Confocal Laser Endomicroscopy for Diagnosis of Barrett’s Esophagus

Barrett’s esophagus (BE) is established as a premalignant condition in the distal esophagus. Current surveillance guidelines recommend random biopsies every 1–2 cm at intervals of 3–5 years. Advanced endoscopic imaging of BE underwent several technical revolutions within the last decade including broad-field (red-flag) techniques (e.g., chromoendoscopy) and small-field techniques with confocal laser endomicroscopy (CLE) at the forefront. In this review we will focus on advanced endoscopic imaging using CLE for the diagnosis and characterization of BE and associated neoplasia. In addition, we will critically discuss the technique of CLE and provide some tricks and hints for the daily routine practice of CLE for diagnosis of BE

Automatic evaluation of tumor budding in immunohistochemically stained colorectal carcinomas and correlation to clinical outcome

Background: Tumor budding, meaning a detachment of tumor cells at the invasion front of colorectal carcinoma (CRC) into single cells or clusters (<=5 tumor cells), has been shown to correlate to an inferior clinical outcome by several independent studies. Therefore, it has been discussed as a complementary prognostic factor to the TNM staging system, and it is already included in national guidelines as an additional prognostic parameter. However, its application by manual evaluation in routine pathology is hampered due to the use of several slightly different assessment systems, a time-consuming manual counting process and a high inter-observer variability. Hence, we established and validated an automatic image processing approach to reliably quantify tumor budding in immunohistochemically (IHC) stained sections of CRC samples. Methods: This approach combines classical segmentation methods (like morphological operations) and machine learning techniques (k-means and hierarchical clustering, convolutional neural networks) to reliably detect tumor buds in colorectal carcinoma samples immunohistochemically stained for pan-cytokeratin. As a possible application, we tested it on whole-slide images as well as on tissue microarrays (TMA) from a clinically well-annotated CRC cohort. Results: Our automatic tumor budding evaluation tool detected the absolute number of tumor buds per image with a very good correlation to the manually segmented ground truth (R2 value of 0.86). Furthermore the automatic evaluation of whole-slide images from 20 CRC-patients, we found that neither the detected number of tumor buds at the invasion front nor the number in hotspots was associated with the nodal status. However, the number of spatial clusters of tumor buds (budding hotspots) significantly correlated to the nodal status (p-value = 0.003 for N0 vs. N1/N2). TMAs were not feasible for tumor budding evaluation, as the spatial relationship of tumor buds (especially hotspots) was not preserved. Conclusions: Automatic image processing is a feasible and valid assessment tool for tumor budding in CRC on whole-slide images. Interestingly, only the spatial clustering of the tumor buds in hotspots (and especially the number of hotspots) and not the absolute number of tumor buds showed a clinically relevant correlation with patient outcome in our data

Radical nephroureterectomy for pathologic T4 upper tract urothelial cancer: can oncologic outcomes be improved with multimodality therapy?

Purpose To report the outcomes of patients with pathologic T4 UTUC and investigate the potential impact of peri-operative chemotherapy combined with radical nephroureterectomy (RNU) and regional lymph node dissection (LND) on oncologic outcomes. Materials and Methods Patients with pathologic T4 UTUC were identified from the cohort of 1464 patients treated with RNU at 13 academic centers between 1987 and 2007. Oncologic outcomes were stratified according to utilization of perioperative systemic chemotherapy and regional LND as an adjunct to RNU. Results The study included 69 patients, 42 males (61%) with median age 73 (range 43-98). Median follow-up was 17 months (range: 6-88). Lymphovascular invasion was found in 47 (68%) and regional lymph node metastases were found in 31 (45%). Peri-operative chemotherapy was utilized in 29 (42%) patients. Patients treated with peri-operative chemotherapy and RNU with LND demonstrated superior oncologic outcomes compared to those not treated by chemotherapy and/or LND during RNU (3Y-DFS: 35% vs. 10%; P = 0.02 and 3Y-CSS: 28% vs. 14%; P = 0.08). In multivariate Cox regression analysis, administration of peri-operative chemotherapy and utilization of LND during RNU was associated with lower probability of recurrence (HR: 0.4, P = 0.01), and cancer specific mortality (HR: 0.5, P = 0.06). Conclusions Pathological T4 UTUC is associated with poor prognosis. Peri-operative chemotherapy combined with aggressive surgery, including lymph node dissection, may improve oncological outcomes. Our findings support the use of aggressive multimodal treatment in patients with advanced UTUC

Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2<SUP>-/-</SUP> mice

24-norursodeoxycholic acid (norUDCA), a side chain-modified ursodeoxycholic acid derivative, has dramatic therapeutic effects in experimental cholestasis and may be a promising agent for the treatment of cholestatic liver diseases. We aimed to better understand the physiologic and therapeutic properties of norUDCA and to test if they are related to its side chain length and/or relative resistance to amidation. For this purpose, Mdr2-/- mice, a model for sclerosing cholangitis, received either a standard diet or a norUDCA-, tauro norursodeoxycholic acid (tauro- norUDCA)-, or di norursodeoxycholic acid (di norUDCA)-enriched diet. Bile composition, serum biochemistry, liver histology, fibrosis, and expression of key detoxification and transport systems were investigated. Direct choleretic effects were addressed in isolated bile duct units. The role of Cftr for norUDCA-induced choleresis was explored in Cftr-/- mice. norUDCA had pharmacologic features that were not shared by its derivatives, including the increase in hepatic and serum bile acid levels and a strong stimulation of biliary HCO3- -output. norUDCA directly stimulated fluid secretion in isolated bile duct units in a HCO3- -dependent fashion to a higher extent than the other bile acids. Notably, the norUDCA significantly stimulated HCO 3- -output also in Cftr-/- mice. In Mdr2-/- mice, cholangitis and fibrosis strongly improved with norUDCA, remained unchanged with tauro- norUDCA, and worsened with di norUDCA. Expression of Mrp4, Cyp2b10, and Sult2a1 was increased by norUDCA and di norUDCA, but was unaffected by tauro- norUDCA. Conclusion:The relative resistance of norUDCA to amidation may explain its unique physiologic and pharmacologic properties. These include the ability to undergo cholehepatic shunting and to directly stimulate cholangiocyte secretion, both resulting in a HCO3- -rich hypercholeresis that protects the liver from cholestatic injury

The Impact of Previous Ureteroscopic Tumor Ablation on Oncologic Outcomes After Radical Nephrouretectomy for Upper Urinary Tract Urothelial Carcinoma

We investigated whether a history of endoscopic tumor ablation impacts oncologic outcomes after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). Using a multi-institutional database that contained patients who were treated with RNU, oncologic outcomes were assessed according to history of ureteroscopic tumor ablation. Disease-free survival (DFS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier survival analysis. Multivariate Cox regression analyses were performed to determine independent predictors of disease recurrence and cancer-specific mortality after RNU. The study included 1268 patients, 853 men and 415 women, with a mean age of 67.5 years (range 32-94 y) and 52.8 months median follow-up after RNU. A total of 175 (13%) patients underwent RNU after endoscopic tumor ablation and 1093 (87%) patients underwent RNU without a history of endoscopic ablation. The 5-year DFS and CSS rates were 72% and 77% in those with a history of tumor ablation vs 69% and 73% in those without a history of ablation (P = 0.171 and P = 0.365, respectively). In multivariate Cox regression analysis, history of ablation therapy was not associated with disease recurrence or cancer-specific mortality (hazard ratio [HR]: 0.79, P = 0.185 and HR: 0.7, P = 0.078, respectively). Our collaborative international efforts suggest that in selected patients, endoscopic tumor ablation does not adversely affect the recurrence and survival after subsequent RNU for UTUC. Our data support the continued role of ureteroscopic ablation of UTUC in appropriately selected patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90497/1/end-2E2010-2E0396.pd

Upper urinary tract urothelial carcinoma with loco‐regional nodal metastases: insights from the Upper Tract Urothelial Carcinoma Collaboration

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86906/1/j.1464-410X.2011.10075.x.pd

Advanced patient age is associated with inferior cancer-specific survival after radical nephroureterectomy

Study Type – Prognosis (case series) Level of Evidence 4To assess the impact of patient age on outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).Data were collected on 1453 patients treated with RNU at 13 centres. Pathological slides were reviewed by dedicated genitourinary pathologists according to standardized criteria. Age at RNU was analysed both as a continuous and categorical variable (70 years were less likely to undergo lymphadenectomy and to receive adjuvant chemotherapy ( P  ≤ 0.026). In multivariable analyses, being older was associated with decreased all-cause (AC) survival (>60 years) and cancer-specific survival (CSS; >80 years) after controlling for the effects of standard pathological features ( P  ≤ 0.006). However, addition of age did not improve the predictive accuracy of a base model that included standard pathological features for prediction of either disease recurrence, AC survival or CSS.Being older at the time of RNU was associated with decreased survival. This finding could be due to a change in the biological potential of the tumour cell, a decrease in the host’s defence mechanisms, or differences in care patterns. Further work is needed to improve our understanding of UTUC outcomes in this growing segment of the population and to develop strategies to improve cancer control in the elderly.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78588/1/j.1464-410X.2009.09072.x.pd

Interobserver agreement of estimating the extent of intestinal metaplasia in patients with chronic atrophic gastritis

The extent of gastric intestinal metaplasia (GIM) can be used to determine the risk of gastric cancer. Eleven international gastrointestinal expert pathologists estimated the extent of GIM on haematoxylin and eosin (H&E)- and Alcian blue-Periodic acid Schiff (AB-PAS)-stained slides of 46 antrum biopsies in 5% increments. Interobserver agreement was tested with the intraclass correlation coefficient (ICC). Correlation between standard deviation and extent of GIM was evaluated with the Spearman correlation. The interobserver agreement was very good (ICC = 0.983, 95% confidence interval (CI) 0.975–0.990). The use of AB-PAS did not increase the agreement (ICC = 0.975, 95% CI 0.961–0.985). Cases with a higher amount of metaplastic epithelium demonstrated a higher standard deviation (rs = 0.644; p < 0.01), suggesting lower diagnostic accuracy in cases with extensive GIM. In conclusion, estimating the extent of GIM on H&E-stained slides in patients with chronic atrophic gastritis can be achieved satisfactorily with high interobserver agreement, at least among international expert gastrointestinal pathologists.Open access funding provided by Medical University of Graz.https://www.springer.com/journal/428am2023Anatomical Patholog