Clinical Practice Guideline: Recommendations for the Perioperative Management of Pancreatic and Colorectal Cancer Patients

Colorectal and pancreatic carcinoma are the most common cancers of the gastrointestinal tract. Their surgical treatment carries a high morbidity: Complications arise in 25% to 30% of cases, often prolonging recovery times and delaying the initiation of adjuvant therapy, leading, in turn, to worse oncological outcomes. The goal of multimodal perioperative management (mPOM) is to lower the postoperative complication rate through a combination of perioperative measures. This guideline on the perioperative management of gastrointestinal tumors (POMGAT) meets all requirements for an S3 guideline as specified by the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). These include a systematic literature search, quality assessment of the included publications, an evaluation of the reliability of the evidence according to the GRADE approach, and a structured consensus processMeta-analyses have shown that mPOM lowers the complication rates of both pancreatic and colorectal resections (RD 0.96 with 95% confidence interval [0.92; 0.99] and RR 0.66 [0.54; 0.80], respectively). This shortens the hospital stay after pancreatic resections by a median of 2.33 days [-2.98; -1.69] and after colorectal resections by a median of 2.59 days [-3.22; -1.97]. Adherence to the POMGAT-S3 guideline for pancreatic and colorectal cancer surgery is associated with improved recovery, which can lead to a faster return to intended oncological treatment (RIOT) and thus to better long-term outcomes. These recommendations are not restricted to gastrointestinal cancer surgery; they can also be applied to visceral surgery for benign conditions, as well as to gynecological and urological operations.

Borane-catalysed C2-selective indole reductive functionalisation.

Indolines are common motifs within pharamceuticals and natural products. Boron catalysis enables the chemoselective allylation of indoles to give allylic indolines in excellent diastereoselectivity. Mechanistic studies revealed in situ formation of the allylic borane, allylation of the imine tautomer of the indole and B-N/B-H transborylation for catalytic turnover.

Improving Downstream Process Related Manufacturability Based on Protein Engineering-A Feasibility Study.

While bioactivity and a favorable safety profile for biotherapeutics is of utmost importance, manufacturability is also worth of consideration to ease the manufacturing process. Manufacturability in the scientific literature is mostly related to stability of formulated drug substances, with limited focus on downstream process-related manufacturability, that is, how easily can a protein be purified. Process-related impurities or biological impurities like viruses and host cell proteins (HCP) are present in the harvest which have mostly acid isoelectric points and need to be removed to ensure patient safety. Therefore, during molecule design, the surface charge of the target molecule should preferably differ sufficiently from the surface charge of the impurities to enable an efficient purification strategy. In this feasibility study, we evaluated the possibility of improving manufacturability by adapting the surface charge of the target protein. We generated several variants of a GLP1-receptor-agonist-Fc-domain-FGF21-fusion protein and demonstrated proof of concept exemplarily for an anion exchange chromatography step which then can be operated at high pH values with maximal product recovery allowing removal of HCP and viruses. Altering the surface charge distribution of biotherapeutic proteins can thus be useful allowing for an efficient manufacturing process for removing HCP and viruses, thereby reducing manufacturing costs.

Recommendations to improve use and dissemination of patient versions of oncological clinical practice guidelines in Germany: results of a multi-stakeholder workshop.

BACKGROUND: Oncological patients have high information needs that are often unmet. Patient versions of oncological clinical practice guidelines (PVG) translate clinical practice guidelines into laypersons' language and might help to address patients' information needs. Currently, 30 oncological PVG have been published in Germany and more are being developed. Following a large multi-phase project on oncological PVGs in Germany, recommendations to improve use and dissemination of PVG were adopted in a multi-stakeholder workshop. METHODS: Organisations representing users of PVGs (patients, medical personnel, and multipliers), creators, initiators/funding organisations of PVGs, and organisations with methodological expertise in the development of clinical practice guidelines or in patient health information were invited to participate. The workshop included a World Café for discussion of pre-selected recommendations and structured consensus procedure for of all recommendations. Recommendations with agreement of > 75% were approved, and in case of ≤ 75% agreement, recommendations were rejected. RESULTS: The workshop took place on 24th April 2023 in Cologne, Germany. Overall, 23 people from 24 organisations participated in the discussion. Of 35 suggested recommendations 28 recommendations reached consensus and were approved. The recommendations referred to the topics dissemination (N = 13), design and format (N = 7), (digital) links (N = 5), digitalisation (N = 4), up-to-dateness (N = 3), and use of the PVG in collaboration between healthcare providers and patients (N = 3). CONCLUSION: The practical recommendations consider various perspectives and can help to improve use and dissemination of oncological PVG in Germany. The inclusion of different stakeholders could facilitate the transfer of the results into practice.

Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.

The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.

A tidal volume of 7 mL/kg PBW or higher may be safe for COVID-19 patients.

PURPOSE: The novel coronavirus disease (COVID-19) has revived the debate on the optimal tidal volume during acute respiratory distress syndrome (ARDS). Some experts recommend 6 mL/kg of predicted body weight (PBW) for all patients, while others suggest 7-9 mL/kg PBW for those with compliance >50 mL/cmH2O. We investigated whether a tidal volume ≥ 7 ml/kg PBW may be safe in COVID-19 patients, particularly those with compliance >50 mL/cmH2O. MATERIALS AND METHODS: This secondary analysis of a multicenter study compares the Intensive Care Unit (ICU) mortality among 600 patients ventilated with <7 or ≥ 7 mL/kg PBW. Compliance was categorized as <40, 40-50, or > 50 mL/cmH2O. RESULTS: 346 patients were ventilated with <7 (6.2 ± 0.5) mL/kg PBW and 254 with ≥7 (7.9 ± 0.9) mL/kg PBW. ICU mortality was 33 % and 29 % in the two groups (p = 0.272). At multivariable regression analysis, tidal volume ≥ 7 mL/kg PBW was associated with lower ICU mortality in the overall population (odds ratio: 0.62 [95 %-confidence interval: 0.40-0.95]) and in each compliance category. CONCLUSIONS: A tidal volume ≥ 7 (up to 9) mL/kg PBW was associated with lower ICU mortality in these COVID-19 patients, including those with compliance <40 mL/cmH2O. This finding should be interpreted cautiously due to the retrospective study design. TRIAL REGISTRATION: ClinicalTrails.govNCT04388670.

Clinical Practice Guideline: Recommendations for the Perioperative Management of Pancreatic and Colorectal Cancer Patients.

BACKGROUND: Colorectal and pancreatic carcinoma are the most common cancers of the gastrointestinal tract. Their surgical treatment carries a high morbidity: Complications arise in 25% to 30% of cases, often prolonging recovery times and delaying the initiation of adjuvant therapy, leading, in turn, to worse oncological outcomes. The goal of multimodal perioperative management (mPOM) is to lower the postoperative complication rate through a combination of perioperative measures. METHODS: This guideline on the perioperative management of gastrointestinal tumors (POMGAT) meets all requirements for an S3 guideline as specified by the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). These include a systematic literature search, quality assessment of the included publications, an evaluation of the reliability of the evidence according to the GRADE approach, and a structured consensus process. RESULTS: Meta-analyses have shown that mPOM lowers the complication rates of both pancreatic and colorectal resections (RD 0.96 with 95% confidence interval [0.92; 0.99] and RR 0.66 [0.54; 0.80], respectively). This shortens the hospital stay after pancreatic resections by a median of 2.33 days [-2.98; -1.69] and after colorectal resections by a median of 2.59 days [-3.22; -1.97]. CONCLUSION: Adherence to the POMGAT-S3 guideline for pancreatic and colorectal cancer surgery is associated with improved recovery, which can lead to a faster return to intended oncological treatment (RIOT) and thus to better long-term outcomes. These recommendations are not restricted to gastrointestinal cancer surgery; they can also be applied to visceral surgery for benign conditions, as well as to gynecological and urological operations.

Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.

Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.

Lipid-polymer nanoparticles to probe the native-like environment of intramembrane rhomboid protease GlpG and its activity.

Polymers can facilitate detergent-free extraction of membrane proteins into nanodiscs (e.g., SMALPs, DIBMALPs), incorporating both integral membrane proteins as well as co-extracted native membrane lipids. Lipid-only SMALPs and DIBMALPs have been shown to possess a unique property; the ability to exchange lipids through 'collisional lipid mixing'. Here we expand upon this mixing to include protein-containing DIBMALPs, using the rhomboid protease GlpG. Through lipidomic analysis before and after incubation with DMPC or POPC DIBMALPs, we show that lipids are rapidly exchanged between protein and lipid-only DIBMALPs, and can be used to identify bound or associated lipids through 'washing-in' exogenous lipids. Additionally, through the requirement of rhomboid proteases to cleave intramembrane substrates, we show that this mixing can be performed for two protein-containing DIBMALP populations, assessing the native function of intramembrane proteolysis and demonstrating that this mixing has no deleterious effects on protein stability or structure.

Complications related to short peripheral intravenous catheters in patients with acute stroke: a prospective, observational, single-cohort study.

Patients with acute stroke often require venous access to facilitate diagnostic investigations or intravenous therapy. The primary aim of this study was to describe the rate and type of complications associated with the placement of a short peripheral catheter (SPC) in patients with acute ischemic or hemorrhagic stroke. A prospective, observational, single-cohort study was conducted at Niguarda Hospital, Italy, with enrolment in the Emergency Department. Adult patients with an ischemic or hemorrhagic stroke requiring an SPC were enrolled. Complications, such as infiltration, occlusion, phlebitis and dislodgment, were recorded daily. Descriptive statistics were used, and the incidence rate ratio (IRR) was estimated to assess the difference in complications, considering catheter calibre, dominant side, exit site, limb, and limb mobility, ictus type (ischemic/haemorrhagic), impairment deficit (language, motor, visual) and EA-DIVA score. A total of 269 participants and 755 SPC were analysed. Removal of SPC due to at least one local complication occurred in 451 (60%). Dislodgment was the major cause of SPC removal (31%), followed by infiltration (18%), occlusion (6%), and phlebitis (5%). The SPC calibre (22G), exit-site other than antecubital and forearm, visual deficit and EA-DIVA ≥ 8 were associated with a higher rate of SPC complications: IRR, 1.71 [1.31; 2.31]; 1.27 [1.01; 1.60], 1.38 [1.06; 1.80], 1.30 [1.04; 1.64], respectively. No other differences in complication rates were observed according to the insertion site, i.e. dominant side, left side, plegic/hyposthenic limb, or exit site. This study provides novel insights into the frequency and types of complications associated with SPC in patients with acute stroke. Compared to the literature, a higher dislodgment rate was observed, being the first cause of SPC removal, whereas no differences in the number of infiltrations, occlusions, and phlebitis were recorded.

CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy.

Transporting and translating mRNAs in axons is crucial for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects long-lived axonal mitochondria from damage; however, the regulatory factors involved are largely unknown. We show that CLUH, which binds mRNAs encoding mitochondrial proteins, prevents peripheral neuropathy and motor deficits in the mouse. CLUH is enriched in the growth cone of developing spinal motoneurons and is required for their growth. The lack of CLUH affects the abundance of target mRNAs and the corresponding mitochondrial proteins more prominently in axons, leading to ATP deficits in the growth cone. CLUH interacts with ribosomal subunits, translation initiation, and ribosome recycling components and preserves axonal translation. Overexpression of the ribosome recycling factor ABCE1 rescues the mRNA and translation defects, as well as the growth cone size, in CLUH-deficient motoneurons. Thus, we demonstrate a role for CLUH in mitochondrial quality control and translational regulation in axons, which is essential for their development and long-term integrity and function.

Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.

Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.

Quantitative Computed Tomography and Response to Pronation in COVID-19 ARDS.

BACKGROUND: The use of prone position (PP) has been widespread during the COVID-19 pandemic. Whereas it has demonstrated benefits, including improved oxygenation and lung aeration, the factors influencing the response in terms of gas exchange to PP remain unclear. In particular, the association between baseline quantitative computed tomography (CT) scan results and gas exchange response to PP in invasively ventilated subjects with COVID-19 ARDS is unknown. The present study aimed to compare baseline quantitative CT results between subjects responding to PP in terms of oxygenation or CO2 clearance and those who did not. METHODS: This was a single-center, retrospective observational study including critically ill, invasively ventilated subjects with COVID-19-related ARDS admitted to the ICUs of Niguarda Hospital between March 2020-November 2021. Blood gas samples were collected before and after PP. Subjects in whom the PaO2 /FIO2 increase was ≥ 20 mm Hg after PP were defined as oxygen responders. CO2 responders were defined when the ventilatory ratio (VR) decreased during PP. Automated quantitative CT analyses were performed to obtain tissue mass and density of the lungs. RESULTS: One hundred twenty-five subjects were enrolled, of which 116 (93%) were O2 responders and 51 (41%) CO2 responders. No difference in quantitative CT characteristics and oxygen were observed between responders and non-responders (tissue mass 1,532 ± 396 g vs 1,654 ± 304 g, P = .28; density -544 ± 109 HU vs -562 ± 58 HU P = .42). Similar findings were observed when dividing the population according to CO2 response (tissue mass 1,551 ± 412 g vs 1,534 ± 377 g, P = .89; density -545 ± 123 HU vs -546 ± 94 HU, P = .99). CONCLUSIONS: Most subjects with COVID-19-related ARDS improved their oxygenation at the first pronation cycle. The study suggests that baseline quantitative CT scan data were not associated with the response to PP in oxygenation or CO2 in mechanically ventilated subjects with COVID-19-related ARDS.

Use, applicability, and dissemination of patient versions of clinical practice guidelines in oncology in Germany: a qualitative interview study with healthcare providers.

BACKGROUND: People with cancer have high information needs; however, they are often inadequately met. Patient versions of clinical practice guidelines (PVGs), a special form of evidence-based information, translate patient-relevant recommendations from clinical practice guidelines into lay language. To date, little is known about the experience of PVGs from healthcare providers' perspective in healthcare. This study aims to investigate the use, applicability, and dissemination of PVGs in oncology from the healthcare providers' perspective in Germany. METHODS: Twenty semi-structured telephone interviews were conducted with oncological healthcare providers in Germany between October and December 2021. Interviews were recorded and transcribed verbatim. Mayring's qualitative content analysis with MAXQDA software was utilised to analyse the data. RESULTS: A total of 20 healthcare providers (14 female, 6 male), mainly working as psychotherapists/psycho-oncologists and physicians, participated. Most participants (75%) were aware of the existence of PVGs. The content was predominantly perceived as comprehensible and relevant, whereas opinions on the design and format were mixed. The perceived lack of up-to-date information limited participants' trust in the content. Most felt that PVGs positively impact healthcare owing to the fact that they improve patients' knowledge about their disease. Additionally, PVGs served as a guide and helped healthcare providers structure physician-patient talks. Healthcare provider's unawareness of the existence of PVGs was cited as an obstructive factor to its dissemination to patients. CONCLUSION: Limited knowledge of the existence of PVGs among healthcare providers, coupled with alternative patient information, hinders the use and dissemination of PVGs in healthcare. However, the applicability of PVGs seemed to be acceptable owing to their content and good comprehensibility, especially with respect to physician-patient communication.