Low-grade Neoplasia Research Articles

Loss of MTAP Expression by Immunohistochemistry Is a Surrogate Marker for Homozygous 9p21.3 Deletion in Urothelial Carcinoma

Homozygous deletion of the chromosomal region 9p21.3 is common in urothelial carcinoma (UC) and leads to loss of several genes, including CDKN2A and MTAP, resulting in loss of MTAP protein expression. Here, we aimed to explore the diagnostic potential of MTAP immunohistochemistry (IHC) as a surrogate marker for homozygous 9p21.3 deletion (9p21 homozygous deletion [HD]) in UC. MTAP status was determined by IHC on 27 UC tissue specimens with known 9p21.3 status as defined by fluorescence in situ hybridization in matched cytological specimens, by IHC and fluorescence in situ hybridization on a tissue microarray (TMA) containing 359 UC at different stages, and by IHC on 729 consecutive UC from routine practice. Moreover, we analyzed a longitudinal series of matched specimens from 38 patients with MTAP-negative recurrent UC. MTAP loss by IHC was found in all 17 patients with 9p21 HD and in 2/8 cases without 9p21 HD. In the TMA, MTAP loss was more common in metastases (53%) than in muscle-invasive (33%) and non–muscle-invasive UC (29%) (P = .03). In the consecutive series, 164/729 (22%) cases showed loss of MTAP expression. In 41 of these 164 cases (25%), loss of MTAP expression was heterogenous. We also discovered loss of MTAP expression in flat urothelium adjacent to MTAP-negative low-grade UC, suggesting true flat low-grade neoplasia that could not be diagnosed by morphology alone. Longitudinal analysis of recurrences showed persistent negative MTAP status over time in 37/38 (97%) patients. MTAP IHC can serve as a surrogate marker for 9p21 HD in UC and as a diagnostic tool to differentiate reactive urothelium from urothelial neoplasia. It also provides a unique opportunity to study clinicopathological associations and the heterogeneity of 9p21 HD across the whole spectrum of UC manifestations.

Resectability of Small Duodenal Tumors: A Randomized Controlled Trial Comparing Underwater Endoscopic Mucosal Resection and Cold Snare Polypectomy.

Underwater endoscopic mucosal resection (UEMR) and cold snare polypectomy (CSP) are novel endoscopic procedures for superficial nonampullary duodenal epithelial tumors (SNADET). However, consensus on how to use both procedures appropriately has not been established. In this study, we evaluated treatment outcomes of both procedures, including resectability. In this single-center randomized controlled study conducted between January 2020 and June 2022, patients with SNADET ≤12 mm were randomly allocated to UEMR and CSP groups. The primary end point was sufficient vertical R0 resection (SVR0), which was defined as R0 resection including a sufficient submucosal layer. We compared treatment outcomes including SVR0 rate between groups. The SVR0 rate was significantly higher in the UEMR group than in the CSP group (65.6% vs 41.5%, P = 0.01). By contrast, the R0 resection rate was not significantly different between study groups (70.3% vs 61.5%, P = 0.29). The submucosal layer thickness was significantly greater in the UEMR group than in the CSP group (median 546 [range, 309-833] μm vs 69 [0-295] μm, P < 0.01). CSP had a shorter total procedure time (median 12 [range, 8-16] min vs 1 [1-3] min, P < 0.01) and fewer total bleeding events (9.4% vs 1.5%, P = 0.06). UEMR has superior vertical resectability compared with CSP, but CSP has a shorter procedure time and fewer bleeding events. Although CSP is preferable for most small SNADET, UEMR should be selected for lesions that cannot be definitively diagnosed as mucosal low-grade neoplasias.

Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is characterized by multisystem, low-grade neoplasia involving the lung, kidneys, brain, and heart. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting almost exclusively women. TSC and LAM are both caused by mutations in TSC1 and TSC2 that result in mTORC1 hyperactivation. Here, we report that single-cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid biosynthesis pathway. Accordingly, the expression of acid ceramidase (ASAH1) and dihydroceramide desaturase (DEGS1), key enzymes controlling sphingolipid and ceramide metabolism, was significantly increased in TSC2-null cells. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids, and suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) resulted in markedly decreased TSC2-null cell viability. In vivo, 17a significantly decreased the growth of TSC2-null cell-derived mouse xenografts and short-term lung colonization by TSC2-null cells. Combined rapamycin and 17a treatment synergistically inhibited renal cystadenoma growth in Tsc2+/- mice, consistent with increased ASAH1 expression and activity being rapamycin insensitive. Collectively, the present study identifies rapamycin-insensitive ASAH1 upregulation in TSC2-null cells and tumors and provides evidence that targeting aberrant sphingolipid biosynthesis pathways has potential therapeutic value in mechanistic target of rapamycin complex 1-hyperactive neoplasms, including TSC and LAM.

Determining the relationship between serum acute phase reactants and cervical premalignant lesions: a cohort study.

Acute phase reactants play a role in the progression and prognosis of many malignant and premalignant tumors. This study investigated the diagnostic value of certain reactants as markers for cervical premalignant lesions. Despite advanced screening and vaccination programs, cervical cancer remains a serious health problem worldwide. We aimed to determine the possible relationship between premalignant cervical disease and serum acute phase reactant levels. This study included 124 volunteers who underwent cervical cancer screening. We divided the patients into three groups according to cervical cytology and histopathological findings as follows: no cervical lesion, low-grade neoplasia, or high-grade neoplasia. We included women aged 25-65 years with benign smear or colposcopy results, low- and high-grade squamous intraepithelial lesions. The benign group was based only on cytology findings, whereas the other groups were based on histopathology findings. Demographic data and serum albumin, fibrinogen, ferritin, and procalcitonin levels were evaluated in the three groups. We found significant differences among the three groups in terms of age, albumin level, albumin/fibrinogen ratio, and procalcitonin level. The regression analysis revealed lower serum albumin levels in the low- and high-grade squamous intraepithelial lesion groups compared with the benign group. This is the first study to evaluate the importance of serum inflammatory markers in cervical intraepithelial lesions. Our results indicate that serum albumin level, albumin/fibrinogen ratio, procalcitonin level, and neutrophil values differ among cervical intraepithelial lesions.

A one-dimensional convolutional neural network based deep learning for high accuracy classification of transformation stages in esophageal squamous cell carcinoma tissue using micro-FTIR

Among the most frequently diagnosed cancers in developing countries, esophageal squamous cell carcinoma (ESCC) ranks among the top six causes of death. It would be beneficial if a rapid, accurate, and automatic ESCC diagnostic method could be developed to reduce the workload of pathologists and improve the effectiveness of cancer treatments. Using micro-FTIR spectroscopy, this study classified the transformation stages of ESCC tissues. Based on 6,352 raw micro-FTIR spectra, a one-dimensional convolutional neural network (1D-CNN) model was constructed to classify-five stages. Based on the established model, more than 93% accuracy was achieved at each stage, and the accuracy of identifying proliferation, low grade neoplasia, and ESCC cancer groups was achieved 99% for the test dataset. In this proof-of-concept study, the developed method can be applied to other diseases in order to promote the use of FTIR spectroscopy in cancer pathology.

Shenbai Jiedu Fang inhibits AOM/DSS-induced colorectal adenoma formation and carcinogenesis in mice via miRNA-22-mediated regulation of the PTEN/PI3K/AKT signaling pathway

To observe the inhibitory effect of Shenbai Jiedu Fang (SBJDF, a compound recipe of traditional Chinese herbal drugs) on chemically induced carcinogenesis of colorectal adenoma in mice and explore the role of PTEN/PI3K/AKT signaling pathway in mediating this effect. Four-week-old male C57BL/6 mice were randomly divided into control group (n=10), AOM/DSS model group (n=20), low-dose (14 g/kg) SBJDF group (n=10) and high-dose (42 g/kg) SBJDF group (n= 10). In the latter 3 groups, the mice were treated with azoxymethane (AOM) and dextran sodium sulphate (DSS) to induce carcinogenesis of colorectal adenoma. In the two SBJDF treatment groups, SBJDF was administered daily by gavage during the modeling. The survival rate, body weight, general condition of the mice, and intestinal adenoma formation and carcinogenesis were observed. The expressions of proteins associated with the PTEN/PI3K/AKT signaling pathway in the intestinal tissue were detected using immunohistochemistry. Compared with those in the model group, the mice treated with SBJDF, especially at the high dose, showed a significantly lower incidence of intestinal carcinogenesis and had fewer intestinal tumors with smaller tumor volume. Pathological examination showed the occurrence of adenocarcinoma in the model group, while only low-grade and high-grade neoplasia were found in low-dose SBJDF group; the mice treated with high-dose SBJDF showed mainly normal mucosal tissues in the intestines with only a few lesions of low-grade neoplasia of adenoma. Compared with those in the control group, the mice in the model group had significantly elevated plasma miRNA-222 level (P < 0.05), which was obviously lowered in the two SBJDF groups (P < 0.01). The results of immunohistochemistry revealed that compared with the model group, the two SBJDF groups, especially the high-dose group, had significantly up-regulated expressions of PTEN, P-PTEN and GSK-3β and down-regulated expressions of p-GSK-3 β, PI3K, AKT, P-AKT, β-catenin, c-myc, cyclinD1 and survivin in the intestinal tissues. SBJDF can significantly inhibit colorectal adenoma formation and carcino-genesis in mice possibly through regulating miRNA-222 and affecting PTEN/PI3K/AKT signaling pathway.

S3636 MALT Lymphoma: An Unlikely Diagnosis of Gastric Subepithelial Lesion

Introduction: MALT lymphoma is one of the most common types of extra-nodal non-Hodgkin lymphomas which originate from marginal zone B-cells in the gastrointestinal mucosal-associated lymphoid tissues. Although the most frequent location which MALT can be found is stomach, it is a rare disorder. Most cases are associated with h. pylori infection of the stomach. It is typically a low-grade neoplasia, characterized by a dense lymphoid infiltration that invades and destroys gastric glands and results in the so-called “lymphoepithelial lesion”. We present a case that was an atypical presentation of Malt lymphoma. Case Description/Methods: A 56-year-old male presented with anemia. Initial endoscopic evaluation revealed several large gastric subepithelial lesions in the antrum and body of the stomach that were ulcerated. After biopsies showed only chronic inflammation, the patient was referred to our center for further evaluation with EUS. There were multiple bulky confluent submucosal hypoechoic lesions seen with ulcerated mucosa overlying involving the gastric body, angularis and proximal antrum. Given the large size it was difficult to determine from which wall layer they originated. Also, there were multiple malignant appearing lymph nodes seen adjacent to the stomach. Biopsies through both fine needle biopsy and forceps biopsies, the pathology report revealed low grade B-cell lymphoma with clonal plasmacytic differentiation, suggestive of marginal zone of mucosa-associated lymphoid tissue lymphoma (MALT). (Figure) Discussion: MALT lymphoma is typically an indolent low-grade tumor that usually presents with a more subtle endoscopic appearance. In this case of MALT lymphoma, the tumor was bulky, ulcerated and had metastasized to lymph nodes around the stomach. Also, there was no evidence of h. pylori infection. MALT lymphoma should considered on the differential diagnosis of any gastric lesion given the presentation can be so varied.Figure 1.: EGD and EUS showing the lesion.

Application of deep learning in the real-time diagnosis of gastric lesion based on magnifying optical enhancement videos

Background and aimMagnifying image-enhanced endoscopy was demonstrated to have higher diagnostic accuracy than white-light endoscopy. However, differentiating early gastric cancers (EGCs) from benign lesions is difficult for beginners. We aimed to determine whether the computer-aided model for the diagnosis of gastric lesions can be applied to videos rather than still images.MethodsA total of 719 magnifying optical enhancement images of EGCs, 1,490 optical enhancement images of the benign gastric lesions, and 1,514 images of background mucosa were retrospectively collected to train and develop a computer-aided diagnostic model. Subsequently, 101 video segments and 671 independent images were used for validation, and error frames were labeled to retrain the model. Finally, a total of 117 unaltered full-length videos were utilized to test the model and compared with those diagnostic results made by independent endoscopists.ResultsExcept for atrophy combined with intestinal metaplasia (IM) and low-grade neoplasia, the diagnostic accuracy was 0.90 (85/94). The sensitivity, specificity, PLR, NLR, and overall accuracy of the model to distinguish EGC from non-cancerous lesions were 0.91 (48/53), 0.78 (50/64), 4.14, 0.12, and 0.84 (98/117), respectively. No significant difference was observed in the overall diagnostic accuracy between the computer-aided model and experts. A good level of kappa values was found between the model and experts, which meant that the kappa value was 0.63.ConclusionsThe performance of the computer-aided model for the diagnosis of EGC is comparable to that of experts. Magnifying the optical enhancement model alone may not be able to deal with all lesions in the stomach, especially when near the focus on severe atrophy with IM. These results warrant further validation in prospective studies with more patients. A ClinicalTrials.gov registration was obtained (identifier number: NCT04563416).Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04563416.

Diagnostic and prognostic impact of fluorodeoxyglucose-positron emission tomography in diagnosing intraductal papillary neoplasms of the bile duct of the liver.

PurposeMalignant intraductal papillary neoplasm of the bile duct of the liver (IPNB-L) cannot readily be diagnosed through preoperative CT or MRI, but fluorodeoxyglucose (FDG)-PET is a viable alternative. This study evaluated the diagnostic and prognostic impacts of FDG-PET in patients with IPNB-L.MethodsThis was a retrospective single-center study of 101 IPNB-L patients who underwent hepatectomy between 2010 and 2019.ResultsMean age was 64.4 ± 8.3 years and 76 (75.2%) were male. Anatomical hepatic resection was performed in 99 (98.0%). Concurrent bile duct resection and pancreaticoduodenectomy were performed in 41 (40.6%) and 1 (1.0%), respectively. R0 and R1 resections were performed in 88 (87.1%) and 13 (12.9%), respectively. Low-grade intraepithelial neoplasia and high-grade neoplasia/invasive carcinoma were diagnosed in 19 (18.8%) and 82 (81.2%), respectively. Median FDG-PET maximal standardized uptake values (SUVmax) in low-grade neoplasia and high-grade neoplasia/carcinoma were 3.6 (range, 1.7–7.6) and 5.2 (range, 1.5–18.7) (P = 0.019), respectively. Receiver operating characteristic curve analysis of SUVmax showed area under the curve of 0.674, with sensitivity of 84.2% and specificity of 47.4% at SUVmax cutoff of 3.0. This cutoff had no significant influence on tumor recurrence (P = 0.832) or patient survival (P = 0.996) in patients with IPNB-L of high-grade neoplasia or invasive carcinoma.ConclusionIPNB-L is a rare type of biliary neoplasm and encompasses a histological spectrum ranging from benign disease to invasive carcinoma. An FDG-PET SUVmax cutoff of 3.0 appears to effectively discern high-grade neoplasia/carcinoma from low-grade neoplasia, which will assist with the surgical strategy for these cases.

Compound Endoscopic Morphological Features for Identifying Non-Pedunculated Lesions ≥20 mm with Intramucosal Neoplasia.

Simple SummaryPiecemeal endoscopic mucosal resection (EMR) has proved to be an excellent resection technique for large colorectal polyps. However, a key limitation is the inaccurate histologic assessment of the sample in cases where there is invasion of the submucosa. Thus piecemeal EMR should be avoided if submucosal invasion is suspected. Furthermore, both western and eastern scientific societies have recently recommended that treatment should be based on optical diagnosis (ideally with magnification) which estimates the histology endoscopically. However, experience with magnification in western countries is limited. This study primarily aims to develop a classification system based on endoscopic features to identify intramucosal neoplasia (absence of submucosal invasion) in non-pedunculated lesions ≥20 mm assessed by western endoscopists with narrow band imaging (NBI) and without magnification. We observed that non-ulcerated LST-granular type and LST-non-granular flat elevated lesions represent 58.8% of all non-pedunculated lesions ≥20 mm and are associated with a low risk of submucosal invasion (3.8%). Therefore, we suggest these lesions be treated by piecemeal EMR. In the remaining lesions further diagnostic techniques such as magnifying endoscopy or en bloc resection should be considered.Background: The major limitation of piecemeal endoscopic mucosal resection (EMR) is the inaccurate histological assessment of the resected specimen, especially in cases of submucosal invasion. Objective: To classify non-pedunculated lesions ≥20 mm based on endoscopic morphological features, in order to identify those that present intramucosal neoplasia (includes low-grade neoplasia and high-grade neoplasia) and are suitable for piecemeal EMR. Design: A post-hoc analysis from an observational prospective multicentre study conducted by 58 endoscopists at 17 academic and community hospitals was performed. Unbiased conditional inference trees (CTREE) were fitted to analyse the association between intramucosal neoplasia and the lesions’ endoscopic characteristics. Result: 542 lesions from 517 patients were included in the analysis. Intramucosal neoplasia was present in 484 of 542 (89.3%) lesions. A conditional inference tree including all lesions’ characteristics assessed with white light imaging and narrow-band imaging (NBI) found that ulceration, pseudodepressed type and sessile morphology changed the accuracy for predicting intramucosal neoplasia. In ulcerated lesions, the probability of intramucosal neoplasia was 25% (95%CI: 8.3–52.6%; p < 0.001). In non-ulcerated lesions, its probability in lateral spreading lesions (LST) non-granular (NG) pseudodepressed-type lesions rose to 64.0% (95%CI: 42.6–81.3%; p < 0.001). Sessile morphology also raised the probability of intramucosal neoplasia to 86.3% (95%CI: 80.2–90.7%; p < 0.001). In the remaining 319 (58.9%) non-ulcerated lesions that were of the LST-granular (G) homogeneous type, LST-G nodular-mixed type, and LST-NG flat elevated morphology, the probability of intramucosal neoplasia was 96.2% (95%CI: 93.5–97.8%; p < 0.001). Conclusion: Non-ulcerated LST-G type and LST-NG flat elevated lesions are the most common non-pedunculated lesions ≥20 mm and are associated with a high probability of intramucosal neoplasia. This means that they are good candidates for piecemeal EMR. In the remaining lesions, further diagnostic techniques like magnification or diagnostic +/− therapeutic endoscopic submucosal dissection should be considered.

Fine-tuning Pre-trained Convolutional Neural Networks for Gastric Precancerous Disease Classification on Magnification Narrow-band Imaging Images

Gastric cancer(GC) is the fourth leading cause of cancer death worldwide. To prevent the occurrence of advanced GCs, there is a need for immediate detection and treatment of gastric precancerous and early cancerous lesions. Magnification endoscopy with narrow-band imaging (M-NBI) system as an advanced diagnostic imaging technology is widely used in evaluating gastric lesion types, which can interpret gastric lesion characteristics by enhancing contrasts between vessels and mucosal surfaces. Based on microvascular morphologies presented on M-NBI images, physicians can manually diagnose gastric lesions; but this is a tough work for unexperienced doctors and it is lacking of objectivity. In this study, we propose a transfer learning framework by fine-tuning pre-trained convolutional neural networks (CNNs) to classify gastric M-NBI images into three classes: chronic gastritis (CGT), low grade neoplasia (LGN) and early gastric cancer (EGC). The method we choose is used to compare with three kinds of traditional handcraft texture feature extraction methods and CNN models trained directly by our dataset. Results show that the performance of fine-tuned CNNs outperforms traditional handcraft features and trained CNNs. Experiments also illustrate that ResNet50 can achieve 0.96 accuracy, 0.92, 0.91 and 0.99 f1-scores for classifying M-NBI images into CGT, LGN and EGC. In conclusion, the proposed framework is suit for multi-classification tasks of gastric M-NBI images.

Serous Adenocarcinoma of Fallopian Tubes: Histological and Immunohistochemical Aspects.

BackgroundAlthough primary cancer of the fallopian tubes is a relatively rare type of tumor in female reproductive organs, its mortality is quite high. It is important to identify molecular and biological markers of this malignancy that determine its specific phenotype.MethodsThe study was carried out on samples received from 71 female patients with primary cancer of the fallopian tubes. The main molecular and biological properties, including hormone status (estrogen receptor [ER], progesterone receptor [PR]), human epidermal growth factor receptor (HER2)/neu expression, proliferative potential (Ki-67), apoptosis (p53, Bcl-2), and pro-angiogenic (vascular endothelial growth factor) quality of serous tumors were studied in comparison with clinical and morphological characteristics.ResultsER and PR expression is accompanied by low grade neoplasia, early clinical disease stage, and absence of lymphogenic metastasis (p < .001). HER2/neu expression is not typical for primary cancer of the fallopian tubes. Ki-67 expression is characterized by an inverse correlation with ER and PR (p < .05) and is associated with lymphogenic metastasis (p < .01). p53+ status correlates with high grade malignancy, tumor progression, metastasis, negative ER/PR (p < .001), and negative Bcl-2 status (p < .05). Positive Bcl-2 status is positively correlated with ER and PR expression and low grade malignancy.ConclusionsComplex morphologic (histological and immunohistochemical) study of postoperative material allows estimation of the degree of malignancy and tumor spread to enable appropriate treatment for each case.

Guidelines for Cervical Cancer Screening in Immunosuppressed Women Without HIV Infection.

Executive SummaryThe risk of cervical cancer (CC) among women immunosuppressed for a variety of reasons is well documented in the literature. Although there is improved organ function, quality of life and life expectancy gained through use of immunosuppressant therapy, there may be increased long-te

Association of increased B7 protein expression by infiltrating immune cells with progression of gastric carcinogenesis.

B7 negative costimulatory molecules are a group of molecules associated with the occurrence, development, and therapy of cancers. Here, we aimed to determine the clinical significance of PD-L1, B7-H3, and B7-H4 and their expression in CD8 and CD68 positive cells at different stages of gastric carcinogenesis.We detected PD-L1, B7-H3, B7-H4, CD8, and CD68 expression in samples by immunohistochemical staining of 62 chronic superficial gastritis (CSG) samples, 72 chronic atrophic gastritis (CAG) samples, 68 low-grade intraepithelial neoplasia (LIN) samples, 65 high-grade intraepithelial neoplasia (HIN) samples obtained from gastroscopic biopsies and 50 gastric adenocarcinoma (GA) samples obtained from surgical resections. Then we statistically analyzed the expression differences and correlations.Our results indicated that B7 and CD68 expression on infiltrating immune cells was associated with disease progression. However, infiltration of CD8+ cells decreased with disease progression. B7-H3 expression was markedly enhanced at neoplasia and GA stages. B7-H3 in tumor cells was negatively correlated with CD8-expressing cells. Conversely, B7-H3 expression in tumor-infiltrating immune cells was positively correlated with CD68-expressing cells. B7-H4 expression was found in the cell membrane at the stages of gastritis and low-grade neoplasia and was gradually expressed in the cytoplasm at high-grade neoplasia and GA stages. High B7-H4 expression in infiltrating immune cells was also significantly associated with lower CD8-positive and higher CD68-positive cell densities.Increased B7 protein expression by infiltrating immune cells was associated with disease progression, and specifically, the level of B7-H3 expression and localization of B7-H4 expression differed significantly among different stages of gastric carcinogenesis.

Human Papillomavirus and Cervical Intra-Epithelial Neoplasia: Epidemiological and Cytological Study in Lubumbashi Women

The objective of this study is to show that the presence of koilocytosis on the cervical smear is the only possibility to detect Papillomavirus infection in cervical intra-epithelial neoplasia in women living in Lubumbashi. This is a cross-sectional analytical study on the data collected from the register of women who participated in the cervix lesion screening campaign organized in Lubumbashi in March 2012 by the Congolese League Against Cancer. A total of 545 women with cervical lesions have been selected. The following results were observed: the frequency of HPV infection is 35% in Lubumbashi women. The risk of developing intraepithelial neoplasia is 38.3 times higher in women infected with HPV compared to uninfected ones (OR = 38.3, 95% CI = 16.3-90.3). HPV is predominantly present in intraepithelial neoplasia (92.7%) and this regardless of their grade: 91.9% for low-grade neoplasia and 95% for high-grade neoplasia. HPV is found in both older women and older women, respectively in 45% of women aged less than 36 years and in 55% of women aged over 36 years old. This study shows that it is necessary to put in place adequate means for the detection of HPV in order to contribute to the fight against cervical cancer in Lubumbashi.

Renal cancer: new models and approach for personalizing therapy

BackgroundClear cell RCC (ccRCC) accounts for approximately 75% of the renal cancer cases. Surgery treatment seems to be the best efficacious approach for the majority of patients. However, a consistent fraction (30%) of cases progress after surgery with curative intent. It is currently largely debated the use of adjuvant therapy for high-risk patients and the clinical and molecular parameters for stratifying beneficiary categories. In addition, the treatment of advanced forms lacks reliable driver biomarkers for the appropriated therapeutic choice. Thus, renal cancer patient management urges predictive molecular indicators and models for therapy-decision making.MethodsHere, we developed and optimized new models and tools for ameliorating renal cancer patient management. We isolated from fresh tumor specimens heterogeneous multi-clonal populations showing epithelial and mesenchymal characteristics coupled to stem cell phenotype. These cells retained long lasting-tumor-propagating capacity provided a therapy monitoring approach in vitro and in vivo while being able to form parental tumors when orthotopically injected and serially transplanted in immunocompromised murine hosts.ResultsIn line with recent evidence of multiclonal cancer composition, we optimized in vitro cultures enriched of multiple tumor-propagating populations. Orthotopic xenograft masses recapitulated morphology, grading and malignancy of parental cancers. High-grade but not the low-grade neoplasias, resulted in efficient serial transplantation in mice. Engraftment capacity paralleled grading and recurrence frequency advocating for a prognostic value of our developed model system. Therefore, in search of novel molecular indicators for therapy decision-making, we used Reverse-Phase Protein Arrays (RPPA) to analyze a panel of total and phosphorylated proteins in the isolated populations. Tumor-propagating cells showed several deregulated kinase cascades associated with grading, including angiogenesis and m-TOR pathways.ConclusionsIn the era of personalized therapy, the analysis of tumor propagating cells may help improve prediction of disease progression and therapy assignment. The possibility to test pharmacological response of ccRCC stem-like cells in vitro and in orthotopic models may help define a pharmacological profiling for future development of more effective therapies. Likewise, RPPA screening on patient-derived populations offers innovative approach for possible prediction of therapy response.

Abstract ES2-1: The pathology of high risk proliferative lesions of the breast

Abstract A number of breast lesions diagnosed by pathologic examination of breast tissue are known to confer an increased risk for future development of breast cancer. Atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) are lesions conferring a moderately increased risk of 4-5x over baseline. Lobular carcinoma in situ (LCIS) and variants confer a markedly increased risk of 8-10x over the baseline. The magnitude of the risk, the effect of the patient's age and family history, the laterality of the future malignancy and the type of subsequent cancer development are different between all these high risk proliferative breast lesions. In addition, the spectrum of columnar cell lesions of the breast are thought to represent an early non-obligate precursor in the development of the low grade neoplasia of the breast. Of interest, many of these lesions share common genetic abnormalities that are different than those seen in high grade in situ and invasive carcinomas of the breast. These observations have implications for our current understanding of the breast cancer progression model and our recommendations for the therapeutic management of patients with high risk proliferative lesions of the breast. Citation Format: Siziopikou KP. The pathology of high risk proliferative lesions of the breast [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES2-1.

MALT Lymphoma: A Dramatic Change Before and After Treatment of H. pylori

Mucosa-associated lymphoid tissue (MALT) lymphoma is usually a low-grade neoplasia that is associated with Helicobacter pylori (H. pylori) infection. It accounts for 2-8% of all tumors of the stomach The clinical presentation of gastric MALT lymphoma is non-specific, and includes dyspepsia, epigastric pain, and less frequently, alarm symptoms, such as gastrointestinal bleeding or persistent vomiting. Here in, we present a 68 y/o male with a medical history of hypertension, dyslipidemia, chronic kidney disease (stage 3), osteoporosis, and anemia, who presented for evaluation of chronic epgiastric abdominal pain. Upper endoscopy showed a large ulcer just distal to the GE junction with raised edges and superficial necrosis (Figure 1A). Biopsy was consistent with MALT lymphoma and H. pylori. The patient was started on a 2 week course of proton pump inhibitor (PPI), clarithromycin, and amoxicillin. Eradication of H. pylori was confirmed by negative H. pylori stool antigen 4 weeks following completion of treatment regimen. After 8 months, repeat upper endoscopy demonstrated eradication of lymphoma (Figure 1B). Biopsies were negative for MALT lymphoma. While the frequency of MALT lymphoma is on the rise, it continues to be a rare clinical entity. Furthermore, though MALT lymphoma is a B-cell neoplasia, classic B symptoms are extremely rare. The treatment of MALT lymphoma targets H. pylori eradication as first line therapy where 75% of patients achieve remission. Data suggests that in H. pylori negative patients, H. pylori treatment has been successful in 15% of patients. For the management of patients who fail to achieve lymphoma remission following H. pylori eradication, alternative or second-line therapies include radiotherapy, chemotherapy and, in selected cases, surgery.Figure: Stomach MALT lymphoma before (A) and after (B) treatment.

Hue-texture-embedded region-based model for magnifying endoscopy with narrow-band imaging image segmentation based on visual features

Background and objectiveMagnification endoscopy with narrow-band imaging (ME-NBI) has become a feasible tool for detecting diseases within the human gastrointestinal tract, and is more applied by physicians to search for pathological abnormalities with gastric cancer such as precancerous lesions, early gastric cancer and advanced cancer. In order to improve the reliability of diseases detection, there is a need for applying or proposing computer-assisted methodologies to efficiently analyze and process ME-NBI images. However, traditional computer vision methodologies, mainly segmentation, do not express well to the specific visual characteristics of NBI scenario. MethodsIn this paper, two energy functional items based on specific visual characteristics of ME-NBI images have been integrated in the framework of Chan–Vese model to construct the Hue-texture-embedded model. On the one hand, a global hue energy functional was proposed representing a global color information extracted in H channel (HSI color space). On the other hand, a texture energy was put forward presenting local microvascular textures extracted by the PIF of adaptive threshold in S channel. ResultsThe results of our model have been compared with Chan–Vese model and manual annotations marked by physicians using F-measure and false positive rate. The value of average F-measure and FPR was 0.61 and 0.16 achieved through the Hue-texture-embedded region-based model. And the C-V model achieved the average F-measure and FPR value of 0.52 and 0.32, respectively. Experiments showed that the Hue-texture-embedded region-based outperforms Chan–Vese model in terms of efficiency, universality and lesion detection. ConclusionsBetter segmentation results are acquired by the Hue-texture-embedded region-based model compared with the traditional region-based active contour in these five cases: chronic gastritis, intestinal metaplasia and atrophy, low grade neoplasia, high grade neoplasia and early gastric cancer. In the future, we are planning to expand the universality of our proposed methodology to segment other lesions such as intramucosal cancer etc. As long as these issues are solved, we can proceed with the classification of clinically relevant diseases in ME-NBI images to implement a fully automatic computer-assisted diagnosis system.

Multiple behavioral factors are associated with occurrence of large, flat colorectal polyps.

The prevalence of advanced dysplasia and synchronous lesions is particularly high in patients with large, flat colorectal polyps. However, the impact of lifestyle on the development of such polyps is poorly investigated. Hence, this study aims to identify associations between behavioral factors and the occurrence of large, flat colorectal polyps. Behavioral factors were retrospectively analyzed in patients with large, flat polyps and control patients with at most one diminutive polyp. Information on lifestyle factors, comorbidities, and demographic parameters were determined by a structured, self-administered questionnaire. Questionnaires of 350 patients with large, flat polyps and 489 control patients were included in the analysis. Most large, flat colorectal polyps contained adenoma with low-grade neoplasia and were located in the right colon. Multivariate analysis showed that advanced age (per 1-year increase-OR 1.09, CI 1.07-1.11, p<0.0001), frequent cigarette smoking (OR 2.04, CI 1.25-3.32, p=0.0041), daily consumption of red meat (OR 3.61, CI 1.00-12.96, p=0.0492), and frequent bowel movements (OR 1.62, CI 1.13-2.33, p=0.0093) were independent risk factors for occurrence of large, flat colorectal polyps. In contrast, frequent intake of cereals (OR 0.62, CI 0.44-0.88, p=0.0074) was associated with a reduced risk. Multiple behavioral factors modulate the risk for developing large, flat colorectal polyps. This knowledge can be used to improve prevention of colorectal cancer.