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Objective To report clinical, histopathological and molecular features of ‘salmon patch’-like conjunctival lesions in paediatric and adolescent patients, and discuss management of these patients and outcome. Methods Patients who presented between 2000 and 2011 with a conjunctival ‘salmon-patch’-like lesion in the plical area, were identified by chart review. Clinical parameters, demographic characteristics and details of ophthalmic imaging were collected, and the effect of treatment examined. Results Eleven patients aged 6–21 years, presented with an elevated pink conjunctival mass in the plical area of one or both eyes. Nine patients underwent an excisional biopsy that histopathologically disclosed extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (also termed ‘MALT lymphoma’) in two cases and reactive lymphoid hyperplasia (RLH) in seven cases. Molecular diagnosis showed polyclonal B cells in six patients, monoclonal B cells in two patients, and a questionable status in one patient. Systemic examination disclosed localised ocular adnexal disease in the patients with MALT lymphoma, and none had either local or systemic recurrence during follow-up. Two other patients were treated with antiallergic medication with resolution of the lesion, and were therefore diagnosed clinically with RLH. Conclusions It is clinically difficult to differentiate between conjunctival RLH and MALT lymphoma in the paediatric and adolescent population. Both lesions are rare in this age group, particularly MALT lymphoma. Molecular analysis of excised lesions does not always correlate with histopathology. A short treatment course with antiallergic drops may sometimes assist diagnosis without compromising the patients due to the indolent nature of lymphoma in that area.

Objectives: To assess correlations of patient demographics, including enzyme replacement therapy (ERT) with bone histology, to facilitate decisions of whether and when to perform hip replacement surgery in patients with Gaucher disease. Methods: We examined the histology of surgically removed femoral heads and categorized findings by the presence or extent of osteonecrosis, Gaucher cell (GC) infiltration, and bone regeneration qualifiers using a tripartite histology-based scoring system. Results: Twenty-two patients with 26 bone specimens were evaluated. Seventeen patients (77%) were splenectomized, 16 (73%) received ERT, and 12 (55%) had the putatively milder genotype ( N370S / N370S ), with the rest putatively at increased risk for skeletal disease ( N370S /other). The 3 histology subscores were applicable to all specimens. Osteonecrotic bone was seen in 19 of 26 (73%); osteoarthritis was seen in all cartilage specimens. Gaucher cell infiltration was not correlated with demographics or disease severity. A trend was noted between reduced GC infiltration and ERT (ρ = 0.407), but regeneration qualifiers were not correlated with ERT or other features. Conclusions: Histologic findings of GC infiltration and bone regeneration qualifiers did not correlate with demographics or with exposure to ERT. Most specimens unexpectedly showed good regenerative responses to osteonecrosis despite heavy GC infiltration.

Although 90–95% of adults recover completely from Hepatitis B (HBV) infection, a minority are unable to clear the virus.[1][1] Epidemiological studies have demonstrated an increased risk of B-NHL among those with persistent HBV and B-NHL.[2][2]–[5][3] However, the roles of exposure per se

Objectives Carcinoma-associated fibroblasts are reported to communicate microenvironment-derived signals through chemokine/chemokine receptor interaction, influencing carcinogenesis. We sought to characterize roles of CXCL12/CXCR4 in crosstalk between non–small cell lung cancer epithelial cell and carcinoma-associated fibroblasts and in tumor growth. Methods Non–small cell lung cancer tumor samples obtained at surgery and from tumor arrays, as well as primary carcinoma-associated fibroblast and epithelial cell lines generated from fresh tumors, were assessed for CXCL12/CXCR4 expression, tissue localization, and production. Colony assays, extracellular signal–regulated kinase signaling, and chemokine production were measured to assess cancer cell responsiveness to CXCL12 stimulation with or without CXCR4 antagonists. Results CXCL12 and CXCR4 were detected in all major subtypes of non–small cell lung cancer. CXCL12-expressing carcinoma-associated fibroblasts were mostly located near CXCL12-negative tumor cells, whereas CXCL12-positive tumor cells were mostly surrounded by CXCL12-negative stroma. Intratumoral CXCL12 levels were significantly higher than serum levels. CXCL12 expression correlated with advanced disease stage. In vitro, tumor cell lines produced variable amounts of CXCL12 and expressed high levels of CXCR4. Carcinoma-associated fibroblasts cell lines produced high amounts of CXCL12 and expressed variable levels of CXCR4. Stimulation of non–small cell lung cancer neoplastic cells with CXCL12 increased colony-forming capacity, induced extracellular signal–regulated kinase phosphorylation, and production of the proinflammatory chemokine CCL20. CXCR4 antagonists attenuated these effects. Conclusions Interaction between carcinoma-associated fibroblasts and tumor epithelial cells through the CXCL12/CXCR4 axis plays a role in non–small cell lung cancer tumor proliferation, marking this axis as a target for immune intervention.

We present a case of a 52-year-old male who was evaluated due to anorexia, persistent diarrhea, weight loss, and liver enzyme elevations, with no hematologic laboratory abnormalities. Imaging modalities revealed several tissue lesions involving the pancreas, the right kidney, and an axillary lymph node. Diagnosis of Castleman disease was reached only due to the tissue obtained from the lymph node. Chemotherapy and immunosuppression led to a short remission. The patient underwent autologous stem cell transplantation, and has since been in remission. This case demonstrates the cryptogenic and chameleon-like nature of Castleman disease. Challenges in treating Castleman disease patients reflect current limitations and the need for a greater understanding of disease pathogenesis.

Female rats develop haemolytic anaemia and disseminated thrombosis and infarction in multiple organs, including bone, when exposed to 2-butoxyethanol (BE). There is growing evidence that vascular occlusion of the subchondral bone may play a part in some cases of osteoarthritis. The subchondral bone is the main weight bearer as well as the source of the blood supply to the mandibular articular cartilage. Vascular occlusion is thought to be linked to sclerosis of the subchondral bone associated with disintegration of the articular cartilage. The aim of this study was to find out whether this model of haemolysis and disseminated thrombosis supports the vascular hypothesis of osteoarthritis. Six female rats were given BE orally for 4 consecutive days and the two control rats were given tap water alone. The rats were killed 26 days after the final dose. The mandibular condyles showed histological and radiological features consistent with osteoarthritis in three of the four experimental rats and in neither of the control rats. These results may support the need to explore the vascular mechanism of osteoarthritis further.

Rosai-Dorfman disease is a benign non-neoplastic proliferative disorder of histiocytes originally described in the cervical lymph nodes. Extranodal sites were later recognized, and by 1990, they were shown to represent over 40% of cases; however, central nervous system involvement is still considered rare. We review the literature, which shows a steady increase in reports of Rosai-Dorfman disease involving the brain and/or spine.A literature search was performed for the period 1969-2008, using multiple search engines, with keywords Rosai-Dorfman disease, central nervous system Rosai-Dorfman disease and sinus histiocytosis with massive lymphadenopathy.By December 2008, 111 cases of Rosai-Dorfman disease involving the central nervous system had been reported in the literature, including our cases. In the central nervous system, Rosai-Dorfman disease is ubiquitous. Although it is characterized by unique, indeed pathognomonic, histopathological cytoarchitecture, it may be mistaken for many other neoplastic and inflammatory histioproliferative diseases. Surgical resection with post-operative corticosteroids remains the treatment of choice.Rosai-Dorfman disease involving the central nervous system appears to be more common than previously thought and may well assume a more prominent place in the differential diagnoses of dural-based lesions. Expert awareness of the characteristic histopathology and immunohistochemistry of the disease is required for accurate diagnosis.

Objective Past studies are inconsistent with regard to the role of matrix metalloproteinase 12 in lung tumorigenesis. This is due, in part, to differential tumorigenesis based on tumor-derived versus immune-derived matrix metalloproteinase 12 expression. Our study aims to thoroughly dissect the role of matrix metalloproteinase 12 in lung tumorigenesis. Methods We tested matrix metalloproteinase 12 expression and the association with prognosis using a tissue array and a published non–small cell lung cancer gene expression database. In addition, we characterized the contribution of matrix metalloproteinase 12 to tumor propagation in the lung using a series of in vitro and in vivo studies. Results Tumor cells of a diverse set of human lung cancers stained positive for matrix metalloproteinase 12, and high matrix metalloproteinase 12 mRNA levels in the tumor were associated with reduced survival. The lung microenvironment stimulated endogenous production of matrix metalloproteinase 12 in lung cancer cells (human 460 lung cancer cell line, Lewis lung carcinoma). In vitro, matrix metalloproteinase 12 knockout Lewis lung carcinoma and Lewis lung carcinoma cells had the same proliferation rate, but Lewis lung carcinoma showed increased invasiveness. In vivo, deficiency of matrix metalloproteinase 12 in Lewis lung carcinoma cells, but not in the host, reduced tumor growth and invasiveness. Conclusions We suggest that tumor cell–derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.

Rats with portal hypertension and experimental liver disease may exhibit increased susceptibility of the gastric mucosa to damage by noxious agents, and increased bacterial translocation through the bowel wall. The aim of this study was to determine mucosal gastric and colonic generation of vasoactive substances, because they may contribute to the altered mucosal function. Rats with partial vein ligation (n = 7), complete bile duct ligation (n = 6) and sham-operated rats (n = 10) were studied. Three weeks following surgery rats were anesthetized, splenic pulp pressure was measured, stomachs and colons were removed and mucosa was extracted for determination of prostaglandin E2, thromboxane B2, leukotriene B4, leukotriene C4 and endothelin-1 by radioimmunoassay (ng/g) and platelet activating factor activity (pg/10 mg) by platelet aggregation. Pulp pressure was > 13 mmHg in partial vein ligated rats and bile duct ligated rats and 6 mmHg in sham-operated rats. No macroscopic or microscopic lesions were seen any of the removed tissues. Gastric mucosal prostaglandin E2 and thromboxane B2 generation were decreased by 35% and 7%, respectively, in bile duct ligated rats (bile duct ligated versus sham-operated, p < 0.05 for prostaglandin E2 and thromboxane B2). Gastric leukotriene B4 and C4 generation, platelet activating factor activity and endothelin-1 content did not differ significantly among the three groups. A different pattern of changes was observed in the colon. Colonic leukotriene B4 generation and endothelin-1 content were increased in bile duct ligated rats by 105% and 210%, respectively (bile duct ligated versus sham-operated, p < 0.05 for leukotriene B4 and endothelin-1). The decreased gastric mucosal prostaglandin E2 generation of bile duct ligated rats may render the gut mucosa of these animals relatively ischemic and vulnerable to damage by noxious agents. The increased colonic leukotriene B4 generation and the increased endothelin-1 content of the colonic mucosa of bile duct ligated rats may promote inflammatory and ischemic changes in the colonic mucosa and may enable bacterial translocation.

Background Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the accumulation of abnormal Langerhans cells in one or several organs where they cause local tissue damage. The pathophysiology is not well understood. The aim of this study was to examine expression of various gene products that play a role in cell cycle and cell death and to look for an association with the extent of the disease at the time of diagnosis and with “risk bone” involvement. Procedure Histologic slides from cases with biopsy proven disease were stained immunohistochemically for Bcl-2, caspase-3, Ki-67, p53, and nuclear factor-kappaB (NF-κB) and the results were quantitated and compared with the clinical extent of the disease. Results In patients with multisystem disease and “risk” bone involvement, a higher percentage of Langerhans cells stained with the anti-apoptotic gene product Bcl-2 (P = 0.0004; P = 0.001 respectively) and a lower percentage of these cells stained with the apoptosis marker caspase-3 compared to patients with single system disease (P = 0.0001; P = 0.01 respectively). Proliferation marker Ki-67 was expressed more frequently in multisystem disease compared to single system disease (P = 0.02) but an association with “risk” bone involvement was not found. Expression of p53 and NF-κB did not discriminate between clinical subgroups. Conclusions The findings suggest that cell proliferation and suppression of apoptosis may be mechanisms of cell survival in the more aggressive forms of LCH (multisystem, risk bone involvement). Pediatr Blood Cancer 2008;50:304–307. © 2007 Wiley-Liss, Inc.

Objective: To evaluate the diagnostic efficacy of image-guided cutting-edge-needle biopsy of peripheral lymph nodes and superficial masses for the diagnosis of lymphoma, for which many still advocate open surgical resection. Methods: A retrospective analysis was performed of the medical records of 114 lymphoma patients who presented with peripheral lymphadenopathy and superficial masses and who underwent diagnostic image-guided biopsy. There were 69 non-Hodgkin lymphoma patients, 38 Hodgkin lymphoma patients, and 7 patients who were evaluated for histologic transformation of CLL or high grade lymphoma. Results: Image-guided needle biopsy was diagnostic in 96/114 (84.2%) patients. The procedure was diagnostic in 59/69 (85.5%) of NHL patients and in 30/38 of Hodgkin disease patients (79%). Diagnoses were achieved for all 7 cases where histologic transformation was suspected. Conclusion: Percutaneous image-guided needle biopsy is a safe and reliable procedure with a high diagnostic yield. It can be used as a first step in patients suspected of having lymphoma presenting with enlarged peripheral lymph nodes and superficial masses.

BACKGROUND Central nervous system involvement is a well recognized complication of systemic non-Hodgkin lymphoma. Most central nervous system recurrences occur within the first 2 years after the initial diagnosis and are considered to represent clonally related recurrence of systemic disease. The authors attempted to investigate the clonal relation between the late-delayed central nervous system involvement and the original systemic tumor. METHODS The authors studied archival, formalin fixed, paraffin embedded tissue samples from 8 patients with isolated cerebral involvement diagnosed > 3 years after their initial presentation with aggressive, systemic, B-cell non-Hodgkin lymphoma. The rearranged immunoglobulin heavy-chain variable region genes (VH) from both sites were amplified by polymerase chain reaction and were sequenced when necessary. RESULTS In three of five patients who had interpretable results, a distinct, monoclonal, VH family-specific band profile was obtained from the cerebral and systemic lymphoma. In the other two patients, a similar VH band pattern was observed and also was compared using direct sequencing, which demonstrated sequence differences between tumors from the two sites. CONCLUSIONS Clonal variance between the cerebral and systemic lymphoma in these patients suggested the possibility that some instances of late-delayed recurrence in the central nervous system represent a second, new B-cell lymphoma rather than a true recurrence of the original systemic tumor, a finding that may have significant clinical and biologic implications. Cancer 2004. © 2004 American Cancer Society.

Here we present a 40-yr-old male patient with an aggressive B-cell lymphoma, who presented 2 yr earlier with polyarthritis, and was responsive to steroids and oral methotrexate. Thereafter he developed skin and lung lesions which on biopsy consisted of mixed 'inflammatory' infiltrates with granulomatous vasculitis. A diagnosis of seronegative Wegener's granulomatosis was made and the patient received a combination of prednisone and cyclophosphamide with clinical improvement and clearance of the radiological lesions in the lungs. The patient was now completely asymptomatic for 1 yr, but then generalized lymphadenopathy appeared, which was shown by histopathology to be large B-cell lymphoma, also involving the bone marrow. Despite intensive chemotherapy, his disease could not be controlled because of primary chemoresistance, which was perhaps in some way related to exposure to the suboptimal doses of chemotherapy given during the 'inflammatory' period before the diagnosis of lymphoma was established. This case illustrates the occasional difficulty in distinguishing between extranodal lymphoproliferative diseases and autoimmune disorders especially when clonality cannot be proved. It also shows the possible risk of 'masking' a true lymphoma by treating non-malignant diseases with immunosuppressive agents, which may eventually contribute to the development of chemoresistant lymphoma.

Objective: Pleural fluid parameters that predict a diagnostic closed pleural needle biopsy were investigated.Design: A retrospective analysis.Setting: The Institute of Pulmonology, Hadassah University Hospital.Patients and methods: Forty-four patients who underwent closed pleural needle biopsies were included in this study. Pleural fluid values of protein, glucose, lactate dehydrogenase (LDH), pH, and white blood cell count with differential cell counts, from patients with diagnostic and non-diagnostic pleural biopsies were compared.Results: Thirteen patients (29%) had diagnostic biopsies. Malignancy was identified in 10 patients (23%), of whom 70% had adenocarcinoma. Three other patients had non-malignant specific diagnosis. LDH levels in pleural fluid from patients with diagnostic pleural biopsy were higher than in patients with non-diagnostic pleural biopsies (1436±333 U l−1 vs. 775±109 U l−1; P

Background: The etiology of osteopenia in cholestatic liver disease is uncertain. An animal model is needed in order to study the efficacy of therapeutic agents. Aims: In order to characterise the bone disease in rats with cholestatic liver disease. Methods: Four-month old male Sprague–Dawley bile duct-ligated (BDL) and sham-operated (SO) rats were studied. Twenty-eight days after surgery serum osteocalcin, a bone-formation marker, urinary deoxypyridinoline (DPD) cross-links, a resorption marker, and 25-hydroxyvitamin D3 were determined. Static and dynamic (tetracycline-based) histomorphometric analysis was performed on femurs and tibiae. Results: All BDL rats developed biliary cirrhosis. Bile duct-ligated rats had lower bone mass, reflected in statistically significantly 13.5% lower femoral dry-weight, 16% lower femoral ash-weight, 42.7% lower tibial cancellous bone area and 19% lower trabecular thickness, compared with SO rats. Bile duct-ligated rats exhibited decreased bone formation manifested by statistically significantly 70% lower tetracycline double-labelling, 40% lower mineralising surface, 51% lower bone-formation rate and 47% lower osteocalcin compared with SO rats. Deoxypyridinoline levels were 20% lower in BDL rats. Bile duct-ligated rats had 52% lower serum 25-hydroxyvitamin D3 level, but no significant increase in cortical osteoid area. Conclusions: Bile duct-ligated rats develop osteopenia characterised by low bone-formation rate, and can be used for studying therapeutic agents for patients with cholestatic liver disease displaying similar bone changes.

Novel therapeutic regimens containing purine analogs and monoclonal antibodies have led to significant improvement in the course of indolent lymphoproliferative diseases (LPD). Complete clinical and even molecular remissions have been achieved in an increasing proportion of patients. In parallel to their tumor cytotoxic effect, these agents are inevitably associated with prolonged immunosuppression inherent to their mechanism of antilymphocytic activity. Until now, attention has been paid mainly to opportunistic infection occuring as a result of the above drug-induced immunosuppression and less to other possible complications, such as malignancy or tumor progression in the immunocompromised host. Here we briefly report nine patients with previously treated indolent LPD in whom the onset of large-cell transformation occured during or shortly after the initiation of regimens containing these agents before transformation occured. One patient had received rituximab alone, three fludarabine-containing regimens and five received sequential regimens containing both agents. This ‘switch’ in the histopathology could merely reflect the natural course of progressive lymphoma and be unrelated to the therapy given. The onset of this complication during, or so soon after, administration of these regimens seems to us more than just a chance relationship in these cases; however, we have no conclusive evidence to prove this hypothesis definitively. We draw attention to this phenomenon.

Overexpression of tumor suppressor gene p53, cell proliferation nuclear antigen Ki-67, and proto-oncogene HER-2/ neu are associated with poor prognosis in some tumors. We studied p53, Ki-67, and HER-2/ neu immunohistochemical expression in archival biopsies of 37 patients with Ewing's sarcoma (ES). Patients with ES were treated at four Israeli hospitals between 1982 and 2000. Formalin-fixed paraffin-embedded tissue sections were stained by immunohistochemistry for p53, Ki-67, and HER-2/ neu. More than 300 cells were counted on each slide, and the percentage of positively stained nuclei was computed. p53 overexpression was defined as nuclear staining of >2.3% of cells, Ki-67 overexpression as nuclear staining of >8.3% malignant cells. HER-2/ neu staining was scored semiquantitatively on a scale of 0 to 4+. Twenty-two of 37 patients are alive and well, with mean follow-up time of 38 months. There was overexpression of p53 in 16 patients (43%) and of Ki-67 in 21 patients (57%). The correlation between p53 and Ki-67 overexpressions was 0.61. We found no overexpression of HER-2/ neu. Median relapse-free survival (RFS) was statistically significantly shorter for patients with p53 overexpression (25 months) than for patients with negative staining (>92 months). The prognostic value of p53 overexpression was also significant after adjusting for tumor location and age. Median RFS was shorter for patients with positive Ki-67 staining (40 months) than for patients with negative staining (80 months) but did not reach statistical significance. Our study suggests that p53 is a predictor of RFS in patients with ES. More patients must be studied to assess the validity of this observation. HUM PATHOL 33:170-174. Copyright 2002, Elsevier Science (USA). All rights reserved.

Background: Risk factors for B-cell non-Hodgkin lymphoma (B-NHL) have not been assessed among Palestinian Arabs (PA) and Israeli Jews (IJ). Methods: In a case-control study we investigated self-reported medical and lifestyle exposures, reporting odds ratios (ORs) and 95% confidence intervals [CIs], by ethnicity, for overall B-NHL and subtypes. Results: We recruited 823 cases and 808 healthy controls. Among 307 PA/516 IJ B-NHL cases (mean age at diagnosis = 51 [±17] versus 60 [±15] years, respectively) subtype distributions differed, with diffuse large B-cell lymphoma (DLBCL) being prominent among PA (71%) compared to IJ (41%); follicular lymphoma (FL), was observed in 14% versus 28%, and marginal zone lymphoma, in 2% versus 14%, respectively. Overall B-NHL in both populations was associated with recreational sun exposure OR = 1.43 [CI:1.07-1.91], black hair-dye use OR = 1.70 [CI:1.00-2.87], hospitalization for infection OR = 1.68 [CI:1.34-2.11], and first-degree relative with hematopoietic cancer, OR = 1.69 [CI:1.16-2.48]. An inverse association was noted with alcohol use, OR = 0.46 [CI:0.34-0.62]. Subtype-specific exposures included smoking (FL, OR = 1.46 [CI:1.01-2.11]) and >monthly indoor pesticide use (DLBCL, OR = 2.01 [CI:1.35-3.00]). Associations observed for overall B-NHL in PA only included: gardening OR = 1.93 [CI:1.39-2.70]; history of herpes, mononucleosis, rubella, blood transfusion (OR>2.5, P

The prognostic role of CD68 tumor-associated macrophages in classic Hodgkin lymphoma (cHL) remains controversial. We stained diagnostic biopsies and scored for CD68 using the PGM1 antibody among 98 consecutive patients with cHL from our center followed over a median of 45 months for progression-free survival (PFS). Among 79 patients we assessed interim and post-treatment positron emission tomography-computed tomography (PET-CT). Residual mass (RM) size was based on the greatest diameter of the largest mass seen in post-treatment imaging, and percent reduction was calculated by comparing RM size with its greatest pretreatment diameter. We found a significant association between CD68 positivity and absolute size of initial disease mass (p = 0.014) and residual mass at the end of therapy (p = 0.006) but no association was observed with interim PET-CT results or PFS. Our findings suggest that macrophages may influence tumor size by altering the microenvironment. This study does not support a prognostic role of CD68 positivity in predicting survival.

Background Predicting patient specific risk of fracture in femurs with metastatic tumors and the need for surgical intervention are of major clinical importance. Recent patient-specific high-order finite element methods (p-FEMs) based on CT-scans demonstrated accurate results for healthy femurs, so that their application to metastatic affected femurs is considered herein. Methods Radiographs of fresh frozen proximal femur specimens from donors that died of cancer were examined, and seven pairs with metastatic tumor were identified. These were CT-scanned, instrumented by strain-gauges and loaded in stance position at three inclination angles. Finally the femurs were loaded until fracture that usually occurred at the neck. Histopathology was performed to determine whether metastatic tumors are present at fractured surfaces. Following each experiment p-FE models were created based on the CT-scans mimicking the mechanical experiments. The predicted displacements, strains and yield loads were compared to experimental observations. Results The predicted strains and displacements showed an excellent agreement with the experimental observations with a linear regression slope of 0.95 and a coefficient of regression R 2 = 0.967. A good correlation was obtained between the predicted yield load and the experimental observed yield, with a linear regression slope of 0.80 and a coefficient of regression R 2 = 0.78. Discussion CT-based patient-specific p-FE models of femurs with real metastatic tumors were demonstrated to predict the mechanical response very well. A simplified yield criterion based on the computation of principal strains was also demonstrated to predict the yield force in most of the cases, especially for femurs that failed at small loads. In view of the limited capabilities to predict risk of fracture in femurs with metastatic tumors used nowadays, the p-FE methodology validated herein may be very valuable in making clinical decisions.

Renal involvement as part of systemic lymphoma (LY) is quite frequent, however, primary extranodal renal non-Hodgkin's lymphoma (NHL) is extremely rare, and only about 65 cases have been reported in the world literature. In a retrospective study of renal manifestations in 700 patients with documented LY and chronic lymphocytic leukemia (CLL) seen at our hospital during 1986-95, 83 patients had signs of acute renal failure. Only five of these had proven renal infiltration, but none of them satisfied the criteria for primary renal LY. Glomerulonephritis (GN) has also rarely been reported in association with LY and CLL, and only 37 glomerular lesions in NHL and 42 in CLL have been documented, respectively. GN may precede, coexist, or follow the diagnosis of LY by several years. Of the 42 cases of CLL reported worldwide, 36 had nephrotic syndrome. Renal failure was seen in about one third. The most common glomerular lesion reported is membranoproliferative GN, followed by membranous GN. In our study, we found only five biopsy-proven cases with GN amongst the 700 patients seen. In this report we also briefly describe some rare interesting associated renal syndromes in CLL and NHL.

Treatment with the purine analog 2-chlorodeoxyadenosine (2-CDA) achieves a complete response in close to 90% of patients with hairy cell leukemia, with approximately 75% remaining in prolonged remission. Recently, we unexpectedly noted foci of hypoplasia and aplasia in routine follow-up bone marrow biopsies of several hairy cell leukemia patients in remission with normal blood counts. Because of this finding we examined all available biopsies to assess the incidence of this phenomenon. A total of 94 biopsies in 31 patients were reviewed. Of these, 23 were prior to 2-CDA therapy and 71 (in 30 patients) were obtained 2–76 (mean 22) months following one or more courses of treatment. Nine patients had also received prior interferon and 7 (of whom 3 had also received interferon) had undergone splenectomy. Hypocellular foci were found in only 3 (13%) of the pre-therapy biopsies. Forty-seven of the 71 post-therapy biopsies (in 23 patients) (66%) had a total of 176 hypocellular foci. Of these 47 biopsies, 39 were without evidence of disease. A simultaneous complete blood count was normal in 34 of the 47 hypoplastic biopsies (72%). This suggests that these hypoplastic areas may not be representative of the entire bone marrow and that normal hematopoiesis may take place at other sites. However, since the longest follow-up is less than 7 yr, the potential long-term significance of these findings, such as progressive bone marrow aplasia or dysplasia, may still be unrecognised.

Fludarabine phosphate, a purine analogue currently used in the therapy of hematological malignancies, is known to cause immunosuppression and long-lasting T cell lymphopenia. In this study, the effect of fludarabine on murine graft-versus-host disease occurring after marrow transplantation across major and minor histocompatibility barriers was evaluated. Survival of (BALB/c x C57BL/6)F1 mice irradiated and transplanted across the major histocompatibility barrier with C57BL/6 spleen cells, and subsequently treated with fludarabine was significantly longer than that of the control animals (P < 0.0001). On the other hand, fludarabine had no effect on the graft-versus-host disease and survival of CBA mice transplanted by B10.BR and of BALB/c mice transplanted by B10.D2 spleen cells across the minor histocompatability barrier. The results indicate that in certain murine models, particularly a major mismatch, fludarabine has the potential to induce bilateral tolerance and stable chimerism after marrow transplantation. Bone Marrow Transplantation (2000) 25, 263-266.

Gaucher's disease is a familial storage disease caused by a deficiency of the enzyme glucocerebrosidase. Pulmonary involvement is considered rare in Gaucher's disease, especially type I. Sporadic case reports have shown various types of lung involvement, but the spectrum of pulmonary pathology in Gaucher's disease has not been described. Nine cases of Gaucher's disease were retrieved from the autopsy file of Hadassah Medical Center, Jerusalem, Israel. There were six cases with type I Gaucher's disease and three cases with type II. Lung sections were evaluated, and special stains were employed, including immunohistochemical stains for CD68, cytokeratin, and CD34. Gaucher cells were found in the lungs in all nine cases. The involvement was considered pathologically significant in five of nine cases and clinically significant in three of nine cases. Four distinct patterns of pulmonary involvement by Gaucher cells emerged: intracapillary (9 of 9), patchy interstitial infiltrates in a lymphatic distribution (2 of 9), massive interstitial thickening of alveolar septa (1 of 9), and intra-alveolar infiltrates (2 of 9). The universal involvement of pulmonary capillaries indicates that this is probably systemic in nature and not intrinsic to the lungs. Pulmonary involvement in Gaucher's disease is commoner than previously recognized. Immunocytochemical stains help to identify isolated Gaucher cells and distinguish them from native alveolar macrophages.

Cutaneous T-cell lymphomas (CTCL) are diseases characterized by cutaneous infiltrates of malignant clonally expanded T cells. CTCL cells exhibit a cytokine profile consistent with T helper-2 type (TH2) cells. Eosinophilic pneumonias are individual syndromes characterized by eosinophilic pulmonary infiltrates and commonly peripheral blood eosinophilia. CTCL and chronic eosinophilic pneumonia are rare clinical entities. We report a patient with the association of CTCL and chronic eosinophilic pneumonia. To understand the mechanism leading to the eosinophilia, we examined the patient's cytokine profile. This was consistent with a high TH2 activity. Her interleukin (IL) 5, 6, and 10 levels were extremely high, while her IL-2 and interferon-gamma (IFN-gamma) levels (TH1 profile) were low. We believe that eosinophilic pneumonia in this patient is probably secondary to high TH2 cytokine levels induced by tumor cells. We suggest that eosinophilic pneumonia should be considered as a possible diagnosis in patients with CTCL who have respiratory complaints.

BACKGROUND The past decade has witnessed a growing frequency of therapy-related secondary tumors. The authors studied nine children with secondary malignancies. The primary tumors were bilateral retinoblastoma, neuroblastoma, brain tumor, Wilms' tumor, colon adenocarcinoma, and Hodgkin's disease. The secondary tumors were osteosarcoma at the site of previous radiotherapy, myelodysplastic syndrome, acute myelocytic leukemia, glioblastoma, thyroid carcinoma, and B-cell lymphoma. METHODS DNA was extracted from the primary and secondary tumors and analyzed for genetic alterations in the p53 gene and in 7 separate microsatellites. RESULTS The authors found p53 mutations in 7 patients, loss of heterozygosity in 1 patient, and both mutation and loss of heterozygosity in 1 patient. Mutations were demonstrated in the primary tumors only in two patients and in the secondary tumors only in three patients. Two patients had a mutation in both the primary and the secondary tumor; in both patients the two mutations were in different exons. Microsatellite instability (MIN) was identified in five to seven loci in the secondary tumors of all patients. CONCLUSIONS The observed MIN is compatible with the presence of a mutator phenotype that predisposes these children to the development of secondary malignancies. Cancer 1999;85:504–10. © 1999 American Cancer Society.

Gammadelta T cell lymphoma is usually either subcutaneous or hepato-splenic and involvement of other extranodal sites is rare. Here we report an unusual case of gammadelta T cell lymphoma involving the subcutaneous tissue, vocal cords, gastric mucosa and the central nervous system with a rapidly progressive clinical course and fatal outcome. Epstein-Barr virus (EBV) was shown to be present in the tumor cells, and is thought to play a role in the pathophysiology of this particular case of lymphoma.

Two patients with Kaposi's sarcoma developing in an area of lymphedematous arm postmastectomy are reported. The Kaposi's sarcoma occurred after latent periods of 26 and 7 years following radical and modified-radical mastectomy, respectively, in the edematous tissue of the ipsilateral arm. The cutaneous nodules were purple in color and ranged in size from a few millimeters to > 1 cm in diameter. The results of routine laboratory tests were all within normal limits. Human immunodeficiency virus (HIV) antibody and cytomegalovirus (CMV) antigen, using enzyme-linked immunosorbent assay (ELISA), were negative.

A 64-year-old woman with chronic myelogenous leukemia (CML) was admitted due to prolonged fever and lung infiltrates. An open lung biopsy was required to make the diagnosis of pulmonary alveolar proteinosis (PAP) and infection with Mycobacterium kansasii. She was treated successfully with combined antimycobacterial therapy for 14 months. However, the leukemia progressed and the patient developed recurrent bilateral lung infiltrates. Blood and bronchoalveolar fluid cultures yielded growth of Acinetobacter. She died shortly thereafter due to septic shock. The relationship between M. kansasii infection, PAP, and abnormal host defense in CML is discussed.

Here we present an unusual case of anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALCL), appearing as a primary tumor of the pancreas which invaded into the adjacent duodenal wall, causing upper gastrointestinal bleeding. After complete resection of the tumor (Whipple's operation), the patient received 4 cycles of CHOP chemotherapy. Currently, 2 years after diagnosis the patient still remains lymphoma free. Primary ALCL of the pancreas is very rare and has only been reported on one previous occasion. Nevertheless, lymphoma should be considered in the differential diagnosis of pancreatic tumors and an attempt to obtain tissue diagnosis is always necessary before continuing with radical surgery, especially in young patients.

Two recent studies have shown that retreatment of patients with relapsed indolent NHL with rituximab (RI) can be as effective as primary treatment, provided the lymphoma was initially responsive to primary RI therapy. From the available data, it remains unknown as to whether this approach is also effective for extranodal relapse. Here, we describe a 47-year-old male with stage 4B follicular lymphoma (FL), initially also involving skin, who achieved complete remission (CR) after a combination of fludarabine, cyclophosphamide and RI that lasted only 5 months. He soon relapsed with systemic disease and a number of extranodal sites including liver, lungs and bone marrow. After retreatment with RI alone (four cycles, 375 mg/m 2 ), the patient achieved a second CR. Another four infusions of RI were given 6 months later as maintenance therapy. The duration of CR is already 18 months longer than the first CR. This case illustrates the fact that even in relapsed advanced FL, with multiple sites of extranodal disease, RI given as a single agent may be extremely effective in achieving an additional meaningful complete response. The Hematology Journal (2003) 4, 151–153. doi:10.1038/sj.thj.6200208

Diabetes is associated with an increased risk of fracture of bone and impaired fracture healing. Wound complications are more serious and the rate of postoperative complications is higher than that in non diabetic subjects. The etiology and pathogenesis of impaired bone repair in human subjects and animal models of type I and type II diabetes are reviewed. In addition the adequacy of bone repair around orthopedic and dental implants is addressed and a role for hyperglycosylation in impaired bone repair in diabetic subjects is discussed.

A 52-year-old male with severe gastrointestinal graft-versus-host disease (GVHD), developed dyspnea and irreversible airflow obstruction, 11 weeks post-allogeneic bone marrow stem cell transplantation. Based on the clinical picture and presence of 'mosaic attenuation' pattern on chest high-resolution computerized tomography (HRCT), he was presumed to have bone marrow transplantation-related bronchiolitis obliterans. Post-mortem examination revealed invasive airway aspergillosis with no evidence of bronchiolitis obliterans.

Summary Although the etiology of sarcoidosis is unknown, genetic susceptibility has been demonstrated. Granuloma formation is a key feature in the pathophysiology of sarcoidosis and Crohn's Disease, raising the possibility that these diseases share common pathogenetic pathways. An association between sarcoidosis and the protein "CD14", a molecule that is part of the lipopolysaccharide (LPS) cell surface receptor complex, has been suggested. In the current study we evaluated the CD14 gene promoter 159 C → T polymorphic site and soluble CD14 levels in a cohort of 74 sarcoidosis patients compared to 85 healthy controls. We further sought to identify correlations between clinical phenotype, specific genotypes and soluble CD14 levels. We found the TT genotype to be more prevalent in the sarcoidosis patient group than in controls ( p =0.03). Serum levels of soluble CD14 were higher in the sarcoidosis patients ( p =0.001). Within the patient cohort, CC homozygous patients presented at an older age with milder disease as assessed with the SAC score, longer time to diagnosis, and less impairment of pulmonary function tests. Our study suggests a role of CD14 in the pathogenesis of sarcoidosis, and a clinical phenotype-genotype association. Further mechanistic and epidemiologic studies are needed in order to establish the specific role of CD14 in the etiology, pathogenesis and clinical phenotype of sarcoidosis.

Obstructive jaundice developed in a patient concomitantly with the diagnosis of breast carcinoma. Abdominal exploration disclosed a metastatic tumor in the head of the pancreas, the distal bile duct, and the gallbladder. A cholecystectomy and choledochojejunostomy were performed and later, because of intestinal obstruction, the patient underwent gastrojejunostomy. Pathological examination demonstrated metastatic lobular carcinoma of breast with strongly positive staining for estradiol. Additional hormonal therapy has been given to the patient since the operation. The patient is alive 16 months after the diagnosis of her disease. This case suggests that a vigorous diagnostic approach should be adopted in every jaundiced patient with metastatic breast cancer in order to exclude causes of jaundice other than diffuse metastatic involvement of the liver. Patients with extrahepatic biliary metastasis should be treated by aggressive surgical treatment, combined with systemic therapy which can offer them significant palliation and better survival.

Foreign-body granulomas within intramyocardial arteries were detected in three domestic pigs ( Sus scrofa domestica) in a routine transcoronary safety assessment study. The foreign bodies stained light grayish-blue by hematoxylin and eosin (H&E) and were strongly birefringent by polarized light microscopy. By their morphological features, they were identified as cotton fibers. Embolization of foreign-body material into the myocardial arteries following catheter-based procedures is an unusual event, and its occurrence may lead to granulomatous foreign-body reaction and misinterpretation of histological results.

Background and objectives: A high rate of glycolysis may reflect the inflammatory activity of interstitial lung disease (ILD). This prospective study investigated whether PET can distinguish IPF, a primarily fibrotic process, from other entities of ILD that have a marked inflammatory component. Methods: Twenty-one patients referred for surgical lung biopsy because of diffuse ILD underwent PET at the time of the lung biopsy. PET transmission scans were obtained after injecting 18FDG intravenously. Regions of interest (ROI) were drawn on the lung images, and the standardized uptake value (SUV) was calculated for these ROI. Results: Of the 21 patients studied, 14 had IPF, four had non-specific interstitial pneumonia, and the remaining three patients each had respiratory bronchiolitis-ILD, sarcoidosis and Langerhan's cell histiocytosis. There was no statistically significant difference in the SUV between IPF patients and non-IPF patients (P = 0.26), although patients with IPF tended to have higher SUV. Radiographic changes tended to be more prominent in the lung bases in patients with IPF compared with non-IPF patients; however, the median ratio of SUV measured in the upper fields to the whole lungs in IPF patients was not significantly different compared with the median ratio in non-IPF patients (P = 0.31). Conclusion: PET does not allow differentiation of IPF from a non-IPF diffuse interstitial pulmonary process.

Background EBV associated hemophagocytic syndrome (HPS) is an aggressive and potentially life-threatening condition. So far, most EBV associated HPS has been characterized mainly in infants and children in Asian countries. Results Here, we report six cases of EBV associated HPS occurring in previously healthy adults in a non-endemic area within a short period of 3 years. All patients presented with fever, hepatosplenomegaly and pancytopenia as well as disturbed liver function tests and coagulopathy. Half were diagnosed as having lymphoma. While EBV-specific serological assays were non-diagnostic in four of the six patients, the presence of EBV DNA in plasma allowed the diagnosis of EBV associated HPS in all patients. Conclusion EBV associated HPS may be more prevalent in non-Japanese adults than was previously considered. Screening for hemophagocytic syndrome, in adults as well as in children, should include real-time PCR for EBV.

In 2001, the World Health Organization (WHO) published its new classification of tumors of hematopoietic and lymphoid tissues, including an entity named posttransplantation lymphoproliferative disorder (PTLD). Because oral PTLD is of clinical relevance to oral health providers, the importance of distinguishing between PTLD and nontransplantation related lymphoma is outlined, and the clinical implications of oral PTLD are discussed.

Study objectives: Prolonged survival of transplanted kidney or liver allografts has been associated with prolonged chimerism resulting from donor-origin leukocytes carried within the allograft parenchyma. The present study, performed in a murine model, examined whether simultaneous administration of donor bone marrow cells after reduced intensity conditioning allows acceptance of heterotopic tracheal allografts and prevents the formation of the airway fibroproliferative lesion, which mimics bronchiolitis obliterans (BO). Methods: Allogeneic tracheal allografts from C57BL/6 mice were grafted subcutaneously into BALB/c mice (n = 6) [day 0]. Conditioning consisted of total lymphoid irradiation (200 cGy) at day − 1, donor marrow cells (3 × 10 7 ) administered IV on day 0, intraperitoneal cyclophosphamide (200 mg/kg) on day 1 to eliminate alloreactive marrow cells, followed by a repeated dose of donor marrow cells on day 2. Control groups consisted of one group (n = 4) that underwent similar conditioning without donor marrow cells, and another group (n = 4) that received syngeneic BALB/c marrow cells. None of these groups were administered maintenance immunosuppression. Grafts were harvested and histopathology findings were evaluated semiquantitatively at day 28, day 55, and day 95. Results: Tracheal allografts from donor marrow cell recipients still maintained a patent airway with intact airway epithelium at 95 days after transplant. However, grafts from control animals not receiving donor marrow cells or mice administered syngeneic marrow cells had lumen obliteration by 28 days after transplant. Chimerism in animals receiving allogeneic bone marrow was confirmed. Graft vs host disease did not develop in animals receiving allogeneic marrow cells. Conclusions: Further investigation may verify this approach to be applicable for the prevention of posttransplantation BO.

Pulmonary Langerhans cell histiocytosis, also known as eosinophilic granuloma, is an uncommon interstitial lung disease. A solitary nodule, usually parenchymal, may rarely be the only manifestation of the disease. We describe a case of Langerhans cell histiocytosis presenting as an obstructing tracheal lesion in a 55-year-old woman. Following complete resection of the lesion via flexible bronchoscopy, full recovery was achieved. This case represents a unique cause for tracheal obstruction, as well as an unreported manifestation of pulmonary Langerhans cell histiocytosis.

Primary pulmonary artery sarcoma is an uncommon tumor. Mandelstamm in 1923 was the first to describe the disease in an autopsy. Since then, less than 200 cases were reported. The incidence is 0.001-0.03%, they are always highly malignant sarcoma, and women are involved twice as often as men. The presentation is often cough, dyspnea, and chest pain, and patients are usually diagnosed as suffering from pulmonary emboli, and primary tumor of the pulmonary artery is not usually considered in the differential diagnosis. The diagnosis of pulmonary artery sarcoma is made of the "clot" resected during pulmonary artery thrombendarterectomy. Our suggestion is that in patients with unilateral pulmonary artery occlusive disease, no evidence of positive hypercoagulability tests, and no history of thromboembolism, a high suspicion of pulmonary artery sarcoma should be kept in mind, and an angiographic-guided biopsy from the intra-arterial occlusive material should be considered. The treatment is surgery. The survival without operation is less than 2 months. Some patients were treated with adjuvant chemotherapy. We report on a woman with undifferentiated sarcoma of the pulmonary artery, mimicking chronic pulmonary artery emboli. This case illustrates the need to consider malignancy in the differential diagnosis of patients having pulmonary emboli.

A case of clear cell chondrosarcoma of the rib in a 30-year-old man is described. The tumor developed at the site of repetitive low-impact trauma (on the arm of a wheelchair) over a period of 24 years. An association between chondrosarcoma and external trauma has not been previously reported. Chondrosarcoma has been described in previously irradiated bone and in Paget's disease. In both these examples there is an increase in new bone formation associated with necrosis of bone and increased resorption of bone, respectively. A possible mechanism in our case is increased new bone formation elicited by repeated microfractures of trabeculae of rib bone.

Panniculitis-like T-cell lymphoma is an uncommon type of extranodal T-cell lymphoma which presents clinically with subcutaneous nodules. The clinical course can either be indolent or rapidly progressive, often complicated by hemophagocytic syndrome. We report a patient with primary subcutaneous disease and initial complete response to combination chemotherapy. The patient experienced an early relapse which responded to salvage chemotherapy. However, she died shortly thereafter with hemophagocytic syndrome, polymicrobial sepsis and systemic fungal infection. At autopsy there was no evidence of lymphoma in the bone marrow or other organs. We emphasize that a fatal hemophagocytic syndrome can occur despite minimal or even without evidence: of clinically active lymphoma as demonstrated by autopsy in this case.

Graft-versus-host disease (GVHD) is a severe disorder and despite therapeutic efforts to decrease its distressing clinical manifestations, treatment is still not optimal. Here we report the results of studies, in which the purine analogue, fludarabine phosphate, was used in an attempt to modify and decrease GVHD after stem cell transplantation, across major histocompatibility barriers for murine leukemia. B-cell leukemia (BCL-1) bearing (BALB/c x C57BL/6) F1 mice received two cycles of fludarabine (0.8 mg/kg) for 5 days every 2 weeks, followed by 400 mg/kg cyclophosphamide i.p. Animals were then transplanted with C57BL/6 precursor cells and the development of leukemia and extent of GVHD was monitored both clinically and histopathologically. In the fludarabine-treated group, only nine of 28 (32%) mice developed leukemia, compared to 25 of 33 (76%) of control animals (P=0.0006 ). Mice treated with fludarabine-containing regimens prior to transplantation also had much less GVHD both clinically and at autopsy, while graft-versus-leukemia appeared to be augmented in the same animals.

Osteoporosis is well documented in type I diabetes, but its occurrence is controversial in type II diabetes. Microangiopathy is a major complication of type I and type II diabetes. We studied bone and microvascular changes in the Cohen diabetic rat, a unique nonobese model of noninsulin-dependent diabetes mellitus. The aim of this study was to find whether there is a temporal correlation between the onset of these two complications. The diabetic rats were divided into three groups (A, B, and C) according to duration of diabetes (2 months, 3 months, and 7 to 8 months, respectively). Trabecular bone area was assessed by computerized image analysis and microangiopathy by means of renal function tests, histologic examination of the kidneys, and ultrastructural measurement of the width of capillary basement membranes. Bone density of the distal femur and vertebra was significantly reduced in the diabetic rats relative to the control rats in all three groups (Group A femur: 11.5 +/- 1.6% versus 21.8 +/- 3.0%, p0.02; Group A vertebra: 15.9 +/- 1.6% versus 28.5 +/- 2.0%, p0.02; Group C femur: 7.9 +/- 1.1% versus 29.6 +/- 3.5%, p0.001; Group C vertebra: 11.4 +/- 0.7% versus 37.1 +/- 1.9%, p0.002). Renal function tests were normal in the Group A diabetic rats and there was marked albuminuria in the Group C diabetic rats. Histologic changes in the kidneys were seen only in the Group C diabetic rats. Five of 15 Group C diabetic rats showed no albuminuria or histologic evidence of kidney damage. The bone density in this subgroup was reduced relative to controls to the same degree as that of the rats with renal damage. There was no evidence of capillary basement membrane thickening in the Group A diabetic rats. Our findings indicate that in the Cohen diabetic rat, osteoporosis precedes the onset of microangiopathy. Microangiopathy probably does not play an important role in the pathogenesis of osteoporosis in this animal model.

This case report deals with an unusual leukostatic complication in a 56-year-old woman with acute myeloblastic leukemia (AML) and extreme hyperleukocytosis (316 x 10(9)/L) who presented with acute myocardial infarction (MI). After leukopheresis the patient achieved hemodynamic stabilization and rapid neurologic recovery of encephalopathy that had also developed after the infarction. Considering the central role of WBC in the remodeling of post MI myocardial tissue, it was obvious that administration of chemotherapy with its subsequent inevitable pancytopenia could impose an increased risk for further cardiac complications including myocardial rupture. Nevertheless, cytarabine-based induction chemotherapy was initiated 3 days after admission, and she achieved prolonged complete remission. Coronary angiography disclosed segmental atherosclerosis, but the only significant obstruction was in the right coronary artery. The patient died with relapsed leukemia 7 years later without recurrence of any cardiac symptoms or signs. Autopsy disclosed segmental coronary atherosclerosis involving the LAD (60% obstruction), suggesting that atherosclerosis was a predisposing risk factor. Additional compromise to blood perfusion due to leukostasis had led to this unusual complication of AML involving a major vessel. This is the first documented case of leukostasis causing coronary artery occlusion as well as the first report of successful induction chemotherapy for AML during a myocardial infarction.