Specific serum and skin immunological profiles of patients with bullous pemphigoid requiring biologic therapies.

THU0187 Memory B Cells Produce More TNF Than Other B Cell Subtypes and Their Percentage at Baseline Could Help to Predict Response to TNF-Inhibitors

Antigen Specificity in Subsets of Mucous Membrane Pemphigoid

Patients with severe pulmonary hypertension associated with chronic lung disease have a poor prognosis. Targeted pulmonary arterial hypertension therapies might improve exercise capacity and outcome, but there are no guidelines on treatments which are not recommended because of an unproven benefit, with discordant results from few studies in this context. The aim of our study was to evaluate targeted pulmonary arterial hypertension therapies for severe group 3 pulmonary hypertension patients. We conducted an observational retrospective monocentre study on patients with severe group 3 pulmonary hypertension diagnosed on right heart catheterisation treated with targeted therapies. Primary outcome was an improvement of the distance on 6-min walk test of ≥30 m. Secondary end-points included changes in haemodynamics (pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (mPAP)) and identification of potential predictive factors of therapeutic response. 139 patients were enrolled. Most patients had monotherapy with phosphodiesterase 5 inhibitors (n=128; 92%). Mean change in 6-min walk distance was +1.5 m after treatment (p=0.59). Forced expiratory volume in 1 s and forced vital capacity were not predictive factors for response. We found a significant improvement of PVR and mPAP of -1.0 Wood Units (p<0.001) and -4 mmHg (p<0.001), respectively, under treatment. 18% of patients had to withdraw treatment for intolerance. Treatment duration <3 months was associated with poor survival (hazard ratio 2.75, p=0.0005). Oral targeted pulmonary arterial hypertension therapies do not improve exercise capacity in patients with severe pulmonary hypertension associated with chronic lung disease, but could improve haemodynamic parameters.

Epidermal growth factor receptor (EGFR)-targeted therapies are a valid therapeutic option for advanced non-small-cell lung cancer (NSCLC), but unequivocally recognised predictive factors for therapeutic response are lacking. However, intrinsic resistance might occur due to loss of EGFR expression during the course of the disease or its treatment. Paraffin-embedded tissue from cases with metastatic NSCLC obtained at autopsy was retrieved from our archive. Specimens of primary tumour (n=39; 64% adenocarcinoma) and of all corresponding metastases (n=70) were immunohistochemically stained for EGFR expression. Two observers independently scored staining intensity and evaluated the percentage of positively stained cells. Identical staining intensity and < or = 10% difference in number of stained cells were defined as perfect concordance; and one-increment difference in staining intensity and less than 30% difference in number of stained cells were defined as good concordance. Twenty-seven out of 39 primary tumours (69%) were EGFR-positive on immunohistochemistry (IHC), with 12/27 (44%) of positive tumours exhibiting intense or moderate EGFR expression. The median number of EGFR-expressing cells in primary tumours was 50% (range 0-100%). Overall Spearman's rank correlations for staining intensity and percentage of positively stained cells between primary tumours and paired metastases were 0.78 (p<0.001) and 0.60 (p<0.001), respectively. Perfect concordance was observed in 51% (20/39) and good concordance in 18% (7/39) of corresponding pairs, respectively, whereas 9/12 metastases showing discordant staining with their corresponding primary tumours had lacked EGFR expression. In most NSCLCs, EGFR status of primary tumours correlates with EGFR status of corresponding metastases. Hence, loss of EGFR expression is unlikely during disease progression, local or non-EGFR-targeting systemic treatment.

Cancer-associated hypersialylation is believed to be related to the metastatic cell phenotype and the suppression of sialyltransferases (SiaTs) has been suggested to be a potent preventive strategy against metastasis. The present research discovered SiaTs-related genes for cervical cancer (CC). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were applied to obtain the relevant samples. Mutation dataset were processed using mutect2 software. The gene modules were obtained via weighted gene co-expression network analysis (WGCNA), and the enrichment analysis on the genes within the modules was implemented. Cox regression analysis and "glmnet" R package were applied to establish the relevant risk model. "MCPcounter" R package, ESTIMATE algorithm and TIMER online tools were used to depict the tumor immune microenvironment in CC. The mutation landscape was additionally plotted, and the response to immunotherapy in different cohorts were compared. Further reverse-transcription quantitative PCR and Transwell assays were performed to verify the expression and potential function of the screened key genes. Mutation of 14 SiaTs was seen in CC. Subsequently, WGCNA-based identification of SiaTs-related gene modules was significantly enriched in metabolism-related pathways. The established RiskScore model manifested excellent prognostic classification efficiency. A poorer prognosis and occurrence of both immune evasion and reduced immunoreactivity may be seen in high-risk patients yet relatively higher immune cell scores were noticeable in low-risk patients. Angiogenesis and MYC target V2 may be the differentially activated pathways in high-risk patients, while those in low-risk patients were KRAS Signaling DN and Interferon alpha response. In addition, most immune checkpoint-correlated genes were identified to express higher in low-risk patients, while higher sensitivities to chemotherapy drugs was discovered in high-risk patients. Cellular assays have revealed that KCNK15, LIF, TCN2, SERPINF2, and CXCL3 were highly expressed yet PIH1D2, DTX1 and GCNT2 were low-expressed in Hela cells and that silencing CXCL3 diminished the number of migrated and invaded Hela cells. In this study, we systematically constructed and validated a risk scoring model based on SiaTs-related genes, which can effectively predict the prognosis and potential response to immunotherapy and chemotherapy in CC patients. This provides a new molecular basis and clinical reference for achieving individualized treatment.

To compare empiric and calculated I activities using 2013 EANM recommendations. To look for predictive factors of therapeutic response to an empiric activity of I. To assess clinical situations favoring calculated treatment modalities. Prospective monocentric study of clinical outcomes at 1 year follow-up in 86 patients with GD and MNG who received empiric I therapeutic activities (348-939 MBq). Differences between empiric and calculated activities were confronted to clinical outcomes. Physicians were not aware of the calculated activity at the time of prescription. One year after treatment, 9% (5/57) of GD patients and 7% (2/29) of MNG patients were still in a hyperthyroid state. Thyroid volume was reduced by 67% for GD and by 50% for MNG. In GD, empiric I activities were higher than calculated ones (564±131 vs. 316±319 MBq, P<0.001) in 93% (53/57) of patients. Pretherapeutic thyroid volume (>26 ml for GD; >40 ml for MNG) was associated with persistent hyperthyroidism. Empirically administered I for GD and MNG was associated with very high efficacy in thyroid function control and no side effects. Thyroid volume reduction did not preclude treatment efficacy. Activity calculation could be a useful method for treating patients with GD and thyroid volumes higher than 26 ml or patients with MNG and thyroid volumes higher than 40 ml. A selective approach based on pretherapeutic thyroid volume and radioiodine biokinetics might improve treatment success.

Chronic Hepatitis B Virus (HBV) infection poses a significant global health burden. Although, effective treatment and vaccinations against HBV are available, challenges still exist, particularly in the development of curative therapies. The dynamic nature and unique features of HBV such as viral variants, integration of HBV DNA into host chromosomes, and extrahepatic reservoirs are considerations towards understanding the virus biology and developing improved anti-HBV treatments. In this review, we highlight the importance of these viral characteristics in the context of treatment and oncogenesis. Viral genotype and genetic variants can serve as important predictive factors for therapeutic response and outcomes in addition to oncogenic risk. HBV integration, particularly in coding genes, is implicated in the development of hepatocellular carcinoma. Furthermore, we will discuss emerging research that has identified various HBV nucleic acids and infection markers within extrahepatic sites (lymphoid cells). Intriguingly, the presence of hepatocellular carcinoma (HCC)-associated HBV variants and viral integration within the lymphoid cells may contribute towards the development of extrahepatic malignancies. Improved understanding of these HBV characteristics will enhance the development of a cure for chronic HBV infection.

To evaluate the influence of facial biotype in the therapeutic effect of mandibular advancement devices (MADs) according to polysomnographic records in patients diagnosed with sleep apnea-hypopnea syndrome (SAHS). A total of 46 patients were recruited. Patients were classified according to facial biotype (mesofacial, brachyfacial, or dolichofacial). The quantitative variables were described as the arithmetic mean and standard deviation or the median and interquartile range. Hypothesis tests used were Pearson's chi-square, paired-sample Student's t- test, the Wilcoxon test, one-way analysis of variance, Kruskal-Wallis test, and Mann-Whitney U-test. P < .05 was considered statistically significant. A total of 46 patients were categorized into three facial biotype subgroups with no significant differences among them in age, body mass index, neck circumference, and sex. The respiratory disturbance index (RDI) results were as follows: brachyfacial patients had a reduction to 15 events/h (P < .001), the mesofacial patients had a reduction to 14 events/h (P < .001), and the dolichofacial patients did not show a significant reduction. The oxygen desaturation index (ODI) results were as follows: brachyfacial patients had a reduction in ODI episodes to 45 episodes/h (P = .001), mesofacial patients had a reduction to 18 episodes/h (P = .001). In the brachyfacial group, the number of awakenings with MAD therapy was reduced to 23 events/h (P = .003), while, in the mesofacial group, it was reduced to 37 episodes/h (P = .012). The facial biotype influences the effectiveness of MAD therapy and is considered a good predictive factor.

BACKGROUND: Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram. METHODS: We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018. RESULTS: Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041). CONCLUSIONS: Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients. Citation Format: Rui Kitadai, Akihiro Yoshimura, Tadaaki Yamada, Yusuke Okuma, Takayuki Takeda, Takanori Kanematsu, Junji Uchino, Yasuhiko Nishioka, Koichi Takayama. Retrospective analysis of docetaxel in combination with ramucirumab for previously treated non-small cell lung cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4306.

ObjectiveThe safety and efficacy of transcranial magnetic stimulation (TMS) in the acute treatment of major depressive disorder (MDD) is well established. However, it is not well understood which patient-related factors are associated with a more robust antidepressant response. Identifying predictive factors for therapeutic response to TMS treatment in depression will guide clinicians in patient selection.MethodsBy systematic review of clinical trial data, the current study aims to identify and analyze reported patient-specific predictors of response to an acute course of TMS treatment for MDD. PubMed was searched for randomized controlled trials of TMS for patients with depression. Studies were appraised for risk of bias using components recommended by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.ResultsTMS data were available from 375 studies, 18 of which were included in this review. Treatment response is inversely associated with treatment refractoriness and age.ConclusionInadequate sample size and large heterogeneity in study parameters among clinical trials limit any strong conclusions from being drawn; nonetheless, despite these limitations, there is mounting evidence, which points to age and treatment refractoriness as candidate variables for predicting clinical outcome. Implications of these findings for treatment of MDD are discussed.

The current standard therapy for chronic hepatitis C is pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy. Recently, it has been reported that amino acid (aa) substitutions in the core region, as well as the IFN-sensitivity-determining region (ISDR), were predictive of non-virological response (NVR), sustained virological response (SVR) and early virological response. Despite the importance of these two predictive factors for combination therapy, their interaction is poorly understood. A total of 117 patients who were treated with PEG-IFN-α2b plus RBV combination therapy were selected for participation in this study. We determined the aa sequences in the core region and ISDR by direct sequencing and analysed them along with clinical data to identify predictive factors for therapeutic response. The aa sequences in the core region and γ-glutamyl transpeptidase (GTP) levels were associated with SVR and NVR, but aa sequences in the ISDR were not. However, substitutions at both aa 70 and aa 91 in the core region without substitutions in the ISDR and higher levels of γ-GTP were independent predictive factors for NVR. Wild-type aa 70 and aa 91 in the core region, higher platelet counts and lower levels of γ-GTP were independent predictive factors for SVR. These results indicate that analyses of aa substitutions in both the core region and the ISDR are useful for predicting the effectiveness of combination therapy, and could help to avoid therapy exposure for patients who have a low probability of SVR.

Circumscribed choroidal haemangioma (CCH) can cause visual impairment, primarily managed with photodynamic therapy (PDT). This study aimed to identify predictive factors of therapeutic response in patients with CCH treated with PDT and to analyse serial anatomical outcomes, focusing on visual acuity, tumour characteristics, and inner retinal microstructures. This retrospective study included patients diagnosed with CCH at Severance Eye Hospital, Yonsei University, from January 2005 to December 2022. We reviewed patient records and multimodal imaging, assessing demographics, including post-PDT visual acuity changes, age, laterality and sex, and multimodal imaging features such as tumour location and height, presence of subfoveal subretinal fluid (SRF), enhanced reflectivity of the retinal pigment epithelium and external limiting membrane (ELM) disruption. Among 114 patients with CCH (82 men, 65.6%; mean age 52.1±14.0 years), 45 (39.5%) had asymptomatic CCH, while 69 (60.5%) presented with symptomatic CCH. PDT was administered to 41 symptomatic patients (59.4%). The pretreatment LogMAR visual acuity was 0.50±0.63, which remained stable 1 year after PDT (0.53±0.64, p=0.666). However, it worsened 3 years after PDT (0.81±0.89, p=0.024), around the time tumour regrowth was observed. At 1-year post-PDT, tumour volume and height decreased by an average of 34.6% and 32.4%, respectively, accompanied by a 75.0% reduction in SRF. Patients with >75% vol reduction showed greater SRF persistence, while a higher initial SRF height was associated with complete SRF absorption following PDT. ELM disruption was identified as a significant predictor of poorer visual acuity, reduced tumour volume response and limited SRF absorption. The presence of SRF predicts favourable tumour size reduction and SRF absorption post-PDT, while ELM disruption serves as an important prognostic factor for visual acuity and structural outcomes, aiding in pre-PDT treatment planning.

Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram. We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018. Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041). Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients.

Predictors of response to repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder

Symptom Pattern At Baseline Predicts Treatment Response in Erosive Esophagitis Patients