Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy.

Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P < .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.

Distal Pancreatectomy: Extent of Resection Determines Surgical Risk Categories.

BACKGROUND: Recently, subclassification of pancreatoduodenectomy in 4 differing types has been reported, because additional major vascular and multivisceral resections have been shown to be associated with an increased risk of postoperative morbidity and mortality. OBJECTIVE: To classify distal pancreatectomy (DP) based on the extent of resection and technical difficulty and to evaluate postoperative outcomes with regards to this classification system. METHODS: All consecutive patients who had undergone DP between 2001 and 2020 in a high-volume pancreatic surgery center were included in this study. DPs were subclassified into 4 distinct categories reflecting the extent of resection and technical difficulty, including standard DP (type 1), DP with venous (type 2), multivisceral (type 3), or arterial resection (type 4). Patient characteristics, perioperative data, and postoperative outcomes were analyzed and compared among the 4 groups. RESULTS: A total of 2135 patients underwent DP. Standard DP was the most frequently performed procedure (64.8%). The overall 90-day mortality rate was 1.6%. Morbidity rates were higher in patients with additional vascular or multivisceral resections, and 90-day mortality gradually increased with the extent of resection from standard DP to DP with arterial resection (type 1: 0.7%; type 2: 1.3%; type 3: 3%; type 4: 8.7%; P <0.0001). Multivariable analysis confirmed the type of DP as an independent risk factor for 90-day mortality. CONCLUSIONS: Postoperative outcomes after DP depend on the extent of resection and correlate with the type of DP. The implementation of the 4-type classification system allows standardized reporting of surgical outcomes after DP improving comparability of future studies.

Protocol of a randomised controlled phase II clinical trial investigating PREoperative endoscopic injection of BOTulinum toxin into the sphincter of Oddi to reduce bile leakage after hepatic resection: the PREBOT-II trial.

INTRODUCTION: Bile leakage represents a major cause of morbidity following hepatic resection. Although most patients can be managed non-operatively, this complication requires diagnostics and therapeutic interventions. Preoperative endoscopic injection of botulinum toxin (BTX) into the sphincter of Oddi represents an innovative approach to prevent bile leakage. The aim of the PREBOT-II trial is to generate the first randomised controlled trial data on the safety, feasibility and efficacy of preoperative endoscopic BTX injection into the sphincter of Oddi to prevent bile leakage following hepatic resection. METHODS AND ANALYSIS: The PREBOT-II trial is an investigator-initiated, exploratory, multicentre, randomised, controlled, open-label, phase II clinical trial with two parallel study groups. 70 patients scheduled for hepatic resection will be randomised to either the intervention or the control group. Patients of the intervention group will undergo preoperative endoscopic injection of BTX into the sphincter of Oddi 3-10 days before surgery, whereas in the control group only hepatic resection will be performed. The primary endpoint is the occurrence of a postoperative bile leakage within 30 days after hepatic resection according to the definition of the International Study Group of Liver Surgery. The secondary endpoints comprise further postoperative morbidity parameters such as severity of postoperative bile leakage, post-hepatectomy haemorrhage or liver failure, mortality and quality of life up to 3 months after hepatic resection. Safety and feasibility of the procedure will also be recorded. ETHICS, FUNDING AND DISSEMINATION: The PREBOT-II trial has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4044932) and the Ethics Committee of Heidelberg University (reference number AFmu-558/2021). This trial is supported by the German Federal Ministry of Education and Research. The results will be presented at national and international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: DRKS00024061, EudraCT: 2020-006001-35.

Open irreversible electroporation for isolated local recurrence of pancreatic ductal adenocarcinoma after primary surgery.

BACKGROUND/OBJECTIVES: Irreversible electroporation (IRE) is an emerging treatment for locally advanced pancreatic cancer (LAPC) which in some cohorts has been associated with severe complications. Additionally, re-resection of isolated local recurrence (ILR) after pancreatic ductal adenocarcinoma (PDAC) can improve survival. We investigated safety, feasibility and oncologic outcomes in the first report on open IRE for unresectable ILR of PDAC in a staged surgical approach. METHODS: Records of the prospectively documented institutional database were screened for patients undergoing laparotomy in IRE-standby due to questionable resectability. Endpoints were morbidity, mortality and overall (OS) and progression free survival (PFS). Data of LAPC and ILR were compared statistically for safety and feasibility analysis. RESULTS: Intraoperative IRE was performed in 11 ILR and 14 LAPC. Six (54.5%) ILR and 10 (71.4%) LAPC patients had postoperative complications, type and frequency did not differ significantly. Major complications occurred in one ILR and two LAPC patients. Median OS was 20.0 months (95% CI: 2.7-37.3) after IRE for ILR and 28 (17.4-38.6) for LAPC. Median PFS after IRE was seven months for both ILR (4.1-9.9; n = 9) and LAPC (2.3-11.7; n = 13). CONCLUSION: Open IRE for unresectable ILR was associated with acceptable perioperative risk. In this small, highly selected subset of patients with limited therapeutic options ancillary treatment with IRE might improve survival. Randomized treatment studies are required to establish the definitive role of IRE as compared to palliative standards of care in unresectable recurrence of PDAC and inconvertible LAPC.

FYCO1 Regulates Cardiomyocyte Autophagy and Prevents Heart Failure Due to Pressure Overload In Vivo.

Autophagy is a cellular degradation process that has been implicated in diverse disease processes. The authors provide evidence that FYCO1, a component of the autophagic machinery, is essential for adaptation to cardiac stress. Although the absence of FYCO1 does not affect basal autophagy in isolated cardiomyocytes, it abolishes induction of autophagy after glucose deprivation. Likewise, Fyco1-deficient mice subjected to starvation or pressure overload are unable to respond with induction of autophagy and develop impaired cardiac function. FYCO1 overexpression leads to induction of autophagy in isolated cardiomyocytes and transgenic mouse hearts, thereby rescuing cardiac dysfunction in response to biomechanical stress.

Loss of collagen VII is associated with reduced transglutaminase 2 abundance and activity.

Absence of collagen VII leads to widespread cellular and tissue phenotypes. However, the underlying molecular mechanisms are not well understood. To gain insights into cellular responses to loss of collagen VII, we undertook a quantitative disease proteomics approach. By using recessive dystrophic epidermolysis bullosa (RDEB), a skin blistering disease caused by collagen VII deficiency, as a genetic model, collagen VII-dependent differences in cellular protein abundances and protein-protein interactions were analyzed. Absence of collagen VII led to alterations of intracellular protein compositions and to perturbations in cell adhesion, protein trafficking, and the turnover pathway autophagy. A potential linker of the different cellular phenotypes is transglutaminase 2 (TGM2), a multifunctional enzyme important for protein cross-linking. TGM2 was identified as a stable interaction partner of collagen VII. In RDEB, both abundance and activity of TGM2 were reduced, accounting not only for diminished adhesion and perturbed autophagy but also for reduced cross-linking of the extracellular matrix and for decreased epidermal-dermal integrity in RDEB.

Global remodelling of cellular microenvironment due to loss of collagen VII.

The mammalian cellular microenvironment is shaped by soluble factors and structural components, the extracellular matrix, providing physical support, regulating adhesion and signalling. A global, quantitative mass spectrometry strategy, combined with bioinformatics data processing, was developed to assess proteome differences in the microenvironment of primary human fibroblasts. We studied secreted proteins of fibroblasts from normal and pathologically altered skin and their post-translational modifications. The influence of collagen VII, an important structural component, which is lost in genetic skin fragility, was used as model. Loss of collagen VII had a global impact on the cellular microenvironment and was associated with proteome alterations highly relevant for disease pathogenesis including decrease in basement membrane components, increase in dermal matrix proteins, TGF-ß and metalloproteases, but not higher protease activity. The definition of the proteome of fibroblast microenvironment and its plasticity in health and disease identified novel disease mechanisms and potential targets of intervention.

Viral mediated redirection of NEMO/IKKγ to autophagosomes curtails the inflammatory cascade.

The early host response to viral infections involves transient activation of pattern recognition receptors leading to an induction of inflammatory cytokines such as interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNFα). Subsequent activation of cytokine receptors in an autocrine and paracrine manner results in an inflammatory cascade. The precise mechanisms by which viruses avert an inflammatory cascade are incompletely understood. Nuclear factor (NF)-κB is a central regulator of the inflammatory signaling cascade that is controlled by inhibitor of NF-κB (IκB) proteins and the IκB kinase (IKK) complex. In this study we show that murine cytomegalovirus inhibits the inflammatory cascade by blocking Toll-like receptor (TLR) and IL-1 receptor-dependent NF-κB activation. Inhibition occurs through an interaction of the viral M45 protein with the NF-κB essential modulator (NEMO), the regulatory subunit of the IKK complex. M45 induces proteasome-independent degradation of NEMO by targeting NEMO to autophagosomes for subsequent degradation in lysosomes. We propose that the selective and irreversible degradation of a central regulatory protein by autophagy represents a new viral strategy to dampen the inflammatory response.

Comparative quantitation of proteome alterations induced by aging or immortalization in primary human fibroblasts and keratinocytes for clinical applications.

We monitor proteome changes of primary human skin fibroblasts and keratinocytes during cell culture and compare them to respective immortalized cell lines using stable isotope labeling by amino acids to address their suitability as cell models for clinical disease proteomics.

Mechanisms of fibroblast cell therapy for dystrophic epidermolysis bullosa: high stability of collagen VII favors long-term skin integrity.

Here, we report on the first systematic long-term study of fibroblast therapy in a mouse model for recessive dystrophic epidermolysis bullosa (RDEB), a severe skin-blistering disorder caused by loss-of-function of collagen VII. Intradermal injection of wild-type (WT) fibroblasts in >50 mice increased the collagen VII content at the dermal-epidermal junction 3.5- to 4.7-fold. Although the active biosynthesis lasted <28 days, collagen VII remained stable and dramatically improved skin integrity and resistance to mechanical forces for at least 100 days, as measured with a digital 3D-skin sensor for shear forces. Experiments using species-specific antibodies, collagen VII-deficient fibroblasts, gene expression analyses, and cytokine arrays demonstrated that the injected fibroblasts are the major source of newly deposited collagen VII. Apart from transitory mild inflammation, no adverse effects were observed. The cells remained within an area

Inhibition of proinflammatory and innate immune signaling pathways by a cytomegalovirus RIP1-interacting protein.

TNFalpha is an important cytokine in antimicrobial immunity and inflammation. The receptor-interacting protein RIP1 is an essential component of the TNF receptor 1 signaling pathway that mediates the activation of NF-kappaB, MAPKs, and programmed cell death. It also transduces signals derived from Toll-like receptors and intracellular sensors of DNA damage and double-stranded RNA. Here, we show that the murine CMV M45 protein binds to RIP1 and inhibits TNFalpha-induced activation of NF-kappaB, p38 MAPK, and caspase-independent cell death. M45 also inhibited NF-kappaB activation upon stimulation of Toll-like receptor 3 and ubiquitination of RIP1, which is required for NF-kappaB activation. Hence, M45 functions as a viral inhibitor of RIP1-mediated signaling. The results presented here reveal a mechanism of viral immune subversion and demonstrate how a viral protein can simultaneously block proinflammatory and innate immune signaling pathways by interacting with a central mediator molecule.