Responder Group Research Articles

MP28-13 PERIPHERAL FUCOSYLATED HAPTOGLOBIN FEATURES PREDICT DURABLE RESPONSES TO ANTI-PD-1 THERAPY IN ADVANCED RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023MP28-13 PERIPHERAL FUCOSYLATED HAPTOGLOBIN FEATURES PREDICT DURABLE RESPONSES TO ANTI-PD-1 THERAPY IN ADVANCED RENAL CELL CARCINOMA Taigo Kato, Koichi Morishita, Eisuke Tomiyama, Kazutoshi Fujita, Yu Ishizuya, Yoshiyuki Yamamoto, Koji Hatano, Atsunari Kawashima, Eiji Miyoshi, and Norio Nonomura Taigo KatoTaigo Kato More articles by this author , Koichi MorishitaKoichi Morishita More articles by this author , Eisuke TomiyamaEisuke Tomiyama More articles by this author , Kazutoshi FujitaKazutoshi Fujita More articles by this author , Yu IshizuyaYu Ishizuya More articles by this author , Yoshiyuki YamamotoYoshiyuki Yamamoto More articles by this author , Koji HatanoKoji Hatano More articles by this author , Atsunari KawashimaAtsunari Kawashima More articles by this author , Eiji MiyoshiEiji Miyoshi More articles by this author , and Norio NonomuraNorio Nonomura More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003256.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: With the spread of immune checkpoint inhibitors (ICIs), it is urgent to pursue novel noninvasive biomarkers of responses to ICIs that allow the “early” determination of clinical benefits. Recently, immune cells in the tumor microenvironment are thought to produce fucosylated haptoglobin as a result from immunohistochemical study (IHC) associating with tumor immunity. Thus, the evaluation of fucosylated haptoglobin in the peripheral blood has the potential to demonstrate noninvasive predictive biomarkers for the clinical efficacy of ICIs. METHODS: In this study, a total of 31 advanced renal cell carcinoma (RCC) patients treated with PD-1 antibody (Nivolumab) were enrolled and defined as the patients of responder (CR, PR and long SD, n=21) and non-responder (Short SD and PD, n=10) by RECIST criteria. We collected plasma samples before and 1, 3 months after starting treatment and performed ELISA analysis of plasma samples using 10-7G monoclonal antibody that specifically recognizes fucosylated haptoglobin. RESULTS: We first measured total haptoglobin (tHP) before anti-PD-1 therapy and the tHP value could not predict the clinical response. Interestingly, we found that median of plasma 10-7G values was significantly higher in responder group (p=0.031, Figure 1A). When we focused on the utility of 10-7G values for distinguishing PD with ICI treatment, PD patients had significantly higher 10-7G values compared to patients with CR, PR, and SD (p=0.0006, Figure 1B). We also confirmed the utility of 10-7G values for the predicting PD with ICI treatment (the area under the curve 0.816, Figure 1C). Accordingly, the overall survival rate was significantly correlated with the high 10-7G values (p=0.0011). CONCLUSIONS: Plasma fucosylated haptoglobin levels represent a novel biomarker that reflects predicting clinical efficacy of ICIs in advanced RCC. Source of Funding: This work was supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research (C), grant number 21K09343 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e376 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Taigo Kato More articles by this author Koichi Morishita More articles by this author Eisuke Tomiyama More articles by this author Kazutoshi Fujita More articles by this author Yu Ishizuya More articles by this author Yoshiyuki Yamamoto More articles by this author Koji Hatano More articles by this author Atsunari Kawashima More articles by this author Eiji Miyoshi More articles by this author Norio Nonomura More articles by this author Expand All Advertisement PDF downloadLoading ...

High tumor mutational burden predicts favorable response to anti-PD-(L)1 therapy in patients with solid tumor: a real-world pan-tumor analysis

BackgroundTumor mutation burden (TMB) is an important biomarker to predict response to anti-PD-L1 treatment across cancer types. TruSight Oncology 500 (TSO500) is currently used globally as a routine assay for...

MP24-04 RANDOMIZED PLACEBO-CONTROLLED N-OF-1 TRIALS OF TAMSULOSIN FOR LOWER URINARY TRACT SYMPTOMS

You have accessJournal of UrologyCME1 Apr 2023MP24-04 RANDOMIZED PLACEBO-CONTROLLED N-OF-1 TRIALS OF TAMSULOSIN FOR LOWER URINARY TRACT SYMPTOMS Kevin Li, Scott Bauer, Stacey Kenfield, Kaiwei Lu, Charles McCulloch, Michael Steinman, Akinyemi Oni-Orisan, Natalie Rios, Anthony Enriquez, and Benjamin Breyer Kevin LiKevin Li More articles by this author , Scott BauerScott Bauer More articles by this author , Stacey KenfieldStacey Kenfield More articles by this author , Kaiwei LuKaiwei Lu More articles by this author , Charles McCullochCharles McCulloch More articles by this author , Michael SteinmanMichael Steinman More articles by this author , Akinyemi Oni-OrisanAkinyemi Oni-Orisan More articles by this author , Natalie RiosNatalie Rios More articles by this author , Anthony EnriquezAnthony Enriquez More articles by this author , and Benjamin BreyerBenjamin Breyer More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003249.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Alpha blockers such as tamsulosin are considered 1st line for lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). Despite widespread use, their efficacy versus placebo is modest/highly variable and adverse effects including orthostatic hypotension/falls in older men are costly. A personalized approach can identify patients in whom benefits outweigh harms and those who can be deprescribed without worsening LUTS or causing complications. METHODS: We conducted placebo-controlled N-of-1 trials in men ≥55 on tamsulosin ≥12 months for BPH. To ensure tolerance of tamsulosin discontinuation, all men completed a one week run-in without taking tamsulosin or study pills. Participants then completed 2 block-randomized cycles, each comprised of two 2-week treatment periods of tamsulosin/placebo separated by 1 week of washout on placebo, and completed daily symptom assessment on REDCap (International Prostate Symptom Score (IPSS) modified for 24 h recall). Linear mixed models adjusted for treatment period were used to calculate predicted random effects, representing the mean effect of tamsulosin for each participant. RESULTS: 30/71 eligible patients contacted were enrolled. 4 failed run-in and were excluded. The remaining 26 were grouped by mean change in daily IPSS on tamsulosin vs. placebo and categorized as minimal (11/26, 42%), moderate (11/26, 42%), or strong responders (4/26, 15%) based on preset cutoffs (Figure 1). Demographics, social/health-related behaviors, and medical history except coronary artery disease (p = 0.005) were similar across groups (Table 1). Responder groups significantly differed in perceived fatigue from LUTS (p=0.024) at baseline. CONCLUSIONS: It is feasible to conduct placebo-controlled N-of-1 trials in older men receiving tamsulosin using daily symptom reporting. Patients identified as minimal responders are candidates for deprescribing and alternative interventions. Source of Funding: UCSF-RAP © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e318 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kevin Li More articles by this author Scott Bauer More articles by this author Stacey Kenfield More articles by this author Kaiwei Lu More articles by this author Charles McCulloch More articles by this author Michael Steinman More articles by this author Akinyemi Oni-Orisan More articles by this author Natalie Rios More articles by this author Anthony Enriquez More articles by this author Benjamin Breyer More articles by this author Expand All Advertisement PDF downloadLoading ...

Role of F-18 FDG PET/CT in Predicting Response to Neoadjuvant Chemotherapy in Invasive Ductal Breast Cancer.

The role of baseline and post-treatment standardized uptake value (SUVmax) values in predicting pathological response in patients with breast cancer after neoadjuvant chemotherapy (NAC). Thirty patients with invasive ductal breast cancer were included in this retrospective study. F-18 fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) examinations were performed before and after NAC. Pretreatment SUVmax (SUVmax I), post-treatment SUVmax (SUVmax II) and ΔSUVmax values of primary breast cancer were obtained. Breast tumor pathology preparations were examined for the evaluation of tumor response according to the Miller and Payne classification. Patients were grouped as responding to treatment (pCR) and unresponsive to treatment (nonpCR). In all analyses, p<0.05 was considered statistically significant. The mean age of the 30 patients included in the study was 51.2±11.98 years. In the study-defined grouping, 13 patients (43.3%) were nonresponders and 17 patients (56.7%) were responders. ΔSUVmax was significantly greater in the responders group compared to the nonresponders group, while SUVmax II was lower (p = 0.001 and p = 0.004, respectively). There was no significant difference between the responders and nonresponders in terms of age, tumor diameter, and SUVmax I values. Multivariate logistic regression analysis showed ΔSUVmax to be the only independent predictive factor for pCR. F-18 FDG PET/CT was an effective method in evaluating the treatment response after NAC in breast cancer, and ΔSUVmax and post-treatment SUVmax can be used to predict the response of the primary tumor to treatment.

Improving mental health and daytime function in adult insomnia patients predict cognitive behavioral therapy for insomnia effectiveness: A case-control study

ObjectiveThis study investigated demographic, sleep related symptoms and mental health status as predictors of clinically significant treatment responses to cognitive behavioral therapy in adults who have good adherence for the cognitive behavioral therapy for insomnia (CBT-I) program in primary insomnia. MethodsA total of 42 adults with primary insomnia disorder were treated with CBT-I at a university hospital from June 2020 to January 2021. Demographic variables were surveyed and sleep-related symptoms were measured using self-reported questionnaires before and after the intervention, comprising a 6-week interval. The treatment responder group was defined as patients with an Insomnia Severity Index change score >7 compared to baseline. Logistic regression and paired t-test examined whether these factors predicted treatment outcomes for CBT-I. ResultsDemographic variables did not predict treatment outcomes. Higher levels of anxiety were associated with a higher likelihood of treatment response (odds ratio [OR] = 1.234; confidence interval [CI]: 1.008–1.511). More severe insomnia at baseline was associated with a greater likelihood of treatment response (OR = 1.450; CI: 1.121–1.875). The lesser the dysfunctional beliefs and attitudes about sleep, the more effective the treatment response (OR = 0.943; CI: 0.904–0.984). Unlike the group of treatment responders, daytime function, depressive mood, and anxiety status did not improve in the group of treatment non-responders after CBT-I intervention. ConclusionsPatients with severe insomnia and anxiety at baseline should be treated more aggressively with CBT-I. During treatment, patients’ mental health problems and daytime activities should be continuously monitored, in order to help improve these problems which might strengthen the effectiveness of CBT-I.

Stimulation techniques and protocols for poor responders in IVF cycles, future prospective methods and techniques, precaution programs.

Purpose: To identify trends regarding approaches, currently used by IVF centers in Greece, in order to treat poor responders. Methods: A retrospective evaluation utilizing the results of a web-based survey was performed. Results: Responses from 36 IVF centers via a web-based survey in Greece was conducted to elucidate optimal treatment strategies of poor responders. IVF specialized Doctors of units with a median of 300 IVF cycles per year were asked to anonymously fill in a set of questions on this complex topic. Results were analyzed, treatment strategies or combinations of protocols or adjuvant therapies used were compared. Also compared number of oocytes retrieved, as well as fertility and pregnancy rates among various IVF centers, based on their responses. A total of 36 centers participated in our survey, (from total 59 IVF centers) forming a web-based questionnaire. Due to responses on question if they observe an increase in the prevalence of poor responders ranging from: 1 - 3 % (8.6%, n=3), 4 - 9% ,(11.1% ,n=4), mainly 20% (47.21% ,n=17), but also greater than 20% (33.3% ,n=12) in total of cases treated in Greek IVF centers. Also, the most common age group of poor responders is 40-50 years of age according to 80%(n=29) of respondents. (Table 1). The review of international medical literature compared with answers received to our questionnaire suggests that no ideal treatment stimulation protocol exist. The following protocols have been described and compared:1).Long protocol with Agonist (25.%,n=9)2).Short protocol with Antagonist (52.8%,n=19)3).Short protocol with Agonist (19.4%,n=7)4).Stimulation only with Gonadotropins (5.6%,n=2)5).Natural Cycle (66.7%,n=24)6).Flare-up protocol (13.9%,n=5)7).Duo-Stim Protocol (11.1%9,n=4)8).Delayed start protocol (11.% ,n=4)9).Protocol with cofifollitropine (13.9%,n=5)10). Clomiphene Citrate Protocol with or without Gonadotropins (41.7%, n=15)11). Clomiphene Citrate Protocol with or without Aromatase inhibitors (19.4%, n=7)12).Letrozole with or without recombinant FSH GnRH Antagonist Use (2.8%, n=1)13). Letrozole with Clomiphene Citrate plus FSH &amp; LH (2.8%, n=1)14). Letrozole with FSH &amp; LH plus GnRH antagonist (2.8%, n=1)15).Protocol with Antagonists in combination with Letrozole(27.8%,n=10) . (Table 2). We also represent results regarding the use of adjuvant treatment modalities to further improve results of stimulation cycles such as: a)Oestrogens(52.2%,n=12),b)Growth Hormone (4.3%,n=1),c)Testosterone (8.7%,n=2),d)Co-enzyme Q10 (56.5%,n=13),e)DHEA (78.3%,n=18). (Table 3). All available therapeutic strategies used and according to international literature and in accordance with data derived from Greek IVF centers, oocyte harvesting ranges at low levels, around 2 to 4 oocytes (88.6% ,n=3), 0-1 (8.6%,n=3), 5-8 (11.4%,n=4) and none of the IVF specialists collected more than 8 oocytes. Oocyte quality is also compromised, in (54.3%, n=19) only one oocyte of A quality was harvested, while 2 and 0, 3 or 4 oocytes of A quality were collected in (49.2%,n=15)and(5.7%,n=2).(Table 4.) , according with data fully verifying the term poor responders. Moreover, we observed that abortion rates are increased &gt;20% (41.2%, n=14), 10-20% (29.4%,n=10), 5-10% (11.8%,n=4) and 1-5% (17.6%,n=6) )(Table 5), as well as pregnancy rates are affected 5-10% (29.4%,n=10) and 10-20% (29.4%,n=10) )(Table 6), while percentages of live pregnancies over 20% is observed in (17,6%,n=6) and under 6% in (23.5%,n=8)(Table 7). Conclusion: All responses from the IVF specialists demonstrate the difficulty of treating this heterogenic group of subfebrile women. The egg donation is the treatment with increased success rate in comparison with different used treatments with agonists , antagonists cc, natural cycle, adjuvant treatments , the success rates of treatment in poor responders in IVF stimulation fluctuates from 7 to 24%. Prognosis is further improved if IVF specialist proposes and proceeds timely to the proper individualized therapeutic strategy.

Evaluation of the Clinical Features and Laboratory Data of Patients with Severe Eosinophilic Asthma Classified as Super-Responders, Partial Responders, or Nonresponders to Mepolizumab Treatment: A Real-Life Study

Introduction: Mepolizumab is a treatment option in patients with severe eosinophilic asthma, which inhibits interleukin-5. The aim of this study was to evaluate the clinical features and laboratory data of patients with severe eosinophilic asthma who were classified as super-responders, partial responders, or nonresponders to mepolizumab treatment. Methods: In this retrospective real-life study, the clinical features and laboratory data were compared between groups of patients with severe eosinophilic asthma who were classified as super-responders, partial responders, or nonresponders to mepolizumab treatment. Results: Evaluation was made of a total of 55 patients, comprising 17 (30.9%) males and 38 (69.1%) females with a mean age of 51.28 ± 14.32 years. All the patients were receiving mepolizumab treatment for severe eosinophilic asthma, with 17 (30.9%) patients evaluated as super-responders, 26 (47.3%) as partial responders, and 12 (21.8%) as nonresponders. After mepolizumab treatment, there was a statistically significant decrease in asthma exacerbations, the number of oral corticosteroids (OCSs) used, the rate of hospitalization due to asthma attacks, and the eosinophil count (cells/µL) (p < 0.001, p < 0.001, p < 0.001, and <0.001, respectively). A statistically significant increase was determined in the forced expiratory volume in 1 s (FEV1) value (p = 0.010) and asthma control test (ACT) score (p < 0.001) after mepolizumab treatment. The baseline eosinophil count, eosinophil/lymphocyte ratio and FEV1 (%) values were significantly higher in the super-responder and partial responder groups (p < 0.001, p = 0.002, and p = 0.002, respectively). The baseline ACT score and the rate of chronic sinusitis with nasal polyps were significantly higher in the partial responder group (p = 0.004, p = 0.015, respectively). The rate of regular OCS use before mepolizumab treatment was significantly higher in the nonresponder group (p = 0.049). As a result of the receiver operating characteristics curve analysis, the blood eosinophil count (area under the curve [AUC]: 0.967, p < 0.001), eosinophil/lymphocyte ratio (AUC: 0.921, p < 0.001), and FEV1 (%) (AUC: 0.828, p = 0.002) were found to have diagnostic value in predicting the response to mepolizumab treatment in patients with severe eosinophilic asthma. Conclusion: Baseline eosinophil count, eosinophil/lymphocyte ratio, and FEV1 (%) were found to be important predictors of response to mepolizumab treatment. Further studies are needed to define the characterization of mepolizumab responders in the real world.

Safety and real-world efficacy of lemborexant in the treatment of comorbid insomnia

AimTo investigate the real-world effectiveness and safety of lemborexan for treating comorbid insomnia associated with other psychiatric disorders, and whether lemborexant helps reduce the dose of benzodiazepines (BZs). MethodsThis retrospective observational study was conducted on outpatients and inpatients treated by physicians of Juntendo University Hospital Mental Clinic between April 2020 and December 2021. ResultsData of 649 patients who were treated with lemborexant were eventually enrolled. About 64.5% of patients were classified as the responder group. Response rates of ≥60% were recorded for most psychiatric disorders. Upon administration of lemborexant, diazepam-equivalent dose of BZs had been significantly reduced in participants (3.7 ± 8.2 vs. 2.9 ± 7.9, p < 0.001). The results of logistic regression analysis showed that outpatient (odds ratios: 2.310; 95% confidence interval [CI]: 1.32–4.05), shorter duration of BZ use (<1 year) (odds ratios: 1.512; 95% CI: 1.02–2.25), no adverse events (odds ratios: 10.369; 95% CI: 6.13–17.54), larger reduction of diazepam-equivalent dose of BZs upon introducing lemborexant prescription (odds ratios: 1.150; 95% CI: 1.04–1.27), and suvorexant was the replacement drug (odds ratios: 2.983; 95% CI: 1.44–6.19), which were significant predictors of good response. ConclusionAlthough this is a retrospective and observational study with many limitations, our study results suggest that lemborexant is effective and safe.

Normal Pressure Hydrocephalus Following Cranial Radiation: Identification of Shunting Responders

We examined cognitive, brain MRI, and lumbar infusion test (LIT) features to identify predictors of response to ventriculoperitoneal shunting (VPS) in long-term cancer survivors with suspected normal pressure hydrocephalus (NPH) following cranial radiotherapy (RT). Patients who completed cranial RT at least 2 years before with clinically suspected NPH and an Evans' index (EI) ≥ 0.30 underwent a cognitive and a cerebrospinal fluid (CSF) volumetric (MRI) analysis (n = 36). For those in whom VPS was placed (n = 14), we explored whether adding a CSF volumetric analysis to classical MRI and LIT (Tap Test) features would better identify VPS responders. Nearly 80% exhibited cognitive impairment. The CSF volume at NPH diagnoses was significantly larger in the group of VPS responders (p = 0.04). The addition of CSF volume to NPH diagnoses increased accuracy to 93%, with a positive and negative predictive value of 91% and 100%, respectively. The addition of a quantitative MRI analysis of CSF volume to classical MRI and LIT NPH criteria, along with a high clinical suspicion of NPH, may help to identify VPS responders, thus improving the clinical management and prognosis of long-term survivors.

Peripheral lymphocyte fluctuation as an indicator of severe immune-related adverse events in patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have proven to be effective treatments for various cancers, but can also elicit immune-related adverse events (irAEs). Given that severe irAEs can be life-threatening, biomarkers that can predict the occurrence of irAEs are of paramount importance. ICIs affect the dynamics of lymphocytes, and alterations in these dynamics may play a role in the development and severity of irAEs. The aim of this study was to investigate the correlation between irAEs and changes in lymphocyte counts. Information on irAEs was collected from 226 ICI cases from 2014 to 2020. We compared lymphocyte counts before treatment and at the onset of irAE and investigated the association between lymphocyte count fluctuations and the presence and severity of irAE, the course after steroid treatment, and overall survival. Of the 226 cases, 27 patients developed grade 3 or higher irAE. Compared to the other groups, the lymphocyte count in this group was significantly decreased at the time of irAE (p < 0.01). There was a trend toward a rapid increase in lymphocyte count in the steroid responder group compared to the non-responder group. Regarding overall survival, patients with irAE had significantly longer survival than those without irAE (p=0.0025). However, there was no association between changes in lymphocyte count and survival in patients with irAE. The percentage change in lymphocyte count was found to correlate with the incidence of severe irAEs. Close monitoring of the patient's condition is crucial when the lymphocyte count decreases during ICI treatment.

Prognostic factors in the treatment of androgenetic alopecia with minoxidil

Introduction. Androgenetic alopecia (AGA) is the most common type of alopecia, characterized by diffuse progressive thinning of the hair in the fronto-parietal area in patients with a genetic predisposition. Topical minoxidil remains the primary pharmacological treatment for AGA both in men and women. The efficacy in hair regrowth is reported to be between 40 and 50%.Aim. To evaluate prognostic factors of minoxidil response in AGA patients.Matherials and methods. The prospective open study was carried out. Thirty participants with AGA were enrolled and completed the study (twenty one women I–II Ludwig stage and nine men I–III Hamilton – Norwood stage). Primary outcomes consisted of measuring of hair density, telogen hair rate, the percentage of vellus hairs and hair diameter at baseline and repeated at 4 months. The SULT1A1 enzyme activity and the concentration of ATP in plucked hairs were measured at baseline. Patients were treated with 5% topical minoxidil applying daily for 4 months. In order to investigate prognostic factors in groups of responders and non-responders to minoxidil treatment these measured morphometric and biochemical characteristics were assessed.Results. After 4 months of treatment 77% of patients demonstrated hair regrowth and improvement of hair density, hair diameter and decrease of vellus hairs level. The SULT1A1 enzyme activity (p = 0.0008), the concentration of ATP (p = 0.004) in plucked hairs and baseline total hair density (p = 0.01) was significantly lower in group of non-responders compared to group of responders. The study demonstrated strong positive correlation between SULT1A1 enzyme activity and increase of total hair density (r = 0.7, р = 0.00002); moderate positive correlation was founded between concentration of ATP and increase of total hair density (r = 0.6, р = 0.0004).Conclusion. The negative prognostic factors for minoxidil treatment of AGA include SULT1A1 enzyme activity, concentration of ATP in plucked hairs and low total hair density at baseline.

New 6-Minute-Walking Test Parameter-Distance/Desaturation Index (DDI) Correctly Diagnoses Short-Term Response to Immunomodulatory Therapy in Hypersensitivity Pneumonitis.

6MWT parameters (distance, initial saturation, final saturation, desaturation, distance-saturation product (DSP), and DDI) were analyzed at baseline and after 3 to 6 months of treatment with corticosteroids alone or in combination with azathioprine. 91 consecutive HP patients diagnosed and treated in a single pulmonary unit from 2005 to 2017 entered the study. There were 44 (48%) males and 52 (57%) patients with fibrotic HP (fHP). Sixty-three patients (69%) responded to treatment (responders) and 28 (31%) did not respond (non-responders). In the responders group, all parameters assessed during 6MWT significantly improved, whereas in non-responders, they worsened. Medians (95% CI) of best indices were post-treatment DDI/baseline DDI-1.67 (1.85-3.63) in responders versus 0.88 (0.7-1.73) in non-responders (p = 0.0001) and change in walking distance-51 m (36-72 m) in responders, versus 10.5 m (-61.2-27.9) in non-responders (p = 0.0056). The area under the curve (AUC) of receiver operating characteristics (ROC) for post-treatment DDI/baseline DDI was 0.74 and the optimal cut-off was 1.075, with 71% of specificity and 71% of sensitivity. 6MWT may be used as a tool to assess and monitor the response to immunomodulatory therapy in HP patients, especially if indices incorporating both distance and desaturation are used. Based on the present study results, we recommend 6MWD and DDI use, in addition to FVC and TL,co, to monitor treatment efficacy in patients with interstitial lung diseases.

Zinc aspartate induces proliferation of resting and antigen-stimulated human PBMC under high-density cell culture condition

BackgroundZinc, one of the most important essential trace elements in the human body, regulates a wide range of cellular functions of immune cells, such as proliferation, differentiation and survival. Zinc deficiency affects both the innate and adaptive immune system. Zinc supplementation was discussed as possible therapy for infectious diseases and T cell-mediated autoimmune diseases. However, the influence of commercial zinc preparations on proliferation and cytokine production of resting and antigen-stimulated peripheral blood mononuclear cells (PBMC) has not yet been completely investigated. MethodsHere, we examined whether zinc aspartate (Unizink®), an approved drug to treat zinc deficiency in patients, induces proliferation, cytokine production, and induction of apoptosis/caspase 3/7 activity of resting PBMC under high-density cell culture condition. In addition, we performed antigen-specific proliferation experiments, where PBMCs of healthy donors vaccinated against Influenza A (H1N1) and/or SARS-CoV-2 were stimulated with Influenza A (H1N1) peptides or SARS-CoV-2 peptides as well as the Mixed Lymphocyte Culture (MLC) in the presence of increasing concentrations of zinc aspartate. ResultsWe observed a dose-dependent enhancement of proliferation and induction of cytokine production (IFN-γ, IL-5, GM-CSF and CXCL10) of resting PBMC in presence of zinc aspartate. The number of cells with active caspase 3/7 and, consecutively, the amount of cells undergoing apoptosis steadily decreased in presence of zinc aspartate. Moreover, zinc aspartate was capable of stimulating antigen-specific PBMC proliferation using MLC or influenza A (H1N1) and SARS-CoV-2 peptides in both a dose-dependent and a donor-specific manner. In the absence of zinc aspartate, we clearly could discriminate two groups of responders: low and high responders to antigenic stimulation. The addition of increasing concentration of zinc aspartate significantly stimulated the proliferation of PBMC from low responders, but not from high responders. ConclusionTaken together, our results suggest that zinc aspartate induces the proliferation of resting and antigen-stimulated PBMCs under high-density cell culture conditions. Thus, zinc might represent a supportive treatment in patients suffering from infectious diseases.

A New Signature That Predicts Progression-Free Survival of Clear Cell Renal Cell Carcinoma with Anti-PD-1 Therapy.

Immunotherapy has greatly improved the survival time and quality of life of patients with renal cell carcinoma, but the benefits are limited to a small portion of patients. There are too few new biomarkers that can be used to identify molecular subtypes of renal clear cell carcinoma and predict survival time with anti-PD-1 treatment. Single-cell RNA data of clear cell renal cell carcinoma (ccRCC) treated with anti-PD-1 were obtained from public databases, then 27,707 high-quality CD4 + T and CD8 + T cells were obtained for subsequent analysis. Firstly, genes set variation analysis and CellChat algorithm were used to explore potential molecular pathway differences and intercellular communication between the responder and non-responder groups. Additionally, differentially expressed genes (DEGs) between the responder and non-responder groups were obtained using the "edgeR" package, and ccRCC samples from TCGA-KIRC (n = 533) and ICGA-KIRC (n = 91) were analyzed by the unsupervised clustering algorithm to recognize molecular subtypes with different immune characteristics. Finally, using univariate Cox analysis, least absolute shrinkage and selection operator (Lasso) regression, and multivariate Cox regression, the prognosis model of immunotherapy was established and verified to predict the progression-free survival of ccRCC patients treated with anti-PD-1. At the single cell level, there are different signal pathways and cell communication between the immunotherapy responder and non-responder groups. In addition, our research also confirms that the expression level of PDCD1/PD-1 is not an effective marker for predicting the response to immune checkpoint inhibitors (ICIs). The new prognostic immune signature (PIS) enabled the classification of ccRCC patients with anti-PD-1 therapy into high- and low-risk groups, and the progression-free survival times (PFS) and immunotherapy responses were significantly different between these two groups. In the training group, the area under the ROC curve (AUC) for predicting 1-, 2- and 3-year progression-free survival was 0.940 (95% CI: 0.894-0.985), 0.981 (95% CI: 0.960-1.000), and 0.969 (95% CI: 0.937-1.000), respectively. Validation sets confirm the robustness of the signature. This study revealed the heterogeneity between the anti-PD-1 responder and non-responder groups from different angles and established a robust PIS to predict the progression-free survival of ccRCC patients receiving immune checkpoint inhibitors.

Identification of Specific Biomarkers and Pathways in the Treatment Response of Infliximab for Inflammatory Bowel Disease: In-Silico Analysis.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. In biological therapy, infliximab became the first anti-tumor necrosis factor (TNF) agent approved for IBD. Despite this success, infliximab is expensive, often ineffective, and associated with adverse events. Prediction of infliximab resistance would improve overall potential outcomes. Therefore, there is a pressing need to widen the scope of investigating the role of genetics in IBD to their association with therapy response. In the current study, an in-silico analysis of publicly available IBD patient transcriptomics datasets from Gene Expression Omnibus (GEO) are used to identify subsets of differentially expressed genes (DEGs) involved in the pathogenesis of IBD and may serve as potential biomarkers for Infliximab response. Five datasets were found that met the inclusion criteria. The DEGs for datasets were identified using limma R packages through the GEOR2 tool. The probes' annotated genes in each dataset intersected with DGEs from all other datasets. Enriched gene Ontology Clustering for the identified genes was performed using Metascape to explore the possible connections or interactions between the genes. 174 DEGs between IBD and healthy controls were found from analyzing two datasets (GSE14580 and GSE73661), indicating a possible role in the pathogenesis of IBD. Of the 174 DEGs, five genes (SELE, TREM1, AQP9, FPR2, and HCAR3) were shared between all five datasets. Moreover, these five genes were identified as downregulated in the infliximab responder group compared to the non-responder group. We hypothesize that alteration in the expression of these genes leads to an impaired response to infliximab in IBD patients. Thus, these genes can serve as potential biomarkers for the early detection of compromised infliximab response in IBD patients.

Abstract P4-01-39: Real-world efficaccy of dual antiHER2 therapy in first line metastatic HER2-positive breast cancer and the possibility of prediction of long-term response

Abstract Background: Although huge progress has been made in treating HER2-positive metastatic breast cancer in the last decade, it remains an incurable disease. Dual anti-HER2 therapy with pertuzumab and trastuzumab combined with chemotherapy represents the standard first line treatment of metastatic HER2-positive breast cancer, in view of the impressive CLEOPATRA study results. The aim of this study was to analyze the efficacy of dual antiHER2 therapy in real-world clinical practice and determine the differences in the clinicopathological characteristics of the long-term responders in comparison with short-term responders. Methods: Retrospective analysis of dual antiHER2 therapy efficacy was done and correlated to clinical and pathological characteristics of patients with different duration of response (DoR) in the first line metastatic HER2-positive breast cancer. The study was conducted at the UHC Zagreb, Croatia and approved by the Ethics Committee. Long-term responders were defined as patients with a duration of response (DoR) to dual antiHER2 therapy ≥ 36 months, and short-term responders were defined as patients with DoR ≤ 12 months. Progression-free survival was estimated using the Kaplan-Meier method. The reverse Kaplan-Meier method was used to estimate median follow-up duration. The non-parametric Chi-Square test (between categorical variables) and Mann-Whitney U-test (between continuous variables) were used to determine the differences between long-term and short-term responders groups. The significance level was set at p &amp;lt; 0.05. Results: Altogether, 128 patients treated with dual antiHER2 therapy for HER2-positive metastatic breast cancer from October 2015 to May 2022 were included in the study. By data cut-off, 50.8 % (N=63) of patients had progressed or died. The median follow-up time was 36 months. The median PFS was 31 months for the total cohort (95% CI 22.6 -39.3). Overall, 29 patients among the long-term responders and 32 patients in the short-term responders group were identified. A comparison of clinical and pathological characteristics between the two groups is shown in Table 1. Even though patients in the group of long-term responders were younger (54.5 years vs. 56.5 years), had less visceral involvement (69 % vs. 81.3%), and were more often trastuzumab ”naive“ (75.9% vs. 68.7%), no statistically significant differences were found between the two groups. Conclusion: In this real-life study, the median PFS was 31 months for the total cohort, even longer than in the referent CLEOPATRA trial, which confirms the effectiveness of dual antiHER2 therapy in a real-world setting. No possible clinical or pathological predictors of long-term response were identified, but larger studies may be able to distinguish patients’ characteristics associated with long-term response. Table 1: A comparison of clinical and pathological characteristics between the group of long-term responders and short-term responders Citation Format: Marija Križić, Tajana Silovski, Marina Popović, Natalija Dedić Plavetić. Real-world efficaccy of dual antiHER2 therapy in first line metastatic HER2-positive breast cancer and the possibility of prediction of long-term response [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 P4-01-39.

Factors associated with bone response to teriparatide in young postmenopausal women with osteoporosis.

To investigate the factors associated with changes in vertebral bone mineral density during teriparatide treatment. Single centre, longitudinal study involving 145 osteoporotic postmenopausal women treated with teriparatide. Clinical evaluation, bone mineral density (BMD) measurements assessment and laboratory analyses were performed at baseline then after 12 and 18months of treatment. Bone non-response to treatment was defined as no significant increase in BMD at 18months as compared to baseline. Of the 145 women initially included, 109 completed the 18-month course of the treatment. 75% of them had a history of prior osteoporotic treatment. Baseline mean age was 60 ± 8years. Mean baseline vertebral T-score was -3.7 ± 0.7 and 83 (76%) women had suffered at least one vertebral fracture. At the end of treatment, 18 women (17%) were classified as non-responders. In the responder group (n = 91), vertebral BMD increased by 0.091 ± 0.04g/cm2 (12.2 ± 5.3%). Clinical characteristics, baseline BMDs and the percentage of women previously treated with bisphosphonates as well as the duration of prior treatment did not significantly differ between the two groups of responders and non-responders. At baseline, non-responders had significant mean lower C-terminal fragment of type 1 collagen (CTX) values than responders (p < 0.01). Only baseline CTX values (r = 0.30 p < 0.01) were independently correlated to vertebral BMD changes during teriparatide treatment. A minority of treated women had no vertebral densitometric gain after 18months of teriparatide therapy. Low levels of baseline bone remodeling were the main factor associated with poor response to treatment.

Dynamic Changes in Peripheral Systemic Immunity Markers During Chemotherapy in HER2-negative Advanced Breast Cancer.

The immune system has a pivotal role in modulating the response to chemotherapy in breast cancer (BC). However, the immune status during chemotherapy remains unclear. We evaluated the sequential changes in peripheral systemic immunity markers in BC patients treated with various chemotherapeutic agents. We examined the correlation between the peripheral systemic immunity markers, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC) and the local cytolytic activity (CYT) score obtained by quantitative reverse-transcription polymerase chain reaction of 84 preoperative BC patients. Next, we observed the sequential changes in the peripheral systemic immunity markers during treatment with four anticancer drugs: oral 5-fluorouracil derivative; S-1, epirubicin plus cyclophosphamide; paclitaxel plus the anti-vascular endothelial growth factor antibody bevacizumab, and eribulin in 172 HER2-negative advanced BC patients. Finally, we examined the correlation between the changes in the peripheral systemic immunity markers, time to treatment failure (TTF) and progression-free survival (PFS). A negative correlation was found between ALC and NLR. ALC-low and NLR-high cases were positively associated with CYT score-low cases. The ratio of ALC-increase and NLR-decrease varies depending on the anticancer drugs used. The responder group (TTF ≥3 months) had a higher NLR-decrease ratio than the nonresponder group (TTF <3 months). Patients with a high NLR-decrease ratio showed higher PFS. The change in ALC or NLR varies according to the anticancer drugs, suggesting differential immunomodulatory effects of the drugs. Furthermore, the change in NLR reflects the therapeutic efficacy of chemotherapy in advanced BC.

Combined Left Ventricular Ejection Fraction and N-Terminal pro-B-type Natriuretic Peptide after Sacubitril/Valsartan for Predicting Outcomes in Patients with Heart Failure with Reduced Ejection Fraction.

The aim of this study was to determine whether a combined increase of ≥ 10% in left ventricular ejection fraction (LVEF) and decrease in N-terminal pro-B-type natriuretic peptide (NT pro-BNP) to < 1000 pg/mL after treatment with sacubitril/valsartan (SAC/VAL) in patients with heart failure with reduced ejection fraction (HFrEF) translated to better treatment outcomes in a real-world Taiwanese population. This is a single-center, prospective, non-randomized, observational study. Consecutive patients with HFrEF were treated with SAC/VAL and followed up for at least 12 months. The primary endpoint was a change in LVEF and reduction in NT pro-BNP at 12 months. The secondary outcomes were death and heart failure (HF) rehospitalization. A total of 105 patients were analyzed after 12 months of SAC/VAL treatment. The mean age was 66.0 ± 11.6 years, and the mean LVEF and NT pro-BNP were 33.6 ± 6.7% and 4462.7 ± 5851.7 pg/mL respectively. The mean LVEF significantly increased to 50.5 ± 10.3% (p < 0.001), while NT pro-BNP decreased to 1270.3 ± 2368.2 pg/mL (p = 0.001) at 12 months, with the greatest changes occurring in the first 3 months of treatment (p < 0.001). Five patients died and 12 were rehospitalized for HF. None of the patients in the responder group died compared to 5 deaths in the non-responder group (p = 0.039). Combined ≥ 10% LVEF increase and NT pro-BNP of < 1000 pg/mL was an independent predictor of death and HF rehospitalization (p = 0.019). SAC/VAL treatment resulted in significant improvements in LVEF, reduced NT pro-BNP level, death and HF hospitalization. Taken separately, an NT pro-BNP level of < 1000 pg/mL was a better predictor than ≥ 10% LVEF increase. Combining both variables predicted fewer deaths and HF rehospitalizations. Even with failure to reach the target dose, SAC/VAL still had significantly beneficial treatment outcomes in Taiwanese patients.

Predictors of response to galcanezumab in patients with chronic migraine: a real-world prospective observational study.

Despite high efficacy and tolerability, not all patients with chronic migraine benefit from anti-CGRP monoclonal antibodies. We aimed to identify the clinical predictors of the response to galcanezumab treatment in patients with chronic migraine from real-world data. We prospectively recruited patients with CM who underwent galcanezumab injections between December 2019 and February 2022. Treatment response was determined after three months of follow-up and was defined as ≥ 50% reduction in monthly headache days. The migraine characteristics, comorbidities, and other treatment responses were compared between the responder and non-responder groups. Of 238 patients with CM, 153 (64.3%) showed treatment response. The responder group was younger, had lower frequency of baseline headache days, and had more accompanying symptoms such as nausea, vomiting, and photophobia. Better triptan response and less depression were also observed in the responder group. Multivariable regression analysis revealed that the everyday headache (OR = 0.351, 95% CI = 0.133-0.874, p = 0.017), depression (OR = 0.439, 95% CI = 0.216-0.896, p = 0.024) and absence of accompanying symptoms (OR = 0.314, 95% CI = 0.118-0.834, p = 0.020) were significantly associated with response to galcanezumab treatment. Our real-world data showed the efficacy of galcanezumab in patients with CM, regardless of medication overuse. Everyday headache, presence of depression, and absence of accompanying symptoms of migraine were significant predictors of a poor response.