Current Standard Of Care Research Articles

Assessing health plan payer's budget impact of etranacogene dezaparvovec for the treatment of hemophilia B in the United States.

Etranacogene dezaparvovec is a recently approved gene therapy for people with hemophilia B (PwHB). Current standard of care is prophylaxis with factor IX (FIX) to prevent bleeding. Etranacogene dezaparvovec increases blood FIX levels such that FIX prophylaxis could be eliminated. To estimate the budgetary impact of etranacogene dezaparvovec adoption and utilization in a commercial health plan of the United States. A budget impact model was developed to evaluate the introduction of etranacogene dezaparvovec to treat severe or moderately severe hemophilia B. The model considered a hypothetical 1-million-member plan over a 5-year horizon. FIX therapy prophylaxis use was estimated based on a weighted average of relevant brands using US market share data. A scenario of etranacogene dezaparvovec adoption/utilization was compared with one without etranacogene dezaparvovec utilization. Two etranacogene dezaparvovec uptake (market share growth) analyses were performed: one with gradual uptake and alternatively assuming all eligible PwHB received etranacogene dezaparvovec in year 1. The one-time cost of etranacogene dezaparvovec was assumed to be $3.5 million. Other costs (FIX prophylaxis, disease monitoring, bleed management, and adverse events) were estimated from published literature. All costs were in 2022 US dollars. Bleed and adverse event rates were sourced from the HOPE-B trial comparing etranacogene dezaparvovec to previous FIX therapy prophylaxis. The model estimated annual and per-member per-month costs over 5 years. Secondary analyses were performed considering a 10-year horizon. In the 1-million-member health plan, an estimated 1.8 PwHB were eligible for treatment with etranacogene dezaparvovec. Gradual uptake of etranacogene dezaparvovec resulted in cumulative 5-year budget impact of $848,509 compared with a scenario without etranacogene dezaparvovec. In years 1-5, the incremental annual and per-member per-month costs ranged from $79,824 to $271,435 and from $0.007 to $0.023, respectively. In the alternative uptake analysis, etranacogene dezaparvovec became cost saving annually beginning in year 2 and cumulatively beginning in year 5, for a 5-year savings of $754,844. Secondary analyses over 10 years found both uptake analyses cost saving. Other scenarios considered did not affect results substantially. Introducing etranacogene dezaparvovec as treatment for PwHB would have a modest budget increase within 5 years after treatment but may become cost saving if all eligible PwHB were treated in year 1. Initiating PwHB on etranacogene dezaparvovec sooner may produce greater overall savings and earlier annual savings. Etranacogene dezaparvovec is a treatment option that may provide overall cost savings for US commercial health plans, which would increase as the plan size increases.

Mechanism of Notch Signaling Pathway in Malignant Progression of Glioblastoma and Targeted Therapy

Glioblastoma multiforme (GBM) is the most aggressive form of glioma and the most common primary tumor of the central nervous system. Despite significant advances in clinical management strategies and diagnostic techniques for GBM in recent years, it remains a fatal disease. The current standard of care includes surgery, radiation, and chemotherapy, but the five-year survival rate for patients is less than 5%. The search for a more precise diagnosis and earlier intervention remains a critical and urgent challenge in clinical practice. The Notch signaling pathway is a critical signaling system that has been extensively studied in the malignant progression of glioblastoma. This highly conserved signaling cascade is central to a variety of biological processes, including growth, proliferation, self-renewal, migration, apoptosis, and metabolism. In GBM, accumulating data suggest that the Notch signaling pathway is hyperactive and contributes to GBM initiation, progression, and treatment resistance. This review summarizes the biological functions and molecular mechanisms of the Notch signaling pathway in GBM, as well as some clinical advances targeting the Notch signaling pathway in cancer and glioblastoma, highlighting its potential as a focus for novel therapeutic strategies.

Quality Improvement Initiative: Utilization of Video Postoperative Instructions in Breast Reduction Enhances Patient Experience

Abstract Goals/Purpose The current standard of care for providing postoperative instructions to patients undergoing elective, ambulatory surgeries often falls short in efficiency, clarity, and patient-centeredness. Patients are given a single set of written instructions at the time of discharge after their surgery, which often leads to confusion and increased reliance on phone calls, urgent clinic appointments, and even unnecessary visits to the emergency department. Recognizing this, we propose a quality improvement initiative to enhance postoperative instructions for breast reduction patients through a video format. Methods/Technique With institutional IRB approval, all adult patients undergoing bilateral breast reduction (CPT 19318) at an urban academic hospital were included over a 3-month period. A 2-minute video with standardized narrative instructions and visual aids was created. Patients viewed the video during the preoperative visit, and a QR code link to the video was provided in the visit summary on the day of surgery. A Spanish version of the video was available if a Spanish interpreter was used during informed consent. The number of phone calls and emergency department visits within 30 days were recorded and compared to a cohort of patients before this intervention. Qualitative surveys were administered pre- and post-operatively to collect patient feedback. Results/Complications During the study period, 59 patients received breast reduction surgery and were given the standardized video instructions pre- and post-operatively (video group). In comparison, 75 breast reduction patients from the prior 3 months, who received nonstandardized, written instructions post-operatively, served as the control group. In the video group, 47% of patients (28 out of 59) made at least one phone call to the clinic, averaging 0.7 calls per patient, while 56% of the control group patients (42 out of 75) made at least one phone call, averaging 1.1 calls per patient. Categorizing reasons for the calls, there was a significantly higher proportion of calls related to wound dehiscence or minor drainage in the video group (41%) compared to the control group (22%; p=0.03). This shift may be attributed to a reduction in routine postoperative care questions due to the clarity provided by the video instructions (FIGURE1). There were 4 unnecessary emergency department visits within 30 days post-surgery in the study period, slightly decreased from the control period's 6 visits (after excluding 1 visit with the patient diagnosed with pulmonary embolism); however, the difference was not statistically significant. Fifteen patients who received the video instruction completed a survey, with 80% rating the video as very helpful, and 80% were able to access the QR code without assistance. These patients scored an average of 81 out of 100 on satisfaction with information measured using the BREAST-Q module after receiving the video instruction. There was no difference in complication between the two groups of patients. Conclusion Video instruction proves to be a viable format for patient education and postoperative instruction, offering consistency, multilingual support, and enhanced learning through visual aids. Patient acceptance is high, indicating good baseline digital literacy and encouraging the use of this technology among surgery providers.

Ultrasoft platelet-like particles stop bleeding in rodent and porcine models of trauma.

Uncontrolled bleeding after trauma represents a substantial clinical problem. The current standard of care to treat bleeding after trauma is transfusion of blood products including platelets; however, donated platelets have a short shelf life, are in limited supply, and carry immunogenicity and contamination risks. Consequently, there is a critical need to develop hemostatic platelet alternatives. To this end, we developed synthetic platelet-like particles (PLPs), formulated by functionalizing highly deformable microgel particles composed of ultralow cross-linked poly (N-isopropylacrylamide) with fibrin-binding ligands. The fibrin-binding ligand was designed to target to wound sites, and the cross-linking of fibrin polymers was designed to enhance clot formation. The ultralow cross-linking of the microgels allows the particles to undergo large shape changes that mimic platelet shape change after activation; when coupled to fibrin-binding ligands, this shape change facilitates clot retraction, which in turn can enhance clot stability and contribute to healing. Given these features, we hypothesized that synthetic PLPs could enhance clotting in trauma models and promote healing after clotting. We first assessed PLP activity in vitro and found that PLPs selectively bound fibrin and enhanced clot formation. In murine and porcine models of traumatic injury, PLPs reduced bleeding and facilitated healing of injured tissue in both prophylactic and immediate treatment settings. We determined through biodistribution experiments that PLPs were renally cleared, possibly enabled by ultrasoft particle properties. The performance of synthetic PLPs in the preclinical studies shown here supports future translational investigation of these hemostatic therapeutics in a trauma setting.

Burn Wounds And Enzymatic Debridement (Ed) - Past, Present, And Future.

Excision of necrotic and devitalized tissues of deep burns is key for optimal care of burn injuries. However, the modality of early tangential excision followed by skin grafting proposed by Zora Janzekovic five decades ago was not received initially with great enthusiasm. At present, it developed to become the standard of care (SOC) despite the special expertise it necessitates and the general anesthesia it requires in addition to several drawbacks including excessive blood loss, risk of hypothermia, and most important potential excision of normal non-burned tissues. Conservative non-surgical selective enzymatic debridement (ED) at present is becoming more popular as an adjunct or even an alternative approach. A systematic review of PubMed electronic database was conducted to identify all experimental and clinical studies about ED of burn wounds. Additional separate searches were also conducted to identify any reports missed by the initial systematic review. Full texts of 59 reports (42 clinical and 17 experimental studies) were retrieved for analysis. 46 studies (11 experimental and 35 clinical) were about the pineapple extract debriding agent. 23 clinical studies describing promising favorable results with pineapple bromelain-based debridement (BBD) concentrate were published in the last 3 years (2020-2023). Though available evidence is not entirely in favor of replacing the current surgical SOC with BBD, it certainly presents ED as a highly advantageous modality for management of burn wounds. Newly described keratinase and SN514 also are promising new products. They both still await further investigation before being clinically adopted.

Abstract LB155: Intra-cranial administration of MTL-004, a promising post-resection treatment for glioblastoma

Abstract Objectives Gliomas (GBM), are exceptionally hard to treat, aggressive and genetically heterogeneous tumors. This study reports the control of tumor recurrence and improved survival in male and female rats by combining a single intra-cranial dose of MTL-004 (5-(aziridine-1- yl)-4 hydroxylamino-2-nitrobenzamide), in a bioresorbable paste (a blend of poly DL-lactic acid-co-glycolic acid; (PLGA) and poly ethylene glycol; (PEG)) to surgical resection of primary glioma tumors. Comparison is made with oral temozolomide (TMZ), the current standard of care (SOC), following resection. Experimental procedures On day 0, 2 mm3 tumor fragments were implanted into the brains of healthy female and male Fischer rats. On day 5 rats the growing tumors were removed using microsurgery. Treatments started as follows: •Group 1 (Placebo) received a single intracranial dose of excipient powder in PGLA/PEG paste; •Group 2 (SOC) received 5 daily oral doses of TMZ at 50 mg/kg; •Group 3 (MTL-004) received a single intracranial dose of excipient powder containing 1 mg/kg MTL-004 in PGLA/PEG paste. Results Body Weight Between day 0 and 5, no groups had statistically significant body weight changes. Between days 5 to 9, mean body weight of rats receiving TMZ was significantly reduced. Tumor Volumes Tumor volumes from MRI were evaluated when at least 80% of rats were still alive in each group (day 14 post tumor resection/treatment initiation). Mean tumor volume was significantly higher in the placebo groups compared to MTL-004 and TMZ treatments. Survival Rats were studied for 58-days post tumor resection/treatment. At this time out of twelve rats per group, none or one survived on TMZ, two or no animals were still alive on placebo, and seven or ten rats treated with MTL-004 were still alive (male or female respectively). Post resection median survival time was between 20.5 to 27.5 days for rats treated with oral placebo or TMZ. Rats treated with MTL-004 had a significantly higher survival compared to both placebo and TMZ groups and remained in apparent good health for the 58 days of the study. Conclusions Consistent trends were observed in each group of male and female rats following tumor resection. •PGLA/PEG paste with MTL-004 or without (placebo) or were both well tolerated. •Treatment with MTL-004 in PGLA/PEG paste provided good tumor control, was better tolerated and led to significantly greater survival than oral TMZ or placebo. •Oral TMZ (SOC) provided control of tumor volume but was associated with significant, transient body weight losses and no significant survival gain compared to placebo. Our data highlight significant survival benefits associated with a single intracranial dose of MTL-004 with PLGA/PEG paste post-surgery. In conclusion, surgery followed by MTL-004 in PGLA/PEG paste is a well-tolerated and promising treatment for glioblastoma, suitable for clinical evaluation. Citation Format: Mike Hudson, Sylvie Maubant, Elisabeth Bertrand, Marie Lux, Jordan Longin, Elodie Marie Dit Chatel, Maxime Ramelet, Olivier Duchamp. Intra-cranial administration of MTL-004, a promising post-resection treatment for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB155.

Pain Management Strategies in Osteoarthritis

Pain is the major symptom of osteoarthritis (OA) and is an important factor in strategies to manage this disease. However, the current standard of care does not provide satisfactory pain relief for many patients. The pathophysiology of OA is complex, and its presentation as a clinical syndrome is associated with the pathologies of multiple joint tissues. Treatment options are generally classified as pharmacologic, nonpharmacologic, surgical, and complementary and/or alternative, typically used in combination to achieve optimal results. The goals of treatment are the alleviation of symptoms and improvement in functional status. Several studies are exploring various directions for OA pain management, including tissue regeneration techniques, personalized medicine, and targeted drug therapies. The aim of the present narrative review is to extensively describe all the treatments available in the current practice, further describing the most important innovative therapies. Advancements in understanding the molecular and genetic aspects of osteoarthritis may lead to more effective and tailored treatment approaches in the future.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted-prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is known for their relative chemosensitivity and indolent clinical course among diffuse gliomas of adult type. Based on the data from phase 3 clinical trials, the standard of post-surgical care for those tumors is considered to be initial chemoradiotherapy regardless of histopathological grade, particularly with PCV. However, partly due to its renewed definition in late years, prognostic factors in patients with those tumors are not well established. Moreover, the survival rate declines over 15years, with only a 37% OS rate at 20years for grade 3 tumors, even with the current standard of care. Given that most of this disease occurs in young or middle-aged adults, further improvements in treatment and management are necessary. Here, we discuss prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy in those tumors.

Ocular blood flow in preterm neonates

Retinopathy of prematurity (ROP) is a disorder affecting low birthweight, preterm neonates. In the preterm eye, the retina is not fully developed and neovascularization may occur at the margin between the developed vascular retina and undeveloped avascular retina. Without timely treatment by laser or intravitreal anti-vascular endothelial growth factor (VEGF) therapy, this can lead to tractional retinal detachment and blindness. Visualization of the retina in regular examinations by indirect ophthalmoscopy is hence the current standard of care, but the exams are stressful and interpretation of images is subjective. The upregulation of VEGF in ROP would suggest an increase in ocular blood flow. In this report, we evaluate the potential of ultrafast plane-wave Doppler ultrasound (PWU) to detect increased flow velocities in the orbital vessels supplying the eye in a gentle exam with objective findings. We imaged both eyes of 50 low-birthweight preterm neonates using 18 MHz PWU. Flow velocity in the central retinal artery (CRA) and vein (CRV), and the short posterior ciliary arteries were determined and values at each ROP Stage compared. We found significantly increased velocities in the CRA and CRV in Stage 3 ROP eyes, where intervention would be considered. We compared multivariate models for identifying Stage 3 eyes comprised solely of clinical factors, solely of Doppler parameters, and clinical plus Doppler parameters. The respective models provided areas under their respective ROC curves of 0.760, 0.812, and 0.904. PWU Doppler represents a gentle, objective means for identifying neonates at risk for ROP that could complement ophthalmoscopy.

Involved-site radiotherapy is equally effective and less toxic than Involved-field radiotherapy in patients receiving combined modality treatment for early-stage unfavorable Hodgkin lymphoma - an analysis of the randomized phase III HD17 trial of the German Hodgkin Study Group

PurposeCombined modality treatment (CMT) with chemotherapy followed by consolidation radiotherapy (RT), provides excellent outcomes for patients with early-stage Hodgkin lymphoma (HL). The international standard of care for consolidation RT, involved-site/involved-node radiotherapy (ISRT/INRT), has never been evaluated in a randomized phase III trial against the former standard involved-field radiotherapy (IFRT). Methods and materialsIn the multicenter phase III AnonymizedStudyGroupXXX AnonymizedStudyYYY trial, patients with early stage unfavorable HL were randomized between the standard CMT group and a positron-emission tomography (PET) -guided group. In the standard group, patients received two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) and two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gray (Gy) IFRT. In the experimental group patients received no further therapy if post-chemotherapy PET was negative, and 30 Gy AnonymizedStudyGroupXXX -INRT, comparable and therefore termed here ISRT, if PET was positive. Here, we analyze the interim PET positive patients in a post hoc analysis, and therefore the randomized comparison of IFRT versus INRT/ISRT. Results1,100 patients were randomized, of which 311 had a positive PET after chemotherapy. Kaplan-Meier estimates of 4-year progression-free survival (PFS) were 96.8 % (95% CI: 91.6% – 98.8%) in the IFRT group and 95.4% (95% CI: 89.9% – 97.9%; HR: 1.40, 95% CI: 0.44 – 4.42) in the ISRT group. Pattern of recurrence analyses indicated that none of the cases of disease progression or recurrence in the ISRT group would have been prevented by the use of IFRT. Acute grade III/IV toxicities occurred in 8.5% of IFRT patients and 2.6% of ISRT patients (p=0.03). ConclusionsFor the first time, consolidation INRT/ISRT was randomly compared to IFRT in a phase III trial. Regarding PFS, no advantage for IFRT could be demonstrated. In summary, our data confirm the place of INRT/ISRT as the current standard of care.

349 Addressing the Gaps in Diabetic Foot Ulcer Management: Prediction and Prevention

OBJECTIVES/GOALS: Globally, diabetes affects 537 million people and 15-25% will develop a foot ulcer in their lifetime. Diabetic foot ulcers (DFU) tend to be chronic and non-healing due to the poor wound healing environment, leading to infection or amputation. Our study aims to develop a method to predict and prevent DFU formation. METHODS/STUDY POPULATION: Our preliminary plan is to develop a method to detect high plantar pressures, coupled with the ability to automatically adjust an orthotic device to offload excess pressure. Our current aim is to create a “smart orthotic” which will link with foot mapping technology to automatically offload high pressure areas, reducing the need for a separate clinic visit for orthotic adjustment. We aim to prove that our device will normalize plantar pressure distribution, which will prevent callus and subsequent DFU formation. The current target population includes those with diagnosed diabetes and are ambulatory. RESULTS/ANTICIPATED RESULTS: With our technology, we anticipate normalization of plantar pressure distribution in a more frequent fashion than is currently done. Because annual orthotic fittings, which is current standard of care, do not provide regular enough adjustments to match the rate of diabetic foot structural changes and peak plantar pressure redistribution, our device will address two gaps in management. One, patients will receive near-instantaneous changes in plantar pressure offloading, allowing for near continuous orthotic customization. Secondly, our device would reduce the clinical appointment burden, which would be especially important for patients with multiple medical comorbidities or experience other barriers to accessing healthcare. DISCUSSION/SIGNIFICANCE: While DFUs are commonplace and their complications are well recognized, there still exists a gap in ulcer prevention. Our proposed solution will redistribute pathologic plantar pressures, allow for more frequent monitoring, automatic therapy, and aid in the management of high ulcer risk patients.

Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair–Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D

BackgroundThe phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient (MSS/pMMR) metastatic colorectal cancer (mCRC). Patients and MethodsPatients with MSS/pMMR mCRC received pembrolizumab 200 mg every 3 weeks plus mFOLFOX7 (previously untreated; cohort B) or FOLFIRI (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate (ORR) per RECIST v1.1 was secondary and biomarker analysis was exploratory. ResultsThirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3/4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3/4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. ORR was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than non-responders. No association between tumor mutational burden and response was observed. ConclusionsPembrolizumab plus mFOLFOX7/FOLFIRI demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. ClinicalTrials.gov IdentifierClinicalTrials.gov; NCT03374254

Cost-effectiveness of bevacizumab therapy in the care of patients with hereditary hemorrhagic telangiectasia

AbstractNo US Food and Drug Administration– or EMA-approved therapies exist for bleeding due to hereditary hemorrhagic telangiectasia (HHT), the second-most common inherited bleeding disorder worldwide. The current standard of care (SOC) includes iron and red cell supplementation, alongside the necessary hemostatic procedures, none of which target underlying disease pathogenesis. Recent evidence has demonstrated that bleeding pathophysiology is amenable to systemic antiangiogenic therapy with the anti–vascular endothelial growth factor bevacizumab. Despite its high cost, the addition of longitudinal bevacizumab to the current SOC may reduce overall health care resource use and improve patient quality of life. We conducted, to our knowledge, the first cost-effectiveness analysis of IV bevacizumab in patients with HHT with the moderate-to-severe phenotype, comparing bevacizumab added to SOC vs SOC alone. The primary outcome was the incremental net monetary benefit (iNMB) reported over a lifetime time horizon and across accepted willingness-to-pay thresholds, in US dollar per quality-adjusted life year (QALY). Bevacizumab therapy accrued 9.3 QALYs while generating $428 000 in costs, compared with 8.3 QALYs and $699 000 in costs accrued in the SOC strategy. The iNMB of bevacizumab therapy vs the SOC was $433 000. No parameter variation and no scenario analysis, including choice of iron supplementation product, changed the outcome of bevacizumab being a cost-saving strategy. Bevacizumab therapy also saved patients an average of 133 hours spent receiving HHT-specific care per year of life. In probabilistic sensitivity analysis, bevacizumab was favored in 100% of all 10 000 Monte Carlo iterations across base-case and all scenario analyses. Bevacizumab should be considered for more favorable formulary placement in the care of patients with moderate-to-severe HHT.

Point-of-care testing and treatment of sexually transmitted and genital infections to improve birth outcomes in high-burden, low-resource settings (WANTAIM): a pragmatic cluster randomised crossover trial in Papua New Guinea

Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and bacterial vaginosis have been associated with adverse maternal and perinatal outcomes, but there is conflicting evidence on the benefits of antenatal screening and treatment for these conditions. We aimed to determine the effect of antenatal point-of-care testing and immediate treatment of C trachomatis, N gonorrhoeae, T vaginalis, and bacterial vaginosis on preterm birth, low birthweight, and other adverse maternal and perinatal outcomes compared with current standard of care, which included symptom-based treatment without laboratory confirmation. In this pragmatic cluster randomised crossover trial, we enrolled women (aged ≥16 years) attending an antenatal clinic at 26 weeks' gestation or earlier (confirmed by obstetric ultrasound), living within approximately 1 h drive of a study clinic, and able to provide reliable contact details at ten primary health facilities and their catchment communities (clusters) in Papua New Guinea. Clusters were randomly allocated 1:1 to receive either the intervention or control (standard care) in the first phase of the trial. Following an interval (washout period) of 2-3 months at the end of the first phase, each cluster crossed over to the other group. Randomisation was stratified by province. Individual participants were informed about trial group allocation only after completing informed consent procedures. The primary outcome was a composite of preterm birth (livebirth before 37 weeks' gestation), low birthweight (<2500 g), or both, analysed according to the intention-to-treat population. This study is registered with ISRCTN Registry, ISRCTN37134032, and is completed. Between July 26, 2017, and Aug 30, 2021, 4526 women were enrolled (2210 [63·3%] of 3492 women in the intervention group and 2316 [62·8%] of 3687 in the control group). Primary outcome data were available for 4297 (94·9%) newborn babies of 4526 women. The proportion of preterm birth, low birthweight, or both, in the intervention group, expressed as the mean of crude proportions across clusters, was 18·8% (SD 4·7%) compared with 17·8% in the control group (risk ratio [RR] 1·06, 95% CI 0·78-1·42; p=0·67). There were 1052 serious adverse events reported (566 in the intervention group and 486 in the control group) among 929 trial participants, and no differences by trial group. Point-of-care testing and treatment of C trachomatis, N gonorrhoeae, T vaginalis, and bacterial vaginosis did not reduce preterm birth or low birthweight compared with standard care. Within the subgroup of women with N gonorrhoeae, there was a substantial reduction in the primary outcome. UK Department of Health and Social Care; UK Foreign, Commonwealth and Development Office; UK Medical Research Council; the Wellcome Trust; the Australian National Health and Medical Research Council; and Swiss National Science Foundation.

205 Microglia-Mediated Survival Outcomes in Preoperative Radiation for Glioblastoma: Insights From a Preclinical Model

INTRODUCTION: Glioblastoma (GBM) is the most common and devastating primary brain tumor in adults. The current standard of care includes maximal safe resection followed by concurrent radiation and temozolomide-based chemotherapy. However, preoperative radiotherapy is used in different cancer types and commonly used for brain metastasis to shrink tumors, but it has never been used in for primary GBM. METHODS: Thirty-nine immunocompromised adult athymic nude female rats were orthotopically engrafted with a GBM1A patient-derived glioma cell line and randomized to either receive radiotherapy prior to tumor resection (RTRE) or postoperative radiotherapy (RERT). The rats received 30 Gy hypofractionated stereotactic radiation in 5 fractions of 6 Gy. Kaplan-Meier curve was used to plot the survival. Hematoxylin-eosin staining, microglia/macrophages using IBA-1 and TMEM119 markers were used in resected and recurrent tumor tissues. Moreover, nuclei area was measured on all tumor samples. Student’s T-test and analysis of variance (ANOVA) were used for statistical analysis. RESULTS: Kaplan-Meier analysis showed a significant survival benefit in the RTRE group, with median survival of 18.28 weeks compared to 14.85 weeks for RERT (p &lt; 0.001), which correlated with the time of recurrence. Simultaneously, an increase in the nuclei area was found in the resected tumor tissues from the RTRE group (p &lt; 0.001) and RERT recurrent tumor tissues (p &lt; 0.001). Interestingly, we found lower microglia/macrophage recruitment in RTRE in the recurrent tumors (p &lt; 0.01) and throughout the tumor areas compared to the RERT group. CONCLUSIONS: Our study represents the first preclinical study demonstrating the feasibility and longer overall survival using RTRE instead of RERT in vivo. Moreover, RTRE shows an important effect in the macrophages/microglia recruitment and in the immune profile. This suggests strong superiority for new clinical radiation strategies.

144 Use of Intraoperative Sodium Fluorescein During Nerve Tumor Surgery: A Systematic Review

INTRODUCTION: Nerve tumors are categorized into various classifications based on location, origin, and malignant potential. Symptoms and signs of nerve tumors result from direct infiltration of the nerve, compression on adjacent tissues, or the mass effect of the tumor. The primary treatment approach for nerve tumors is complete surgical resection. This should be achieved while preserving the function of the nerve. Sodium fluorescein holds promise in achieving this objective. METHODS: PubMed, EMBASE, Web-of-Science, and SCOPUS were searched to include studies reporting the use of sodium fluorescein in nerve tumors surgery. Intervention-related outcomes were systematically reviewed following the PRISMA guidelines. RESULTS: Our review comprised 5 studies encompassing 177 patients with a total of 179 tumors. Of these patients, 98 (55.4%) were female, and 101 (69.1%) had sporadic (non-syndromic) tumors. Histopathological examination revealed that 125 (69.8%) tumors were schwannoma WHO grade 1. No post-operative complications were reported in 149 (88.7%) patients. Gross total resection was achieved in 152 (84.9%) tumors. High tumor fluorescence was reported in 150 (94.3%) tumors, while absent and low parent nerve fluorescence was reported in 121 (79.6%) and 27 (17.8%) tumors, respectively. No side effects of the fluorescent dye were reported among the 179 tumor cases. The median latency period was 30 (range: 7-95) minutes, and the median duration of surgery was 51.5 (range: 24-92) minutes. CONCLUSIONS: Intraoperative sodium fluorescein shows promise as an aid in nerve tumor surgery, facilitating differentiation between the tumor, parent nerve, and surrounding soft tissue. Future prospective studies are necessary to determine its effect on surgical duration, postoperative complication rates, and extent of resection in comparison to current standard of care.

200 DWI and ADC Changes in Patients With Glioblastoma IDH-Wild Type Following Surgical Tumor Resection

INTRODUCTION: Current standard of care for glioblastoma (GBM) entails maximal tumor resection to achieve better outcomes while preserving neurological function. Early postoperative DWI has elucidated that peritumoral ischemia is common following glioma resection, but radiographic characteristics, risk factors, and outcomes have not been well described. METHODS: This retrospective cohort included 324 patients (18-86 years) who underwent surgical resection for glioblastoma IDH-wildtype between 2005 and 2022. All patients had structural MRI and DWI acquired preoperatively and within 72 hrs after resection. Areas of restricted diffusion on postoperative DWI were classified as rim, sector, mixed, or remote. RESULTS: Areas of restricted diffusion on postoperative DWI were found in 173 (53%) patients. 55 (32%) were rim-shaped, 103 (59%) sector-shaped, 10 (6%) mixed, and 5 (3%) remote. Preoperative tumor volume was positively correlated with areas of ischemia (p = 0.048), but peritumoral DWI was not correlated with decreased overall survival (OS) or Karnofsky Performance Score (KPS). In the full cohort analysis, gross total resection (GTR) correlated with improved OS compared to subtotal total resection (STR) (p = 0.016); however, subgroup analysis revealed that this survival benefit was exclusively found in patients without peritumoral infarction on DWI (21 months vs. 13 months, p = 0.043). CONCLUSIONS: Larger tumor volume was a risk factor for larger peritumoral infarction. The survival benefit of GTR was only seen in patients who did not experience postoperative peritumoral infarction, underscoring the importance of maximal safe tumor resection. Future study on specific causes of postoperative peritumoral infarctions may improve surgical management and outcomes in glioblastoma patients.

Advances in Radioligand Theranostics in Oncology.

Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177Lu-DOTATATE and 177Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2.

The Evolution of Central Venous-to-arterial Carbon Dioxide Difference (PCO2 Gap) during Resuscitation Affects ICU Outcomes: A Prospective Observational Study.

The usual methods of perfusion assessment in patients with shock, such as capillary refill time, skin mottling, and serial serum lactate measurements have many limitations. Veno-arterial difference in the partial pressure of carbon dioxide (PCO2 gap) is advocated being more reliable. We evaluated serial change in PCO2 gap during resuscitation in circulatory shock and its effect on ICU outcomes. This prospective observational study included 110 adults with circulatory shock. Patients were resuscitated as per current standards of care. We recorded invasive arterial pressure, urine output, cardiac index (CI), PCO2 gap at ICU admission at 6, 12, and 24 hours, and various patient outcomes. Significant decrease in PCO2 gap was observed at 6 h and was accompanied by improvement in serum lactate, mean arterial pressure, CI and urine output in (n = 61). We compared these patients with those in whom this decrease did not occur (n = 49). Mortality and ICU LOS was significantly lower in patients with low PCO2 gap, while more patients with high PCO2 gap required RRT. We found that a persistently high PCO2 gap at 6 and 12 h following resuscitation in patients with shock of various etiologies, was associated with increased mortality, need for RRT and increased ICU LOS. High PCO2 gap had a moderate discriminative ability to predict mortality. Zirpe KG, Tiwari AM, Kulkarni AP, Vaidya HS, Gurav SK, Deshmukh AM, et al. The Evolution of Central Venous-to-arterial Carbon Dioxide Difference (PCO2 Gap) during Resuscitation Affects ICU Outcomes: A Prospective Observational Study. Indian J Crit Care Med 2024;28(4):349-354.

Cervical Cancer Associated with Pregnancy: Current Challenges and Future Strategies.

Cancer during pregnancy is defined as a tumor diagnosed in a pregnant woman or up to 1-year post-partum. While being a rare disease, cervical cancer is probably one of the most challenging medical conditions, with the dual stake of treating the cancer without compromising its chances for cure, while preserving the pregnancy and the health of the fetus and child. To date, guidelines for gynecological cancers are provided through international consensus meetings with expert panels, giving insights on both diagnosis, treatment, and obstetrical care. However, these expert guidelines do not discuss the various approaches than can be found within the literature, such as alternative staging modalities or innovative surgical approaches. Also, the obstetrical care of women diagnosed with cervical cancer during pregnancy requires specific considerations that are not provided within our current standard of care. This systematic review aims to fill the gap on current issues with regards to the management of cervical cancer during pregnancy and provide future directions within this evolving landscape.