Excellent Responders Research Articles

Dopa Responsiveness in Parkinson's Disease.

Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these. We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters. 1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1-74.3%). We identified 3 response groups: "Striking" (n = 29, 8.7%); "Excellent" (n = 110; 32.7%) and "Modest" (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01). Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid.

Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world

BackgroundAnti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who...

Evaluating Magnetic Seed Localization in Targeted Axillary Dissection for Node-Positive Early Breast Cancer Patients Receiving Neoadjuvant Systemic Therapy: A Comprehensive Review and Pooled Analysis.

Background/Objectives: De-escalation of axillary surgery is made possible by advancements in both neoadjuvant systemic therapy (NST) and in localisation technology for breast lesions. Magseed®, developed in 2013 by Dr. Michael Douk of Cambridge, United Kingdom, is a wire-free localisation technology that facilitates the localisation and retrieval of lymph nodes for staging. Targeted axillary dissection (TAD), which entails marked lymph node biopsy (MLNB) and sentinel lymph node biopsy (SLNB), has emerged as the preferred method to assess residual disease in post-NST node-positive patients. This systematic review and pooled analysis evaluate the performance of Magseed® in TAD. Methods: The search was carried out in PubMed and Google Scholar. An assessment of localisation, retrieval rates, concordance between MLNB and SLNB, and pathological complete response (pCR) in clinically node-positive patients post NST was undertaken. Results: Nine studies spanning 494 patients and 497 procedures were identified, with a 100% successful deployment rate, a 94.2% (468/497) [95% confidence interval (CI), 93.7-94.7] localisation rate, a 98.8% (491/497) retrieval rate, and a 68.8% (247/359) [95% CI 65.6-72.0] concordance rate. pCR was observed in 47.9% (220/459) ) [95% CI 43.3-52.6] of cases. Subgroup analysis of studies reporting the pathological status of MLNB and SLNB separately revealed an FNR of 4.2% for MLNB and 17.6% for SLNB (p = 0.0013). Mean duration of implantation was 37 days (range: 0-188). Conclusions: These findings highlight magnetic seed localisation's efficacy in TAD for NST-treated node-positive patients, aiding in accurate axillary pCR identification and safe de-escalation of axillary surgery in excellent responders.

Abstract PS05-07: Early prediction of response to Neoadjuvant Immunotherapy in Triple Negative Breast Cancer (TNBC) with DCE-MRI

Abstract Purpose: Neoadjuvant immunotherapy (NIT) in combination with neoadjuvant chemotherapy (NCT) was recently approved for treatment of TNBC patients with increased rates of pathologic complete response (pCR) compared to NCT alone. The aim of this study was to evaluate if dynamic contrast-enhanced (DCE)-MRI performed after 2 and/or 4 cycles of NIT + NCT, can predict which patients will achieve pCR, potentially triaging them to continuation of NIT+NCT or, when appropriate, to de-escalation trials. Alternatively, identified chemoresistant tumors who are unlikely to achieve pCR may be directed to other treatment strategies, including novel targeted trials, and avoid the unnecessary toxicity of NIT. Methods and Materials: Preliminary analysis included 64 patients from prospective IRB-approved study (NCT02276443) with stage I-III TNBC who underwent DCE-MRI at baseline (BL), after 2 cycles (C2), and 4 cycles (C4) of NIT combined with standard of care NCT (Paclitaxel +/- carboplatin). Tumor volumes were calculated using 3 axis measurements of the index lesion at the DCE MRI and percent tumor volume reduction (TVR) between BL, C2, and C4 was calculated. pCR was assessed at surgery after completion of neoadjuvant treatment. Correlation between pCR and TVR was evaluated using ROC analysis. Results: 59% (38/64) of TNBC patients achieved pCR after NIT+NCT. DCE-MRI after 2 cycles of NIT+NCT was able to predict pCR with an AUC of 0.71 (95% CI: 0.57-0.84). TVR &amp;gt;90% at C2 predicted pCR with PPV 86%, and TVR &amp;lt; 35% predicted chemoresistance with NPV 100%. Following 4 cycles of treatment DCE-MRI was able to predict pCR with an AUC of 0.81 (95% CI: 0.69-0.92). TVR &amp;gt;95% at C4 was predictive of chemosensitivity with PPV 82%, while TVR &amp;lt; 75% was predictive of chemoresistance with NPV 100%. Conclusions: DCE-MRI volumetric changes early during NIT + NCT were able to predict pCR status of TNBC patients as either excellent responders or nonresponders, triaging them to SOC neoadjuvant therapy with option for de-escalation trials, or targeted therapies, respectively. These preliminary results will be validated in the larger cohort after completion of the ongoing prospective clinical trial. Citation Format: Gaiane Rauch, Mary Guirguis, Miral Patel, Rosalind Candelaria, Rania Mohamed, Tanya Moseley, H. T. Carisa Le-Petross, Jessica Leung, Gary Whitman, Deanna Lane, Marion Scoggins, Frances Perez, Jia Sun, Sanaz Pashapoor, Zhan Xu, Jason White, Peng Wei, Brandy Reed, Jong Bum Son, Ken-Pin Hwang, Bikash Panthi, Anil Korkut, Lei Huo, Kelly Hunt, Alyson Clayborn, Jennifer Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Wei Yang, Jingfei Ma, Beatriz Adrada. Early prediction of response to Neoadjuvant Immunotherapy in Triple Negative Breast Cancer (TNBC) with DCE-MRI [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-07.

Lithium response in bipolar disorder: Epigenome-wide DNA methylation signatures and epigenetic aging

Lithium (Li) is the first-line treatment for bipolar disorder (BD) even though only 30 % of BD patients are considered excellent responders. The mechanisms by which Li exerts its action are not clearly understood, but it has been suggested that specific epigenetic mechanisms, such as methylation processes, may play a role. In this regard, DNA methylation patterns can be used to estimate epigenetic age (EpiAge), which is accelerated in BD patients and reversed by Li treatment. Our first aim was to compare the DNA methylation profile in peripheral blood between BD patients categorized as excellent responders to Li (Ex-Rp) and non-responders (N-Rp). Secondly, EpiAge was estimated to detect differential age acceleration between the two groups.A total of 130 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) between Ex-Rp (n = 26) and N-Rp (n = 37) were identified (FDR adjusted p-value < 0.05). We found 122 genes mapping the DMPs and DMRs, nine of which (HOXB6, HOXB3, HOXB-AS3, TENM2, CACNA1B, ANK3, EEF2K, CYP1A1, and SORCS2) had previously been linked to Li response. We found genes related to the GSK3β pathway to be highly represented. Using FUMA, we found enrichment in Gene Ontology Cell Component for the synapse. Gene network analysis highlighted functions related to the cell cycle, nervous system development and function, and gene expression. No significant differences in age acceleration were found between Ex-Rp and N-Rp for any of the epigenetic clocks analysed.Our findings indicate that a specific methylation pattern could determine the response to Li in BD patients. We also found that a significant portion of the differentially methylated genes are closely associated with the GSK3β pathway, reinforcing the role of this system in Li response. Future longitudinal studies with larger samples will help to elucidate the epigenetic mechanisms underlying Li response.

P053 Sub-optimal response to first biologic in axial spondyloarthritis: real world data showing clinician decisions in a tertiary centre

Abstract Background/Aims Up to 50% of patients respond inadequately to their first biologic treatment for axial spondyloarthritis (axSpA). Whilst NICE advises that if the BASDAI improves by ≤ 2 or ≤ 50% in 12 weeks the treatment should be discontinued, we were interested to assess the real-world application of this, and particularly how clinicians manage sub-optimal response: namely patients whose BASDAI decreases by two points but remains moderately raised above four. Methods We retrospectively assessed clinical records of axSpA patients attending the Royal National Hospital for Rheumatic Diseases, Bath who started a biologic for axSpA between 2016 and 2018. Based on their post-biologic BASDAI, patients were divided into excellent-, sub-optimal- (drop of ≥ 2 in the BASDAI but the score remained ≥4) and non-responders. Results 93 patients were included, of which 55% of patients were male with a mean age of 42 at the time of starting their first biologic. There was a 65:35 split in diagnosis between radiographic and non-radiographic axial spondyloarthritis. 50/93 (54%) patients had an excellent response. 31/93 (33%) patients were non-responders, with post-biologic BASDAI dropping &amp;lt;2 from baseline. Of the non-responders, 13/31 (42%) patients switched or stopped biologic due to primary inefficacy at the first review after an average of 6.4 months, while the remaining 18/31 (58%) patients were kept under review for another 6-12 weeks. 9/18 (50%) improved on average 8.1 months after baseline and met NICE criteria to continue treatment; and 9/18 (50%) switched on average 29.9 months later with primary or secondary inefficacy, almost five times longer than those switched immediately (p=0.0009). 7/13 (54%) who switched due to primary inefficacy switched between anti-TNF and anti-IL-17 classes, whereas all five patients with secondary inefficacy switched between biologic classes. Notably, 19% of poor responders were current smokers compared to 8% of excellent responders (p=0.0004). The remaining 12/93 (13%) patients were classified as sub-optimal responders. Of these, 5/12 (42%) patients switched to a second anti-TNF after an average 12.4 months. 7/12 (58%) patients continued with their first biologic. Pre-biologic, four patients had high CRPs (≥5mg/L) and eight had normal CRPs (&amp;lt;5mg/L). There was no change between these categories for seven patients who had CRP checked during their sub-optimal response. Conclusion Our research shows that clinicians’ decisions with sub-optimal biologic response vary, with a 42:58 split between patients switching or persevering with their biologic treatment. It appears that if patients are going to respond, they should do so within eight months and non-responders should be switched at that point to avoid poor outcomes. Smoking is a known poor prognostic factor which might suggest we should switch sooner with sub-optimal response, but we have been unable to show any benefit of the CRP in guiding management of sub-optimal responders. Disclosure E. Gates: None. M. Ho: None. C. Cavill: Honoraria; Abbvie, Eli Lilly, Novartis, Pfizer. R. Sengupta: Honoraria; Abbvie, Biogen, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB.

Prognostic factors and treatment responses among patients with gross residual disease in differentiated thyroid cancer.

Various postoperative staging systems were developed to assess the outcome of differentiated thyroid cancer from initial risk after surgery to dynamic changing prognosis during follow-up. The objective of our retrospective cohort study was to identify risk factors contributing to macroscopic positive surgical margin (R2 resection) and parameters in discriminating the treatment responses and prognosis among R2 patients. In total, 242 differentiated thyroid cancer patients with extrathyroidal extension who underwent a thyroidectomy at Kaohsiung Chang Gung Memorial Hospital between January 2013 and July 2018, were included. The patients were grouped according to the presence or absence of gross residual disease (R2). The R2 patients were further classified into two categories according to their treatment response into excellent and nonexcellent groups. The parameters and treatment outcomes were compared between these groups. The mean follow-up time was 45.3 months. Two hundred seven (85.5%) patients had either surgery-free or microscopic margins (R0/R1), while 35 (14.5%) had R2 resection. In the R2 group (n = 35), 15 (42.9%) patients achieved an excellent response, while 20 (57.1%) achieved a nonexcellent response. Statistically significant differences were observed in the extent of neck dissection, TSH-Tg level, post-RAI Tg level, nodal status, and recurrence between the two groups. The Kaplan-Meier curves for 5-year local and distant recurrence-free survival of R0/R1 versus R2 patients were 90.0% versus 66.3%, and 98.4% versus 90.7%, respectively ( p < 0.001). Among the R2 patients, the excellent responders had a higher local recurrence-free survival than nonexcellent responders (93.3% vs. 45.1%, p = 0.008). There are significant disparities in recurrence-free survival among R2 patients with different treatment responses. The nodal status of papillary thyroid cancer and thyroglobulin level after thyroidectomy and RAI were factors contributing to difference in their treatment responses.

Increased Body Mass Index Correlates with Less Favorable Postoperative Outcomes After Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea: A Retrospective Cohort Study

Obstructive sleep apnea is associated with high morbidity. Hypoglossal nerve stimulation (HNS) has become a novel (neuro-) surgical treatment strategy for obstructive sleep apnea, demonstrating good success rates. Beyond predefined inclusion and exclusion criteria, no precise data are available, enabling individual preoperative risk assessment. To improve preoperative risk stratification, this study analyzed individual patient factors that affect outcomes of HNS. Fourteen patients treated with unilateral HNS were analyzed retrospectively. Assessed risk factors included: hypertension, diabetes mellitus, depression, smoking, alcohol consumption, body mass index (BMI), and disease duration. Treatment success was defined as a reduction in the postoperative apnea-hypopnea index (AHI) to≤20 events/hour, with a relative reduction of at least 50% compared to baseline. A significant reduction in the postoperative apnea-hypopnea index was observed in all patients (P < 0.0001). BMI correlated significantly with postoperative AHI scores (95% confidence interval, 0.1519-0.8974; P= 0.018). Significant treatment success was observed in 50% of patients. Compared with the "Excellent Responder group," the "Responder group" demonstrated a significantly higher BMI (95% confidence interval, 1.174-6.226; P= 0.0078). Diabetes, hypertension, disease duration, smoking, depression, and alcohol consumption were not significantly associated with AHI reduction. Our findings suggest that BMI may be an independent risk factor for the response to HNS, with patients who had less benefit from therapy having significantly higher BMI than "Excellent Responders." Therefore, carefully selecting patients is crucial in obtaining optimal outcomes with HNS therapy, especially those with a high BMI.

Long-term clinical efficacy and safety of thalidomide in patients with transfusion-dependent β-thalassemia: results from Thal-Thalido study

Regular blood transfusion is the mainstay of treatment in transfusion-dependent β-thalassemia (TDT); however, transfusions culminate in an array of serious complications. Therefore, a single-arm, non-randomized clinical trial was conducted in hydroxyurea refractory TDT patients to explore the long-term safety and efficacy of thalidomide. The primary outcomes for efficacy were rise in hemoglobin (Hb) level and changes in transfusion frequency. Whereas, several clinical and laboratory parameters were assessed for safety of thalidomide. Secondary outcomes included changes in serum ferritin, serum lactate dehydrogenase (LDH), serum uric acid, red blood cell indices, and size of liver and spleen. A total of 532 patients were followed for a period of 30 months. Significant increase in mean Hb level was identified at 6 months (1.4 g/dL, p ≤ 0.001) and 30 months (2 g/dL, p ≤ 0.001) in comparison with baseline. A total of 408 (76.7%) patients responded to thalidomide therapy (excellent responders 25.8%, good responders 31%, and partial responders 19.9%) and attained transfusion independence within 6 months of therapy. A significant decline in mean ferritin, LDH level, liver size, and spleen size was observed. No unfavorable effects were observed on kidney and liver functions. Mild adverse events were reported in 48 (9%) patients and serious adverse events, including cerebral vascular accident and portal vein thrombosis were reported in two patients each. This study concludes that thalidomide is an effective and well-tolerated drug that can improve Hb levels and reduce transfusion burden in hydroxyurea refractory TDT patients.Trial registration: This trial is registered at http://www.clinicaltrial.gov as # NCT03651102.

Long-term effectiveness and predictors of bisphosphonate treatment in type I complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a painful disease that leads to chronic pain and disability. Bisphosphonates are largely used in the real-life for the treatment of CRPS, but data on long-term effectiveness and its predictors are lacking. We conducted a longitudinal observational study on patients with type I CRPS treated with IV neridronate (100 mg on 4 occasions). Clinical and demographic characteristics were collected at baseline, after 3 months (M3) and after 12 months (M12). Multivariable logistic regression was employed to determine the factors associated with long-term response to treatment. 103 patients with type I CRPS treated with IV neridronate were included in the study. Mean VAS pain at baseline was 79.1 mm and decreased significantly at M3 (-45.9 mm, 95% CI 40.1 to 51.8) and M12 (-61.6 mm, 95% CI 55.3 to 67.9). Hyperalgesia and allodynia resolved in 84.3% and 88.1% of patients at M12. Loss of motion resolved in 53.5% of patients. The predictors of excellent response were gender (male better), predisposing event to CRPS (no event being better than any predisposing event), site of CRPS (lower limb being better), and early response at M3 on VAS pain (2.5 times the chance of being excellent responder every 10 mm decrease). In this real-life study neridronate was associated with rapid and progressive improvement of symptoms of CRPS which was maintained up to 3 years of follow-up. The predictors of excellent response were early response, lower limb localisation, absence of predisposing events and male gender.

Impact of auricular percutaneous electrical nerve field stimulation on gut microbiome in adolescents with irritable bowel syndrome: A pilot study.

Percutaneous electrical nerve field stimulation (PENFS) has documented efficacy for irritable bowel syndrome (IBS) via plausible vagal neuromodulation effects. The vagus nerve may affect gut microbiome composition via brain-gut-microbiome signaling. We aimed to investigate gut microbiome alterations by PENFS therapy in adolescent IBS patients. A prospective study of females with IBS aged 11-18 years receiving PENFS therapy for 4 weeks with pre- and post-intervention stool sampling was conducted. Outcome surveys completed pre-therapy, weekly, and post-therapy included IBS-Severity Scoring System (IBS-SSS), Visceral Sensitivity Index (VSI), Functional Disability Inventory (FDI), and the global symptom response scale (SRS). Bacterial DNA was extracted from stool samples followed by 16S rRNA amplification and sequencing. QIIME 2 (version 2022.2) was used for analyses of α and β diversity and differential abundance by group. Twenty females aged 15.6 ± 1.62 years were included. IBS-SSS, VSI, and FDI scores decreased significantly after PENFS therapy (P < 0.0001, P = 0.0003, P = 0.0004, respectively). No intra- or interindividual microbiome changes were noted pre- versus post-therapy or between responders and non-responders. When response was defined by 50-point IBS-SSS score reduction, α diversity was higher in responders compared with non-responders at week 4 (P = 0.033). There was higher abundance of Blautia in excellent responders versus non-responders. There were no substantial microbial diversity alterations with PENFS. Subjects with excellent therapeutic response showed an enrichment of relative abundance of Blautia, which may indicate that patients with specific microbial signature have a more favorable response to PENFS.

RESPONSE TO INTRADERMAL ROUTE OF HEPATITIS B VACCINATION IN CHILDREN ON MAINTENANCE HEMODIALYSIS: A SINGLE CENTER EXPERIENCE

Background: To determine the response of intradermal route of hepatitis B vaccine (HBV) in pediatric dialysis patients. Material and Methods: Prospective, observational study carried out in the Hemodialysis Unit, Sindh Institute of Urology and Transplantation (SIUT), Karachi, from October 2021 to September 2022.Patients younger than 18 years, Hepatitis B surface antigen negative irrespective of primary vaccination status, were tested for anti-Hepatitis B antibody titers. Those with levels less than 10IU/L were recruited for intradermal vaccination at 0,1 and 6 months and titers rechecked in the 2nd and 7th month of study. Results: Of the 168 children screened, 81 (48%) patients were eligible for vaccination, however, 52 agreed to participate. Males were 27 (52%). Mean age was 12.18± 2.61 years. End-stage kidney disease due to unknown etiology was the most common cause in 27 (52%) patients with mean dialysis duration being 1.43±1 years. Most, 48 (92%) patients were hypertensive and majority, 47 (90%) patients tested negative for hepatitis C. Final analysis was done on 38 patients. Thirty-four (89.4%) patients responded; 25 (65.8%) being good and excellent responders. Mean antibody titers before intradermal vaccination of 2.87±3 IU/L improved to 383±397 IU/L. Ages 11-15 years showed a statistically significant association with the development of anti-Hepatitis B antibody titers (p value: 0.02) while gender, dialysis duration, pre-vaccination HBs titers, hepatitis C status, hypertension and cause of end-stage kidney disease did not have any effect. Conclusion: ID route of HBV is efficacious in producing seroprotective anti-HBs titers in pediatric ESKD patients. Children 11-15 years had more robust response. Keywords: Children, Hemodialysis, Hepatitis B, Intradermal, Vaccination

Abstract P1-05-15: DCE-MRI for early prediction of excellent response versus chemoresistance in triple negative breast cancer

Abstract PURPOSE Triple-negative breast cancer (TNBC) is a heterogeneous disease with variable response to neoadjuvant therapy (NAT). Pathologic complete response (pCR) has become a prognostic marker for overall and disease-free survival. The aim of this study was to determine if dynamic contrast-enhanced (DCE)-MRI after 2 and/or 4 cycles of NAT can identify patients with a high likelihood of achieving pCR, triaging them to standard of care (SOC), or, when appropriate, to de-escalation trials. Conversely, we aimed to identify chemoresistant tumors that are unlikely to achieve pCR and may benefit from escalated targeted trials. METHOD AND MATERIALS 309 patients with stage I-III TNBC underwent DCE-MRI (temporal resolution: 9-12 sec) at baseline (BL), 2 cycles (C2), and 4 cycles (C4) of SOC doxorubicin/cyclophosphamide (AC) NAT as part of a prospective IRB-approved study (NCT02276443). Tumor volumes of the index lesion were calculated using 3 axis measurements during the early phase of the DCE-MRI (60s). Percent tumor volume reduction (TVR) between BL, C2, and C4 was calculated. Patients were randomly assigned to a training or a validation cohort in a 1:1 ratio. pCR was assessed at surgery after completion of SOC NAT. Correlation between pCR and TVR was evaluated using ROC analysis. RESULTS Of 309 TNBC patients, 136 (44%) achieved pCR. Following 2 cycles of NAT, TVR &amp;gt;80% was predictive of pCR (chemosensitivity), while TVR ≤ 55% was predictive of non-pCR (chemoresistance) with PPV 80%, NPV 89%, AUC 0.811 (0.73~0.893, p&amp;lt; 0.0001) in the training cohort, and PPV 82%, NPV 85%, AUC 0.815 (CI:0.736~0.894, p&amp;lt; 0.0001) in the validation cohort. Following 4 cycles of NAT, TVR &amp;gt;90% was predictive of pCR, while TVR ≤80% was predictive of non-pCR with PPV 80%, NPV 84%, AUC 0.827 (0.756~0.898, p&amp;lt; 0.0001) in the training cohort and with PPV 73%, NPV 82%, AUC 0.785 (CI:0.709~0.862, p&amp;lt; 0.001) in the validation cohort. Using this model, the pCR status was correctly classified in 50% of TNBC patients using C2 DCE-MRI in the training cohort, and 54% in the validation cohort. Only 8% were misclassified in the training cohort, and 10% in the validation cohort. Using C4 DCE-MRI, the pCR status of 61% and 57% of TNBC was correctly classified in the validation and the testing cohorts, respectively. 12% were misclassified in the validation cohort, and 21% in the testing cohort. CONCLUSION DCE-MRI after 2 and 4 cycles of AC-based NAT correctly predicted the pCR status of 54% and 57% of TNBC patients, respectively, as either excellent responders or nonresponders with high AUC 0.811 and 0.827. This may allow patients to be triaged to SOC NAT with option of de-escalation or early targeted therapies for non-responders. Citation Format: Mary S. Guirguis, Beatriz Adrada, Miral Patel, Frances Perez, Rosalind Candelaria, Wei Yang, Jia Sun, Rania M. Mohamed, Medine Boge, H. T. Carisa Le-Petross, Jessica Leung, Gary J. Whitman, Deanna L. Lane, Marion E. Scoggins, Tanya Moseley, Benjamin Musall, Jason White, Sanaz Pashapoor, Peng Wei, Jong Bum Son, Ken-Pin Hwang, Bikash Panthi, Mark Pagel, Lei Huo, Kelly K. Hunt, Elizabeth Ravenberg, Alastair M. Thompson, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Stacy Moulder, Clinton Yam, Jingfei Ma, Gaiane Rauch. DCE-MRI for early prediction of excellent response versus chemoresistance in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-15.

Staging Breast Cancer with MRI, the T. A Key Role in the Neoadjuvant Setting.

Breast cancer (BC) is the most common cancer among women worldwide. Neoadjuvant chemotherapy (NACT) indications have expanded from inoperable locally advanced to early-stage breast cancer. Achieving a pathological complete response (pCR) has been proven to be an excellent prognostic marker leading to better disease-free survival (DFS) and overall survival (OS). Although diagnostic accuracy of MRI has been shown repeatedly to be superior to conventional methods in assessing the extent of breast disease there are still controversies regarding the indication of MRI in this setting. We intended to review the complex literature concerning the tumor size in staging, response and surgical planning in patients with early breast cancer receiving NACT, in order to clarify the role of MRI. Morphological and functional MRI techniques are making headway in the assessment of the tumor size in the staging, residual tumor assessment and prediction of response. Radiomics and radiogenomics MRI applications in the setting of the prediction of response to NACT in breast cancer are continuously increasing. Tailored therapy strategies allow considerations of treatment de-escalation in excellent responders and avoiding or at least postponing breast surgery in selected patients.

Excellent Response to OnabotulinumtoxinA: Different Definitions, Different Predictors.

The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle.

Optimizing the dynamic treatment regime of in-hospital warfarin anticoagulation in patients after surgical valve replacement using reinforcement learning.

Warfarin anticoagulation management requires sequential decision-making to adjust dosages based on patients' evolving states continuously. We aimed to leverage reinforcement learning (RL) to optimize the dynamic in-hospital warfarin dosing in patients after surgical valve replacement (SVR). 10408 SVR cases with warfarin dosage-response data were retrospectively collected to develop and test an RL algorithm that can continuously recommend daily warfarin doses based on patients' evolving multidimensional states. The RL algorithm was compared with clinicians' actual practice and other machine learning and clinical decision rule-based algorithms. The primary outcome was the ratio of patients without in-hospital INRs &gt;3.0 and the INR at discharge within the target range (1.8-2.5) (excellent responders). The secondary outcomes were the safety responder ratio (no INRs &gt;3.0) and the target responder ratio (the discharge INR within 1.8-2.5). In the test set (n = 1260), the excellent responder ratio under clinicians' guidance was significantly lower than the RL algorithm: 41.6% versus 80.8% (relative risk [RR], 0.51; 95% confidence interval [CI], 0.48-0.55), also the safety responder ratio: 83.1% versus 99.5% (RR, 0.83; 95% CI, 0.81-0.86), and the target responder ratio: 49.7% versus 81.1% (RR, 0.61; 95% CI, 0.58-0.65). The RL algorithms performed significantly better than all the other algorithms. Compared with clinicians' actual practice, the RL-optimized INR trajectory reached and maintained within the target range significantly faster and longer. RL could offer interactive, practical clinical decision support for sequential decision-making tasks and is potentially adaptable for varied clinical scenarios. Prospective validation is needed. An RL algorithm significantly optimized the post-operation warfarin anticoagulation quality compared with clinicians' actual practice, suggesting its potential for challenging sequential decision-making tasks.

Abstract 1175: Spatially resolved transcriptomics to understand mechanisms of response to neoadjuvant chemotherapy

Abstract Background: Clinical response to therapy of patients diagnosed with high-grade serous ovarian carcinoma (HGSC) is highly variable. Mechanisms underlying response to treatment are not well understood. We previously performed bulk multi-omics analysis aimed at identifying biological differences between poor (PR) and excellent responders (ER) to neoadjuvant chemotherapy (NACT). Although differences were found, these were not as extensive as we had anticipated, suggesting that important molecular differences between such tumors may not be fully evident by bulk analyses. Thus, we carried out in-depth spatial analysis of HGSC to explore heterogeneity of disease and determine how the dynamic behavior between the tumor and the tumor microenvironment varies between PR and ER groups. Methods: We selected a cohort of patients with highly annotated HGSC samples categorized by response to NACT (PR and ER) and analyzed pre-treatment tumor tissues using bulk RNA sequencing (bRNASeq) and Visium Spatial Gene Expression. The definition of PR was stable or progressive disease after 3-4 cycles and/or suboptimal interval cytoreduction after NACT. ER was complete response or only microscopic disease left at the time of interval surgery. Results: To generate expression profiles, we used an unsupervised approach and identified nine distinct clusters, with at least 20 cell types. A comparison of the cell populations identified more stroma-dominated cell groups in the PR group. ER tumors contained more immune-related areas, with a high proportion of T, B and natural killer cells. This finding supports the established role of cytotoxic immune cells in strengthening chemotherapy response and better overall survival. In comparison with bRNASeq, we observed a blending phenomenon that hides deeper heterogeneity of the tumor. Some pathways, such as epithelial-mesenchymal transition (EMT), were statistically enriched in specific clusters of PR compared with the ER group, proving that deep characterization of tumor heterogeneity can be achieved only when exploring specific clusters of cells. The spatial distribution of the clusters showed that in the PR group, the clusters tended to be physically larger and distributed throughout the whole tissue. The ligand-receptor analysis revealed that co-expression of specific ligand-receptor pairing exists depending on their geographical localization, with closer interactions leading to stronger co-expression patterns. Conclusion: Two important findings emerged: importance of the stromal component as a potential driver of poor response to NACT; and identification of differential clusters (distribution and composition) in ER compared with PR tissues. Comparison of the in situ technique with bRNASeq allowed characterization of specific cell subpopulations that might be important determinants of lack of response to therapy, representing candidate therapeutic targets. Citation Format: Elaine Stur, Sara Corvigno, Mingchu Xu, Ken Chen, Sanghoon Lee, Jinsong Liu, Emilly Ricco, Nicole Fleming, Emine Bayraktar, Daniel Kraushaar, Jianhua Zhang, Anil K. Sood. Spatially resolved transcriptomics to understand mechanisms of response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1175.

Abstract 5738: Transcriptomic profiles of response to neoadjuvant chemotherapy in patients with high-grade serous ovarian cancer

Abstract Background: High-grade serous ovarian cancer (HGSC) is the most aggressive epithelial ovarian cancer, exhibiting tumor heterogeneity, molecular abnormality, and variable clinical outcomes. The heterogeneity and apparent adaptability of the HGSC genome under selective pressure by chemotherapy likely explain the high rates of drug resistance in HGSC. However, the underlying mechanisms of drug resistance are not well understood. Following our previous findings of significant distinct molecular and cellular characteristics in pre-treatment tumor samples from highly clinically annotated HGSC patients who received neoadjuvant chemotherapy (NACT), we examined post-treatment transcriptomic changes associated with excellent or poor responders to NACT in HGSC patients. Methods: Thirty tumor tissues (pre- and post-treatment) after 3 to 4 cycles of NACT were collected from HGSC patients at interval cytoreductive debulking surgery from the following groups: excellent response to NACT with carboplatin/paclitaxel (post-ER, n=8); poor response to NACT (post-PR, n=8). Primary or metastatic sites for each patient were obtained (n=13, post-ER; n=17, post-PR) and subjected to RNA sequencing. The downstream bioinformatics analysis was then performed and compared with the data from the matched pre-NACT samples from the same patients (Lee et al., Cell Reports, 2020). Results: We identified a total of 9,764 upregulated and 2,762 downregulated differentially expressed genes (DEGs, absolute log2FC &amp;gt;=2, adj-p&amp;lt;0.05) in the post-NACT samples vs the pre-NACT samples in the ER group. In contrast, 11,246 upregulated and 1,320 downregulated DEGs were found in the NACT-PR group. Ovarian cancer-related genes, including KRAS, NRAS, BRCA1/2, RB1, NF1, MLH1, PIK3CA, MSH2, AKT1, and NOTCH3 were differentially expressed in post-NACT vs pre-NACT in both ER and PR groups. TP53 was exclusively upregulated in post-ER vs pre-ER, and GABRA6 was exclusively upregulated in post-PR vs pre-PR. In signaling pathway analysis, apoptosis and DNA repair-related pathways were exclusively downregulated in post-ER vs pre-ER. Interestingly, the percentage of immune cells − CD8 and macrophages M0 were significantly elevated in post-ER (p&amp;lt;0.05), while γδ T cells and activated dendritic cells were significantly decreased in the post-ER (p&amp;lt;0.05), not in the PR. Neutrophil cells were significantly lower in post-PR vs pre-PR, but not in ER group. We also found that the level of ESR1 decreased significantly in post-ER vs post-PR (p&amp;lt;0.05). The level of PAX8 significantly increased in post-PR vs post-ER (p&amp;lt;0.05). Conclusions: Our transcriptomic analysis revealed distinct transcripts changes in post-NACT vs pre-NACT tumor tissues from HGSC patients with excellent or poor response to the NACT. These findings could enhance treatment decision-making and rationale for developing alternative therapies for patients with HGSC. Citation Format: Sanghoon Lee, Li Zhao, Nicole D. Fleming, Joseph Celestino, Richard A. Hajek, Margaret B. Morgan, Yan Liu, Shannon N. Westin, Amir A. Jazaeri, Jinsong Liu, Jianhua Zhang, P Andrew Futreal, Anil K. Sood. Transcriptomic profiles of response to neoadjuvant chemotherapy in patients with high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5738.

Modified dynamic risk stratification system further predicts individual outcome in patients with intermediate-risk papillary thyroid cancer

ObjectiveWe assessed the contribution of initial treatment response to further refining prediction of individual outcomes in intermediate-risk papillary thyroid cancer (PTC) on the American Thyroid Association (ATA) risk stratification system. Dynamic risk stratification (DRS) as originally proposed by Tuttle et al. in 2010 was modified to also include serum antithyroglobulin antibodies (TgAb) as a surrogate marker of the likelihood of persistent disease, specifically in patients with thyroglobulin assay interference by TgAb. MethodsThree hundred and seventy-three patients with ATA intermediate-risk PTC were enrolled retrospectively upon reviewing medical records. Patients were followed at the National Cancer Institute in Bogota, Colombia after being treated with total thyroidectomy and I-131 therapy between 2009 and 2013. Best response to initial therapy was classified as excellent, indeterminate, biochemically incomplete or structurally incomplete. Final disease status after a median follow-up of 7.1 years was classified as no evidence of disease (NED), indeterminate, or persistent disease (either biochemically or structurally). The rate of recurrence was determined in excellent responders. ResultsExcellent response was achieved by 164 patients (43.9%). At a median follow-up of 42 months, 19 (11.6%) had experienced recurrence. 87.4% of initially excellent responders available at the final checkpoint were NED, compared to 28% of those with biochemically or structurally incomplete response and to 60.2% of all ATA intermediate-risk PTC patients in our cohort. ConclusionsModified DRS further predicted individual outcomes in intermediate-risk PTC, potentially allowing ongoing management to be tailored accordingly.

Spatially resolved transcriptomics of high-grade serous ovarian carcinoma

SummaryBulk and single-cell RNA sequencing do not provide full characterization of tissue spatial diversity in cancer samples, and currently available in situ techniques (multiplex immunohistochemistry and imaging mass cytometry) allow for only limited analysis of a small number of targets. The current study represents the first comprehensive approach to spatial transcriptomics of high-grade serous ovarian carcinoma using intact tumor tissue. We selected a small cohort of patients with highly annotated high-grade serous ovarian carcinoma, categorized them by response to neoadjuvant chemotherapy (poor or excellent), and analyzed pre-treatment tumor tissue specimens. Our study uncovered extensive differences in tumor composition between the poor responders and excellent responders to chemotherapy, related to cell cluster organization and localization. This in-depth characterization of high-grade serous ovarian carcinoma tumor tissue from poor and excellent responders showed that spatial interactions between cell clusters may influence chemo-responsiveness more than cluster composition alone.