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Background and Objective: Initial studies show that 41Ca may be employed as a useful diagnostic bioassay for monitoring metabolic bone disease and its treatment management. The 41Ca-based pharmacokinetic model is developed to assess its feasibility in monitoring bone disease and clinical responsiveness to therapeutic regimens.Methods: A four-compartment calcium kinetic model is developed to interpret the results of clinically measured 41Ca tracer kinetics for oral and intravenous dose. This model is extended to simulate changes in bone turnover due to osteoporosis by using Gompertzian function with and without cellular accommodation. The rate constants obtained by fitting to the experimental data on drug intervention are used to simulate the impact of strategic treatment intervention.Results: The present model fits well with the available experimental data on 41Ca tracer kinetics. In the simulated osteoporotic model, the negative bone balance (i.e. bone loss) reflected by 41Ca/Ca urine ratio is used to demonstrate slow/fast increase over time compared to the normal state. The cellular accommodation impact is reflected by a recovery from perturbed balance. The model's predictive ability on the impact of therapeutic intervention is verified using published experimental data. The effect of bisphosphonate intervention results in positive bone balance (i.e. bone gain).Conclusion: The four-compartment 41Ca tracer kinetic model can be flexibly used in the interpretation of results obtained from ongoing clinical studies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the effectiveness of intrauterine lignocaine as an anaesthetic during endometrial sampling. DESIGN: Prospective, randomised, double-blind, placebo-controlled trial. SETTING: Outpatient gynaecological minor operation unit in a public hospital. POPULATION: Two hundred premenopausal women scheduled for endometrial sampling because of abnormal uterine bleeding. METHODS: Transcervical intrauterine instillation of 5 mL of 2% lignocaine or 5 mL of normal saline before performing endometrial sampling with vacuum aspirator. MAIN OUTCOME MEASURES: Evaluation of pain associated with the procedure using a visual analogue scale. RESULTS: The use of intrauterine lignocaine reduced pain during suction curettage in endometrial sampling. CONCLUSIONS: Transcervical instillation of lignocaine reduced pain during endometrial sampling. [ABSTRACT FROM AUTHOR]

Background/objectives: Bone marrow (BM) adipocytes are critical in progressing solid tumor metastases and hematological malignancies across pediatric to aging populations. Single-point biopsies remain the gold standard for monitoring BM diseases, including hematologic malignancies, but are limited in capturing the full complexity of loco-regional and global BM microenvironments. Non-invasive imaging techniques like Magnetic Resonance Imaging (MRI), could offer valuable alternatives for real-time evaluation of BM diseases in both preclinical translational and clinical studies., Methods: We developed a preclinical proton density fat fraction (PDFF) MRI technique for quantitative BM composition assessment, focusing on fat fraction (FF) within mouse femurs. We validated this method using aging mice and young mice subjected to 10 Gy X-ray irradiation, compared with young unirradiated mice as controls. Water-fat phantoms (0% to 100% fat content) were used to optimize the imaging sequence, and immunohistochemical (IHC) staining with H&E validates equivalent adipose content in the femur BM regions., Results: Significant differences in FF were observed across age groups (p = 0.001 for histology and p = 0.0002 for PDFF) and between irradiated and control mice (p = 0.005 for histology and p = 0.002 for PDFF). A strong correlation (R 2 ∼ 0.84) between FF values from PDFF and histology validates the accuracy of the technique., Conclusions: These findings demonstrate the potential of PDFF MRI as a non-invasive real-time imaging biomarker for quantifying BM fat fraction in preclinical mice model studies, particularly in evaluating the effects of aging, disease progression, and irradiation therapy in pediatric and translational oncology research.

Objective: This study aims to evaluate and compare the Cervex-Brush ® and Orcellex ® Brush as sampling devices for vaginal vault smear cytology in cervical cancer patients treated primarily with radiotherapy., Method: A randomized crossover trial was conducted at a gynecological oncology center in Hong Kong to compare the Cervex-Brush ® and Orcellex ® Brush in terms of their vault smear adequacy rate in cervical cancer patients who underwent radiotherapy., Results: One hundred sixty cervical cancer patients treated with primary radiotherapy and undergoing follow-up surveillance by vaginal vault cytology were recruited. The smear adequacy rate was 90.6% for Cervex-Brush ® and 91.9% for Orcellex ® Brush. The rates of low cellularity for both brushes were similar (76.8% for Cervex-Brush ® vs. 76.1% for Orcellex ® Brush). The detection rates of abnormal smears were also not significantly different (2.8% for Cervex-Brush ® vs. 4.2% for Orcellex ® Brush). The 2 brushes were also not significantly different in terms of pain score and degree of bleeding. It was further observed that the second smear collection was more painful and patients who were on hormonal replacement therapy demonstrated less bleeding., Conclusion: There was no difference between the Orcellex ® brush and the Cervex-Brush ® in terms of smear adequacy rate, rate of high cellularity and the detection of abnormal smears. There was also no significant difference between the 2 brushes in terms of pain and the degree of bleeding. Therefore, the Orcellex ® Brush can be considered a suitable alternative sampling device for vault smear collection in patients who have undergone radiotherapy for cervical cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT04461574., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: There is a need for therapies that can mitigate bone marrow dysfunction and organ toxicity that occur following myeloablative injury and reduced intensity conditioning regimens used in patients undergoing bone marrow transplantation (BMT). The pathogenesis of adverse effects from BMT conditioning has been linked to injury to the vascular endothelium, bone marrow (BM), and other organs., Objective: To evaluate the impact of the thrombopoietin mimetic drug JNJ-26366821 (TPOm) on BM vascular recovery in mice undergoing myeloablative radiation conditioning followed by BMT., Study Design: TPOm (doses: 0 µg, 300 µg, 1000 µg per Kg body weight) was administered on Days 0 and 7 after BMT, in mice receiving a total body irradiation (TBI) conditioning regimen (5.5 Gy x 2) before congenic BMT. BM donner cell engraftment was analyzed using flow cytometry on Days 7, 14, and 30 post-BMT. The morphological and biophysical properties of the BM vasculature were evaluated by intravital multiphoton microscopy (MPM) and immunofluorescence confocal imaging. Herein, morphological properties involve microvascular density (MVD), vessel diameter, and vascular area, while biophysical properties include transfer rate (K trans ) of contrast within the BM vascular niche, as well as the fractional volume ( v ec ) of extracellular extravascular tissue (EES)., Results: No significant difference in donor chimerism was observed at days 7, 14, and 30 post-BMT, between TPOm and PBS-treated mice. TPOm intervention improved BM vasculature regeneration in transplanted mice. The MVD, K trans, and BM vasculature as well as vascular endothelial growth factor receptor-2 (VEGFR2) in the BM, showed a dose dependent improvement in mice treated with TPOm. On day 14 post-BMT, the group receiving 1000 µg/Kg TPOm showed significant shifts (p-value < 0.05) in MVD, K trans , and VEGFR2 expression from their corresponding control types (TPOm dose 0 µg) towards levels comparable to healthy controls., Conclusion: TPOm intervention augments BM vascular structure and function, which may be important for hematopoietic recovery and bone marrow function in radiation conditioned hematopoietic stem cell transplant patients, in addition to enhancing platelet recovery., Competing Interests: SH received honoraria from and consults for Janssen Research & Development. CG received honoraria from and consults for Janssen Research & Development. Also, CG is the Scientific advisor for focused ultrasound foundation and Co-founder of BioCovergent Health. GE participated in this work as an employee of Johnson & Johnson and its subsidiary Janssen Pharmaceuticals and stands to benefit financially from the successful development of the compound. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ghimire, Sargur Madabushi, Vercellino, Brooks, Zuro, Lim, Vishwasrao, Abdelhamid, Strome, Eichenbaum, Al Malki, Guha and Hui.)

This study proposed a semisupervised loss function named level-set loss (LSLoss) for cerebral white matter hyperintensities (WMHs) segmentation on fluid-attenuated inversion recovery images. The training procedure did not require manually labeled WMH masks. Our image preprocessing steps included biased field correction, skull stripping, and white matter segmentation. With the proposed LSLoss, we trained a V-Net using the MRI images from both local and public databases. Local databases were the small vessel disease cohort (HKU-SVD, n = 360) and the multiple sclerosis cohort (HKU-MS, n = 20) from our institutional imaging center. Public databases were the Medical Image Computing Computer-assisted Intervention (MICCAI) WMH challenge database (MICCAI-WMH, n = 60) and the normal control cohort of the Alzheimer's Disease Neuroimaging Initiative database (ADNI-CN, n = 15). We achieved an overall dice similarity coefficient (DSC) of 0.81 on the HKU-SVD testing set (n = 20), DSC = 0.77 on the HKU-MS testing set (n = 5), and DSC = 0.78 on MICCAI-WMH testing set (n = 30). The segmentation results obtained by our semisupervised V-Net were comparable with the supervised methods and outperformed the unsupervised methods in the literature., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: Graft-versus-host disease (GvHD) is a leading cause of non-relapse mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. The Perugia Bone Marrow Transplantation Unit designed a new conditioning regimen with total marrow/lymphoid irradiation (TMLI) and adaptive immunotherapy. The present study investigated the impact of radiotherapy (RT) doses on the intestine on the incidence of acute GvHD (aGvHD) in transplant recipients, analyzing the main dosimetric parameters., Materials and Methods: Between August 2015 and April 2021, 50 patients with hematologic malignancies were enrolled. All patients underwent conditioning with TMLI. Dosimetric parameters (for the whole intestine and its segments) were assessed as risk factors for aGvHD. The RT dose that was received by each intestinal area with aGvHD was extrapolated from the treatment plan for each patient. Doses were compared with those of the whole intestine minus the affected area., Results: Eighteen patients (36%) developed grade ≥2 aGvHD (G2 in 5, G3 in 11, and G4 in 2). Median time to onset was 41 days (range 23-69 days). The skin was involved in 11 patients, the intestine in 16, and the liver in 5. In all 50 TMLI patients, the mean dose to the whole intestine was 7.1 Gy (range 5.07-10.92 Gy). No patient developed chronic GvHD (cGvHD). No dosimetric variable emerged as a significant risk factor for aGvHD. No dosimetric parameter of the intestinal areas with aGvHD was associated with the disease., Conclusion: In our clinical setting and data sample, we have found no clear evidence that current TMLI dosages to the intestine were linked to the development of aGvHD. However, due to some study limitations, this investigation should be considered as a preliminary assessment. Findings need to be confirmed in a larger cohort and in preclinical models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saldi, Fulcheri, Zucchetti, Abdelhamid, Carotti, Pierini, Ruggeri, Tricarico, Chiodi, Ingrosso, Bini, Velardi, Martelli, Hui and Aristei.)

Total body irradiation (TBI) is a commonly used conditioning regimen for hematopoietic stem cell transplant (HCT), but dose heterogeneity and long-term organ toxicity pose significant challenges. Total marrow irradiation (TMI), an evolving radiation conditioning regimen for HCT can overcome the limitations of TBI by delivering the prescribed dose targeted to the bone marrow (BM) while sparing organs at risk. Recently, our group demonstrated that TMI up to 20 Gy in relapsed/refractory AML patients was feasible and efficacious, significantly improving 2-year overall survival compared to the standard treatment. Whether such dose escalation is feasible in elderly patients, and how the organ toxicity profile changes when switching to TMI in patients of all ages are critical questions that need to be addressed. We used our recently developed 3D image-guided preclinical TMI model and evaluated the radiation damage and its repair in key dose-limiting organs in young (~8 weeks) and old (~90 weeks) mice undergoing congenic bone marrow transplant (BMT). Engraftment was similar in both TMI and TBI-treated young and old mice. Dose escalation using TMI (12 to 16 Gy in two fractions) was well tolerated in mice of both age groups (90% survival ~12 Weeks post-BMT). In contrast, TBI at the higher dose of 16 Gy was particularly lethal in younger mice (0% survival ~2 weeks post-BMT) while old mice showed much more tolerance (75% survival ~13 weeks post-BMT) suggesting higher radio-resistance in aged organs. Histopathology confirmed worse acute and chronic organ damage in mice treated with TBI than TMI. As the damage was alleviated, the repair processes were augmented in the TMI-treated mice over TBI as measured by average villus height and a reduced ratio of relative mRNA levels of amphiregulin/epidermal growth factor ( areg / egf ). These findings suggest that organ sparing using TMI does not limit donor engraftment but significantly reduces normal tissue damage and preserves repair capacity with the potential for dose escalation in elderly patients., Competing Interests: Susanta K. Hui receives honoraria from and consults for Janssen Research & Development, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lim, Sargur Madabushi, Vishwasrao, Song, Abdelhamid, Ghimire, Vanishree, Lamba, Dandapani, Salhotra, Lemecha, Pierini, Zhao, Storme, Holtan, Aristei, Schaue, Al Malki and Hui.)

Image-guided small animal radiation research platforms allow more precise radiation treatment. Commercially available small animal X-ray irradiators are often equipped with a CT/cone-beam CT (CBCT) component for target guidance. Besides having poor soft-tissue contrast, CBCT unfortunately cannot provide molecular information due to its low sensitivity. Hence, there are extensive efforts to incorporate a molecular imaging component besides CBCT on these radiation therapy platforms. As an extension of these efforts, here we present a theranostic fluorescence tomography/CBCT-guided irradiator platform that provides both anatomical and molecular guidance, which can overcome the limitations of stand-alone CBCT. The performance of our hybrid system is validated using both tissue-like phantoms and mice ex vivo . Both studies show that fluorescence tomography can provide much more accurate quantitative results when CBCT-derived structural information is used to constrain the inverse problem. The error in the recovered fluorescence absorbance reduces nearly 10-fold for all cases, from approximately 60% down to 6%. This is very significant since high quantitative accuracy in molecular information is crucial to the correct assessment of the changes in tumor microenvironment related to radiation therapy., Competing Interests: The authors declare no conflicts of interest., (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Objectives: The purpose of our study is to evaluate clinical outcomes of CO2 laser vaporization in patients with high-grade vaginal intraepithelial neoplasia (VAIN), and analyze potential risk factors for unfavourable outcome., Study Design: A retrospective cohort study was carried out on all patients with high-grade VAIN treated by laser vaporization from Jan 2001 to Dec 2020 in a gynae-oncology training centre in Hong Kong., Results: A total of 116 women underwent laser therapy for high-grade VAIN during the study period and the median follow-up time was 49.5 months. Disease regression was achieved in 75% of patients after first laser treatment. However, 23% of them had disease recurrence after initial regression. Regression rate declined significantly at subsequent laser treatment for disease persistence or recurrence, from 75% after the first laser, to 52.9% after the second laser and 26.5% after the third or more laser (p < 0.001). Eleven patients (9.4%) had disease progression to cancer during subsequent follow-ups. VAIN 3 was the only independent risk factor for unfavourable outcome after multivariable logistic regression (OR = 2.86, 95% CI 1.16-7.06, p = 0.023)., Conclusion: CO2 laser vaporization is a safe and effective treatment modality for high-grade VAIN, but with high recurrence rate. Patients should be carefully counselled about treatment failure, recurrence risk, and the need for long-term surveillance for any progression to cancer. Alternative treatment modalities should be considered in patients who failed to regress after two episodes of laser treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Bivalirudin is a direct thrombin inhibitor that is being increasingly used for anticoagulation in children after ventricular assist device (VAD) implantation. While the data on bivalirudin use in pulsatile flow VADs are growing, reports on its use in patients on continuous flow (CF) VAD as well as comparisons of associated outcomes with unfractionated heparin (UFH) remain limited., Design: Retrospective cohort study., Setting: Single tertiary-quaternary referral center., Patients: All patients less than 21 years old on CF-VAD support who received bivalirudin or UFH for anticoagulation between the years 2016 and 2020., Interventions: Not applicable., Measurements and Main Results: Clinical characteristics compared between the cohorts included time to target range of anticoagulation, markers of hemolysis, and prevalence of hemocompatibility-related adverse events such as major hemorrhagic complications, ischemic stroke, and pump thrombosis. In 42 unique patients (41 HeartWare HVAD [Medtronic, Minneapolis, MN], one HeartMate 3 LVAD [Abbott Laboratories, Abbott Park, IL]) during the study period, a total of 67 encounters of IV anticoagulation infusions (29 UFH and 38 bivalirudin) were retrospectively reviewed. In comparison with use of UFH, bivalirudin was associated with lesser odds of major bleeding complications (odds ratio [OR], 0.29; 95% CI, 0.09-0.97; p = 0.038). We failed to identify any difference in odds of major thrombotic complications (OR, 2.53; 95% CI, 0.47-13.59; p = 0.450). Eight of the patients (28%) on UFH were switched to bivalirudin due to hemorrhagic or thrombotic complications or inability to achieve therapeutic anticoagulation, while two of the patients (5%) on bivalirudin were switched to UFH due to hemorrhagic complications. Bivalirudin was used for a "washout" in eight cases with concern for pump thrombosis-six had resolution of the pump thrombosis, while two needed pump exchange., Conclusions: Use of bivalirudin for anticoagulation in patients on CF-VAD support was associated with lesser odds of hemorrhagic complications compared with use of UFH. Bivalirudin "washout" was successful in medical management of six of eight cases of possible pump thrombosis., Competing Interests: Drs. Puri, Tunuguntla, Spinner, and Adachi disclosed the off-label product use of HeartWare HVAD for ventricular assist device support. Drs. Puri, Tunuguntla, Hensch, and Teruya disclosed the off-label product use of bivalirudin for first-line anticoagulation. Dr. Adachi reported consultant/proctor for Berlin Heart, Medtronic, Abbott, Abiomed, Jarvik, BiVACOR, and Sony-Olympus Medical Solutions. Dr. Teruya received funding from Hemosonics and UptoDate. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Sickle cell disease (SCD) is a serious global health problem, and currently, the only curative option is hematopoietic stem cell transplant (HCT). However, myeloablative total body irradiation (TBI)-based HCT is associated with high mortality/morbidity in SCD patients. Therefore, reduced-intensity (2-4 Gy) total body radiation (TBI) is currently used as a conditioning regimen resulting in mixed chimerism with the rescue of the SCD disease characteristic features. However, donor chimerism gradually reduces in a few years, resulting in a relapse of the SCD features, and organ toxicities remained the primary concern for long-term survivors. Targeted marrow irradiation (TMI) is a novel technique developed to deliver radiation to the desired target while sparing vital organs and is successfully used for HCT in refractory/relapsed patients with leukemia. However, it is unknown if TMI will be an effective treatment for a hematological disorder like SCD without adverse effects seen on TBI. Therefore, we examined preclinical feasibility to determine the tolerated dose escalation, its impact on donor engraftment, and reduction in organ damage using our recently developed TMI in the humanized homozygous Berkley SCD mouse model (SS). We show that dose-escalated TMI (8:2) (8 Gy to the bone marrow and 2 Gy to the rest of the body) is tolerated with reduced organ pathology compared with TBI (4:4)-treated mice. Furthermore, with increased SCD control (AA) mice (25 million) donor BM cells, TMI (8:2)-treated mice show successful long-term engraftment while engraftment failed in TBI (2:2)-treated mice. We further evaluated the benefit of dose-escalated TMI and donor cell engraftment in alleviating SCD features. The donor engraftment in SCD mice completely rescues SCD disease features including recovery in RBCs, hematocrit, platelets, and reduced reticulocytes. Moreover, two-photon microscopy imaging of skull BM of transplanted SCD mice shows reduced vessel density and leakiness compared to untreated control SCD mice, indicating vascular recovery post-BMT., Competing Interests: KG: Honoraria: Tautona Group, Novartis and CSL Behring. Research Grants: Cyclerion, 1910 Genetics, Novartis, Zilker LLC, Grifols, UCI Foundation and SCIRE Foundation. SH receives honoraria from and consults for Janssen Research and Development, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sargur Madabushi, Fouda, Ghimire, Abdelhamid, Lim, Vishwasrao, Kiven, Brooks, Zuro, Rosenthal, Guha, Gupta and Hui.)

Total marrow irradiation (TMI) has significantly improved radiation conditioning for hematopoietic cell transplantation in hematologic diseases by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. Recently, preclinical three-dimensional image-guided TMI has been developed to enhance mechanistic understanding of the role of TMI and to support the development of experimental therapeutics. However, a dosimetric comparison between preclinical and clinical TMI reveals that the preclinical TMI treatment lacks the ability to reduce the dose to some of the vital organs that are very close to the skeletal system and thus limits the ability to evaluate radiobiological relevance. To overcome this limit, we introduce a novel Sparse Orthogonal Collimator (SOC)-based TMI and evaluate its ability to enhance dosimetric conformality. The SOC-TMI-based dose modulation technique significantly improves TMI treatment planning by reducing radiation exposures to critical organs that are close to the skeletal system that leads to reducing the gap between clinical and preclinical TMI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abdelhamid, Jiang, Zuro, Liu, Madabushi, Ghimire, Wong, Saldi, Fulcheri, Zucchetti, Pierini, Sheng, Aristei and Hui.)

Purpose: Recent initial findings suggest that radiation therapy improves blood perfusion and cellular chemotherapy uptake in mice with leukemia. However, the ability of radiation therapy to influence drug accumulation in the extracellular bone marrow tissue is unknown, due in part to a lack of methodology. This study developed longitudinal quantitative multiphoton microscopy (L-QMPM) to characterize the bone marrow vasculature (BMV) and drug accumulation in the extracellular bone marrow tissue before and after radiation therapy in mice bearing leukemia., Methods and Materials: We developed a longitudinal window implant for L-QMPM imaging of the calvarium BMV before, 2 days after, and 5 days after total body irradiation (TBI). Live time-lapsed images of a fluorescent drug surrogate were used to obtain measurements, including tissue wash-in slope (WIS tissue ) to measure extracellular drug accumulation. We performed L-QMPM imaging on healthy C57BL/6 (WT) mice, as well as mice bearing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)., Results: Implants had no effects on calvarium dose, and parameters for wild-type untreated mice were stable during imaging. We observed decreased vessel diameter, vessel blood flow, and WIS tissue with the onset of AML and ALL. Two to 10 Gy TBI increased WIS tissue and vessel diameter 2 days after radiation therapy in all 3 groups of mice and increased single-vessel blood flow in mice bearing ALL and AML. Increased WIS tissue was observed 5 days after 10 Gy TBI or 4 Gy split-dose TBI (2 treatments of 2 Gy spaced 3 days apart)., Conclusions: L-QMPM provides stable functional assessments of the BMV. Nonmyeloablative and myeloablative TBI increases extracellular drug accumulation in the leukemic bone marrow 2 to 5 days posttreatment, likely through improved blood perfusion and drug exchange from the BMV to the extravascular tissue. Our data show that neo-adjuvant TBI at doses from 2 Gy to 10 Gy conditions the BMV to improve drug transport to the bone marrow., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Gynaecological cancers account for 15% of newly diagnosed cancer cases in women worldwide. In recent years, increasing evidence demonstrates that traditional approaches in perioperative care practice may be unnecessary or even harmful. The enhanced recovery after surgery (ERAS) programme has therefore been gradually introduced to replace traditional approaches in perioperative care. There is an emerging body of evidence outside of gynaecological cancer which has identified that perioperative ERAS programmes decrease length of postoperative hospital stay and reduce medical expenditure without increasing complication rates, mortality, and readmission rates. However, evidence-based decisions on perioperative care practice for major surgery in gynaecological cancer are limited. This is an updated version of the original Cochrane Review published in Issue 3, 2015., Objectives: To evaluate the beneficial and harmful effects of perioperative enhanced recovery after surgery (ERAS) programmes in gynaecological cancer care on length of postoperative hospital stay, postoperative complications, mortality, readmission, bowel functions, quality of life, participant satisfaction, and economic outcomes., Search Methods: We searched the following electronic databases for the literature published from inception until October 2020: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PubMed, AMED (Allied and Complementary Medicine), CINAHL (Cumulative Index to Nursing and Allied Health Literature), Scopus, and four Chinese databases including the China Biomedical Literature Database (CBM), WanFang Data, China National Knowledge Infrastructure (CNKI), and Weipu Database. We also searched four trial registration platforms and grey literature databases for ongoing and unpublished trials, and handsearched the reference lists of included trials and accessible reviews for relevant references., Selection Criteria: We included randomised controlled trials (RCTs) that compared ERAS programmes for perioperative care in women with gynaecological cancer to traditional care strategies., Data Collection and Analysis: Two review authors independently screened studies for inclusion, extracted the data and assessed methodological quality for each included study using the Cochrane risk of bias tool 2 (RoB 2) for RCTs. Using Review Manager 5.4, we pooled the data and calculated the measures of treatment effect with the mean difference (MD), standardised mean difference (SMD), and risk ratio (RR) with a 95% confidence interval (CI) to reflect the summary estimates and uncertainty., Main Results: We included seven RCTs with 747 participants. All studies compared ERAS programmes with traditional care strategies for women with gynaecological cancer. We had substantial concerns regarding the methodological quality of the included studies since the included RCTs had moderate to high risk of bias in domains including randomisation process, deviations from intended interventions, and measurement of outcomes. ERAS programmes may reduce length of postoperative hospital stay (MD -1.71 days, 95% CI -2.59 to -0.84; I 2 = 86%; 6 studies, 638 participants; low-certainty evidence). ERAS programmes may result in no difference in overall complication rates (RR 0.71, 95% CI 0.48 to 1.05; I 2 = 42%; 5 studies, 537 participants; low-certainty evidence). The certainty of evidence was very low regarding the effect of ERAS programmes on all-cause mortality within 30 days of discharge (RR 0.98, 95% CI 0.14 to 6.68; 1 study, 99 participants). ERAS programmes may reduce readmission rates within 30 days of operation (RR 0.45, 95% CI 0.22 to 0.90; I 2 = 0%; 3 studies, 385 participants; low-certainty evidence). ERAS programmes may reduce the time to first flatus (MD -0.82 days, 95% CI -1.00 to -0.63; I 2 = 35%; 4 studies, 432 participants; low-certainty evidence) and the time to first defaecation (MD -0.96 days, 95% CI -1.47 to -0.44; I 2 = 0%; 2 studies, 228 participants; low-certainty evidence). The studies did not report the effects of ERAS programmes on quality of life. The evidence on the effects of ERAS programmes on participant satisfaction was very uncertain due to the limited number of studies. The adoption of ERAS strategies may not increase medical expenditure, though the evidence was of very low certainty (SMD -0.22, 95% CI -0.68 to 0.25; I 2 = 54%; 2 studies, 167 participants)., Authors' Conclusions: Low-certainty evidence suggests that ERAS programmes may shorten length of postoperative hospital stay, reduce readmissions, and facilitate postoperative bowel function recovery without compromising participant safety. Further well-conducted studies are required in order to validate the certainty of these findings., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical manifestation has yielded several trials, so far five CAR-T cell therapies have received US Food and Drug Administration (FDA) approval. However, emerging clinical data and recent findings have identified some immune-related toxicities due to CAR-T cell therapy. Given the outcome and utilization of the same proof of concept, further investigation in other hematological malignancies, such as leukemias, is warranted. This review discusses the previous findings from the pre-clinical and human experience with CAR-T cell therapy. Additionally, we describe recent developments of novel targets for adoptive immunotherapy. Here we present some of the early findings from the pre-clinical studies of CAR-T cell modification through advances in genetic engineering, gene editing, cellular programming, and formats of synthetic biology, along with the ongoing efforts to restore the function of exhausted CAR-T cells through epigenetic remodeling. We aim to shed light on the new targets focusing on acute myeloid leukemia (AML).

Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models., Methods and Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry., Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI., Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Among patients with acute myocardial infarction (AMI) complicated by heart failure [HF; clinical HF or left ventricular (LV) systolic dysfunction], we explored the probability of subsequent non-fatal cardiovascular (CV) events and sudden cardiac death (SCD)., Methods and Results: The high-risk myocardial infarction (HRMI) database contains 28 771 patients with signs of HF or reduced LV ejection fraction (<40%) after AMI. We evaluated the temporal association between SCD with preceding non-fatal CV event [HF hospitalization, recurrent myocardial infarction (MI), or stroke]. Median follow-up was 1.9 years. Mean age was 65.0 ± 11.5 years and 70% were male. The incidence of CV death was 7.9 per 100 patient-years and for SCD was 3.1 per patient-years (40% of CV deaths). The incidence of SCD preceded by HF hospitalization was greater than SCD without preceding HF hospitalization (P < 0.05). However, overall, SCD was less likely to be preceded by a non-fatal CV event compared to other causes of death: 9.6% of SCD events were preceded by an MI (vs. 46.6% for non-sudden CV death); 17.0% of SCD events were preceded with an HF hospitalization (vs. 25.4% for non-sudden CV death); and 2.7% of SCD events were preceded by stroke (vs.12.9% for non-sudden CV death)., Conclusion: Among patients with AMI complicated by HF, SCD, compared with other causes of death, was less likely to be preceded by a non-fatal CV event. As patients are less likely to have preceding non-fatal CV events to alert the healthcare team of a possible impending SCD event, additional strategies for risk stratification for SCD are needed., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Introduction: Activated partial thromboplastin time (aPTT) and antifactor Xa (anti-Xa) activity are used to monitor unfractionated heparin therapy in children on extracorporeal membrane oxygenation (ECMO). Elevated C-reactive protein (CRP) can prolong aPTT and cause discrepancy between these two assays. We aimed to evaluate CRP effect on aPTT and anti-Xa assays in the presence of heparin and to determine whether elevated CRP affects laboratory monitoring in pediatric ECMO patients., Materials and Methods: Citrated normal specimens were spiked with CRP, heparin, and recombinant factor VIII (FVIII) and followed by measurement of aPTT and anti-Xa activity. Additionally, aPTT, anti-Xa activity, FVIII, fibrinogen, and CRP were measured in 18 ECMO specimens., Results: Elevated CRP prolonged aPTT in normal specimens with or without heparin, but did not affect anti-Xa assay. In contrast, ECMO specimens showed similar aPTT and anti-Xa values regardless of CRP level. Elevated CRP in specimens was accompanied by increased fibrinogen and FVIII activity. Additional in vitro experiments confirmed that FVIII spiked simultaneously with CRP attenuated CRP-induced aPTT prolongation in heparinized specimens., Conclusion: In vitro CRP-induced aPTT prolongation is not observed in pediatric ECMO samples due to concomitant FVIII increase. Discordant changes of CRP and FVIII in plasma could contribute to aPTT/anti-Xa discrepancies observed during heparin therapy in the pediatric population. The anti-Xa assay is preferable for heparin monitoring in pediatric ECMO settings., (© 2020 John Wiley & Sons Ltd.)

Purpose: Although vascular alterations in solid tumor malignancies are known to decrease therapeutic delivery, the effects of leukemia-induced bone marrow vasculature (BMV) alterations on therapeutic delivery are not well known. Additionally, functional quantitative measurements of the leukemic BMV during chemotherapy and radiation therapy are limited, largely due to a lack of high-resolution imaging techniques available preclinically. This study develops a murine model using compartmental modeling for quantitative multiphoton microscopy (QMPM) to characterize the malignant BMV before and during treatment., Methods and Materials: Using QMPM, live time-lapsed images of dextran leakage from the local BMV to the surrounding bone marrow of mice bearing acute lymphoblastic leukemia (ALL) were taken and fit to a 2-compartment model to measure the transfer rate (K trans ), fractional extracellular extravascular space (ν ec ), and vascular permeability parameters, as well as functional single-vessel characteristics. In response to leukemia-induced BMV alterations, the effects of 2 to 4 Gy low-dose radiation therapy (LDRT) on the BMV, drug delivery, and mouse survival were assessed post-treatment to determine whether neoadjuvant LDRT before chemotherapy improves treatment outcome., Results: Mice bearing ALL had significantly altered K trans , increased ν ec , and increased permeability compared with healthy mice. Angiogenesis, decreased single-vessel perfusion, and decreased vessel diameter were observed. BMV alterations resulted in disease-dependent reductions in cellular uptake of Hoechst dye. LDRT to mice bearing ALL dilated BMV, increased single-vessel perfusion, and increased daunorubicin uptake by ALL cells. Consequently, LDRT administered to mice before receiving nilotinib significantly increased survival compared with mice receiving LDRT after nilotinib, demonstrating the importance of LDRT conditioning before therapeutic administration., Conclusion: The developed QMPM enables single-platform assessments of the pharmacokinetics of fluorescent agents and characterization of the BMV. Initial results suggest BMV alterations after neoadjuvant LDRT may contribute to enhanced drug delivery and increased treatment efficacy for ALL. The developed QMPM enables observations of the BMV for use in ALL treatment optimization., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

We review the state-of-the-art in bone and marrow tissue engineering (BMTE) and hematological cancer tissue engineering (HCTE) in light of the recent interest in bone marrow environment and pathophysiology of hematological cancers. This review focuses on engineered BM tissue and organoids as in vitro models of hematological cancer therapeutics, along with identification of BM components and their integration as synthetically engineered BM mimetic scaffolds. In addition, the review details interaction dynamics of various BM and hematologic cancer (HC) cell types in co-culture systems of engineered BM tissues/phantoms as well as their relation to drug resistance and cytotoxicity. Interaction between hematological cancer cells and their niche, and the difference with respect to the healthy niche microenvironment narrated. Future perspectives of BMTE for in vitro disease models, BM regeneration and large scale ex vivo expansion of hematopoietic and mesenchymal stem cells for transplantation and therapy are explained. We conclude by overviewing the clinical application of biomaterials in BM and HC pathophysiology and its challenges and opportunities.

Objective: Our objective was to compare women with and without invasive placentation for whom the massive transfusion protocol (MTP) was activated. In addition, we evaluated the differences in clinical management and blood product utilization between the two groups and described the activation of MTP over time. Study design: This is a retrospective cohort study of women for whom the MTP was activated from January 2012 through July 2016. Two groups were compared, those with invasive placentation (accreta, increta, percreta) and those without. Results: We identified 87 women for whom the MTP was activated, the majority (62.1%) did not have invasive placentation. Women with invasive placentation were more likely to have had a prior cesarean delivery and placenta previa (both p  < .001). Women with invasive placentation were more likely to undergo hysterectomy, experience more blood loss, and receive cell salvage (all p  ≤ .04). Blood product utilization was similar between the two groups, with the exception of cell-salvage, which was more commonly used for women with invasive placentation. The proportion of deliveries necessitating MTP activation ranged from 1.4 to 2.6 per 1000 deliveries. Conclusion: Invasive placentation accounts for less than half of the cases complicated by activation of an MTP. Cases with invasive placentation were more likely to result in a vertical uterine and skin incision or a hysterectomy. With the exception of cell-salvage, blood product utilization was similar.

Heparin-like substances (HLS) have been described in various clinical situations, including in settings of liver disease associated with infection, transplant, and metastasis. HLS are generally attributed to circulating glycosaminoglycans. Initial results for this patient showed coagulopathy due to liver disease without HLS. Two weeks after liver transplantation, a 10 year-old female with liver failure patient began to bleed from catheter insertion sites, mouth, and nares and HLS was suspected. The patient subsequently died and these clinical samples resulted in the isolation of a single heparan sulfate (HS) present at high concentrations in the plasma. Analysis of this HS showed it had an intermediate between heparin and HS with low antithrombin-mediated anticoagulant activity. We speculate that this 10-year old patient might have a platelet function defect influenced by this unusual HS. Endothelial defects not measurable by our methods might have also contributed to the observed bleeding complications., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Hypofractionated stereotactic body radiotherapy treatments (SBRT) have demonstrated impressive results for the treatment of a variety of solid tumors. The role of tumor supporting vasculature damage in treatment outcome for SBRT has been intensely debated and studied. Fast, non-invasive, longitudinal assessments of tumor vasculature would allow for thorough investigations of vascular changes correlated with SBRT treatment response. In this paper, we present a novel theranostic system which incorporates a fluorescence molecular imager into a commercial, preclinical, microCT-guided, irradiator and was designed to quantify tumor vascular response (TVR) to targeted radiotherapy. This system overcomes the limitations of single-timepoint imaging modalities by longitudinally assessing spatiotemporal differences in intravenously-injected ICG kinetics in tumors before and after high-dose radiation. Changes in ICG kinetics were rapidly quantified by principle component (PC) analysis before and two days after 10 Gy targeted tumor irradiation. A classifier algorithm based on PC data clustering identified pixels with TVR. Results show that two days after treatment, a significant delay in ICG clearance as measured by exponential decay (40.5±16.1% P=0.0405 Paired t-test n=4) was observed. Changes in the mean normalized first and second PC feature pixel values (PC1 & PC2) were found (P=0.0559, 0.0432 paired t-test), suggesting PC based analysis accurately detects changes in ICG kinetics. The PC based classification algorithm yielded spatially-resolved TVR maps. Our first-of-its-kind theranostic system, allowing automated assessment of TVR to SBRT, will be used to better understand the role of tumor perfusion in metastasis and local control.

Purpose: Acute myeloid leukemia (AML) is a highly aggressive form of leukemia, which results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific noninvasive imaging method to detect disease, including in extramedullary organs, representing an unmet clinical need. About 85% to 90% of human myeloid leukemia cells express CD33 cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET., Experimental Design: We evaluated whether [ 64 Cu]Cu-DOTA-anti-CD33 murine mAb can be used for immunoPET imaging of AML in a preclinical model. MicroCT was adjusted to detect spatial/anatomical details of PET activity. For translational purposes, a humanized anti-CD33 antibody was produced; we confirmed its ability to detect disease and its distribution. We reconfirmed/validated CD33 antibody-specific targeting with an antibody-drug conjugate (ADC) and radioimmunotherapy (RIT)., Results: [ 64 Cu]Cu-DOTA-anti-CD33-based PET-CT imaging detected CD33 + AML in mice with high sensitivity (95.65%) and specificity (100%). The CD33 + PET activity was significantly higher in specific skeletal niches [femur ( P < 0.00001), tibia ( P = 0.0001), humerus ( P = 0.0014), and lumber spine ( P < 0.00001)] in AML-bearing mice (over nonleukemic control mice). Interestingly, the hybrid PET-CT imaging showed high disease activity in the epiphysis/metaphysis of the femur, indicating regional spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC ( P = 0.02) and [ 225 Ac]Ac-anti-CD33-RIT ( P < 0.00001) significantly reduced disease burden over that of respective controls., Conclusions: We have successfully developed a novel anti-CD33 immunoPET-CT-based noninvasive modality for AML and its spatial distribution, indicating a preferential skeletal niche., (©2019 American Association for Cancer Research.)

Objective: In a 2015 Maternal-Fetal Medicine Units Network study, only half of placenta accreta spectrum cases were suspected before delivery, and the outcomes in the anticipated cases were paradoxically poorer than in unanticipated placenta accreta spectrum cases. This was possibly because the antenatally suspected cases were of greater severity. We sought to compare the outcomes of expected vs unexpected placenta accreta spectrum in a single large US center with multidisciplinary management protocol., Study Design: This was a retrospective cohort study carried out between Jan. 1, 2011, and June 30, 2018, of all histology-proven placenta accreta spectrum deliveries in an academic referral center. Patients diagnosed at the time of delivery were cases (unexpected placenta accreta spectrum), and those who were antentally diagnosed were controls (expected placenta accreta spectrume). The primary and secondary outcomes were the estimated blood loss and the number of red blood cell units transfused, respectively. Variables are reported as median and interquartile range or number (percentage). Analyses were made using appropriate parametric and nonparametric tests., Results: Fifty-four of the 243 patients (22.2%) were in the unexpected placenta accreta spectrum group. Patients in the expected placenta accreta spectrum group had a higher rate of previous cesarean delivery (170 of 189 [89.9%] vs 35 of 54 [64.8%]; P < .001) and placenta previa (135 [74.6%] vs 19 [37.3%]; P < .001). There was a higher proportion of increta/percreta in expected placenta accreta spectrum vs unexpected placenta accreta spectrum (125 [66.1%] vs 9 [16.7%], P < .001). Both primary outcomes were higher in the unexpected placenta accreta spectrum group (estimated blood loss, 2.4 L [1.4-3] vs 1.7 L [1.2-3], P = .04; red blood cell units, 4 [1-6] vs 2 [0-5], P = .03)., Conclusion: Our data contradict the Maternal-Fetal Medicine Units results and instead show better outcomes in the expected placenta accreta spectrum group, despite a high proportion of women with more severe placental invasion. We attribute this to our multidisciplinary approach and ongoing process improvement in the management of expected cases. The presence of an experienced team appears to be a more important determinant of maternal morbidity in placenta accreta spectrum than the depth of placental invasion., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: One of the major complications of the placenta accreta spectrum (PAS) is the development of coagulopathy. The detection, prevention and prompt treatment of coagulopathy may be lifesaving., Objective: Our objective was to study selected factors associated with coagulopathy in the management of PAS by a well-established multidisciplinary team., Study Design: This is a retrospective review of all patients with pathologically proven PAS (including placenta accreta, increta or percreta) who underwent surgery by our multidisciplinary team between January 2011 and February 2017. Coagulopathy in this setting was defined as a platelet count of <100,000/mm 3 , international normalized ratio >1.5, and/or fibrinogen <300 mg/dL based on institutional protocols developed by our Division of Transfusion Medicine & Coagulation. The outcomes of those patients with and without coagulopathy were compared with appropriate adjustments. Receiver operating characteristics curves (ROCs) were constructed to assess the ability of select variables to discriminate between women with and without coagulopathy, and the area under the curves (AUCs) were calculated., Results: Of 123 singleton patients with PAS, 37 (30.1%; 95%CI 22.1-39.0) developed coagulopathy and 86 (69.9%; 95%CI 61.0-77.9) did not. Baseline patient demographic characteristics did not differ significantly between these groups. Estimated blood loss (median and Inter-quartile range) was 2100cc (1800, 400) and 1400 (1000, 2500) in the presence and absence of coagulopathy, respectively (P < 0.01). The overall number of units of red blood cells (RBC) transfused was greatest in the coagulopathy group [3 (2, 9) vs. 1 (0, 4); P < 0.01]. Univariate regression analysis confirmed the association between coagulopathy and (i) the number of units of RBC's transfused, and (ii) the estimated blood loss. ROC curves showed that an estimated blood loss ≥ 1500 mL had the best discriminating power. Depth and/or severity of placental invasion were not associated with coagulopathy in patients with PAS., Conclusions: Coagulopathy in patients with PAS undergoing hysterectomy is strongly associated with blood loss and replacement. It may be prudent to establish protocols that aggressively monitor for, and treat, coagulopathy when EBL exceeds 1500 mL in such surgeries, prior to the development of clinical coagulopathy which if uncorrected may lead to massive blood loss., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: BRCA mutation (BRCAmut) testing is an important tool for the risk assessment, prevention and early diagnosis of breast cancer (BC) and ovarian cancer (OC), and more recently, for determining patient susceptibility to targeted therapy. This study assessed the current BRCAmut testing patterns and explored physicians' perspectives on the utilities and optimal sequencing of the testing, in order to facilitate and standardize testing practices., Methods: Medical specialists in BC and OC in Hong Kong were invited to complete a questionnaire on BRCAmut testing practices. A panel of specialists with extensive BRCAmut testing experience was also convened to develop consensus statements on testing, using the Delphi method and an anonymous electronic voting system., Results: The survey respondents (n = 71) recognized family history (FH) of BC and/or OC and an early age of onset as key factors for referring BRCAmut testing. The proportion of respondents who would test all OCs regardless of FH or age, as per the recent international guideline, was low (28.2%). The largest hurdles to testing were the cost, as well as the availability of next-generation sequencing-accredited testing and genetic counseling facilities. The panelists suggested that the sequence of somatic testing followed by germline testing may help address both the imminent need of treatment planning and longer term hereditary implications. The potential emotional and financial burdens of BRCAmut testing should be weighed against the potential therapeutic benefits, and the type and timing of testing personalized., Conclusions: Accessibility of BRCAmut testing to all at-risk individuals will be achievable through improvements in testing affordability, as well as widened availability of accredited testing and genetic counseling facilities., (© 2019 John Wiley & Sons Australia, Ltd.)

Prostate cancer is one of the most commonly diagnosed cancers and a pressing health challenge in men worldwide. Radiation therapy (RT) is widely considered a standard therapy for advanced as well as localized prostate cancer. Although this primary therapy is associated with high cancer control rates, up to one-third of patients undergoing radiation therapy becomes radio-resistant and/or has tumor-relapse/recurrence. Therefore, focus on new molecular targets and pathways is essential to develop novel radio-sensitizing agents for the effective and safe treatment of prostate cancer. Here, we describe functional studies that were performed to investigate the role of structural maintenance of chromosome-1 (SMC1A) in radioresistance of metastatic prostate cancer cells. Short hairpin RNA (shRNA) was used to suppress SMC1A in metastatic castration-resistant prostate cancer cells, DU145 and PC3. Clonogenic survival assays, Western blot, RT-PCR, and γ-H2AX staining were used to assess the effect of SMC1A knockdown on radiation sensitivity of these prostate cancer cells. We demonstrate that SMC1A is overexpressed in human prostate tumors compared to the normal adjacent tissue. SMC1A knockdown limits the clonogenic potential, epithelial-mesenchymal transition (EMT), and cancer stem-like cell (CSC) properties of DU145 and PC3 cells and enhanced efficacy of RT in these cells. Targeted inhibition of SMC1A not only plays a critical role in overcoming radio-resistance in prostate cancer cells, but also suppresses self-renewal and the tumor-propagating potential of x-irradiated cancer cells. We propose that SMC1A could be a potential molecular target for the development of novel radio-sensitizing therapeutic agents for management of radio-resistant metastatic prostate cancer., (© 2018 Wiley Periodicals, Inc.)

Both percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are options for revascularization in multi-vessel coronary artery disease (CAD). However, the best form of revascularization remains controversial. Results from clinical trials (FREEDOM, SYNTAX, NOBLE, EXCEL) have identified factors related to CAD severity such as diabetes and SYNTAX score as indicators that patients may have better outcomes with CABG compared to PCI. Nevertheless, the discovery of other predictors of optimal revascularization therapy is necessary to improve decision-making and personalize the treatment of multi-vessel CAD. Genome-wide association studies have identified numerous previously unknown DNA variants that increase predisposition for CAD. Recently, a composite polygenic risk score has been developed to better assess the relative contribution of multiple SNPs and quantify overall genetic risk for CAD. High polygenic risk score is associated with increased coronary events and greater benefit from statin therapy in large observational studies. This effect is independent from traditional cardiovascular risk factors. At the same time, randomized clinical trials have shown that CAD severity is a determinant of optimal revascularization treatment. It remains unknown whether polygenic risk score is robustly associated with increased CAD severity at presentation, and whether this score can be used to identify patients who will show greater benefit from revascularization with CABG or with PCI., Competing Interests: Conflicts of interestThe authors declare that they have no conflicts of interest., (© Indian Association of Cardiovascular-Thoracic Surgeons 2018.)

A 3-month-old male infant developed an extremely severe episode of atypical hemolytic uremic syndrome (aHUS) associated with partial deficiencies of full-length complement factor H (FH; ∼15% of infant normal) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (39% of normal) and autoantibodies reactive with both proteins. His FH and ADAMTS13 genes were normal, indicating that the partial deficiencies were acquired, probably as the result of autoantibodies against full-length FH and ADAMTS13. The child also had a homozygous deletion of the complement factor H-related (CFHR)3-CFHR1 portion in the complement factor H ( CFH ) gene cluster. He therefore had deficiency of CFHR proteins and autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) with an unusual early onset associated with a partial deficiency of ADAMTS13 and an anti-ADAMTS13 autoantibody. His clinical episode of aHUS responded to plasma infusion and subsequent treatment with mycophenolate and rituximab. We believe that this is the first report of DEAP-HUS in an infant with partial deficiencies in both ADAMTS13 and full-length FH acquired in association with autoantibodies to both proteins.

Purpose of Review: Patients with multivessel coronary artery disease (CAD) may undergo revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). This review will discuss the use of polygenic risk scores for risk-stratification of patients with multivessel CAD in order to guide the choice of revascularization., Recent Findings: A 57-single nucleotide polymorphism (SNP)-polygenic risk score can accurately risk-stratify patients with CAD and identify those who will receive greater benefit from statin therapy. The most recent genomic studies reveal 243 different SNPs are now significantly associated with CAD. Randomized clinical trials comparing PCI vs. CABG (FREEDOM, SYNTAX, NOBLE, EXCEL) have uncovered factors related to CAD severity (diabetes, SYNTAX score) are critical determinants of outcomes after revascularization., Summary: There is a need to discover predictors of outcomes after PCI vs. CABG to improve clinical decision-making in multivessel CAD. High polygenic risk score is associated with increased CAD severity and better outcomes with statin therapy. Randomized clinical trials indicate CAD severity is associated with better outcomes after CABG compared with PCI. Accordingly, polygenic risk score could also be associated with better outcomes after CABG vs. PCI and used to optimize revascularization for patients with multivessel CAD.

Objective: Whether the aortopathy associated with bicuspid aortic valve (BAV) disease occurs secondary to genetic or hemodynamic factors remains controversial. In this article we describe the natural history of the aortic root in patients with bicuspid versus tricuspid aortic valves (TAVs) after replacement of the aortic valve and ascending aorta., Methods: From 1990 to 2010, 406 patients (269 BAV, 137 TAV) underwent aortic valve and ascending aorta replacement at a single institution. Patients with aortic dissection, endocarditis, previous aortic surgery, or Marfan syndrome were excluded. All available follow-up imaging was reviewed., Results: Mean imaging follow-up was 5.5 (±5.3) years. Of all patients, 66.5% had at least 1 aortic root measurement after the index operation. Baseline aortic diameter was comparable between groups. In patients with BAV, aortic root diameter increased at a clinically negligible rate over time (0.654 mm per year; 95% confidence interval, 0.291-1.016; P < .001), similar to patients with TAV (P = .92). Mean clinical follow-up was 8.1 (±5.4) years. During follow-up, 18 patients underwent reoperation, 89% for a degenerated bioprosthetic aortic valve. Only 1 patient underwent reoperation for a primary indication of aortic aneurysmal disease, 22 years after the index operation. There were no differences in cumulative incidence rates of aortic reoperation (P = .14) between patients with BAV and TAV., Conclusions: Mid-term imaging after aortic valve and ascending aorta replacement indicates that if the aortic root is not dilated at the time of surgery, the risk of enlargement over time is minimal, negating the need for prophylactic root replacement in patients with BAV or TAV., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML-derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell-supporting factors (for example, CXCL12, KITL and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion.

Objective: To compare outcomes between planned and urgent cesarean hysterectomy for morbidly adherent placenta managed by a multidisciplinary team., Methods: This is a retrospective case-control study of women with singleton pregnancies with antenatally suspected and pathologically confirmed morbidly adherent placenta who underwent cesarean hysterectomy between January 1, 2011, and February 30, 2017. Timing of delivery was classified as either planned (delivery at 34-35 weeks of gestation) or urgent (need for urgent delivery as a result of uterine contractions, bleeding, or both). The primary outcome variable was composite maternal morbidity. Logistic regression analysis was used to evaluate risk factors for urgent delivery., Results: One hundred thirty patients underwent hysterectomy. Sixty (46.2%) required urgent delivery. Composite maternal morbidity was identified in 34 (56.7%) of the urgent and 26 (37.1%) of the planned deliveries (P=.03). Fewer units of red blood cells and fresh frozen plasma were transfused in the planned delivery group (red blood cells, median interquartile range 3 [0-8] versus 1 [0-4], P=.02; fresh frozen plasma, median interquartile range 1 [0-2] versus 0 [0-0], P=.001). Rates of low Apgar score and respiratory distress syndrome were higher in the urgent compared with the planned delivery group (5-minute Apgar score less than 7, 34 [59.6%] versus 14 [23.3%], P<.01; respiratory distress syndrome, 34 [61.8%] versus 16 [27.1%], P<.01). A history of two or more prior cesarean deliveries was an independent predictor of urgent delivery (adjusted odds ratio 11.4, 95% CI 1.8-71.1)., Conclusion: Women with morbidly adherent placenta requiring urgent delivery have a worse outcome than women with planned delivery. Women with morbidly adherent placenta and two or more prior cesarean deliveries are at increased risk for urgent delivery. In such women, scheduling delivery before the standard 34- to 35-week timeframe may be reasonable.

Objective: To examine whether professional guidance promoting a policy of restrictive blood transfusion is being followed., Methods: A retrospective analysis of post-delivery transfusion data from 17 maternity units in the UK (1988-2000) was undertaken. Additionally, an audit was performed of women receiving one or two units of red cells 6-24 hours after delivery at three centers in the UK and USA in 2013-2016., Results: Between 1988 and 2000, 4700 women received one or two transfusions: 303 (6.4%) received one unit and 4397 (93.6%) received two. Median estimated blood loss (EBL) was similar in both groups (600 mL [IQR 400-1000] vs 700 mL [IQR 400-1000], respectively; P=0.862]. Between 2013 and 2016, 41, 22, and 64 women received one or two units during transfusion at centers A, B, and C, respectively. Two units were transfused for 40 (97.6%) of the women in center A, 21 (95.5%) at center B, and 58 (90.6%) at center C. Median EBL was similar, irrespective of whether one or two units were given., Conclusion: Current transfusion practice deviates from evidence-based guidelines. Either by default or longstanding tradition, more women receive two rather than one unit despite similar EBL., (© 2017 International Federation of Gynecology and Obstetrics.)