PurposeMantle cell lymphomas (MCLs) represent a clinically aggressive lymphoma subtype with a poor prognosis. To explore a potential progress in outcome a historical comparison was performed using data from the Kiel Lymphoma Study Group (KLSG; 1975 to 1986) and the German Low Grade Lymphoma Study Group (GLSG; 1996 to 2004).Patients and MethodsAll patients with the histologically confirmed diagnosis of advanced-stage nonblastoid MCL were eligible. To minimize the potential heterogeneity of different risk profiles frequency matching was pursued. In addition, we adjusted for potential confounding variables by multiple Cox regression.ResultsA total of 520 patients were assessable, 150 from KLSG and 370 from GLSG studies. The median overall survival was 2.7 years for KLSG patients as compared with 4.8 years for GLSG patients (P <.0001). The 5-year survival rates were 22% in the KLSG group (95% CI, 13% to 31%) as compared with 47% for GLSG treated patients (95% CI, 38% to 55%). The hazard ratio adjusted for performance status, lactate dehydrogenase, and age was 0.44 for GLSG patients (95% CI, 0.32 to 0.59).ConclusionMedian overall survival of patients with advanced nonblastoid MCL almost doubled during the past 30 years. Potential reasons for this apparent improvement in overall survival include the application of anthracycline-containing regimens and new approaches, such as antilymphoma antibodies or stem cell transplantation. Advances in general supportive care, new diagnostic tools, and general improvement of life span might have also reinforced this effect. However, our results are questioning the validity of historical comparisons which had been frequently applied in previous trials.

Mantle cell lymphoma (MCL) is an aggressive lymphoma with accepted risk factors such as proliferation markers. To date, the different follicular dendritic cell (FDC) patterns have never been analyzed in comparison with the overall survival time. Lymph node biopsy specimens from 96 patients were analyzed by conventional morphology and immunohistochemistry with antibodies against cluster differentiation (CD)20, CD5, CD23, cyclin D1, and FDC (Ki-M4P). Two groups can be distinguished with different FDC patterns: a nodular pattern in 79 cases and a diffuse pattern in 17 cases. A Kaplan–Meier analysis revealed significantly better survival for the nodular group (p=0.0312). This group was subdivided into a group with a nodular FDC pattern similar to the FDC distribution in primary follicles (PF-nodular in 72 cases) and one with a nodular FDC pattern resembling the colonization of germinal centers (GCs) by tumor cells (GC-nodular in seven cases). A Kaplan–Meier analysis showed that patients with MCL with a PF-nodular FDC pattern had a significantly better clinical outcome than patients with the other two patterns (p=0.0033). If only cases with classical cytology (n=79) were analyzed (blastoid types excluded), patients with a PF-nodular FDC pattern had a better clinical outcome (p=0.0008). The distribution of FDC in MCL is a diagnostic tool for identifying patients with a better clinical prognosis.

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. We investigated immunohistochemically the expression of the apoptotic marker caspase 3 in relation to the clinical course. Biopsy specimen from 84 untreated patients enrolled in two multicenter prospective trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, Caspase3. The Caspase3 expression was analyzed in three groups: less than 1 positive cell per high power field (HPF), more than 1 positive cell per HPF and more than 2 positive cells per HPF. The expression was compared with the overall survival data analysed according to Kaplan and Meier. In 75 cases the caspase 3 staining could be analyzed. The caspase 3 expression had a range of 0.1–4.7 positive cells per HPF (median value:1.1, mean:1.3). Patients with mantle cell lymphoma that had less than 1 caspase 3 positive cell per HPF (33 cases) had a median overall survival time of 48 months compared to 27 months for patients with more than 1 positive cell per HPF (24 cases) and 15 months for more than 2 positive cells per HPF (18). The Kaplan-Meier analysis showed a significant difference in the overall survival time between these groups (p<0.0001). The immunohistochemical detection of caspase 3 in mantle cell lymphoma is a predictor for survival in MCL.

Minichromosome maintenance protein 6 (MCM6) is one of six proteins of the MCM family which are involved in the initiation of DNA replication and thus represent a marker of proliferating cells. Since the level of cell proliferation is the most valuable predictor of survival in mantle cell lymphoma (MCL), we investigated lymph node biopsy specimens from 70 patients immunohistochemically with a monoclonal antibody against MCM6. The percentage of MCM6 expressing lymphoma cells ranged from 12.0 to 95.6%, with a mean of 61.0%, and was significantly higher than the percentage of Ki-67-positive cells (P<0.0001). Surprisingly, the ratio of MCM6-positive cells to Ki-67-positive cells was higher than in normal stimulated peripheral blood mononuclear cells, indicating a cell early G1-phase arrest in MCL. A high MCM6 expression level of more than 75% positive cells was associated with a significantly shorter overall survival time (16 months) compared to MCL with a low MCM6 expression level of less than 25% (no median reached, P<0.0001). Multivariate analysis revealed MCM6 to be an independent predictor of survival that is superior to the international prognostic factor and the Ki-67 index. Therefore, aside from gene expression profiling, immunohistochemical detection of MCM6 seems to be the most promising marker for predicting the outcome in MCL.

In malignant tumors beside cell proliferation also cell death plays role for cell survival. Apoptosis regulating genes can be divided into two groups: death antagonists and death agonists such as bax. The ratio of death agonists and antagonists determines if a cell goes into apoptosis. We investigated in a large collective the immunohistochemical expression of the apoptotic marker p53 and bax in relation to the clinical course. Biopsies were stained immunohistochemically with monoclonal antibodies against bax and p53 and the expression was subdivided in three groups: negative, weak positive and strong positive. The expression profiles were analyzed with the overall survival data according to Kaplan and Meier. Patients with mantle cell lymphoma that had negative p53 expression had a median overall survival time of 38.1 months compared to 22.3 months for patients with a weak and 11.3 months for a strong p53 expression (0<0.0001). The bax expression was in the majority of cases positive. Only one case showed a negative staining. Patients with weak and strong bax expression showed no differences in clinical outcome (median overall survival time: 23 vs 33 months, p=0.6051). The immunohistochemical detection of p53 in mantle cell lymphoma is a good predictor for the clinical outcome.

Objectives: Proliferation indices are important prognostic factors for the clinical outcome of patients with mantle cell lymphoma (MCL). We investigated whether the expression of repp86 (restrictedly expressed proliferation-associated protein 86 kDa), a new proliferation specific marker expressed in the cell cycle phases G(2), S and M, but not in G(1), correlates with the clinical course in patients with MCL. Patients and Methods: Biopsy specimens from 94 untreated patients enrolled in two multicenter trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, and repp86 (Ki-S2). Results: Patients with 0-1% repp86 expression had a median overall survival time of 71.0 months, compared with 38.2 months for patients with 1-5% positive cells and 25.4 months for patients with 5-10% positive tumor cells. Patients with repp86 expression of more than 10% showed the shortest survival (median: 15.0 months). Kaplan-Meier analysis revealed a significant difference in the overall survival time between patients with very high (> 10%) and very low (0-1%) repp86 expression (P < 0.0001) in the tumor cells. The multivariate analysis revealed repp86 expression to be superior to other clinical characteristics as a prognostic factor (P = 0.0016). Conclusion: Based on these findings, repp86 expression is a new important prognostic factor in MCL.

The expression of bcl2 was typically observed in follicular lymphoma with a t(14;18) but also in CLL and mantle cell lymphoma (MCL). Up to now no study investigated the expression of bcl2 in correlation with the clinical outcome in a large collective of patients with MCL. We investigated immunohistochemically the expression of the apoptotic marker bcl2 in relation to the clinical course. 90 biopsy specimens were investigated immunohistochemically with antibodies against CD20, CD5, CD3, CD23, cyclin D1 and bcl2. The expression was analyzed in three groups: negative, 5–50% positive cells (weak positive) and more than 50% positive cells (strong positive). The expression profils were compared with the overall survival data analysed according to Kaplan and Meier. In none of thae cases a negative staining was found. 16 cases (18%) had a weak and 74 cases (82%) a strong bcl2 expression. Patients with mantle cell lymphoma that had a weak positive expression (n=16) had a median overall survival time of 21 months compared to 32 months for patients with a strong expression (n=74) (p=0.0402). In contrast to DLBL high levels of bcl2 expression had a better prognosis than pathients with low levels.

Gene expression profiles revealed that proliferation associated genes are important prognostic factors in the clinical outcome in mantle cell lymphoma (MCL). Beside this well accepted markers also analysis of apoptotic proteins are now under investigation. We investigated immunohistochemically the expression of the apoptotic marker NF-kB in relation to the clinical course in 89 patients enrolled in two multicenter prospective trials. Biopsies were recut and stained with mandatory antibodies (CD20, CD5, CD3, CD23, cyclin D1) and NF-kB. The NF-kB expression was analyzed in three groups: negative, cytoplasmatic positive and nuclear positive (more than 1/HPF). The expression was compared with the overall survival data analyzed according to Kaplan and Meier. In 13 cases a negative NF-kB staining was detected. Fifty-seven cases were positive only in the cytoplasma and in 17 cases more than 1 cell per high power field showed nuclear activity. Patients with mantle cell lymphoma that had negative and cytoplasmatic positive expression had a median overall survival time of 35.7 months compared to 22.4 months for patients with a nuclear NF-kB expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time (p=0.0121). The immunohistochemical detection of NF-kB in mantle cell lymphoma is possible and a tool to identify patients with a poor prognosis.

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. Treatment usually consists of combination chemotherapy, often including topoisomerase (topo) inhibitors such as doxorubicin, etoposide and mitoxantrone. Topo II α is an enzyme that is needed whenever uncoiling of DNA is necessary during the cell cycle. The enzyme is a marker of cell proliferation. We analyzed the expression of topo II α in relation to Ki-67 and the clinical outcome in patients with MCL. Biopsy specimens from 95 untreated patients enrolled in two multicenter trials (1975–1985) were investigated immunohistochemically with monoclonal antibodies against topo II α (Ki-S4) and Ki-67 (Ki-S5). Patients with low (0–10%) topo II α expression had a median overall survival time of 49.0 months, compared to 17.0 months for patients with high (more than 10%) topo II α expression. The Kaplan–Meier analysis showed a significant difference in the overall survival time related to the percentage of topo II α ( P <0.001) and Ki-67 ( P <0.001) positive tumor cells. Multivariate Cox regression analysis revealed the expression of topo II α as the most important prognostic factor ( P <0.001) in MCL superior to the international prognostic index (IPI), the Ki-67 index and other clinical characteristics.

Mantle cell lymphoma is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. Proliferation indices are important prognostic factors in the clinical outcome. We investigated immunohistochemically the expression of the apoptotic marker CD95L (Fas Ligand) in relation to the clinical course. Biopsy specimen from 69 untreated patients enrolled in two multicenter prospective trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, CD95L. The CD95L expression was analyzed into three groups: negative, weak positive and strong positive. The expression was compared with the overall survival data analysed according to Kaplan and Meier. Patients with mantle cell lymphoma that had negative and weak positive CD95L expression had a median overall survival time of 32.0 months compared to 18.3 months for patients with a strong CD95L expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time between the patients with strong CD95L expression and the group of patients with negative or weak positive tumor cells (p<0.0038). Based on these findings, the immunohistochemical detection of CD95L in mantle cell lymphoma is a prognostic factor.

Intracoronary brachytherapy is a novel, meanwhile established therapy. It is currently the only interventional procedure which has proven to effectively reduce the restenosis rates after intervention of long and diffuse in-stent restenosis. For this indication, brachytherapy can be regarded as the current treatment of choice. Randomized studies yield promising results for bypass interventions or interventions in small vessels or diabetic patients. These findings may encourage the decision to perform a percutaneous, transluminal intervention in such high-risk patients. In clinical practice, implantation of new stents in combination with brachytherapy procedures should be avoided as far as possible. In any case, the combined antiaggregatory therapy should be conducted sufficiently long to minimize the danger of late stent thrombosis. Under this treatment, the expected thrombosis rates ar within the range of placebo-treated patients. The length of the radiation source should be sufficient to cover the entire interventional injury length to avoid recurrent edge stenosis. De novo lesions are currently not a routine indication for intracoronary brachytherapy. Although intracoronary brachytherapy may effectively reduce restenosis rates in sufficiently irradiated de novo lesion segments, de novo lesions should be treated only within the set-up of controlled studies. The current available data with a follow-up period of up to 5 years show that intracoronary brachytherapy is also in the mid-term a safe and effective therapy for the reduction of restenosis after coronary interventions.

Primary malignant lymphoma of the thyroid gland is a rare disease comprising about 1%–3% of the thyroid malignancies, and this uncommon lymphoma represent less than 1% of all non-Hodgkinlymphomas (NHL). According to the modified Ann-Arbor-Classification primary thyroid lymphoma by definition is a lymphoma that is restricted to the thyroid gland (stage I E ) or involves the thyroid gland and supradiaphragmatic predominantly adjacent thyroid lymph nodes (stage II E ). Primary thyroid lymphoma is a heterogenous disease encompassing a wide variety of lymphoma entities. The diagnosis and treatment of this lymphoma are emphasis of this article.

We treated 153 patients with de novo acute myeloid leukemia (AML) with two induction courses of conventional-dose cytosine arabinoside (ara-C) and idarubicin (AIDA) followed by either a third course of AIDA, high-dose ara-C or bone-marrow transplantation. The complete remission (CR) rate for all patients was 63.4%, with a higher CR rate for patients with a normal (versus unfavorable) karyotype (73.2% vs 52.5%; P=0.038). The probability of overall survival (OS) was 30.7% after 5 years (26.3% after 7 years). Improved OS at 5 years could be observed for patients up to 50 years old versus patients older than 50 years of age (37.6% vs 19.9%; P=0.001) and patients with a normal (versus unfavorable) karyotype (42.9% vs 14.1%; P=0.0016). Disease-free survival (DFS) after 5 years was 33.2% for all 97 CR patients and was significantly better for patients with a normal (versus unfavorable) karyotype (44.3% vs 12.3%; P= 0.003). Multivariate analysis revealed that the age for OS (P < 0.02) and the karyotype for both OS (P<0.03) and DFS (P< 0.05) were independent prognostic factors. In conclusion, AIDA is an effective and well-tolerated induction regimen (even in elderly patients) with a 5-year survival of more than 30% when combined with ara-C-containing postremission therapy. The karyotype is the most powerful prognostic factor for predicting the outcome of patients treated with this protocol.