Evaluating the interreader agreement and intrareader reproducibility of Visual Field Defects in Thyroid Eye Disease- Compressive Optic Neuropathy

PURPOSE To categorize visual field (VF) defects according to Freitag and Tanking's (FT) classification in Thyroid Eye Disease-Compressive Optic Neuropathy (TED-CON) and evaluate the interreader agreement and intrareader reproducibility of the classification. SUBJECTS AND METHODS In this retrospective, observational study we included medical reports of 96 eyes (51 patients), who underwent VF testing with TED-CON in Ludwig-Maximilians-University (2008-2019). Two readers separately examined the VFs at the time of the TED-CON diagnosis, each offering two readings of the same VF in a time interval of 1 month. None of our patients were diagnosed with only VF testing. The visual field testing was only performed when the inclusion criteria for TED-CON were met. RESULTS The most common VF defects upon TED-CON diagnosis were stage 1b defects in FT classification (34.4% for reader 1, 35.4% for reader 2), followed by stage 2b (10.4% for reader 1, 14.6% for reader 2), and stage 3 (10.4% for both readers). The overall interreader agreement between 2 examiners was substantial for the first reading (69.8% agreement, kappa 0.635 (95% CI 0.525-0.745)) and moderate for the second reading (66.7{\%} agreement, kappa 0.598 (95{\%} CI 0.488-0.708)). The intrareader reproducibility ranged from substantial to almost perfect (78.1{\%} agreement) between readings (kappa 0.736 (95{\%}CI 0.638-0.834)) for reader 1 and 90.6{\%} agreement (kappa 0.885 (95{\%}CI 0.814-0.956)) for reader 2. CONCLUSION We found good BCVA (LogMAR $\leq$ 0.2), in nearly half of the cases (44 eyes, 45.8{\%}) and also, strikingly near perfect visual acuity (BCVA LogMAR $\leq$0.1) in 22.9{\%} of the cases (22 eyes) with TED-CON. We conclude that clinicians should be alert to VF defects in the inferior region (stage 1a/1b in the FT classification) even in patients with a good BCVA

A pathological indicator for dysthyroid optic neuropathy: tritan color vision deficiency

PURPOSE To investigate the sensitivity of the color vision test by Arden in patients with dysthyroid optic neuropathy (DON) to improve diagnosis. METHODS In this observational, retrospective study, we included the medical records of 92 eyes (48 patients) with diagnosis of DON between 2008 and 2019 in order to evaluate the full spectrum of findings from the color vision test by Arden, and to determine potential importance of this test. Thirty-five patients were female, and 13 patients were male. The mean age was 58.0~years (range: 34-79) at the time of the DON diagnosis. RESULTS Forty-one eyes displayed relatively good BCVA with ≤ 0.2 LogMAR. We found a protan value exceeding the threshold of ≥ 8% in 57 eyes (30 patients) at the time of the diagnosis. The sensitivity of protan was 61.9% (95% CI 51.2-71.8%), while that of tritan was a striking 98.9% (95% CI 94.1-99.9%). We discovered one pathological sign, tritan deficiency (based on a threshold of ≥ 8%) consistently in all eyes but one at the time of the diagnosis, regardless of the visual field defects or any changes in best-corrected visual acuity (BCVA). CONCLUSION We found blue-yellow (tritan) deficiency, to be a sensitive and reliable indicator of dysthyroid optic neuropathy. We conclude that, in cases with suspected DON, a color vision test that can detect tritan deficiency is an essential tool for the adequate assessment, diagnosis, and treatment of DON

Computational modeling of methionine cycle-based metabolism and DNA methylation and the implications for anti-cancer drug response prediction

The relationship between metabolism and methylation is considered to be an important aspect of cancer development and drug efficacy. However, it remains poorly defined how to apply this aspect to improve preclinical disease characterization and clinical treatment outcome. Using available molecular information from Kyoto Encyclopedia of Genes and Genomes (KEGG) and literature, we constructed a large-scale knowledge-based metabolic in silico model. For the purpose of model validation, we applied data from the Cancer Cell Line Encyclopedia (CCLE) to investigate computationally the impact of metabolism on chemotherapy efficacy. In our model, different metabolic components such as MAT2A, ATP6V0E1, NNMT involved in methionine cycle correlate with biologically measured chemotherapy outcome (IC50) that are in agreement with findings of independent studies. These proteins are potentially also involved in cellular methylation processes. In addition, several components such as 3,4-dihydoxymandelate, PAPSS2, UPP1 from metabolic pathways involved in the production of purine and pyrimidine correlate with IC50. This study clearly demonstrates that complex computational approaches can reflect findings of biological experiments. This demonstrates their high potential to grasp complex issues within systems medicine such as response prediction, biomarker identification using available data resources

Colonoscopy and polypectomy: beside age, size of polyps main factor for long-term risk of colorectal cancer in a screening population

PURPOSE Despite national and international guideline recommendations, few studies have been conducted to estimate the impact of colonoscopy screening on long-term colorectal cancer incidence. Aim of this study was to determine the long-term impact of a full colonoscopy with polypectomy on colorectal cancer incidence in a large screening population. METHODS In this prospective observational cohort study, a total of 10,947 colonoscopy screening participants from within the scope of the Munich Cancer Registry were consecutively recruited from participating gastroenterology practices and their subsequent colorectal cancer incidence assessed. Predictive factors associated with colorectal cancer were also evaluated in univariate and multivariate analyses. RESULTS After a median follow-up of 14.24~years (95% CI 14.21-14.25), 93 colorectal cancer cases were observed. This is equivalent to a truncated age-standardized rate of 69.0 (95{\%} CI 43.3-94.7) for male and 43.4 (95{\%} CI 29.4-57.5) for female participants ($\geq$ 50~years at colonoscopy). The ratio of this observed to the expected rate from cancer registry data showed a 67{\%} decrease in colorectal cancer incidence in the male and 65{\%} in the female participants (p {\textless} 0.0001). In multivariate analysis of screening patients, age at screening (p {\textless} 0.0001) was the main predictive factor for colorectal cancer. In the subgroup with positive polyp findings, age (p {\textless} 0.0001) and the polyp size (p = 0.0002) were associated with colorectal cancer. CONCLUSION These results underline the significance of a full colonoscopy screening combined with polypectomy in reducing the total disease burden of colorectal cancer

Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids

Background Targeted anti-HER2 therapy has greatly improved the prognosis for many breast cancer patients. However, treatment for HER2 negative disease is currently still selected from a multitude of untargeted chemotherapeutic treatment options. A predictive test was developed using patient-derived spheroids to identify the most effective therapy for patients with HER2 negative breast cancer of all stages, for clinically relevant subgroups, as well as individual patients. Methods Tumor samples from 120 HER2 negative patients obtained through biopsy or surgical excision were tested in the breast cancer spheroid model using scaffold-free cell culture. Similarly, spheroids were also generated from established HER2 negative breast cancer cell lines T-47D, MCF7, HCC1143, and HCC1937 to compare treatment efficacy of heterogeneous cell populations from patient tumor tissue with homogeneous cell lines. Spheroids were treated in vitro with guideline-recommended compounds. Treatment mediated impact on cell survival was subsequently quantified using an ATP assay. Results Differences were observed in the metabolic activity of the untreated spheroids, whereby cell lines consistently achieved higher values compared to tissue spheroids (p < 0.001). A higher number of cells per spheroid correlated with a higher basal metabolic activity in tissue-derived spheroids (p < 0.01), while the opposite was observed for cell line spheroids (p < 0.01). Recurrent tumors showed a higher mean vitality (p < 0.01) compared to primary tumors. Except for taxanes, treatment efficacy for most tested compounds differed significantly between breast cancer tissue spheroids and breast cancer cell lines. Overall a high variability in treatment response in vitro was seen in the tissue spheroids regardless of the tested substances. A greater response to anthracycline/docetaxel was observed for hormone receptor negative samples (p < 0.01). A higher response to 5-FU (p < 0.01) and anthracycline (p < 0.05) was seen in high grade tumors. Smaller tumor size and negative lymph node status were both associated with a higher treatment efficacy to anthracycline treatment combined with 5-FU (cT1/2 vs cT3/4, p = 0.035, cN+ vs cN−, p < 0.05). Conclusions The tissue spheroid model reflects current guideline treatment recommendations for HER2 negative breast cancer, whereas tested cell lines did not. This model represents a unique diagnostic method to select the most effective therapy out of several equivalent treatment options

Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy--the SpheroNEO study

Background Aim of this prospective study was to predict response to neoadjuvant therapy in breast cancer patients using an in vitro breast cancer spheroid model. Methods Three-dimensional spheroids were directly generated from fresh breast tumor biopsies of 78 patients eligible for neoadjuvant therapy. Cell survival was measured after in vitro exposure to the equivalent therapeutic agents in the breast cancer spheroid model. Treatment results in vitro were correlated with pathological complete response (pCR, i.e. ypT0 ypN0) determined at surgery. Results A mean cell survival of 21.8 % was found in the breast cancer spheroid model for 22 patients with pCR versus 63.8 % in 56 patients without pCR (P = .001). The area under the receiver operator characteristic curve to predict pCR was 0.86 (95 % CI: 0.77 to 0.96) for cell survival in vitro compared to 0.80 (95 % CI: 0.70 to 0.90) for a combined model of conventional factors (hormone- and HER2 receptor, and age). A cutoff at 35 % cell survival for the spheroid model was proposed. Out of the 32 patients with values below this threshold, 21 patients (65.6 %) and one patient (2.2 %) with a cell survival greater than 35 % achieved pCR respectively; (sensitivity 95.5 % (95 % CI: 0.86 to 1.00); specificity 80.4 % (95 % CI: 0.70 to 0.91)). Extent of residual disease positively correlated with increased cell survival (P = .021). Conclusion The breast cancer spheroid model proved to be a highly sensitive and specific predictor for pCR after neoadjuvant chemotherapy in breast cancer patients

Loss of SATB2 Occurs More Frequently Than CDX2 Loss in Colorectal Carcinoma and Identifies Particularly Aggressive Cancers in High-Risk Subgroups

BACKGROUND Special AT-rich sequence-binding protein 2 (SATB2) has emerged as an alternative immunohistochemical marker to CDX2 for colorectal differentiation. However, the distribution and prognostic relevance of SATB2 expression in colorectal carcinoma (CRC) have to be further elucidated. METHODS SATB2 expression was analysed in 1039 CRCs and correlated with clinicopathological and morphological factors, CDX2 expression as well as survival parameters within the overall cohort and in clinicopathological subgroups. RESULTS SATB2 loss was a strong prognosticator in univariate analyses of the overall cohort (p \textless 0.001 for all survival comparisons) and in numerous subcohorts including high-risk scenarios (UICC stage III/high tumour budding). SATB2 retained its prognostic relevance in multivariate analyses of these high-risk scenarios (e.g., UICC stage III: DSS: p = 0.007, HR: 1.95), but not in the overall cohort (DSS: p = 0.1, HR: 1.25). SATB2 loss was more frequent than CDX2 loss (22.2% vs. 10.2%, p \textless 0.001) and of higher prognostic relevance with only moderate overlap between SATB2/CDX2 expression groups. CONCLUSIONS SATB2 loss is able to identify especially aggressive CRCs in high-risk subgroups. While SATB2 is the prognostically superior immunohistochemical parameter compared to CDX2 in univariate analyses, it appears to be the less sensitive marker for colorectal differentiation as it is lost more frequently