Peripheral T-cell lymphoma: From biology to practice to the future.

Recent advancements in comprehending peripheral T-cell lymphomas (PTCLs) validate and broaden our perspective, highlighting their diverse nature and the varying molecular mechanisms underlying the entities. Based on a comprehensive accumulated understanding, the PTCLs currently overcome the most challenging features of any disease: rarity, incredible heterogeneity, and a lack of any established standard of care. The treatments deployed in the front-line are extrapolated from regimens developed for other diseases. The recent approval of the three drugs brentuximab vedotin (BV), pralatrexate, and belinostat for patients with relapsed or refractory disease has provided clues about pathophysiology and future directions, though challenges satisfying post-marketing requirements (PMR) for those accelerated approvals have led to one of those drugs being withdrawn and put the other two in jeopardy. Edits of the front-line regimens, often called CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-plus approaches, look more like CHOP-minus strategies, as the toxicity of five-drug regimens often reduces the dose intensity of the added 'novel' drug, nullifying any hope of an advance. The turmoil in the field produced by the aforementioned, coupled with an ever-changing classification, has left the field uncertain about the path forward. Despite these challenges, empiric findings from studies of novel drug approaches, coupled with a logic emerging from studies of PTCL lymphomagenesis, have begun to illuminate, albeit faintly for some, a potential direction. The empiric finding that drugs targeting the discrete components of the PTCL epigenome, coupled with the description of multiple mutations in genes that govern epigenetic biology, offers, at the very least, an opportunity to finally be hypothesis-driven. The most recent recognition that the only combination of drugs shown to markedly improve progression-free survival (PFS) in patients with relapsed disease is one based on dual targeting of different and discrete components of that epigenetic biology has established a possibility that circumnavigating chemotherapy addition studies is both plausible, feasible, and likely the best prospect for a quantum advance in this disease. Herein, we analyze PTCL through a 2025 lens, highlighting and underscoring walls that have impeded progress. We will critically explore all the clues and the panoramic view of PTCL research.

Pooled analysis of pralatrexate single-agent studies in patients with relapsed/refractory peripheral T-cell lymphoma.

ABSTRACT: Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.

Mature T-cell and NK-cell lymphoma involvement of the central nervous system: a single center experience.

Mature T-cell and NK-cell lymphomas (MTNKL) are rare and heterogeneous lymphoproliferative disorders with poor clinical outcomes despite novel therapeutic advances. Although infrequent, central nervous system (CNS) involvement by MTNKL is associated with poor outcomes with a median overall survival (OS) of <12 months based on retrospective studies. We performed a retrospective analysis of patients who developed CNS involvement of MTNKL diagnosed at a single center from 1999 through 2020. Twenty-five patients were identified. Characteristics such as a diagnosis of adult T-cell leukemia/lymphoma, extranodal involvement, and poor performance status were associated with a higher risk of CNS involvement (p < 0.01). The median OS after diagnosis with CNS involvement was approximately 1 month (0.03-103.97 months). Patients exposed to novel therapeutics and/or clinical trial enrollment tolerated treatment without safety concerns and appeared to derive reasonable therapeutic benefit. Despite advances in the field, new therapeutic approaches are needed for patients with MTNKL with CNS involvement.

Analytic Morphomics in Myositis-Related Interstitial Lung Disease.

PURPOSE: Interstitial lung disease (ILD) is the most common non-musculoskeletal manifestation of idiopathic inflammatory myopathies (IIM). Identification of body composition change may enable early intervention to improve prognosis. We investigated muscle quantity and quality derived from cross-sectional imaging in IIM, and its relationship to ILD severity. METHODS: A retrospective cohort study assessing IIM of ILD patients (n = 31) was conducted. Two datasets separated in time were collected, containing demographics, biochemical data, pulmonary function testing and thoracic CT data. Morphomic analysis of muscle quantity (cross-sectional area) and quality (density in Hounsfield Units) on thoracic CT were analysed utilising a web-based tool allowing segmentation of muscle and fat. Bilateral erector spinae and pectoralis muscle (ESM&PM) were measured at defined vertebral levels. RESULTS: FVC and DLCO decreased but within acceptable limits of treatment response (FVC: 83.7-78.7%, p < 0.05, DLCO 63.4-60.6%, p < 0.05). The cross-sectional area of the PM and ESM increased (PM: 39.8 to 40.7 cm2, p = 0.491; ESM: 35.2 to 39.5 cm2, p = 0.098). Density significantly fell for both the PM and ESM (PM: 35.3-31 HU, p < 0.05; ESM: 38-33.7, p < 0.05). Subcutaneous fat area increased from 103.9 to 136.1 cm2 (p < 0.05), while the visceral fat area increased but not reaching statistical significance. The change in PM density between time points demonstrated an inverse correlation with DLCO (p < 0.05, R = - 0.49). CONCLUSION: Patients with IIM ILD demonstrated significant body composition changes on CT imaging unlikely to be detected by traditional measurement tools. An increase in muscle area with an inverse decrease in density suggests poor muscle quality.

Replacing Plain Radiograph with ultra-low dose CT thorax in cystic fibrosis (CF) in the era of CFTR modulation and its impact on cumulative effective dose.

BACKGROUND: Medical radiation exposure is of increasing concern in patients with cystic fibrosis (PWCF) due to improving life expectancy. We aimed to assess and quantify the cumulative effective dose (CED) in PWCF in the context of CFTR-modulator therapy and the advancement of dose reduction techniques. METHODS: We performed a retrospective observational study in a single University CF centre over a 11-year period. We included PWCF, aged over 18 years who exclusively attended our institution. Relevant clinical data (demographics, transplantation history and modulator status) and radiological data (modality, quantity, and radiation exposure measured as CED) were collected. For those on modulator therapy the quantified imaging and radiation data was dichotomised into pre-and-post therapy periods. RESULTS: The study included 181 patients: 139 on CFTR modulator therapy, 15 transplant recipients and 27 with neither exposure. 82% of patients received <25 mSv over the study period. Mean study duration was 6.9 ± 2.6 years pre-modulation and 4.2 ± 2.6 years post-modulation. Pre-modulation CT contributed 9.6% of total chest imaging (n = 139/1453) and 70.9% of the total CED. Post-modulation CT use increased contributing 42.7% of chest imaging (n = 444/1039) and comprised 75.8% of CED. Annual CED was 1.55 mSv pre and 1.36 mSv post modulation (p = 0.41). Transplant recipients had an annual CED of 64 ± 36.1mSv. CONCLUSION: Chest CT utilisation for PWCF is rising in our institution, replacing chest radiography amidst CFTR-modulation. Despite the increasing use of CT, no significant radiation dose penalty was observed with a reduction in mean annual CED, primarily due to the influence of CT dose reduction strategies.

Longitudinal Single-Cell Imaging of Engineered Strains with Stimulated Raman Scattering to Characterize Heterogeneity in Fatty Acid Production.

Understanding metabolic heterogeneity is critical for optimizing microbial production of valuable chemicals, but requires tools that can quantify metabolites at the single-cell level over time. Here, longitudinal hyperspectral stimulated Raman scattering (SRS) chemical imaging is developed to directly visualize free fatty acids in engineered Escherichia coli over many cell cycles. Compositional analysis is also developed to estimate the chain length and unsaturation of the fatty acids in living cells. This method reveals substantial heterogeneity in fatty acid production among and within colonies that emerges over the course of many generations. Interestingly, the strains display distinct types of production heterogeneity in an enzyme-dependent manner. By pairing time-lapse and SRS imaging, the relationship between growth and production at the single-cell level are examined. The results demonstrate that cell-to-cell production heterogeneity is pervasive and provides a means to link single-cell and population-level production.

HX009, a novel BsAb dual targeting PD1 x CD47, demonstrates potent anti-lymphoma activity in preclinical models.

Both PD1/PD-L1 and CD47 blockades have demonstrated limited activity in most subtypes of NHL save NK/T-cell lymphoma. The hemotoxicity with anti-CD47 agents in the clinic has been speculated to account for their limitations. Herein we describe a first-in-class and rationally designed bispecific antibody (BsAb), HX009, targeting PD1 and CD47 but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD1 interaction, potentially reducing toxicity. In vitro characterization confirmed: (1) Both receptor binding/ligand blockade, with lowered CD47 affinity; (2) functional PD1/CD47 blockades by reporter assays; (3) T-cell activation in Staphylococcal-enterotoxin-B-pretreated PBMC and mixed-lymphocyte-reaction. In vivo modeling demonstrated antitumor activity in Raji-B and Karpass-229-T xenograft lymphomas. In the humanized mouse syngeneic A20 B-lymphoma (huCD47-A20) HuGEMM model, which has quadruple knocked-in hPD1xhPD-L1xhCD47xhSIRPα genes and an intact autologous immune-system, a contribution of effect is demonstrated for each targeted biologic (HX008 targeting PD1 and SIRPα-Fc targeting CD47), which is clearly augmented by the dual targeting with HX009. Lastly, the expression of the immune-checkpoints PD-L1/L2 and CD47 seemed co-regulated among a panel of lymphoma-derived-xenografts, where HX009 maybe more effective in those with upregulated CD47. Our data warrants HX009's further clinical development for treating NHLs.

Uterine Artery Embolisation of Fibroids and the Phenomenon of Post-Embolisation Syndrome: A Systematic Review.

Post-embolisation syndrome (PES) is a prevalent complication that occurs in patients following uterine artery embolisation (UAE) for the treatment of uterine fibroids. The aetiology of PES remains incompletely understood, although postulated to result secondary to tissue infarction resulting in release of inflammatory mediators. We followed PRISMA guidelines and performed a systematic review of studies of PES following UAE from inception to October 2022. Our published protocol was prospectively registered. Our search yielded 54 results. We reviewed 22 full texts, and nine articles were included. Observational studies comprised 6/9 relevant studies, with 5/9 retrospective design. The rate of PES was documented in 5/8 studies (excluding case report) with a reported incidence ranging from 4-34.6%. Five of the nine studies studies postulated that the aetiological basis of PES is inflammatory related. Further research is necessary to advance our understanding of PES to define the biological basis of the syndrome with more certainty and gain a consensus on peri-procedure management to reduce incidence and improve patient outcomes.

An evaluation of the impact of the Coronavirus (COVID 19) pandemic on interventional radiographers' wellbeing.

BACKGROUND: Interventional radiographers have substantially contributed to patient care during the pandemic by providing imaging guidance during minimally invasive procedures. The aim of this research is to quantify the impact of the pandemic on an interventional radiographers' wellbeing during the COVID-19 pandemic. METHODS: Ethical approval was obtained at the outset of this study. An explanatory sequential mixed methods approach, using questionnaires and interviews, was used to explore and evaluate interventional radiographers' wellbeing; physical, mental and social. An electronic self-administered questionnaire was administered to interventional radiographers and a semi-structured interview was conducted on two respondents. RESULTS: Responses were received from 40 interventional radiographers. Physical, mental and social wellbeing of interventional radiographers deteriorated since the onset of COVID-19. All forms of wellbeing were negatively impacted during the pandemic with mental wellbeing (82.5%) the most impacted, closely followed by physical (75%) and social wellbeing (50%). Half of responding interventional radiographers reported being "highly stressed" while working during COVID-19. Physical activity levels decreased, caffeine consumption increased and consumption of a healthy diet decreased. Almost all interventional radiographers (95%) had anxiety about passing the virus onto family or friends and 60% of noted a deterioration in relationship with friends. Three key themes identified included the importance of teamwork, the physical demand and mental impacts of working in interventional radiology during the pandemic. CONCLUSIONS: The COVID-19 pandemic has had a negative effect on interventional radiographers' wellbeing. The implications of staff having a diminished sense of wellbeing is that productivity is likely to have been reduced and potentially related burnout can lead to illness. This research highlights the need to focus on identifying methods of addressing the shortcomings in support services and identifying the specific needs of interventional radiographers to improve their wellbeing.

Role of stem cell transplant in CD30+ PTCL following frontline brentuximab vedotin plus CHP or CHOP in ECHELON-2.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas, the majority of which have high relapse rates following standard therapy. Despite use of consolidative stem cell transplant (SCT) following frontline therapy, there remains no consensus on its utility. The double-blind randomized phase 3 ECHELON-2 study (#NCT01777152; clinicaltrials.gov) demonstrated improved progression-free survival (PFS) and overall survival with frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP). Herein, we conducted an exploratory subgroups analysis of the impact of consolidative SCT on PFS in patients with previously untreated CD30+ PTCL (ALK- anaplastic large cell lymphoma [ALCL] and non-ALCL) who were in complete response (CR) after frontline treatment with A+CHP or cyclophosphamide, doxorubicin, vincristine, and prednisone. Median PFS follow-up was 47.57 months. The PFS hazard ratio was 0.36, equating to a 64% reduction in the risk of a PFS event in patients who underwent SCT. The median PFS in patients who underwent SCT was not reached, vs 55.66 months in patients who did not undergo SCT. PFS results favored the use of SCT in both ALK- ALCL and non-ALCL subgroups. These data support the consideration of consolidative SCT in patients with CD30+PTCL who achieve CR following treatment with A+CHP.

An evaluation of information online on artificial intelligence in medical imaging.

BACKGROUND: Opinions seem somewhat divided when considering the effect of artificial intelligence (AI) on medical imaging. The aim of this study was to characterise viewpoints presented online relating to the impact of AI on the field of radiology and to assess who is engaging in this discourse. METHODS: Two search methods were used to identify online information relating to AI and radiology. Firstly, 34 terms were searched using Google and the first two pages of results for each term were evaluated. Secondly, a Rich Search Site (RSS) feed evaluated incidental information over 3 weeks. Webpages were evaluated and categorized as having a positive, negative, balanced, or neutral viewpoint based on study criteria. RESULTS: Of the 680 webpages identified using the Google search engine, 248 were deemed relevant and accessible. 43.2% had a positive viewpoint, 38.3% a balanced viewpoint, 15.3% a neutral viewpoint, and 3.2% a negative viewpoint. Peer-reviewed journals represented the most common webpage source (48%), followed by media (29%), commercial sources (12%), and educational sources (8%). Commercial webpages had the highest proportion of positive viewpoints (66%). Radiologists were identified as the most common author group (38.9%). The RSS feed identified 177 posts of which were relevant and accessible. 86% of posts were of media origin expressing positive viewpoints (64%). CONCLUSION: The overall opinion of the impact of AI on radiology presented online is a positive one. Consistency across a range of sources and author groups exists. Radiologists were significant contributors to this online discussion and the results may impact future recruitment.

DeLTA 2.0: A deep learning pipeline for quantifying single-cell spatial and temporal dynamics.

Improvements in microscopy software and hardware have dramatically increased the pace of image acquisition, making analysis a major bottleneck in generating quantitative, single-cell data. Although tools for segmenting and tracking bacteria within time-lapse images exist, most require human input, are specialized to the experimental set up, or lack accuracy. Here, we introduce DeLTA 2.0, a purely Python workflow that can rapidly and accurately analyze images of single cells on two-dimensional surfaces to quantify gene expression and cell growth. The algorithm uses deep convolutional neural networks to extract single-cell information from time-lapse images, requiring no human input after training. DeLTA 2.0 retains all the functionality of the original version, which was optimized for bacteria growing in the mother machine microfluidic device, but extends results to two-dimensional growth environments. Two-dimensional environments represent an important class of data because they are more straightforward to implement experimentally, they offer the potential for studies using co-cultures of cells, and they can be used to quantify spatial effects and multi-generational phenomena. However, segmentation and tracking are significantly more challenging tasks in two-dimensions due to exponential increases in the number of cells. To showcase this new functionality, we analyze mixed populations of antibiotic resistant and susceptible cells, and also track pole age and growth rate across generations. In addition to the two-dimensional capabilities, we also introduce several major improvements to the code that increase accessibility, including the ability to accept many standard microscopy file formats as inputs and the introduction of a Google Colab notebook so users can try the software without installing the code on their local machine. DeLTA 2.0 is rapid, with run times of less than 10 minutes for complete movies with hundreds of cells, and is highly accurate, with error rates around 1%, making it a powerful tool for analyzing time-lapse microscopy data.

Making computed tomography safer for patients with Crohn's disease.

Background and aims: Computed tomography (CT), often more accessible than magnetic resonance imaging (MRI), remains widely used though radiation exposure is an obvious disadvantage. We previously showed that modern CT technology can achieve over 70% reduction in radiation-dose without loss of accuracy. Here, we compare low- versus conventional-dose CT in patients with known Crohn's disease to assess clinical confidence and accuracy of the low-dose procedure in the semi-acute setting.Methods: A comparative study of low-dose CT with full iterative reconstruction (IR) versus conventional-dose CT was conducted in 50 consecutive outpatients with Crohn's disease. Clinicians were provided with the low-dose images and reports, whereas conventional-dose images were reviewed after 4 weeks.Results: The clinical question was adequately addressed with low-dose IR imaging in all cases. Complications of Crohn's were detected in 37/50 (74%) with no disagreement between low- and conventional-dose imaging. The effective radiation dose reduction was 76.5% (low-dose mean 2.15 mSv versus conventional-dose CT 6.99 mSv).Conclusion: Low-dose IR CT is safe and accurate for evaluating distribution and complications of known Crohn's disease in the outpatient setting. We propose that low-dose radiation imaging should be adopted as standard-of-care for the evaluation of Crohn's disease and an acceptable alternative to MR particularly in the acute setting. ClinicalTrials.gov: NCT03140306.

Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies.

Phosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other tumor types [n = 25]) who were treated with the recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%]), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.

Body Composition, Inflammation, and 5-Year Outcomes in Colon Cancer.

Importance: Obesity, particularly visceral obesity and sarcopenia, are poor prognostic indicators in colon cancer. Objectives: To explore the association between body composition profiles and 5-year colon cancer outcomes and delineate the associated underlying inflammatory processes. Design, Setting, and Participants: This multicenter translational cohort study included patients with nonmetastatic colon cancer who did not have underlying chronic inflammatory disorders and were not receiving anti-inflammatory drugs referred to tertiary cancer centers from 2009 to 2015. Preoperative acute phase proteins (white cell count, C-reactive protein, and albumin), cytokines (interleukin [IL]-1b, IL-2, IL-6, IL-10, interferon γ, and tumor necrosis factor α), vascular endothelial growth factor (VEGF), and cell surface receptor expression levels (CD11b and CD14) were measured. All patients underwent follow-up for at least 5 years. Data were analyzed in December 2020. Exposure: Nonmetastatic colon cancer. Main Outcomes and Measures: The associations of body composition profiles with 5-year cancer recurrence and disease-specific mortality were analyzed using Mantel Cox log-rank test and Kaplan-Meier curves. Results: A total of 28 patients were included (median [interquartile range] age, 67 [58-72] years; 22 [78.6%] men). Low skeletal muscle area (SMA) and high visceral to total fat ratio were associated with poor clinical and oncological outcomes, including increased 5-year recurrence (low SMA: hazard ratio [HR], 2.30 [95% CI, 1.41-2.89]; P = .04; high visceral to total fat ratio: HR, 5.78 [95% CI, 3.66-7.95]; P = .02). High visceral to total fat ratio was associated with increased 5-year disease-specific mortality (HR, 5.92 [95% CI, 4.04-8.00]; P = .02). Patients with low SMA who developed a cancer recurrence, compared with those who did not, had higher C-reactive protein (mean [SD], 31.24 [6.95] mg/dL vs 8.11 [0.58] mg/dL; P = .003), IL-6 (mean [SD], 1.93 [1.16] ng/mL vs 0.88 [0.14] ng/mL; P = .004), VEGF (mean [SD], 310.03 [122.66] ng/mL vs 176.12 [22.94] ng/mL; P = .007), and CD14 (mean [SD], 521.23 [302.02] ng/mL vs 322.07 [98.35] ng/mL; P = .03) expression and lower albumin (mean [SD], 3.8 [0.6] g/dL vs 43.50 [3.69] g/dL; P = .01), IL-2 (mean [SD], 0.45 [0.25] ng/mL vs 0.94 [0.43] ng/mL; P < .001), IL-10 (mean [SD], 8.15 [1.09] ng/mL vs 16.32 [4.43] ng/mL; P = .004), and interferon γ (mean [SD], 2.61 [1.36] ng/mL vs 14.87 [3.43] ng/mL; P = .02) levels. Patients with high visceral to total fat ratio who developed recurrence had higher levels of IL-6 (mean [SD], 5.26 [7.05] ng/mL vs 2.76 [3.11] ng/mL; P = .03) and tumor necrosis factor α (mean [SD], 5.74 [4.53] ng/mL vs 4.50 [1.99] ng/mL; P = .03). Conclusions and Relevance: These findings suggest that low SMA and high visceral to total fat ratio were associated with worse colon cancer outcomes and with increased expression of proinflammatory cytokines and VEGF and inhibition of anti-inflammatory cytokines.

Endovascular management of pelvic trauma.

Traumatic pelvic injuries are an important group of acquired pathologies given their frequent association with significant vascular compromise. Potentially fatal as a consequence of rapid hemorrhage, achievement of early hemostasis is a priority; endovascular management of traumatic pelvic arterial injuries is an important potential option for treatment. Precipitated by any number of mechanisms of trauma, pelvic vascular injury necessitates timely patient assessment. Variable patterns of arterial injury may result from blunt, penetrating or iatrogenic trauma. Selection of the most appropriate imaging modality is a priority, ensuring streamlined access to treatment. In the case of CT, this is complemented by acquisition of the most appropriate phase of imaging; review of both arterial and delayed phase imaging improves the accuracy of detection of low-flow hemorrhage. In cases where surgical intervention is not deemed appropriate, endovascular treatment provides an alternative means for cessation of hemorrhage associated with pelvic injuries. This may be achieved in a selective or nonselective manner depending on the patient's clinical status and time constraints. Consequently, a detailed understanding of vascular anatomy is essential, including an appreciation of the normal variant anatomy between males and females. Additional consideration must be given to variant anatomy which may co-exist in both sexes. This review article aims to provide a synopsis of endovascular management of pelvic vascular injury. Through case examples, available treatment options will be discussed, including thrombin injection and transcatheter arterial embolization. Furthermore, potential adverse complications of pelvic arterial embolization will be highlighted. Finally, in view of the potential severity of these injuries, a brief overview of initial management of the hemodynamically unstable patient is provided.

Characterization of newly established Pralatrexate-resistant cell lines and the mechanisms of resistance.

BACKGROUND: Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic resistance or develop acquired resistance. Here, we evaluated the mechanisms underlying acquired resistance to PDX and explored potential therapeutic strategies to overcome PDX resistance. METHODS: To investigate PDX resistance, we established two PDX-resistant T-lymphoblastic leukemia cell lines (CEM and MOLT4) through continuous exposure to increasing doses of PDX. The resistance mechanisms were evaluated by measuring PDX uptake, apoptosis induction and folate metabolism-related protein expression. We also applied gene expression analysis and methylation profiling to identify the mechanisms of resistance. We then explored rational drug combinations using a spheroid (3D)-culture assay. RESULTS: Compared with their parental cells, PDX-resistant cells exhibited a 30-fold increase in half-maximal inhibitory concentration values. Induction of apoptosis by PDX was significantly decreased in both PDX-resistant cell lines. Intracellular uptake of [14C]-PDX decreased in PDX-resistant CEM cells but not in PDX-resistant MOLT4 cells. There was no significant change in expression of dihydrofolate reductase (DHFR) or folylpolyglutamate synthetase (FPGS). Gene expression array analysis revealed that DNA-methyltransferase 3ß (DNMT3B) expression was significantly elevated in both cell lines. Gene set enrichment analysis revealed that adipogenesis and mTORC1 signaling pathways were commonly upregulated in both resistant cell lines. Moreover, CpG island hypermethylation was observed in both PDX resistant cells lines. In the 3D-culture assay, decitabine (DAC) plus PDX showed synergistic effects in PDX-resistant cell lines compared with parental lines. CONCLUSIONS: The resistance mechanisms of PDX were associated with reduced cellular uptake of PDX and/or overexpression of DNMT3B. Epigenetic alterations were also considered to play a role in the resistance mechanism. The combination of DAC and PDX exhibited synergistic activity, and thus, this approach might improve the clinical efficacy of PDX.

Development and implementation of an ultralow-dose CT protocol for the assessment of cerebrospinal shunts in adult hydrocephalus.

BACKGROUND: Cerebrospinal fluid shunts in the treatment of hydrocephalus, although associated with clinical benefit, have a high failure rate with repeat computed tomography (CT) imaging resulting in a substantial cumulative radiation dose. Therefore, we sought to develop a whole-body ultralow-dose (ULD) CT protocol for the investigation of shunt malfunction and compare it with the reference standard, plain radiographic shunt series (PRSS). METHODS: Following ethical approval, using an anthropomorphic phantom and a human cadaveric ventriculoperitoneal shunt model, a whole-body ULD-CT protocol incorporating two iterative reconstruction (IR) algorithms, pure IR and hybrid IR, including 60% filtered back projection and 40% IR was evaluated in 18 adult patients post new shunt implantation or where shunt malfunction was suspected. Effective dose (ED) and image quality were analysed. RESULTS: ULD-CT permitted a 36% radiation dose reduction (median ED 0.16 mSv, range 0.07-0.17, versus 0.25 mSv (0.06-1.69 mSv) for PRSS (p = 0.002). Shunt visualisation in the thoracoabdominal cavities was improved with ULD-CT with pure IR (p = 0.004 and p = 0.031, respectively) and, in contrast to PRSS, permitted visualisation of the entire shunt course (p < 0.001), the distal shunt entry point and location of the shunt tip in all cases. For shunt complications, ULD-CT had a perfect specificity. False positives (3/22, 13.6%) were observed with PRSS. CONCLUSIONS: At a significantly reduced radiation dose, whole body ULD-CT with pure IR demonstrated diagnostic superiority over PRSS in the evaluation of cerebrospinal fluid shunt malfunction.