Response Evaluation Research Articles

Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer

Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07–0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48–17.34]; Group 3: PD-L1− and thyroid irAE− : 30.49 [6.60–140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor–Node–Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.

Impact of milk feeding regimens on growth, intake, efficiency, and costs in pre-weaned crossbred calves

The high milk (20% of weight) feeding in initial life is beneficial for growth, feed efficiency, and welfare of calves. The experiment aimed to evaluate the impact of different milk-feeding regimens on the growth, intake, physiological responses, blood and faeces attributes, feed efficiency, and feeding cost in crossbred calves. Thirty (n=30) healthy pre-weaned crossbred calves (75% HF × 25% Kankrej) were divided into five groups using a completely randomized design. The calves were fed milk 10% of body weight (T1); 4 L/day during the entire experiment (T2); 6,4,2 L/day during 2-6, 7-9, and 10-13 weeks of age (T3); and early weaning protocols 7, 5 L/day during 2-6, and 7-9 weeks of age (T4); as well as 8, 4 L/day during 2-6, and 7-9 weeks of age (T5), respectively after an adaptation of seven days. The feeding of concentrate, dry, and green fodder was common in all groups. The effect of milk-feeding regimens on body weight, body measurements, intake, and feed efficiency were non-significant. The evaluation of physiological responses, faecal consistency score, and blood haematology indicated that it was safe to feed different milk regimens. The milk feeding up to 13 weeks of age (T1, T2, T3) significantly lowered the cost of feeding for weight gain than the early weaning protocol (T4, T5). Among them, the feeding of T3 regimen was economical for weight gain without affecting the growth performance, feed efficiency, and health attributes of crossbred calves.

Integrative analysis of multiple cell death model for precise prognosis and drug response prediction in gastric cancer.

Gastric cancer (GC) is a common upper gastrointestinal tumor. However, the evaluation of prognosis and treatment response in patients with gastric cancer remains a challenge. Programmed cell death (PCD) is one of the important terminal paths for the cells of metazoans, and is involved in a variety of biological events that include morphogenesis, maintenance of tissue homeostasis, and elimination of harmful cells. The objective of this project is to investigate the predictive significance of cell death pathways and create prognostic signatures associated to cell death, with the purpose of forecasting prognosis and providing guidance for the treatment of gastric cancer. Gene transcription profiles and corresponding clinical data of gastric cancer patients were collected from The Cancer Genome Atlas (TCGA-STAD, n = 448) and the Gene Expression Comprehensive Database (GSE84437, n = 483). Thirteen types of cell death-related genes, including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy, cuprotosis, parthanatos, entotic cell death, netotic cell death, lysosome-dependent cell death, alkaliptosis, oxeiptosis, and disulfidptosis, were analysed. Cell death-related genes associated with prognosis were identified in the TCGA-STAD training cohort using Lasso-Cox regression to generate a risk score. Patients were categorized into high and low-risk groups based on the median risk score for survival difference analysis. Cell death-related genes associated with prognosis were identified in the TCGA-STAD training cohort using Lasso-Cox regression to generate a risk score. Additionally, the response to immunotherapy in the high-risk and low-risk groups was calculated using the oncoPredict algorithm. Futhermore, the model genes were validated in the GEO validation set. A total of 324 differential programmed cell death (PCD)-related genes were identified, and 65 were selected through single-factor Cox analysis. Six PCD-related genes were ultimately identified by Lasso regression to construct a prognostic risk score model. The log-rank test revealed that patients in the high-risk group had inferior survival time compared with those in the low-risk group. The area under the ROC curve (AUC) for the training group at years 1, 3, and 5 were 0.684, 0.713, 0.743, respectively, while the AUC for the validation cohort at years 1, 3, and 5 were 0.695, 0.704, and 0.707, respectively. Unsupervised clustering identified potential subtypes included in the model, and a survival difference was also observed between the two subgroups. Multifactor Cox results, combined with clinical information, demonstrated that the prognostic risk score can serve as an independent prognostic factor, irrespective of other clinical features. By comprehensively analyzing multiple cell death patterns, we have established a novel model that accurately forecasts the clinical prognosis and drug sensitivity of gastric cancer. It was found that all 12 representative drugs may not be suitable for patients in high-risk groups.

Evaluation of the immune response of peripheral blood mononuclear cells cultured on Ti6Al4V-ELI polished or etched surfaces.

While titanium and its alloys exhibit excellent biocompatibility and corrosion resistance, their polished surfaces can hinder fast and effective osseointegration and other biological processes, such as angiogenesis, due to their inert and hydrophobic properties. Despite being commonly used for orthopedic implants, research focuses on developing surface treatments to improve osseointegration, promoting cell adhesion and proliferation, as well as increasing protein adsorption capacity. This study explores a chemical treatment intended for titanium-based implants that enhances tissue integration without compromising the mechanical properties of the Ti6Al4V substrate. However, recognizing that inflammation contributes to nearly half of early implant failures, we assessed the impact of this treatment on T-cell viability, cytokine production, and phenotype. Ti6Al4V with extra low interstitial (ELI) content discs were treated with hydrofluoric acid followed by a controlled oxidation step in hydrogen peroxide that creates a complex surface topography with micro- and nano-texture and modifies the chemistry of the surface oxide layer. The acid etched surface contains an abundance of hydroxyl groups, crucial for promoting bone growth and apatite precipitation, while also enabling further functionalization with biomolecules. While cell viability remained high in both groups, untreated discs triggered an increase in Th2 cells and a decrease of the Th17 subset. Furthermore, peripheral blood mononuclear cells exposed to untreated discs displayed a rise in various pro-inflammatory and anti-inflammatory cytokines compared to the control and treated groups. Conversely, the treated discs showed a similar profile to the control, both in terms of immune cell subset frequencies and cytokine secretion. The dysregulation of the cytokine profile upon contact with untreated Ti6Al4V-ELI discs, namely upregulation of IL-2 could be responsible for the decrease in Th17 frequency, and thus might contribute to implant-associated bacterial infection. Interestingly, the chemical treatment restores the immune response to levels comparable to the control condition, suggesting the treatment's potential to mitigate inflammation by enhancing biocompatibility.

Evaluation of immune sensor responses to a viral small noncoding RNA.

Gammaherpesviruses are widespread pathogens causing persistent infections linked to the development of numerous types of lymphomas in humans. During latency, most of the viral protein-coding genes are suppressed, facilitating evasion of adaptive immune recognition of protein antigens. In contrast, many noncoding RNA (ncRNA) molecules are expressed in infected cells and can regulate key cellular pathways while simultaneously evading adaptive immune recognition. To counteract this, many cells express internal pattern recognition receptors that can intrinsically sense ongoing infections and initiate cellular defenses. Murine gammaherpesvirus 68 (MHV68) is a valuable model to study in vivo aspects of gammaherpesvirus pathogenesis. The MHV68 ncRNA TMER4 (tRNA-miRNA-encoding RNA 4) promotes lymph node egress of infected B cells: in the absence of TMER4, MHV68-infected B cells accumulate in the lymph node in a manner similar to B cells activated through specific antigen encounter. We hypothesized that TMER4 may alter intrinsic immune activation. In research described here, we aimed to explore the immunomodulatory functions of TMER4 by evaluating its impact on signaling through the critical immune sensors Toll-like receptor 4 (TLR4), TLR3, TLR7, and retinoic acid-inducible gene I (RIG-I). To accomplish this, we developed a system to test noncoding RNAs using commercially available reporter cell lines. We optimized the experimental procedure to ensure ncRNA expression and to quantify immune sensory molecule induction or inhibition by the expressed ncRNA. Expression of TMER4 RNAs from plasmid constructs did not alter TLR or RIG-I signaling. This study provides a clear experimental framework that can be applied to test other small ncRNAs for their impact on various innate immune sensor proteins.

Evaluation of Antibody Response and Reinfection in Improved Hypertensive, Cardiac, and Diabetic Patients with COVID-19 for Six Months in Unvaccinated Outpatients

Background: This study presents a unique investigation into the relationship between the persistence of IgG antibody levels and reinfection in recovered coronavirus disease 2019 (COVID-19) patients. By shedding light on this aspect, we aim to address concerns about the risk of reinfection in unvaccinated patients, offering a fresh perspective in the current COVID-19 research landscape. Objectives: This study takes a novel approach by focusing on the antibody response and reinfection in COVID-19 patients who were treated in outpatient settings for six months. This approach distinguishes our research within the broader context of COVID-19 studies. Methods: Our comprehensive and rigorous prospective cohort study included 149 COVID-19 outpatients referred to Imam Ali Clinic in Dezfoul City, Khuzestan province, Iran. Data was meticulously collected from September 2021 to February 2022. All unvaccinated patients underwent RT-PCR testing, and their anti-SARS-CoV-2 IgM/IgG levels were measured at the onset of illness. Serum IgG levels were then measured again after three and six months using ELISA. Results: All COVID-19 patients had their IgG antibody levels tested three times (on days two to four of the illness, at three months, and at six months). Significant differences in IgG antibody levels were observed between the vaccinated and unvaccinated groups during each period (P &lt; 0.05). Additionally, there were substantial differences between the hypertension and non-hypertension groups (P = 0.032). Importantly, our findings reaffirm the impartiality of our research, as no significant differences were found between reinfection rates and various demographic or disease-related factors. Conclusions: The findings of this study suggest that high levels of IgG antibodies in unvaccinated patients could potentially reduce the risk of reinfection. This insight could have important implications for public health strategies and the management of COVID-19 in unvaccinated populations, providing valuable information for decision-makers in the field.

Role of Immunotherapy in Non-Small Cell Lung Cancer (NSCLC)

Background: Non-small cell lung cancer accounts for approximately 85% of all lung cancers and presents a serious public health challenge due to an increasing incidence and poor prognosis, with only a 5-year survival rate of 5-10% in advanced disease stages. Objective: The aim of this work is an overview of the clinical efficacy and safety profile of ICIs in NSCLC patients, mainly focusing on the predictive role played by PD-L1 expression and tumor mutational burden as predictive biomarkers of treatment response. Methods: A total of 63 NSCLC patients treated with ICIs at a Department of Respiratory Medicine, Dhaka National Medical Institute Hospital, Dhaka, Bangladesh and National Institute of Diseases of the Chest and Hospital (NIDCH), and National Institute of Cancer Research &amp; Hospital (NICRH), Mohakhali, Dhaka, Bangladesh from July 2023 to December 2023, were retrospectively analyzed. Demographical information, treatment regimens, and clinical outcomes were collected and analyzed. Treatment responses were evaluated based on Response Evaluation Criteria in Solid Tumors, and safety was assessed through monitoring adverse events. Results: The median age of the cohort was 62 years, with presentation in advanced stages, III and IV in 70%. An objective response rate of 42% was observed; median PFS was 8.5 months. Of note, patients with high PD-L1 expression of ≥ 50% had a response rate of 60%, whereas those with lower expression had a rate of 30%. It was observed in TMB analysis that high mutational burden is associated with a median PFS of 10 months versus 5 months in the case of low TMB. About 15% of patients developed adverse events, mostly immune-mediated. Conclusion: This study has exemplified the promising efficacy of ICIs in the improvement of treatment outcomes for patients with NSCLC and underlined critical roles that PD-L1 expression and TMB have played in guiding personalized treatment strategies. Although encouraging, these findings are retrospective and ..

Pembrolizumab for the First-Line Treatment of Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma: Results from the Single-Arm, Open-Label, Phase III KEYNOTE-913 Study.

The phase III KEYNOTE-913 study was conducted to evaluate the efficacy and safety of pembrolizumab as first-line therapy in patients with advanced Merkel cell carcinoma (MCC). The aim was to report results from the primary analysis of KEYNOTE-913. Patients with recurrent locally advanced or metastatic MCC received pembrolizumab 200mg intravenously every 3weeks for up to 35 treatments (~2 years). The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary end points were duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, overall survival (OS), and safety and tolerability. Fifty-five patients were treated with pembrolizumab. The median time from first dose to data cutoff (February 15, 2024) was 50.3 months (range 38.7-59.4). The ORR was 49% (95% confidence interval [CI] 35-63), with 12 complete responses and 15 partial responses. The median DOR was 39.8 months (range 4.8-52.5+), and the 24-month DOR rate was 69%. The median PFS was 9.3 months (95% CI 3-26), and the 24-month PFS rate was 39%. The median OS was 24.3 months (95% CI 12.4 to not reached), and the 24-month OS rate was 51%. Any-grade treatment-related adverse events (AEs) occurred in 38 patients (69%); 13 patients (24%) experienced grade 3-5 AEs. The most common treatment-related AEs were fatigue (n = 12 [22%]), pruritus (n = 12 [22%]), and lipase increase (n = 10 [18%]). One patient died of treatment-related Guillain-Barré syndrome. Pembrolizumab provided durable antitumor activity and promising survival and had a manageable safety profile in patients with recurrent locally advanced or metastatic MCC, supporting its use in this population. Clinicaltrials.gov, NCT03783078.

Experimenting with artificial shelters to assist habitat restoration for medium‐sized ground‐dwelling mammals

Many terrestrial vertebrates require microhabitat shelter structures for survival. Where anthropogenic or environmental disturbances have degraded or depleted shelter, artificial shelters are increasingly used to provide supplementary habitat for various taxa. However, their application to medium‐sized ground‐dwelling mammals (MGMs) remains largely unexplored. We installed rudimentary artificial shelters in a conservation reserve to emulate the vegetative cover used as refuge by three Australian MGMs: the long‐nosed (Perameles nasuta) and northern brown bandicoots (Isoodon macrourus), and the vulnerable long‐nosed potoroo (Potorous tridactylus). We used multi‐method occupancy modeling and behavioral analysis to compare the detections and behaviors of the target species with those of four non‐target species. Our study design included three plot types (treatments)—artificial shelter, baited lure, and disturbance control—enabling unambiguous evaluation of responses to the shelters. The bandicoots showed no difference in detection among treatments, whereas detection of the potoroo was highest at control plots. Detection of non‐target species was generally highest at baited plots. The target species demonstrated a much higher willingness to enter the shelters compared to the non‐target species. The use of the structures appeared to be exploratory, with no evidence that individuals remained in shelters during the day. There was limited evidence that the shelters reduced the target species' perceptions of predation risk and no evidence that predators were attracted to the shelters. The high availability of natural shelter and our small sample size likely influenced these findings. Nevertheless, they lay the foundation for research and refinement into more effective shelter designs.

Efficacy and safety of Anlotinib based neoadjuvant chemotherapy for locally advanced triple negative breast cancer (TNBC)

BackgroundAnlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC.MethodsLocally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common.ConclusionsAnlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted.

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer

BackgroundThere are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib...

Prediction and validation of pathologic complete response for locally advanced rectal cancer under neoadjuvant chemoradiotherapy based on a novel predictor using interpretable machine learning

BackgroundPrecise evaluation of pathological complete response (pCR) is essential for determining the prognosis of patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (NCRT) and can offer clues for the selection of subsequent treatment strategies. Most current predictive models for pCR focus primarily on pre-treatment factors, neglecting the dynamic systemic changes that occur during neoadjuvant chemoradiotherapy, and are constrained by low accuracy and lack of integrity. PurposeThis study devised a novel predictor of pCR using dynamic alterations in systemic inflammation-nutritional marker indexes (SINI) during neoadjuvant therapy and developed a machine-learning model to predict pCR. MethodsTwo cohorts of patients with LARC from center one from 2012 to 2017 and from center two from 2020 to 2023 were integrated for analysis. This study compared dynamic changes in blood indexes before and after neoadjuvant therapy and surgical operation. A least absolute shrinkage and selection operator (LASSO) regression analysis was conducted to mitigate collinearity and identify key indexes, constructing the SINI. Univariate and multiple logistic regression analyses were used to identify the independent risk factors associated with pCR. Additionally, 10 machine learning algorithms were employed to develop predictive models to assess risk. The hyperparameters of the machine learning models were optimized using a random search and 10-fold cross-validation. The models were assessed by examining various metrics, including the area under the receiver operating characteristic curves (AUC), the area under the precision-recall curve (AUPRC), decision curve analysis, calibration curves, and the precision and accuracy of the internal and external validation cohorts. Additionally, Shapley's additive explanations (SHAP) were employed to interpret the machine learning models. ResultsThe study cohort comprised 677 patients from the center one and 224 patients from the center two. Six key indexes were identified, and a predictive index, SINI, was constructed. Univariate and multiple logistic regression analyses revealed that SINI, clinical T-stage, clinical N-stage, tumor size, and the distance from the anal verge were independent risk factors for pCR in patients with LARC following NCRT. The mean AUC value of the extreme gradient boosting (XGB) model in the 10-fold cross-validation of the training set was 0.877. The XGB model demonstrated superior performance in the internal and external validation sets. Specifically, in the internal test set, the XGB model achieved an AUC of 0.86, AUPRC of 0.707, accuracy of 0.82, and precision of 0.80. In the external validation set, the XGB model exhibited an AUC of 0.83, AUPRC of 0.702, accuracy of 0.81, and precision of 0.81. Additionally, the predictions generated by the XGB model were analyzed using SHAP. ConclusionThis study involved developing and validating an XGB model using SINI to predict pCR in patients with LARC. Besides, a SINI-based machine learning model shows promise in accurately predicting pCR following NCRT in patients with resectable LARC, offering valuable insights for personalized treatment approaches.

Creation of a Prediction Model of Local Tumor Recurrence After a Successful Conventional Transcatheter Arterial Chemoembolization Using Cone-Beam Computed Tomography Based-Radiomics.

To create and evaluate prediction models of local tumor recurrence after successful conventional transcatheter arterial chemoembolization (c-TACE) via radiomics analysis of lipiodol deposition using cone-beam computed tomography (CBCT) images obtained at the completion of TACE. A total of 103 hepatocellular carcinoma nodules in 71 patients, who achieved a complete response (CR) based on the modified Response Evaluation Criteria in Solid Tumors 1month after TACE, were categorized into two groups: prolonged CR and recurrence groups. Three types of areas were segmented on CBCT: whole segment (WS), tumor segment (TS), and peritumor segment (PS). From each segment, 105 radiomic features were extracted. The nodules were randomly divided into training and test datasets at a ratio of 7:3. Following feature reduction for each segment, three models (clinical, radiomics, and clinical-radiomics models) were developed to predict recurrence based on logistic regression. The clinical-radiomics model of WS showed the best performance, with the area under the curve values of 0.853 (95% confidence interval: 0.765-0.941) in training and 0.752 (0.580-0.924) in test dataset. In the analysis of radiomic feature importance of all models, among all radiomic features, glcm_MaximumProbability, shape_MeshVolume and shape_MajorAxisLength had negative coefficients. In contrast, shape_SurfaceVolumeRatio, shape_Elongation, glszm_SizeZoneNonUniformityNormalized, and gldm_GrayLevelNonUniformity had positive coefficients. In this study, a machine-learning model based on cone-beam CT images obtained at the completion of c-TACE was able to predict local tumor recurrence after successful c-TACE. Nonuniform lipiodol deposition and irregular shapes may increase the likelihood of recurrence.

8785 Does Somatostatin Receptor Expression Intensity Impact Prognosis in Non Pituitary Neuroendocrine Tumors Treated with Somatostatin Analogues?

Abstract Disclosure: N. Saleh Jouneghani: None. S. Fazeli: None. S. Chang: None. A. Hosseini: None. R. Marandi: None. A. Siddiqui: None. M. Talley: None. B. Salehian: None. Does Somatostatin Receptor Expression Intensity Impact Prognosis in Non Pituitary Neuroendocrine Tumors Treated with Somatostatin Analogues? Introduction: Non-pituitary neuroendocrine tumors (NETs) show different somatostatin receptor subtype (SSTR) expression, but their role in tumor progression and prognosis is not well known. We hypothesized that NETs with higher expression of SSTR2, SSRT5, or co-expression of SSTR2 and SSTR5 will have better outcome when treated with Somatostatin Analogues (SSA). Method: Retrospectively, patients with non-pituitary neuroendocrine tumors, followed for more than one year between 1985 and 2022, and treated with SSA (Octreotide or Lanreotide) who had available tissue were selected. Tissue immunostaining performed for SSTR2 and SSTR5 with use of monoclonal antibodies. Expression analysis of the SSTR2 and SSTR5 were evaluated by the validated semi-quantitatively method, reported by an intensity score of 0 -3. The progression free survival and overall survival were calculated by Kaplan Meier and compared in different subgroups with SSTR expression intensity. Response evaluation was assessed using RECIST v1.1. Results: Of 279 non-pituitary neuroendocrine tumors, 51 meet the criteria and tissue sent for analysis. The median age at diagnosis was 62; male 49%, with median follow up 7 years, 85% stage IV at diagnosis, most common primary tumor was in gut 54% followed by pancreas 33%. Positive SSRT5 tumors had 93% SSRT2 co-expression. There were no significant differences in progression-free survival (PFS) observed between tumors with low or high SSTR2 intensity expression (P=0.62). The presence or absences of SSRT5 expression did not have any impact on PFS (p=0.57) or overall survival (p=0.3). Conclusion: in the patient with non-pituitary neuroendocrine tumors, higher SSTR2 expression intensity or having SSRT5 co-expression, did not correlate with a better PFS or overall survival in response to SSA, in our study. Further prospective studies are needed to clarify if higher expression intensity of SSRTs correlates with better response to SSAs in NETs. Presentation: 6/1/2024

Optical Coherence Tomography and Optical Coherence Tomography Angiography in Optic Nerve Disorders

Optic nerve disorders encompass a wide range of diseases. While it may be an isolated disease, such as optic disc drusen, it may also occur as a symptom of pathology in the central nervous system, such as multiple sclerosis. Optical coherence tomography (OCT) is an important auxiliary test used in optic nerve disorders as it allows cross-sectional imaging of the retina and optic nerve head at high resolution. OCT is used in the diagnosis of optic nerve disorders, evaluation of response to treatment, and prediction of visual prognosis by measuring retinal layers such as the ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL).

Evaluating response to radium-223 using 68Ga-PSMA PET/CT imaging in patients with metastatic castration-resistant prostate cancer.

Conventional imaging techniques and prostate-specific antigen (PSA) values are not useful to follow-up patients during Radium-223 treatment. The study aimed to evaluate the predictive value of prostate-specific membrane antigen PSMA PET/CT-based response in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Radium-223 dichloride treatment. Patients treated with radium-223, having performed two 68Ga-PSMA-11 PET/CT scans (baseline 1month before treatment initiation and follow-up 2weeks after the third cycle), were retrospectively evaluated. Visual and quantitative PET image analyses were performed, and patients were dichotomized into progressive (PD) and non-PD according to Response Evaluation Criteria in PSMA‑imaging (RECIP1.0) and PSMA-PET Progression criteria (PPP). The primary endpoint was overall survival (OS). Cohen's Kappa (κ) was used to test the agreement between the two criteria. The Cox regression hazard model and Kaplan-Meier method were used for survival analyses. Twenty-eight mCRPC patients were evaluated. Sixteen (43%) and 18 (64%) patients had PD according to RECIP1.0 and PPP, respectively; κ = 0.85 (95% CI 0.65-1.00). After a median follow-up of 16months (interquartile IQR 9-33), 20 (71%) patients died. Patients with PSMA PD showed a higher risk of death than non-PD according to RECIP1.0 (HR = 2.9; 95% CI 1.14-7.46; p = 0.029) and PPP (HR = 2.8; 95% CI 1.04-7.64; p = 0.042). For both criteria, the median OS was shorter for PD than non-PD (37 vs. 12months, Log-rank; p < 0.05). The C-index for RECIP1.0 and PPP were almost equal (0.66 and 0.63; respectively). This study demonstrated that PSMA-PET/CT imaging is valuable for monitoring radium-223 treatment. Both PSMA PET/CT response criteria (RECIP1.0 and PPP) perform similarly predicting OS at follow-up after three cycles of radium-223. These findings urge further validation in prospective trials.

Long-Term Outcome of a Multicenter Prospective Study on Efficacy and Safety of High-Dose Stereotactic Body Radiation Therapy ≥48-h Interfraction Interval for ≤5 cm Hepatocellular Carcinoma

Introduction: The goal of this study was to evaluate the efficacy and safety of high-dose stereotactic body radiation therapy (SBRT) with an extended (48 h or more) interfraction interval for hepatocellular carcinoma (HCC) ≤5 cm in size after incomplete response to transarterial chemoembolization (TACE). Methods: This multicenter prospective study included 54 patients with inoperable HCC of ≤5 cm size between July 2012 and June 2015. A total SBRT dose of 60 Gy in 3 fractions was administered within 14 days with ≥48-h interfraction interval to patients who showed an incomplete response after 1–5 sessions of TACE. Treatment responses were defined according to the modified Response Evaluation Criteria for Solid Tumors. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Results: Forty-eight patients were evaluated with a median follow-up period of 66 months (range, 2–126 months). The median tumor size was 2.0 cm (range, 1.0–4.5 cm), and most patients (87.5%) had a single lesion. The 1-, 2-, and 5-year local control (LC) rates were 100%, 94.8%, and 90.7%, respectively. The 1-, 2-, and 5-year progression-free survival (PFS) rates were 63.4%, 56.9%, and 24.9%, respectively. The 1-, 2-, and 5-year overall survival (OS) rates were 95.6%, 90.9%, and 76.5%, respectively. None of the patients experienced grade 3+ gastrointestinal toxicity, while 1 patient developed non-classic radiation-induced liver disease 2 months after SBRT. Conclusion: High-dose SBRT with a ≥48-h interfraction interval after incomplete response to TACE is effective for HCC ≤5 cm in size as evidenced by the high rates of LC and OS and acceptable treatment-related toxicity.

Influence of the vertical seismic component on the response of continuous RC bridges

This paper investigates the influence of vertical seismic accelerations on the seismic response of RC bridges through numerical simulations using an enhanced non-linear numerical model. Results confirm that the incorporation of vertical accelerations, either through actual records or scaled horizontal records, can considerably modify the seismic response and the collapse mechanism. In the case of actual vertical records, the vertical component significantly contributes to premature structural deterioration, intensifying demand and accelerating failure mechanisms. On the other hand, the study underscores the inadequacy of using scaled horizontal records to represent vertical accelerations, as suggested by some seismic codes, as it not only distorts seismic response evaluation but also alters failure modes. The analysis of vertical vibration reveals higher displacements, increasing flexural demand on the deck, and leading to a progressive loss of vertical support at the central column. The research establishes the need to accurately account for vertical seismic accelerations in bridge design evaluations, as their impact on structural response and failure mechanisms cannot be underestimated. The work highlights the importance of a highly detailed 3D numerical model in assessing traditional parameters and capturing complex collapse mechanisms arising from material and geometric nonlinearities.

Dose-escalation, tolerability, and efficacy of intratumoral and subcutaneous injection of hemagglutinating virus of Japan envelope (HVJ-E) against chemotherapy-resistant malignant pleural mesothelioma: a clinical trial

The hemagglutinating virus of Japan envelope (HVJ-E) is an inactivated Sendai virus particle with antitumor effect and inducing antitumor immunity. However, its dosage and efficacy have not been verified. We conducted a phase I clinical study on chemotherapy-resistant malignant pleural mesothelioma (MPM) aiming to determine the recommended dosage for a phase II study through dose-limiting toxicity and evaluate HVJ-E’s preliminary efficacy. HVJ-E was administered intratumorally and subcutaneously to the patients with chemotherapy-resistant MPM. While no serious adverse events occurred, known adverse events of HVJ-E were observed. In the preliminary antitumor efficacy using modified response evaluation criteria in solid tumors (RECIST) criteria, three low-dose patients exhibited progressive disease, while all high-dose patients achieved stable disease, yielding disease control rates (DCRs) of 0% and 100%, respectively. Furthermore, the dose-dependent effect of HVJ-E revealed on DCR modified by RECIST and the baseline changes in target lesion size (by CT and SUL-peak; p < 0.05). Comparing targeted lesions receiving intratumoral HVJ-E with non-injected ones, while no clear difference existed at the end of the study, follow-up cases suggested stronger antitumor effects with intratumoral administration. Our findings suggest that HVJ-E could be safely administered to patients with chemotherapy-resistant MPM at both study doses. HVJ-E exhibited some antitumor activity against chemotherapy-resistant MPM, and higher doses tended to have stronger antitumor effects than lower doses. Consequently, a phase II clinical trial with higher HVJ-E doses has been conducted for MPM treatment. Trial registration number: UMIN Clinical Trials Registry (#UMIN000019345).

Assessment of Y-90 Radioembolization Treatment Response for Hepatocellular Carcinoma Cases Using MRI Radiomics.

This study aimed to investigate the ability of radiomics features extracted from magnetic resonance imaging (MRI) images to differentiate between responders and non-responders for hepatocellular carcinoma (HCC) cases who received Y-90 transarterial radioembolization treatment. Thirty-six cases of HCC who underwent MRI scans after Y-90 radioembolization were included in this study. Tumors were segmented from MRI T2 images, and then 87 radiomic features were extracted through the LIFEx package software. Treatment response was determined 9 months after treatment through the modified response evaluation criteria in solid tumours (mRECIST). According to mRECIST, 28 cases were responders and 8 cases were non-responders. Two radiomics features, "Grey Level Size Zone Matrix (GLSZM)-Small Zone Emphasis" and "GLSZM-Normalized Zone Size Non-Uniformity", were the radiomics features that could predict treatment response with the area under curve (AUC)= 0.71, sensitivity= 0.93, and specificity= 0.62 for both features. Whereas the other 4 features (kurtosis, intensity histogram root mean square, neighbourhood gray-tone difference matrix strength, and GLSZM normalized grey level non-uniformity) have a relatively lower but acceptable discrimination ability range from AUC= 0.6 to 0.66. MRI radiomics analysis could be used to assess the treatment response for HCC cases treated with Y-90 radioembolization.