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Consensus Recommendations for Systemic Therapies in the Management of Relapsed Ewing Sarcoma: A Report From the National Ewing Sarcoma Tumor Board
No full textEwing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR-ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR-ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high-dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR-ES. Plain Language Summary: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults. This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES. Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs
Circumventing Resistance Within the Ewing Sarcoma Microenvironment by Combinatorial Innate Immunotherapy
No full textBackground Pediatric patients with recurrent/metastatic Ewing sarcoma (ES) have a dismal 5-year survival. Novel therapeutic approaches are desperately needed. Natural killer (NK) cell number and function are low in ES patient tumors, in large part due to the immunosuppressive tumor microenvironment (TME). Melanoma cell adhesion molecule (MCAM) is highly expressed on ES and associated with ES metastasis. NKTR-255 is a polymer-conjugated recombinant human interleukin-15 (IL-15) agonist improving NK cell activity and persistence. Magrolimab (MAG) is a CD47 blockade that reactivates the phagocytic activity of macrophages. Methods Transcriptome profiling coupled with CIBERSORT analyses in both ES mouse xenografts and human patient tumors were performed to identify mechanisms of NK resistance in ES TME. A chimeric antigen receptor (CAR) NK cell targeting MCAM was engineered by CAR mRNA electroporation into ex vivo expanded NK cells. In vitro cytotoxicity assays were performed to investigate the efficacy of anti-MCAM-CAR-NK cell alone or combined with NKTR-255 against ES cells. Interferon-γand perforin levels were measured by ELISA. The effect of MAG on macrophage phagocytosis of ES cells was evaluated by in vitro phagocytosis assays. Cell-based and patient-derived xenograft (PDX)-based xenograft mouse models of ES were used to investigate the antitumor efficacy of CAR-NK alone and combined with NKTR-255 and MAG in vivo. Results We found that NK cell infiltration and activity were negatively regulated by tumor-associated macrophages (TAM) in ES TME. Expression of anti-MCAM CAR significantly and specifically enhanced NK cytotoxic activity against MCAM high but not MCAM-knockout ES cells in vitro, and significantly reduced lung metastasis and extended animal survival in vivo. NKTR-255 and MAG significantly enhanced in vitro CAR-NK cytotoxicity and macrophage phagocytic activity against ES cells, respectively. By combining with NKTR-255 and MAG, the anti-MCAM-CAR-NK cell significantly decreased primary tumor growth and prolonged animal survival in both cell- and PDX-based ES xenograft mouse models. Conclusions Our preclinical studies demonstrate that immunotherapy via the innate immune system by combining tumor-targeting CAR-NK cells with an IL-15 agonist and a CD47 blockade is a promising novel therapeutic approach to targeting MCAM high malignant metastatic ES
Utilization of Liver Machine Perfusion Is Associated With Increase in Center Level Liver Transplant Volume
No full textImpact of Robotic Total Mesorectal Excision Upon Pathology Metrics in Overweight Males With Low Rectal Cancer: A Pooled Analysis of 836 Cases
No full textThe aim of this pooled analysis was to evaluate the impact of robotic total mesorectal excision (TME) on pathology metrics in Male Overweight patients with Low rectal cancer (MOL). This was a multicenter retrospective pooled analysis of data. Two groups were defined: MOL (Male, Overweight, Low rectal cancer) and non-MOL. Overweight was defined as BMI ≥ 25 kg/m2. Low rectal cancer was defined as cancer within 6 cm from the anal verge. The primary endpoints of this study were histopathological metrics, namely circumferential resection margin (CRM) (mm), CRM involvement rate (%), and the quality of TME. Circumferential resection margin (CRM) was involved if \u3c 1 mm. 836 (106 MOL and 730 non-MOL) patients that underwent robotic TME by six surgeons over 3 years were compared. No significant differences in demographics and perioperative variables were found, except for operating time, distal margin, and number of lymph nodes harvested. CRM involvement rate did not significantly differ (7.5% vs. 5.5%, p = 0.395). Mean CRM was statistically significantly narrower in MOL patients (6.6 vs. 7.7 mm, p = 0.04). Quality of TME did not differ. Distance of tumor from the anal verge was the only independent predictor of CRM involvement. Robotic TME may provide optimal pathology metrics in overweight males with low rectal cancer. Although CRM was a few millimeters narrower in MOL, the values were within the range of uninvolved margins making the difference statistically significant, but not clinically. Being MOL was not a risk factor for involvement of circumferential resection margin
High Rate of Kidney Graft Failure After Simultaneous Heart-Kidney Transplantation
No full textBackground The indications and outcomes of simultaneous heart-kidney transplantation (SHKT) remain suboptimally defined. Risk factors for renal graft failure after SHKT also remain poorly defined. Methods We analyzed the renal graft outcomes among SHKT recipients using United Network for Organ Sharing database from 2015 to 2020. To evaluate for factors associated with poor renal outcomes, we compared SHKT and kidney transplantation alone recipients using propensity score matching. Results Among SHKT recipients, the rate of primary nonfunction (PNF) of kidney graft was 3%, the 30-day kidney graft failure rate was 7.0%, and the 30-day post-transplant mortality rate was 4.1%. The incidence of kidney delayed graft function was 27.5%. Kidney graft failure was seen early post-SHKT with most common causes of patient death (43.9%) and PNF of kidney graft (41.5%). One- and 2-year patient survival was 89.2% and 86.5%, and 1- and 2-year freedom from kidney graft failure was 85.4% and 82.7%, respectively. In subgroup analysis of SHKT recipients, use of pretransplant mechanical cardiac support (adjusted odds ratio [aOR], 2.57; P = 0.017), higher calculated panel reactive antibody (aOR, 1.76; P = 0.016), and older donor age per 10 years (aOR, 1.94; P = 0.001) were associated with PNF. Pretransplant extracorporeal membrane oxygenation support was associated with the increased risk of 30-day recipient mortality (aOR, 5.55; P = 0.002). Increased 30-day graft failure was seen in SHKT recipients with pretransplant mechanical cardiac support (aOR, 1.77; P = 0.038) and dialysis at the time of transplant (aOR, 1.72; P = 0.044). Multivariable Cox hazard analysis demonstrated that SHKT, when compared with kidney transplantation alone, is associated with increased kidney graft failure (hazard ratio, 2.56; P \u3c 0.001) and recipient mortality (hazard ratio, 2.65; P \u3c 0.001). Conclusions SHKT is associated with high rates of kidney graft failure. Identification of risk factors of renal graft failure can help optimize recipient selection for SHKT versus kidney after heart transplantation, especially after introduction of the new safety-net policy
Skilled Lactation Support Using Telemedicine in the Neonatal Intensive Care Unit
No full textBackground: NICU mothers face unique challenges in initiating and sustaining breastfeeding, but previous studies have focused on outpatient breastfeeding support. We conducted a retrospective study of NICU breastfeeding outcomes before and after implementing telelactation. Methods: Pre-Telemedicine mothers received in-person support by NICU lactation consultants, while Telemedicine mothers received solely telemedicine consults after maternal discharge. Results: Exclusive breastmilk feeding at discharge increased in the Telemedicine group. Notably, babies in the Telemedicine cohort who were fed any formula on admission experienced significant improvement in exclusive breastmilk feeding at discharge, and those whose mothers received at least one NICU lactation consult had the greatest improvement in exclusive breastfeeding rates at discharge. Conclusions: This study is the first to validate the use of telemedicine as a means of maintaining access to skilled lactation support in the NICU when in-person consults are not feasible. Incorporating telemedicine can ensure access and continuity of skilled lactation support, and sustain breastfeeding rates
Rapid Switching of a C-Series Linear Accelerator Between Conventional and Ultrahigh-Dose-Rate Research Mode With Beamline Modifications and Output Stabilization
No full textPurpose: In this study, a C-series linear accelerator was configured to enable rapid and reliable conversion between the production of conventional electron beams and an ultrahigh-dose-rate (UHDR) electron beamline to the treatment room isocenter for FLASH radiation therapy. Efforts to tune the beam resulted in a consistent, stable UHDR beamline. Methods and Materials: The linear accelerator was configured to allow for efficient switching between conventional and modified electron output modes within 2 minutes. Additions to the air system allow for retraction of the x-ray target from the beamline when the 10 MV photon mode is selected. With the carousel set to an empty port, this grants access to the higher current pristine electron beam normally used to produce clinical photon fields. Monitoring signals related to the automatic frequency control system allows for tuning of the waveguide while the machine is in a hold state so a stable beam is produced from the initial pulse. A pulse counting system implemented on an field-programmable gate array-based controller platform controls the delivery to a desired number of pulses. Beam profiles were measured with Gafchromic film. Pulse-by-pulse dosimetry was measured using a custom electrometer designed around the EDGE diode. Results: This method reliably produces a stable UHDR electron beam. Open-field measurements of the 16-cm full-width, half-maximum gaussian beam saw average dose rates of 432 Gy/s at treatment isocenter. Pulse overshoots were limited and ramp up was eliminated. Over the last year, there have been no recorded incidents that resulted in machine downtime due to the UHDR conversions. Conclusions: Stable 10 MeV UHDR beams were generated to produce an average dose rate of 432 Gy/s at the treatment room isocenter. With a reliable pulse-counting beam control system, consistent doses can be delivered for FLASH experiments with the ability to accommodate a wide range of field sizes, source-to-surface distances, and other experimental apparatus that may be relevant for future clinical translation
Commissioning an Ultra-High-Dose-Rate Electron Linac With End-To-End Tests
No full textObjective. The FLASH effect can potentially be used to improve the therapeutic ratio of radiotherapy (RT) through delivery of Ultra-high-dose-rate (UHDR) irradiation. Research is actively being conducted to translate UHDR-RT and for this purpose the Mobetron is capable of producing electron beams at both UHDR and conventional dose rates for FLASH research and translation. This work presents commissioning of an UHDR Mobetron with end-to-end tests developed for preclinical research. Approach. UHDR electron beams were commissioned with an efficient approach utilizing a 3D-printed water tank and film to fully characterize beam characteristics and dependences on field size, pulse width (PW) and pulse repetition frequency (PRF). This commissioning data was used to implement a beam model using the GAMOS Monte Carlo toolkit for the preclinical research. Then, the workflow for preclinical FLASH irradiation was validated with end-to-end tests delivered to a 3D-printed mouse phantom with internal inhomogeneities. Main results. PDDs, profiles and output factors acquired with radiochromic films were precisely measured, with a PRF that showed little effect on the UHDR beam energy and spatial characteristics. Increasing PW reduced the D max and R50 by 2.08 mm µs−1 and 1.28 mm µs−1 respectively. An end-to-end test of the preclinical research workflow showed that both profiles in head-foot and lateral directions were in good agreement with the MC calculations for the heterogeneous 3D printed mouse phantom with Gamma index above 93% for 2 mm/2% criteria, and 99% for 3 mm/3%. Significance. The UHDR Mobetron is a versatile tool for FLASH preclinical research and this comprehensive beam model and workflow was validated to meet the requirements for conducting translational FLASH research
Expanding Indications of Nonvitamin K Oral Anticoagulants Beyond Nonvalvular Atrial Fibrillation and Venous Thromboembolism: A Review of Emerging Clinical Evidence
No full textDirect oral anticoagulants (DOAC) have emerged as a new therapy for patients who need and can tolerate oral anticoagulation. DOACs were initially approved for nonvalvular atrial fibrillation (NVAF) and treatment for deep vein thrombosis (DVT) and pulmonary embolism (PE). Ease of administration, no requirement of bridging with other anticoagulants, and less frequent dosing have made DOACs preferable choice for anticoagulation. Studies are showing promising results regarding use of DOACs beyond the common indications. Studies have been done to show the potential benefit of DOACs in valvular atrial fibrillation, heart failure, acute coronary syndrome, stroke, and peripheral arterial disease. Data have shown safety as well as comparable bleeding incidences with DOACs compared to vitamin K antagonist anticoagulants. Naturally interest is growing to see the use of DOACs apart from the NVAF, DVT, or PE. Authors have highlighted various study results to show the potential beneficial role of DOACs in the above-mentioned situations
Assessing Low-Dose Oral Minoxidil Efficacy in Androgenetic Alopecia: A Comparative Study of AGA and AGA Unmasked by Telogen Effluvium
No full textAndrogenetic alopecia (AGA) significantly impacts patients’ psychological well-being, and treatment options have historically been limited. However, the advent of low-dose oral minoxidil (LDOM) has revolutionized AGA management. This study compares the treatment response and safety of LDOM in patients with AGA alone versus those with AGA unmasked by telogen effluvium. Our findings indicate that LDOM is effective and safe for both groups, showing comparable efficacy and safety profiles. These results support the use of LDOM as a reliable treatment option for AGA, potentially improving patient outcomes and quality of life