Background & Aims: Epithelial tumors generally resemble the cellular architecture of their tissue of origin. However, this link remains largely unexplored in the pancreas. Methods: Using Nanostring GeoMx DSP®, Resolve Molecular Cartography® and Nanostring CosMx®, and integration with single cell RNAseq datasets, we mapped the human pancreatic ductal epithelium in non-neoplastic pancreas, and compared it to pancreatic cancer subtypes. Results: Groups of Keratin-5+ cells among the Pan-Cytokeratin+ cells in the duct have a gene signature reminiscent of stem cells and (supra)basal cells from other tissues. In spatial analysis at single cell resolution, the pancreatic duct manifests as a stratified epithelium comprising a basal and four luminal populations; In large ducts, KRT5+ basal (BAS) cells express ∆Np63 while KRT5+ luminal (LUM)-B cells reside supra-basally and are distinct from the common KRT5- LUM-A cells. LUM-C and LUM-D cells pertain to intercalated ducts and ductal glands, respectively. LUM-A and -C cells express gel-forming mucins while LUM-B cells have membrane-bound MUC4 and MUC16. In cancer, BAS and LUM-B signatures associate with the basal-like pancreatic ductal adenocarcinoma (PDAC) and correlate with lower survival but exhibit a mixed spatial pattern with a diffracted gene signature. In contrast, adenosquamous cancers of the pancreas (ASCP) preserve the normal spatially unmixed identity of LUM-B cells and BAS cells that is regulated by ∆Np63. Next to ∆Np63, conserved drug targets were identified for both populations. Conclusion: This study offers a refined pancreatic tumor classification based on the native ductal architecture, with better preservation of the LUM-B and BAS cell population identity in ASCP than in PDAC, including the conserved drug targets. ### Competing Interest Statement The authors have declared no competing interest.

A ‘classical’ and a ‘basal‐like’ subtype of pancreatic cancer have been reported, with differential expression of GATA6 and different dosages of mutant KRAS. We established in situ detection of KRAS point mutations and mRNA panels for the consensus subtypes aiming to project these findings to paraffin‐embedded clinical tumour samples for spatial quantitative analysis. We unveiled that, next to inter‐patient and intra‐patient inter‐ductal heterogeneity, intraductal spatial phenotypes exist with anti‐correlating expression levels of GATA6 and KRASG12D. The basal‐like mRNA panel better captured the basal‐like cell states than widely used protein markers. The panels corroborated the co‐existence of the classical and basal‐like cell states in a single tumour duct with functional diversification, i.e. proliferation and epithelial‐to‐mesenchymal transition respectively. Mutant KRASG12D detection ascertained an epithelial origin of vimentin‐positive cells in the tumour. Uneven spatial distribution of cancer‐associated fibroblasts could recreate similar intra‐organoid diversification. This extensive heterogeneity with functional cooperation of plastic tumour cells poses extra challenges to therapeutic approaches. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Sinusoidal obstruction syndrome (SOS) is a rare but potentially life-threatening complication, usually described in the setting of hematopoietic stem cell transplantation (HSCT). The very severe forms have a high mortality rate (>80%) and need fast recognition and urgent treatment. In this case report, we describe a unique and successful treatment strategy. We present a 27-year-old patient with newly diagnosed CD33+ acute myeloid leukemia (AML). She was treated with induction chemotherapy (7+3 regimen) and gemtuzumab ozogamicin (GO). In the absence of other major risk factors, she developed a very severe SOS with multiple organ failure. She was successfully treated with the urgent insertion of a transjugular intrahepatic portosystemic shunt (TIPS), defibrotide, and high-dose corticosteroids. This case of successful treatment for very severe SOS supports a combination strategy involving the immediate mechanical reduction of portal hypertension through TIPS and drug-mediated inhibition of microvascular thrombosis. Furthermore, this case shows the need for an improved prevention strategy, including the identification of additional risk factors and biomarkers.

Background Persistent inguinal lymphadenopathy can range from benign to malignant causes. Lymphogranuloma venereum (LGV), a sexually transmitted infection (STI), is a possible cause, particularly in individuals engaged in sexual practices associated with a higher likelihood of transmitting STIs. This case series outlines the diagnostic challenges of LGV. Case Presentation Two male patients, aged 36 and 48, with sexual practices associated with an elevated risk of STI transmission, presented with inguinal lymphadenopathy. Initial investigations, including rectal and genital nucleic acid amplification tests (NAATs) for STIs, were negative. Patient one underwent two fine-needle aspirations, both inconclusive. An excisional biopsy later confirmed LGV through a positive NAAT for Chlamydia trachomatis and consistent pathology. The diagnosis took several years, included three PET scans, and was complicated by a surgical site infection with Staphylococcus aureus. Patient 2, despite negative NAAT results, was empirically treated for LGV based on clinical suspicion, with resolution after doxycycline. Intervention and Outcome Both patients improved significantly with doxycycline. Retrospective serology showed elevated Chlamydia trachomatis IgG titers, supporting this diagnosis. Conclusion This case series emphasizes the need to consider LGV in patients with persistent lymphadenopathy and sexual practices that may increase the likelihood of STIs.

Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)-21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8+ T cells and their capacity to produce granzyme B and IFN-gamma, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8+ T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.

Background & AimsChronic liver disease (CLD) remains a global health issue associated with a significant burden of disease. Liver fibrosis, one of the hallmarks of CLD, is characterized by the activation of hepatic stellate cells (HSCs) that gain pro-fibrotic characteristics including increased extracellular matrix protein production. Currently, no anti-fibrotic therapies are available in the clinic partly due to the lack of HSC-specific drug targets. Here, we aimed to identify HSC-specific membrane proteins that can serve as targets for anti-fibrotic drug development.MethodsSmall interfering RNA-mediated knock-down of GPR176 was used to assess its in vitro function in HSCs and precision cut liver slices (PCLS). The in vivo role of GPR176 was assessed in the carbon tetrachloride (CCl4) and common bile duct ligation (BDL) models in wild-type and GPR176 knock-out mice. GPR176 in human CLD was assessed by immunohistochemistry of diseased human livers and RNA expression analysis in human primary HSCs and transcriptomic data sets.ResultsWe identified Gpr176, an orphan G-protein coupled receptor, as an HSC-enriched activation associated gene. In vitro, Gpr176 is strongly induced upon culture-induced and hepatocyte-damage-induced activation of primary HSCs. Knock-down of GPR176 in primary mouse HSCs or PCLS cultures resulted in reduced fibrogenic characteristics. Absence of Gpr176 does not affect liver homeostasis, but Gpr176-/- mice develop less severe fibrosis in CCl4 and BDL fibrosis models. In humans, GPR176 expression is correlated with in vitro HSC activation and with fibrosis stage in patients suffering from CLD.ConclusionsGPR176 is a functional protein during liver fibrosis and reducing its activity attenuates fibrogenesis. These results highlight the potential of GPR176 as an HSC-specific anti-fibrotic candidate to treat CLD.Impact and implicationsThe lack of effective anti-fibrotic drugs is partly due to insufficient knowledge about the mechanisms involved in liver fibrosis development. We demonstrate G-protein coupled receptor 176 contributes to fibrosis development. Since GPR176 is specifically expressed on the membrane of activated hepatic stellate cells and is linked with fibrosis progression in humans, it opens avenues for the development of targeted interventions.

Background and purpose: Primary angiosarcoma of the spleen (PAS), an exceptionally rare and aggressive neoplasm with high metastatic risk (70%–85%), is frequently diagnosed in an advanced or metastatic stage. It presents diagnostic challenges due to its nonspecific symptomatology and resemblance to benign vascular lesions in various imaging modalities. Patients and methods: This case series aims to clarify the diagnostic difficulties by comparing imaging characteristics (CT-scan, MRI, and [18F]FDG-PET/CT) as well as pathological findings of three PAS cases diagnosed in different stages of the diseases (localized, metastatic, and metastatic with organ failure). Furthermore, a brief review on diagnostic and therapeutic features is included. Results and interpretation: We suggest [18F]FDG-PET/CT as a differentiating tool between benign and malignant splenic lesions and propose a flowchart of a diagnostic algorithm for PAS. For treatment, we advocate for early splenectomy and when systemic therapy is warranted, paclitaxel emerges as a viable first-line option. While it is crucial to acknowledge that further trial data is required to evaluate the efficacy of emerging treatment regimens, designing and conducting trials for PAS is challenging given its scarcity and aggressive behavior. Therefore case reporting remains important.

Heterotopia of the salivary gland occurs mainly in the head and neck region of the human body, rarely in regions such as the rectum, but has never been demonstrated in the pancreas. Within a screening effort of pancreatic samples for detecting ΔNp63 expression, we discovered two pancreatic samples from a 35-year-old male showing salivary gland heterotopia. Immunohistochemical stainings were done for markers of healthy and neoplastic salivary glands and showed expression of calponin, CD142 and KRT14 but not of S100p, GFAP or CD117. A PAS-staining and Alcian Blue staining showed the presence of acid mucins. These staining patterns were consistent with non-neoplastic submandibular gland tissue comprised of abundant seromucous glands, basal cells and myoepithelial cells, all features typically absent in the pancreas. Also, no pancreatic islets of Langerhans were detected. We show for the first time that salivary gland heterotopia can occur at the location of the pancreas.

Introduction Pure androgen-secreting adrenocortical tumors are a rare but important cause of peripheral precocious puberty. Case presentation Here, we report a pure androgen-secreting adrenocortical tumor in a 2.5-year-old boy presenting with penile enlargement, pubic hair, frequent erections, and rapid linear growth. We confirmed the diagnosis through laboratory tests, medical imaging, and histology. Furthermore, genetic testing detected a pathogenic germline variant in the TP53 gene, molecularly confirming underlying Li–Fraumeni syndrome. Discussion Only 15 well-documented cases of pure androgen-secreting adrenocortical tumors have been reported so far. No clinical or imaging signs were identified to differentiate adenomas from carcinomas, and no other cases of Li–Fraumeni syndrome were diagnosed in the four patients that underwent genetic testing. However, diagnosing Li–Fraumeni syndrome is important as it implies a need for intensive tumor surveillance and avoidance of ionizing radiation. Conclusion In this article, we emphasize the need to screen for TP53 gene variants in children with androgen-producing adrenal adenomas and report an association with arterial hypertension.

ObjectiveThe aggressive basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) harbours a ΔNp63 (p40) gene expression signature reminiscent of a basal cell type. Distinct from other epithelia with basal tumours, ΔNp63+basal cells reportedly do not exist in the normal pancreas.DesignWe evaluated ΔNp63 expression in human pancreas, chronic pancreatitis (CP) and PDAC. We further studied in depth the non-cancerous tissue and developed a three-dimensional (3D) imaging protocol (FLIP-IT, Fluorescence Light sheet microscopic Imaging of Paraffin-embedded or Intact Tissue) to study formalin-fixed paraffin-embedded samples at single cell resolution. Pertinent mouse models and HPDE cells were analysed.ResultsIn normal human pancreas, rare ΔNp63+cells exist in ducts while their prevalence increases in CP and in a subset of PDAC. In non-cancer tissue, ΔNp63+cells are atypical KRT19+duct cells that overall lack SOX9 expression while they do express canonical basal markers and pertain to a niche of cells expressing gastrointestinal stem cell markers. 3D views show that the basal cells anchor on the basal membrane of normal medium to large ducts while in CP they exist in multilayer dome-like structures. In mice, ΔNp63 is not found in adult pancreas nor in selected models of CP or PDAC, but it is induced in organoids from larger Sox9lowducts. In HPDE, ΔNp63 supports a basal cell phenotype at the expense of a classical duct cell differentiation programme.ConclusionIn larger human pancreatic ducts, basal cells exist. ΔNp63 suppresses duct cell identity. These cells may play an important role in pancreatic disease, including PDAC ontogeny, but are not present in mouse models.

Introduction Sarcoidosis is a systemic granulomatous disease, characterized by the formation of non-necrotizing granulomas. Even though granulomas are frequently found in liver biopsy, related symptoms rarely occur. In the current article, a case report is pictured to increase the knowledge on portal hypertension in hepatic sarcoidosis.Clinical situation A 62-year-old female was diagnosed with variceal bleeding for which elastic banding was performed. The patient was admitted to the intensive care unit (ICU) as the bleeding persisted and she evolved in hemorrhagic shock. Liver ultrasound detected nodular hepatomegaly and partial portal thrombosis. Chest CT showed diffuse hilar adenopathies and interstitial micronodular lesion. Finally, PET-CT detected metabolic active liver, bone marrow, and upper and lower diaphragmatic adenopathies.Clinical resolution Multidisciplinary discussion brought major advantages in rapid diagnosis and prompt effective treatment. Cirrhosis was diagnosed by liver nodularity on imaging and liver biopsy. Sarcoidosis diagnosis was supported by the biopsies of liver and lymph node, which yielded non-caseating granulomas infiltration. Chest CT scan and PET-CT were also consistent with this diagnosis. The complementary analysis excluded differential diagnosis. The patient was treated with high-dose methylprednisolone with notable clinical improvements and discharge from the ICU.Conclusion Hepatic sarcoidosis can present as life-threatening bleeding due to variceal bleeding caused by portal hypertension. Differential diagnosis is broad when hepatic sarcoidosis is suspected. Therefore, a multidisciplinary discussion is warranted. Anatomopathological examination of two potentially involved organs should be considered to make the appropriate diagnosis. Further studies are requested to investigate the pathophysiological mechanism of portal hypertension.

Emerging anticancer agents such as the pan-FGFR Inhibitor have achieved remarkable improvements in the survival of patients with metastatic malignancies. Nevertheless they are still associated with specific ophthalmic toxicities. Understanding their pathophysiology can lead us to better clinical practice of life-threatening and vision-threatening circumstances. To investigate choroidal alterations as a potential pathophysiological mechanism of a serous detachment in bilateral pan-FGFR Inhibitor-Associated Retinopathy (FGFRAR), the morphology of the choroid and choriocapillaris were assessed. The choroidal thickness (ChT) and choriocapillaris flow void were measured by macular optical coherence tomography (OCT) and angiography (OCT-A), respectively. Data were collected at the baseline, then at one-month and two-months follow-ups after starting erdafitinib, in a single case of pulmonary angiosarcoma. Choroidal and choriocapillaris morphology showed stable ChT and choriocapillaris flow void at FGFRAR onset and relapse. To the best of our knowledge, this is the first analyzed case reported with flow-void OCT-angiography. Considering these results, FGFRAR in this patient does not seem to match the pachychoroid spectrum disorder definition; rather, an intracellular mechanism based on intracellular transduction pathways may be at work.