Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer.

Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b.

Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD(+)-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1, and IGF2BP3. This epigenetic program defines a distinct subset with a poor prognosis, representing 30%-40% of human PDAC, characterized by reduced SIRT6 expression and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor and uncover the Lin28b pathway as a potential therapeutic target in a molecularly defined PDAC subset. PAPERCLIP.

Androgen Deficiency in Aging Males (ADAM) Score as a Predictor of Total Testosterone Levels in Type 2 Diabetes Mellitus: A Prospective, Cross-sectional Study.

OBJECTIVE: Assessment of Androgen Deficiency in Aging Males (ADAM) questionnaire in predicting serum testosterone levels in type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A single centre, prospective, cross-sectional epidemiological study in 250 male individuals with T2DM. ADAM questionnaire and serum total testosterone (TT) levels were analyzed for correlation using a Chi-squared test. Jaccard analysis to evaluate the concordance and dissimilarity between ADAM score and TT levels, providing insights into ADAM's predictive ability for testosterone levels. RESULTS: The mean age of the study population was 49.1 ± 7.8 years. The mean duration of diabetes was 6.2 ± 5.1 years. 27.6% were diagnosed with hypogonadism, while 72.4% were eugonadal. The mean age was 51.1 and 48.4 years in the hypogonadal and eugonadal cohorts, respectively (p < 0.02). The mean TT in the hypogonadal cohort was 220.6 ± 61.3 ng/dL, and in the eugonadal cohort was 475.4 ± 152.9 ng/dL (p < 0.001). The mean body mass index (BMI) in the hypogonadal cohort was 26.5 ± 4.0 kg/m2, and in the eugonadal group was 25.2 ± 3.6 kg/m2 (p < 0.02). Chi-square analysis established a strong positive correlation between the positive ADAM score and hypogonadism (p < 0.011). Of the 69 hypogonadal subjects, 84.05% had a positive ADAM score, yielding a sensitivity of 84.05% in detecting hypogonadism with a specificity of 32.04%. CONCLUSION: The ADAM questionnaire is a practical and cost-effective initial screening tool for identifying symptoms suggestive of testosterone deficiency. It has high sensitivity in identifying men with hypogonadism, while caution must be in place as it has a very low specificity. In resource-poor settings, ADAM score could be a clinical marker of hypogonadism.

Osteogenic Sarcoma of the Head and Neck: Is Chemotherapy Needed?

OPINION STATEMENT: Head and neck osteosarcoma (HNOS) is a rare subtype of sarcoma that most commonly arises in the mandible or maxilla. Treatment for HNOS typically involves a multidisciplinary and multimodal approach depending on the size, grade, and histological subtype. Surgery by sarcoma-experienced head and neck surgeons and orthopedic oncologists remains a crucial component of treatment in all subtypes of HNOS, particularly for those with low-grade histology, which can be treated definitively with surgical resection if negative margins are obtained. Negative surgical margins are of utmost prognostic importance, and neoadjuvant or adjuvant radiation should be considered in patients with positive (or anticipated positive) margins/residual postoperative disease. Current data favors the use of (neo)adjuvant chemotherapy in patients with high-grade HNOS to improve overall survival but must be individualized to weigh benefits and risks of the short- and long-term effects of treatment. Our center uses a multidisciplinary treatment plan and notes anecdotal improvement in treatment outcomes with a combined surgical and ifosfamide-containing chemotherapeutic approach with radiotherapy for local control if positive margins. Large volume cohorts and adequate randomized control trials assessing the efficacy of chemotherapy in HNOS are scant and additional research and multi-institutional collaboration are needed to study polychemotherapeutic and radiation treatment regimens and outcomes more adequately.

Diagnostic Utility of Computed Tomography Perfusion in the Telestroke Setting.

BACKGROUND: Definitive diagnosis of acute ischemic stroke is challenging, particularly in telestroke settings. Although the prognostic utility of CT perfusion (CTP) has been questioned, its diagnostic value remains under-appreciated, especially in cases without an easily visible intracranial occlusion. We assessed the diagnostic accuracy of routine CTP in the acute telestroke setting. METHODS: Acute and follow-up data collected prospectively from consecutive suspected patients with stroke assessed by a state-wide telestroke service between March 2020 and August 2021 at 12 sites in Australia were analyzed. All patients in the final analysis had been assessed with multimodal CT, including CTP, which was post-processed with automated volumetric software. Diagnostic sensitivity and specificity were calculated for multimodal CT and each individual component (noncontrast CT [NCCT], CT angiogram [CTA], and CTP). Final diagnosis determined by consensus review of follow-up imaging and clinical data was used as the reference standard. RESULTS: During the study period, complete multimodal CT examination was obtained in 831 patients, 457 of whom were diagnosed with stroke. Diagnostic sensitivity for ischemic stroke increased by 19.5 percentage points when CTP was included with NCCT and CTA compared with NCCT and CTA alone (73.1% positive with NCCT+CTA+CTP [95% CI, 68.8-77.1] versus 53.6% positive with NCCT+CTA alone [95% CI, 48.9-58.3], P<0.001). No difference was observed between specificities of NCCT+CTA and NCCT+CTA+CTP (98.7% [95% CI, 98.5-100] versus 98.7% [95% CI, 96.9-99.6], P=0.13). Multimodal CT, including CTP, demonstrated the highest negative predictive value (75.0% [95% CI, 72.1-77.7]). Patients with stroke not evident on CTP had small volume infarcts on follow-up (1.2 mL, interquartile range 0.5-2.7mL). CONCLUSIONS: Acquisition of CTP as part of a telestroke imaging protocol permits definitive diagnosis of cerebral ischemia in 1 in 5 patients with normal NCCT and CTA.

IgG4-related disease is characterised by the overexpression of immunomodulatory proteins.

AIMS: Immunoglobulin 4-related disease (IgG4-RD) is a multisystem disease, characterised by tumefactive lesions and a swift response to immunosuppressive therapy. Although elevated serum and tissue IgG4 are characteristic, T cells appear to be the primary driver of this immunologically mediated disease. The overarching goal was to examine the role of immunomodulatory cells in IgG4-RD. METHODS AND RESULTS: Biopsies from patients with IgG4-RD (n = 39) and mimics of this disease (n = 78) were evaluated for IgG4, IgG, CD8, programmed cell death ligand 1 (PD-L1) and a subset (n = 18) evaluated for CD4, purine rich box 1 (PU.1), forkhead box protein 3 (FoxP3), PD-L1, programmed cell death 1 (PD-1), indoleamine 2,3-dioxygenase 1 (IDO1) and lymphocyte-activation gene 3 (LAG3). Data pertaining to demographics and laboratory findings at baseline evaluation was extracted from electronic medical records. When compared to mimics, IgG4-RD showed increased numbers of PD-L1- (P = 0.0001), PD-1- (P = 0.001), IDO1- (P = 0.03), LAG3- (P = 0.04) and FoxP3- (P = 0.04)-positive immune cells. The PD-L1-positive cells were enriched within aggregates of CD4 and CD8-positive T cells. Thirty-one of 39 (80%) IgG4-RD cases showed greater than five PD-L1-positive cells per high-power field (HPF), while four of 78 (5%) mimics of this disease exceeded this cut-point. In IgG4-RD, PD-L1-positive macrophages correlated with PD-1- (P = 0.002), LAG3- (P = 0.001) and IDO1-positive cells (P = 0.001); a-positive correlation was also noted between IgG4/IgG ratio and PD-L1-, PD-1- and IDO1-positive cells. CONCLUSIONS: IgG4-RD shows expansion of mechanisms that maintain peripheral tolerance. The spatial and temporal relationship between T cells and the PD-L1-PD-1 axis and the up-regulation of multiple immunomodulatory proteins suggests that these immunoregulatory mechanisms play a significant role in IgG4-RD.

Quasimesenchymal phenotype predicts systemic metastasis in pancreatic ductal adenocarcinoma.

Metastasis following surgical resection is a leading cause of mortality in pancreatic ductal adenocarcinoma. Epithelial-mesenchymal transition is thought to play an important role in metastasis, although its clinical relevance in metastasis remains uncertain. We evaluated a panel of RNA in-situ hybridization probes for epithelial-mesenchymal transition-related genes expressed in circulating tumor cells. We assessed the predictive value of this panel for metastasis in pancreatic ductal adenocarcinoma and, to determine if the phenotype is generalizable between cancers, in colonic adenocarcinoma. One hundred fifty-eight pancreatic ductal adenocarcinomas and 205 colonic adenocarcinomas were classified as epithelial or quasimesenchymal phenotype using dual colorimetric RNA-in-situ hybridization. SMAD4 expression on pancreatic ductal adenocarcinomas was assessed by immunohistochemistry. Pancreatic ductal adenocarcinomas with quasimesenchymal phenotype had a significantly shorter disease-specific survival (P = 0.031) and metastasis-free survival (P = 0.0001) than those with an epithelial phenotype. Pancreatic ductal adenocarcinomas with SMAD4 loss also had lower disease-specific survival (P = 0.041) and metastasis-free survival (P = 0.001) than those with intact SMAD4. However, the quasimesenchymal phenotype proved a more robust predictor of metastases-area under the curve for quasimesenchymal = 0.8; SMAD4 = 0.6. The quasimesenchymal phenotype also predicted metastasis-free survival (P = 0.004) in colonic adenocarcinoma. Epithelial-mesenchymal transition defined two phenotypes with distinct metastatic capabilities-epithelial phenotype tumors with predominantly organ-confined disease and quasimesenchymal phenotype with high risk of metastatic disease in two epithelial malignancies. Collectively, this work validates the relevance of epithelial-mesenchymal transition in human gastrointestinal tumors.

The histological diagnosis of IgG4-related disease on small biopsies: challenges and pitfalls.

AIMS: The pathological diagnosis of IgG4-related disease (IgG4-RD) relies on histology, IgG4-positive cells, and an increased IgG4/IgG ratio. Small biopsies from patients with a presumptive diagnosis of IgG4-RD often fail to meet consensus histological criteria. The aims of this study were to evaluate consecutive small biopsies from patients with a presumptive diagnosis of IgG4-RD, and to assess the significance of the pathological findings. METHODS AND RESULTS: We evaluated 55 small biopsies from patients with a presumptive diagnosis of IgG4-RD. The retrospective cohort comprised 71 patients with IgG4-RD and 57 mimics. We performed immunohistochemistry (IHC) and in-situ hybridisation (ISH) for IgG4 and IgG. Twenty-six patients from the prospective cohort met the histological criteria for IgG4-RD (definite); 29 patients lacked one or more pathological features (borderline). Twenty biopsies (36%) lacked both storiform fibrosis and obliterative phlebitis, and nine (16%) lacked an increase in the number of IgG4-positive plasma cells. Ninety-three per cent of patients showed an IgG4/total IgG ratio of >40% (>30% by ISH). There were no differences in the incidence of multiorgan disease (P = 0.9), serum IgG4 levels (P = 0.6) and response to therapy between the definite and borderline groups. A strong correlation (Pearson 0.77) between the IHC and ISH platforms was noted with regard to the IgG4/total IgG ratio. CONCLUSION: Patients with a presumptive diagnosis of IgG4-RD but lacking the characteristic pathological features of this disease appear to be clinically similar to those who meet the current pathological criteria. An elevated IgG4/total IgG ratio is the most sensitive pathological feature, and ISH provides a robust quantification platform. We recommend evaluating tumefactive lymphoplasmacytic infiltrates with an increased IgG4/IgG ratio, regardless of histological features, for IgG4-RD.

Improved Detection of Circulating Epithelial Cells in Patients with Intraductal Papillary Mucinous Neoplasms.

BACKGROUND: Recent work has demonstrated early shedding of circulating epithelial cells (CECs) from premalignant intraductal papillary mucinous neoplasms (IPMNs). However, the potential use of CECs as a "liquid biopsy" for patients with IPMNs has been limited by antigen dependence of CEC isolation devices and the lack of robust detection biomarkers across CEC phenotypes. MATERIALS AND METHODS: We utilized a negative depletion microfluidic platform to purify CECs from contaminating leukocytes and coupled this platform with immunofluorescence, RNA in situ hybridization, and RNA sequencing (RNA-seq) detection and enumeration. RESULTS: Using established protein (EpCAM, cytokeratins) and novel noncoding RNA (HSATII, cytokeratins) biomarkers, we detected CECs in 88% of patients bearing IPMN lesions. RNA-seq analysis for MUC genes confirm the likely origin of these CECs from pancreatic lesions. CONCLUSION: Our findings increase the sensitivity of detection of these cells and therefore could have clinical implications for cancer risk stratification. IMPLICATIONS FOR PRACTICE: This work describes a high-sensitivity platform for detection of epithelial cells shed from preneoplastic lesions at high risk of malignant transformation. Further research efforts are underway to define the transcriptional programs that might allow discrimination between circulating cells released from tumors that will become malignant and cells released from tumors that will not. After further refinement, this combination of technologies could be deployed for monitoring and early detection of patients at high risk for developing new or recurrent pancreatic malignancies.

The Ability to Diagnose Intrahepatic Cholangiocarcinoma Definitively Using Novel Branched DNA-Enhanced Albumin RNA In Situ Hybridization Technology.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) often is a diagnosis determined by exclusion. Distinguishing ICC from other metastatic adenocarcinomas based on histopathologic or immunohistochemical analysis often is difficult and requires an extensive workup. This study aimed to determine whether albumin, whose expression is restricted to the liver, has potential as a biomarker for ICC using a novel and highly sensitive RNA in situ hybridization (ISH) platform. METHODS: Modified branched DNA probes were developed for albumin RNA ISH. The study evaluated 467 patient samples of primary and metastatic lesions. RESULTS: Of the 467 samples evaluated, 83 were ICCs, 42 were hepatocellular carcinomas (HCCs), and 332 were nonhepatic carcinomas including tumors arising from the perihilar region and bile duct, pancreas, stomach, esophagus, colon, breast, ovary, endometrium, kidney, and urinary bladder. Albumin RNA ISH was highly sensitive for cancers of liver origin, staining positive in 82 (99 %) of 83 ICCs and in 42 HCCs (100 %). Perihilar and distal bile duct carcinomas as well as carcinomas arising at other sites tested negative for albumin. Notably, 6 (22 %) of 27 intrahepatic tumors previously diagnosed as carcinomas of undetermined origin tested positive for albumin. CONCLUSIONS: Albumin RNA ISH is a sensitive and highly specific diagnostic tool for distinguishing ICC from metastatic adenocarcinoma to the liver or carcinoma of unknown origin. Albumin RNA ISH could replace the extensive diagnostic workup, leading to timely confirmation of the ICC diagnosis. Additionally, the assay could serve as a guide to distinguish ICC from perihilar adenocarcinoma.

Albumin expression distinguishes bile duct adenomas from metastatic adenocarcinoma.

AIMS: Bile duct adenomas may be difficult to distinguish from metastatic carcinomas, particularly well-differentiated pancreatic ductal adenocarcinoma. Prior studies have evaluated the utility of various immunohistochemical markers, although these markers are notable for low sensitivity and/or specificity. The aim of this study was to investigate the utility of albumin and BRAFV600E expression in distinguishing between metastatic pancreatic adenocarcinoma and bile duct adenoma. METHODS AND RESULTS: We studied 26 bile duct adenomas, three bile duct hamartomas, and 158 pancreatic ductal adenocarcinomas. Branched-chain in-situ hybridization (bISH) for albumin was performed; bISH is based on the branched DNA technology, wherein signal amplification is achieved via a series of sequential steps. Additionally, BRAFV600E immunohistochemistry (IHC) was performed on a subset of cases. Twenty-three of 25 (92%) bile duct adenomas were positive for albumin; 18 (72%) showed diffuse staining, and five showed focal staining (20%), including two challenging examples. Two bile duct hamartomas also stained positively. All pancreatic adenocarcinomas were negative for albumin. Seven of 16 (44%) bile duct adenomas and five of 106 (5%) pancreatic ductal adenocarcinomas were positive for BRAFV600E by IHC. The sensitivity and specificity of expression of albumin, as detected by bISH, for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 92% and 100%, respectively; the sensitivity and specificity of BRAFV600E IHC for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 43.8% and 95.3%, respectively. CONCLUSIONS: Diagnostically challenging examples of bile duct adenoma may be distinguished from metastatic pancreatic adenocarcinoma by the use of albumin bISH.

Histologic Manifestations of Gastrointestinal Adenovirus Infection After Stem Cell Transplant.

Adenovirus can cause severe disease in hematopoietic stem cell transplant (HSCT) patients. Histopathologic features of this infection in gastrointestinal biopsies and their distinction from graft-versus-host disease (GVHD) have been incompletely studied. We retrospectively identified patients with gastrointestinal adenovirus infection. H&E-stained sections were reviewed and the histologic features were recorded. The extent of immunostaining was determined using a semiquantitative scale and a maximum number of positive cells per high-power field. Information regarding the clinical course and endoscopic findings were obtained from the electronic medical records. The study group included 32 HSCT patients. Most (81%) presented with diarrhea and detectable virus in the serum. Twenty patients had multiorgan involvement in the gastrointestinal tract, mostly in the duodenum (62%) and colon (56%). Characteristic features included apoptotic epithelial cells with nuclear disarray (84%) and tufted aggregates of degenerating epithelial cells (69%), the latter of which was more commonly seen in the study population more than a control group of HSCT patients with GI involvement by GVHD. Viral inclusions were limited to the superficial epithelium in 59% of samples, and the density of viral inclusions within biopsies was variable (grade 1: 40%, grade 2: 38%, and grade 3: 22%). Following therapy, 10 patients (30%) improved and 14 (42%) had progressive disease. Patients with disease progression were often older (64 vs. 36 years, P =0.01) with higher serologic viral loads, prior history of GVHD, multifocal involvement, and increased number and density of immunoreactive nuclei. Adenovirus infection elicits a spectrum of histologic changes that can simulate or occur in combination with gastrointestinal GVHD. Patients with progressive disease are more likely to have high viral loads and more extensive infection of the gastrointestinal tract.

The Clinical Septet of Van Wyk-Grumbach Syndrome: A Case Series from a Tertiary Care Centre in Kalyana Karnataka, India.

Van Wyk-Grumbach syndrome is a rare, female juvenile hypothyroidism disorder that is characterized by precocious puberty with clinical, radiological and hormonal pathologies. We present a case series of three patients with this unusual condition who were evaluated and followed up over a 3-year period between January 2017 and June 2020. All three patients presented with short stature (<3rd centile), low weight (<3rd centile), absence of goitre, no axillary or pubic hair, delayed bone age by more than 2 years, elevated thyroid-stimulating hormone with low T3 and T4 (primary hypothyroidism), and raised follicle-stimulating hormone with pre-pubertal levels of luteinizing hormone. Abdominal ultrasonography showed bilateral multi-cystic ovaries in two patients and a right-sided bulky ovary in the third patient. One of the patients also had a pituitary 'macroadenoma'. All the patients were successfully managed with levothyroxine. We discuss the pathophysiological mechanisms with a brief literature review.

Patient acceptability of a wheel chair recliner developed to perform dental procedures at wheelchair itself: A cross-sectional study.

Aim: Transfer from a wheelchair and discomfort in dental chair are two important barriers for access to dental care among wheelchair-bound patients. The authors have devised an automated wheelchair recliner that helps to mimic the dental chair functioning at wheelchair itself. The aim of this study was to analyze the performance and acceptability of wheelchair recliner among wheelchair-bound patients. Settings and Design: Tertiary care settings, cross-sectional design. Materials and Methods: A total of 100 wheelchair-bound adult patients (aged >21 years) were evaluated for acceptability of the recliner. The patients were assessed using eight-item covering patient comfort/acceptability related to positioning, reclining, repositioning, fear of falls, joy, discomfort, perception regarding dentist's discomfort, and use in future on a scale of 0-4 with 0 indicating least satisfying and four indicating most satisfying experience. Overall, patient experience was graded as poor, fair, good, very good, and excellent. The Chi-square test was used to compare the results. Statistical Analysis Used: IBM Stats package 21.0 was used. Mean ± standard deviation, Numbers/percentages and Chi-square test were used to compare results. The confidence level of the study was 95%. Results: The age of patients ranged from 22 to 83 years (mean age 52.26 ± 18.58 years). Majority were males (58%) and had temporary (60%) disability. On a 4-point scale, the mean scores of patients ranged from 2.47 ± 1.23 (positioning) to 3.40 ± 0.74 (intent to use in future). Overall experience was rated as good to very good by 77% of patients. No significant association of age, sex, or type of disability was seen with overall patient experience. Conclusion: The acceptability rates were good to very good among wheelchair-bound patients and were unaffected by their age, sex, and type of disability.

Fibrous Dysplasia Masquerading as Sternal Malignancy: A Rare and Challenging Presentation.

This case report presents a rare and challenging manifestation of polyostotic fibrous dysplasia (FD), a skeletal developmental anomaly characterized by the proliferation of fibrous connective tissue intermingled with irregular bony trabeculae. While monostotic FD is more common, polyostotic FD can occur in the context of McCune-Albright syndrome, a multisystem developmental disorder. Our patient, a 55-year-old female with a history of diabetes, hypothyroidism, and dyslipidemia, presented with progressively worsening dysphagia, sternal pain, and swelling over three years. Clinical examination revealed a tender and hard swelling in the upper sternal area, prompting further evaluation. Laboratory results, including bone turnover markers, were unremarkable. Imaging studies unveiled a sizable anterior mediastinal lesion with heterogeneous enhancement and coarse calcifications, initially raising concerns of malignancy. Subsequent positron emission tomography scan findings confirmed FD involvement in both the sternum and right femur. Histopathology of the mediastinal mass revealed a spindle cell neoplasm with bony metaplasia, consistent with FD, supported by immunohistochemistry. A multidisciplinary team affirmed the diagnosis of polyostotic FD, and follow-up imaging after one year demonstrated no significant change in lesion size, confirming a benign etiology. While bisphosphonate therapy was planned, regrettably, the patient was lost to follow-up. This case underscores the importance of a comprehensive, multidisciplinary approach in diagnosing and managing complex presentations of FD, ultimately contributing to improved patient care and outcomes in such instances.

Intratendinous Calcified Chondroid Mesenchymal Neoplasm: A Case Report.

Introduction: We present a case report concerning calcified chondroid mesenchymal neoplasms (CCMN), a novel category of tumors that exhibit chondroid formation and contain fibronectin 1-receptor tyrosine kinase fusions. Case Report: Our report focuses on a 73-year-old female patient who presented with pain in her right hip and gluteal region. Initially, the condition was misdiagnosed as calcific tendinitis based on X-ray imaging. However, a subsequent magnetic resonance imaging (MRI) revealed a solid lobulated mass originating from the right hamstring tendon origin, exhibiting heterogeneously hypointense T1-weighted signal, heterogeneously isointense proton density fat-suppressed signal, and heterogeneous contrast-enhancement compared to skeletal muscle. Further, investigation through computed tomography (CT) demonstrated intratumoral calcifications accompanied by erosive changes in the adjacent right ischial tuberosity. Histologic examination of a CT-guided biopsy confirmed the presence of large calcium pyrophosphate crystal deposits, along with benign chondroid tissue, thus supporting the diagnosis of CCMN. Notably, there is considerable overlap in the imaging characteristics of CCMN and the more commonly encountered calcific tendinitis (calcium hydroxyapatite depositional disease). Contrast-enhanced MRI findings play a crucial role in distinguishing between these two conditions. Conclusion: To the best of our knowledge, this is the first documented report describing the imaging features of CCMN across multiple modalities, including radiography, CT, and MRI.

Ultrasensitive detection of circulating LINE-1 ORF1p as a specific multi-cancer biomarker.

Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. While proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1, L1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible detectable expression in corresponding normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore the potential of ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10-17 M) ORF1p concentrations in patient plasma samples across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multi-analyte panel, and provides early therapeutic response monitoring in gastric and esophageal cancers. Together, these observations nominate ORF1p as a multi-cancer biomarker with potential utility for disease detection and monitoring.

Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker.

Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10-17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. SIGNIFICANCE: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 µL plasma are novel, rapid, cost-effective tools in cancer detection and monitoring. See related commentary by Doucet and Cristofari, p. 2502. This article is featured in Selected Articles from This Issue, p. 2489.