Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer, which is characterized by an immunosuppressive microenvironment. Yet, the spatial distribution of the ...immune infiltrate and how it changes during IPMN progression is just beginning to be understood.
We obtained tissue samples from patients who underwent pancreatic surgery for IPMN, and performed comprehensive immunohistochemical analyses to investigate the clinical significance, composition and spatial organization of the immune microenvironment during progression of IPMNs. Survival analysis of pancreatic cancer patients was stratified by tumour infiltrating immune cell subtypes.
The immune microenvironment evolves from a diverse T cell mixture, comprising CD8+ T cells, Th/c1 and Th/c2 as major players combined with Th9, Th/c17, Th22, and Treg cells in low-grade IPMN, to a Treg dominated immunosuppressive state in invasive pancreatic cancer. Organized lymphoid clusters formed in IPMN surrounding stroma and accumulated immunosuppressive cell types during tumour progression. Survival of pancreatic cancer patients correlated with Th2 signatures in the tumour microenvironment.
The major change with regards to T cell composition during IPMN progression occurs at the step of tissue invasion, indicating that malignant transformation only occurs when tumour immune surveillance is overcome. This suggests that novel immunotherapies that would boost spontaneous antitumor immunity at premalignant states could prevent pancreatic cancer development.
The present work was supported by German Cancer Aid grants (70,112,720 and 70,113,167) to S. R., and the Olympia Morata Programme of the Medical Faculty of Heidelberg University to S. R.
The extracellular matrix molecule periostin (POSTN, encoded by POSTN ), which is secreted by activated pancreatic stellate cells, has important functions in chronic pancreatitis and pancreatic ...cancer. However, the role of POSTN in acute pancreatitis and subsequent regeneration processes has not been addressed so far. We analyzed the function of POSTN in pancreatic exocrine regeneration after the induction of a severe acute pancreatitis. Postn -deficient mice and wild-type control animals received repetitive cerulein injections, and a detailed histologic analysis of pancreatic tissues was performed. Although there was no difference in pancreatitis severity in the acute inflammatory phase, the recovery of the exocrine pancreas was massively impaired in Postn -deficient mice. Loss of Postn expression was accompanied by strong pancreatic atrophy and acinar-to-adipocyte differentiation, which was also reflected in gene expression patterns. Our data suggest that POSTN is a crucial factor for proper exocrine lineage-specific regeneration after severe acute pancreatitis.
Background
Site-specific outcomes of resection for periampullary cancer have not been analyzed on a large, registry-based scale.
Methods
We assessed data on periampullary cancers from the SEER ...database. Site- and stage-specific outcomes were analyzed. Resection was compared to no resection.
Results
Resection was the main therapy in stages 1 and 2 (resection vs. no resection, 8644 vs. 7208 patients), was less frequent in stage 3 (1248 vs. 2783 patients) and was rarely—but still—used in stage 4 disease (541 vs. 11,212 patients). Pancreatic head (75.7%), 11.4% distal bile duct, 7.7% ampullary, and 5.3% duodenal cancers. Cancer subtype-independent median survival was 22.0 (resection) vs. 7.0 months (no resection) in stages 1 and 2, 21.0 vs. 8.0 months in stage 3, and 10.0 vs. 3.0 months in stage 4. Subtype-dependent median survival (resection vs. no resection) was 18.0 vs. 5.0 months in pancreatic head, 19.0 vs 4.0 months in distal bile duct, 41.0 vs 7.0 months in ampullary, and 38.0 vs 4.0 months in duodenal adenocarcinoma. On multivariable analysis, patient comorbidities, marital and insurance status, and income all influenced the decision to undergo resection.
Conclusions
Surgery is still underutilized in the treatment of periampullary cancers. Patients with cancers originating from the duodenum or the ampulla of Vater benefit most from resectional surgery.
Neoadjuvant therapy (NT) for advanced PDAC is an emerging concept, affecting both stroma and tumor. The Activated Stroma Index (ASI; ratio of activated cancer-associated fibroblasts (CAF) to collagen ...deposition) is a prognostic marker in upfront resected pancreatic adenocarcinoma (PDAC). We assessed ASI and its prognostic relevance after NT. Tissue from resection specimens of n = 48 PDAC patients after neoadjuvant chemotherapy with FOLFIRINOX (FOL; n = 31), gemcitabine + nab-paclitaxel (GEM; 7) or combination treatment (COMB; 10) was compared with upfront resected matched controls (RES; 69). Activated CAFs were assessed by immunohistochemistry for α-SMA, and collagen was stained with aniline blue; the stained area was then determined by computational imaging analysis and ASI was calculated. In GEM, ASI was significantly higher and collagen deposition lower than in controls and FOL. The lowest quartile of ASI values had significantly longer overall survival (OS) in RES, whereas in FOL, the highest quartile had the best prognosis. After NT, OS was significantly improved in the α-SMA-high group; in RES, however, survival was independent of α-SMA. Reversed prognostic association of ASI thus points to the differing significance of stromal composition after FOL, while improved prognosis with high CAF abundance suggests a synergistic effect of myofibroblasts with chemotherapy. These divergences impede usability of ASI after NT.
Background
Aim of the current study was to present the results of the implementation phase of a robotic liver surgery program and to assess the validity of the IWATE difficulty score in predicting ...difficulty and postoperative complications in robotic liver surgery.
Methods
Based on the prospective database of the Interdisciplinary Robotic Center of Ulm University Hospital, the first 100 robotic liver surgeries were identified and analyzed. Perioperative parameters (duration of surgery and blood loss) and postoperative parameters including morbidity, mortality, and length of hospital stay were assessed and the results were compared between different IWATE difficulty categories.
Results
From November 2020 until January 2023, 100 robotic liver surgeries were performed (41 female, 59 male; median age 60.6 years, median BMI 25.9 kg/m
2
). Median duration of surgery was 180 min (IQR: 128.7), and median blood loss was 300 ml (IQR: 550). Ninety-day mortality was 2%, and overall morbidity was 21%, with major complications occurring in 13% of patients (≥ grade 3 according to Clavien/Dindo). A clinically relevant postoperative biliary leakage was observed in 3 patients. Posthepatectomy liver failure occurred in 7% (4 Grade A, 3 Grade B). Duration of surgery (
p
< 0.001), blood loss (
p
< 0.001), CCI (
p
= 0.004), overall morbidity (
p
= 0.004), and length of hospital stay (
p
< 0.001) were significantly increased in the IWATE ‘expert’ category compared to lower categories.
Discussion
Robotic surgery offers a minimally invasive approach for liver surgery with favorable clinical outcomes, even in the implementation phase. In the current study the IWATE difficulty score had the ability to predict both difficulty of surgery as well as postoperative outcomes when assessing the complexity of robotic liver surgery. Therefore, the role of the IWATE score in predicting these outcomes highlights its importance as a tool in surgical planning and decision-making.
Abstract Introduction The risk of malignancy in branch duct intraductal papillary mucinous neoplasia of the pancreas (BD-IPMN) is controversially debated. An increasing number of studies report on ...outcomes using the Sendai or Fukuoka consensus criteria for treatment decision-making. The objective of this work was to evaluate the diagnostic accuracy of the Sendai and Fukuoka criteria. Methods We systematically reviewed studies on Sendai or Fukuoka criteria-guided management of BD-IPMN. Pooled sensitivity, specificity and diagnostic odds ratios as compound measures of diagnostic accuracy were calculated from studies matching the inclusion criteria. The meta-analysis was performed using a random effects model. Results Fifteen studies with a total of 2710 patients were included. Twelve of these used the Sendai criteria. In these studies, 23% of Sendai-negative patients had a high grade dysplastic lesion or an invasive carcinoma in final histology. Pooled sensitivity was 56%, specificity was 74% and the diagnostic odds ratio for malignancy in Sendai-positive lesions was 7.45. When the results of follow-up examinations were included, diagnostic accuracy improved significantly (14.66, p < 0.001). Three studies were identified that used the Fukuoka criteria for decision making. Of 200 patients with Fukuoka-negative lesions who underwent surgery, 22 had a malignant lesion in final histology (11%). Pooled sensitivity was 83%, specificity was 53% and the diagnostic odds ratio was 8.76. Conclusion The Fukuoka criteria have considerably improved sensitivity but still lack adequate specificity. For further reduction of a potential surgical overtreatment of BD-IPMN, the development of criteria with an increased specificity is required.
Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells’ neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 ...(Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target.
A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2–RNAPII complex.
We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types.
Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.
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Agr2 is a novel mediator for the nuclear import of RNA polymerase II. Agr2-dependent nuclear import of RNA polymerase II constitutes a pharmaceutically accessible target for prevention and treatment in pancreatic ductal adenocarcinoma in the context of p53.
Although endocannabinoids constitute one of the first lines of defense against pain, the anatomical locus and the precise receptor mechanisms underlying cannabinergic modulation of pain are ...uncertain. Clinical exploitation of the system is severely hindered by the cognitive deficits, memory impairment, motor disturbances and psychotropic effects resulting from the central actions of cannabinoids. We deleted the type 1 cannabinoid receptor (CB1) specifically in nociceptive neurons localized in the peripheral nervous system of mice, preserving its expression in the CNS, and analyzed these genetically modified mice in preclinical models of inflammatory and neuropathic pain. The nociceptor-specific loss of CB1 substantially reduced the analgesia produced by local and systemic, but not intrathecal, delivery of cannabinoids. We conclude that the contribution of CB1-type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount, which should enable the development of peripherally acting CB1 analgesic agonists without any central side effects.
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