Citations

Abstract Disclosure: M. Salama: None. A.N. Lteif: None. Introduction: Intravenous propofol is widely employed for procedural sedation, monitored anesthesia care, and induction of general anesthesia. It can be administered as a bolus or an infusion. While extensively used, reports in adults and animal studies suggest potential implications of propofol on adrenal steroidogenesis. In this study, we present findings detailing transient adrenal suppression in two pediatric patients following propofol infusion. Case: The first case involves a 5-year-old boy diagnosed with left cerebellar high-grade glioma, having undergone tumor resection and proton beam irradiation. Morning cortisol levels measured twice post-propofol sedation (20 mg bolus followed by infusion at a rate of 275 mcg/kg/min prior to radiation therapy were 3.1 and 1.2 mcg/dl (ref range: 2.4-15 mcg/dl), accompanied by an undetectable ACTH level. Subsequent non sedated cortisol testing done four days later revealed a robust reading of 24 mcg/dl, with an ACTH level of 46 pg/ml.The second case is a 4-year-old boy diagnosed with right cerebellar high-grade astrocytoma glioma, who underwent total resection two months before his initial cortisol assessment. Following proton beam irradiation and propofol sedation (20 mg bolus followed by propofol infusion at a rate of 300 mcg/kg/min) for therapy, his morning cortisol obtained 45 minutes after starting propofol infusion was low at 2 mcg/dL (ref range: 2.4-15 mcg/dl). A repeat cortisol test eight days later showed an increase to 5.6 mcg/dL. Notably, neither patient was on exogenous steroids or medications impacting the adrenal axis. Discussion: The transient decline in cortisol and ACTH observed in these cases gains significance as the patients were not on any medication known to potentially induce adrenal suppression. Additionally, the gliomas were not parasellar in location and radiation had just begun. These findings align with prior reports linking propofol administration with the suppression of the hypothalamic-pituitary-adrenal axis. The impact of propofol on adrenal function needs to be considered especially in pediatric patients undergoing procedures or treatments. Conclusion: Our cases shed light on the potential transient influence of propofol on adrenal function in pediatric patients. Further studies are warranted to comprehensively evaluate the effects of propofol injections and infusions on adrenal function in pediatric cohorts. Presentation: 6/3/2024

Abstract Disclosure: A.Y. Chang: None. D.Z. Erickson: None. W.F. Young: None. K. Grennan: None. J.C. Andrews: None. E. Kapoor: None. Background: While mild androgen excess is frequently encountered in endocrine practices, severe symptoms, rapid onset or markedly abnormal biochemical testing lead to further evaluation for rare ovarian androgen-producing tumors, ovarian hyperthecosis or androgen-secreting adrenal tumors. Combined ovarian and adrenal vein sampling (COAVS) might be necessary to identify the source of androgen hypersecretion and guide treatment. The utility of COAVS has been studied in limited case series, combining case reports and different centers. There is no consensus regarding the testosterone gradient that localizes the androgen source or the added value of COAVS when a pathologic source of androgen excess is suspected. The additional clinical benefit of adrenal vein sampling (AVS) when combined with ovarian vein sampling (OVS) has also not been examined. Objectives: We sought to determine: a) the optimal total testosterone (TT) gradient for identifying unilateral vs bilateral source of hyperandrogenism and b) the utility of AVS in addition to OVS. Methods: We performed a retrospective chart review of all adult women who had COAVS at Mayo Clinic, Rochester from 1996 to 2023. Pathologic sources of androgen excess were defined as ovarian hyperthecosis (OH) as well as ovarian and adrenal tumors. We calculated the ratio of dominant OV or AV divided by the nondominant OV or AV. Results: 22 COAVS procedures from 7 premenopausal and 15 postmenopausal women were included in the study: 12 (55%) women had adrenal abnormalities seen on computed cross sectional imaging and 5 (23%) had unilateral ovarian imaging abnormalities. Of the 22 participants in the case series, successful 4-vessel catheterization was completed in 20 (1 right ovarian vein could not be cannulated, and 1 had bilateral oophorectomy). Nine (41%) women had unilateral and 10 (45%) bilateral ovarian androgen hypersecretion. Eleven (50%) women had pathologic causes for elevated TT (5 ovarian tumors, 6 cases of OH), 5 lacked follow-up pathology and 5 had benign pathology. AVS did not diagnose an adrenal source of androgen hypersecretion. TT concentrations were significantly greater in patients with unilateral compared to those with bilateral ovarian androgen hypersecretion (median 262.5 ng/dL [245- 401.5 IQR] vs 104 ng/dL [82-190], P = 0.01). In addition, TT concentrations were higher in those women with a pathologic source of TT hypersecretion compared to those with benign ovaries (349 ng/dL [251-538] vs 115 ng/dL [93-195], P = 0.03). All cases of unilateral ovarian disease had a dominant OV gradient of TT ≥ 2.1 compared to the nondominant OV. Conclusion: In a series of successful COAVS in women with androgen hypersecretion, an ovarian side-to-side gradient of ≥ 2.1 diagnosed all sources of unilateral ovarian pathology. AVS did not diagnose any pathologic source of adrenal androgen excess in this patient cohort. Presentation: 6/3/2024

Abstract Disclosure: A.Y. Chang: None. D.Z. Erickson: None. W.F. Young: None. J.C. Andrews: None. E. Kapoor: None. Background: While mild androgen excess is frequently encountered in endocrine practices, severe symptoms, rapid onset or markedly abnormal biochemical testing lead to further evaluation for rare ovarian androgen-producing tumors, ovarian hyperthecosis or androgen-secreting adrenal tumors. Combined ovarian and adrenal vein sampling (COAVS) might be necessary to identify the source of androgen hypersecretion and guide treatment. The utility of COAVS has been studied in limited case series, combining case reports and different centers. There is no consensus regarding the testosterone gradient that localizes the androgen source or the added value of COAVS when a pathologic source of androgen excess is suspected. The additional clinical benefit of adrenal vein sampling (AVS) when combined with ovarian vein sampling (OVS) has also not been examined. Objectives: We sought to determine: a) the optimal total testosterone (TT) gradient for identifying unilateral vs bilateral source of hyperandrogenism and b) the utility of AVS in addition to OVS. Methods: We performed a retrospective chart review of all adult women who had COAVS at Mayo Clinic, Rochester from 1996 to 2023. Pathologic sources of androgen excess were defined as ovarian hyperthecosis (OH) as well as ovarian and adrenal tumors. We calculated the ratio of dominant OV or AV divided by the nondominant OV or AV. Results: 22 COAVS procedures from 7 premenopausal and 15 postmenopausal women were included in the study: 12 (55%) women had adrenal abnormalities seen on computed cross sectional imaging and 5 (23%) had unilateral ovarian imaging abnormalities. Of the 22 participants in the case series, successful 4-vessel catheterization was completed in 20 (1 right ovarian vein could not be cannulated, and 1 had bilateral oophorectomy). Nine (41%) women had unilateral and 10 (45%) bilateral ovarian androgen hypersecretion. Eleven (50%) women had pathologic causes for elevated TT (5 ovarian tumors, 6 cases of OH), 5 lacked follow-up pathology and 5 had benign pathology. AVS did not diagnose an adrenal source of androgen hypersecretion. TT concentrations were significantly greater in patients with unilateral compared to those with bilateral ovarian androgen hypersecretion (median 262.5 ng/dL [245- 401.5 IQR] vs 104 ng/dL [82-190], P = 0.01). In addition, TT concentrations were higher in those women with a pathologic source of TT hypersecretion compared to those with benign ovaries (349 ng/dL [251-538] vs 115 ng/dL [93-195], P = 0.03). All cases of unilateral ovarian disease had a dominant OV gradient of TT ≥ 2.1 compared to the nondominant OV. Conclusion: In a series of successful COAVS in women with androgen hypersecretion, an ovarian side-to-side gradient of ≥ 2.1 diagnosed all sources of unilateral ovarian pathology. AVS did not diagnose any pathologic source of adrenal androgen excess in this patient cohort. Presentation: 6/3/2024

Abstract Disclosure: J. Saini: None. R. Nathani: None. J. Larson: None. V. Fell: None. I. Bancos: None. Background: Surgical menopause due to bilateral salpingo-oophorectomy (BSO) at a younger age is associated with an increased risk of cardiovascular disease, cognitive decline, and increased mortality. Aging is associated with abnormalities in steroid metabolome, most notably an increased glucocorticoid to androgen ratio (“adrenal aging”). We hypothesized that in postmenopausal women of the same age, the duration of menopause is associated with adrenal aging. Objective: To determine the differences in the adrenal steroid metabolome of women with a history of BSO as compared to age-matched women following natural menopause. Methods: We conducted a single-center cross-sectional study in postmenopausal women with or without a history of BSO, between December 2020 to December 2022 Each participant collected 24-hour urine, which was analyzed for steroid profiling by liquid chromatography-tandem mass spectrometry (25 steroids). Exclusion criteria were inability to collect a 24h urine sample, exogenous glucocorticoid use, advanced malignancy, and chronic opioid use. Primary endpoints were glucocorticoid/androgen ratio, 11β-hydroxysteroid dehydrogenase type 2 activity (cortisol/cortisone, Tetrahydrocortisol (THF) + 5 α-tetrahydrocortisol (5 α-THF)/ Tetrahydrocortisone, THE) and 5 α-reductase type activity (Tetrahydrocortisol (THF)/5 α-tetrahydrocortisol (5 α-THF) and Etiocholanolone/Androsterone, Et/An). Results: A total of 245 women were enrolled: 124 women (median age of 66 years, IQR 63-72) with a history of BSO and 121 women (median age of 68 years, IQR 64-71) who underwent natural menopause (P=0.214). Median age at menopause was 44 years (IQR 41-46) in the BSO group, and 50 years (IQR 48-53) in the natural menopause group. History of hormone replacement therapy with estrogen was reported in 161 (66%) women, more frequently (92% vs 39%, P<0.001) and for a longer duration (median 12 years (IQR 6-16) vs 6 years (IQR 3-9), P<0.001) in in the BSO group, as compared to the natural menopause group. Although both groups had similar levels of urinary androgens (median 1387 vs 1686 mcg/24h, P=0.063) and total glucocorticoids (median 10877 vs 10277 mcg/24h, P=0.354), women with a history of BSO demonstrated a higher glucocorticoid/androgen ratio (median 7.9 (IQR 5.0-11.1) vs 6.7 (4.3-9.9), P=0.014), and a lower Et/An ratio (median 1.4 vs 1.6, P=0.045), but not THF/5aTHF ratio (median 1.7 vs 1.8, P=0.380) in comparison to women with natural menopause. No differences were found in other ratios. Conclusion: Women with a history of BSO demonstrated a higher glucocorticoid/androgen ratio in comparison to women undergoing natural menopause, suggestive of BSO-induced accelerated “adrenal aging”. Future studies need to examine associations between the abnormal steroid metabolome and increased cardiovascular morbidity, frailty, and mortality reported following BSO. Presentation: 6/3/2024

ABSTRACT Introduction: ASPS is a rare, soft tissue tumor which represents 0.2-1 % of soft tissue sarcomas. A characteristic nonreciprocal translocation is found in nearly all cases. The resulting ASPSCR1-TFE3 fusion gene is postulated to be involved in the pathogenesis of this tumor. Case report: 29 years-old female presented with abdominal pain for few months. MRI and CT revealed a large necrotic abdominopelvic mass, which is extra-uterine, extra-ovarian, and peritoneal nodules. Exploratory laparotomy revealed a large mass arising from the distal part of the descending colon involving the mesentery and the surrounding peritoneum. She underwent left colectomy with primary anastomosis, and resection of the involved adjacent peritoneal and mesenteric surface nodules. Histopathology revealed ASPS involving the outer serosal layer of the large bowel wall negative margins. It also involved the resected mesenteric fat, greater omentum, and peritoneum. No further treatment was received as the patient traveled to home country. Discussion: The treatment of early-stage ASPS involves radical surgical excision of the primary tumor. Traditionally, patients with advanced ASPS have limited therapeutic options because of the resistance of the tumor to conventional cytotoxic chemotherapy, however, it is a targetable sarcoma. The response rate of metastatic ASPS to targeted therapy is clinically meaningful, and comparable to that of first-line chemotherapy. Most patients who received targeted therapy achieved disease control. Patients who had refractory or progressive disease to one targeted agent demonstrated a response to other agents. More randomized trials are warranted to expand treatment options and compare them to standard care regimens. Conclusion: In conclusion, while radical surgical excision remains crucial for early-stage ASPS, the landscape for advanced cases is evolving with targeted therapies showing promising results. However, further randomized trials are necessary to broaden the treatment options available and to evaluate these new therapies against existing standard care regimens. This ongoing research is vital to improving outcomes for patients with ASPS and tailoring more effective treatment strategies. Highlights

ABSTRACTBackgroundDespite many people awaiting kidney transplant, kidney allografts from acute kidney injury (AKI) donors continue to be underutilized. We aimed to cluster kidney transplant recipients of AKI kidney allografts using an unsupervised machine learning (ML) approach.MethodsUsing Organ Procurement and Transplantation Network–United Network for Organ Sharing (OPTN/UNOS) data, a consensus clustering cohort analysis was performed in 12 356 deceased donor kidney transplant recipients between 2015 and 2019 in whom donors had a terminal serum creatinine ≥1.5 mg/dL. Significant cluster characteristics were determined, and outcomes were compared.ResultsThe median donor terminal creatinine was 2.2 (interquartile range [IQR] 1.7–3.3) mg/dL. Cluster analysis was performed on 12 356 AKI kidney recipients, and three clinically distinct clusters were identified. Young, sensitized kidney re‐transplant patients characterized Cluster 1. Cluster 2 was characterized by first‐time kidney transplant patients with hypertensive and diabetic kidney diseases. Older diabetic recipients characterized Cluster 3. Clusters 1 and 2 donors were young and met standard kidney donor profile index (KDPI) criteria; Cluster 3 donors were older, more likely to have hypertension or diabetes, and meet high KDPI criteria. Cluster 1 had a higher risk of acute rejection, 3‐year patient death, and graft failure. Cluster 3 had a higher risk of death‐censored graft failure, patient death, and graft failure at 1 and 3 years. Cluster 2 had the best patient‐, graft‐, and death‐censored graft survival at 1 and 3 years. Compared to non‐AKI kidney recipients, the AKI clusters showed a higher incidence of delayed graft function (DGF, AKI: 43.2%, 41.7%, 45.3% vs. non‐AKI: 25.5%); however, there were comparable long‐term outcomes specific to death‐censored graft survival (AKI: 93.6%, 93.4%, 90.4% vs. non‐AKI: 92.3%), patient survival (AKI: 89.1%, 93.2%, 84.2% vs. non‐AKI: 91.2%), and overall graft survival (AKI: 84.7%, 88.2%, 79.0% vs. non‐AKI: 86.0%).ConclusionsIn this unsupervised ML approach study, AKI recipient clusters demonstrated differing, but good clinical outcomes, suggesting opportunities for transplant centers to incrementally increase kidney utilization from AKI donors.

ABSTRACT Artificial intelligence (AI) is revolutionizing cardiac imaging, including echocardiography. However, AI has scarce penetration in resource‐limited regions. The implementation of AI‐aided echocardiography (AIE) poses unique challenges and opportunities in resource‐limited areas. Some obvious advantages of AIE include aiding image acquisition, interpretation, and triaging patients based on severity. The challenges AIE faces in resource‐limited regions include a lack of data accessibility for model development, physician apprehension, and an outdated regulatory framework. Based on our early experience with AI, we believe AIE in resource‐limited regions will enhance health equity, improve access to the technology, and lead to cost savings. However, significant efforts are needed to realize these objectives.

OBJECTIVE Advances in surgical technology and microneurosurgery have led to increased utilization of so-called minimally invasive approaches, including the supraorbital eyebrow (SE) and minipterional (MPT) approaches for lesions involving the interpeduncular region. This study aimed to describe and compare anatomical landmarks, along with highlighting the advantages and disadvantages of the SE and MPT approaches to the interpeduncular region. METHODS Ten formalin-fixed, latex-injected cadaveric specimens were used to perform bilateral SE and MPT approaches to the interpeduncular region. The operative depth of each approach to key anatomical landmarks was measured. Forty-five axial thin-slice computed tomography studies were reviewed to calculate the operative angles, with consideration of the midline as a reference. A 3D interactive anatomical model generated through the photogrammetry scanning technique was described. RESULTS The depths of the operative corridors of the SE and MPT approaches to the interpeduncular fossa were 83.4 ± 1.8 mm and 67.7 ± 3.2 mm, respectively (p < 0.001). The mean angle of the MPT approach to the interpeduncular fossa was significantly wider than the one provided by the SE approach (39.9° ± 5.1° vs 28.4° ± 3.6°, p < 0.001). The interpeduncular region can consistently be accessed through the carotid-oculomotor triangle with the SE approach, as well as with the MPT approach. Furthermore, the SE route offered adequate access to the interpeduncular fossa through the opticocarotid triangle. The MPT route provided direct access to the upper prepontine cistern and anterior mesencephalic zone (AMZ). CONCLUSIONS The MPT approach provides a wider and shorter operative corridor and can be employed for lesions in the interpeduncular region with extension to the prepontine cistern and ventrolateral midbrain lesions requiring access through the AMZ. The SE approach is better suited for ventromedial midbrain lesions requiring access via the interpeduncular fossa safe entry zone. Additional studies analyzing these approaches in a clinical setting will help to delineate their reliability and efficacy.

Background Intraventricular hemorrhage is a calamitous type of stroke where bleeding into the ventricular system can be defined as: primary, if confined within the ventricles; or secondary, due to intracerebral hemorrhage extending from adjacent parenchyma. Intraventricular blood clot can lead to secondary insult and inflammatory responses that culminates in hydrocephalus as the most common cause of death. Purpose THerein, we report a patient with a high modified Graeb scale and low Glasgow coma scale. She spontaneously recanalized her fourth ventricle, decompressed her reticular activating system with remarkable spontaneous bilateral eye opening, and a consequently experienced a halfway drop in her mGS. Results This is the first reported case of a spontaneous recanalization of 4th ventricle obstruction secondary to IVH without intervention and subsequent dramatic neurological improvement. We believe that the apixaban primarily preserved the liquid state of hemorrhage and her presumed elevated ICP was sufficient to push out the liquified blood in the 4th ventricle into the upper spinal canal , recanalizing the 4th ventricle by continuously creating downward CSF pressure waves. Given the RAS location around the 4th ventricle, we hypothesize spontaneous decompression from the clot lysis triggered the RAS activation with sudden arousal manifested as spontaneous bilateral eyes opening. Hence, we refer to this as the reticular activating system reactivation after ventricular hemorrhage evacuation, or simply the “REVIVE” phenomenon. Conclusion This dramatic improvement from coma to awake state is worthy of recognition for future neurotherapeutic interventions.

Abstract Background The loss-of-function (LOF) classification of most missense variants in tumor suppressor breast cancer genes BRCA1, BRCA2, PALB2 , and RAD51C remains unclassified and confounds clinical actionability. Classifying these variants is challenging due to their rarity, leading clinicians to rely on in silico predictive methods. Protein stability changes are associated with function, making stability predictors valuable. Stability predictions upon missense variant perturbations require high-resolution protein structures. However, the availability of these high-resolution structures is lacking. This study explores using generative AI to predict high-resolution protein structures, which can then be analyzed with in silico protein stability prediction methods to assess LOF activity in ordered regions of the protein. This study also determines the appropriate in silico protein stability and dedicated in silico missense prediction methods in dbNSFP v4.7 database to predict LOF activity in ordered regions of these four genes. Functional classifications from homology recombination DNA repair (HDR) assays and variant classifications from the ClinVar database provide a reliable dataset for evaluating the performance of these in silico prediction methods. Results Complex AlphaFold2 structures of the BRCA1-C terminal (BRCT) domain and the DNA-binding (DB) domain of BRCA2, analyzed using protein stability tool FoldX predicts LOF activity from missense variants significantly better than experimentally-derived structures in ordered regions. The BRCT domain achieved an Area Under the Curve (AUC)= 0.861 (95 % CI:0.858–0.863) and AUC= 0.842 (95 % CI:0.840–0.845), while the DB domain achieved an AUC= 0.836 (95 % CI:0.8322–0.841), compared to AUC= 0.847 (95 % CI:0.844–0.850) and AUC= 0.835 (95 % CI:0.832–0.837) from the BRCT domain, and AUC= 0.830 (95 % CI:0.821–0.8320) from the DB domain from experimentally-derived structures. Protein stability does not predict LOF activity from missense variants better than dedicated in silico missense predictors. Overall, we find that AlphaMissense ranks highly, with an average AUC= 0.890 (95 % CI 0.886–0.895) from ordered regions across these four cancer genes, compared to all other in silico missense predictors present in the dbNSFP database. Conclusions The study reveals that generative AI protein predicted structures can outperform experimentally-derived structures in evaluating LOF activity from predicted protein stability in ordered regions of genes BRCA1, BRCA2, PALB2 and RAD51C. The study also highlights the predictive performance of AlphaMissense as the premier in silico missense prediction method to predict LOF activity from missense variants in these four tumor suppressor breast cancer genes. The code for this study can be downloaded for free on GitHub ( https://github.com/rohandavidg/CarePred )