Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies against self-antigens.

Intratumoral B cell responses are associated with more favorable clinical outcomes in human pancreatic ductal adenocarcinoma (PDAC). However, the antigens driving these B cell responses are largely unknown. We sought to discover these antigens by using single-cell RNA sequencing (scRNA-Seq) and immunoglobulin (Ig) sequencing of tumor-infiltrating immune cells from 7 primary PDAC samples. We identified activated T and B cell responses and evidence of germinal center reactions. Ig sequencing identified plasma cell (PC) clones expressing isotype-switched and hypermutated Igs, suggesting the occurrence of T cell-dependent B cell responses. We assessed the reactivity of 41 recombinant antibodies that represented the products of 235 PCs and 12 B cells toward multiple cell lines and PDAC tissues and observed frequent staining of intracellular self-antigens. Three of these antigens were identified: the filamentous actin (F-actin), the nucleic protein RuvB like AAA ATPase 2 (RUVBL2), and the mitochondrial protein heat shock protein family D (Hsp60) member 1 (HSPD1). Antibody titers against F-actin and HSPD1 were substantially elevated in the plasma of patients with PDAC compared with healthy donors. Thus, PCs in PDAC produce autoantibodies reacting with intracellular self-antigens, which may result from promotion of preexisting, autoreactive B cell responses. These observations indicate the chronic inflammatory microenvironment of PDAC can support the adaptive immune response.

Pancreatic Cancer Patient-derived Organoids Can Predict Response to Neoadjuvant Chemotherapy.

OBJECTIVE: To evaluate if patient-derived organoids (PDOs) may predict response to neoadjuvant (NAT) chemotherapy in patients with pancreatic adenocarcinoma. BACKGROUND: PDOs have been explored as a biomarker of therapy response and for personalized therapeutics in patients with pancreatic cancer. METHODS: During 2017-2021, patients were enrolled into an IRB-approved protocol and PDO cultures were established. PDOs of interest were analyzed through a translational pipeline incorporating molecular profiling and drug sensitivity testing. RESULTS: One hundred thirty-six samples, including both surgical resections and fine needle aspiration/biopsy from 117 patients with pancreatic cancer were collected. This biobank included diversity in stage, sex, age, and race, with minority populations representing 1/3 of collected cases (16% Black, 9% Asian, 7% Hispanic/Latino). Among surgical specimens, PDO generation was successful in 71% (15 of 21) of patients who had received NAT prior to sample collection and in 76% (39 of 51) of patients who were untreated with chemotherapy or radiation at the time of collection. Pathological response to NAT correlated with PDO chemotherapy response, particularly oxaliplatin. We demonstrated the feasibility of a rapid PDO drug screen and generated data within 7 days of tissue resection. CONCLUSION: Herein we report a large single-institution organoid biobank, including ethnic minority samples. The ability to establish PDOs from chemotherapy-naive and post-NAT tissue enables longitudinal PDO generation to assess dynamic chemotherapy sensitivity profiling. PDOs can be rapidly screened and further development of rapid screening may aid in the initial stratification of patients to the most active NAT regimen.

Patient-Derived Triple-Negative Breast Cancer Organoids Provide Robust Model Systems That Recapitulate Tumor Intrinsic Characteristics.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, highlighting the unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDO) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBC). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven, basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, this study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and tailored treatment options. SIGNIFICANCE: A comprehensive analysis of patient-derived organoids of TNBC provides insights into cellular heterogeneity and mechanisms of tumorigenesis at the single-cell level.

Olaparib-Induced Immune-Mediated Liver Injury.

Immune-mediated drug-induced liver injury can be triggered by multiple classes of medications including immunotherapies. Olaparib is a first-in-class oral inhibitor of poly (adenosine diphosphate-ribose) polymerase (an enzyme involved in DNA replication and repair) that is approved as maintenance treatment in platinum-sensitive, epithelial ovarian, tubal, or primary peritoneal cancers with breast cancer 1/2 mutation. We report the first case in the United States of an acute and severe liver injury with associated jaundice and liver synthetic dysfunction secondary to olaparib. The liver injury was resolved with drug cessation and treatment with prednisone taper.

A rare case of Polyarteritis Nodosa associated with autoimmune hepatitis: a case report.

BACKGROUND: Polyarteritis nodosa is a type of vasculitis affecting medium- and small-sized arteries that has been associated with hepatitis B but does not have an established relationship with autoimmune hepatitis. Here we report the case of an adult patient with autoimmune hepatitis who, shortly after diagnosis, developed life-threatening polyarteritis nodosa. CASE PRESENTATION: A 45-year-old woman was diagnosed with autoimmune hepatitis after initially presenting with a two-month history of fatigue, nausea, and anorexia and a three-week history of scleral icterus. Her liver biopsy showed mild portal fibrosis and her liver chemistries improved with prednisone and azathioprine. Three months later, she presented to the emergency department with fever, bilateral ankle pain, rash, oral ulcers, and poor vision. Physical examination was notable for erythema nodosum, anterior uveitis, retinal vasculitis, and frosted branch angiitis (frosted branch angiitis (a widespread florid translucent perivascular exudate). She subsequently developed repeated episodes of ischemic acute bowel necrosis that required multiple surgeries and extensive small bowel resections. Surgical pathology of the small bowel resection revealed ischemic necrosis, medium and small vessel vasculitis with microvascular thrombi consistent with polyarteritis nodosa. Azathioprine was discontinued and she was treated with pulse steroids followed by a prednisone taper, cyclophosphamide, and intravenous immune globulin with overall improvement in her symptomatology. Since her hospitalization, she has been maintained on low-dose prednisone and mycophenolate mofetil. CONCLUSIONS: In patients with recent diagnosis of autoimmune hepatitis, there should be a modest suspicion for concomitant polyarteritis nodosa if symptoms and signs of multisystem vasculitis develop.

Mesenteric Arteriovenous Dysplasia/Vasculopathy Mimicking Crohn's Disease: A Case Report.

Mesenteric arteriovenous vasculopathy (MAVD/V) is an extremely rare and poorly understood disease and its incidence is probably underestimated. It is an uncommon, non-inflammatory and non-atherosclerotic form of mesenteric vascular injury, first reported in 2016, with characteristic histopathologic evidence of fibromuscular dysplasia-like vascular changes. We present the case of a chronically ill 84-year-old female with a 5 year history of recurrent small bowel obstruction, who underwent segmental resection of the small bowel. Intraoperative examination showed bowel stricture with fibrosis, intraluminal pill fragments and creeping mesenteric adipose tissue clinically compatible with Crohn's disease. Histological examination showed acute and chronic mucosal injury characterized by crypt distortion, ulcerations with granulation tissue, pseudo-pyloric metaplasia, areas of fibrosis and serosal adhesions. Multiple blood vessels (including both veins and arteries) demonstrated wall hyalinization, elastic degeneration and non-atherosclerotic luminal occlusion. The pattern of the mucosal injury is, in this case, potentially a consequence of acute and chronic ischemic processes secondary to mesenteric arteriovenous vasculopathy.

Brown Bowel Syndrome: A Multi-institutional Case Series.

Brown bowel syndrome (BBS) is a rare condition associated with vitamin E deficiency and defined by prominent lipofuscin deposition in the muscularis propria. Eight unique cases of BBS were identified: 5 men and 3 women (mean age=58.6 y). Pertinent comorbidities included bariatric surgery=2, malnourishment=2, Crohn=2, cystic fibrosis=1, alcohol and cocaine abuse=1, and prior small bowel resections=1. Presenting symptoms included abdominal pain=3, bleeding=1, nausea and vomiting=1, and nonresponsiveness=1. Imaging studies were often abnormal: thickened bowel wall=3 (1 with a mass), small bowel obstruction=2, and edematous and dilated bowel wall=2. Most specimens were surgical resections (n=7, autopsy=1): extended right colectomy=2, small bowel only=5 (terminal ileum=3, jejunum=2). Two specimens were grossly described as mahogany, and 1 case contained a perforation. Histologic sections of all cases showed finely granular, brown cytoplasmic pigment in smooth muscle cells on hematoxylin and eosin. This pigment was most conspicuous in the muscularis propria (small bowel>colon), and it was not identified in the mucosa. The pigment was reactive with Fontana-Masson, carbol lipofuscin, Periodic acid-Schiff, and Periodic acid-Schiff with diastase, and electron microscopy was compatible with lipofuscin. The mean clinical follow-up was 208 weeks: 1 patient died of complications of encephalitis, the others were alive and well. BBS is important to recognize because it is linked with malnutrition, specifically vitamin E deficiency, and it can (rarely) clinically simulate malignancy. The diagnosis is based on the identification of the lipofuscin pigment in the cytoplasm of smooth muscle cells, which is most easily seen in the muscularis propria of the small bowel.

Malignant transformation of liver fatty acid binding protein-deficient hepatocellular adenomas: histopathologic spectrum of a rare phenomenon.

The molecular classification of hepatocellular adenomas highlights a distinctive genotype-phenotype correlation. Malignant transformation is an exceptionally rare complication of hepatocyte nuclear factor 1α (HNF1A)-inactivated hepatocellular adenomas. This subtype is characterized by loss of liver fatty acid binding protein immunoexpression. In this study, we characterized the histopathologic spectrum of 13 liver fatty acid binding protein-deficient hepatocellular adenoma cases showing malignant transformation from multiple centers. Clinicopathologic characteristics of these patients were evaluated. Stains for reticulin, liver fatty acid binding protein, beta-catenin and glutamine synthetase were applied to these lesions. Moreover, the findings were compared to patients with ß-catenin mutated hepatocellular adenoma. Liver fatty acid binding protein-deficient hepatocellular adenomas with borderline features/carcinoma were seen predominantly in females (77%) with an average age of 46 ± 18 years and multiple lesions (77%; five patients with adenomatosis). Meanwhile, ß-catenin mutated hepatocellular adenoma patients with malignant transformation were predominantly male (67%, p = 0.018) with single lesion (86%, p = 0.0009). The largest liver fatty acid binding protein-deficient hepatocellular adenoma nodule in each patient ranged from 4 to 15.5 cm. Loss of liver fatty acid binding protein by immunohistochemistry was noted in all adenoma and borderline/carcinoma components. Features of malignant transformation were pseudoglandular architecture (85%), cytologic atypia (85%), architectural atypia (100%) and lack of steatosis (100%). Other findings included myxoid change (39%), peliosis (46%) and sinusoidal dilatation (46%). Molecular studies confirmed somatic inactivation of HNF1A in 3 cases and absence of TERT promotor and exon 3 CTNNB1 mutations in five cases. To summarize, liver fatty acid binding protein-deficient hepatocellular adenoma with malignant transformation is most frequently seen in female patients with multiple lesions. Most of these lesions demonstrate pseudoglandular architecture, cytologic and architectural atypia, with lack of steatosis. The natural history of these lesions is relatively benign with the exception of disease recurrence in 1 patient.

Volumetric laser endomicroscopy features of dysplasia at the gastric cardia in Barrett's oesophagus: results from an observational cohort study.

OBJECTIVE: Volumetric laser endomicroscopy (VLE) is an advanced imaging modality used in Barrett's oesophagus (BE) to help identify dysplasia in the oesophagus. VLE criteria exist for oesophageal dysplasia but not for dysplasia in the gastric cardia. The aim of this study was to determine if there are in vivo VLE features that can predict gastric cardia dysplasia in BE. DESIGN: This was a single-centre observational cohort study from August 2016 to August 2018. Patients were included if they had BE, were undergoing a VLE exam as standard of care, and had a suspicious target laser marked at the gastric cardia. The following VLE features were correlated to histology to determine if an association existed between histology subtype and VLE feature: wide crypts, irregular surface, one large isolated gland, multiple glands, and complex glands. RESULTS: A total of 110 in vivo gastric cardia targets in 77 patients with BE were analysed. The following abnormalities were identified: 61 wide crypts, 34 isolated glands, 16 irregular surfaces, 15 multiple glands, and 11 complex glands. Complex glands were the only VLE feature that correlated to any histology subtype. They were present in 71% of targets with high-grade dysplasia (HGD), T1a cancer or T1b cancer and had a sensitivity, specificity, and accuracy of 71%, 99%, and 85%, respectively. Of the 10 patients with complex glands on VLE and HGD/cancer on histology, 4 had a normal-appearing mucosa (40%) on endoscopy. CONCLUSION: Identification of complex glands on VLE may aid in detection of HGD or early cancer in the gastric cardia in BE. This is particularly important, as dysplasia at the gastric cardia can be difficult to see endoscopically.

Use of volumetric laser endomicroscopy for determining candidates for endoscopic therapy in superficial esophageal squamous cell carcinoma.

BACKGROUND: Accurate staging of superficial esophageal squamous cell cancer (ESCC) for endoscopic therapy is challenging. Optical coherence tomography (OCT) has been shown to be superior to high-resolution endoscopic ultrasound (EUS). Volumetric Laser Endomicroscopy (VLE), a second-generation OCT, has recently become commercially available. OBJECTIVE: To assess if VLE can determine which patients with superficial ESSC can undergo endoscopic therapy. METHODS: This is a multi-center retrospective study. Patients were included if (a) they had visible ESCC, (b) they underwent VLE and EUS for staging, and c) if superficial disease was suspected then endoscopic resection had to be performed to have accurate histology to compare the VLE scan to. VLE scans were then compared to the gold standard: histology for superficial disease and EUS for disease T1b and greater. RESULTS: Seventeen patients were included with the following disease: squamous intraepithelial neoplasia (4 patients), T1a disease (6 patients), T1b (2 patients), T2 disease (2 patients) and T3 disease (3 patients). VLE was able to distinguish superficial disease, defined as disease limited up to the lamina propria, from non-superficial disease in all cases. CONCLUSIONS: VLE may be able to determine which ESCC patients are candidates for endoscopic therapy. Prospective studies are needed to confirm this.

Identification of volumetric laser endomicroscopy features of colon polyps with histologic correlation.

BACKGROUND AND AIMS: There are limited data on the use of volumetric laser endomicroscopy (VLE) for imaging colon polyps. Our aim was to identify VLE features of colon polyps. METHODS: A total of 45 patients were included; 43 underwent endoscopic mucosal resection of colorectal polyps 2 cm or greater. These polyps were then scanned with VLE immediately after resection. Two patients who underwent partial colonic resection served as controls. RESULTS: Forty-three polyps were included with review of matching histology: 3 intramucosal cancer (IMCA), 5 tubular adenoma (TAs)/tubulovillous adenoma (TVA) with high-grade dysplasia (HGD), 9 TVA with only low-grade dysplasia (LGD), 5 serrated adenoma, and 21 TA with LGD. All TAs and TVAs were hyper-reflective compared with normal tissue. Effacement occurred in 82.4% (14/17) of the colonic polyps with advanced pathology (TVA with HGD/IMCA) compared with 11.6% (3/26) with non-advanced pathology (TA with LGD and serrated adenoma) (P < .0001). Forty-seven percent (8/17) of polyps with advanced pathology had greater than 5 glands on VLE compared with none in the non-advanced pathology group (P = .0001). An irregular surface mainly occurred in polyps with high-grade pathology (HGD/IMCA) versus TAs. Eighty-eight percent of polyps with HGD/IMC had an irregular surface (7/8) versus 6% (2/35) of TAs (P < .0001). CONCLUSIONS: In this ex vivo clinicopathologic study, we show that there are distinct VLE features of colon polyps that may help identify polyps or features of a higher-grade lesion. This may have implications for possible in vivo application to aid in dysplasia or polyp detection.

Pathological and molecular evaluation of pancreatic neoplasms.

Pancreatic neoplasms are morphologically and genetically heterogeneous and include a wide variety of tumors ranging from benign to malignant with an extremely poor clinical outcome. Our understanding of these pancreatic neoplasms has improved significantly with recent advances in cancer sequencing. Awareness of molecular pathogenesis brings new opportunities for early detection, improved prognostication, and personalized gene-specific therapies. Here we review the pathological classification of pancreatic neoplasms from the molecular and genetic perspectives.

Metastatic Malignant Melanoma to Urinary Bladder: A Potential Pitfall for High-Grade Urothelial Carcinoma.

We present a case of a 61-year-old female presenting with a bladder tumor that occurred 7 years after her previous diagnosis of Clark's level III mid-back melanoma. The bladder tumor was submitted to histopathology without accompanying clinical history, and an initial diagnosis of high-grade urothelial carcinoma was rendered based on epithelioid and sarcomatoid appearing pleomorphic histopathology. We present this case to highlight the diagnostic challenge presented by the rare occurrence of metastatic melanoma to the urinary bladder and the potential pitfall of this lesion being diagnosed as high-grade urothelial carcinoma in the presence of limited clinical history.

Metastatic medullary carcinoma of thyroid presenting as a dural-based mass: case report and review of literature.

Dural metastasis from medullary thyroid carcinoma (MTC) is not well established in English literature. We present the case report of MTC with unusual clinical presentation as a dural-based mass in a 39-year-old male with no family history of multiple endocrine neoplasia syndrome. Magnetic resonance imaging showed an extra-axial dural-based mass in right frontal lobe with calvarium and soft tissue extension to the right superior orbit. Histopathology showed MTC with variegated morphology and various patterns. Thyroid mass and widespread metastases from medullary thyroid carcinoma were subsequently identified.

Glomangiosarcoma in the shoulder of a 51-year-old man.

Glomangiosarcoma is a very rare type of soft tissue neoplasm. Here we report such a case in the shoulder of a 51-year-old man.

Microcystic meningioma presenting as a cystic lesion with an enhancing mural nodule in elderly women: report of three cases.

Cystic meningioma with an enhancing mural nodule is uncommon and can present as a radiologic and clinical dilemma with wide differential. We report a series of rare and unique presentation of microcystic meningioma in three elderly women aged 76 (case 1), 72 (case 2), and 76 (case 3) years, respectively. The first patient presented with a 3-year history of vertigo and past history of carotid artery stenosis, hypertension, and hypothyroidism. The second patient presented with headache and an acute episode of weakness in her legs. The third patient presented with headache, vomiting, and confusion. Magnetic resonance imaging for these three cases showed a cystic lesion with an enhancing mural nodule in the right frontal lobe. The preoperative differential diagnoses included hemangioblastoma and well-circumscribed gliomas for the first two cases. Glioblastoma and metastatic tumor were the working diagnoses for the third case because of vasogenic brain edema and marked mass effect. The final pathological diagnosis was microcystic meningioma for all three cases. Case reports are mainly of fibrous or meningothelial meningiomas with cystic formation. Male predominance and young age are most commonly reported. Our series is unique because of the rare and unusual clinical-radiologic presentation of microcystic meningioma in elderly women.