Citations

The structure-activity relationship studies of neurotensin and its analogs have revealed that i) the C-terminal hexapeptide NT (8-13) (H-ArgB­ Arg9-Pro1o_Tyr1LIIe12-Leu13.QH) is equipotent to or more potent than the native NT(1-13) and retains all the intrinsic biological properties of neurotensin, ii) the N-terminal peptide fragment up to NT(1-7) does not significantly contribute to the binding potency, iii) Pro1o that can form a reverse-turn conformation is required, iv) an aromatic amino acid is important at Tyr11 position, v) the lipophilic side chain of Leu 13 is also crucial to the biological activities, and, vi) L-form amino acids are essential at critical positions for the binding potency. In addition to many peptidic neurotensin analogs, highly potent, orally active, and selective non-peptidic analogs as antagonists of NT receptors, which have long lasting effects and the ability to cross the blood­ brain barrier (e. g. SR 142948 A and SR 48692), have been discovered.

Abstract Background: Survival advantages with neoadjuvant chemotherapy (NACT) have been observed in patients (pts) with locally advanced breast cancer (BC) who achieve pathological complete response (pCR). Predicting risk of early recurrence in pts without pCR remains difficult. Circulating tumor DNA (ctDNA) may be a biomarker of neoadjuvant therapy response and recurrence. This study applied tumor genotyping of peripheral blood in pts with HER2− tumor BRCA-mutated (tBRCAm) BC treated with neoadjuvant niraparib. The relationship between ctDNA and tumor response was also characterized, with a focus on circulating TP53 mutant allelic frequency (MAF). Methods: Blood was collected from 21 pts enrolled in the study (NCT03329937) evaluating neoadjuvant niraparib in pts with localized HER2− tBRCAm BC. Pts received niraparib 200 mg once daily for two 28-day cycles. After 2 cycles, pts underwent surgery or received up to 6 cycles of niraparib and/or NACT prior to surgery. Blood samples were collected at screening, Cycle 1 Day 28 (C1D28), Cycle 2 Day 28 (C2D28), and pre-surgery. Ultrasound (USG) was done after each cycle and MRI after Cycle 2. Next-generation sequencing of cell-free plasma DNA was carried out using a proprietary target capture and analysis (Paweletz, Clin Cancer Res 2016). Results: ctDNA and TP53 mutations (TP53m) were detected at screening in 10/21 pts (47.6%). Across all 21 pts there was a correlation between TP53 MAF and baseline tumor stage (T) (mean [standard deviation], T1 0 [0], T2 0.05 [0.09], and T3 0.21 [0.12]; P=0.005). Linear regression modelling showed a positive correlation between tumor volume and baseline TP53 MAF (R2=0.206, P=0.0386). Baseline TP53 MAF also appeared to be associated with advanced disease stage (Table 1). Depletion of detectable TP53m from baseline was evident by C1D28 and persisted to pre-surgery (Table 2). This corresponded with decreases in tumor volume at C1D28 and further decreases at C2D28. Of 11 pts analyzed, 6 pts with >90% tumor volume decreases by MRI or USG at C2D28 had sustained TP53m depletion. Three pts had pCR; of these, 2 had sustained TP53m depletion (data unavailable for third pCR pt). Two pts with less robust tumor responses had increased pre-surgery TP53 MAF. Conclusions: We report the potential utility of ctDNA as a predictive biomarker for neoadjuvant niraparib response in pts with HER2− tBRCAm BC. Although sample size limited analysis of genes other than TP53, baseline ctDNA strongly correlated with tumor volume, and TP53 MAF was associated with tumor volume and trended towards association with disease stage. Longitudinal analysis of TP53 MAF suggested a correlation with niraparib response. Further study of ctDNA dynamics during NACT and correlation with pCR and long-term clinical outcomes is warranted. Funding: GlaxoSmithKline (GSK) study 213355; NCT03329937. Medical writing support was provided by Fishawack Indicia, part of Fishawack Health, funded by GSK. Table 1.Baseline TP53 MAF association with disease stage and subtypeTP53 MAFDisease Stage (I–III)Disease SubtypeStage IStage IIStage IIIHR+TNBC(n=8)(n=10)(n=3)(n=6)(n=15)Mean (SD)0.01 (0.02)0.07 (0.12)0.10 (0.05)0.02 (0.02)0.06 (0.10)HR, hormone receptor; MAF, mutant allelic frequency; SD, standard deviation; TNBC, triple-negative breast cancer. Table 2.TP53 MAF correlation with tumor volume decrease by ultrasound and MRIOutcomeScreeningCycle 1 Day 28 Cycle 2 Day 28 Pre-Surgeryn11997TP53 MAF, mean, (SD)0.09 (0.11)000.01 (0.02)n11112Percent change in tumor volume from baseline by MRI, mean (SD)-N/A*−72.6 (22.5)N/A*Percent change in tumor volume from baseline by ultrasound, mean (SD)-−60.8 (24.0)−80.6 (21.8)−95.9 (4.3)*MRI was only performed at Cycle 2 Day 28. MAF, mutant allelic frequency; MRI, magnetic resonance imaging; N/A, not applicable; SD, standard deviation. Citation Format: Ming Shan, Laura Spring, Minetta C Liu, Erika Hamilton, Hanna Irie, Cesar A Santa-Maria, Steven J Isakoff, James Reeves, Leif W Ellisen, Lee P Lim, Kavita Garg, Caterina Bertucci, Bin Feng, Hailei Zhang, Kaiming Sun, Julie R Graham, Erin Hofstatter, Hyo Han. Relationship between circulating tumor DNA and response to neoadjuvant niraparib in HER2-negative, BRCA-mutated breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-21.

Abstract Polatuzumab vedotin (PV) is an antibody–drug conjugate targeting CD79b that is approved for patients with relapsed/refractory large B-cell lymphoma (LBCL). Patients who relapse after chimeric antigen receptor (CAR) T-cell therapy were not included in the registration study, and reports of PV use after CAR T cells are limited. This multicenter retrospective analysis included patients with LBCL who relapsed or progressed after CAR T-cell therapy and subsequently received PV with or without rituximab and bendamustine between July 2019 and May 2021. Response to treatment and progression were assessed based on the 2014 Lugano criteria. Fifty-seven patients were included in the study: 18 (32%) patients were primary refractory to CAR T-cell therapy, and 34 (60%) patients received PV-based therapy immediately after CAR T-cell therapy. PV was combined with rituximab in 54 (95%) patients and administered with bendamustine in 35 (61%) patients. A response was achieved in 25 (44%) patients, including complete remission in 8 (14%). No significant association between baseline characteristics and response was observed. After a median follow-up of 47 weeks (95% confidence interval [CI], 40-54), 46 (81%) patients had disease progression or died, and the median progression-free survival was 10 weeks (95% CI, 5-15). On a multivariate analysis, bone marrow involvement (hazard ratio, 5.2; 95% CI, 1.8-15; P = .003) and elevated lactate dehydrogenase levels (hazard ratio, 5.0; 95% CI, 1.4-16; P = .01) were associated with shorter progression-free survival. Studies aimed at better characterizing the intrinsic mechanism of resistance and identifying optimal consolidation strategies for these patients are warranted.

AbstractPurposeAs a typical chronic kidney disease (CKD), hypertensive nephrosclerosis (HN) is a common syndrome of hypertension, characterized by chronic kidney microvascular damage. Early diagnosis of microvascular damage using conventional ultrasound imaging encounters challenges in sensitivity and specificity owing to the inherent diffraction limit. Ultrasound localization microscopy (ULM) has been developed to obtain microvasculature and microvascular hemodynamics within the kidney, and would be a promising tool for the early diagnosis of CKD.MethodsIn this study, the advantage of quantitative indexes obtained by using ULM (mean arterial blood flow speeds of different segments of interlobular arteries) over indexes obtained using conventional clinical serum (β2‐microglobulin, serum urea nitrogen, and creatinine) and urine (24‐h urine volume and urine protein) tests and ultrasound Doppler imaging (peak systolic velocity [PSV], end‐diastolic velocity [EDV], and resistance index [RI]) and contrast‐enhanced ultrasound imaging (CEUS; rise time [RT], peak intensity [IMAX], mean transit time [mTT], and area under the time‐intensity curve [AUC]) for early diagnosis of HN were investigated. Examinations were carried out on six spontaneously hypertensive rats (SHR) and five normal Wistar–Kyoto (WKY) rats at the age of 10 weeks.ResultsThe experimental results show that the indicators derived from conventional clinical inspections (serum and urine tests) and ultrasound imaging (PSV, EDV, RI, RT, IMAX, mTT, and AUC) do not show significant difference between hypertensive and healthy rats (p > 0.05), while the TTP of the SHR group (28.52 ± 5.52 s) derived from CEUS is significantly higher than that of the WKY group (18.68 ± 7.32 s; p < 0.05). The mean blood flow speed in interlobular artery of SHR (12.47 ± 1.06 mm/s) derived from ULM is significantly higher than that of WKY rats (10.13 ± 1.17 mm/s; p < 0.01).ConclusionThe advantages of ULM over conventional clinical inspections and ultrasound imaging methods for early diagnosis of HN were validated. The quantitative results show that ULM can effectively diagnose HN at the early stage by detecting the blood flow speed changes of interlobular arteries. ULM may promise a reliable technique for early diagnosis of HN in the future.

277 Background: The prognostic importance of local failure (LF) after definitive radiotherapy (RT) in patients with NCCN intermediate- (IRPCa) and high-risk prostate cancer (HRPCa) remains unclear, particularly given the likelihood that occult distant metastases (DMs) at presentation may be the true driver of natural history. Here, we leverage individual patient data (IPD) from 18 randomized control trials (RCTs) to evaluate the prognostic impact of LF and the kinetics of DM after RT. Methods: IPD for 18 RCTs were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium, comprising a total of 12533 patients (6288 HRPCa & 6245 IRPCa). Multivariable Cox proportional hazards (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), DM-free survival (DMFS) & LF as a time-dependent covariate, adjusted for clinicodemographic parameters. Markov PH models, defined via transitions between 4 states, were developed to evaluate the aforementioned relationship. Proportional hazards assumption was imposed and examined for both models. Time is from randomization. Results: Median follow-up was 9.1 years. There were 795 (13%) LF & 1288 (21%) DM events for patients with HRPCa; these numbers were 449 (7%) & 451 (7%) for IRPCa. For HRPCa & IRPCa, 81% and 81% of DMs developed from a clinically relapse-free state (cRFS), with a median time of 46 and 60 months, respectively (p < 0.0001). 39% & 13% of DM events occurred within 2 years after RT for HRPCa & IRPCa, respectively. At later time points, DM events were more likely to emerge after an LF event for both HRPCa (9% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.001) and IRPCa (10% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.008). LF was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75-2.33) & DMFS (HR 1.94, 95% CI 1.75–2.15) (p < 0.01 for all) in patients with HRPCa. LF was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not OS in patients with IRPCa. Patients who had not transitioned to the LF state had a significantly lower HR of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.32, 95% CI 0.21–0.50, p < 0.001). Conclusions: LF is an independent prognosticator of OS, PCSS & DMFS in HRPCa and of DMFS in IRPCa. The predominant mode of DM development is from the cRFS state, underscoring the importance of accurate upfront staging & systemic therapy. However, particularly at late time points, an increasing proportion of DM events originated after diagnosis of a LF, constituting a “second wave” of DM events. This suggests that optimizing local control is also important, though the majority of DM events appear prior to a clinically-detected LF.

265 Background: A recent study ( Fossati et al, 2018) found that higher lymph node count at radical prostatectomy was associated with improved outcomes in patients treated with salvage radiation for elevated prostate-specific antigen (PSA) after surgery. We sought to validate these results in NRG/RTOG 9601, a randomized controlled trial of men with pT2/T3 disease who underwent either radiation (RT) alone or RT+antiandrogen (bicalutamide) therapy for PSA elevation following radical prostatectomy from 1998-2003. Methods: We reviewed available pathology reports for all patients in NRG/RTOG 9601 to determine the nodal count at radical prostatectomy. Clinical data was as of 11/5/2015, same as the primary endpoint for the trial. Cox proportional hazards models were used to assess the effect of number of positive lymph nodes, treatment arm (RT alone or RT+bicalutamide), Gleason score, positive margins, and seminal vesicle invasion on the following endpoints: times to local and distant failure and overall and disease specific survival. Results: Out of the 760 patients originally eligible in the trial, 552 (73%, 276 in each arm) had complete data available. Median node count in the entire cohort was 6 (range 0-33, Q1-Q3 3-9). There were no significant differences between treatment arms in terms of patient demographic or clinical characteristics, including total lymph nodes removed in either arm (RT alone vs RT+bicalutamide median 5 vs 6, p = 0.11). There was no significant association between total lymph nodes and overall survival with both arms combined (HR = 1.00, 95% CI:0.97-1.03, p = 0.87) or in the individual arms alone (RT+Casodex: HR = 1.01, 95% CI:0.97-1.05, p = 0.65; RT+Placebo: HR = 0.98, 95% CI: 0.94-1.03, p = 0.45). There was also no significant association between total lymph nodes and disease-specific survival with both arms combined (HR = 1.00, 95% CI:0.95-1.04, p = 0.84) and in the arms alone (RT+Casodex: HR = 1.00, 95% CI:0.95-1.05, p = 0.92; RT+Placebo: HR = 0.99, 95% CI: 0.92-1.07, p = 0.86). In multivariable analysis performed on the two arms, Gleason score was the only feature associated with worse overall and disease-specific survival, seen only in the RT alone arm. Similar findings were seen when evaluating times to local and distant failure. Conclusions: Lymph node yield in NRG/RTOG 9601 did not show any association with adverse outcomes in the entire cohort, or in either treatment arm alone. The therapeutic benefit of an extensive lymph node dissection in this population remains uncertain. Clinical trial information: NCT00002874.

Abstract Background Strategies to optimize antibiotic prescribing at discharge are not well understood. Methods In fall 2019, we surveyed 39 Michigan hospitals on their antibiotic stewardship strategies. The association of reported strategies with discharge antibiotic overuse (unnecessary, excess, suboptimal fluoroquinolones) for community-acquired pneumonia (CAP) and urinary tract infection (UTI) was evaluated in 2 ways: (1) all strategies assumed equal weight and (2) strategies were weighted based on the ROAD (Reducing Overuse of Antibiotics at Discharge) Home Framework (ie, Tier 1—Critical infrastructure, Tier 2—Broad inpatient interventions, Tier 3—Discharge-specific strategies) with Tier 3 strategies receiving the highest weight. Results Between 1 July 2017 and 30 July 2019, 39 hospitals with 20 444 patients (56.5% CAP; 43.5% UTI) were included. Survey response was 100%. Hospitals reported a median (interquartile range [IQR]) 12 (9–14) of 34 possible stewardship strategies. On analyses of individual stewardship strategies, the Tier 3 intervention, review of antibiotics prior to discharge, was the only strategy consistently associated with lower antibiotic overuse at discharge (adjusted incident rate ratio [aIRR] 0.543, 95% confidence interval [CI]: .335–.878). On multivariable analysis, weighting by ROAD Home tier predicted antibiotic overuse at discharge for both CAP and UTI. For diseases combined, having more weighted strategies was associated with lower antibiotic overuse at discharge (aIRR 0.957, 95% CI: .927–.987, per weighted intervention); discharge-specific stewardship strategies were associated with a 12.4% relative decrease in antibiotic overuse days at discharge. Conclusions The more stewardship strategies a hospital reported, the lower its antibiotic overuse at discharge. However, Tier 3, or discharge-specific strategies, appeared to have the largest effect on antibiotic prescribing at discharge.