Citations

Abstract Optic pathway gliomas (OPG) are generally low-grade lesions arising from the astrocytes of the visual pathway, most commonly of the optic nerves and chiasm. Uncertainty remains regarding the optimal management of this patient population. We sought to leverage population-level data from the Surveillance, Epidemiology, and End Results program database to develop a predictive calculator for overall survival (OS) amongst pediatric patients with OPG. A total of 1,052 patients who had been diagnosed with OPG were included. Multivariate cox proportional hazard model demonstrated patients of “other” race (hazard ratio [HR]=4.109, 95% confidence interval [CI] 1.076-15.694, p=0.039) exhibited a decreased overall survival, while patients with a median household income ≥$55,000 (HR=0.172, 95% CI 0.065-0.457, <0.001) and those who underwent subtotal resection (HR=3.549, 95% CI 1.092-13.364, p=0.047) had a higher overall survival rate. An online, interactive survival prediction tool (https://spine.shinyapps.io/optic_glioma/) was created to estimate 5-, 10-, and 15-year overall survival probability as well as median survival months. C-index was 0.722 (95% CI 0.642-0.776) for the training set and 0.745 (95% CI 0.661-0.790) for the validation set. Good concordance between the predicted probability and the actual probability of the dataset was also observed. This calculator may serve as a useful clinical tool during patient counseling. Further investigations aimed at developing calculators of visual acuity preservation and progression-free survival are merited; progress toward this end will benefit from continued multicenter collaborations.

e20646 Background: Thymic carcinomas tend to be aggressive malignancies with variable patterns of immunostaining. We aimed to assess whether the outcome of patients with thymic carcinomas was associated with immunoreactivity for conventional and emerging immunohistochemical markers of thymic carcinoma versus thymoma. Methods: Scoring of CD5, CD117, EZH2, POU2F3, BAP1, and MTAP immunohistochemistry on whole slide sections was compared to overall survival (OS) and progression free survival (PFS) for 36 thymic carcinoma patients, 28 of whom had complete tumor resection and 8 of whom had incomplete tumor resection. Results: Positive CD5 staining (defined as staining in ≥50% of tumor cells) was present in 13/36 cases (36%) and was significantly associated with longer OS (P = 0.005, hazard ratio = 0.18, CI 0.03-0.63) but not PFS (P = 0.14, hazard ratio = 0.48, CI 0.16-1.26), whereas the other markers were not significantly associated with OS or PFS. Positive CD5 staining remained significantly associated with OS in squamous cell carcinoma subgroup analysis (n = 23, HR = 0.17, CI 0.03-0.65, P = 0.009), patients who did not receive neo-adjuvant treatment (n = 24, HR = 0.21, CI 0.03-0.85, P = 0.03) and after adjusting for incomplete resection (HR = 0.20, CI0.03-0.73, P = 0.01), M1 stage (HR = 0.19, CI 0.03-0.71, P = 0.01) or neoadjuvant treatment (HR = 0.19, CI 0.03-0.71, P = 0.01) in bivariate models. Positive CD5 staining was also significantly associated with age ≥60 years, absence of neoadjuvant treatment, and positive POU2F3 staining. Conclusions: CD5 staining in ≥50% of tumor cells was significantly associated with longer OS for thymic carcinoma patients. Our study supports the notion that CD5 immunohistochemistry may have utility as a prognostic marker for thymic carcinomas.

1535 Background: Ambulatory management of select patients with febrile neutropenia (FN) may substantially decrease patients’ burden of illness and improve their quality of life, and is recommended by American Society of Clinical Oncology (ASCO) guidelines. However, in the United States, inpatient management remains the universal standard. We hereby report the health care utilization associated with the DEFeNDR remote patient monitoring (RPM) program, which leverages technology and virtual centralized nurse monitoring to facilitate ambulatory management of FN as an alternative to hospital-based care. Methods: Adult patients with cancer hospitalized with FN were assessed daily for eligibility to participate in the DEFeNDR program. Eligibility criteria included MASCC score >21 (per ASCO guidelines), and clinical judgment of the attending provider. Patients receiving cellular therapy (CAR-T, BMT) in the prior 100 days were excluded. Eligible patients agreeing to participate in the 30-day program were provided a kit containing cellular-enabled, pre-connected devices to facilitate monitoring, including twice-daily vital signs and electronic symptom questionnaires. Data were EHR-integrated in real-time and embedded decision trees facilitated alerts for adverse trends. RPM nurses responded to alerts and escalated care as indicated by pre-specified care pathways. Program assessment was performed at 20 weeks after full implementation. The primary outcome was the mean proportion of evaluable days spent inpatient (mPEDI) within 30 days of eligibility compared between those who participated in the program vs. those who declined. Results: 35 patients were offered participation in the DEFeNDR program. Of these, 17 participated and 18 declined. Baseline characteristics are provided. Participating patients experienced mPEDI of 6.9% (Standard Error [SE], 3.7%), compared with 17.7% (SE, 3.6%) for patients who declined participation. Due to small sample size, this difference (10.8%) did not reach statistical significance (Wilcoxon Rank Sums p-value, 0.15). 30-day mortality did not differ between groups. Mean inpatient days were also lower for patients participating in the program. Additionally, when readmitted, patients participating in RPM experienced a trend toward shorter length of stay and lower rates of intensive care unit utilization. Conclusions: A trend towards decreased burden of inpatient care is evident among patients participating in the DEFeNDR program. Further studies are warranted to assess comparative effectiveness of this model vs usual care.[Table: see text]

TPS623 Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (<11, 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% vs 91.6% for the omission of RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1% per yr. Some of the T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. Current accrual (02-08-2023) is 370 screened and 323 randomized (~87% of predicted accrual). Clinical trial information: NCT04852887 .

Introduction: Dent Disease type 1 (DD1) results from X-linked, mutations in CLC-5 (2Cl-/H+ exchanger) and results in progressive renal failure by 20-40. DD1 is characterized by kidney Ca2+ mishandling, and subsequent hypercalcuria, calcium oxalate (CaOx) kidney stones, and kidney calcification as well as proteinuria. We identified Drosophila Clc-c as the CLC-5 homolog with conserved amino acids at DD1 mutation sites. We hypothesize that Clc-c shares functional similarities in Cl- transport, Ca2+ homeostasis and protein processing. Methods and Results: By voltage clamping Xenopus oocytes expressing Clc‑c and CLC-5, we find that both are electrogenic and have the same outward-rectifying current in Cl- solutions. Cl- transport (current at +80mV) was lowered by acidity (2.37±0.55 μA, pH 6.0, P=0.06), but not by alkaline solution (4.45±0.96 μA, pH 8.5, P= 0.7) when compared to the standard solution of pH 7.5 (4.97±1.12 μA). Similarly, Cl- transport was lowered by homologous DD1 mutations S393L (0.67±0.098 μA, P<0.0001), R494W (2.9±0.46 μA, P =0.006), and Q777x (1.13±0.28 μA, P =0.0001) vs. WT (7.4±1.2 μA) as observed previously for CLC-5 DD1 mutations: S244L, R345W, and Q629x (Tang et al, Physiol Rep 4[8], 2016). To determine cell membrane and possible intracellular localization of DD1 mutations, HA-tagged Clcc and mutations (identical placement as in CLC-5-HA, Tang 2016) were made. Likewise, transgenic Drosophila expressing Clc-c-GFP were made to localize Clc-c in cell and intracellular membranes of renal tubules (Malpighian tubules, MT) in vivo (Judd-Mole, U Monash, Dissertation, 2016). RNAi MT knockdowns of Clc-c (Clc-c-KD) were made and resulted in 50% decrease in Clc-c mRNA expression. CaOx crystals in anterior MT (7 days after eclosure) were present in all Clc-c-KD and were more abundant (15±4 crystals/fly) than w1118 controls (5±2 crystals/fly, P= 0.02). MT secretions showed that Clc-c KD flies contained higher [Ca2+] while all other cations (Na+, NH4+, K+, Mg2+), and volume were the same as w1118 . Similarly, urinary protein concentration (4-6 pooled flies per n) appears elevated in DD1 flies (1.41 ± 0.14 mg/mL, n=3) vs w1118 (1.16 ± 0.08 mg/mL, n=5). Conclusion: Drosophila Clc-c has similarities to human CLC-5 including impaired function of voltage-gated Cl- transport, homologous DD1 mutations, increased CaOx crystal formation, and elevated urinary [Ca2+] and protein. Our results indicate that the Drosophila Clc-c avatar may help to provide more direct insights to the cellular and organismal pathophysiology for future investigations of Cl- transport, Ca2+ homeostasis and urinary protein loss in DD1. F32 DK128987, T32 DK007013 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Anoctamins (ANO) are activated by intracellular Ca2+ and function as phospholipid scramblases and/or Cl- channels. ANO4 is mutated in miniature schnauzers with calcium oxalate stones (CaOx), and ANO4 protein in urinary extracellular vesicles is decreased in human CaOx stone formers. In Drosophila Malpighian tubules (MT), subdued (ANO4-homolog) functions as Ca2+-activated Cl- channel, scramblase, and plays a role in host defense against gram-negative bacteria. Increasing evidence shows the participation of bacteria in urinary stone formation in humans. We used a Drosophila avatar to investigate whether subdued changes CaOx crystallization and if crystallization increases with bacterial infection.Uro:Gal4 flies were crossed with UAS:subdued-RNAi flies to knockdown (KD) subdued in MT principal cells (PC) or with w1118 flies to generate normal controls (WT). F1 generation underwent CaOx crystallization in association or not with uropathogenic E. coli (UPEC) infection. In vivo, flies were fed on diet supplemented with 20mM sodium Ox (NaOx) + UPEC:eGFP for 4 days. For ex vivo assays, dissected MTs were submerged in solution containing 10mM NaOx+ UPEC:eGFP for 90 minutes. subdued-KD in PC reduced subdued mRNA by 56% in MT. Neither crystal number nor size were changed by subdued-KD after prolonged NaOx feeding. However, when UPEC is introduced with the NaOx diet, subdued-KD flies exhibited a large bacterial presence in MT lumen and produced enlarged CaOx crystals compared to WT flies. Similar augmented presence of UPEC in subdued-KD MTs was observed during ex vivo assays. Short-term exposure to NaOx+UPEC resulted in increased number of crystals in subdued-KD MTs compared to WT MTs, but no difference was observed in crystal size.Fly cell atlas ( flycellatlas.org ) revealed that subdued is also found in MT stellate cells (SC; water and Cl- secretion). C724:Gal4>UAS:subdued-RNAi flies were used to assess the effect of subdued-KD in SC. This s ubdued-KD slightly increased bacterial infection but did change CaOx crystallization in MTs after 4 days of NaOx+UPEC feeding.The presence of subdued in PC limits CaOx crystals formation and aggregation through reducing bacterial invasion in the MT lumen. These Drosophila results suggest a role for ANO4 in bacterial-related human and dog kidney stone formation. Future experiments will determine whether other functional aspects of subdued affect CaOx crystallization. U54-DK100227, R01-DK092408, FAPESP (2022/01226-1), Mayo Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract Introduction Transthyretin–mediated (ATTR) amyloidosis is a progressive, multisystem, fatal disease. Patisiran, an IV RNAi therapeutic, is approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. The safety and efficacy of patisiran in patients with wild–type or hereditary ATTR amyloidosis with cardiomyopathy (CM) is being investigated in the ongoing APOLLO–B study. Methods Patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, and ATTR amyloid by tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM. Medical history of heart failure (HF) due to ATTR amyloidosis with ≥1 prior hospitalization or current clinical evidence of HF was required. Patients were randomized 1:1 to patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6–MWT at Month 12 (M12) with patisiran vs placebo. Results APOLLO–B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age (range), 76.0 (41, 85) yrs; male, 89%; wtATTR, 80%. Baseline characteristics were consistent between patients on tafamidis at baseline (91/360 [25%]) and those who were not. Patisiran achieved a rapid and sustained reduction in serum TTR, irrespective of baseline tafamidis treatment. At M12, patisiran showed a significant benefit vs placebo in 6–MWT (median [95% CI] change from baseline: patisiran, –8.15 [–16.42, 1.50]; placebo, –21.35 [–34.05, –7.52]; HL estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162) and KCCQ–OS (LS mean [SEM] change from baseline: patisiran, 0.300 [1.263]; placebo, –3.408 [1.277]; LS mean [SEM] difference: 3.709 [1.796]; p=0.0397). Consistent benefits with patisiran in 6–MWT and KCCQ–OS were observed across predefined patient subgroups. Time to first event of all–cause hospitalization, urgent HF visit, or death directionally favored patisiran vs placebo (HR [95% CI], 0.839 [0.557, 1.263]), as did all–cause mortality (HR [95% CI], 0.355 [0.110, 1.138]), but all composite outcomes endpoints did not achieve statistical significance over 12 months. Patisiran was well tolerated; most AEs were mild or moderate in severity, and there were no cardiac safety concerns. Conclusions Benefits at 12 months were observed with patisiran vs placebo in functional capacity, and health status and quality of life, in patients with ATTR amyloidosis with CM. The efficacy and safety of patisiran continues to be studied in the APOLLO–B open–label extension.

Abstract Introduction Transthyretin–mediated (ATTR) amyloidosis is a progressive and fatal disease. Patients with hereditary or wild–type ATTR amyloidosis frequently develop cardiomyopathy (CM). Patisiran, an IV RNAi therapeutic that inhibits synthesis of wt and variant TTR, is approved for the treatment of hATTR amyloidosis with polyneuropathy. Methods In APOLLO–B, patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, ATTR amyloid deposition on tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM, and had prior hospitalization for heart failure (HF) due to ATTR amyloidosis or clinical evidence of HF. Patients were randomized 1:1 to patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6–MWT at Month 12 (M12) with patisiran vs placebo. Exploratory parameters at M12 included changes in cardiac biomarkers, echocardiography and Tc scintigraphy. Results APOLLO–B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age, 76.0 yrs; male, 89%; wtATTR, 80%; on tafamidis at baseline, 25%. Patisiran showed a significant benefit compared with placebo in 6–MWT (median [95% CI] change from baseline: patisiran, –8.15 [–16.42, 1.50]; placebo, –21.35 [–34.05, –7.52]; HL estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162). Patisiran demonstrated favorable trends in change from baseline of NT–proBNP (mean fold change ratio [95% CI]: 0.80 [0.73, 0.89]; p=1.825×10–5) and troponin I (mean fold change ratio [95% CI]: 0.87 [0.80, 0.95]; p=0.0011) at M12 vs placebo. Patisiran also demonstrated a trend towards benefit in change from baseline of most evaluated echocardiographic parameters at M12 vs placebo. Patisiran–treated patients evaluable for scintigraphy (n=37) experienced a reduction (37.8%) or no change (62.2%) in Perugini grade at M12 compared with baseline. Among placebo patients (n=28) at M12, none experienced a reduction from baseline in Perugini grade, and 1 (3.6%) increased in grade. Patisiran demonstrated an acceptable safety profile; AEs were mostly mild or moderate in severity, and there were no cardiac safety concerns. Conclusions Exploratory analyses after 12 months provide further evidence for the potential benefit of patisiran treatment on cardiac biomarkers and manifestations of cardiac amyloid involvement in patients with ATTR amyloidosis. The long–term impact of patisiran will be assessed in the ongoing APOLLO–B open–label extension.