Pre- vs. postoperative initiation of thromboprophylaxis in liver surgery

Background: Thromboprophylaxis protocols in liver surgery vary greatly worldwide. Due to limited research, there is no consensus whether the administration of thromboprophylaxis should be initiated pre-or postoperatively. Methods: Patients undergoing liver resection in Helsinki University Hospital between 2014 and 2017 were reviewed retrospectively. Initiation of thromboprophylaxis was changed in the institution in the beginning of 2016 from postoperative to preoperative. Patients were classified into two groups for analyses: thromboprophylaxis initiated preoperatively (Preop-group) or postoperatively (Postop-group). The incidences of VTE and haemorrhage within 30 days of surgery were compared between these groups. Patients with permanent anticoagulation were excluded. Results: A total of 512 patients were included to the study (Preop, n = 253, Postop, n = 259). The incidence of VTE was significantly lower in the Preop-group compared to the Postop-group (3 (1.2%) vs. 25 (9.7%), P =Peer reviewe

Randomised sham-controlled double-blind trial evaluating remote ischaemic preconditioning in solid organ transplantation : a study protocol for the RIPTRANS trial

Introduction Remote ischaemic preconditioning (RIPC) using a non-invasive pneumatic tourniquet is a potential method for reducing ischaemia-reperfusion injury. RIPC has been extensively studied in animal models and cardiac surgery, but scarcely in solid organ transplantation. RIPC could be an inexpensive and simple method to improve function of transplanted organs. Accordingly, we aim to study whether RIPC performed in brain-dead organ donors improves function and longevity of transplanted organs. Methods and analyses RIPTRANS is a multicentre, sham-controlled, parallel group, randomised superiority trial comparing RIPC intervention versus sham-intervention in brain-dead organ donors scheduled to donate at least one kidney. Recipients of the organs (kidney, liver, pancreas, heart, lungs) from a randomised donor will be included provided that they give written informed consent. The RIPC intervention is performed by inflating a thigh tourniquet to 300 mm Hg 4 times for 5 min. The intervention is done two times: first right after the declaration of brain death and second immediately before transferring the donor to the operating theatre. The sham group receives the tourniquet, but it is not inflated. The primary endpoint is delayed graft function (DGF) in kidney allografts. Secondary endpoints include short-term functional outcomes of transplanted organs, rejections and graft survival in various time points up to 20 years. We aim to show that RIPC reduces the incidence of DGF from 25% to 15%. According to this, the sample size is set to 500 kidney transplant recipients. Ethics and dissemination This study has been approved by Helsinki University Hospital Ethics Committee and Helsinki University Hospital's Institutional Review Board. The study protocol was be presented at the European Society of Organ Transplantation congress in Copenhagen 14-15 September 2019. The study results will be submitted to an international peer-reviewed scientific journal for publication.Peer reviewe

Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates

An UPLC-MS/MS method was developed for the determination of serotonin (5-HT), dopamine (DA), their phase I metabolites 5-HIAA, DOPAC and HVA, and their sulfate and glucuronide conjugates in human brain microdialysis samples obtained from two patients with acute brain injuries, ventricular cerebrospinal fluid (CSF) samples obtained from four patients with obstructive hydrocephalus, and a lumbar CSF sample pooled mainly from patients undergoing spinal anesthesia in preparation for orthopedic surgery. The method was validated by determining the limits of detection and quantification, linearity, repeatability and specificity. The direct method enabled the analysis of the intact phase II metabolites of 5-HT and DA, without hydrolysis of the conjugates. The method also enabled the analysis of the regioisomers of the conjugates, and several intact glucuronide and sulfate conjugates were identified and quantified for the first time in the human brain microdialysis and CSF samples. We were able to show the presence of 5-HIAA sulfate, and that dopamine-3-O-sulfate predominates over dopamine-4-O-sulfate in the human brain. The quantitative results suggest that sulfonation is a more important phase II metabolism pathway than glucuronidation in the human brain.Peer reviewe

Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates

An UPLC-MS/MS method was developed for the determination of serotonin (5-HT), dopamine (DA), their phase I metabolites 5-HIAA, DOPAC and HVA, and their sulfate and glucuronide conjugates in human brain microdialysis samples obtained from two patients with acute brain injuries, ventricular cerebrospinal fluid (CSF) samples obtained from four patients with obstructive hydrocephalus, and a lumbar CSF sample pooled mainly from patients undergoing spinal anesthesia in preparation for orthopedic surgery. The method was validated by determining the limits of detection and quantification, linearity, repeatability and specificity. The direct method enabled the analysis of the intact phase II metabolites of 5-HT and DA, without hydrolysis of the conjugates. The method also enabled the analysis of the regioisomers of the conjugates, and several intact glucuronide and sulfate conjugates were identified and quantified for the first time in the human brain microdialysis and CSF samples. We were able to show the presence of 5-HIAA sulfate, and that dopamine-3-O-sulfate predominates over dopamine-4-O-sulfate in the human brain. The quantitative results suggest that sulfonation is a more important phase II metabolism pathway than glucuronidation in the human brain.Peer reviewe

Health-Related Quality of Life in Metastatic Colorectal Cancer Patients Treated with Curative Resection and/or Local Ablative Therapy or Systemic Therapy in the Finnish RAXO-Study

Metastasectomy and/or local ablative therapy in metastatic colorectal cancer (mCRC) patients often provide long-term survival. Health-related quality of life (HRQoL) data in curatively treated mCRC are limited. In the RAXO-study that evaluated repeated resectability, a multi-cross-sectional HRQoL substudy with 15D, EQ-5D-3L, QLQ-C30, and QLQ-CR29 questionnaires was conducted. Mean values of patients in different treatment groups were compared with age- and gender-standardized general Finnish populations. The questionnaire completion rate was 444/477 patients (93%, 1751 questionnaires). Mean HRQoL was 0.89–0.91 with the 15D, 0.85–0.87 with the EQ-5D, 68–80 with the EQ-5D-VAS, and 68–79 for global health status during curative treatment phases, with improvements in the remission phase (disease-free >18 months). In the remission phase, mean EQ-5D and 15D scores were similar to the general population. HRQoL remained stable during first- to later-line treatments, when the aim was no longer cure, and declined notably when tumour-controlling therapy was no longer meaningful. The symptom burden affecting mCRC survivors’ well-being included insomnia, impotence, urinary frequency, and fatigue. Symptom burden was lower after treatment and slightly higher, though stable, through all phases of systemic therapy. HRQoL was high in curative treatment phases, further emphasizing the strategy of metastasectomy in mCRC when clinically meaningful

Health-Related Quality of Life in Metastatic Colorectal Cancer Patients Treated with Curative Resection and/or Local Ablative Therapy or Systemic Therapy in the Finnish RAXO-Study

Metastasectomy and/or local ablative therapy in metastatic colorectal cancer (mCRC) patients often provide long-term survival. Health-related quality of life (HRQoL) data in curatively treated mCRC are limited. In the RAXO-study that evaluated repeated resectability, a multi-cross-sectional HRQoL substudy with 15D, EQ-5D-3L, QLQ-C30, and QLQ-CR29 questionnaires was conducted. Mean values of patients in different treatment groups were compared with age- and gender-standardized general Finnish populations. The questionnaire completion rate was 444/477 patients (93%, 1751 questionnaires). Mean HRQoL was 0.89–0.91 with the 15D, 0.85–0.87 with the EQ-5D, 68–80 with the EQ-5D-VAS, and 68–79 for global health status during curative treatment phases, with improvements in the remission phase (disease-free >18 months). In the remission phase, mean EQ-5D and 15D scores were similar to the general population. HRQoL remained stable during first- to later-line treatments, when the aim was no longer cure, and declined notably when tumour-controlling therapy was no longer meaningful. The symptom burden affecting mCRC survivors’ well-being included insomnia, impotence, urinary frequency, and fatigue. Symptom burden was lower after treatment and slightly higher, though stable, through all phases of systemic therapy. HRQoL was high in curative treatment phases, further emphasizing the strategy of metastasectomy in mCRC when clinically meaningful

Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

Background Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied. Methods This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status. Results Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups. Conclusions There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status.Peer reviewe

Repeated centralized multidisciplinary team assessment of resectability, clinical behavior, and outcomes in 1086 Finnish metastatic colorectal cancer patients (RAXO): A nationwide prospective intervention study

Background: Resection of colorectal cancer (CRC) metastases provides good survival but is probably underused in real-world practice.Methods: A prospective Finnish nationwide study enrolled treatable metastatic CRC patients. The intervention was the assessment of resectability upfront and twice during first-line therapy by the multidisciplinary team (MDT) at Helsinki tertiary referral centre. The primary outcome was resection rates and survival.Findings: In 2012-2018, 1086 patients were included. Median follow-up was 58 months. Multiple metastatic sites were present in 500 (46%) patients at baseline and in 820 (76%) during disease trajectory. In MDT assessments, 447 (41%) were classified as resectable, 310 (29%) upfront and 137 (18%) after conversion therapy. Sixhundred and ninety curative intent resections or local ablative therapies (LAT) were performed in 399 patients (89% of 447 resectable). Multiple metastasectomies for multisite or later developing metastases were performed in 148 (37%) patients. Overall, 414 liver, 112 lung, 57 peritoneal, and 107 other metastasectomies were performed. Median OS was 80.4 months in R0/1-resected (HR 0.15; CI95% 0.12-0.19), 39.1 months in R2-resected/LAT (0.39; 0.29-0.53) patients, and 20.8 months in patients treated with "systemic therapy alone" (reference), with 5-year OS rates of 66%, 40%, and 6%, respectively.Interpretation: Repeated centralized MDT assessment in real-world metastatic CRC patients generates high resectability (41%) and resection rates (37%) with impressive survival, even when multisite metastases are present or develop later. </p

Surgical Perspectives on Liver and Extrahepatic Resections in Metastatic Colorectal Cancer : Prospective Centralised Multidisciplinary Assessment, Prognostic Factors, and Treatment Outcomes

Five-year survival for patients with metastatic colorectal cancer (mCRC) is only 14%-25%, but selected patients have a 66% chance of surviving 5 years after curative resection. Multidisciplinary teams (MDT) have emerged to ensure optimal care for these patients. Technical resectability evaluation is based on meticulous examination of radiologic imaging and is especially important for patients who are not initially considered to have resectable disease. The prospective, investigator-initiated, nationwide Finnish RAXO study included 1086 patients with metastatic colorectal cancer eligible for first-line systemic therapy between 2012 and 2018. The aims of the study were to evaluate the value of repeated centralised resectability assessment in central MDT, rates of conversion to resectability, patient outcomes, experimental MRI/MRS protocols, and the significance of RAS and BRAF mutations. There was discrepancy between the central MDT and the local assessments with both local overestimation and underestimation of resectability. Fifty-three percent of patients with liver-only metastatic disease were upfront resectable, and a further 21% were converted to resectable. Resectability was comparable for RAS&BRAFwt and RASmt, but lower for BRAFmt. Median overall survival (mOS) from diagnosis of liver-only mCRC was 80 months after R0-1 resection, 32 months after R2/ablation, and 21 months with systemic therapy only, with 5-year OS rates of 68%, 37%, and 9%, respectively. After R0-1 resection mOS was 79 months, with 65% 5-year OS, for patients with liver and extrahepatic disease. Patients who were successfully converted to resectable had similar survival after R0-1 resection as upfront resectable patients. The 5-year OS rate after resection of mCRC was highest for RAS&BRAFwt (67%), lower for RASmt (60%), and lowest for BRAFmt (24%). Decrease in apparent diffusion coefficient (ADC) values on diffusion-weighted MRI during systemic therapy were associated with improved survival. High resectability, conversion, and resection rates for patients with mCRC can be achieved with repeated centralised MDT assessment. Patients who can be converted to resectable have survival rates comparable to those with upfront resectable disease. Long-term survival is possible for many resected mCRC patients with RAS&BRAFwt and RAS mutations and also for some patients with BRAF mutations.Levinneen suolistosyövän (mCRC) 5-vuotisennuste nousee 66 %:iin onnistuneen kasvainpesäkkeiden poistoleikkauksen jälkeen. Hoitavien erikoisalojen yhteistyön parantamiseksi on perustettu moniammatillisia tiimejä (MDT). Leikkaushoidon mahdollisuuksien tekninen arviointi perustuu kuvantamistutkimuksiin. Etenevään tutkijalähtöiseen valtakunnalliseen suomalaiseen RAXO-tutkimukseen osallistui vuosina 2012–2018 1086 levinnyttä suolistosyöpää sairastavaa potilasta, joille suunniteltiin ensimmäisen linjan systeemihoitoja. Tavoitteena oli arvioida keskitetyn toistetun MDT-arvion merkitystä etäpesäkekirurgiassa, etäpesäkkeiden muuntumista leikattavaksi, hoidon tuloksia, kokeellista magneettikuvausprotokollaa sekä RAS- ja BRAF-mutaatioiden merkitystä. Paikallinen arviointi sekä yli- että aliarvioi hoitomahdollisuuksia keskitettyyn MDT:hen verrattuna. Jos etäpesäkkeet todettiin vain maksassa, 53 % potilaista oli suoraan leikattavissa ja 21 % muuntui leikattaviksi systeemihoidoilla. RAS- ja erityisesti BRAF-mutaatio laski maksametastaasipotilaiden todennäköisyyttä edetä parantavaan leikkaukseen. Vain maksaan levinneen suolistosyöpäpotilaan keskimääräinen elossaoloaika oli 80 kk diagnoosista, mikäli tauti hoidettiin parantavalla leikkauksella ja 21 kk vain systeemihoitoa saaneilla, 5-vuotisennusteet olivat 68 % ja 9 %. Mikäli syöpä oli levinnyt maksan lisäksi myös muualle elimistöön, elossaoloaika oli 79 kk ja 5-vuotisennuste 65 % parantavan leikkauksen jälkeen. Viisi vuotta etäpesäkkeiden leikkauksen jälkeen RAS- & BRAF-villityypin potilaista elossa oli 67 %, RAS-mutatoituneista 60 % ja BRAF-mutatoituneista 24 %. Diffuusiomagneettikuvantamisella todettu apparent diffusion coefficient (ADC) -arvon lasku systeemihoidolla yhdistyi parempaan ennusteeseen. Toistetulla keskitetyllä moniammatillisella arviolla voidaan saavuttaa korkeat leikattavuus-, konversio- ja leikkausluvut, mikäli suolistosyöpä on levinnyt vain maksaan, sekä osalle potilaista, joilla tauti on levinnyt muuallekin elimistöön. Merkittävä osa leikkaukseen lähtökohtaisesti huonosti soveltuvista potilaista on muunnettavissa leikattaviksi, ja näiden muuntuneiden potilaiden elinajanennuste ei poikkea suoraan leikattavissa olevista potilaista. Pitkäaikaisselviytyminen on mahdollista monille onnistuneesti leikatuille levinnyttä suolistosyöpää sairastaville potilaille, jopa osalle BRAF-mutatoituneista potilaista