A novel highly differentially expressed gene in wheat endosperm associated with bread quality.

Analysis of gene expression in developing wheat seeds was used to identify a gene, wheat bread making (wbm), with highly differential expression (~1000 fold) in the starchy endosperm of genotypes varying in bread making quality. Several alleles differing in the 5'-upstream region (promoter) of this gene were identified, with one present only in genotypes with high levels of wbm expression. RNA-Seq analysis revealed low or no wbm expression in most genotypes but high expression (0.2-0.4% of total gene expression) in genotypes that had good bread loaf volume. The wbm gene is predicted to encode a mature protein of 48 amino acids (including four cysteine residues) not previously identified in association with wheat quality, possibly because of its small size and low frequency in the wheat gene pool. Genotypes with high wbm expression all had good bread making quality but not always good physical dough qualities. The predicted protein was sulphur rich suggesting the possibility of a contribution to bread loaf volume by supporting the crossing linking of proteins in gluten. Improved understanding of the molecular basis of differences in bread making quality may allow more rapid development of high performing genotypes with acceptable end-use properties and facilitate increased wheat production.

Exercise for improving balance in older people.

BACKGROUND: Diminished ability to maintain balance may be associated with an increased risk of falling. In older adults, falls commonly lead to injury, loss of independence, associated illness and early death. Although some exercise interventions with balance and muscle strengthening components have been shown to reduce falls it is not known which elements, or combination of elements, of exercise interventions are most effective for improving balance in older people. OBJECTIVES: To present the best evidence for effectiveness of exercise interventions designed to improve balance in older people living in the community or in institutional care. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (Feb 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 1), MEDLINE (1966 to February 2006), EMBASE (1980 to February 2006), other databases and reference lists of articles. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised trials testing exercise interventions designed to improve balance in older people were included. We excluded trials of interventions targeting individuals with specific conditions in order not to broaden the scope of this review too widely. Trials were included where participants were randomised to receive the following: a single exercise intervention or a multiple exercise intervention and a control group (usual activities or attention or recreational activity). Trials comparing two or more exercise interventions and a control group were also included. DATA COLLECTION AND ANALYSIS: Three pairs of members of the review team independently assessed trial quality and extracted data. For each trial, relative risk and 95% confidence intervals were calculated for dichotomous outcomes, and mean differences and 95% confidence intervals calculated for continuous outcomes. Where appropriate, results of comparable groups of trials were pooled and 95% confidence intervals calculated. MAIN RESULTS: For the 34 included studies there were 2883 participants at entry. Statistically significant improvements in balance ability were observed for exercise interventions compared to usual activity. Interventions involving gait; balance; co-ordination and functional exercises; muscle strengthening; and multiple exercise types appear to have the greatest impact on indirect measures of balance. There was trend towards an improvement in balance with cycling on a static cycle. However, there was limited evidence that effects were long-lasting. AUTHORS' CONCLUSIONS: Exercise appears to have statistically significant beneficial effects on balance ability in the short term but the strength of evidence contained within these trials is limited. Many of these mainly small studies demonstrated a range of methodological weaknesses. The failure across the included studies to apply a core set of standardised outcome measures to determine balance ability restricts the capacity to compare or pool different trials from which firm conclusions regarding efficacy can be made. Further standardisation in timing of outcome assessment is also required as is longer term follow-up of outcomes to determine any lasting effects.

Gastrointestinal lymphoproliferative disorders.

Malignant lymphomas can be first detected in some patients in endoscopic biopsies of the gastrointestinal (GI) tract. However, their recognition and accurate classification often pose problems for the pathologist for several reasons. First, the small sampling size limits pattern recognition and the number of ancillary studies which can be performed. Second, the immune system of the GI tract is capable of intense hyperplastic responses which may mimic lymphoma. Third, in a fashion similar to cutaneous lesions, those in the alimentary tract may be visualized and biopsied at a very early phase in their development when differentiation into neoplasia may be incomplete. Some forms of immune response actually pass through a poorly defined transition into lymphoma. Examples of such 'dysplasia' of the gut immune system include Helicobacter gastritis, coeliac disease and multicentric lymphoid hyperplasia associated with underlying immunodeficiency. With ever increasing endoscopic scrutiny of the gut by gastroenterologists, it is not surprising that the frequency of these indeterminate cases seems to be growing. In combination with careful clinical correlation and conventional microscopic analysis, selective immunohistochemical studies currently constitute the most powerful ancillary method in the pathologist's effort to recognize and classify GI lymphomas accurately.

Ki67 staining pattern as a diagnostic tool in the evaluation of lymphoproliferative disorders.

AIMS: To evaluate a group of lymphoid proliferations using only Ki67-stained slides to determine the value of the pattern of proliferating cells in diagnosis. Ki67 immunohistochemistry allows evaluation of the distribution of proliferating cells in addition to simply determining the proliferation rate of cells. METHODS AND RESULTS: Three observers, using a Ki67-stained slide only, studied 149 cases from five diagnostic groupings: follicular hyperplasia, mixed pattern hyperplasia, localized Castleman's disease, follicular lymphoma and marginal zone lymphoma. The sensitivity for benign lesions varied from 94% to 97% among the three observers. Follicular lymphomas were recognized as neoplastic with a sensitivity of 96% and 100% by two of the observers. Marginal zone lymphoma was recognized as neoplastic in 67-73% of cases. CONCLUSIONS: The Ki67 stain alone is a powerful tool for distinguishing benign from malignant proliferations within the selected groups. Nuances and pitfalls in the interpretation of Ki67 staining pattern are discussed.

Primary endometrial T-cell lymphoma. A case report.

Primary lymphomas of the female genital tract are rare. Most involve the cervix rather than the uterine corpus. All of those previously reported have been B-cell lymphomas, with the exception of 1 case report of an endometrial T-cell lymphoma in a Japanese woman. We report the case of a white woman from the United States with a diffuse large cell lymphoma of the endometrium, characterized as a peripheral T-cell type on the basis of immunophenotypic and molecular probe studies. Staging evaluation revealed tumor limited to the endometrium (stage IE). The patient underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection and received 6 cycles of combination chemotherapy, after which she remained free of disease at last follow-up of 36 months. Unusual features of this lymphoma case are discussed, with emphasis on differential diagnosis and speculation on histogenesis. This case illustrates that, while most peripheral T-cell lymphomas are widely disseminated at presentation, those limited to a single extranodal site may have a favorable outcome akin to that associated with high-grade extranodal B-cell lymphomas of early stage.

Epstein-Barr virus-positive primary gastrointestinal Hodgkin's disease: association with inflammatory bowel disease and immunosuppression.

Inflammatory bowel disease (IBD) is associated with an increased risk of lymphoma, which is usually extraintestinal but sometimes may involve the diseased bowel itself. Most lymphomas described in this setting are of non-Hodgkin's type, but rare cases of Hodgkin's disease (HD) have been reported. We describe the clinicopathologic and molecular features of four patients with primary gastrointestinal HD. Three patients had preexistent Crohn's disease (CD), for which two of them had received immunosuppressive therapy. The fourth patient had a longstanding history of diverticulitis and myasthenia gravis and was receiving immunosuppressive therapy for the latter. Multifocal involvement of the bowel by HD was noted in all four cases. Disease was staged as IVA in one patient, IIIB in one patient, and IE in one patient, and the fourth patient died in the postoperative period before further workup. Two patients received chemotherapy, one of whom was dead at 9 months, whereas the other has no evidence of disease at 25 months' follow-up. The patient with IE disease did not receive any therapy because only a few microscopic foci of disease were present and is also without any evidence of disease at 17 months. The Reed-Sternberg (RS) cells in all four cases expressed CD30, CD15, EBER-1, and LMP-1; two of four were focally CD20-positive. VJ-polymerase chain reaction for immunoglobulin heavy chain (IgH) rearrangement showed a polyclonal pattern in all four cases. In two cases, laser capture microdissection was used to isolate individual RS and Hodgkin's cells, which contained rearranged immunoglobulin genes, confirming a B-cell genotype. Whereas one case showed a dominant clonal band present in all isolates, cells from the patient with stage IE disease clearly showed a polyclonal population of RS cells. Our findings indicate that HD arising in the setting of IBD or chronic inflammation is the result of an Epstein-Barr virus-driven lymphoproliferation, analogous to that found in other immunodeficient states. Disordered immunoregulation inherent to CD and immunosuppressive therapy for the latter may contribute to its development. The finding of polyclonal RS cells in a patient with early stage disease and apparent cure by surgical resection versus monoclonal RS cells in the patient with disseminated disease suggests that HD in the setting of immunodeficiency also may show molecular progression, in a manner similar to that occurring in conventional B-cell lymphoproliferative disorders arising in the same setting.

New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia.

PURPOSE: To determine the incidence of and risk factors for second malignancies after allogeneic bone marrow transplantation (BMT) for childhood leukemia. PATIENTS AND METHODS: We studied a cohort of 3, 182 children diagnosed with acute leukemia before the age of 17 years who received allogeneic BMT between 1964 and 1992 at 235 centers. Observed second cancers were compared with expected cancers in an age- and sex-matched general population. Risks factors were evaluated using Poisson regression. RESULTS: Twenty-five solid tumors and 20 posttransplant lymphoproliferative disorders (PTLDs) were observed compared with 1.0 case expected (P <.001). Cumulative risk of solid cancers increased sharply to 11.0% (95% confidence interval, 2.3% to 19.8%) at 15 years and was highest among children at ages younger than 5 years at transplantation. Thyroid and brain cancers (n = 14) accounted for most of the strong age trend; many of these patients received cranial irradiation before BMT. Multivariate analyses showed increased solid tumor risks associated with high-dose total-body irradiation (relative risk [RR] = 3.1) and younger age at transplantation (RR = 3.7), whereas chronic graft-versus-host disease was associated with a decreased risk (RR = 0.2). Risk factors for PTLD included chronic graft-versus-host disease (RR = 6.5), unrelated or HLA-disparate related donor (RR = 7. 5), T-cell-depleted graft (RR = 4.8), and antithymocyte globulin therapy (RR = 3.1). CONCLUSION: Long-term survivors of BMT for childhood leukemia have an increased risk of solid cancers and PTLDs, related to both transplant therapy and treatment given before BMT. Transplant recipients, especially those given radiation, should be monitored closely for second cancers.

Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study.

We evaluated 18,014 patients who underwent allogeneic bone marrow transplantation (BMT) at 235 centers worldwide to examine the incidence of and risk factors for posttransplant lymphoproliferative disorders (PTLD). PTLD developed in 78 recipients, with 64 cases occurring less than 1 year after transplantation. The cumulative incidence of PTLD was 1.0% +/- 0.3% at 10 years. Incidence was highest 1 to 5 months posttransplant (120 cases/10,000 patients/yr) followed by a steep decline to less than 5/10,000/yr among >/=1-year survivors. In multivariate analyses, risk of early-onset PTLD (<1 year) was strongly associated (P <.0001) with unrelated or human leukocyte antigen (HLA) mismatched related donor (relative risk [RR] = 4.1), T-cell depletion of donor marrow (RR = 12.7), and use of antithymocyte globulin (RR = 6.4) or anti-CD3 monoclonal antibody (RR = 43.2) for prophylaxis or treatment of acute graft-versus-host disease (GVHD). There was a weaker association with the occurrence of acute GVHD grades II to IV (RR = 1.9, P =.02) and with conditioning regimens that included radiation (RR = 2.9, P =.02). Methods of T-cell depletion that selectively targeted T cells or T plus natural killer (NK) cells were associated with markedly higher risks of PTLD than methods that removed both T and B cells, such as the CAMPATH-1 monoclonal antibody or elutriation (P =.009). The only risk factor identified for late-onset PTLD was extensive chronic GVHD (RR = 4.0, P =.01). Rates of PTLD among patients with 2 or >/=3 major risk factors were 8.0% +/- 2.9% and 22% +/- 17.9%, respectively. We conclude that factors associated with altered immunity and T-cell regulatory mechanisms are predictors of both early- and late-onset PTLD.

Microscopic mimicry of lymphomas: diagnostic pitfalls.

A common, critical challenge for the pathologist is the distinction between lymphoma and lymphoma simulators. Ancillary studies are effective in making this distinction and should be used in descending order of their likely reliability according to the particular differential diagnostic consideration at hand. Clinical case information is essential to avoid misinterpretation. Lymphoma simulators can be grouped into several major categories: nonlymphoid neoplasms, usually high-grade, simulating high-grade lymphomas; chronic lymphoid hyperplasias simulating low-grade lymphomas; and acute lymphoid hyperplasias simulating high-grade lymphomas.

MALT lymphomas in 1997. Where do we stand?

Steady advances in our scientific understanding of primary extranodal mucosa-associated lymphoid tissue-type lymphomas have been achieved during the past 14 years, leading to their inclusion within the International Lymphoma Study Group (revised European-American classification of lymphoid neoplasms, known as REAL) classification as extranodal B-marginal zone lymphomas. Although most cases conform to prototype criteria, exceptional cases, such as those discussed at the Fourth Slide Workshop of the Society for Hematopathology on Extranodal Hematopoietic/Lymphoid Disorders, September 11-13, 1997, raise issues relating to microscopic, immunophenotypic, and clinical behavioral limits for diagnostic criteria. Furthermore, questions about therapeutic management have only begun to be addressed.

Multiple myeloma with hairy cell-like features.

Hairy cell leukemia (HCL) and multiple myeloma (MM) are well-described disease entities with characteristic clinical and pathologic features. We describe two patients initially treated for MM in whom atypical clinical and morphologic features subsequently developed that raised the possibility of HCL. Although the cytologic appearance and immunophenotype were not diagnostic of HCL, these cases challenge the criteria used to diagnose MM, HCL, and other recently described villous neoplasms.

Translocations of 11q13 in mantle cell lymphoma fail to disrupt the S mu bp-2 gene.

We recently cloned a gene whose protein product binds to the Epstein-Barr virus BZLF1 gene promoter. The same gene has been previously cloned by another group who named it S mu bp-2 because its protein product binds to the S mu motif of the immunoglobulin heavy chain gene where it is postulated to function in immunoglobulin class switching. In the current study, we confirm that the S mu bp-2 gene is located on chromosome 11q13, a locus known to be altered by translocation in 50-70% of mantle cell lymphomas. We used Southern blot analysis to determine whether the S mu bp-2 gene was structurally rearranged in any of 25 mantle cell lymphomas. We found no evidence of rearrangement in any of these lymphomas including 18 that were proven to contain t(11;14) by cytogenetic analysis. These data suggest that structural alteration of the S mu bp-2 gene is not an underlying mechanism of tumorigenesis in mantle cell lymphomas.

Inflammatory pseudotumors of lymph node origin show macrophage- derived spindle cells and lymphocyte-derived cytokine transcripts without evidence of T-cell receptor gene rearrangements. Implications for pathogenesis and classification as an idiopathic retroperitoneal fibrosis-like sclerosing immune reaction.

Sclerosing pseudotumorous immune reactions of the retroperitoneum have been shown to consist of HLA-DR-positive spindle-shaped fibroblasts and macrophages that resemble fibroblasts, and in some instances they contain clonal populations of T lymphocytes not found in granulation tissue, keloids, nodular fasciitis, or fibromatoses. In patients who are iatrogenically immunosuppressed, circulating monocytes may be induced in vitro to transform into spindle-shaped macrophages, and secrete collagen after stimulation by conditioning medium from activated T lymphocytes. The authors investigated a series of five inflammatory pseudotumors (IPT) of lymph node origin for identification of spindle-shaped macrophages, T-cell receptor gene rearrangements, and lymphocyte-derived cytokine mRNA production. All cases of IPT demonstrated spindle-shaped macrophages resembling fibroblasts or myofibroblasts characterized by vimentin, CD45 (LCA), CD68 (KP1) or HAM-56, and HLA-DR(LN3) immunoreactivity and demonstrated production of procollagen-alpha1 (I) mRNA by in situ hybridization. Clonal T-cell receptor chain gene rearrangements were undetectable by polymerase chain reaction. Strong specific lymphocyte-derived interleukin-1beta and interleukin-6 mRNA cytokine transcripts were identified. Although all patients with IPT were managed with steroids and nonsteroidal anti-inflammatory medication, some had treatment-refractory disease. Because all-trans retinoic acid has been demonstrated to inhibit the in vitro transformation of monocytes into collagen-producing spindle-shaped macrophages ("neofibroblasts"), it may be of benefit for patients with IPT.

Clinicopathological factors relating malignant lymphoma with Sjögren's syndrome.

This study was undertaken to summarize the current status of the clinicopathologic factors related to non-Hodgkin's lymphoma (NHL) development in patients with Sjögren's syndrome (SS). Through a MEDLINE search, pertinent articles on SS, monoclonality, and NHL were found and reviewed. Malignant lymphoma description was based on the International Lymphoma Study Group classification. Patients with SS are known to have an increased risk for developing B-cell NHL (B-NHL). However, such a complication occurs in less than 10% of patients, being reported mainly in those with primary SS. Extranodal low-grade B-NHL are observed most frequently. Persistent enlargement of parotid glands, adenopathy, monoclonal gammopathy, and cross-reactive idiotypes are all signs suggesting possible lymphoma evolution. Although monoclonality does not mean malignancy unequivocally, it is considered to be a precursor for NHL development in SS. Factors implicated into lymphomagenesis in SS include dysregulation in the mechanisms leading to apoptosis, hyperstimulation of B-1 cells, and an infectious agent. Polyclonal lymphoproliferation characterizing SS might in some instances transform into monoclonal, and then to malignancy. Further studies on the mechanism whereby NHL develops in SS are warranted.

Epstein-Barr virus and lymphoproliferation in methotrexate-treated rheumatoid arthritis.

Generalized lymphadenopathy developed in a 60-year-old female receiving methotrexate and prednisone for treatment of rheumatoid arthritis. Histologic examination of an enlarged right axillary lymph node revealed effacement of normal architecture by a polymorphic population of lymphocytes. The recognition that the patient was medically immunosuppressed and the similarity of lymph node histology to that of a polymorphic post-transplantation lymphoid proliferation led to suspicion that the adenopathy might represent an immunosuppression-related lymphoid proliferation. This possibility was supported by regression of the adenopathy on discontinuation of methotrexate, despite continued corticosteroid therapy, which is an outcome reminiscent of the remissions observed with reduction of immunosuppressive therapy in post-transplantation lymphoproliferative disorders. Subsequent ancillary laboratory studies of lymph node tissue included genetic probe analysis, which revealed a monoclonal population of B-lymphocytes containing clonal Epstein-Barr virus DNA. In situ hybridization studies performed on lymph node tissue revealed expression of Epstein-Barr virus-encoded RNA 1 transcripts, and immunohistochemical studies revealed expression of Epstein-Barr virus latent membrane protein 1. These ancillary studies confirmed the similarity to post-transplantation lymphoproliferative disorder. Although immunosuppression-related lymphoproliferative disorders share features with malignant lymphoma, the possibility of resolution in situations in which immunosuppression can be reversed provides a distinction from true malignancy and is of profound importance in therapeutic decision making.

Leukemia following low-dose total body irradiation and chemotherapy for non-Hodgkin's lymphoma.

PURPOSE: Low-dose total body irradiation (TBI) is used to treat non-Hodgkin's lymphoma (NHL) and several other malignancies. Large volumes of bone marrow and other tissue receive considerable exposure, but few studies have quantified late carcinogenic sequelae. PATIENTS AND METHODS: A cohort of 61 2-year survivors of NHL treated initially with low-dose TBI was monitored for second cancer occurrence. Data on primary and subsequent therapy were collected, and cumulative dose of radiation to active bone marrow (ABM) (median, 5.2 Gy) was reconstructed. RESULTS: Thirteen second primary cancers occurred. Four patients developed acute nonlymphocytic leukemia (ANLL), which represents a relative risk (RR) of 117 (95% confidence interval [CI], 31.5 to 300) compared with population rates. A fifth patient was diagnosed with myelodysplastic syndrome (MDS). All five patients with secondary hematologic malignancies subsequently received salvage treatment, with either alkylating agents alone (n = 1) or combined modality therapy (CMT) (n = 4). Overall, eight solid tumors were observed (RR = 2.0; 95% CI, 0.9 to 4.0). The 15-year cumulative risks of all second cancers and secondary ANLL were 37% and 17%, respectively. CONCLUSIONS: Despite the small number of subjects, a considerable risk of leukemia was observed among patients treated with low-dose TBI in combination with CMT including alkylating agents. Based on these results, approximately eight to nine excess ANLLs might be expected to occur among 100 NHL patients treated with low-dose TBI and salvage treatment and followed-up for 15 years.

Human immunodeficiency virus-associated Hodgkin's disease contains latent, not replicative, Epstein-Barr virus.

Severe immunodeficiency is associated with reactivation of latent Epstein-Barr virus (EBV) that is manifested by virus replication. It is unknown whether EBV replication also occurs in the Hodgkin's disease (HD) tissue of patients infected with the human immunodeficiency virus (HIV). Therefore, we studied paraffin-embedded lymph nodes from 13 cases of HIV-associated HD to determine the latent or replicative state of EBV infection. All patients were seropositive HIV-infected men; additional clinical information was available for 12 patients. The risk factor(s) for HIV infection were homosexuality (n = 7), intravenous drug abuse (n = 2), homosexuality and intravenous drug abuse (n = 1), sexual promiscuity (n = 1), or hemophilia (n = 1). Advanced clinical stage and B symptoms were common at the time of initial diagnosis of HD. The histological subtype of Hodgkin's disease was universally mixed cellularity, except for a single case classified as nodular sclerosis. Seven cases exhibited foci of relative lymphoid depletion. Five cases contained foci of necrosis. Reed-Sternberg (RS) cells and RS cell variants were positive for CD30/BerH2 and negative for CD45/LCA, CD45RO/UCHL1, and CD20/L26 in all cases. Tumor cells were positive for CD15/LeuM1 in seven cases. In all 13 cases, RS cells and RS cell variants were infected by latent EBV as shown by in situ hybridization to EBV-encoded ribonucleic acid (EBER1). In 12 of 13 cases neoplastic cells coexpressed EBV latent membrane protein 1 (LMP1). EBV replication was examined by two different methods: immunohistochemistry to identify EBV-encoded BZLF1 protein and in situ hybridization to detect EBV BHLF1 transcripts. No positivity in RS or RS cell variants was detected with either assay of EBV replication (95% confidence interval [CI] = 0% to 23%). The findings confirm that EBV is detected more frequently in HIV-associated HD when compared with immunocompetent patients with HD. The findings also suggest that EBV is tightly latent within RS and RS cell variants of HIV-associated HD. It appears that factors other than host immune status are important in maintaining EBV latency in HIV-associated HD.

Epstein-Barr virus is detected in undifferentiated nasopharyngeal carcinoma but not in lymphoepithelioma-like carcinoma of the urinary bladder.

The Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC) and with lymphoepithelioma-like carcinomas developing in certain anatomic sites. In this study, an in situ hybridization was used to identify EBV-encoded ribonucleic acid (RNA) (EBER1) transcripts in 32 of 45 cases of NPC but not in any of the 11 lymphoepithelioma-like carcinomas developing in the urinary bladder. EBER1 was most commonly detected in those NPCs having undifferentiated or nonkeratinizing squamous histology rather than the keratinizing squamous cell subtype of NPC. The EBV-encoded latent membrane protein 1 (LMP1) was expressed focally in only seven of 21 EBER1-positive NPCs by an immunohistochemical technique. These findings imply that EBER1 hybridization is more sensitive than LMP1 immunohistochemistry on paraffin sections in detecting carcinoma-associated virus. Previous in vitro studies have suggested that LMP1 expression might be a function of differentiation, but this study of naturally infected NPCs showed no strong correlation between LMP1 positivity and degree of tumor differentiation, albeit a limited spectrum of differentiation that could be examined. In two cases in which frozen tissue was available, the NPCs were monoclonal with respect to viral DNA structure, implying that the virus was present before malignant transformation. Unlike NPCs, the lymphoepithelioma-like carcinomas of the bladder were uniformly EBV negative, lending further evidence to the growing body of literature linking EBV with lymphoepithelial carcinomas of foregut-derived tissues but not with similar-appearing tumors developing in other anatomic sites.