Host CCL3L1 Gene Copy Number in Relation to HIV-1-Specific CD4+and CD8+T-Cell Responses and Viral Load in South African Women.

HIV-specific T-cell responses play an important role in control of infection. Because CCL3 has immune modulatory and antiviral activities, we hypothesized that host CCL3 genotype (CCL3L1 gene duplications) would influence the development of effective HIV-specific immune responses. Copy numbers of CCL3L1 were determined for 71 HIV-infected women, and HIV-specific CD4and CD8T-cell responses to overlapping peptide pools spanning the HIV-1 subtype C genome were simultaneously measured by an interferon-gamma and interleukin-2 whole-blood flow cytometric assay. Host CCL3L1 copy number correlated negatively with viral load (r = 20.239, P = 0.045), as did magnitudes of Gag CD4(r = 20.362, P = 0.002) and CD8(r = 20.261, P = 0.028) T-cell responses. Patients with a Gag CD4response (P =0.002)or dominant Gag CD8(P = 0.006) response had significantly lower viral loads than those whose dominant response targeted another region of the genome, whereas a dominant Nef-specific CD8T-cell response was associated with higher HIV viral load. CCL3L1 copy number greater than or equal to the population median of 5 was significantly associated with increased magnitude of CD4Gag responses (P = 0.017), and women who had CD4and CD8Gag-specific responses had significantly lower viral loads (P = 0.004) and higher CCL3L1 copy number (P = 0.015) than those women with only CD8Gag-specific responses.

Shalekoff S, Meddows-Taylor S, Schramm DB, Donninger SL, Gray GE, Sherman GG, Coovadia AH, Kuhn L, Tiemessen CT.

From the *AIDS Virus Research Unit, National Institute for Communicable Diseases, and University of the Witwatersrand, Johannesburg, South Africa; †Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa; ‡National Health Laboratory Services and Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa; §Coronation Hospital, Wits Paediatric HIV Working Group, Johannesburg, South Africa; and the ∥Gertrude H. Sergievsky Centre, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY.

Ependymomas of the Central Nervous System and Adult Extra-axial Ependymomas are Morphologically and Immunohistochemically Distinct-A Comparative Study With Assessment of Ovarian Carcinomas for Expression of Glial Fibrillary Acidic Protein.

Extra-axial ependymomas are very rare but have been reported in the ovary, broad ligament, sacrococcygeal region, lung, and mediastinum. The histogenesis is obscure, and a thorough immunohistochemical analysis is lacking. We reviewed the morphologic and immunohistochemical features of 5 extra-axial ependymomas occurring in adults, 1 arising in an infantile sacrococcygeal teratoma, and a control group of 10 central nervous system (CNS) ependymomas in adults. All cases were evaluated for expression of epithelial membrane antigen, estrogen receptor (ER), progesterone receptor (PR), WT1, CD99, CK18, AE1:3, CAM 5.2, 34betaE12, CK7, CK20, synaptophysin, chromogranin, and glial fibrillary acidic protein (GFAP) using formalin-fixed, paraffin-embedded tissue. One hundred twelve ovarian carcinomas in 3 tissue microarrays were also studied with GFAP. The adult extra-axial cases demonstrated more architectural variability than the CNS cases. We observed that both the CNS and adult extra-axial ependymomas expressed GFAP diffusely, whereas only 9 stage III, high-grade ovarian serous papillary carcinomas stained with GFAP (2 strongly and diffusely and 7 exhibiting focally weak expression). There were significant immunophenotypic differences between adult extra-axial and CNS ependymomas, with extra-axial cases preferentially expressing 34betaE12 (60% vs. 0%), CK18 (100% vs. 20%), CAM 5.2 (60% vs. 10%), CK7 (80% vs. 10%), ER (100% vs. 10%), and PR (80% vs. 20%). Two spinal cord ependymomas expressed CK18, 1 expressed CK7, and 1 expressed CAM 5.2. CNS ependymomas more frequently expressed CD99 (100% vs. 20%). The following stains were not differentially expressed: epithelial membrane antigen (expressed in 2 of 15 cases, including both extra-axial and CNS ependymomas), synaptophysin (1/15), chromogranin (0/15), WT1 (8/15), AE1:3 (10/15), and CK20 (0/15). The ependymal elements of the sacrococcygeal tumor failed to express 34betaE12, CK18, CAM 5.2, and CK7, like most CNS ependymomas. The morphologic and immunophenotypic differences between extra-axial and CNS ependymomas suggest that they derive from distinct precursors and/or differentiate along distinct pathways. The differential diagnosis of extra-axial ependymomas is extensive, and GFAP expression in primary ovarian serous carcinomas, although rare, could theoretically contribute to diagnostic difficulties. ER and PR expression in extra-axial ependymomas may provide targets for hormonal therapy.

Idowu MO, Rosenblum MK, Wei XJ, Edgar MA, Soslow RA.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.

Is Nonsmall Cell Type High-grade Neuroendocrine Carcinoma of the Tubular Gastrointestinal Tract a Distinct Disease Entity?

Although small cell carcinoma of the gastrointestinal (GI) tract is well-recognized, nonsmall cell type high-grade neuroendocrine carcinoma (HGNEC) of this site remains undefined. At the current time, neither the World Health Organization nor American Joint Committee on Cancer includes this condition in the histologic classifications, and consequently it is being diagnosed and treated inconsistently. In this study, we aimed at delineating the histologic and immunophenotypical spectrum of HGNECs of the GI tract with emphasis on histologic subtypes. Guided primarily by the World Health Organization/International Association for the Study of Lung Cancer criteria for pulmonary neuroendocrine tumors, we were able to classify 87 high-grade GI tract tumors that initially carried a diagnosis of either poorly differentiated carcinoma with or without any neuroendocrine characteristics, small cell carcinoma, or combined adenocarcinoma-neuroendocrine carcinoma into the following 4 categories. The first was small cell carcinoma (n=23), which had features typical of pulmonary small cell carcinoma, although the cells tended to have a more round nuclear contour. The second was large cell neuroendocrine carcinoma (n=31), which had a morphology similar to its pulmonary counterpart and showed positive immunoreactivity for either chromogranin (71%) or synaptophysin (94%) or both. The third was mixed neuroendocrine carcinoma (n=11), which had intermediate histologic features (eg, cells with an increased nuclear/cytoplasmic ratio but with apparent nucleoli), and positive immunoreactivity for at least 1 neuroendocrine marker. The fourth was poorly differentiated adenocarcinoma (n=17). In addition, 5 of the 87 tumors showed either nonsmall cell type neuroendocrine morphology (n=3) or immunohistochemical reactivity for neuroendocrine markers (n=2), but not both. Further analysis showed that most HGNECs arising in the squamous lined parts (esophagus and anal canal) were small cell type (78%), whereas most involving the glandular mucosa were large cell (53%) or mixed (82%) type; associated adenocarcinomas were more frequent in large cell (61%) or mixed (36%) type than in small cell type (26%); and focal intracytoplasmic mucin was seen only in large cell or mixed type. As a group, the 2-year disease-specific survival for patients with HGNEC was 25.4% (median follow-up time, 11.3 mo). No significant survival difference was observed among the different histologic subtypes. In conclusion, our study demonstrates the existence of both small cell and nonsmall cell types of HGNEC in the GI tract, and provides a detailed illustration of their morphologic spectrum. There are differences in certain pathologic features between small cell and nonsmall cell types, whereas the differences between the subtypes of nonsmall cell category (large cell versus mixed) are less distinct. Given the current uncertainty as to whether large cell neuroendocrine carcinoma is as chemosensitive as small cell carcinoma even in the lung, our data provide further evidence in favor of a dichotomous classification scheme (small cell vs. nonsmall cell) for HGNEC of the GI tract. Separation of nonsmall cell type into large cell and mixed subtypes may not be necessary. These tumors are clinically aggressive. Prospective studies using defined diagnostic criteria are needed to determine their biologic characteristics and optimal management.

Shia J, Tang LH, Weiser MR, Brenner B, Adsay NV, Stelow EB, Saltz LB, Qin J, Landmann R, Leonard GD, Dhall D, Temple L, Guillem JG, Paty PB, Kelsen D, Wong WD, Klimstra DS.

Departments of *Pathology †Surgery (Colorectal Surgery Service) ‡Medicine (Gastrointestinal Oncology Service), Memorial Sloan-Kettering Cancer Center, New York, NY §Department of Pathology, Emory University School of Medicine, Atlanta, GA ∥Department of Pathology, University of Virginia, Charlottesville, VA ¶Biostatistics Research Branch, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD.

Mandatory Second Opinion in Surgical Pathology Referral Material: Clinical Consequences of Major Disagreements.

Second opinion in pathology is intended to expose clinically significant errors that have a direct impact on patient care. Before definitive treatment of referred patients, our institution requires a second opinion of outside surgical pathology slides. We sought to determine if this local standard of practice has a measurable impact on patient care via clinical and pathologic follow-up. 5629 second opinion surgical pathology cases seen at the University of Iowa Hospitals and Clinics were studied. Each case was classified as: no diagnostic disagreement, minor diagnostic disagreement, or major diagnostic disagreement by the second opinion pathologist at the time of referral. A major diagnostic disagreement was defined as a change in pathologic diagnosis with potential for significant change in treatment or prognosis. Major diagnostic disagreements were categorized by organ system and according to the clinical significance of the changed diagnosis based on clinical and pathologic follow-up. Second opinion surgical pathology resulted in 132 (2.3% of total cases) major diagnostic disagreements and 507 (9.0%) cases with minor disagreements. The organ systems involved in the majority of the major disagreements were the female reproductive tract (32), gastrointestinal tract (27), and skin (24). Of the 132 major diagnostic disagreements, 68 (1.2% of total cases reviewed) prompted changes in the clinical management as a result of the second opinion interpretation. These findings support the idea that mandatory second opinion is an important part of patient care in the referral setting.

Manion E, Cohen MB, Weydert J.

Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA.

PDGFRA Immunostaining Can Help in the Diagnosis of Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are characterized by the presence of activating mutations affecting the c-Kit or the PDGFRA gene. Although these mutations are mutually exclusive, their proteins are coexpressed in many GISTs with various modulations of immunostaining depending on which gene is mutated. CD117 expression is currently considered a sensitive (although not entirely specific) marker of KIT activation, but there is no consensus concerning the reliability of PDGFRA antibody. Our database contains 236 molecularly analyzed GISTs, and we here describe the 180 cases that underwent KIT/PDGFRA immunophenotyping. By correlating the immunophenotype with the molecular status of the genes expected to be involved, we observed the coexpression of KIT and PDGFRA in the majority of the mutated c-Kit and wild-type c-Kit/PDGFRA GISTs, whereas the -/+ immunophenotype (0% vs. 48.6%) and PDGFRA dotlike immunostaining (P<0.005) segregated with the PDGFRA-mutated GISTs. Taking either the dotlike decoration (26 cases) or -/+ immunophenotype (5 cases) as hallmarks of PDGFRA mutation, the presence of a PDGFRA mutation was predicted in 31 (83.8%) of the 37 PDGFRA mutated GISTs. Our findings suggest that, when critically applied, the routine use of CD117/PDGFRA immunophenotyping is a useful diagnostic tool (especially in CD117-negative cases) as it correctly predicts the presence of PDGFRA mutations in most cases.

Miselli F, Millefanti C, Conca E, Negri T, Piacenza C, Pierotti MA, Tamborini E, Pilotti S.

*Experimental Molecular Pathology Unit, Department of Pathology †Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Mucosal Intraepithelial T-lymphocytes in Refractory Celiac Disease: A Neoplastic Population With a Variable CD8 Phenotype.

Celiac disease (CD) is characterized by villous atrophy and an increase in intraepithelial lymphocytes (IEL). The IEL usually exhibit a suppressor/cytotoxic phenotype (CD3 and CD8) and display a polyclonal profile for T-cell receptor (TCR) rearrangement as opposed to the monoclonality of refractory CD (RCD) with CD8 IEL. A complication of CD is the loss of response to a gluten-free diet called RCD that may progress to an enteropathy-associated T-cell lymphoma. We reviewed 20 uncomplicated CD and 23 complicated CD (19 RCD and 4 diagnosed at the same time as enteropathy-associated T-cell lymphoma). In complicated CD, the IEL phenotype was CD8 in 9 cases and CD8 in 14 cases. In 100% of cases, IEL showed a monoclonal TCR rearrangement. All the 9 CD8 complicated CD exhibited a monoclonal TCR rearrangement and 3 of them were associated with a T-cell lymphoma (2 at the same time as CD and 1 after 43-mo follow-up) and bore the same monoclonal rearrangement in IEL and in lymphoma. Interestingly, the 13 cases (100%) of CD with a CD8 phenotype were also found monoclonal and 2 of them were associated with a T-cell lymphoma diagnosed at the same time as CD and exhibiting the same rearrangement in IEL and in lymphoma. An aberrant CD3 CD8 IEL phenotype is a good criterion for RCD diagnosis. However, cases with a normal CD3 CD8 IEL phenotype may correspond to RCD. In such cases, we suggest that molecular analysis of TCR-gamma genes is a useful method for identifying cases with RCD.

de Mascarel A, Belleannée G, Stanislas S, Merlio C, Parrens M, Laharie D, Dubus P, Merlio JP.

Department of Pathology, CHU de Bordeaux, Hôpital Haut-Lévêque, 33604 Pessac. EA2406 Histology and Pathology, University of Bordeaux 2, 33076 Bordeaux, France.

Pharmacokinetic/Pharmacodynamic Drug Interaction Between Rosiglitazone and Mycophenolate Mofetil in Kidney Transplantation: A Case Report.

Cattaneo D, Bitto A, Baldelli S, Cortinovis M, Gotti E, Perico N, Remuzzi G.

Department of Medicine and Transplantation, Azienda Ospedaliera Ospedali Riuniti, Bergamo and Mario Negri Institute for Pharmacological Research, Bergamo, Italy, Center for Research on Organ Transplantation, “Chiara Cucchi De Alessandri & Gilberto Crespi”, Azienda Ospedaliera Ospedali Riuniti, Bergamo and Mario Negri Institute for Pharmacological Research, Bergamo, Italy (Cattaneo, Bitto, Baldelli, Cortinovis) Department of Medicine and Transplantation, Azienda Ospedaliera Ospedali Riuniti, Bergamo and Mario Negri Institute for Pharmacological Research, Bergamo, Italy (Gotti) Department of Medicine and Transplantation, Azienda Ospedaliera Ospedali Riuniti, Bergamo and Mario Negri Institute for Pharmacological Research, Bergamo, Italy, Center for Research on Organ Transplantation, “Chiara Cucchi De Alessandri & Gilberto Crespi”, Azienda Ospedaliera Ospedali Riuniti, Bergamo and Mario Negri Institute for Pharmacological Research, Bergamo, Italy (Perico, Remuzzi).

Retraction: Peritransplant Tolerance Induction with Anti-CD3-Immunotoxin: A Matter of Proinflammatory Cytokine Control.

Thomas JM, Contreras JL, Wang PX, Eckhoff DE, Asiedu C, Hubbard WJ, Cartner S, Thomas FT, Robbin ML, Nadler S, Cook WJ, Sharff J, Neville DM Jr, Shiloach J.

Transplant Immunology Section, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL (Thomas) Division of Transplant Immunology, Department of Surgery and Transplant Center, University of Alabama at Birmingham, Birmingham, AL (Contreras, Wang, Eckhoff, Asiedu, Hubbard, Cartner, Thomas) Department of Radiology, University of Alabama at Birmingham, Birmingham, AL (Robbin) Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ (Nadler) Department of Pathology, University of Alabama at Birmingham, Birmingham, AL (Cook) Rockville, MD (Sharff) National Institutes of Health, Laboratory of Molecular Biology, NIMH, Bethesda, MD (Neville) Biotechnology Unit, Laboratory of Cellular and Developmental Biology, NIDDK, Bethesda, MD (Shiloach).

Similar Long-Term Outcomes for Laparoscopic Versus Open Live-Donor Nephrectomy Kidney Grafts: An OPTN Database Analysis of 5532 Adult Recipients.

Prior studies that included both adult and pediatric recipients suggested slower early graft function for laparoscopically (vs. openly) procured live donor kidney grafts (LD-Ktxs). Any potential long-term impact, however, remains unknown. We compared long-term outcomes of 2685 (49%) laparoscopic vs. 2847 (51%) open LD-Ktxs reported to the Organ Procurement and Transplantation Network performed in adult (>/=18 yrs) recipients between November 1999 and December 2000, with follow-up to February 2006. Acute and chronic rejection accounted for 152 laparoscopic (51%) vs. 148 (46%) open graft losses (P=NS). At discharge and at 5 years, graft function was similar for both groups; graft survival at 5 years was 79% (laparoscopic) vs. 80% (open) (P=NS). We conclude that despite prior reports of slower early laparoscopic LD-Ktx function, both laparoscopic and open nephrectomy are equally effective for procurement of kidneys for adult recipients with regard to short- and long-term (>5 years) function and survival. Future studies must investigate whether these findings apply also to pediatric LD-Ktx recipients.

Troppmann C, Perez RV, McBride M.

1 Department of Surgery, University of California, Davis, Sacramento, CA. 2 Department of Research, UNOS, Richmond, VA.

Induction of NKG2D Ligands by Gamma Radiation and Tumor Necrosis Factor-alpha May Participate in the Tissue Damage During Acute Graft-Versus-Host Disease.

Immunopathology of acute graft-versus-host disease (aGVHD) involves secretion of proinflammatory cytokines with subsequent expression of danger signals by injured host tissues. This explanation, however, does not explain the cluster of aGVHD target organs (skin, gut, and liver). NKG2D ligands (MICA/B and ULBP1-3 proteins) are stress-induced molecules that act as danger signals to alert NK and alphabeta or gammadelta CD8 T cells through engagement of the activating NKG2D receptor. We observed a strong and reversible induction of MICA/B expression in skin and liver sections during aGVHD. Tumor necrosis factor-alpha and gamma-radiation up-regulated expression of MICA/B and ULBP proteins in vitro on skin and intestine epithelial cell lines and ex vivo in normal skin explants. This NKG2D-ligand induction was regulated by a complex interplay between NFkB and JNK activation pathways. Our data suggest that NKG2D ligand induction might participate in the amplification loop that leads to tissue damage during aGVHD.

Gannagé M, Buzyn A, Bogiatzi SI, Lambert M, Soumelis V, Dal Cortivo L, Cavazzana-Calvo M, Brousse N, Caillat-Zucman S.

1 Institut National de la Santé et de la Recherche Medicale (INSERM), U561, Hôpital St-Vincent de Paul; Université Paris Descartes, Faculté de Médecine, Paris, France. 2 AP-HP, Hôpital Necker-Enfants Malades, Service dʼHématologie, Université Paris Descartes, Faculté de Médecine, Paris, France. 3 INSERM, U653, and Laboratoire dʼImmunologie Clinique, Institut Curie, Paris, France. 4 AP-HP, Hôpital Necker-Enfants Malades, Département de Thérapie Cellulaire et Génique, Université Paris Descartes, Faculté de Médecine, Paris, France. 5 AP-HP, Hôpital Necker-Enfants Malades, Service dʼAnatomie Pathologique, Université Paris Descartes, Faculté de Médecine, Paris, France.