Search

Duodenal eosinophilia may play a role in functional dyspepsia (FD), but existing study results are conflicted. We investigated the association between duodenal eosinophils (count and degranulation) and FD symptoms, accounting for atopic conditions, medications, and seasonal variations. In a cross-sectional study conducted in the Michael E. DeBakey VA Medical Center in Houston, Texas, we analyzed duodenal histopathology of 436 patient samples from a prospective cohort with a validated symptom survey data and chart reviews. FD was defined using Rome II symptom criteria. Eosinophil count was number per 5 high-power fields (HPF), and eosinophil degranulation was eosinophilic granules in the stroma both determined by two independent investigators. The study cohort was predominantly male (87.4%) with a mean age of 59.3 (standard deviation (SD) ± 9.8). Mean and median eosinophil counts were 75.5 (± 47.8) and 63 (IQR: 43, 101) per five HPF, respectively. Duodenal eosinophilia (defined as ≥ 63 per 5 HPF) and eosinophil degranulation were present in 50.5% and 23.1% of patient samples, respectively. FD was observed in 178 patients (41.7%), but neither the mean eosinophil count nor duodenal eosinophilia was associated with FD. Eosinophil degranulation was independently associated with FD overall (OR 1.74; 95% CI 1.08, 2.78; p = 0.02) and early satiety (OR 2.04; 95% CI 1.26, 3.30; p = 0.004). In this large, ethnically diverse cohort of adult patients, we found no significant association between duodenal eosinophilia and FD. However, the presence of duodenal eosinophilic degranulation, an activated eosinophil marker, was significantly associated with FD, especially early satiety.

Background & Aims Nonalcoholic steatohepatitis (NASH) is associated with an increase in healthcare resource use and poor health-related quality of life (HRQoL). We assessed the humanistic and economic burden of NASH, disease management, and patient journey. Methods We performed a cross-sectional analysis of data, collected from July through November 2017, from the Growth from Knowledge Disease Atlas Real-World Evidence program, reported by physicians in United States, France, and Germany. We extracted demographic and medical data from medical records. Some patients voluntarily completed a survey that provided information on disease history, treatment satisfaction, and patient-reported outcomes. Results We analyzed data from 1216 patients (mean age, 54.9±12.3 years; 57.5% male; mean body mass index, 31.7±6.9); 64.6% had biopsy-confirmed NASH and comorbidities were recorded for 41.3%. Treatments included lifestyle modification (64.6%) or use of statins (25.0%), vitamin E (23.5%), or metformin (20.2%). Patients with biopsy-confirmed NASH reported more physician (4.5 vs 3.7) and outpatient visits (1.8 vs.1.4) than patients with suspected NASH not confirmed by biopsy. Among the 299 patients who completed the survey, 47.8% reported various symptoms associated to their NASH. Symptomatic patients reported significantly lower HRQoL than patients without symptoms. Conclusions In an analysis of data from 3 countries, we found NASH to be associated with regular use of medical resources; patients with symptoms of NASH had reduced HRQoL. The burden of NASH appears to be underestimated. Studies are needed to determine the burden of NASH by fibrosis stage and disease severity.

Background & Aims Limitations of endoscopic sampling may result in missed dysplasia at the diagnosis of Barrett’s esophagus (BE). However, the role of close follow-up endoscopy is unclear. The aim was to evaluate the proportion of patients diagnosed with “missed” dysplasia within 18 months of their index nondysplastic BE (NDBE) diagnosis. Methods This was a retrospective analysis of a cohort of BE patients diagnosed during 1990–2019 at the Houston VA. Patients with BE on index esophagogastroduodenoscopy (EGD) were classified as NDBE, indefinite dysplasia, or dysplastic (low- or high-grade dysplasia) based on initial biopsies. We identified NDBE patients who had follow-up EGD within 3–18 months after index EGD. We used logistic regression models to estimate odds ratios and 95% confidence intervals for risk factors of dysplasia on follow-up EGD. Results We identified 614 patients who had BE on index EGD. Among those with NDBE and follow-up EGD within 3–18 months (n = 271), 4.1% had definite dysplasia on follow-up, and an additional 14.0% had indefinite dysplasia. Proportions of definite or indefinite dysplasia at follow-up within 3–18 months significantly decreased from 32.6% among patients with index EGD before 2009 to 11.7% among patients with index EGD after 2013 (P for trend = .068). Those with any indefinite or definite dysplastic BE at follow-up within 3–18 months after index EGD (n = 49) were more likely to have BE length ≥3 cm on index EGD (odds ratio, 3.39; 95% confidence interval, 1.63–7.08) than those with persistent NDBE or no BE on follow-up. Conclusions The occurrence of missed dysplasia on an index EGD has decreased over time. However, those with long segment BE were more than 3 times as likely to have missed dysplasia, and this group could benefit from dysplasia surveillance within 18 months of BE diagnosis.

Microscopic colitis (MC), a subtype of inflammatory bowel disease, is a chronic condition of unknown etiology. Recent evidence has linked MC with intriguing changes in the stool microbiota, which may be linked to disease pathogenesis. The composition of the mucosal microbiome in patients with MC remains unclear. We performed a cross-sectional study comparing colonic tissue samples from patients with MC to those of healthy controls at the Michael E. DeBakey VA Medical Center. We included adults older than 18 who underwent a colonoscopy with biopsies to evaluate chronic diarrhea. Cases were defined by histology consistent with MC and controls by the absence of histologic disease. We conducted structured chart review to exclude other gastrointestinal diseases and obtain demographic (age, sex, race) and clinical (duration of symptoms and concurrent medications) information for cases and controls. We extracted bacterial DNA from formalin-fixed paraffin-embedded tissue samples and sequenced the v4 region of the 16S rRNA gene. Operational taxonomic unit (OTU) clustering was performed using UPARSE, and OTUs were assigned using the SILVA database. Statistical analysis was performed in QIIME and LEfSe. Comparisons with FDR-adjusted p values of less than 0.05 were considered statistically significant. We included 20 MC patients and 20 controls with mean ages of 62 and 54, respectively. Most cases were White (95%), 60% had symptoms for greater than 12 months, and 50% were taking PPIs and NSAIDs at the time of their diagnosis. Compared to controls, MC patients had a significant increase in the proinflammatory sulfur-reducing bacterial family Desulfovibrionales. The Coriobacteriaceae family, abundant in the healthy gut, was significantly decreased in MC cases. There was also an increase in the genus Actinomyces in MC patients on PPI and an increase in the class Bacilli among those taking NSAIDs. Patients with MC have an increase in the proinflammatory family Desulfovibrionales. Actinomyces and Bacilli were associated with medications (PPI and NSAID) known to increase the risk of MC. Our findings may have important implications for understanding the pathogenesis of MC.

Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non–small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which Pten and Smad4 (Pts4d/d) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. Pts4d/d mice globally lacking in IL17a (Pts4d/dIl17a–/–) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103+ dendritic cells, and adoptive transfer of IL17a-sufficient CD4+ T cells reversed early tumor development and metastasis in Pts4d/dIl17a–/– mice. Together, these findings support a key role for Th17 cells in TILs associated with the Pts4d/d model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. Cancer Immunol Res; 6(6); 645–57. ©2018 AACR.

Tumor response to neoadjuvant therapy is a significant predictive indicator of recurrence-free survival. We measured tumor response using residual tumor thickness at the tumor-normal tissue interface (TNI) and evaluated its association with outcome in patients with liver metastasis of breast cancer. We included 48 patients who underwent neoadjuvant therapy followed by partial liver resection at MD Anderson Cancer Center between 1997 and 2010. The hematoxylin-eosin–stained tumor sections were evaluated for both pathologic response and the residual tumor thickness at the TNI by 3 pathologists who were blinded to the clinical information, treatment regimen, and patient outcome. The residual tumor thickness at the TNI was correlated with recurrence-free survival using Kaplan-Meier method and log-rank test. Cox proportional hazard model was used to identify predictors of recurrence-free survival. All patients were women with a median age of 43 years. The median duration of follow-up was 52.1 months. Residual tumor thickness less than or equal to 3 mm at the TNI correlated with major pathologic response and was associated with longer recurrence-free survival in both univariate and multivariate analyses. Residual tumor thickness at the TNI predicts recurrence-free survival and provides an objective outcome end point in patients who underwent neoadjuvant therapy and liver resection of metastatic breast cancer. We suggest using both the pathologic response and the residual tumor thickness at the TNI to measure tumor response to therapy to improve accuracy.

As a putative marker for cancer stem cells in human malignant tumors, including ovarian cancer, CD133 expression may define a tumor-initiating subpopulation of cells and is associated with the clinical outcome of patients. However, at this time its clinical significance in ovarian cancer remains uncertain. The aim of this study was to clarify the clinical role of CD133 expression in human ovarian cancer. Immunohistochemical staining of CD133 expression was performed in 400 ovarian carcinoma samples using tissue microarray. The associations among CD133 expression and clinical factors (diagnosis, tumor grade, cancer stage, and clinical response to chemotherapy), overall survival and disease-free survival time were analyzed. CD133 expression was found in 31% of ovarian carcinoma samples. Fisher’s exact test and one-way analysis of variance suggested that CD133 expression was associated with high-grade serous carcinoma (P = 0.035), late-stage disease (P < 0.001), ascites level (P = 0.010), and non-response to chemotherapy (P = 0.023). CD133 expression was also associated with shorter overall survival time (P = 0.007) and shorter disease-free survival time (P < 0.001) by log-rank test. Moreover, CD133 expression was an independent predictor of shorter disease-free survival time in an unconditional logistic regression analysis with multiple covariates (P = 0.024). Our results thus show that CD133 expression is a predictor of poor clinical outcome for patients with ovarian cancer, supporting the proposed link between CD133 and cancer stem cells.

Perry K D, Reynolds C, Rosen D G, Edgerton M E, Albarracin C T, Gilcrease M Z, Sahin A A, Abraham S C & Wu Y (2011) Histopathology59, 619–630 Metastatic neuroendocrine tumour in the breast: a potential mimic of in-situ and invasive mammary carcinoma Aims: The aim of this study was to review the clinicopathological characteristics of neuroendocrine tumours (NETs) metastasizing to the breast, in order to identify features that could be useful in distinguishing these metastatic lesions from primary breast neoplasms. Methods and results: Eighteen metastatic NETs in the breast were identified from two large hospitals over a 15-year period. Eleven (62%) tumours originated in the gastrointestinal tract, 5 (28%) originated in the lung, and the other two were of indeterminate origin. Eight (44%) cases were initially misdiagnosed as primary mammary carcinomas. In retrospect, all metastatic tumours exhibited architectural and cytological features that would suggest neuroendocrine differentiation. Immunohistochemistry can further aid in the distinction between metastatic neuroendocrine and primary mammary carcinoma. All 11 tumours from the gastrointestinal tract expressed CDX-2, 3 (60%) of five tumours from the lung expressed thyroid transcription factor-1, and only 2 (11%) of 18 showed weak oestrogen receptor positivity. Additionally, unlike primary carcinomas, the majority (82%) of metastatic NETs were negative for cytokeratin 7, and all were negative for gross cystic disease fluid protein 15 and mammoglobin. Conclusions: There is a high propensity for metastatic NETs to mimic primary breast carcinomas. Careful attention to cytological and architectural features can help to identify cases that require further immunophenotypic workup with a panel of tissue-specific antibodies. However, clinical history is paramount for optimal diagnosis.

In March and early April 2009, cases of a new swine-origin influenza A (H1N1) virus were diagnosed in Mexico and the United States. Influenza virus presents as a respiratory infection with high morbidity and mortality. We describe the postmortem findings of eight confirmed cases of influenza A/H1N1 in a medical examiner setting. The eight cases falling under the jurisdiction of the Harris County Medical Examiner (Houston, TX, USA) with confirmed influenza A/H1N1 infection between June and September 2009 were included in this study. All cases were males between 6 months and 54 years of age. All adult patients had a body mass index from 31 to 49.8 kg/m(2). Five cases had comorbid conditions including one case with sleep apnea and mental retardation, three cases with chronic ethanolism, and one case with thymoma, sarcoidosis, and myasthenia gravis. The remaining three cases had no pre-existing medical conditions. All patients presented with severe flu-like symptoms; yet, only five were febrile. Rapid influenza diagnostic tests were performed in three cases by primary-care physicians, two of which were negative. None of the patients received antiviral medication. The average disease duration time was 8.2 days (3-14 days). A wide range of histopathological findings including tracheitis, necrotizing bronchiolitis, alveolitis, intra-alveolar hemorrhage, and hyaline membranes, both in a focal and in a diffuse distribution, were identified. Influenza A/H1N1 viral infection presents with a wide range of histological findings in a diffuse or focal distribution; most consistently with tracheitis, necrotizing bronchiolitis, and alveolitis with extensive alveolar hemorrhage. These histopathological findings at autopsy along with a clinical history of flu-like symptoms should raise suspicion for influenza A/H1N1 infection, and postmortem analysis by the reverse transcription-polymerase chain reaction (RT-PCR) is recommended for an accurate diagnosis.

OBJECTIVE To describe a biinstitutional experience with fine needle aspiration (FNA) of breast lesions occurring in men over a period of over 10 years and to assess the role of FNA in detecting male breast cancer. STUDY DESIGN Computer patient records were searched from January 1990 to September 2007. Male patients who had a diagnosis of carcinoma on breast biopsy or resection were identified, and detailed chart review was done to assess demographics and correlate biopsy and FNA results. RESULTS A total of 346, 792 patients' charts were searched, and 217 male patients were found to have had a breast mass and subsequent FNA. Combined in both institutions, FNA results were positive for carcinoma in 12 (5.5%) cases, negative in 181 (83.4%) cases, suspicious in 5 (2.3%) cases, indeterminate/inconclusive in 3 (1.4%) cases and unsatisfactory in 16 (7.4%) cases. Matching biopsies to confirm FNA results were available in 26 (12%) of the 217 cases. The calculated sensitivity and specificity for the malignant cases reached 100%. When suspicious cases were calculated for diagnostic accuracy, the sensitivity was 67% and the specificity 100%. CONCLUSION This biinstitutional study demonstrates that FNA is a reliable but underutilized procedure for the management of male breast lesions.

Background Annexin A1 (ANXA1) is a potential marker of development of breast cancer. However, previous studies of ANXA1 expression in primary breast carcinoma and lymph node metastasis have yielded conflicting results. Therefore, to accurately characterize the ANXA1 expression pattern, we used microarray analysis and matched patient samples to evaluate progressive alterations in ANXA1 protein expression during malignant transformation and metastasis. Design We constructed a tissue microarray using 82 pairs of primary breast cancers and lymph node metastases from archival materials. We also identified 21 cases of breast carcinoma for which a single slide contained the entire progression from benign breast tissue, carcinoma in situ, to invasive carcinoma. Immunohistochemical staining for ANXA1 and various prognostic markers was performed. Result Microarray analysis revealed that ANXA1 expression was lost in 79% of breast carcinomas, and there was no difference in ANXA1 expression between primary breast carcinoma and lymph node metastasis. Most ANXA1-negative tumors were positive for estrogen and progesterone receptors but negative for HER2/neu and epidermal growth factor receptor. In contrast, most ANXA1-positive tumors were negative for estrogen, progesterone, and HER2/neu. In the whole tissue sections, ANXA1 is heterogeneously expressed in benign epithelium and is lost in both in situ carcinoma and invasive carcinoma. Conclusions The lack of ANXA1 expression in the majority of breast carcinomas and the early loss of ANXA1 expression in in situ carcinoma, which is maintained in both invasive and metastatic tumors, suggests a possible role for ANXA1 in the early events of malignant transformation.

Fluorescent contrast agents were topically applied in vivo to colon tissue in a mouse model of colorectal cancer. Excised tissue was imaged with confocal microscopy ex vivo to differentiate dysplasia from normal tissue and benign inflammatory lesions.

Background. When ovarian carcinoma is diagnosed in stage I, up to 90% of patients can be cured with surgery and currently available chemotherapy. At present, less than 25% of cases are diagnosed at this stage. To increase the fraction of ovarian cancers detected at an early stage, screening strategies have been devised that utilize a rising serum CA125 level to trigger the performance of transvaginal sonography. One limitation of CA125 as an initial step in such a screening strategy is that up to 20% of ovarian cancers lack expression of the antigen. Serum tumor markers that can be detected in ovarian cancers that lack CA125 expression might improve the sensitivity for early detection. Methods. From 296 ovarian cancers, 65 (22%) were found to have weak or absent CA125 expression on immunoperoxidase staining. Tissue expression of CA125 was compared to serum CA125 levels. Using immunoperoxidase staining of tissue arrays, we have assessed expression of 10 potential serum tumor markers in the 65 epithelial ovarian cancers with little or no CA125 expression and in ovarian cystadenomas, tumors of low malignant potential, normal ovaries, and 16 other normal tissues. Results. Low or absent expression of CA125 in surgical specimens of epithelial ovarian cancer was associated with low levels of serum CA125 in pre-operative serum specimens. In ovarian cancers that lacked CA125, all specimens (100%) expressed human kallikrein 10 (HK10), human kallikrein 6 (HK6), osteopontin (OPN), and claudin 3. A smaller fraction of CA125-deficient ovarian cancers expressed DF3 (95%), vascular endothelial growth factor (VEGF) (81%), MUC1 (62%), mesothelin (MES) (34%), HE4 (32%), and CA19-9 (29%). When reactivity with normal tissues was considered, however, MES and HE4 showed the greatest specificity. Differential expression was also found for HK10, OPN, DF3, and MUC1. Conclusions. At the level of tissue expression, each of 10 potential serum markers could be detected in 29–100% of ovarian cancers that had low or absent expression of CA125. Several markers exhibited more intense expression in cancers than in normal organs. Further investigation is needed to demonstrate complementary expression of markers in serum.

A variety of biomarkers have been developed to monitor growth of ovarian cancer and to detect disease at an early interval. CA125 (MUC16) has provided a useful serum tumor marker for monitoring response to chemotherapy, detecting disease recurrence, distinguishing malignant from benign pelvic masses, and potentially improving clinical trial design. A rapid fall in CA125 during chemotherapy predicts a favorable prognosis and could be used to redistribute patients on multiarmed randomized clinical trials. Several studies now document that CA125 can serve as a surrogate marker for response in phase II trials. Serial measurement of CA125 might also provide a useful marker for monitoring stabilization of disease with cytostatic targeted therapeutic agents. The greatest potential for serum markers may be in detecting ovarian cancer at an early stage. A rising CA125 can be used to trigger transvaginal sonography (TVS) in a small fraction of patients. An algorithm has been developed that calculates risk of ovarian cancer based on serial CA125 values and refers patients at highest risk for TVS. Use of the algorithm is currently being evaluated in a trial with 200,000 women in the UK that will test critically the ability of a two-stage screening strategy to improve survival in ovarian cancer. Whatever the outcome, as 20% of ovarian cancers have little or no expression of CA125, additional serum markers will be required to detect all patients in an initial phase of screening. More than 30 serum markers have been evaluated alone and in combination with CA125 by different investigators. Some of the most promising include: HE4, mesothelin, M-CSF, osteopontin, kallikrein(s), and soluble EGF receptor. Two proteomic approaches have been used: one examines the pattern of peaks on mass spectroscopy and the other uses proteomic analysis to identify a limited number of critical markers that can be assayed by more conventional methods. Both approaches are promising and require further development. Several groups are placing markers on multiplex platforms to permit simultaneous assay of multiple markers with very small volumes of serum. Mathematical techniques are being developed to analyze combinations of marker levels to improve sensitivity and specificity. In the future, serum markers should improve the sensitivity of detecting recurrent disease as well as facilitate earlier detection of ovarian cancer.

Receptors for estrogen (ER), progesterone (PR), or androgen (AR) are predictive and prognostic markers of malignancy of multiple endocrine organs, including endometrial and breast cancer. However, the role of ERs, PRs, or ARs in the carcinogenesis of ovarian cancer, another sex hormone-dependent malignancy, is still controversial despite numerous studies that have attempted to determine their role. The disagreement in the findings may result from the fact that the numbers of tumor samples in studies have been small and that different immunohistochemical methods have been used that can introduce variation in the scoring of the histology. We therefore examined the pattern of expression of ERs, PRs, and ARs in a large number of samples of primary ovarian carcinoma by using a tissue microarray technique.We constructed a tissue microarray with 322 samples of primary ovarian carcinoma obtained at surgery performed at The University of Texas M. D. Anderson Cancer Center between 1990 and 2000. Immunohistochemistry studies were performed by using the immunoperoxidase technique against primary antibodies (ER, PR, and AR).ERs, PRs, and ARs were differently expressed in different histotypes of ovarian cancer: ERs were expressed in 77.3% of all cases but more highly expressed in serous and endometrioid types; PRs were expressed in 26.2% of all cases but most highly expressed in the endometrioid type64.2%; and ARs were expressed in 43.7% of all cases but were most highly expressed in serous (47.5%) carcinomas. Of particular importance, the expression of PRs, but not ERs or ARs, was associated with better survival (P0.0001) in univariate and multivariate analyses.The PR is an independent marker, with its overexpression associated with a favorable prognosis in women with ovarian cancer.

Background and Aims Previous studies show that microendoscopic images can be interpreted visually to identify the presence of neoplasia in patients with Barrett's esophagus (BE), but this approach is subjective and requires clinical expertise. This study describes an approach for quantitative image analysis of microendoscopic images to identify neoplastic lesions in patients with BE. Methods Images were acquired from 230 sites from 58 patients by using a fiberoptic high-resolution microendoscope during standard endoscopic procedures. Images were analyzed by a fully automated image processing algorithm, which automatically selected a region of interest and calculated quantitative image features. Image features were used to develop an algorithm to identify the presence of neoplasia; results were compared with a histopathology diagnosis. Results A sequential classification algorithm that used image features related to glandular and cellular morphology resulted in a sensitivity of 84% and a specificity of 85%. Applying the algorithm to an independent validation set resulted in a sensitivity of 88% and a specificity of 85%. Conclusions This pilot study demonstrates that automated analysis of microendoscopic images can provide an objective, quantitative framework to assist clinicians in evaluating esophageal lesions from patients with BE. (Clinical trial registration number: NCT01384227 and NCT02018367.)

Background Non-palpable thyroid nodules can be difficult to access by conventional ultrasound-guided fine needle aspiration, particularly when they are intrathoracic. Many of these patients are subject to multiple follow up scans or invasive diagnostic procedures such as mediastinoscopy or surgical resection. We aim to describe the feasibility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis of thyroid lesions. Methods All EBUS-TBNA performed at our institutions from February 2010 to February 2013 were screened, and those in which a thyroid biopsy was performed were reviewed. Results We identified 12 cases of EBUS-TBNA thyroid biopsy. Nine patients had an indication for EBUS in addition to their thyroid lesions. The median age was 64 years (range 44 to 84 years), and 10 patients were male. Median lesion size was 22.5 mm (range, 10 to 43 mm). Five lesions were strictly intrathoracic. All cases were sampled with a 22G needle and rapid on-site cytologic examination. Adequate samples were obtained in all 12 cases. Malignancy was identified in 3 of the 12 patients (metastatic breast adenocarcinoma, large B-cell lymphoma, and metastatic lung adenocarcinoma). The remaining 9 samples were deemed to be benign nodules. Seven of these were confirmed by clinical follow-up (n = 3), biopsies (n = 3), or surgery (n = 1). There were no EBUS-related complications. Conclusions EBUS-TBNA might be a safe and effective alternative for sampling thyroid lesions, particularly useful for those located below the thoracic inlet. Further prospective studies are required to compare its diagnostic yield and safety profile with standard techniques.

ObjectiveMost patients with epithelial ovarian cancer achieve a complete clinical remission (CCR) with normal CA-125 but will still relapse and die from their disease. The present study was designed to determine whether CA-125 levels before, during, and after primary treatment provide prognostic information for both type I and type II ovarian cancer.MethodsIn this retrospective study, we identified 410 patients with epithelial ovarian cancer who had achieved a CCR between 1984 and 2011. A Cox proportional hazards model and log-rank test were used to assess associations between the nadir CA-125, histotype, and prognosis.ResultsThe baseline serum CA-125 concentration was higher in patients with type II ovarian cancer than in those with type I ovarian cancer (P < 0.001). The nadir CA-125 was an independent predictor of progression-free survival (PFS; P < 0.001) and overall survival (OS; P = 0.035) duration. The PFS and OS durations were 21.7 and 79.4 months in patients with CA-125 of 10 U/mL or less and 13.6 and 64.6 months in those with CA-125 of 11 to 35 U/mL, respectively (P = 0.01 and P = 0.002, respectively). Histotype was an independent predictor of PFS (P = 0.041): the PFS and OS durations of the patients with type I ovarian cancer were longer than those of the patients with type II ovarian cancer (P < 0.001 and P < 0.001, respectively).ConclusionsThe nadir CA-125 and histotype are predictive of PFS and OS durations in patients with ovarian cancers who experienced a CCR. Progression-free survival and OS durations were shorter in the patients with CA-125 levels of 11 to 35 U/mL and type II disease than in those with CA-125 levels of 10 U/mL or less and type I ovarian cancer.

Abstract 14 We developed a novel multimodal video endoscope and evaluated its usefulness for the early detection of gastric neoplastic lesions. The imaging platform is a modified upper GI endoscope capable of white light imaging (WLI), widefield vital-dye fluorescence imaging (VFI) and high-resolution microendoscopy (HRME) in a single endoscopic insertion. A custom filter module is attached to the distal tip of the endoscope to enable VFI; HRME is performed by introducing a fiber optic probe through the endoscope working channel. Proflavine, a vital dye that stains nuclei is used to provide image contrast in both VFI and HRME. VFI images of proflavine stained tissue reveal the glandular patterns of the gastric mucosa, while HRME images reveal nuclear morphology with subcellular resolution. The performance of the platform was evaluated in a pilot study to image 35 patients with known or suspected gastric cancer undergoing either endoscopy or surgical resection. Patients were recruited at Mount Sinai Hospital, NY, and Hospital Evangelico in Siguatepeque, Honduras. For each patient, images were acquired with WLI, VFI and HRME sequentially during endoscopy. Images of neoplasia show disruption and effacement of glandular patterns. These alterations are visualized with enhanced contrast in VFI when compared to WLI; HRME images presenting the nuclear architecture at a subcellular level confirm these findings. Results suggest that this multimodal imaging platform can potentially enable a two-step protocol for early gastric cancer detection, wherein suspicious areas are red flagged with improved contrast using VFI, and then further imaged with HRME to confirm whether neoplasia is present based on changes in nuclear morphology. Given the convenient adaptation of the system design to other commercial endoscopes and the low cost of HRME (< $2,500), the utility of this multimodal imaging platform should be further evaluated in in vivo studies and low-resource settings. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Yubo Tang No relationship to disclose Jennifer Carns No relationship to disclose Timothy Quang No relationship to disclose Enrique M. Reina No relationship to disclose Susana Gonzalez No relationship to disclose Daniel G. Rosen Research Funding: Biotheragnostics Sharmila Anandasabapathy Honoraria: Medial Medical Rebecca R. Richards-Kortum Consulting or Advisory Role: Janssen Global Services Research Funding: Merck

F-18-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans are positive in any condition which increases metabolism in a mass or tissue and are therefore not specific for neoplastic conditions. The use of an SUV cutoff value of 2.5 may not always help discriminate between benign and malignant cases. For a practicing cytopathologist doing adequacy checks during an image-guided procedure, it may be of value to be aware that elevated SUV values are not always indicative of a malignant process, and vice versa.

Serous carcinoma is the most common type of epithelial ovarian cancer. In this review, we provide a comprehensive picture of ovarian serous cancers from multiple aspects: the first part of this review summarizes the morphological, histological, and immunological signatures of ovarian serous carcinoma; subsequently, we review the history of the evolvement of different grading systems used in ovarian serous cancer; in the end, we focus on characterizing the genetics that underlie the 2-tiered pathways through which ovarian serous cancers are believed to arise: the low-grade and the high-grade pathways.

Cerebral sinus thrombosis has been reported as an uncommon complication of ulcerative colitis (UC), occurring in up to 7.5% of cases. It is suspected to be a consequence of genetic predisposition and the hypercoagulable state occurring during disease relapse. We report a case of a 23-year-old male patient with one-year history of UC. He presented to the Emergency Room with left-sided progressive hemiparesis, numbness, hemiparesthesia, and pain, which followed a recent exacerbation of UC. The patient died 3 days after admission and an autopsy revealed superior and inferior sagittal sinus and cortical vein thrombosis with associated cerebral edema, hemorrhagic infarction, and herniation. The gastrointestinal tract had continuous cobblestone appearance extending from rectum to cecum, with hemorrhage and ulceration, consistent with active UC. Awareness of this rare complication of UC can contribute to early recognition and attempts at treatment of this serious and often fatal condition.

Immunohistochemical staining for estrogen receptor (ER) status is widely used in the management of breast cancer. These stains have traditionally been scored manually, which results in generally good agreement among observers when the cases are strongly positive. However, significant interobserver and intraobserver differences in scoring can occur in borderline or weakly staining cases. Recently, automated systems have been proposed to provide a more sensitive and objective method of ER quantification. The ChromaVision Automated Cellular Imaging System and the Applied Imaging Ariol SL-50 quantify the color intensity of the immunoreactive product. To assess the accuracy of these 2 automated systems and to compare them to one another and to manual scoring, we performed immunostaining for ER on 64 cases of breast cancer. The percentages of positive cells were scored manually by 4 pathologists and by the 2 imaging systems. A discrepancy in scoring was defined as that which resulted in the reclassification of a case from negative to positive or vice versa. Our results showed significant agreement between the 2 automated systems. When automated scores were compared with the manual scores, only 5 of the 64 cases (7%) were discrepant. In 4 of these, the percentage of cells staining for ER was low (0% to 20%). Overall, the 2 systems were comparable, and discrepant results were most frequently seen when analyzing tumors with low levels of ER positive cells.

Current imaging tools are associated with inconsistent sensitivity and specificity for detection of Barrett’s-associated neoplasia. Optical imaging has shown promise in improving the classification of neoplasia in vivo. The goal of this pilot study was to evaluate whether in vivo vital dye fluorescence imaging (VFI) has the potential to improve the accuracy of early-detection of Barrett’s-associated neoplasia. In vivo endoscopic VFI images were collected from 65 sites in 14 patients with confirmed Barrett’s esophagus (BE), dysplasia, or esophageal adenocarcinoma using a modular video endoscope and a high-resolution microendoscope (HRME). Qualitative image features were compared to histology; VFI and HRME images show changes in glandular structure associated with neoplastic progression. Quantitative image features in VFI images were identified for objective image classification of metaplasia and neoplasia, and a diagnostic algorithm was developed using leave-one-out cross validation. Three image features extracted from VFI images were used to classify tissue as neoplastic or not with a sensitivity of 87.8% and a specificity of 77.6% (AUC=0.878). A multimodal approach incorporating VFI and HRME imaging can delineate epithelial changes present in Barrett’s-associated neoplasia. Quantitative analysis of VFI images may provide a means for objective interpretation of BE during surveillance.

BACKGROUND Cyclins, cyclin dependent kinases (cdks), and their inhibitors act in combination to regulate progression through the cell cycle and often are dysregulated in carcinoma. The authors hypothesized that cyclin E plays an important role in ovarian carcinogenesis and that its overexpression may be an indicator of a poor prognosis. METHODS Immunohistochemical analysis of cyclin E expression was performed by image analysis in normal ovaries, cystadenomas, tumors of low malignant potential, and 405 primary ovarian carcinomas by using tissue microarray technology. RESULTS Overexpression of cyclin E was found in 63.2% of the samples and was associated with clear cell, poorly differentiated, and serous carcinoma (P ≤ .001), high-grade tumors (P ≤ .001), late-stage disease (P = .002), age older than 60 years at the time of diagnosis (P = .04), and suboptimal cytoreduction (P = .001). A high percentage of cyclin E-expressing cells was associated with a poor outcome in univariate and in multivariate analyses. In addition, cyclin E levels also reduced survival in the late-stage disease group and in patients who underwent suboptimal debulking. CONCLUSIONS Cyclin E was identified as an independent prognostic factor in patients with ovarian carcinoma. The accumulation of cyclin E protein may be a late event in tumorigenesis and may contribute to disease progression in these patients. Cancer 2006. © 2006 American Cancer Society.

While the association between post-transplant nephrotic range proteinuria (PTx-NP) and chronic allograft nephropathy (CAN) has been described, the factors that determine graft survival in such patients are unclear. We retrospectively identified 30 patients with biopsy-proven CAN who presented with PTX-NP between 1988 and 2002. Patients were stratified into two groups according to PTX-NP onset:1 yr vs.1 yr post-transplantation. Both groups were comparable with respect to the degree of renal dysfunction (serum creatinine 4.3 +/- 2.5 mg/dL vs. 3.4 +/- 1.5 mg/dL) and proteinuria (4.7 +/- 1.6 gm/d vs. 5.8 +/- 3 gm/d). After a mean follow-up of 14 months post-biopsy, 87% of patients had lost their grafts in both groups (89% vs. 83%, p = NS). Overall, patients with serum creatinineor=2 mg/dL had better graft survival during follow-up than patients with serum creatinine2 mg/dL (75% vs. 4%, Fisher Exact Probability p = 0.0038). Using Kaplan-Meier estimate, the 5-yr graft survival rate was 100% for patients with serum creatinineor=2 mg/dL and 40% in those with2 mg/dL (p = 0.06). The magnitude of proteinuria beyond 3 gm/d did not influence graft survival. One-half of the patients (n = 15) received therapy with angiotensin converting enzyme inhibitors (ACEI). Graft survival, however, was not different between the patients who received ACEI compared with the patients who did not receive ACEI (13% vs. 13%). PTx-NP related to CAN was associated with poor allograft survival, irrespective of the time of onset of presentation, especially when renal function was reduced at the time of biopsy.

Post-transplant nephrotic syndrome: A comprehensive clinicopathologic study. Background Post-transplant (Tx) nephrotic syndrome (NS) is not well defined. Methods Seventy-four renal transplant recipients with NS were studied. Results Biopsies showed chronic allograft nephropathy (CAN) in 31 patients; recurrent glomerular disease (GN) in 15, de novo GN in 18, and undetermined GN in 9. NS developed 0.25 to 384months post-Tx and was treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in 18 patients; calcium channel blockers in 25; or both drugs in 31. NS remitted in 24% of cases 2 to 28months after onset, and this persisted in all except 3 patients. The remission rate was lowest (9%) for CAN and highest (47%) for de novo GN. Compared with persistent NS, those with remission showed higher prevalence of de novo GN (53% vs. 17%), lower prevalence of CAN (18% vs. 50%), earlier onset of NS (39 vs. 59months), lower serum SCr at onset (2.3 vs. 2.9mg/dL), and higher incidence of treatment with ACE or ARB. The 5-year graft loss rates for CAN, recurrent and de novo GN were 57%, 36%, and 23%, respectively. Compared with the functioning grafts, the failed grafts showed higher prevalence of CAN (60% vs. 16%), lower prevalence of de novo GN (12% vs. 46%), earlier onset of NS (47 vs 65months post-Tx), higher serum SCr at onset (3.3 vs. 2.0mg/dL), lower prevalence of remission of NS (5% vs. 48%), and higher proteinuria at follow-up (5.1 vs. 2.5g/day). Graft survival improved with NS remission (88% vs. 18%). Conclusion Post-Tx NS displays distinctive clinicopathologic features with pathogenetic and therapeutic implications.

4085 Background: Standard of care for locoregional esophageal (EC) and rectal (RC) adenocarcinoma is chemotherapy/radiotherapy (CTRT) followed by surgery. 25-30% of EC and RC patients exhibit extre...

51 Background: Standard of care for localized EC is neoadjuvant CTRT followed by surgery. Although 5-FU based regimens are still commonly used, other regimens (CROSS) are also prescribed. Published EC studies report 20-25% of patients exhibit extreme resistance (exCTRT) to 5-FU based neoadjuvant treatment (NT); these patients may benefit from alternative treatment regimens. We have developed a proprietary assay using a training set of 167 patients to accurately identify patients with exCTRT (ROC 0.96). The results presented herein constitute an independent clinical validation. Methods: Biopsy samples from 71 pts diagnosed to have EC and who had undergone surgical excision following NT were obtained. IHC detection of NF-kB, SHH, and Gli-1 proteins in FFPE sections was performed in a CLIA approved lab. A GI pathologist and an expert clinical scientist blindly evaluated resection specimens and assigned a labeling index (LI) score. The LI for each case was compared to the established training set and the predicted response determined using a logistic regression algorithm. Blinded pathology scoring for exCTRT vs. non-exCTRT was performed for all samples using both CAP Tumor Response Grade (TRG) and the Rohatgi research scale. Results: Of the 71 EC cases in the clinical validation cohort, 24 had an outcome of exCTRT (50% reduction in tumor; TRG 0-2). ROC for the validation cohort was 0.85. The positive predictive value for the validation study was 83%, reflecting an assay that can accurately predict those likely to have some degree of response to chemotherapy / radiation. Conversely, a negative predictive value of 83% with specificity of 94% was achieved indicating accurate identification of those not likely to benefit from neoadjuvant treatment. Conclusions: The analysis of NF-kB, SHH, and Gli-1 in EC tissue can accurately identify patients unlikely to respond to 5-FU based NT. These results are now confirmed using a CLIA accredited lab and a multicenter independent validation cohort of esophageal adenocarcinoma biopsies.