. 600). Participants will be matched by sex and age to controls from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). Physical and biological measures including blood pressure, ankle-brachial index, spirometry, exhaled nitric oxide, electrocardiogram, transthoracic echocardiography, computed tomography (CT) angiography of the heart, unenhanced CT of chest and abdomen and blood samples will be collected using uniform protocols in participants in DACOLT, CGPS, and CCHS. Blood samples will be collected and stored in a research biobank. Follow-up examinations at regular intervals up to 10 years of follow-up are planned. DISCUSSION: There is no international consensus standard for optimal clinical care or monitoring of liver transplant recipients. This study will determine prevalence, incidence and risk factors for comorbidity in liver transplant recipients and may be used to provide evidence for guidelines on management, treatment and screening and thereby contribute to improvement of the long-term survival. Trial registration ClinicalTrials.gov: NCT04777032; date of registration: March 02, 2021.

Model for end-stage liver disease score predicts complications after liver transplantation.

PURPOSE: Increased model for end-stage liver disease (MELD) score measured in the early postoperative course is associated with one-year mortality and graft loss. However, the correlation with postoperative complications has not been investigated. The aim of this study was to investigate the association between postoperative MELD score and subsequent complications. METHODS: Adult liver transplant recipients transplanted from January 2011 until December 2016 were included. MELD score days 1-5 were correlated with complications day 6-30, subdivided into type and severity according to Clavien-Dindo classification. RESULTS: We included 246 adult liver transplant recipients. Between days 6 and 30, 671 complications occurred in 201 of the patients (82%) corresponding to 64% of all postoperative complications in the whole postoperative period (days 0-30). In multivariate analyses adjusted for recipient gender and age, preoperative MELD score, and Eurotransplant Donor Risk Index, postoperative MELD score was significantly associated with having one or more complications, any type of complication except cardiovascular and renal complications, and complication severity. CONCLUSIONS: Postoperative MELD score days 1-5 were associated with complications arising in the subsequent period 6-30 days after transplantation. An increased MELD score should heighten the clinician's awareness of a possible complication.

Classification of death causes after transplantation (CLASS): Evaluation of methodology and initial results.

Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 [51%] SOT and 192 [49%] HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8-48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry.

Clinical evaluation of synthetic aperture harmonic imaging for scanning focal malignant liver lesions.

The purpose of the study was to perform a clinical comparison of synthetic aperture sequential beamforming tissue harmonic imaging (SASB-THI) sequences with a conventional imaging technique, dynamic receive focusing with THI (DRF-THI). Both techniques used pulse inversion and were recorded interleaved using a commercial ultrasound system (UltraView 800, BK Medical, Herlev, Denmark). Thirty-one patients with malignant focal liver lesions (confirmed by biopsy or computed tomography/magnetic resonance) were scanned. Detection of malignant focal liver lesions and preference of image quality were evaluated blinded off-line by eight radiologists. In total, 2,032 evaluations of 127 image sequences were completed. The sensitivity (77% SASB-THI, 76% DRF-THI, p = 0.54) and specificity (71% SASB-THI, 72% DRF-THI, p = 0.67) of detection of liver lesions and the evaluation of image quality (p = 0.63) did not differ between SASB-THI and DRF-THI. This study indicates the ability of SASB-THI in a true clinical setting.

Clinical evaluation of synthetic aperture sequential beamforming ultrasound in patients with liver tumors.

Medical ultrasound imaging using synthetic aperture sequential beamforming (SASB) has for the first time been used for clinical patient scanning. Nineteen patients with cancer of the liver (hepatocellular carcinoma or colorectal liver metastases) were scanned simultaneously with conventional ultrasound and SASB using a commercial ultrasound scanner and abdominal transducer. SASB allows implementation of the synthetic aperture technique on systems with restricted data handling capabilities due to a reduction in the data rate in the scanner by a factor of 64. The image quality is potentially maintained despite the data reduction. A total of 117 sequences were recorded and evaluated blinded by five radiologists from a clinical perspective. Forty-eight percent of the evaluations were in favor of SASB, 33% in favor of conventional ultrasound and 19 % were equal, that is, a clear, but non-significant trend favoring SASB over conventional ultrasound (p = 0.18), despite the substantial data reduction.

[Mesenteric traction syndrome]. / Mesenterielt traktionssyndrom.

Mesenteric traction syndrome (MTS) manifests in 58-87% of patients undergoing upper abdominal surgery and is characterised by a triad of hypotension, tachycardia, and flushing. Prostacyclin is released from the gut mucosa following intestinal eventration and cyclooxygenase antagonists prevent the development of MTS. Also the use of remifentanil appears to increase the incidence of MTS and hypotension is aggravated by epidural analgesia. Yet, prostacyclin may be important for maintaining microcirculation within the splanchnic area and preserve its mucosal barrier.