Trends in specialized palliative care referrals at an oncology center from 2007 to 2019.

BACKGROUND: Early referral to palliative care, at least 3 months before death, should be a standard of care in oncological practice. Real life data in this setting are invaluable since they provide a picture of everyday practice and serve as the basis for future improvements. METHODS: We conducted a retrospective cohort assessment of all patients referred to our specialized palliative care (SPC) services at the Institute of Oncology, Ljubljana, Slovenia. Our analysis includes patient referrals between 2007 and 2019. RESULTS: During the above-specified time period of 13 years, 3234 patients were referred for SPC services at our institution. The median age at SPC referral was 67 years. The majority of patients (63%) were assessed only once, while 31% of patients were seen on more than one occasion. Median time from SPC referral to death was 25 days for the whole group. 1693 patients (52.7%) were referred to SPC in the last 30 days before death, 785 (25.8%) patients between 31 and 90 days and 652 (21.4%) patients more than 3 months before death. Neither age nor sex correlated with the duration of referral time. However, there was a strong correlation between the year of referral to palliative care and the duration of palliative care service (ρ = 0.19, p < 0.001). The median referral to death interval for lymphoma patients and breast cancer patients were 15 and 18 days, respectively, and the median referral to death interval for colorectal cancer and lung tumor patients were 34 and 26 days before death, respectively. CONCLUSION: Throughout the existence of our SPC services we have observed a positive trend in the number of referrals, a lengthening of time between referral and death, as well as an increase in the proportion of patients with an early referral to SPC (more than 3 months before death). Neither age nor sex correlated with the length of referral time.

Long-term outcomes of high dose treatment and autologous stem cell transplantation in follicular and mantle cell lymphomas - a single centre experience.

BACKGROUND: Advanced follicular lymphoma (FL) and mantle cell lymphoma (MCL) are incurable diseases with conventional treatment. The high dose treatment (HDT) with autologous stem cell transplantation (ASCT), however, offers a certain proportion of these patients the prospect of a prolonged disease-free and overall survival. The aim of this study was to investigate the event free survival (EFS) and overall survival (OS) in patients with FL and MCL treated with ASCT. PATIENTS AND METHODS: Seventeen patients with FL and 29 patients with MCL were included, 15 of them were transplanted to consolidate the response to second line treatment and 24 to consolidate their first remission, respectively. All were conditioned with total body irradiation (TBI) and high dose cyclophosphamide between 2006 and 2014 and all were transplanted with peripheral blood stem cells. RESULTS: The estimated 5-year OS for FL was 87.8% (95% confidence interval [CI] 59.5%-96.8%) and for MCL 79.3% (95% CI 56.1%-91.1%), respectively. The estimated 5-year EFS for FL was 76.0% (95% CI 48.0%-90.3%) and for MCL 69.8% (95% CI 45.5%-84.8%), respectively. There were no secondary hematological malignancies observed in either group. CONCLUSIONS: Based on above results, the ASCT with TBI is a good treatment option in terms of long-term survival for patients with follicular and mantle cell lymphoma demonstrating a relatively low rate of late toxicities and secondary malignancies.

Granulomatosis after autologous stem cell transplantation in nonHodgkin lymphoma - experience of single institution and a review of literature.

BACKGROUND: Sarcoidosis before and after treatment of malignancy is an important differential diagnosis that has to be distinguished from lymphoma. PATIENTS AND METHODS: Hodgkin lymphoma, diffuse large B-cell lymphoma and aggressive follicular lymphoma are being staged and treatment effect is evaluated with PET-CT. We report three cases of aggressive lymphoma after high dose therapy and autologous stem cell transplantation with positive lymph nodes on PET-CT, which were histologically diagnosed as sarcoidosis/granulomatosis. In the literature, we found that false positive lymph nodes were more common after allogeneic than after autologous transplantation. CONCLUSIONS: Post-treatment PET-CT positive lymph nodes should always be examined histologically prior to any further treatment decision to avoid unnecessary toxic procedures.

Outcome of severe infections in afebrile neutropenic cancer patients.

BACKGROUND: In some neutropenic cancer patients fever may be absent despite microbiologically and/or clinically confirmed infection. We hypothesized that afebrile neutropenic cancer patients with severe infections have worse outcome as compared to cancer patients with febrile neutropenia. PATIENTS AND METHODS: We retrospectively analyzed all adult cancer patients with chemotherapy-induced neutropenia and severe infection, who were admitted to the Intensive Care Unit at our cancer center between 2000 and 2011. The outcome of interest was 30-day in-hospital mortality rate. Association between the febrile status and in-hospital mortality rate was evaluated by the Fisher's exact test. RESULTS: We identified 69 episodes of severe neutropenic infections in 65 cancer patients. Among these, 9 (13%) episodes were afebrile. Patients with afebrile neutropenic infection presented with hypotension, severe fatigue with inappetence, shaking chills, altered mental state or cough and all of them eventually deteriorated to severe sepsis or septic shock. Overall 30-day in-hospital mortality rate was 55.1%. Patients with afebrile neutropenic infection had a trend for a higher 30-day in-hospital mortality rate as compared to patients with febrile neutropenic infection (78% vs. 52%, p = 0.17). CONCLUSIONS: Afebrile cancer patients with chemotherapy-induced neutropenia and severe infections might have worse outcome as compared to cancer patients with febrile neutropenia. Patients should be informed that severe neutropenic infection without fever can occasionally occur during cancer treatment with chemotherapy.

Immunotoxin - a new treatment option in patients with relapsed and refractory Hodgkin lymphoma.

BACKGROUND: Even though Hodgkin lymphoma is a highly curable disease, some of the patients have either a refractory disease or experience a relapse following a successful primary therapy. Durable responses and remissions in patients with relapsed or refractory disease may be achieved in approximately one-half with salvage chemotherapy followed by high dose chemotherapy (HDT) and autologous hematopoietic cell rescue (SCT). On the other hand, patients who relapse after HDT and autologous SCT or those who have failed at least two prior multi-agent chemotherapy regimens and are not candidates for HDT have limited treatment options. CONCLUSIONS: A new treatment option in this population is an immunotoxin Brentuximab vedotin composed of a CD30 directed antibody linked to the antitubulin agent monomethyl auristatin E. It has demonstrated a substantial effectiveness and an acceptable toxicity. In the pivotal study, the overall response rate was 75% with 34% of complete remissions. The median durations of response were 20.5 and 6.7 months for those with complete remission and all responding patients, respectively. The median overall survival was 40.5 months (3-years overall survival 54%) and the median progression-free survival 9.3 months. The most common non-hematologic toxicities were peripheral sensory neuropathy, nausea, and fatigue while the most common severe side effects were neutropenia, thrombocytopenia, anemia, and peripheral sensory neuropathy.

Clonality analysis of lymphoid proliferations using the BIOMED-2 clonality assays: a single institution experience.

BACKGROUND: Clonality determination in patients with lymphoproliferative disorders can improve the final diagnosis. The aim of our study was to evaluate the applicative value of standardized BIOMED-2 gene clonality assay protocols for the analysis of clonality of lymphocytes in a group of different lymphoid proliferations. MATERIALS AND METHODS: With this purpose, 121 specimens from 91 patients with suspected lymphoproliferations submitted for routine diagnostics from January to December 2011 were retrospectively analyzed. According to the final diagnosis, our series comprised 32 cases of B-cell lymphomas, 38 cases of non-Hodgkin's T-cell lymphomas and 51 cases of reactive lymphoid proliferations. Clonality testing was performed using the BIOMED-2 clonality assays. RESULTS: The determined sensitivity of the TCR assay was 91.9%, while the sensitivity of the IGH assay was 74.2%. The determined specificity of the IGH assay was 73.3% in the group of lymphomas and 87.2% in the group of reactive lesions. The determined specificity of the TCR assay was 62.5% in the group of lymphomas and 54.3% in the group of reactive lesions. CONCLUSIONS: In the present study, we confirmed the utility of standardized BIOMED-2 clonality assays for the detection of clonality in a routine diagnostical setting of non-Hodgkin's lymphomas. Reactions for the detection of the complete IGH rearrangements and reactions for the detection of the TCR rearrangements are a good choice for clonality testing of a wide range of lymphoid proliferations and specimen types while the reactions for the detection of incomplete IGH rearrangements have not shown any additional diagnostic value.

Detection performance and prognostic value of initial bone marrow involvement in diffuse large B-cell lymphoma: a single centre 18F-FDG PET/CT and bone marrow biopsy evaluation study.

BACKGROUND: Detection of bone marrow involvement (BMI) in diffuse large B-cell lymphoma (DLBCL) typically relies on invasive bone marrow biopsy (BMB) that faces procedure limitations, while 18F-FDG PET/CT imaging offers a noninvasive alternative. The present study assesses the performance of 18F-FDG PET/CT in DLBCL BMI detection, its agreement with BMB, and the impact of BMI on survival outcomes. PATIENTS AND METHODS: This retrospective study analyzes baseline 18F-FDG PET/CT and BMB findings in145 stage II-IV DLBCL patients, evaluating both performance of the two diagnostic procedures and the impact of BMI on survival. RESULTS: DLBCL BMI was detected in 38 patients (26.2%) using PET/CT and in 18 patients (12.4%) using BMB. Concordant results were seen in 79.3% of patients, with 20.7% showing discordant results. Combining PET/CT and BMB data, we identified 29.7% of patients with BMI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PET/CT for detecting DLBCL BMI were 88.4%, 100%, 100%, 95.3%, and 96.5%, respectively, while BMB showed lower sensitivity (41.9%) and NPV (46.8%). The median overall survival (OS) was not reached in any gender subgroup, with 5-year OS rates of 82% (total), 84% (female), and 80% (male) (p = 0.461), while different International Prognostic Index (IPI) groups exhibited varied 5-year OS rates: 94% for low risk (LR), 91% for low-intermediate risk (LIR), 84% for high-intermediate risk (HIR), and 65% for high risk (HR) (p = 0.0027). Bone marrow involvement did not impact OS significantly (p = 0.979). CONCLUSIONS: 18F-FDG PET/CT demonstrated superior diagnostic accuracy compared to BMB. While other studies reported poorer overall and BMI 5-year OS in DLBCL, our findings demonstrated favourable survival data.

Tumor vaccine composed of C-class CpG oligodeoxynucleotides and irradiated tumor cells induces long-term antitumor immunity.

BACKGROUND: An ideal tumor vaccine should activate both effector and memory immune response against tumor-specific antigens. Beside the CD8+ T cells that play a central role in the generation of a protective immune response and of long-term memory, dendritic cells (DCs) are important for the induction, coordination and regulation of the adaptive immune response. The DCs can conduct all of the elements of the immune orchestra and are therefore a fundamental target and tool for vaccination. The present study was aimed at assessing the ability of tumor vaccine composed of C-class CpG ODNs and irradiated melanoma tumor cells B16F1 followed by two additional injections of CpG ODNs to induce the generation of a functional long-term memory response in experimental tumor model in mice (i.p. B16F1). RESULTS: It has been shown that the functional memory response in vaccinated mice persists for at least 60 days after the last vaccination. Repeated vaccination also improves the survival of experimental animals compared to single vaccination, whereas the proportion of animals totally protected from the development of aggressive i.p. B16F1 tumors after vaccination repeated three times varies between 88.9%-100.0%. Additionally, the long-term immune memory and tumor protection is maintained over a prolonged period of time of at least 8 months. Finally, it has been demonstrated that following the vaccination the tumor-specific memory cells predominantly reside in bone marrow and peritoneal tissue and are in a more active state than their splenic counterparts. CONCLUSIONS: In this study we demonstrated that tumor vaccine composed of C-class CpG ODNs and irradiated tumor cells followed by two additional injections of CpG ODNs induces a long-term immunity against aggressive B16F1 tumors.

Limited efficacy of pixantrone in refractory diffuse large B-cell lymphoma.

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with poor outcomes in patients ineligible for autologous stem cell transplantation. In this setting, novel treatment approaches are urgently required and the innovative agent pixantrone has shown some promising results in terms of disease-free and overall survival (OS). The present study retrospectively analyzed 12 patients routinely treated with pixantrone in monotherapy or in combinations at the Institute of Oncology Ljubljana, Slovenia, between January 2016 and October 2018. All 12 patients had refractory lymphoma to last treatment and a large proportion of them had other high risk features (high proliferation index, high disease stage, high international prognostic index (IPI) score, high percentage of primary refractory disease and high percentage of refractoriness to anthracyclines) at initiation of pixantrone. All patients progressed during treatment and none of the patients were alive at the time of analysis due to progressive lymphoma. Pixantrone specific median OS was 3.5 months (range, 0.5-10 months). A somewhat superior median OS (P=0.065) was observed in patients primarily sensitive to anthracyclines. Pixantrone has shown only limited efficacy in the present real world study comparable to the results of another real world UK retrospective analysis and substantially worse than the efficacy observed in the PIX301 registration trial. Therefore, an appropriate selection of patients for this treatment is crucial. Despite the limited experience due to a small number of patients, it was recommended to consider only patients with relapsed (and not refractory) disease, patients with non-primary refractory disease and those with fewer lines of prior therapy.

Sensitivity and reproducibility of conventional qualitative and quantitative PCR assays for detection of the t(14;18)(q32;q21) chromosomal translocation in biopsy material from patients with follicular lymphoma.

Follicular lymphoma (FL) is characterized by the t(14;18)(q32;q21) chromosomal translocation which can be detected by polymerase chain reaction (PCR) in approximately 70% of cases. The aim of our retrospective study was to evaluate the sensitivity and the reproducibility of both conventional qualitative and quantitative PCR assays for detection of the t(14;18)(q32;q21) chromosomal translocation in biopsy material. Fifty-seven formalin-fixed, paraffin-embedded tumor lymph node (LN) specimens from 50 patients with FL were included in the study. Qualitative PCR was performed with primer sets specific for the MBR, far3'-MBR and the mcr regions, respectively. Quantitative PCR was performed using the LightCycler instrument and the LightCycler - t(14;18) Quantification Kit (MBR). The overall detection rate of the t(14;18) in our study (52.6%) was in accordance with the literature. Of the t(14;18)-positive cases, 49.1% had breakpoints within the MBR and only 3.5% had breakpoints within the mcr. The most sensitive method was LightCycler-based PCR with a detection rate of 47.4%, followed by MBR1,2 assay (43.9%). We observed good agreement between qualitative MBR1,2 and quantitative LightCycler-based assay with a slightly higher detection rate of the quantitative method. The sensitivities of both methods were in accordance with results from other studies. Since LightCycler-based assay detects only breakpoints within the MBR, qualitative PCR should be employed in routine diagnostic settings for detection of breakpoints within the mcr and far3'-MBR regions.

Comparison of the algorithms classifying the ABC and GCB subtypes in diffuse large B-cell lymphoma.

Different immunohistochemical algorithms for the classification of the activated B-cell (ABC) and germinal center B-cell (GCB) subtypes of diffuse large B-cell lymphoma (DLBCL) are applied in different laboratories. In the present study, 127 patients with DLCBL were investigated, all treated with rituximab and cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP) or CHOP-like regimens between April 2004 and December 2010. Multi-tumor tissue microarrays were prepared and were tested according to 4 algorithms: Hans; modified Hans; Choi; and modified Choi. For 39 patients, the flow cytometric quantification of CD19 and CD20 antigen expression was performed and the level of expression presented as molecules of equivalent soluble fluorochrome units. The Choi algorithm was demonstrated to be prognostic for OS and classified patients into the GCB subgroup with an HR of 0.91. No difference in the expression of the CD19 antigen between the ABC and GCB groups was observed, but the ABC subtype exhibited a decreased expression of the CD20 antigen compared with the GCB subtype.

A single-center report on clinical features and treatment response in patients with intestinal T cell non-Hodgkin's lymphomas.

Intestinal T cell lymphomas are rare, but highly aggressive in their clinical course. Generally diagnosed in advanced stages and presenting as surgical emergencies, they also respond poorly to standard anti-lymphoma therapies. Since these lymphomas are still not well characterized, we aimed our retrospective research at the evaluation of clinical features and treatment response in patients with intestinal T cell lymphomas diagnosed between February 1996 and November 2004. Fifteen patients were identified from the Department of Pathology database at the Institute of Oncology Ljubljana. Details of history, physical examination, staging investigation, treatment and outcome were taken from patient records. Ten (67%) patients had enteropathy-associated T cell lymphoma (EATL) and 5 (33%) had peripheral T cell lymphoma (PTCL). Surgery was performed on 11 patients with 8 cases on an emergency basis; all visible disease was resected in only 3 patients. In the continuation of treatment, all 15 patients received chemotherapy (predominantly CHOP). Six patients were treated with field radiotherapy as a part of the first treatment. In total, complete response was achieved in 6 patients (40%) with a median duration of 5.3 months (range, 2 to 12 months), stable disease in 3 patients (20%), and progressive disease in 6 patients (40%). Results were better in patients with limited disease. The most frequent treatment complications were small bowel perforation, obstruction, gastrointestinal bleeding, and infection. Even though some patients underwent second- and third-line treatment, 13 (87%) of the total 15 patients died from progressive disease or complications of treatment. The actuarial 1- and 5-year survival rates were 33% and 9%, respectively. The prognosis and standard treatment of patients with intestinal T cell lymphomas are unsatisfactory with only a few long-term survivors. Therefore, earlier diagnosis and the development of more effective treatments are urgently required to improve the prospects of these patients.

Changes in expression of genes involved in antitumor immunity in mice vaccinated with tumor vaccine composed of irradiated syngeneic tumor cells and CpG oligodeoxynucleotides.

In our previous studies, it has been demonstrated that in more than 80% of mice long-lasting antitumor immunity has been established following intraperitoneal (i.p.) vaccination with tumor vaccine composed of irradiated syngeneic tumor cells and CpG ODNs class C. The aim of this study was, therefore, to investigate molecular mechanisms through which this vaccine triggers the immunity and to define genes particularly involved in this process. Changes in gene expression were followed in mononuclear cells isolated from peritoneal lavages, spleens and bone marrow samples. The expression of 84 genes significant for T-cell and B-cell activation as well as genes engaged in activation of macrophages, NK cells and DCs was determined using the RT2- Profiler PCR array. It has been observed that this tumor vaccine induces the up-regulation of genes involved in activation, proliferation and survival of memory T-cells (Cd8a, Cd8b1, Prlr, Was, Cxcl12, Il12, Sftpd, Tnfrsf13c, Il15, Il18), and prevents the activation of genes involved in generation of Treg and induction of immune tolerance (Sit1, Sla2, Cd1d1, Pdcd1lg2, Pawr, Socs5, Il27, Il4). We may conclude based on results of gene expression analysis, that tumor vaccine fine-tunes the proportion of cytotoxic to regulatory lymphocytes having an important impact on the induction and maintenance of memory cells in bone marrow.

The impact of FcγRIIa and FcγRIIIa gene polymorphisms on responses to RCHOP chemotherapy in diffuse large B-cell lymphoma patients.

Rituximab is a monoclonal antibody routinely used in the treatment of B-cell non-Hodgkin lymphomas. It mediates antibody-dependent cellular cytotoxicity of B lymphocytes by bridging them with Fcγ receptors (FcγR) on effector cells. Several polymorphisms in the FcγR genes have been identified to influence rituximab binding to FcγR, thus altering its antitumor effect in indolent lymphomas. In the present study, the impact of FcγRIIa and FcγRIIIa polymorphisms on the survival and response to immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone was evaluated in diffuse large B-cell lymphoma (DLBCL) patients. A total of 29 Slovenian DLBCL patients were studied. Genotyping was conducted for FcγRIIa-27, FcγRIIa-131, FcγRIIIa-48 and FcγRIIIa-158 polymorphisms. The median follow-up time was 29.7 months (range, 9.7-45.4 months). No significant impact of the genotypes was observed on the treatment response, progression-free or overall survival of DLBCL patients. There was a non-significant trend of an improved response to chemotherapy without additional irradiation in patients homozygous for Val at FCγIIIa-158 compared to Phe carriers. The findings of the present study indicate that FcγR polymorphisms have no influence on the survival of DLBCL patients.

Late-onset neutropenia following primary treatment of diffuse large B-cell lymphoma with rituximab-containing therapy.

Late-onset neutropenia (LON) following rituximab therapy is a recently recognized adverse effect occurring in various clinical settings. However, the true incidence and pathogenesis of this adverse effect are not fully understood. We retrospectively reviewed the medical records of 160 patients with diffuse large B-cell lymphoma (DLBCL) in complete remission (CR) following first-line treatment with rituximab-containing therapy. The incidence of LON was 26.9% (grade 1, 2, 3 and 4) and the incidence of severe LON (grade 3 and 4) was 7.5%. The risk factors for the occurrence of LON were not identified, and overall survival did not differ between patients who developed LON and those who did not. This study suggests that LON is a quite common complication to rituximab therapy. However, more studies are needed in order to elucidate the true mechanism behind and risk factors for LON.

Eleven years of experience with AIDS-related lymphomas at the Institute of Oncology Ljubljana.

Neoplastic diseases are currently recognized in more than 40% of HIV sero-positive patients, with AIDS-related lymphomas (ARL) being most common. A survey of the ARLs in patients attending our institute from 1998 to 2009 is given along with the clinical and pathological manifestations, treatment and outcomes. We conducted a retrospective chart review of patients treated for ARL between 1998 and 2009 at the Institute of Oncology Ljubljana. Patients were identified from the lymphoma database of our institute. Eight patients with ARL were diagnosed and treated at our Institute according to the then protocol for HIV sero-negative lymphoma patients. Seven patients received HAART. Six patients received prophylaxis for opportunistic infections and febrile neutropenia (FN), and 6 of them had at least one episode of FN. Seven patients are still alive and in complete remission 7-142 months after the diagnosis of ARL. One of the patients died of progressive lymphoma. The low incidence of ARL in the HIV-infected population, early stages at the presentation and the good response to treatment are not in accordance with the data from the literature. Whether this goes on account of the HAART treatment, prophylaxis for opportunistic infections and FN or a better follow-up of these patients remains to be answered. Also, the group is very small to make any definitive conclusions.

The predictive significance of CD20 expression in B-cell lymphomas.

BACKGROUND: In our recent study, we determined the cut-off value of CD20 expression at the level of 25, 000 molecules of equivalent soluble fluorochrome (MESF) to be the predictor of response to rituximab containing treatment in patients with B-cell lymphomas. In 17.5% of patients, who had the level of CD20 expression below the cut-off value, the response to rituximab containing treatment was significantly worse than in the rest of the patients with the level of CD20 expression above the cut-off value. The proportion of patients with low CD20 expression who might not benefit from rituximab containing treatment was not necessarily representative. Therefore the aim of this study was to quantify the CD20 expression in a larger series of patients with B-cell lymphomas which might allow us to determine more reliably the proportion of patients with the CD20 expression below the cut-off. METHODS: Cytological samples of 64 diffuse large B-cell lymphomas (DLBCL), 56 follicular lymphomas (FL), 31 chronic lymphocytic leukemias (CLL), 34 mantle cell lymphomas (MCL), 18 marginal zone lymphomas (MZL) and 15 B-cell lymphomas unclassified were analyzed for CD20 expression by quantitative four-color flow cytometric measurements using FACSCalibur flow cytometer (BD Biosciences). RESULTS: The range of CD20 expression in different B-cell lymphomas was very broad, varying from 2 737 to 115 623 MESF in CLL and 3 549 to 679 577 MESF in DLBCL. However, when we compared the CD20 expression in the groups of patients with DLBCL, FL, MCL, MZL, CLL and B-cell lymphomas unclassified, it was found to be significantly lower (p = 0.002) only in CLL but did not significantly differ in other lymphoma types (p = NS). Fifty-three out of 218 (24.3%) patients with B-cell lymphomas had the CD20 expression below the cut-off value. CONCLUSIONS: The CD20 expression in CLL is significantly lower than in most histological types of mature B-cell lymphomas in which it appears to be comparable. Approximately 25% of B-cell lymphoma patients have the CD20 expression below the cut-off value showing that the low CD20 expression might be more common than presumed from our previous study.

Effect of response quality and line of treatment with rituximab on overall and disease-free survival of patients with B-cell lymphoma.

BACKGROUND: The introduction of rituximab into the treatment of patients with non-Hodgkin's lymphomas has improved the overall response rate, as well as the response duration and the overall survival of patients with B-cell lymphomas. But only a few studies have addressed the question whether the better response (complete response) and the early introduction of rituximab into the treatment translate into the better survival. The aim of this retrospective study was to assess the potential relationship between either the quality of the response or the line of the rituximab treatment and the overall survival (OS) as well as the disease-free survival (DFS) of patients with B-cell lymphomas. PATIENTS AND METHODS.: In the study, we analysed treatment outcomes in patients with different histological types of B-cell lymphomas who were treated at the Institute of Oncology between 2003 and 2007 with rituximab and chemotherapy. We included only patients who had the level of CD20 expression assessed prior to the introduction of the treatment with quantitative flow-cytometric measurements. The OS and DFS were evaluated by Kaplan-Meier survival curves. RESULTS: One hundred and fourteen patients were enrolled in the study. Patients who achieved a complete response after the rituximab containing treatment had a significantly longer OS than those reaching a partial response (hazard ratio [HR], 0.34; 95% CI, 0.05 to 0.91, P = 0.0375) and than patients with stable (hazard ratio [HR], 0.11; 95% CI, 0.0002 to 0.033, P < 0.0001) or progressive disease (hazard ratio [HR], 0.09; 95% CI, 0.003 to 0.03, P < 0.0001). Patients who achieved a complete response (CR; n = 70; 61.4%) had also a significantly longer DFS (hazard ratio [HR], 0.26; 95% CI, 0.021 to 0.538, P = 0.0068) than those reaching only a partial response (PR; n = 17; 14.9%). Patients treated with rituximab as the first-line treatment (n = 50; 43.9%) had a significantly longer OS than those treated with rituximab for the first (hazard ratio [HR], 0.27; 95% CI, 0.106 to 0.645, P = 0.0036) or second relapse (hazard ratio [HR], 0.22; 95% CI, 0.078 to 0.5, P = 0.0006). Also the DFS of patients treated with rituximab as the first-line treatment (n = 46; 52.9%) was significantly longer (hazard ratio [HR], 0.32; 95% CI, 0.088 to 0.9, P = 0.0325) than in patients treated with rituximab for their first relapse (n = 25; 28.7%). CONCLUSIONS: These data indicate that a better response to rituximab therapy presumably translates into an improved OS and DFS for patients with B-cell lymphomas. The early introduction of rituximab into the treatment (i.e. first-line treatment) might improve OS. Therefore, the response adapted first-line therapy with rituximab should be considered when the treatment decision is taken in B-cell lymphoma patients.

Preventive and therapeutic antitumor effect of tumor vaccine composed of CpG ODN class C and irradiated tumor cells is triggered through the APCs and activation of CTLs.

The present study was aimed at assessing the ability of tumor vaccine - CpG ODN class C in combination with irradiated melanoma tumor cells B16F1 to trigger the antitumor immunity in experimental tumor model in mice (i.p. B16F1) as well as at evaluating some of its mechanisms of action. A significant preventive antitumor immunity was achieved with the vaccine and two additional injections of CpG ODN (the proportion of protected mice was between 75% and 100%). In more than 80% of survivors, a long-lasting immunity was triggered. The therapy with the vaccine and two additional injections of CpG ODN significantly prolonged survival of tumor bearing mice. The rates of cured mice were 21.1% and 11.1% in mice with smaller or larger tumor masses, respectively. The mechanism of stimulation of the immune system by this kind of vaccine is likely to be through the augmentation of APC maturation (a significantly increased proportion of CD86+ CD11c+ was determined in vaccinated mice), consequent activation of T lymphocytes (the proportions of CD25+ and CD69+ splenic lymphocytes increased after the exposure to activated DCs) and establishment of memory cells. In conclusion, vaccine composed of CpG ODN class C and irradiated tumor cells powerfully triggers the immune system bringing about both preventive and therapeutic effects.