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Funder: MUG (within the PhD program Molecular Medicine), Funder: Austrian Society of Internal Medicine (Joseph-Skoda Award), Austrian Science Fund (grant P32783), Austrian Society of Hematology and Medical Oncology (Clinical Research Grant) and MEFOgraz, Funder: Austrian Science Fund (grant P 31430-458 B26) and Leukämiehilfe Steiermark, Funder: Austrian Society of Internal Medicine (Joseph-Skoda Award)and Leukämiehilfe Steiermark

ObjectivesImmunocompromised patients are at risk of severe coronavirus disease 2019 and are considered a high priority for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Humoral vaccination response is impaired in these patients when circulating B cells are lacking. We aimed to analyze B-cell subsets at the time of vaccination to identify potential predictors of humoral vaccination response. MethodsPatients (n=120) receiving B-cell-depleting therapy (n=41), those suffering from inborn errors of immunity (n=25) and hematologic malignancies (n=56), and healthy controls (n=79) were vaccinated twice with BNT162b2 or mRNA-1273. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 S immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. ResultsSeroconversion occurred in 100% of the healthy controls, in contrast to 67% (RBD) and 82% (TSP) of the patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating naive B cell was strongly associated with antibody levels (r=0.761, P

Background A combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line therapy for diffuse large B cell lymphoma (DLBCL), the most common aggressive lymphoma in adults. One of the major adverse effects of this regimen is vincristine-induced polyneuropathy which leads to discontinuation of vincristine in up to 30% of DLBCL-patients. Dose reduction of vincristine might worsen treatment outcomes of DLBCL but identification of treatment alternatives for patients exhibiting peripheral neuropathy during R-CHOP is an unmet need in hematology. Methods In this retrospective cohort study, comprising 987 patients with de novo DLBCL, we delineated the role of vinorelbine as a substitute for vincristine in R-CHOP by measuring improvements in neuropathy and outcome variables. Results Five-year overall survival (OS) and progression-free survival (PFS) were 72.6% and 63.1% in patients who received regular doses of vincristine, as compared to 60.6% and 51.7% in patients who received reduced doses of vincristine (p = 0.022 and p = 0.003, respectively). Of 199 patients who switched to vinorelbine, the majority experienced an improvement of neuropathy Furthermore, vinorelbine-switched patients showed favorable oncologic outcomes. Conclusion Replacement of vincristine by vinorelbine due to neuropathy is effective and safe, and results in a significant improvement in neuropathy as compared to treatment with R-CHOP.

Hypermethylation of the paired-like homeodomain transcription factor 2 (PITX2) gene is a strong predictor of the risk of biochemical recurrence in patients with prostate cancer (PCa) after radical prostatectomy. We investigate whether PITX2 methylation is feasible for individualized risk assessment in prostate core biopsies before surgery. A quantitative, methylation-specific real-time PCR was used to measure PITX2 in three cohorts: i) matched samples of neoplastic and nonneoplastic tissue from 24 patients with PCa, ii) a well-characterized cohort of 300 patients with PCa after radical prostatectomy, and iii) core biopsy specimens from 32 patients with PCa and 31 patients with benign prostatic disease. PITX2 methylation discriminated between neoplastic and nonneoplastic tissue in patients with PCa (P 0.001). In the second cohort, PITX2 methylation significantly correlated with clinicopathologic parameters, and PITX2 hypermethylation predicted an increased risk of biochemical recurrence in univariate Cox proportional hazards regression analysis (hazard ratio, 1.77; P = 0.046) and Kaplan-Meier analysis (P = 0.043). In 753 prostate biopsies, 720 (95.6%) were applicable for analysis, rendering the assay feasible for diagnostic biopsies. PITX2 methylation was furthermore significantly increased in tumor-positive biopsies and strongly correlated with International Society of Urological Pathology (ISUP) grade groups. This study indicates that the PITX2 methylation assay is feasible in prostate biopsies and might add valuable prognostic information for risk assessment in a presurgical diagnostic setting.

Objective The purpose of this retrospective study was to evaluate the families’ compliance with recommendations for continued monitoring of babies with high-risk factors for hearing loss. Methods Hearing screening and follow-up results from 604 babies were tracked across a five-year period. Bivariate analysis, including chi-square analysis, t-tests, and one-way analyses of variance were conducted to test whether various factors predicted likelihood of follow up. Results Although 86% of the babies returned for the initial follow-up appointment, few completed the protocol or were diagnosed with hearing loss (10.3%). Excluding the babies who never returned, the average age for initial assessment was near the recommended 3-month target (3.5 months). However, babies were last seen at 9.4 months on average, which is earlier than recommended. Some factors positively predicted follow-up: receipt of ototoxic medication, hyperbilirubinemia requiring transfusion, ECMO, syndromes associated with hearing loss, craniofacial anomalies, and passing the newborn hearing screening. Others were negatively predictive: NICU stay >5 days, younger maternal age, and failing the newborn screening. There was no relationship between the results of the last test and whether the families continued with monitoring. Babies with risks categorized as more likely to be associated with delayed onset hearing loss were more often late to the initial follow up, but also followed up for a longer period of time. Conclusions These results demonstrate the need to focus on the barriers unique to babies with risk factors for late onset/progressive hearing loss in addition to those barriers that generally affect loss to follow up. Tools for parental engagement are recommended.

In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-&kappa, B/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

Purpose: Therapies targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway promote anti-tumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer. Experimental Design: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome. Results: In the training cohort (n = 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67, P < 0.001), Gleason score (P = 0.004), and androgen receptor (AR) expression (P < 0.001). Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR; P = 0.004; HR, 2.37; 95% confidence interval (CI), 1.32–4.25]. In the test cohort (n = 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P = 0.011; HR, 1.49; 95% CI, 1.10–2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P < 0.001). In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P = 0.007; HR, 1.46; 95% CI, 1.11–1.92). Conclusions: We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1–targeted therapy might be a treatment option for hormone-naïve prostate cancers. Clin Cancer Res; 22(8); 1969–77. ©2015 AACR.

Background New treatment modalities and a growing understanding of the complex genetic tumor landscape have improved the outcome of colorectal cancer (CRC) patients. Nonetheless, more individualized treatment regimens, taking individual tumor characteristics into account, have been recently postulated and prognostic biomarkers are needed. We therefore evaluated the prognostic potential of paired-like homeodomain transcription factor 2 ( PITX2 ) promoter methylation in CRC patients. Materials and Methods Data of 2 independent cohorts were investigated. Tissue specimens of cohort A (n = 179) were analyzed for their methylation in the PITX2 promoter region using quantitative methylation-specific polymerase chain reaction and compared with publicly available data ( PITX2 promoter methylation and PITX2 mRNA expression levels) from “The Cancer Genome Atlas Research Network” (cohort B, n = 443). Data were correlated with clinicopathological parameters and outcome. Results Tumor samples of both cohorts showed a decreased PITX2 promoter methylation level (both P PITX2 promoter hypomethylation was prognostic in univariate and multivariate analysis (hazard ratio [HR], 1.97 [95% confidence interval (CI), 1.12-3.47], P = .018 and HR, 1.89 [95% CI, 1.09-3.29], P = .023), and Kaplan–Meier analysis (median overall survival, 53.2 vs. 70.4 months, P = .004). Subanalysis of high-risk vs. low-risk stage II CRC patients also showed a PITX2 hypomethylation of the promoter region in the high-risk group ( P = .006). Conclusion Our results suggest a prognostic role of PITX2 promoter methylation in CRC as biomarker for risk stratification in stage II CRC patients although the results need to be independently validated.

Pleural effusions (PE) are a common clinical problem. The discrimination between benign (BPE), malignant (MPE) and paramalignant (PPE) pleural effusions is highly important to ensure appropriate patient treatment. Today, cytology is the gold standard for diagnosing malignant pleural effusions. However, its sensitivity is limited due to the sometimes low abundance of tumor cells and the challenging assessment of cell morphology in cytological samples. This study aimed to develop and validate a diagnostic test, which allows for the highly specific detection of malignant cells in pleural effusions based on the DNA methylation biomarkers SHOX2 and SEPT9. A quantitative real-time PCR assay was developed which enabled the accurate and sensitive detection of SHOX2 and SEPT9 in PEs. Cytological and DNA methylation analyses were conducted in a case control study comprised of PEs from 114 patients (58 cases, 56 controls). Cytological analysis as well as SHOX2 and SEPT9 methylation resulted in 100% specificity. 21% of the cases were cytologically positive and 26% were SHOX2 or SEPT9 methylation positive. The combined analysis of cytology and DNA methylation resulted in an increase of 71% positively classified PEs from cancer patients as compared to cytological analysis alone. The absolute sensitivity of cytology and DNA methylation was not determinable due to the lack of an appropriate gold standard diagnostic for distinguishing between MPEs and PPEs. Therefore, it was unclear which PEs from cancer patients were malignant (containing tumor cells) and which PEs were paramalignant and resulted from benign conditions in cancer patients, respectively. Furthermore, DNA methylation analysis in PEs allowed the prognosis of the overall survival in cancer patients (Kaplan-Meier analysis, log rank test, p = 0.02 (SHOX2), p = 0.02 (SEPT9)). The developed test may be used as a diagnostic and prognostic adjunct to existing clinical and cytopathological investigations in patients with PEs of unclear etiology.