Autologous stem cell transplantation in adult patients with peripheral T-cell lymphoma: a nation-wide survey.

Limited experience is available on the feasibility and efficacy of high-dose therapy (HDT) supported by autologous stem cell transplantation (ASCT) in patients with peripheral T-cell lymphoma (PTCL). Therefore, a nation-wide survey was conducted in adult patients transplanted for PTCL in Finland during 1990-2001. After histopathology review, 37 patients were identified. The median age was 46 years (16-68) at the time of ASCT. Histology included PTCL not otherwise specified in 14 patients, anaplastic large cell lymphoma (ALCL) in 14 patients, and other in nine patients. Disease status at the time of ASCT was CR/PR1 in 18 patients; CR/PR2 in 14 patients, and other in five patients. HDT consisted of either BEAC (N=22) or BEAM (N=15), supported by blood stem cells in 34 patients (92%). Early transplant-related mortality was 11%. With a median follow-up of 24 months from HDT, 16 patients (43%) have relapsed or progressed. The estimated 5-year overall survival (OS) was 54%. Patients with ALCL had superior OS when compared with other subtypes (85 vs 35%, P=0.007). OS at 5 years was 63% in patients transplanted in CR/PR1 vs 45% in those transplanted in other disease status (P=NS). Prospective studies are needed to define the role of ASCT in this lymphoma type.

Expression of C-KIT and HER-2 tyrosine kinase receptors in poor-prognosis breast cancer.

BACKGROUND: This study investigated the expression of C-KIT and HER-2 receptors and their correlation with histopathological markers of cell proliferation, differentiation and apoptosis in poor-prognosis breast cancer. PATIENTS AND METHODS: Formalin-embedded histopathological samples from forty patients with progressive metastatic breast cancer were reanalyzed to determine HER-2 expression by immunohistochemistry (ICH) and chromogenic in situ hybridization (CISH). C-KIT receptor expression, p53, Bcl-2 and Ki-67 were determined by immunohistochemistry. RESULTS: The mean p53 score was 18.03 (SD 30.69), that of Bcl-2 was 38.13 (39.25) and Ki-67 was 5.8 (SD 9.23), respectively. HER-2 expression was positive in 35% of patients by ICH and in 25% by CISH. C-KIT receptor staining was positive in 82% of the patients. A significant association was observed between HER-2-positive score in ICH and poorly-differentiated histology (p=0.03), negative Er/Pr status (p=0.04) and Bcl-2 expression (p=0.003). With CISH-determined HER-2, the corresponding p values were 0.07, 0.053, and 0.002, respectively. No correlation was found between HER-2 or C-KIT expression (p=0.456). CONCLUSION: CISH and ICH determination of HER-2 correlate similarly to hormone receptor status and Bcl-2 expression in breast cancer. C-KIT expression was commonly present and did not correlate to other prognosticators in poor-prognosis breast cancer.

Expression of cyclooxygenase-1 and -2 in urinary bladder carcinomas in vivo and in vitro and prostaglandin E2 synthesis in cultured bladder cancer cells.

Cyclooxygenases (Coxs) are the rate-limiting enzymes catalysing the formation of prostaglandins, which are involved in various of physiological processes. Increased Cox-2 expression has been observed in several malignancies, but the exact role of Cox-2 in carcinogenesis remains unsolved. We studied the expression of both Cox-1 and Cox-2 by immunohistochemistry in 29 transitional cell carcinomas of the urinary bladder. Diffuse cytoplasmic immunosignal for Cox-2 was detected in all cancer specimens. The expression was moderate in 55% and strong in 31% of the carcinomas. The normal urothelium in the samples stained also for Cox-2, but the intensity of the immunosignal was weak in most specimens. Cox-1 was expressed in the stroma of bladder wall, whereas in the tumour cells, Cox-1 immunosignal was either absent or weak. No correlation was detected between Cox-1 or Cox-2 expression and tumour differentiation or stage of invasion. We also evaluated the mRNA expression of Cox-1 and Cox-2 and synthesis of prostaglandin E2 (PGE2) in three bladder carcinoma cell lines (RT4, 5637, and T24). All cell lines expressed high levels of Cox-2 mRNA, whereas Cox-1 mRNA expression was detected only in T24 cells. There was great variation in the basal levels of PGE2 synthesis in these cell lines. Indomethacin inhibited the synthesis of PGE2 in all three cell lines, although the level of Cox-2 mRNA tended to increase by indomethacin. These results indicate that Cox-2 is widely expressed in human bladder carcinomas and that the role of Cox-2 inhibition in bladder cancer should be further studied.

Cell cycle regulators p27 and pRb in lymphomas - correlation with histology and proliferative activity.

The cell cycle is a complex event in which multiple regulator-proteins participate. The G(1)/S checkpoint of the cell cycle is controlled by pRb protein, which functions in its hypophosphorylated form as a negative regulator of growth. p27 (Kip1), a member of CIP/KIP family of cyclin inhibitory proteins, participates in inhibition of forming complexes that allow pRb to phosphorylate and lead the cell into mitosis. The expression of these important cell cycle regulator proteins was studied in a total of 96 non-Hodgkin's lymphoma (NHL) samples, which were classified according to the REAL classification. The expression of p27, pRb and the cell proliferation marker Ki-67 (MIB-1) was evaluated in lymphomas using immunohistochemistry. This study showed that there were coordinate changes in the expression of p27 and pRb in NHL. When compared to low-grade lymphomas, high-grade lymphomas showed significantly reduced expression of p27 and inversely pRb expression was increased (P< 0.001). Increase in expression of Ki-67 was parallel with pRb expression, and was mainly seen in cells that lacked p27 expression (P< 0.0001). This study suggests that changes in the control of the cell cycle closely relate to the pathobiology of NHL.

Expression of collagenase-3 (matrix metalloproteinase-13) in transitional-cell carcinoma of the urinary bladder.

Expression of collagenase-3 [matrix metalloproteinase-13 (MMP-13)] has been previously demonstrated in squamous-cell carcinomas of both the head and neck and the vulva, cutaneous basal-cell carcinomas, chondrosarcomas and melanomas. Using in situ hybridization, MMP-13 mRNA expression was detected in 13 of 23 (52%) urinary bladder transitional-cell carcinomas (TCCs). Expression was restricted to cells in the invading edges of tumors. No expression of MMP-13 mRNA could be detected in normal urothelium. As detected by immunohistochemistry, MMP-13 protein showed an expression pattern similar to that of MMP-13 mRNA. Expression of MMP-13 mRNA and protein was also detected in 2 bladder carcinoma cell lines (RT4 and T24). In these cell lines, TNF-alpha potently induced MMP-13 mRNA expression. Retinoids and a selective p38 inhibitor, SB203580, potently inhibited MMP-13 mRNA expression. Our results demonstrate MMP-13 expression in human urinary bladder carcinoma cells in vivo and in vitro and suggest that MMP-13 may serve as a marker for transformation and invasion in urinary bladder TCCs.

Effect of local epididymal levonorgestrel on the fertilizing ability of male rat, a model for post-testicular contraception.

A thin levonorgestrel-silicone layer was applied on the capsule of the cauda epididymis of male rats to study a model for post-testicular male contraception. The effect of different levonorgestrel doses on the fertility of males was tested with fertile females. The time-dependent influence of a standard dose of levonorgestrel on serum LH and on testicular histology was estimated. Among the males tested, there was a group of animals where successful contraception with local application of levonorgestrel-silicone membrane was obtained. Sexual behavior was normal and the spermatogenesis was functioning, but the sperm were infertile. Although further research is needed to estimate adequate dose and strength of levonorgestrel in silicone matrix, this study shows that post-testicular contraception is possible to achieve.

Effect of etoposide on experimental testicular teratoma in 129/SvJ mice.

To study the effects of etoposide on experimental testicular teratoma in 129/SvJ mouse we analysed the tumour growth, differentiation, apoptosis and the localisation of mdr1 P-glycoprotein (mdr1-Pgp). In this model the implanted gonadal ridges developed into testicular teratomas in 17 out of 56 implanted testes (30%) and in 14 out of 28 mice (50%). The tumour-bearing mice were treated with etoposide on 4 successive days either 4 weeks or 6 weeks after implantation, and killed 7 days after the last dose. The mice in the control groups did not receive etoposide. The teratomas consisted mainly of neural tissue. The etoposide-treated 4-week teratomas, but not the 6-week teratomas, were significantly smaller than those in the corresponding control groups. The density of apoptotic cells and the distribution of the mdr1-Pgp were not altered by etoposide. The decreased proportion of immature neuroectodermal tissue components was observed in all treated teratomas, converting the histology towards that of a mature teratoma. In addition, a low proportion of immature tissue components was frequently combined with a low density of apoptotic cells. In conclusion, etoposide decreased the immature tissue components of teratomas, while mature tissues remained unaffected. These results may have clinical relevance in man, since they confirm that postchemotherapy mature teratomas cannot be treated with chemotherapy. Despite benign histology, the human residual tumours have a significant malignant potential and require complete surgical excision and close surveillance.

Urinary bladder transitional cell carcinogenesis is associated with down-regulation of NF1 tumor suppressor gene in vivo and in vitro.

The NF1 gene product (neurofibromin) is known to act as a tumor suppressor protein by inactivating ras. The best documented factors involved in urinary bladder transitional cell carcinoma (TCC) are ras proto-oncogene activation and p53 suppressor gene mutations. This is the first study reporting alterations in NF1 gene expression in TCC. We examined NF1 gene expression in a total of 29 surgical urinary bladder TCC specimens representing grades 1 to 3 and in three cell lines, RT4, 5637, and T24 (representing grades 1 to 3, respectively). Decreased NF1 gene expression was observed in 23 of 29 (83%) TCC specimens as estimated by immunohistochemistry, the decrease being more pronounced in high-grade tumors. NF1 mRNA levels were markedly lower in TCC tissue compared with adjacent non-neoplastic urothelium, as studied by in situ hybridization for grade 3 TCC. Immunohistochemistry and Western blotting demonstrated that TCC cell lines expressed NF1 protein at different levels, expression being almost undetectable in T24 (grade 3) cells. Northern blotting for cell lines demonstrated reduced NF1 mRNA levels in grade 3 TCC cells. Reverse transcription polymerase chain reaction for cell lines and selected grade 2 and grade 3 tissue samples demonstrated NF1 type II mRNA isoform predominance in all samples studied. Our results show that both NF1 mRNA and protein levels are decreased in high-grade TCC, suggesting that alterations of NF1 gene expression may be involved in bladder TCC carcinogenesis.

Borrelial lymphocytoma--a historical case.

We here describe a patient with a tick bite in the areola mammae in 1953 followed by erythema migrans. Twenty years later, after another tick bite in the axillary skin, also followed by erythema migrans, a large lymphatic infiltrate developed in the mammary skin, when the margin of the erythema reached the areola. The infiltrate resolved within a year without any therapy. Borrelial DNA was detected by polymerase chain reaction in the paraffin blocks of the lymphatic skin infiltrate. The patient died 9 years later of generalized lymphoma. A similar monoclonal immunoglobulin heavy chain gene rearrangement was detected both in the mammary skin lesion and in the lymphoma specimen.

Use of carbon-11 methionine positron emission tomography to assess malignancy grade and predict survival in patients with lymphomas.

The aim of this study was to investigate whether uptake of carbon-11 methionine (MET) is associated with histological grade of malignancy and survival in patients with newly diagnosed or recurrent lymphoma. Thirty-two patients with histologically confirmed lymphoma participated in the study. Twenty-six (81%) were studied before any therapy and six before treatment for recurrent disease. Twenty-eight patients had non-Hodgkin's lymphoma and four had Hodgkin's disease. An ECAT 931/08-12 positron emission tomography (PET) scanner was used for PET imaging. After the transmission scan, a median dose of 293 MBq of MET was injected intravenously and dynamic images were acquired for 40 min. The uptake of MET in tumour was measured as the standardized uptake value (SUV) and influx constant (Ki). The SUV formula was also adjusted to the predicted value of lean body mass (SUVlean) and body surface area (SUVBSA). The PET results were correlated with the clinical follow-up data. The median SUV in 32 malignant lesions was 6.6 (range, 1.9-12.4) and the median Ki was 0. 116 min-1 (range, 0.025-0.201, n=23). The median SUV was 7.0 (range, 5.4-12.4, n=9) in high, 6.2 (range, 1.9-10.4, n=11) in intermediate and 5.7 (range, 3.8-8.3, n=8) in low grade lymphomas. One intermediate grade lymphoma of the skin was visually negative (SUV 1. 9). In Hodgkin's disease the median SUV was 7.0 (range, 3.2-7.9, n=4). The median Ki value was 0.162 min-1 (range, 0.147-0.197, n=7) in high, 0.099 (range, 0.025-0.152, n=10) in intermediate, and 0.078 (range, 0.056-0.152, n=4) in low grade lymphomas and 0.149 (range, 0. 096-0.201, n=2) in Hodgkin's disease. The difference between high and other grade non-Hodgkin's lymphomas was significant when using Ki (P<0.001), but not with SUV, SUVlean or SUVBSA. The final outcome of the patients was not related to MET uptake. Lymphomas with a high Ki value tended to have a high S-phase fraction (r2=0.46, P=0.043). It is concluded that MET PET is highly sensitive for the detection of untreated and recurrent lymphomas. Differentation of high grade lymphomas from lower malignancy grades seems to be possible if graphical analysis is applied to calculate Ki for MET. However, prediction of survival is not possible with MET PET.

Detection of residual tumours in postchemotherapy testicular cancer by FDG-PET.

The aim of this study was to investigate whether 2-(F-18)-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) could reliably detect testicular cancer in patients following chemotherapy. Twenty FDG-PET studies were performed on 15 patients with metastatic seminoma or non-seminoma. Tracer uptake in the PET study was measured by calculating the standardised uptake value (SUV) for the tracer. Nine lesions out of 20 were judged to be positive based on high FDG uptake. Three proved to represent inflammatory changes in non-cancerous tissue. Eleven PET studies were negative. In one of these, viable tumour was found at retroperitoneal lymphadenectomy. The median SUV values of metastatic tumours and benign residual tumours were 2.7 (range 1.6-9.5, n = 10) and 1.7 (range 0.7-5.5, n = 15), respectively. The large overlap of SUVs between these groups was due to the relatively high FDG uptake in inflammatory tissue (median 4.2, range 2.0-5.5, n = 4). The results indicate that FDG imaging of metastatic testicular cancer after chemotherapy has limited value because of a potentially high accumulation of FDG in inflammatory tissues.

The importance of self-observation of fecal blood in indicating a proper bowel examination.

This study presents a new model of screening for colorectal cancer. Persons aged 50 or over in a city of 160,000 inhabitants were encouraged by a newspaper campaign to act on signs of fecal blood and to come forward for examination. A quantitative immunological human hemoglobin (Hb)-specific test method was employed, and, as a simple discriminatory help to minimize perianal contamination, a constringent local ointment was used. The group of fecal bleeders was examined by colonoscopy. Altogether, 1638 persons came forward to request screening. Of these, 168 were submitted for colonoscopy, and, among those 18 colorectal cancers (11% of colonoscopies) were found. Of the cancers a significant part 28% were early cases (Dukes' A). In addition 28 adenomas were detected. The results show that there exists in the population a group of neglected fecal bleeders. Increasing the population's awareness of this symptom as a possible sign of colorectal cancer combined with prompt and proper medical investigations would lead to the detection of early cases of colorectal cancers.

Oncoprotein expression in human synovial tissue: an immunohistochemical study of different types of arthritis.

Based on the fact that synovial lining cells have some properties of transformed-appearing cells, we have examined the expression of Myc, Myb, Fos, Jun and Ras oncoproteins in synovial tissues from patients with different types of arthritis. Formalin-fixed and paraffin-embedded sections of synovial tissue from 12 patients with rheumatoid arthritis (RA), 14 with reactive arthritis (ReA), nine with other seronegative arthritis (OSA), seven with bacterial arthritis (BA), eight with probable bacterial arthritis (PBA) and eight with osteoarthritis (OA) were studied using the immunoperoxidase staining technique. The oncoproteins studied were expressed both in the synovial lining layer and in the sublining layer, consisting of lymphocytes, other inflammatory cells and blood vessels. Among the six disease entities, RA and OA appeared to be the most distinct, whereas the results obtained for ReA and OSA, and on the other hand for BA and PBA, closely resembled each other. The expression of Myc, Myb, Fos and Jun was significantly correlated both to the degree of synovial hypercellularity and the synovial lymphocytic infiltration. For Ras, such a correlation could not be seen. We conclude that we find no evidence of a cell lineage-specific or a disease-specific abnormality of proto-oncogene products in RA, and the expression of these oncoproteins is consistent with inflammation rather than with any primary abnormality of cell growth.

Antibiotic prophylaxis and treatment of reactive arthritis. Lessons from an animal model.

OBJECTIVE: To study the effect of antibiotic prophylaxis and treatment of reactive arthritis (ReA), using an experimental model. METHODS: Yersinia enterocolitica O:8, when injected intravenously into Lewis rats, causes a sterile arthritis closely resembling human ReA in 70% of the animals. Arthritis develops in 1-2 weeks; in some of the animals it remains chronic, and exacerbations occur. This model was applied to study the effect of a 7-day treatment with ciprofloxacin, using 2 different dosages (20 or 100 mg/kg/day) and 4 different schedules for initiation of treatment. The effects were evaluated by determining the daily arthritis score, the number of rats developing arthritis, and fecal excretion of Yersinia. In addition, weight gain was monitored. At autopsy (35 or 60 days after inoculation with bacteria), samples were obtained for determination of Yersinia-specific antibodies in the serum. At the same time, samples were collected from mesenteric lymph nodes, lung, spleen, and liver for bacterial cultures, and from the ankle joints for histologic evaluation. In a separate experiment, ciprofloxacin concentrations in samples from serum and mesenteric lymph nodes were analyzed by high performance liquid chromatography. RESULTS: A 7-day course with 100 mg/kg/day of ciprofloxacin, started on day 3 after bacterial inoculation, completely prevented the development of ReA and eliminated Yersinia during the 60-day experiment. If a dosage of 20 mg/kg/day was used, development of acute arthritis was prevented, but some of the animals had positive fecal cultures at the end of experiment. If antibiotic treatment was started on day 5, the preventive effect was still observed, but was less pronounced. If the treatment was started at the peak of the development of arthritis, no effect on arthritis was observed. CONCLUSION: These results indicate that if any effect of antibiotic treatment in Yersinia-triggered ReA is to be expected, the treatment must be started early and given in sufficient dosage. However, antibiotic treatment has no effect on fully developed arthritis.

Expression of bcl-2 in rheumatoid arthritis.

Since defective apoptosis has been suggested to play a role in the development of autoimmune diseases, we have investigated the expression of the proto-oncogene bcl-2 in patients with rheumatoid arthritis (RA). The expression of bcl-2 was studied in peripheral blood (PB) and synovial fluid (SF) lymphocytes and synovial tissues (ST) from patients with RA using immunohistochemistry, flow cytometry and nucleic acid hybridization. Patients with reactive arthritis (ReA) or osteoarthritis (OA) and healthy individuals were used as controls. The expression of bcl-2 protein in PB lymphocytes and the expression of bcl-2 mRNA in PB mononuclear cells (PBMC) was similar in healthy controls and patients with RA. However, bcl-2 protein expression was significantly reduced in SF lymphocytes when compared to PB lymphocytes. Similar results were observed with lymphocytes from patients with ReA, and irrespective of whether total lymphocytes, T cells or different T-cell subsets were studied. In the synovial sections, the expression of bcl-2 was restricted to lymphocytes, and bcl-2+ cells were observed in the majority of samples from patients with RA, OA and ReA. These data indicate that the expression of bcl-2 is not increased in the lymphocytes or ST derived from patients with RA. Instead, decreased expression of bcl-2 protein in SF lymphocytes compared to PB lymphocytes was demonstrated. We suggest that bcl-2 does not play a significant role in the pathogenesis of RA.

A fatal case of hard-metal disease.

OBJECTIVES: The purpose of this report is to present a case of hard-metal disease in which the symptoms and findings were minimal early in the disease, but further exposure rapidly led to a fatal outcome. HISTORY: A 22-year-old nonsmoking white male, employed for over four years in hard-metal tool grinding, started experiencing a dry cough and shortness of breath during exercise. Preliminary investigations did not reveal any cause for these symptoms, and the patient continued to work. Several months later he developed clinically apparent alveolitis with recurrent pneumothorax. Pulmonary infiltrates in chest radiographs did not disappear during corticosteroid treatment. Soon it was evident that the patient had irreversible pulmonary failure, and a bilateral lung transplantation was performed. No signs of rejection were seen in the resected lungs. The patient died of pneumonia five months later, but no signs of hard-metal disease were found in the transplanted lung. CONCLUSIONS: This fatal case of hard-metal lung disease demonstrates that symptoms and findings in pulmonary function tests or chest radiographs may be minimal or misleading in the early stages of the disease. Cobalt-exposed workers with inexplicable respiratory symptoms should be closely monitored and the exposure should be suspended.

Increased glucose metabolism in untreated non-Hodgkin's lymphoma: a study with positron emission tomography and fluorine-18-fluorodeoxyglucose.

Glucose metabolism has been shown to be increased in neoplastic tissue. It has been suggested that high activity of glucose metabolism is associated with a high grade of malignancy of human cancer. We studied in vivo glucose metabolism in 22 patients with untreated non-Hodgkin's lymphoma with fluorine-18-fluorodeoxyglucose (FDG) and positron emission tomography (PET). FDG uptake in lymphoma deposits was measured blinded to clinical data, and compared with histologic classification and proliferative activity. Tracer uptake was measured by using two indices of FDG accumulation: the standardized uptake value (SUV) and the regional metabolic rate (rMR) for the tracer. The median SUV of the lymphomas was 8.5 (range, 3.5 to 31.0), and the median rMR 22.7 mumol/100 g/min (range, 9.0 to 124.3 mumol/100 g/min). A high FDG uptake in tumors was associated with high histologic degree of malignancy as defined by the Working Formulation (P = .005 for the SUV, and P = .04 for the rMR) or by the Kiel classification (P = .003 for the SUV, and P = .02 for the rMR). A high FDG accumulation was also associated with a high S-phase fraction (r = .786 for the SUV, P = .0002; and r = .774 for the rMR, P = .02). We conclude that in untreated non-Hodgkin's lymphomas high FDG uptake is associated with high histologic grade of malignancy and a high proliferation rate. This minimally invasive method may find application in assessing lymphoma lesions in patients who are poor candidates for surgery, and it may provide further information in cases where the grade of aggressiveness of lymphoma is not settled based on clinical or histologic data.

Expression of acid cysteine proteinase inhibitor (ACPI) in the normal human prostate, benign prostatic hyperplasia and adenocarcinoma.

Acid cysteine proteinase inhibitor (ACPI or cystatin A) is a protein (12 kDa) which inhibits the action of several cysteine proteinases, e.g. cathepsins B, H, L and S. In this study the cellular location of ACPI has been immunohistochemically investigated in the normal human prostate, in benign prostatic hyperplasia (BPH) and in adenocarcinoma. ACPI was found in the basal epithelial cells of the normal prostate. The secretory epithelial cells did not express ACPI. In the hyperplastic prostate, the expression of ACPI was decreased and it was also expressed more focally in the basal cells. Hyperplastic basal cells also expressed ACPI. In prostatic adenocarcinoma, no ACPI expression was found. The absence of ACPI expression was obvious and if the sections contained both benign and malignant cells, only the benign glandular structures always expressed ACPI. The results suggest that expression of ACPI might be related to prostatic epithelial cell proliferation and differentiation. Possibly the detection of ACPI in tissue sections might be helpful in identifying prostatic adenocarcinoma, especially in cases with small carcinomatous foci.

CD44v6 expression in non-Hodgkin's lymphoma: an association with low histological grade and poor prognosis.

The family of CD44 glycoproteins has diverse functions in cell-cell and cell-matrix interactions. The standard form of CD44 is of importance in the dissemination of lymphoma, whereas the clinical significance of the variant exon v6-containing forms of CD44 (CD44v6) is not known. The expression of different forms of CD44 was investigated by using antibodies against the constant part of CD44 (CD44c) and CD44v6 in 56 primary and 17 recurrent non-Hodgkin's lymphomas and correlated with several clinicopathological parameters and with prognosis. Fifty-seven per cent of the primary non-Hodgkin's lymphomas expressed CD44v6 and 73 per cent expressed the constant epitope. Expression of both CD44c and CD44v6 was associated with low histological grade of malignancy. CD44c expression was associated with a low cellular proliferation rate as assessed by DNA flow cytometry. Of several factors tested, high expression of the variant from v6 was the only factor that was associated with unfavourable recurrence-free survival (P = 0.04). We conclude that CD44v6 is associated with a low histological grade, but, on the other hand, with an unfavourable outcome, which suggests that the combination of CD44v6 and histological grading may form a particularly strong prognostic parameter in non-Hodgkin's lymphoma.