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Background Improvement of liver transplantation (LT) outcomes requires better understanding of factors affecting survival. The presence of RBC alloantibodies (RBCAs) on survival in LT recipients was evaluated. Methods This study was a single-center, retrospective cohort study reviewing transfusion records and all-cause mortality between 2002 and 2021. Results Between 2002 and 2021, 2079 LTs were completed, 1,396 of which met inclusion criteria (1,305 RBCA negative; 91 RBCA positive [6.5%]). The cohorts were similar in age (mean [range], 55.8 [17-79] years vs 56.8 [25-73] years; P = .41, respectively) or sex (RBCA negative, 859 [65%] men and 446 [35%] women vs RBCA positive, 51 [56%] men and 40 [44%] women; P = .0684). Of 132 RBCAs detected, 10 were most common were to E (27.27%), Jka (15.91%), K (9.09%), C (8.33%), M (6.06%), D (5.3%), Fya (4.55%), e (2.27%), c (2.27%), and Jkb (2.27%). Twenty-seven patients (29.7%) had more than 1 RBCA; the most common combinations were C with Jka (7.4%) and E with Dia (7.4%). All-cause mortality was increased in men (men, 14.45 years vs women, 17.27 years; P = .0266) and patients 65 years of age and older (≥65 years of age, 10.21 years vs Conclusions Survival in RBCA-positive LT recipients is no different from that in RBCA-negative LT recipients.

Fine needle aspiration cytology is often used for the initial diagnosis and management of patients with salivary gland tumors. Because of its global usage, a consensus classification schema was devised in 2018 to initiate universal reporting of salivary gland cytology specimens, termed the Milan system for reporting salivary gland cytopathology (MSRSGC) and composed of distinct diagnostic categories. Few retrospective studies have been undertaken to review the MSRSGC within institutions.We analyzed salivary gland fine needle aspirations during a 10-year span from 2011 to 2021, categorized each cytology case to fit the MSRSGC, and subsequently reviewed the corresponding surgical resections, if indicated, to determine the rate of malignancy (ROM) and rate of neoplasia.Our ROM was higher (gt;10%) for the following MSRSGC categories: non-neoplastic, atypia of undetermined significance, and suspicious for malignancy. Also, our data correlated well with the following MSRSGC categories: nondiagnostic, neoplasm-benign, salivary gland neoplasm of uncertain malignant, and malignant.Although the data were indicative of the ROM for surgically resected salivary gland lesions, the ROM for non-neoplastic lesions could truly be lower given that most lesions in this category will not undergo surgical resection. Additionally, determination of the rate of neoplasia could a tool that could be used to further guide our clinical colleagues.

A, MTT cell viability relative absorbance values across multiple cell lines after a 7-day incubation with Veliparib, Olaparib, or Niraparib. Boxes with an asterisk denote that an indicated concentration of PARP inhibitor significantly reduced cell viability relative vehicle treated cells. B, MTT cell viability heat map with numerical values. C, Linear regression analysis between PARP1 protein levels, relative to GAPDH, across all cell lines vs. IC50 values calculated from MTT viability assay on day 7. D, Linear regression analysis between PARP1 activity levels, relative to GAPDH, across all cell lines vs. IC50 values calculated from MTT viability assay on day 7. E, Different exposure of PARP1 Western blot in SJG2, SF188, 462, and 626 cells demonstrating variable PARP1 protein expression. *, **, ***, **** Denotes significance of p

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A and C, Representative immunofluorescence staining for γH2AX and ki67 in SJG2, SF188, KNS42, and DIPG58 cells after a 24 hour incubation with either DMSO vehicle (V) or 5 μM Niraparib (N). DAPI was used as a nuclear counterstain. B and D, Quantification of γH2AX and ki67 in SJG2, SF188, KNS42, and DIPG58 cells. γH2AX images were taken at 63X magnification, scale bar 12 μm, ki67 images were taken at 25X magnification, scale bar 30 μm. **, ***, **** Denotes significance of p

A, Several representative time points of SJG2 cells after immunofluorescent staining for γH2AX with DAPI as a counterstain after 1μM Niraparib, 2 Gy gamma radiation, or 2 Gy radiation pre-treated with 1μM Niraparib. Images were taken at indicated time points at 64X magnification.

PDF file - 432KB, Supplementary Figure 1: Validation of Temozolomide (TMZ) siRNA Screen. Supplementary Figure 2: Base Excision Repair correlates with IC50 of alkylating agents. Supplementary Figure 3: Loss of MPG promotes sensitivity to alkylating agents. Supplementary Figure 4: Over-expression of MPG promotes resistance to TMZ. Supplementary Figure 5: Targeting multiple DNA repair proteins has an additive effect on TMZ sensitivity. Supplementary Figure 6: ATM interacts with MPG and regulates MPG glycosylase activity. Supplementary Figure 7: Methoxyamine enhances cytotoxicity of TMZ in pGBM cell lines. Supplementary Figure 8: Methoxyamine enhances cytotoxicity of TMZ in primary pGBM cultures. Supplementary Figure 9: Normal astrocytes have redundant pathways limiting cytotoxicity when the ATM-MPG pathways are inhibited.

Supplementary Figure Legends

A, B, MTT viability relative absorbance values of SJG2 and SF188 after being treated with an indicated concentration of Niraparib for 72h. C, Western blot for cleaved PARP1 in SJG2 and SF188 after being treated with an indicated concentration of Niraparib for 72h. D, E, Propidium Iodide DNA staining analysis in SJG2, SF188 cells, respectively, after a 72h incubation with an indicated concentration of Niraparib. *, ***, **** Denotes significance of p

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A, Representative immunohistochemical staining for PARP1 in pHGA and DIPG patient samples. Pictures were taken at 10X magnification. Scale bar 100 μm.

Context.— Pathology resident education has a steep learning curve. Specimen sampling (grossing) is a procedural task, and procedural fields add video materials to their curricula to familiarize trainees with procedure(s), reduce errors, and improve patient care. Our team applied this strategy to develop original in-house sampling videos for our program. Objectives.— To evaluate the effect of in-house sampling videos on resident sampling confidence. Design.— Sampling videos covering all major organ systems (AMOS) were created for our postgraduate year 1 (PGY1) trainees. Videos were hosted on a Northwestern cloud server for on-demand access. Trainees completed 3 surveys (0, 6, 12 months) evaluating sampling confidence comparing those who used in-house videos as an educational supplement with those who did not use the videos. Results.— Sampling confidence significantly improved at 6 and 12 months (P < .001) across AMOS and PGY levels. When compared with those who did not use in-house sampling videos, trainees who supplemented their education with in-house sampling videos had significantly higher confidence ratings across AMOS and PGY levels at the start of the study (P < .001) and at 6 months (P = .004). Sampling confidence significantly improved for PGY1 trainees at 6 and 12 months (P < .001); for PGY2 and PGY3 trainees, confidence significantly improved at 6 months (P < .001). When evaluated by organ-specific analyses, sampling and teaching confidence improved across all organ systems and, except for the gastrointestinal system, reached significance at 12 months for all PGY levels. Conclusions.— Sampling videos, when used as a supplement to the existing curriculum, significantly improved trainee confidence.

While the coexistence of focal cortical dysplasia (FCD) and grade 1 noninfiltrative gliomas has been described, to date, only rare case reports have described FCD adjacent to infiltrating gliomas. We therefore sought to determine how often FCD-like findings occur near adult-type diffuse gliomas. This was a retrospective survey of 186 consecutive, newly diagnosed, en bloc glioma resections. Fifty-nine (31.7%) had sufficient adjacent cortex to evaluate for FCD-like features. Among IDH mutant (“IDHmut”) gliomas, 40/77 (52%) had adjacent evaluable cortex, whereas only 19/109 (17%) of IDH wild-type (“IDHwt”) gliomas did (p

Objectives The novel coronavirus, severe acute respiratory syndrome coronavirus 2, causing coronavirus disease 2019 (COVID-19) remains a global health threat and a significant source of human morbidity and mortality. While the virus primarily induces lung injury, it also has been reported to cause hepatic sequelae. Methods We aimed to detect the virus in formalin-fixed tissue blocks and document the liver injury patterns in patients with COVID-19 compared with a control group. Results We were able to detect viral RNA in the bronchioalveolar cell blocks (12/12, 100%) and formalin-fixed, paraffin-embedded tissue of the lung (8/8, 100%) and liver (4/9, 44%) of patients with COVID-19. Although the peak values of the main liver enzymes and bilirubin were higher in the patients with COVID-19 compared with the control group, the differences were not significant. The main histologic findings were minimal to focal mild portal tract chronic inflammation (7/8, 88%, P < .05) and mild focal lobular activity (6/8, 75%, P = .06). Conclusions We found that most patients who died of COVID-19 had evidence of mild focal hepatitis clinically and histologically; however, the virus was detected in less than half of the cases.

Background Despite increased understanding of the genetic events underlying pediatric high-grade gliomas (pHGGs), therapeutic progress is static, with poor understanding of nongenomic drivers. We therefore investigated the role of alterations in mitochondrial function and developed an effective combination therapy against pHGGs. Methods Mitochondrial DNA (mtDNA) copy number was measured in a cohort of 60 pHGGs. The implication of mtDNA alteration in pHGG tumorigenesis was studied and followed by an efficacy investigation using patient-derived cultures and orthotopic xenografts. Results Average mtDNA content was significantly lower in tumors versus normal brains. Decreasing mtDNA copy number in normal human astrocytes led to a markedly increased tumorigenicity in vivo. Depletion of mtDNA in pHGG cells promoted cell migration and invasion and therapeutic resistance. Shifting glucose metabolism from glycolysis to mitochondrial oxidation with the adenosine monophosphate–activated protein kinase activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) or the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) significantly inhibited pHGG viability. Using DCA to shift glucose metabolism to mitochondrial oxidation and then metformin to simultaneously target mitochondrial function disrupted energy homeostasis of tumor cells, increasing DNA damage and apoptosis. The triple combination with radiation therapy, DCA and metformin led to a more potent therapeutic effect in vitro and in vivo. Conclusions Our results suggest metabolic alterations as an onco-requisite factor of pHGG tumorigenesis. Targeting reduced mtDNA quantity represents a promising therapeutic strategy for pHGG.

Pancytokeratins and TTF-1 are used in working up carcinomas of unknown primary and p63 is expressed in many cell lineages. We present a case of a TTF-1, p63, and cytokeratins positive small round blue cell lesion presenting in a patient with enlarged right supraclavicular lymph nodes and multiple solid pulmonary nodules. The preliminary report to the clinical team was "suspicious for carcinoma." However, after a complete work up the final diagnosis of diffuse large B-cell lymphoma, nongerminal center B-cell phenotype, "double expressor," was rendered (based on Han's algorithm). This case brings up significant diagnostic dilemma as some lymphoid malignancies can morphologically mimic poorly differentiated carcinoma and stain positive for carcinoma markers. Additionally, the frequently used TTF-1 SPT23 antibody clone has strong nuclear staining in rare cases of DLBCL, which is a diagnostic pitfall. To our best knowledge this is the first reported case of DLBCL staining positive for three carcinoma markers.

Primary mediastinal germ cell tumors with somatic malignancies are rare. We report a case of a 34-year old man with melanoma arising in a primary mediastinal mixed germ cell tumor. On initial biopsy, the patient was found to have a germ cell tumor containing yolk sac and embryonal components only. After chemotherapy, histopathological evaluation of the residual tumor in the wide local resection specimen revealed a mature teratoma with melanoma. Molecular studies demonstrated that the residual germ cell tumor harbored KIT and NRAS mutations associated with malignant melanoma.

Alzheimer’s disease (AD) and type-2 diabetes mellitus (T2DM) are highly prevalent aging-related diseases associated with significant morbidity and mortality. Some findings in human and animal models have linked T2DM to AD-type dementia. Despite epidemiological associations between the T2DM and cognitive impairment, the inter-relational mechanisms are unclear. The preponderance of evidence in longitudinal studies with autopsy confirmation have indicated that vascular mechanisms, rather than classic AD-type pathologies, underlie the cognitive decline often seen in self-reported T2DM. T2DM is a known risk factor for cardiovascular and cerebrovascular disease (CVD), including increased risk of infarcts and small vessel disease in the brain and other organs. Furthermore, neuropathological examinations of post-mortem brains demonstrated evidence of cerebrovascular disease and little to no correlation between T2DM and β-amyloid deposits or neurofibrillary tangles. Nevertheless, the mechanisms upstream of early AD-specific pathology remain obscure. In this regard, there may indeed be overlap between the pathologic mechanisms of T2DM/”metabolic syndrome”, and AD. More specifically, cerebral insulin processing, glucose metabolism, mitochondrial function, and/or lipid metabolism could be altered in patients in early AD and directly influence symptomatology and/or neuropathology.

Off label use of intraosseous needles (IONs) for contrast media (CM) injection during computed tomographic angiography (CTA) has been reported in small case series and isolated case reports. Presently, complications specific to this novel indication are essentially unknown. In this communication, we report an extravasation of CM from the intramedullary space of the humerus into the glenohumeral joint space during an ION injection of CM during a CTA of the head, neck, and chest. Although clinically insignificant in this case, a more severe intraarticular extravasation could have had both short or long term adverse sequelae. Practitioners of CTA should be aware of this potential complication.

We review the literature on Tau and TDP-43 proteinopathies in aged human brains and the relevant underlying pathogenetic cascades. Complex interacting pathways are implicated in Alzheimer’s disease and related dementias (ADRD), wherein multiple proteins tend to misfold in a manner that is “reactive,” but, subsequently, each proteinopathy may contribute strongly to the clinical symptoms. Tau proteinopathy exists in brains of individuals across a broad spectrum of primary underlying conditions—e.g., developmental, traumatic, and inflammatory/infectious diseases. TDP-43 proteinopathy is also expressed in a wide range of clinical disorders. Although TDP-43 proteinopathy was first described in the central nervous system of patients with amyotrophic lateral sclerosis (ALS) and in subtypes of frontotemporal dementia (FTD/FTLD), TDP-43 proteinopathy is also present in chronic traumatic encephalopathy, cognitively impaired persons in advanced age with hippocampal sclerosis, Huntington’s disease, and other diseases. We list known Tau and TDP-43 proteinopathies. There is also evidence of cellular co-localization between Tau and TDP-43 misfolded proteins, suggesting common pathways or protein interactions facilitating misfolding in one protein by the other. Multiple pleiotropic gene variants can alter risk for Tau or TDP-43 pathologies, and certain gene variants (e.g., APOE e4, Huntingtin triplet repeats) are associated with increases of both Tau and TDP-43 proteinopathies. Studies of genetic risk factors have provided insights into multiple nodes of the pathologic cascades involved in Tau and TDP-43 proteinopathies. Variants from a specific gene can be either a low-penetrant risk factor for a group of diseases, or alternatively, a different variant of the same gene may be a disease-driving allele that is associated with a relatively aggressive and early-onset version of a clinically and pathologically specific disease type. Overall, a complex but enlightening paradigm has emerged, wherein both Tau and TDP-43 proteinopathies are linked to numerous overlapping upstream influences, and both are associated with multiple downstream pathologically- and clinically-defined deleterious effects. Neurodegenerative diseases evolve in multi-factorial manners, yet coherent paradigms are emerging. Both Tau and TDP-43 proteinopathies are linked to multiple upstream influences, and both are connected with numerous deleterious downstream endpoints. Gene variants can be either disease-specific, or, exert influence on the misfolding pathology itself rather than the upstream cause.

The mitochondrion is an important organelle and provides energy for a plethora of intracellular reactions. Metabolic dysregulation has dire consequences for the cell, and alteration in metabolism has been identified in multiple disease states-cancer being one. Otto Warburg demonstrated that cancer cells, in the presence of oxygen, undergo glycolysis by reprogramming their metabolism-termed "aerobic glycolysis". Alterations in metabolism enable cancer cells to gain a growth advantage by obtaining precursors for macromolecule biosynthesis, such as nucleic acids and lipids. To date, several molecules, termed "oncometabolites", have been identified to be elevated in cancer cells and arise from mutations in nuclear encoded mitochondrial enzymes. Furthermore, there is evidence that oncometabolites can affect mitochondrial dynamics. It is believed that oncometabolites can assist in reprogramming enzymatic pathways and providing cancer cells with selective advantages. In this review, we will touch upon the effects of normal and aberrant mitochondrial metabolism in normal and cancer cells, the advantages of metabolic reprogramming, effects of oncometabolites on metabolism and mitochondrial dynamics and therapies aimed at targeting oncometabolites and metabolic aberrations.

Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of PARP1 inhibition in preclinical models of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient samples and tumor-derived cell lines. The effects of PARP inhibitors veliparib, olaparib, and niraparib as monotherapy or as radiosensitizers on cell viability, DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell lines. Survival benefit of niraparib was examined in an orthotopic xenograft model of pHGA. About 85% of pHGAs and 76% of DIPG tissue microarray samples expressed PARP1. Six of 8 primary cell lines highly expressed PARP1. Interestingly, across multiple cell lines, some PARP1 protein expression was required for response to PARP inhibition; however, there was no correlation between protein level or PARP1 activity and sensitivity to PARP inhibitors. Niraparib was the most effective at reducing cell viability and proliferation (MTT and Ki67). Niraparib induced DNA damage (γH2AX foci) and induced growth arrest. Pretreatment of pHGA cells with a sublethal dose of niraparib (1 μmol/L) before 2 Gy of ionizing radiation (IR) decreased the rate of DNA damage repair, colony growth, and relative cell number. Niraparib (50 mg/kg) inhibited PARP1 activity in vivo and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 vs. 25 days). Our data provide in vitro and in vivo evidence that niraparib may be an effective radiosensitizer for pHGA and DIPG. Mol Cancer Ther; 14(11); 2560–8. ©2015 AACR.

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Introduction Perivascular epithelioid cell tumors (PEComas) are defined by the World Health Organization (WHO) as mesenchymal tumors arising from perivascular epithelioid cells with myomelanocytic immunophenotype. In the kidney, they are often referred to as epithelioid angimyolipoma (AML). Most are benign but some can be malignant. Their rarity and wide differential render diagnosis challenging. Case Presentation A 56-year-old male presented with a 3-month history of flank pain. Computed tomography (CT) identified bilateral necrotic heterogeneous enhancing kidney masses, with right significantly larger than left. Initially, the patient underwent a right radical nephrectomy. On gross examination, no tumor infiltration was observed. Histology demonstrated sheets of highly atypical cells with clear cytoplasm and easily identifiable nucleoli. Areas of spindle and rhabdoid differentiation were present. The initial diagnosis was renal clear cell (RCC) carcinoma, Fuhrman grade 4, with extensive rhabdoid and focal sarcomatoid features. A follow-up CT demonstrated a hypodense area within the right hepatic lobe. Status post liver resection and histomorphological examination, the lesion was identical to the renal mass except for focal areas of prominent epithelioid cells with eosinophilic cytoplasm. Immunohistochemical (IHC) stains of both masses were positive for Melan-A, HMB-45, and EMA but negative for PAX8, SOX10, S100, SMA, desmin, and cytokeratin. The initial diagnosis was amended to malignant AML with hepatic metastasis. Discussion and Conclusion Renal PEComa (epithelioid AML) is a rare tumor with a prevalence of 0.44%. While most are benign, some are malignant with metastatic potential. The differential diagnosis for PEComa is broad and includes more common tumors like RCC, melanoma, clear cell sarcoma, and liposarcoma. The presence of spindle and epithelioid histology with eosinophilic cytoplasm in RCC should prompt additional IHC workup (HMB45, Melan-A, SMA, and EMA) in order to exclude PEComa/AML.

Central Nervous System (CNS) involvement in multiple myeloma and/or multifocal solitary plasmacytoma is rare. Although they are unique entities, multiple myeloma (MM) and plasmacytoma represent a spectrum of plasma cell neoplastic diseases that can sometimes occur concurrently. Plasmacytomas very often present as late-stage sequelae of MM. In this case report, we report a 53-year-old female presenting with right abducens cranial nerve (CN) VI palsy as an initial presentation secondary to lesion of the right clivus.

Simulation of a given stimulus situation should produce the same perception as the original. Rogers et al (2009 Perception38 907–911) simulated Wheeler's (1982, PhD thesis, Rutgers University, NJ) motion parallax stimulus and obtained quite different perceptions. Wheeler's observers were unable to reliably report the correct direction of depth, whereas Rogers's were. With three experiments we explored the possible reasons for the discrepancy. Our results suggest that Rogers was able to see depth from the simulation partly due to his experience seeing depth with random dot surfaces.

Alkylating agents are a first-line therapy for the treatment of several aggressive cancers, including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed, increasing therapeutic response while minimizing toxicity. Using an siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular, the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM), were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent–induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM–MPG axis will lead to improved treatment of alkylating agent–resistant tumors. Significance: Inhibition of ATM and MPG-mediated BER cooperate to sensitize tumor cells to alkylating agents, impairing tumor growth in vitro and in vivo with no toxicity to normal cells, providing an ideal therapeutic window. Cancer Discov; 4(10); 1198–1213. ©2014 AACR. See related commentary by Wick and Platten, p. 1120 This article is highlighted in the In This Issue feature, p. 1103