Oscar W. Cummings

Design and validation of a histological scoring system for nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi‐quantitatively: steatosis (0‐3), lobular inflammation (0‐2), hepatocellular ballooning (0‐2), and fibrosis (0‐4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization (“NASH,” “borderline,” or “not NASH”) were evaluated by using weighted kappa statistics. Inter‐rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter‐rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of ≥5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as “not NASH.” (HEPATOLOGY 2005;41:1313–1321.)

Comparison of Endoscopic Ultrasonography and Multidetector Computed Tomography for Detecting and Staging Pancreatic Cancer

Context Clinicians often use multidetector computed tomography or endoscopic ultrasonography to detect and stage pancreatic cancer. Contribution This prospective study found that, among 80 adults with proven pancreatic cancer, the sensitivity of multidetector computed tomography and endoscopic ultrasonography for detecting a pancreatic mass was 86% (CI, 77% to 93%) and 98% (CI, 91% to 100%), respectively. Among 53 patients undergoing surgery, endoscopic ultrasonography was more accurate for staging local tumor spread, but both tests showed similar accuracy for nodal staging and detecting resectability. Cautions Optimal strategies to detect and stage pancreatic cancer may vary across sites depending on the expertise of radiologists and endosonographers. The Editors In the United States for the year 2003, it was estimated that pancreatic cancer would be diagnosed in approximately 30700 patients and contribute to 30000 deaths (1). Complete surgical removal with negative histologic margins (R0 resection) is an independent predictor of postoperative survival (2-4) and remains the only potential curative treatment for pancreatic cancer. At surgical exploration, however, only 5% to 25% of the tumors are amenable to resection (5-8). Therefore, the principle goal of preoperative evaluation is to identify patients with potentially resectable disease while avoiding surgical exploration in those with unresectable disease. There is no evidence-based consensus on the optimal preoperative imaging assessment of patients with suspected pancreatic cancer. Because of widespread availability, helical computed tomography (CT) is usually the initial study for this indication (9, 10). Dual-phase helical CT, during which postinjection contrast image acquisition is obtained in both the pancreatic (arterial) and portal venous phases, has improved detection rate and assessment of resectability in patients with suspected pancreatic cancer (11, 12). Current state-of-the-art CT imaging uses a multiple-row detector with narrow detector collimation, wide x-ray beam, and rapid table translation; these features offer faster acquisition and thinner image slices compared with single-detector CT (13-15). Whether multidetector CT offers improved detection and staging of pancreatic cancer, however, is unknown. Endoscopic ultrasonography has been shown to be superior to conventional CT for the detection (16-20) and staging (19, 20) of pancreatic cancer. When compared with helical CT, however, endoscopic ultrasonography is reported to be either equivalent for detection (21, 22) or superior for detection or staging (23-25). To date, no comparative studies of multidetector CT with other imaging tests, including endoscopic ultrasonography, for suspected pancreatic cancer have been performed. Therefore, we conducted a prospective trial to compare endoscopic ultrasonography and multidetector CT for the detection, staging, and resectability of suspected locoregional pancreatic cancer. Methods Patients The institutional review board at Indiana University Medical Center approved this study, and all patients signed written informed consent. Eligible patients were referred to our hospital with clinically suspected or recently diagnosed solid or cystic pancreatic cancer within the previous 8 weeks. The referral base for our hospital consists of gastroenterologists and surgeons from Indiana and the surrounding contiguous states. Patients were eligible only if they agreed to undergo endoscopic ultrasonography, CT, and surgery (if necessary) at our institution. Patients were excluded if they had previously undergone endoscopic retrograde cholangiopancreatography or endoscopic ultrasonography at our institution for suspected pancreatic cancer; declined or remained undecided about potential surgical intervention; were referred to our institution by surgeons outside our hospital system. Patients were also excluded if they were pregnant, were incarcerated, could not independently provide informed consent, or were considered high surgical risk (American Society of Anesthesiology class III to V). In addition, we excluded patients with known or suspected periampullary masses, cholangiocarcinomas, or cancer with suspected locally advanced arterial (superior mesenteric, hepatic, or celiac) involvement or metastatic disease (ascites, suspicious liver or pulmonary lesions, distant enlarged lymph nodes) detected by previous imaging studies. Patients with suspected nonocclusive involvement of the superior mesenteric vein or portal vein were considered eligible for enrollment. Study Design This was a prospective, single-center, observational study. All enrolled patients had to respond to an initial health and medical questionnaire, which was followed by same-day endoscopic ultrasonography. Computed tomography was performed within 1 week. Within 3 weeks after CT, a surgeon examined the patient and reviewed the results of endoscopic ultrasonography and CT to determine eligibility for potential resection. After surgery or the decision to pursue nonoperative management, we telephoned patients to assess quality of life at 1 month, 3 months, and every 6 months until death or until 24 months if clinical disease remained stable. Endoscopic Ultrasonography Technique Conscious sedation was performed with various combinations of intravenously administered propofol, meperidine, fentanyl, or midazolam. Initially, we examined all patients with a radial echoendoscope (Olympus GF-UM130 [Olympus America Inc., Melville, New York]). We then examined patients with a linear echoendoscope (using either Pentax FG-36UX [Pentax Precision Instruments, Orangeburg, New York] or Olympus GF-UC140P [Olympus America Inc.]). Unless cancer had been definitively confirmed previously, endoscopic ultrasonographyguided fine-needle aspiration was performed with a 22-gauge needle (Wilson-Cook Medical Inc., Winston-Salem, North Carolina) in all patients, when applicable. A cytotechnologist or cytopathologist was on-site for preliminary interpretations of all aspirations. One of 3 experienced gastroenterologists, each of whom had performed at least 1000 pancreatic examinations, performed all procedures. The operator was not blinded to previous radiographic data. Recorded information included the presence or absence, size, echocharacteristics, location, or locoregional extension of any visualized pancreatic mass, lymph nodes, or distant metastases. Lymph nodes that were not accessible to endoscopic ultrasonographyguided fine-needle aspiration were considered malignant if 3 or more of the following criteria were present: diffuse hypoechoic echogenicity, short-axis diameter of 5 mm or greater, well-defined borders, round shape, or location within 5 mm of the tumor. Well-defined hypoechoic or hyperechoic lesions within the liver with a short-axis diameter of 10 mm or greater and not accessible to fine-needle aspiration were defined as metastases. We considered vascular involvement by the tumor to be present if any 1 of the following were noted: loss of the normal hyperechoic interface between tumor and vessel for at least 5 mm (adherence), irregular tumor and vessel interface, tumor within vessel lumen (invasion), vessel encasement, and perigastric or periduodenal collaterals with associated venous occlusion. Immediately after the examination, any visualized mass was designated by the endosonographer as surgically resectable or unresectable and assigned a tumor, node, metastasis (TNM) staging according to the 1997 American Joint Committee on Cancer (AJCC) classification (Appendix Table) for staging of pancreatic cancer (26). Multidetector CT Technique We performed multidetector CT with a quad-channel scanner (MX 8000 Quad, Philips Medical Systems, Cleveland, Ohio) by using 0.5-second gantry rotation time and acquisition of 4 sections per rotation. All patients drank 500 mL of tap water as nonopaque oral intraluminal contrast media. A total of 150 mL (300 mg of iodine/mL) of low-osmolar contrast media (Isovue-300, Bracco Diagnostics, Princeton, New Jersey) was injected with a power injector (CT Envision Injector, Medrad, Pittsburgh, Pennsylvania) at a rate of 4.0 mL/s into an antecubital vein by using either an 18- or 20-gauge cannula. Examination was performed in a dual-phase mode. Image acquisition was first done during the pancreatic phase (35 seconds after the start of contrast infusion) from the top to the bottom of the pancreas with 4.0-mm beam collimation (nominal section thickness, 1.0 mm; effective section thickness, 1.3 mm), 0.5-mm reconstruction interval, 120 kVp, 205 mAs, and a pitch of 1.0 during a single breath-hold of 15 to 20 seconds. The second phase was performed during the portal venous phase (65 seconds after the start of contrast infusion) from the top of the liver to the iliac crests with 10-mm beam collimation (nominal section thickness, 2.5 mm; effective section thickness, 3.2 mm), 1.3-mm reconstruction interval, 120 kVp, 250 mAs, and a pitch of 0.875 during a single breath-hold of 15 seconds. Multiplanar (2-dimensional) reformatting was not routinely performed; however, when it was used, the entire data set was transferred to a workstation (MX View, Philips Medical Systems) for evaluation. No 3-dimensional (volume rendering) postprocessing was used in this study. One of 3 experienced gastrointestinal radiologists who were blinded to the results of the previous endoscopic ultrasonography examination interpreted all scans. Patient information provided to the interpreting radiologist included presenting symptoms; the size, location, and vascular involvement (if known) of any visualized pancreatic mass from previous CT; and the results of any previous endoscopic retrograde cholangiopancreatography (for example, presence or absence of ductal strictures) or pathology (for example, endoscopic brush cytology). Locoregional and distant adenopathy were considered malignant if they were greater than 10 mm in

IL-17–dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpastures syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.

Intraductal papillary mucinous neoplasms: Predictors of malignant and invasive pathology

Objective:Determine whether size and other preoperative parameters predict malignant or invasive intraductal papillary mucinous neoplasia (IPMN). Summary Background Data:From 1991 to 2006, 150 patients underwent 156 operations for IPMN. Methods:Prospectively collected, retrospective review of a single academic institutions experience. All preoperative parameters including a detailed radiologic-based classification of IPMN type, location, distribution, size, number, cytology, and mural nodularity were correlated with IPMN pathology. Results:Malignant IPMN was present in 32% of cases, whereas 19% of cases were invasive. IPMN type and main pancreatic duct diameter were significant predictors of malignant IPMN (P < 0.001). Side-branch lesion number was negatively associated with invasive IPMN (P = 0.03). Side-branch size, location, and distribution did not predict IPMN pathology. The presence of mural nodules was associated with malignant and invasive IPMN (P < 0.001; P < 0.02). Atypical cytopathology was significantly associated with malignant and invasive IPMN (P < 0.001; P < 0.001). Multivariate analysis demonstrated mural nodularity and atypical cytopathology were predictive of malignancy and/or invasion in branch-type IPMN. Conclusions:To lower the rate of invasive pathology, surgery should be recommended for fit patients with main-duct IPMN and for branch-duct IPMN with mural nodularity or positive cytology irrespective of location, distribution, or size.

Endoscopic Ultrasonography, Fine-Needle Aspiration Biopsy Guided by Endoscopic Ultrasonography, and Computed Tomography in the Preoperative Staging of Non-Small-Cell Lung Cancer: A Comparison Study

Accurate staging of non-small-cell lung cancer plays a crucial role in determining the treatment options available to patients with this disease. The preoperative documentation of metastasis to the mediastinal lymph nodes has therapeutic implications that have traditionally focused on palliation but more recently have included neoadjuvant strategies [1, 2]. Metastasis to the mediastinal lymph nodes occurs in nearly half of all patients with non-small-cell lung cancer. The development of mediastinal metastasis is probably the most frequent deterrent to cure, even when the presentation is localized. If metastasis involves contralateral or large, bulky (>1.5 to 2.0 cm) subcarinal lymph nodes, surgery alone may not be curative [3-9]. As a result of recent revisions to the staging systems for lung cancer, ipsilateral mediastinal and subcarinal lymph node involvement is now classified as potentially resectable, N2 disease; contralateral mediastinal lymph node involvement (N3 disease) precludes resection [10-12]. Computed tomography of the chest is the current method by which mediastinal lymphadenopathy is detected in non-small-cell lung cancer. However, its sensitivity for detection of metastasis to the lymph nodes varies; accuracy in previous studies has ranged from 52% to 88% [13-23]. This inconsistency has been attributed to the variable correlation of lymph node size with the presence of malignancy. When enlarged contralateral or ipsilateral mediastinal lymph nodes are seen on computed tomography of the chest, standard practice is to determine more accurate staging by performing aspiration biopsy of the lymph node with computed tomographic guidance; bronchoscopy; or, less commonly, a transthoracic approach. If these procedures are unsuccessful, open biopsy is performed by using mediastinoscopy or limited thoracotomy [24-26]. If contralateral lymph nodes are positive for malignancy, surgical resection of the primary tumor is contraindicated. The development of endoscopic ultrasonography has now made it possible to visualize, with high resolution, not only the gastrointestinal tract but also surrounding structures. Endoscopic ultrasonography has been shown to be superior to computed tomography in evaluating lymph nodes for metastases in esophageal, gastric, and pancreatic cancer [27-29]. Promising results for detecting posterior mediastinal lymph nodes in patients with lung cancer suggest a possible role for endoscopic ultrasonography in staging lymph nodes in patients with non-small-cell lung cancer [30-36]. Fine-needle aspiration biopsy guided by endoscopic ultrasonography was recently reported to further improve the accuracy of endoscopic ultrasonography in predicting malignancy of gastrointestinal masses, with rates as high as 87% to 91% [37-42]. We previously reported the results of endoscopic ultrasonography in 17 patients with lung cancer. This method was very accurate for detecting mediastinal lymphadenopathy; the overall accuracy was 71% compared with 41% for computed tomography (P = 0.032) [43]. During the initial study, however, fine-needle aspiration biopsy guided by endoscopic ultrasonography was not available. The goal of the present study was to prospectively evaluate the accuracy of endoscopic ultrasonography alone, endoscopic ultrasonography-guided fine-needle aspiration biopsy, and computed tomography of the chest in detecting mediastinal lymph node metastasis in patients with non-small-cell lung cancer. Methods Patient Selection The study sample consisted of all patients presenting to the Indiana University Thoracic Oncology Program between July 1993 and June 1995 with a diagnosis of non-small-cell lung cancer. The study was approved by the institutional review board, and all enrolled patients gave informed consent. Patients were excluded if they had documented unresectable disease (that is, distant metastasis or locally advanced staged disease [stage III b]) as shown on computed tomography of the chest or if they had a serious medical illness and a life expectancy of less than 1 year. All patients underwent initial preoperative intravenous contrast-enhanced computed tomography of the chest; the axial technique was used in 60% of patients, and the spiral technique was used in 40%. Computed tomography was done at the referring hospital or Indiana University Medical Center; the scans were read at Indiana University Medical Center by a senior attending radiologist who has recognized expertise in this area and used currently accepted radiographic techniques to stage the tumor. The radiologists determination of the benign or malignant nature of each lymph node was recorded on a preoperative computed tomography lymph node map; the American Thoracic Society mediastinal staging map (Figure 1) was used to describe the location of each node [12]. Any patient who had a questionably enlarged mediastinal lymph node (>1 cm in diameter) and was considered a surgical candidate was then scheduled for endoscopic ultrasonography. Figure 1. American Thoracic Society scheme for mapping mediastinal lymphadenopathy by anatomic location, as seen from behind with endoscopic ultrasonography. Endoscopic Ultrasonography Endoscopic ultrasonography was performed in an outpatient setting on all patients by one of three experienced endosonographers; the radial scanning echoendoscope (GFUM-20, Olympus America, Melville, New York) or the linear-array scanning echoendoscope (FG32UA, Pentax, Orangeburg, New York) was used for all procedures. When done by an experienced operator, endoscopic ultrasonography is similar to standard upper endoscopy both in technique and duration of the procedure. When fine-needle aspiration biopsy is performed, the procedure is slightly prolonged. Patients were sedated with meperidine and midazolam, the doses of which were titrated to achieve adequate conscious sedation. The instrument was advanced into the stomach, and the celiac axis was imaged. The probe was then withdrawn to the gastroesophageal junction and slowly withdrawn at 1-cm intervals. Images were obtained with 7.5- and 12-MHz frequencies at each interval. All imaged mediastinal lymph nodes were mapped by location according to the American Thoracic Society classification scheme [12]. From these data, an objective assessment was made as to whether the mediastinal lymphadenopathy detected by endoscopic ultrasonography was benign or possibly malignant according to the following previously reported criteria for malignancy: round shape; sharp, distinct borders; hypoechoic texture; and a short-axis diameter greater than 5 mm [36-39]. Malignancy was suspected if all of these criteria were present. All patients who were studied before the availability of endoscopic ultrasonography-guided fine-needle aspiration biopsy underwent surgical resection, and endoscopic ultrasonographic findings were correlated to surgical pathologic findings. Patients who were studied after the advent of fine-needle aspiration biopsy and were found to have no suspicious lymph nodes by endoscopic ultrasonography were directly referred for surgery because there was no indication for aspiration biopsy. Endoscopic Ultrasonography-Guided Fine-Needle Aspiration Biopsy Endoscopic ultrasonography-guided aspiration biopsy became available after the first 17 patients were enrolled in our pilot study. All posterior mediastinal lymph nodes that were suspicious for malignant involvement according to the endoscopic ultrasonographic criteria were noted; selected nodes underwent biopsy during the same procedure. Many of the patients had more than one suspicious lymph node. We performed biopsy only on the most suspicious lymph node, which would have the greatest effect on clinical staging (that is, determination of whether the metastasis was contralateral or subcarinal). This technique for ultrasonography-guided aspiration biopsy was initially developed for use with the linear-array instrument (Figure 2) and is described elsewhere [40-42]. We recently reported a similar technique that uses a radial scanning echoendoscope (Figure 3) [37]. Ultrasonography-guided aspiration biopsy involves the insertion of an aspiration catheter needle device through the accessory channel port of the echoendoscope; the needle is then deployed into the lymph node to be sampled under endoscopic ultrasonographic guidance. Aspiration biopsy is done by introducing a specially designed fine-needle aspiration catheter system that consists of a 4-cm long, 23-gauge needle attached to a 180-cm long, 5-French aspiration catheter (Wilson-Cook, Winston-Salem, North Carolina); in and out movements of the catheter are used while the operator firmly grasps the catheter at the point at which it enters the accessory port. Figure 2. A mediastinal lymph node as imaged with the linear-array endoscopic ultrasonography system. arrow Figure 3. Endoscopic ultrasonographic image obtained from the radial scanning instrument showing a large hypoechoic, oval subcarinal lymph node (LN) suspicious for metastatic involvement. Preliminary cytologic findings were obtained during fine-needle aspiration biopsy by a cytopathologist who was present during the procedure. Before the sample was reviewed, Diff-Quik stain (Harleco, Gibbstown, New Jersey) was applied to the slide that contained the deposited specimen. Additional passes were made until a positive cytologic result or a negative result on an adequate tissue sample was obtained [37]. Patients who were considered eligible for surgical resection after staging by computed tomography and endoscopic ultrasonography (that is, patients with a negative result on aspiration biopsy of contralateral or bulky subcarinal lymph nodes or those with nodes that seemed to be benign according to endoscopic ultrasonographic criteria) underwent thoracotomy for pulmonary resection with ipsilateral mediastinal and subcarinal lymph node dissection. During mediastinal dissection, each lymph node was placed in th

Genome-Wide Association Study Identifies Variants Associated With Histologic Features of Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMS Little data are available from genome-wide association studies (GWASs) of liver histology in patients with nonalcoholic fatty liver disease (NAFLD). We conducted a pilot GWAS in patients with NAFLD, characterized by histology, who were enrolled in the NASH Clinical Research Network (CRN) Database Study. METHODS We studied clinical, laboratory, and histologic data from 236 non-Hispanic white women with NAFLD. We analyzed 324,623 single nucleotide polymorphisms (SNPs) from the 22 autosomal chromosomes. Multivariate-adjusted logistic regression analyses were conducted for binary outcomes, and linear regression analysis was applied for quantitative traits. A P value < 1 × 10(-6) was considered to be significant. RESULTS In multivariate models adjusted for age, body mass index, diabetes, waist/hip ratios, and levels of glycated hemoglobin, the NAFLD activity score was associated with the SNP rs2645424 on chromosome 8 in farnesyl diphosphate farnesyl transferase 1 (FDFT1) (P = 6.8 × 10(-7)). The degree of fibrosis was associated with the SNP rs343062 on chromosome 7 (P = 2.7 × 10(-8)). SNPs associated with lobular inflammation included SNP rs1227756 on chromosome 10 in COL13A1 (P = 2.0 × 10(-7)), rs6591182 on chromosome 11 (P = 8.6 × 10(-7)), and rs887304 on chromosome 12 in EFCAB4B (P = 7.7 × 10(-7)). SNPs associated with serum levels of alanine aminotransferase included rs2499604 on chromosome 1 (P = 2.2 × 10(-6)), rs6487679 on chromosome 12 in PZP (P = 1.3 × 10(-6)), rs1421201 on chromosome 18 (P = 1.0 × 10(-5)), and rs2710833 on chromosome 4 (P = 6.3 × 10(-7)). No significant associations were observed between genotypes and steatosis, ballooning degeneration, portal inflammation, or other features of NAFLD. CONCLUSIONS A GWAS significantly associated genetic variants with features of hepatic histology in patients with NAFLD. These findings should be validated in larger and more diverse cohorts.

CT vs MRCP: optimal classification of IPMN type and extent.

IntroductionIntraductal papillary mucinous neoplasms (IPMNs) of the pancreas are being diagnosed with increased frequency. CT scanning commonly serves as the primary imaging modality before surgery. We hypothesized MRCP provides better characterization of IPMN type/extent, which more closely matches actual pathology.MethodsOf 214 patients treated with IPMN (1991–2006), 30 had both preoperative CT and MRCP. Of these, 18 met imaging study criteria. Independent readers performed retrospective, blinded analyses using standardized criteria for IPMN type and extent.ResultsA ductal connection was detected on 73% of MRCP scans and only 18% of CT. IPMN type was classified differently in seven (39%); four (22%) of which were read on CT as having main duct involvement where this was not appreciated on MRCP or found on surgical pathology. MRCP showed multifocal disease in 13(72%) versus only 9(50%) on CT. A different disease distribution was seen in 9(50%). Finally, 101 branch lesions were identified on MRCP compared to 46 on CT.ConclusionsCT falls short of MRCP in detecting a ductal connection, estimating main duct involvement, and identification of small branch duct cysts. These factors influence diagnostic accuracy, cancer risk stratification and operative strategy. MRCP should be employed for optimal management of patients with IPMN.

Variable pathologic interpretation of columnar lined esophagus by general pathologists in community practice

BACKGROUND Pathologic interpretation of biopsy specimens of columnar lined esophagus guides subsequent endoscopic surveillance and/or surgical intervention. The aim of this study was to evaluate pathologic interpretation of columnar lined esophagus by general pathologists in community practice. METHODS Five histologic slides representing different types of columnar lined esophagus were submitted for review by 20 randomly selected general pathologists in community practice. There were three cases with intestinal metaplasia (one with no dysplasia, one with low-grade dysplasia, and one with high-grade dysplasia) and two cases of gastric metaplasia (one fundic-type and one cardia-type). RESULTS High-grade dysplasia was identified as such by 30% of pathologists and was called invasive adenocarcinoma by 20%, low-grade dysplasia by 30%, and moderate dysplasia by the remaining 20%. Low-grade dysplasia was identified as such by 35% of pathologists and was called high-grade dysplasia by 20%, moderate dysplasia by 20%, and no dysplasia by 25%. Specialized columnar epithelium with no dysplasia was identified as such by 35%, called low-grade dysplasia by 35%, moderate dysplasia by 15%, indeterminate for dysplasia by 10%, and invasive adenocarcinoma by 5%. Gastric metaplasia without specialized columnar epithelium was identified as Barretts esophagus in 38% of cases. CONCLUSIONS Pathologic interpretation of columnar lined esophagus by community pathologists may be subject to marked interobserver variation. The term Barretts esophagus is often used to describe columnar lined esophagus without goblet cells. Because this finding is not clearly associated with an increased risk of cancer, these data support recent suggestions that the term Barretts esophagus be abandoned. Interpretations of both high-grade and low-grade dysplasia should be considered for review by experts in esophageal pathology.

Evidence for Immune Responses to a Self-Antigen in Lung Transplantation: Role of Type V Collagen-Specific T Cells in the Pathogenesis of Lung Allograft Rejection

We have reported that lung allograft rejection involves an immune response to a native protein in the lung, type V collagen (col(V)), and that col(V)-induced oral tolerance prevented acute and chronic rejection. In support of these findings col(V) fragments were detected in allografts during rejection, but not in normal lungs. The purpose of the current study was to isolate and characterize col(V)-specific allograft-infiltrating T cells and to determine their contribution to the rejection response in vivo. Two col(V)-specific T cell lines, LT1 and LT3, were isolated from F344 (RT1lv1) rat lung allografts during rejection that occurred after transplantation into WKY (RT1l) recipients. Both cell lines, but not normal lung lymphocytes, proliferated in response to col(V). Neither LT1 nor LT3 proliferated in response to alloantigens. LT1 and LT3 were CD4+CD25− and produced IFN-γ in response to col(V). Compared with normal CD4+ T cells, both cell lines expressed a limited V-β TCR repertoire. Each cell strongly expressed V-β 9 and 16, but differed in expression of other V-βs. Adoptive transfer of each cell line did not induce pathology in lungs of normal WKY rats. In contrast, adoptive transfer of LT1, but not LT3, caused marked peribronchiolar and perivascular inflammation in isograft (WKY) lungs and abrogated col(V)-induced oral tolerance to allograft (F344) lungs. Collectively, these data show that lung allograft rejection involves both allo- and autoimmune responses, and graft destruction that occurs during the rejection response may expose allograft-infiltrating T cells to potentially antigenic epitopes in col(V).

Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis

BACKGROUND & AIMS Autoimmune hepatitis is a common cause of chronic hepatitis, and acute presentation is thought to be uncommon. The aim of this study was to compare clinical, biochemical, and histological features in patients with autoimmune hepatitis presenting with either acute or chronic hepatitis. METHODS Retrospective review of all patients with autoimmune hepatitis presenting to a University medical center from 1993 to 2002. RESULTS One hundred fifteen patients with autoimmune hepatitis were identified. Ten patients with autoimmune hepatitis were identified as having acute presentation (group I), and 20 patients with a classic presentation as chronic hepatitis (group II) served as age- and sex-matched controls. All patients met criteria published by the International Autoimmune Hepatitis Group. Patients with acute presentation differed significantly with regard to encephalopathy, albumin levels, and bilirubin levels. Blinded liver biopsy review demonstrated that those with acute presentation had significantly less fibrosis, and significantly greater interface hepatitis, lobular disarray, lobular hepatitis, hepatocyte necrosis, zone III necrosis, and submassive necrosis. CONCLUSIONS In our study, patients with an acute presentation of autoimmune hepatitis differed from patients with a classical presentation clinically, biochemically, and histologically. In our review, a majority of patients with acute autoimmune hepatitis presented with fulminant hepatic failure. The pattern of zone 3 necrosis may be a specific finding in those with acute autoimmune hepatitis.