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Background: Electrolyte disturbances and dehydration are common after anterior resection for rectal cancer with a defunctioning loop ileostomy. High-quality population-based studies on the impact of a defunctioning loop ileostomy on renal failure are lacking. Methods: This was a nationwide observational study, based on the Swedish Colorectal Cancer Registry of patients undergoing anterior resection for rectal cancer between 2008 and 2016, with follow-up until 2017. Patients with severe co-morbidity, with age greater than 80 years, and with pre-existing renal failure were excluded. Loop ileostomy at index surgery constituted exposure, while a diagnosis of renal failure was the outcome. Acute and chronic events were analysed separately. Inverse probability weighting with adjustment for confounding derived from a causal diagram was employed. Hazards ratios (HRs) with 95 per cent c.i. are reported. Results: A total of 5355 patients were eligible for analysis. At 5-year follow-up, all renal failure events (acute and chronic) were 7.2 per cent and 3.3 per cent in the defunctioning stoma and no stoma groups respectively. In the weighted analysis, a HR of 11.59 (95 per cent c.i. 5.68 to 23.65) for renal failure in ostomates was detected at 1 year, with the largest effect from acute renal failure (HR 24.04 (95 per cent c.i. 8.38 to 68.93)). Later follow-up demonstrated a similar pattern, but with smaller effect sizes. Conclusion: Patients having a loop ileostomy in combination with anterior resection for rectal cancer are more likely to have renal failure, especially early after surgery. Strategies are needed, such as careful fluid management protocols, and further research into alternative stoma types or reduction in stoma formation.

Purpose: Surveillance for hepatocellular carcinoma (HCC) is recommended in at-risk patients, but its effectiveness in Western populations has been questioned. The purpose was to evaluate the effect of surveillance in patients with HCC in a Northern European setting. Patients and Methods: Data on patients diagnosed with HCC between 2009 and 2019 were collected from the nationwide Swedish National Registry for Tumors of the Liver and Bile Ducts (SweLiv). Patients who had undergone HCC surveillance were compared to those who had not (but had an obvious indication for surveillance, ie, liver cirrhosis or hepatic porphyria and an age of ≥50 years) regarding etiology, tumor burden, presence of extrahepatic spread, treatment and lead-time adjusted overall survival. Results: A total of 4979 patients with index HCC were identified and information regarding surveillance was available in 4116 patients. Among these, 1078 had got their HCC diagnosis during surveillance, whereas 1647 had been diagnosed without surveillance despite a presumed indication. The most common underlying etiologies for HCC were hepatitis C (28.2%) and alcoholic liver disease (26.9%), and 94.8% had cirrhosis. The surveillance cohort more frequently met the University of California San Francisco-criteria (79% vs 53%, p <0.001), more often received a potentially curative treatment (62% vs 28%, p <0.001) and had less extrahepatic spread (7.6% vs 22.4% p <0.001). After adjustment for lead-time bias (sojourn time of 270 days), the surveillance group had a significantly longer estimated median survival time than the non-surveillance group (34 months vs 11 months, p <0.001). A multivariable cox regression analysis showed an adjusted hazard ratio of 0.59 (95% CI 0.51–0.67) in favor of surveillance. Conclusion: Surveillance for HCC in at-risk patients is associated with diagnosis at an earlier tumor stage, treatment with curative intent and with improved lead-time adjusted overall survival. These findi

Introduction: Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS. Methods: A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8–25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls. Result: 60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD. Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.

Background: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses. Material and method:s Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot. Results: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies. Discussion: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.

Background: Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood. Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020). Results: Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]). Conclusions: Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis. Trial registration: ClinicalTrials.gov: NCT00628745.

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is endemic in northern Sweden (Västerbotten). The awareness of ATTRv amyloidosis is lower in Stockholm, a non-endemic region in Sweden. The aim of this study was to compare the possible differences in diagnostic delay, disease phenotypes, treatment and survival between a non-endemic and an endemic region in Sweden. Methods: The in- and outpatient diagnosis registry at the Department of Neurology at Karolinska University Hospital and the Amyloidosis Centre at University Hospital of Umeå were used to identify patients between January 2006 and November 2017. Results: In total, 21 patients in Stockholm and 134 patients in Västerbotten were included. The time between symptom onset to time-point of diagnosis was significantly longer in Stockholm vs Västerbotten. This corresponded to a longer median time between first visit at amyloidosis centre to time-point of diagnosis in Stockholm vs in Västerbotten. The most common reason for a diagnostic delay was negative tissue biopsies. Conclusion: There was a diagnostic-, but no patient-delay in non-endemic Stockholm vs endemic Västerbotten. Despite a more severe neuropathic phenotype in Stockholm at the onset, the systemic affection over the course of disease and of survival seems not to be influenced by the diagnosis delay in Stockholm.

Introduction: Epidemiological data on hereditary transthyretin (ATTRv) amyloidosis from the northernmost region of Sweden (Norrbotten) are sparse. Methods: We reviewed the medical records of all incident cases of ATTRv amyloidosis in Norrbotten between 2006 and 2018. Official population and mortality statistics were used to estimate incidence rates and standardised mortality ratios (SMRs). Results: Ninety-three patients were diagnosed with ATTRv amyloidosis between 2006 and 2018 (median age, 72.8 years; 68.8% men; 95.7% Val30Met [p.Val50Met] mutation). The incidence rate per 100,000 persons and year increased from 1.50 (95% confidence interval [CI], 0.84–2.47) cases in 2006–2009 to 4.92 (95%CI, 3.46–6.78) cases in 2016–2018. The SMR in the ATTRv amyloidosis cohort was 2.64 times higher than in the general population in 2006–2018 (95%CI, 1.78–3.77). However, there were indications of lower SMRs over time (2006–2012, 2.96 [95%CI, 1.73–4.74]; 2013–2018, 2.32 [95%CI, 1.23–3.96]) and by use of disease-modifying drugs (no, 3.21 [95%CI, 1.87–5.13]; yes, 2.09 [95%CI, 1.08–3.64]). Conclusion: The incidence of ATTRv amyloidosis increased 3-fold in Norrbotten between 2006 and 2018, most likely due to a previous underdiagnosis–with suggestions of lowered mortality during later years, possibly due to the introduction of disease-modifying drugs.

Aim of the study: Oesophageal and gastric varices are well-known causes of morbidity and mortality in patientswith liver cirrhosis. The aim of this retrospective observational study was to analyse clinical characteristics andoutcomes for patients with oesophageal and gastric varices at Norrland’s University Hospital, Umeå, Sweden. Material and methods: Data from medical records were collected retrospectively from 246 patients with oesophageal and gastric varices between 2006 and 2019. Results: At the end of the study 60.1% of the patients had died at a median age of 69 years (range 26-95).Mortality of patients with gastro-oesophageal varices was significantly greater than that of the general population. Median survival from the time of variceal diagnosis was 59 months (confidence interval [CI] 95%:45-73 months). Five-year and 10-year cumulative survival rates in the entire cohort were 49.7% and 27.7%,respectively, with no sex-related differences. The highest mortality rate was seen in alcoholic cirrhosis with concomitant hepatitis. Mortality was higher in Child-Turcotte-Pugh (CTP) B and C compared to CTP A. Liver failureand liver cancer were the most common causes of death (43.8%). Thirty-one percent of the patients had avariceal haemorrhage. Eleven percent were subjected to liver transplantation, whereas 3.9% of the patients had beensubmitted to a transjugular intrahepatic portosystemic shunt (TIPS) procedure. Conclusions: Despite the latest therapeutic advances, the survival of patients with gastro-oesophageal varicesremains significantly reduced. All-cause mortality was significantly related to CTP class, aetiology, occurrence ofvariceal bleeding, whether variceal bleeding was the primary symptom and whether patients had undergoneliver transplantation or not.

Hereditary transthyretin (ATTRv) amyloidosis is a rare but life-threatening multi-systemic disease with clustering areas in, for example, northern Sweden. Until the 1990s, only symptomatic treatments were available but liver transplantation has, in selected patients, been a good therapeutic option since. The first disease-modifying drug for ATTRv amyloidosis was approved in 2011 and since then, the development of new therapeutic drugs has been rapid and successful. Two gene silencing therapies were approved for the disease in 2018, both showing a robust reduction in serum transthyretin levels and a satisfactory safety profile. Recently, CRISPR-Cas9 gene editing has also shown promising results in patients with ATTRv amyloidosis. The recent developments have had a paramount effect on the management of these patients, and will probably also have a significant positive effect on their life expectancy. However, treatment costs have skyrocketed, which implies future challenges., Lakartidningen.se 2022-06-03

Background Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0.3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (

AIMS/BACKGROUND: Transthyretin amyloid (ATTR) amyloidosis cardiomyopathy is an underdiagnosed, causatively treatable cause of heart failure. The aim of this study was to evaluate the efficacy of electrocardiography (ECG) and echocardiography on patients with increased interventricular septum diameter (IVSd) to identify ATTR cardiac amyloidosis (ATTR-CA) patients. METHODS: We investigated 58 patients with heart failure and an IVSd >14mm. Included were 33 ATTR-CA patients and 25 controls that consisted of non-amyloidosis heart failure (HF) patients with negative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy. We used echocardiography including 2D speckle tracking strain and a 12-lead ECG to test the accuracy to differentiate the groups. RESULTS: We found high diagnostic accuracy (98%) for differentiating ATTR-CA from HF controls using a combination of R amplitude in -aVR from ECG and relative wall thickness acquired from echocardiography. With this combined model (RWT/ R in -aVR), the sensitivity was 100% and specificity was 95% using a cut off value of 0.90. Furthermore, the area under the curve was 99% and the negative predictive value was 100%. CONCLUSION: We found that a simple combination of ECG and echocardiographic parameters used in clinical settings was able to differentiate ATTR-CA from other etiologies of HF with increased interventricular septum thickness. The high sensitivity and negative predictive value render the algorithm useful for selection of patients for further diagnostic procedures for ATTR-CA.

Untargeted metabolomics is a well-established technique and a powerful tool to find potential plasma biomarkers for early diagnosing hereditary transthyretin amyloidosis. Hereditary transthyretin amyloidosis (ATTRv) is a disabling and fatal disease with different clinical features such as polyneuropathy, cardiomyopathy, different gastrointestinal symptoms and renal failure. Plasma specimens collected from 27 patients with ATTRv (ATTRV30M), 26 asymptomatic TTRV30M carriers and 26 control individuals were subjected to gas chromatography (GC)- and liquid chromatography (LC)-mass spectrometry (MS)-based metabolomics analysis. Partial least squares discriminant and univariate analysis was used to analyse the data. The models constructed by Partial least squares-discriminant analysis (PLS-DA) could clearly discriminate ATTRV30M patients from controls and asymptomatic TTRV30M carriers. In total, 24 plasma metabolites (VIP > 1.0 and p <.05) were significantly altered in ATTRV30M patient group (6 increased and 18 decreased). Eleven of these distinguished the ATTRV30M group from both controls and TTRV30M carriers. Plasma metabolomics analysis revealed marked changes in several pathways in patients with ATTRV30M amyloidosis. Statistical analysis identified a panel of biomarkers that could effectively separate controls/TTRV30M carriers from ATTRV30M patients. These biomarkers can potentially be used to diagnose patients at an early stage of the disease.