Correction to: The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence.

In multivariate analysis, GS of the regular prostatectomy specimen was the only statistically significant parameter for pT2R1 prostate cancer.

[Autopsy in oncology : Treatment validation in cancer centers and clinical cancer registries]. / Obduktion bei Tumorerkrankungen : Behandlungsstrategien in Tumorzentren und klinischen Krebsregistern.

The legal recognition of autopsy as a tool of quality assurance will strengthen its importance especially in the care of cancer patients. However, this confidence is relativized by the consideration of the assessment of the autopsy in various effective nonlegislative regulations. This consideration shows that in contrast to earlier years autopsy does not play a major role in the most important programs for the certification of cancer centers or for clinical cancer registration. If clinical autopsy is to play a more important role in the future, then in addition to improving and standardizing its quality the implementation into these systems of quality management is indispensable.

Screening-relevant age threshold of 70 years and older is a stronger determinant for the choice of adjuvant treatment in breast cancer patients than tumor biology.

PURPOSE: The 70-year threshold determines whether patients are eligible or not for the breast cancer screening program in Germany. It is not known whether this age threshold also influences the choice of adjuvant treatment and ultimate outcome. METHODS: 3463 patients were analyzed from the clinical cancer registry Regensburg (Germany) with primary, non-metastatic invasive breast cancer diagnosed between 2000 and 2012. The distribution of tumor biological subtypes was evaluated in breast cancer patients both in those eligible for screening (ESG, 50-69 years) and those not eligible for screening (NESG, ≥70 years). Local and systemic therapies in different subtypes as well as overall survival (OS) were analyzed. RESULTS: 2171 patients (62.7%) pertained to the ESG and 1292 patients (37.3%) referred to the NESG. The distribution of the common subtypes Luminal A, Luminal B, HER2-like, and Basal-like was comparable in both groups. Treatment varied considerably with less systemic therapies in all subtypes in patients in the NESG. Regarding local therapies, patients in the NESG also received less surgery and less radiotherapy. As to Luminal A patients, best OS was seen in patients receiving endocrine therapy (ET) (7-year OS of 95.6%) and CHT plus ET (7-year OS of 93.1%) in the ESG. In the NESG, best OS was seen in patients receiving CHT plus ET (7-year OS of 95.2%), whereas patients receiving only ET had a 7-year OS of 73.9%. CONCLUSIONS: Despite similar tumor biology, elderly patients are undertreated regarding both systemic and local therapies compared to younger patients, leading to reduced OS.

4-IHC classification of breast cancer subtypes in a large cohort of a clinical cancer registry: use in clinical routine for therapeutic decisions and its effect on survival.

The aim of the present study was to evaluate to what extent the combination of standard histopathological parameters determines the biology of breast cancer and the effect on therapy and prognosis. The Clinical Cancer Registry Regensburg (Bavaria, Germany) included n = 4,480 female patients with primary, non-metastatic (M0) invasive breast cancer diagnosed between 2000 and 2012. Immuno-histochemical analyses, i.e., estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 (4-IHC), defined the tumor biological subtypes Luminal A, Luminal B, HER2-like, and Basal-like. Subtype-related differences in therapies and overall survival (OS) were analyzed using multivariable statistical methods. 4344 patients (97.0 %) could be classified into the four common tumor biological subtypes. The two most frequent entities were Luminal A (48.4 %), Luminal B (24.8 %), HER2-like (17.8 %), and Basal-like subtype (9.0 %). A multivariable Cox regression model showed that the best 7-year OS was seen in Luminal A patients and that OS of Luminal B and HER2-like patients was comparable (HR = 1.59, P < 0.001 versus HR = 1.51, P = 0.03). Lowest OS was seen in patients with Basal-like tumors (HR = 2.18, P < 0.001). In conclusion, the classification of tumor biological subtypes by the ER, PR, HER2, and Ki-67 biomarkers is practical in routine clinical work. Providing that quality assurance of these markers is ensured, this classification is useful for making therapy decisions in the routine clinical management of breast cancer patients.

Adjuvant endocrine therapy in pre- versus postmenopausal patients with steroid hormone receptor-positive breast cancer: results from a large population-based cohort of a cancer registry.

PURPOSE: Adjuvant endocrine therapy (ET) is indicated in patients with steroid hormone receptor (HR)-positive breast cancer. The aim of this study was to evaluate the quality of HR determination and adjuvant endocrine treatment of breast cancer patients in a large cohort of more than 7000 women by analyzing data from a population-based regional cancer registry. METHODS: Data from the Clinical Cancer Registry Regensburg (Bavaria, Germany) were analyzed. Female patients with primary, nonmetastatic invasive breast cancer who were diagnosed between 2000 and 2012 (n = 7421) were included. HR-status was available in 97.4 % (n = 7229) of the patients. This data set (n = 7229) was used for subsequent statistical analyses. RESULTS: Since 2009, almost a complete rate of 99.6 % of analyzed HR-status was achieved. In sum, 85.8 % of the patients (n = 6199) were HR-positive, whereas 14.2 % (n = 1030) were HR-negative. Overall, 85.3 % (n = 5285) of HR-positive patients received ET either alone or in combination with chemotherapy (CHT) and/or trastuzumab. The majority of premenopausal patients received CHT plus ET (716 patients, 52.3 %). In postmenopausal patients, the most frequent systemic therapy was ET alone (2670 patients, 55.3 %). Best overall survival (OS) was found in HER2-/HR-positive patients receiving CHT plus ET plus trastuzumab (7-year OS rate of 97.2 % in premenopausal patients versus 86.9 % in postmenopausal patients). Premenopausal patients had a reduced benefit from additional CHT than postmenopausal patients. Premenopausal patients receiving only ET had a 7-year OS rate of 95.3 % compared to 92.7 % of patients receiving CHT plus ET. In contrast, postmenopausal patients treated with CHT plus ET had a 7-year OS rate of 84.0 % in comparison with those patients receiving only ET with a 7-year OS rate of 81.7 %. CONCLUSIONS: Analysis of HR in patients with early breast cancer achieved a very high quality in recent years. The vast majority of HR-positive patients received ET, and this guideline-adherent use improved OS. Inverse effects of the CHT plus ET combination in premenopausal versus postmenopausal patients and a still existing minority of patients not receiving guideline-adherent treatment should be further investigated in future studies.

Preoperative anemia is associated with adverse outcome in patients with urothelial carcinoma of the bladder following radical cystectomy.

PURPOSE: Radical cystectomy (RC) can be associated with significant blood loss, whereas many patients are presenting with anemia preoperatively. To date, there is a lack of data addressing the impact of preoperative anemia (PA) on survival of patients undergoing RC for urothelial carcinoma of the bladder (UCB). METHODS: This retrospective multicenter study includes 684 patients with UCB undergoing RC with pelvic lymph node dissection. The median follow-up was 50 (IQR 29,78) months. Anemia was defined in line with the WHO classification (hemoglobin (Hb): male ≤13 g/dL, female ≤12 g/dL) and based on contemporary gender- and age-adjusted classification (Hb: white male aged <60 years: ≤13.7 g/dL; ≥60 years: ≤13.2 g/dL; white female of all ages ≤12.2 g/dL). Univariable and multivariable Cox regression analyses were used to assess the effects of PA on oncological outcomes. RESULTS: A total of 269 (39.3 %) and 302 (44.2 %) patients were anemic according to the WHO classification versus contemporary classification. Age, increased ECOG performance status, advanced tumor stages, lymph node metastasis, positive surgical margin and anemia were associated with disease recurrence (DR), cancer-specific mortality (CSM) and all-cause mortality (ACM). In multivariable analysis, anemia was an independent predictor of DR, CSM and ACM (WHO and/or contemporary classification). Blood transfusion was significantly associated with ACM in both classifications of anemia. CONCLUSIONS: PA is significantly associated with worse oncological outcome in patients undergoing RC. Based on the additional unfavorable influence of blood transfusion, this emphasizes the importance of early diagnosis and correction of anemia and implementation of alternative methods of blood volume management.

The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence.

PURPOSE: To predict biochemical recurrence respecting the natural course of pT2 prostate cancer with positive surgical margin (R1) and no adjuvant/neoadjuvant therapy. METHODS: A multicenter data analysis of 956 patients with pT2R1N0/Nx tumors was performed. Patients underwent radical prostatectomy between 1994 and 2009. No patients received neoadjuvant or adjuvant therapy. All prostate specimens were re-evaluated according to a well-defined protocol. The association of pathological and clinical features, in regard to BCR, was calculated using various statistical tests. RESULTS: With a mean follow-up of 48 months, BCR was found in 25.4 %. In univariate analysis, multiple parameters such as tumor volume, PSA, Gleason at positive margin were significantly associated with BCR. However, in multivariate analysis, Gleason score (GS) of the prostatectomy specimen was the only significant parameter for BCR. Median time to recurrence for GS ≤ 6 was not reached; 5-year BCR-free survival was 82 %; and they were 127 months and 72 % for GS 3+4, 56 months and 54 % for GS 4 + 3, and 27 months and 32 % for GS 8-10. The retrospective approach is a limitation of our study. CONCLUSIONS: Our study provides data on the BCR in pT2R1-PCa without adjuvant/neoadjuvant therapy and thus a rationale for an individual's risk stratification. The data support patients and physicians in estimating the individual risk and timing of BCR and thus serve to personalize the management in pT2R1-PCa.

Guideline concordant therapy prolongs survival in HER2-positive breast cancer patients: results from a large population-based cohort of a cancer registry.

Even though randomized controlled clinical trials demonstrated improved survival by adjuvant trastuzumab treatment of HER2-positive breast cancer patients, data on its effect in clinical routine are scarce. This study evaluated the use and efficacy of trastuzumab in routine treatment of HER2-positive breast cancer patients. Data from the clinical cancer registry Regensburg (Germany) were analyzed. The present study investigated 6,991 female patients with primary invasive breast cancer. In premenopausal HER2-positive patients a considerable increase of trastuzumab therapy was observed from 58.1% in 2006 to 90.9% in 2011, whereas in postmenopausal patients trastuzumab was rather used on a constant rate of 49.1%. Best overall survival (OS) was found in HER2/steroid hormone receptor-positive patients receiving guideline concordant treatment with trastuzumab plus chemotherapy (CHT) plus antihormone therapy (AHT) with a 7-year OS rate of 96% compared to the non-trastuzumab group with a 7-year OS rate of 92%. In multivariable analysis, HER2-positive patients treated with CHT or AHT who did not get trastuzumab, had a worse 7-year OS (65%, P = 0.006 versus 79%, P = 0.017) than the control groups. This population-based study demonstrated that guideline concordant use of adjuvant trastuzumab improves OS for HER2-positive breast cancer patients treated in routine clinical care.

[Clinical and epidemiological cancer registries: two complementary sources of information on cancer incidence]. / Klinische und epidemiologische Krebsregister : Zwei sich ergänzende Informationsquellen zum Krebsgeschehen.

The law for the development of early cancer detection and quality assurance by clinical cancer registries regulates the duties, the funding, and the functions of the clinical cancer registries and thereby the cooperation between epidemiological and clinical registries. The necessary regulations and interfaces are described here. The progress in new concepts of cancer registration is triggered by fundamental changes in oncological care such as the increasing use of high-quality guidelines and the certification of oncological health-care units.

Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry.

The proliferation marker Ki-67 is one of the most controversially discussed parameters for treatment decisions in breast cancer patients. The purpose of this study was to evaluate the routine use and value of Ki-67 as a prognostic marker, and to analyze the associations between Ki-67 and common histopathological parameters in the routine clinical setting. Data from the clinical cancer registry Regensburg (Bavaria, Germany) were analyzed. Within the total data pool of 4,692 female patients, who had been diagnosed between 2005 and 2011, in 3,658 cases Ki-67 was routinely determined. Thus, a total of 3,658 patients with invasive breast cancer were included in the present study and used for statistical analysis. Ki-67 expression was associated with the common histopathological parameters. The strongest correlation was found between grading and Ki-67 (P < 0.001). In terms of survival analyses, Ki-67 was categorized into five categories (reference category Ki-67 ≤15 %) due to a nonlinear relationship to overall survival (OS). In multivariable analysis, Ki-67 was an independent prognostic parameter both for disease-free survival (DFS) (Ki-67 > 45 %, HR = 1.96, P = 0.001) as well as for OS (Ki-67: 26-35 %, HR = 1.71, P = 0.017; Ki-67: 36-45 %, HR = 2.05, P = 0.011; Ki-67 > 45 %, HR = 2.06, P = 0.002) independent of common clinical and histopathological factors. The 5-year DFS (OS) rate was 86.7 % (89.3 %) in patients with a Ki-67 value ≤15 % compared to 75.8 % (82.8 %) in patients with a Ki-67 value >45 %. Based on the data from a large cohort of a clinical cancer registry, it was demonstrated that Ki-67 is frequently determined in routine clinical work. Ki-67 expression is associated with common histopathological parameters, but is an additional independent prognostic parameter for DFS and OS in breast cancer patients. Future work should focus on standardization of Ki-67 assessment and specification of its role in treatment decisions.

Utility of immunohistochemistry markers in the interpretation of post-high-intensive focussed ultrasound prostate biopsy cores.

PURPOSE: To overcome the difficulties in the interpretation of postoperative tumor obtaining biopsy cores for patients who treated their prostate cancer with high-intensity focussed ultrasound (HIFU) therapy. METHODS: The H&E slides of 58 patients with residual prostate cancer after HIFU treatment were systematically reviewed. Correlation between the pathologist's findings and immunohistochemical expression of MIB-1, alpha-Methyl-Co-Racemase and 34ßE-12 staining was analyzed. RESULTS: Mean time from treatment to biopsy was 40.2 (8-208) weeks. The expert review of the H&E slides identified 40 patients with viable carcinoma in the post-HIFU biopsy cores. 18 patients were revised to necrosis-only-tumors. These biopsies were performed not later than 16 weeks after HIFU treatment (median 10.9 weeks, range 8-14). Both MIB-1 and AMACR staining displayed significant differential expression in viable carcinoma (p < 0.001) compared to necrosis tumors. Referring to viable carcinoma tissue, AMACR staining index was significantly rising, the longer treatment dated back from biopsy (p < 0.002). In this context, 34-ß-E12 stained negative through all tumor areas and positive in the majority (85%) of the surrounding non-neoplastic epithelium. CONCLUSIONS: AMACR and MIB-1 reliably differentiate viable carcinoma from a process of ongoing irreversible necrosis in early post-HIFU prostate biopsy cores and therefore proposed-in addition with 34 beta-E12-as useful markers exposing suspicious tumor foci in difficult cases.

Potentially clinically relevant prostate cancer is found more frequently after complete than after partial histopathological processing of radical cystoprostatectomy specimens.

Incidental prostate cancer is often found in cystoprostatectomy specimens. The presence of a clinically significant tumour has an impact on follow-up strategies. In prostatectomy specimen for prostate cancer, whole-mount sections improve diagnostic accuracy. The present study compares detection of incidental prostate cancer in complete to routine processing. We included 295 consecutive patients who underwent radical cystoprostatectomy. Between 01/1995 and 12/2003 (period I), specimens of 129 patients were partially processed, whereas between 01/2004 and 03/2009 (period II), specimens of 166 patients were completely processed. Incidental prostate cancer was detected overall in 91 (30.8 %) patients. Prostate cancer was detected in 24 (18.6 %) patients in period 1 and in 67 (40.4 %) patients in period 2 (p < 0.001). Potentially clinically significant prostate cancer was detected in 12 (9.2 %) and 29 (17.5 %) patients, respectively (p = 0.044). Complete embedding and processing of cystoprostatectomy specimen yield significantly more potentially clinically relevant prostate cancers. The present data suggest that notably in younger men the specimens should be completely processed.

Direct improvement of quality of life using a tailored quality of life diagnosis and therapy pathway: randomised trial in 200 women with breast cancer.

BACKGROUND: Despite thousands of papers, the value of quality of life (QoL) in curing disease remains uncertain. Until now, we lacked tools for the diagnosis and specific treatment of diseased QoL. We approached this problem stepwise by theory building, modelling, an exploratory trial and now a definitive randomised controlled trial (RCT) in breast cancer, whose results we report here. METHODS: In all, 200 representative Bavarian primary breast cancer patients were recruited by five hospitals and treated by 146 care professionals. Patients were randomised to either (1) a novel care pathway including diagnosis of 'diseased' QoL (any QoL measure below 50 points) using a QoL profile and expert report sent to the patient's coordinating practitioner, who arranged QoL therapy consisting of up to five standardised treatments for specific QoL defects or (2) standard postoperative care adhering to the German national guideline for breast cancer. The primary end point was the proportion of patients in each group with diseased QoL 6 months after surgery. Patients were blinded to their allocated group. RESULTS: At 0 and 3 months after surgery, diseased QoL was diagnosed in 70% of patients. The QoL pathway reduced rates of diseased QoL to 56% at 6 months, especially in emotion and coping, compared with 71% in controls (P=0.048). Relative risk reduction was 21% (95% confidence interval (CI): 0-37), absolute risk reduction 15% (95% CI: 0.3-29), number needed to treat (NNT)=7 (95% CI: 3-37). When QoL therapy finished after successful treatment, diseased QoL often returned again, indicating good responsiveness of the QoL pathway. CONCLUSION: A three-component outcome system including clinician-derived objective, patient-reported subjective end points and qualitative analysis of clinical relevance was developed in the last 10 years for cancer as a complex intervention. A separate QoL pathway was implemented for the diagnosis and treatment of diseased QoL and its effectiveness tested in a community-based, pragmatic, definitive RCT. While the pathway was active, it was effective with an NNT of 7.

Immunohistochemical marker panel differentiates between the three most common subtypes of renal cell carcinoma independent from histomorphologic criteria.

To develop a reliable immunohistochemical marker panel differentiating between the three most common renal cell carcinoma (RCC) subtypes without inclusion of histomorphologic criteria we investigated protein expression of vimentin, glutathione S-transferase alpha (GST-α), CD10, CD117 (C-KIT), carbonic anhydrase 2 (CAII), parvalbumin, alpha-methyl-CoA-racemase (AMACR), and cytokeratin-19 (CK 19) in 65 age and stage matched trios of clear cell carcinoma, papillary renal carcinoma and chromophobe renal carcinoma using tissue microarrays. All markers displayed significant differential expression among the subtypes (p < 0.001) except CAII (p = 0.192). According to positive (LR+) and negative (LR-) likelihood ratio, six markers (CD10, GST-α, AMACR, CK19, C-KIT and arvalbumin) demonstrated acceptable or good values to detect certain subtypes of RCC, but failed in terms of ruling out the respective subtypes. Based on the individual performance of these six markers, we combined them and reviewed each single case: LR+ for detection of clear cell RCC considerably increased by application of the six marker panel, but did not exceed 10. LR- was still >0.1; in case of papillary RCC LR+ rose beyond 10, but LR- remained >0.1. LR+ for recognition of chromophobe RCC rose far beyond 10, but LR- remained >0.1. Thus, the panel can reliably recognize two main RCC subtypes without inclusion of histomorphologic features. Further improvement is needed for consistent detection of clear cell RCC and for dependably ruling out all three main subtypes as well as identification of rare variants and benign lesions like oncocytoma.

[Precursor lesions: epidemiology--is there enough evidence?]. / Vorläuferläsionen: Epidemiologie--sind Aussagen möglich?

Exact knowledge of the incidence and prevalence of precursor lesions of malignant diseases would be of great value for the precise evaluation of their potential clinical-pathological progression and therefore for planning and intervention in individual cases and also for planning and evaluation of prevention and early detection strategies. Concerning these high expectations it is surprising that precise data on incidence, prevalence and the exact risk for progression are lacking. Sources of data (cancer registries, specific registries for precursor lesions, early detection programs and specific designed studies) are analyzed concerning their validity and reliability. Imprecise and redundant terminology represents a crucial reason for the lack of data availability.

[Familial non-polyposis colorectal carcinoma (Lynch syndrome) in Germany - analysis of information, advisory service and family screening]. / "Familiärer Darmkrebs" in Deutschland. Eine Analyse von Information, Beratung und Vorsorge in Familien mit Lynch-Syndrom.

BACKGROUND: Lynch syndrome is associated with an increased incidence of colorectal carcinomas and extracolonic neoplasms. Patients fulfilling the "Revised Bethesda criteria" or the Amsterdam Citeria I or II should be screened for DNA mismatch repair deficiency. Mutation carriers and high risk individuals should undergo intensified annual screening, as recommended by the S3 guideline for colorectal carcinoma. PATIENTS AND METHODS: All families of the Regensburger study group with a verified mutation were included in this study. Data acquisition was conducted by telephone interviews. We determined the number of family members who had been informed about the diagnosis and how many of them participated in the recommended screening program. Additionally, an information letter was sent to family members providing information about the opportunity of a predictive mutation analysis. RESULTS: 90 family members of 12 families with a total of 42 carcinomas and a mean age of tumor diagnosis of 41.3 years were included. At the beginning of the study 97.4 % of the family members were informed about the diagnosis. In the course of the study the number of family members participating in the mutation analysis increased from 29.5 % to 42.3 %. The number of index patients complying with the recommended screening program was over 90 %, in contrast to the number of family members which varied between 30 - 60 %. CONCLUSIONS: Relatives of index patients are not sufficiently informed about the importance of predictive testing and the re-commended surveillance guidelines. An insufficient implementation of Lynch syndrome specific aspects of the S3-guideline can be assumed. For an improved implementation barriers of physicians' adherence must be systemically analyzed. It is essential for these high-risk families to establish and enforce awareness in order to create intensified surveillance.

[Social gradient of PSA screening? 8 years follow up from the cancer registry of the tumor center in Regensburg]. / Mittelstandsorientierung des PSA-Screenings? : 8-Jahres-Nachsorgedaten des Tumorregisters Regensburg.

BACKGROUND: Prostate cancer is the most frequent male cancer. In Germany most tumors are detected by PSA testing. Data on the long-term survival of patients with localized early prostate carcinoma are insufficient. We examined the relative survival of the patients with organ-defined prostate cancer (TNM T1-2N0M0, UICC I-II) compared to the standardized age-adjusted rates of the normal male population. METHODS: Epidemiological and clinical data from 4,124 patients with prostate cancer diagnosed from 1998 to 2007 were extracted from the cancer registry of the tumor center in Regensburg; 2,087 patients suffered from localized early cancer. Kaplan-Meier analysis was used to estimate the overall survival rates in the patient cohorts irrespective of primary cancer therapy. These rates were adjusted for the expected survival rates in a comparable set of individuals from the general population. RESULTS: Eight years after diagnosis, patients with stage I and II localized prostate cancer had an approximately 10% relative increase in survival compared with the normal male population. This relative increase in survival was already observed 3 years after diagnosis. CONCLUSION: Patients with stage I-II localized prostate cancer have improved survival compared with the normal male population. This finding cannot be explained solely by the administration of prostate cancer treatments, which do not affect survival until 8-10 years after treatment, suggesting that men who participate in PSA testing may have a better overall health status. Another hypothesis may be a social gradient of PSA testing in Germany.

[Renal pelvic carcinoma: a different urothelial tumor?]. / Nierenbeckenkarzinom: Ein anderer Urotheltumor?

Urothelial tumors of the renal pelvis and the ureter do not differ from those of the urinary bladder concerning histopathological phenotypes. However, with respect to tumor biology there are relevant differences between the two tumor locations. The originating tissue (urothelium) of the bladder and of the upper urinary tract varies significantly with respect to developmental origin, morphology and physiological function. Specific pathways of tumorigenesis (e.g. hereditary non-polyposis colorectal cancer, HNPCC) and tumor propagation (seeding) are described for tumors of the upper urinary tract. Clinical epidemiological data indicate specific correlations between the two tumor locations.

Different proliferative and survival capacity of CLL-cells in a newly established in vitro model for pseudofollicles.

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B-lymphocytes that manifests in a variety of clinical courses. The accumulation of CLL-cells is primarily caused by defective apoptosis; however, a higher proliferative capacity has also been found to correlate with poorer prognostic factors. Proliferating CLL-cells are confined to specialized structures called pseudofollicles, which contain CLL-cells, T-lymphocytes, and stromal cells. We established an in vitro model for pseudofollicles to characterize the behavior of CLL-cells in relation to clinical courses with different outcomes. Only CLL-cells from progressive clinical cases were inducible to proliferate by a combination of soluble CD40L/IL-2/IL-10 in co-culture with stromal cells. Proliferating CLL-cells showed a higher and more extensive expression of antigens, which are important in T-B-cell interactions such as CD40, MHC II, and adhesion molecules. IL-4 increased interferon regulatory factor-4 expression and induced a specific immunophenotype, which may imply plasmacytic differentiation. Furthermore, it was shown that co-cultured stromal cells protected CLL-cells from apoptosis. CLL-cells from clinically indolent cases had a far worse survival rate in medium than the cells from poor prognostic cases. Thus, we can assume that not only a different resistance to apoptosis, but also proliferation contributes to the progression of CLL resulting in bone marrow failure with thrombocytopenia and anemia.