Citations

The development of vascular access for hemodialysis has come a long way since 1943 when the first hemodialysis treatment was performed in humans by connecting an artery and vein using an external glass canula. Since then, vascular access care has evolved robustly through contributions from numerous countries and professional nephrology societies, worldwide. To understand the global distribution and contribution of different specialties to medical literature on dialysis vascular access care, we performed a literature search from 1991 to 2021 and identified 2768 articles from 74 countries. The majority of publications originated from the United States (41.5%), followed by China (5.1%) and the United Kingdom (4.6%). Our search results comprise of observational studies (43%), case reports/series (27%), review articles (16.5%) and clinical trials (12%). A large proportion of articles were published in Nephrology journals (49%), followed by General Medicine (14%), Surgery (10%), Vascular Medicine (8%), and Interventional Radiology journals (4%). With the introduction of interventional nephrology, nephrologists will be able to assume the majority of the responsibility for dialysis vascular access care and above all maintain a close interdisciplinary collaboration with other specialties to provide optimum patient care. In this review article, we discuss the history, evolving knowledge, challenges, educational opportunities, and future directions of dialysis vascular access care, worldwide.

Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) present a major health burden to society. Changes in brain structure and cognition are generally only observed at the late stage of the disease. Although advanced magnetic resonance imaging (MRI) techniques such as diffusion imaging may allow identification of biomarkers at earlier stages of neurodegeneration, early diagnosis is still challenging. Magnetic resonance elastography (MRE) is a noninvasive MRI technique for studying the mechanical properties of tissues by measuring the wave propagation induced in the tissues using a purpose‐built actuator. Here, we present a systematic review of preclinical and clinical studies in which MRE has been applied to study neurodegenerative diseases. Actuator systems for data acquisition, inversion algorithms for data analysis, and sample demographics are described and tissue stiffness measures obtained for the whole brain and internal structures are summarized. A total of six animal studies and eight human studies have been published. The animal studies refer to 123 experimental animals (68 AD and 55 PD) and 121 wild‐type animals, while the human studies refer to 142 patients with neurodegenerative disease (including 56 AD and 17 PD) and 166 controls. The animal studies are consistent in the reporting of decreased stiffness of the hippocampal region in AD mice. However, in terms of disease progression, although consistent decreases in either storage modulus or shear modulus magnitude are reported for whole brain, there is variation in the results reported for the hippocampal region. The clinical studies are consistent in reports of a significant decrease in either whole brain storage modulus or shear modulus magnitude, in both AD and PD and with different brain structures affected in different neurodegenerative diseases. MRE studies of neurodegenerative diseases are still in their infancy, and in future it will be interesting to investigate potential relationships between brain mechanical properties and clinical measures, which may help elucidate the mechanisms underlying onset and progression of neurodegenerative diseases.Evidence Level1.Technical EfficacyStage 2.

Abstract Background: Isocitrate dehydrogenase 1/2 (IDH1/2) is mutated in a subset of cholangiocarcinoma (CCA), gliomas, and other solid tumors. LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 study of oral LY3410738 in patients (pts) with IDH1/2m CCA, and IDH1m glioma or other solid tumors. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in advanced IDHm CCA and other solid tumors (NCT04521686). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 80 pts including 42 with CCA (33 IDH1m, 9 IDH2m), 27 with glioma (IDH1m), and 11 other tumor types (IDH1m) received LY3410738 dosed at 25-600 mg QD or 300 mg BID. Pts were median 52 years of age (range, 23-80) with a median of 2 prior therapies (range, 1-7). 19% of CCA pts had received prior IDH1 inhibitor. Median time on treatment was 3.7 months (range, 0.1-19). No DLTs or treatment related deaths were observed; the MTD was not reached. Treatment emergent adverse events (TEAEs) ≥15% included nausea (35%), vomiting (21%), and decreased appetite (19%) and were mostly grade 1-2. Most frequent grade ≥3 TEAEs >2% were anemia (4%), cholangitis (3%), headache (3%), decreased lymphocyte count (3%), and hyponatremia (3%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels, including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Among the 42 pts with R/R CCA, the best response included 1 PR and 22 SD. Of the 22 glioma pts with contrast enhancing tumors, best response included 3 PR and 9 SD. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1/2m advanced solid tumors. Consistent with the expectations for IDH inhibitor monotherapy in this setting, CCA and glioma pts exhibited prolonged stable disease. RP2D evaluation is ongoing. Updated data on LY3410738 monotherapy will be presented at the meeting. Citation Format: Jordi Rodon, Lipika Goyal, Teresa Macarulla Mercade, Masafumi Ikeda, Shunsuke Kondo, Do-Youn Oh, Li-Yuan Bai, Makoto Ueno, Antoine Italiano, Kyriakos Papadopoulos, David Spigel, Sani H. Kizilbash, Rasha Cosman, Joon Oh Park, Li-Tzong Chen, Tomoya Yokota, Anita A. Turk, Chih-Yi Liao, Rachna Shroff, Anthony El-Khoueiry, Taroh Satoh, Antoine Hollebecque, Mitesh J. Borad, Nilofer Azad, Kurt A. Jaeckle, Herbert H. Loong, Jorge Adeva, Wei Peng Yong, Junjie Zhao, Hui Liu, Anna M. Szpurka, Ivelina Gueorguieva, Kamnesh R. Pradhan, Xiaojian Xu, James J. Harding. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced IDH-mutant cholangiocarcinoma and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT098.

Abstract Background Medulloblastoma in adults is rare and treatment decisions are largely driven from pediatric literature. We sought to characterize recurrent medulloblastoma in adults. Methods From a single-institution dataset of 200 adult patients diagnosed with medulloblastoma during 1978–2017, those with recurrence were analyzed for clinical features, treatment, and outcome. Results Of the 200 patients, 82 (41%) with median age of 29 years (18–59) had recurrence after a median follow-up time of 8.4 years (95% CI = 7.1, 10.3). Of these, 30 (37%) were standard-risk, 31 (38%) were high-risk, and 21 (26%) had unknown-risk diseases at the time of initial diagnosis. Forty-eight (58%) presented with recurrence outside the posterior fossa, of whom 35 (43%) had distant recurrence only. Median Progression-free survival (PFS) and OS from initial surgery were 33.5 and 62.4 months, respectively. Neither PFS nor OS from initial diagnosis differed between the standard-risk and high-risk groups in those who experience recurrence (P = .505 and .463, respectively). Median OS from first recurrence was 20.3 months, also with no difference between the standard-risk and high-risk groups (P = .518). Recurrences were treated with combinations of re-resection (20 patients; 25%), systemic chemotherapy (61 patients; 76%), radiation (29 patients; 36%), stem cell transplant (6 patients; 8%), and intrathecal chemotherapy (4 patients; 5%). Patients who received radiation at recurrence had better OS (32.9 months) than those who did not (19.2 months) (P = .034). Conclusions Recurrent medulloblastoma in adults has a poor prognosis irrespective of initial risk stratification. Recurrence commonly arises outside the posterior fossa years after initial diagnosis.

AbstractIt has been challenging to target mutant KRAS (mKRAS) in colorectal cancer (CRC) and other malignancies. Recent efforts have focused on developing inhibitors blocking molecules essential for KRAS activity. In this regard, SOS1 inhibition has arisen as an attractive approach for mKRAS CRC given its essential role as a guanine nucleotide exchange factor for this GTPase. Here, we demonstrated the translational value of SOS1 blockade in mKRAS CRC. We used CRC patient‐derived organoids (PDOs) as preclinical models to evaluate their sensitivity to SOS1 inhibitor BI3406. A combination of in silico analyses and wet lab techniques was utilized to define potential predictive markers for SOS1 sensitivity and potential mechanisms of resistance in CRC. RNA‐seq analysis of CRC PDOs revealed two groups of CRC PDOs with differential sensitivities to SOS1 inhibitor BI3406. The resistant group was enriched in gene sets involving cholesterol homeostasis, epithelial−mesenchymal transition, and TNF‐α/NFκB signaling. Expression analysis identified a significant correlation between SOS1 and SOS2 mRNA levels (Spearman's ρ 0.56, p < 0.001). SOS1/2 protein expression was universally present with heterogeneous patterns in CRC cells but only minimal to none in surrounding nonmalignant cells. Only SOS1 protein expression was associated with worse survival in patients with RAS/RAF mutant CRC (p = 0.04). We also found that SOS1/SOS2 protein expression ratio >1 by immunohistochemistry (p = 0.03) instead of KRAS mutation (p = 1) was a better predictive marker to BI3406 sensitivity of CRC PDOs, concordant with the significant positive correlation between SOS1/SOS2 protein expression ratio and SOS1 dependency. Finally, we showed that GTP‐bound RAS level underwent rebound even in BI3406‐sensitive PDOs with no change of KRAS downstream effector genes, thus suggesting upregulation of guanine nucleotide exchange factor as potential cellular adaptation mechanisms to SOS1 inhibition. Taken together, our results show that high SOS1/SOS2 protein expression ratio predicts sensitivity to SOS1 inhibition and support further clinical development of SOS1‐targeting agents in CRC.

Abstract Recurrent chromosomal rearrangements are a hallmark of hematologic malignancies and play critical roles in pathogenesis. The TP53 analog TP63 is rearranged in 5-10% of diverse subtypes of both aggressive T- and B-cell lymphomas. Patients with TP63-rearranged lymphomas have dismal outcomes, with 5-year overall survival rates between 0-17%, depending on cohorts. The function and mechanisms of TP63 rearrangements and TP63 fusion proteins in tumorigenesis are poorly understood. As a result, attempts to treat these patients to date have been largely empiric. Thus, there is an urgent need to understand how TP63 fusions contribute to tumorigenesis and to translate the findings into novel therapeutic options for these patients. Here, we demonstrated that TP63 fusions are essential for the propagation of T-cell lymphomas (TCLs). Knockdown of TP63 fusions with specific shRNAs in TCL cell lines harboring TP63 fusions suppressed both cell growth in vitro and tumor growth in vivo. Retroviral expression of TBL1XR1-TP63, the most common TP63 fusion, conferred cytokine independence in Ba/F3 cells, consistent with its role as an oncogene. To investigate the role of TP63 fusions in T- and B-cell lymphomagenesis, we engineered a CAG-Loxp-Stop-Loxp-TBL1XR1-TP63 conditional knock-in mouse model and crossed with hCD2-Cre mice. This results in expression beginning during early lymphoid development. As observed in patients, transgenic mice developed multiple subtypes of both T- and B-cell lymphoma. To define the effects and mechanisms of TP63 fusions within T cells, we performed CRISPR scanning, transcriptomic, epigenomic, and proteomic analyses. Our data showed that domains within both the N-terminal TBL1XR1 and C-terminal TP63 portions contribute to the function of this fusion. We found that the N-terminal component of TP63 fusions interacts with components of the NCOR/SMRT complex. At the same time, the C-terminal portion of TP63 (which recapitulates the deltaN-p63 isoform expressed in some carcinomas) interacts with the enhancer modifier KMT2D and its complex members. TBL1XR1-TP63 binds to a novel distal enhancer to drive MYC expression, and thus upregulates the expression of the histone H3K27 methylase EZH2. Finally, we assessed whether EZH2 is a vulnerability of TP63-rearranged lymphomas. We found that knockdown of EZH2 in TP63-rearranged lines significantly impaired cell growth, as did treatment with the EZH2 and 1 dual inhibitor valemetostat. Valemetostat, which is now being tested in patients with lymphoma, counteracted the oncogenic effects of TP63 fusions in multiple preclinical models in vivo. Together, our results identify the TP63 fusion as a highly unique oncogenic driver in lymphomagenesis capable of recruiting multiple epigenetic modifier complexes and inducing a targetable dependence on EZH2. Citation Format: Gongwei Wu, Noriaki Yoshida, Jihe Liu, Xiaoyang Zhang, Yuan Xiong, Tayla Heavican-Foral, Huiyun Liu, Geoffrey Nelson, Lu Yang, Renee Chen, Katherine Donovan, Marcus Jones, Mikhail Roshal, Yanming Zhang, Ran Xu, Ajit Nirmal, Salvia Jain, Catharine Leahy, Kristen Jones, Kristen Stevenson, Natasha Galasso, Nivetha Ganesan, Tiffany Chang, Wen-Chao Wu, Abner Louissaint, Lydie Debaize, Hojong Yoon, Paola Dal Cin, Wing Chan Chan, Shannan Ho Sui Ho Sui, Samuel Ng, Andrew Feldman, Steven M. Horwitz, Mathew Meyerson, Karen Adelman, Eric Fischer, Chun-Wei Chen, David Weinstock, Myles Brown. TP63 fusions drive enhancer rewiring, lymphomagenesis, and dependence on EZH2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5755.

AbstractObjectivesT-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell leukemia usually characterized by inv(14)(q11.2q32)/t(14;14)(q11.2;q32). In this study, we aimed to investigate the clinicopathologic features and molecular profile of T-PLL associated with t(X;14)(q28;q11.2).MethodsThe study group included 10 women and 5 men with a median age of 64 years. All 15 patients had a diagnosis of T-PLL with t(X;14)(q28;q11.2).ResultsAll 15 patients had lymphocytosis at initial diagnosis. Morphologically, the leukemic cells had features of prolymphocytes in 11 patients, small cell variant in 3, and cerebriform variant in 1. All 15 patients had hypercellular bone marrow with an interstitial infiltrate in 12 (80%) cases. By flow cytometry, the leukemic cells were surface CD3+/CD5+/CD7+/CD26+/CD52+/TCR α/β+ in 15 (100%) cases, CD2+ in 14 (93%) cases, CD4+/CD8+ in 8 (53%) cases, CD4+/CD8– in 6 (40%) cases, and CD4–/CD8 + in 1 (7%) case. At the cytogenetic level, complex karyotypes with t(X;14)(q28;q11.2) were seen in all 15 patients assessed. Mutational analysis showed mutations of JAK3 in 5 of 6 and STAT5B p.N642H in 2 of 6 patients. Patients received variable treatments, including 12 with alemtuzumab. After a median follow-up of 17.2 months, 8 of 15 (53%) patients died.ConclusionsT-PLL with t(X;14)(q28;q11.2) frequently shows a complex karyotype and mutations involving JAK/STAT pathway, and it is an aggressive disease with a poor outcome.

Objectives: To investigate the correlation between a screw's radiographic relationship to the piriformis fossa with position on CT in the clinical setting. Methods: Intraoperative fluoroscopic images of patients treated with cannulated screw fixation of a femoral neck fracture, who also had a postoperative CT scan, were retrospectively evaluated by 4 fellowship-trained orthopaedic trauma surgeons. The posterosuperior screw on the AP fluoroscopic view was determined to be above the piriformis fossa (APF) or below the piriformis fossa (BPF). Using CT scan to determine IOI placement, the ability to predict IOI position based on fluoroscopic imaging was evaluated by calculating accuracy, sensitivity, specificity, and interobserver reliability. Results: 73 patients met inclusion criteria. The incidence of IOI screw placement was 59% on CT evaluation. The use of the PF landmark accurately predicted CT findings in 89% of patients. A screw placed APF was 90% sensitive and 88% specific in predicting cortical breach, with near-perfect interobserver agreement (κ = 0.81). Conclusion: The use of the PF radiographic landmark is highly sensitive and specific in predicting the placement of an IOI posterosuperior femoral neck screw. Level of Evidence: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.