Dainius Characiejus

Introduction: This review offers clinicians a novel view of tumor markers (TM). We suggest reporting the TM with two values: the TM level itself and the specific growth rate (SGR). Clinicians are well informed about the limitations of TM‐based cancer screening and early recurrence detection. Review of Current TM Interpretation: Current TM interpretation is based merely on the TM value. TM cannot provide the information equivalent to histological data. An asymptomatic patient with rising TM is assigned to imaging procedures only if TM is found above the norm. Proposal to Report TM in Two‐Parameter Format: We offer to universally report TM as a two‐parameter value: (a) TM itself; (b) specific growth rate of TM. The rate of change of TM, rather than the TM norm, is a reliable criterion for recurrence monitoring. For the moment, serial TM values of individual patients are becoming universally available in electronic format. Review of Literature Exploring Velocity, Doubling Time, and SGR in Laboratory Reports and Radiological Assessment: We offer medical laboratories to put into service a specific growth rate (SGR) parameter which precisely associates: (a) the current TM value; (b) the previous TM value; and (c) the time interval between. Radiologic tumor progression with SGR calculations significantly aided prognosis assessment, but the implementation of SGR in laboratory practice has not been tested. This review focuses on clinical data in which SGR could have been employed to guide therapy or to monitor for recurrence. The obvious advantages of the SGR‐TM format are ease of interpretation (it indicates the percentage change in TM per day), cost‐effectiveness, and mathematical consistency.

Background/Aims: Chemotherapy resistance of malignancies is a universal phenomenon which unfavorably affects therapeutic results. Genetic adaptations as well as epigenetic factors can play an important role in the development of multidrug resistance. Cytotoxic drug content in plasma of cancer patients is known to variate up to one hundred-fold regardless of the same dose injected per m² body surface. The relationship between plasma concentrations, tissue uptake, and chemotherapy response is not completely understood. The main objective of this study was to investigate how the identical dose of Doxorubicin (Dox) can result in a different therapeutic response pattern depending on tumor size.

Background: The aim of this study was to analyze the spatial distribution and proliferation of adoptively transferred CD8(+) T-lymphocytes sensitized against allogeneic tumors. Materials and methods: Transgenic beta-actin-luc mice that express luciferase were sensitized against allogeneic SL2 lymphoma. CD8(+) T-lymphocytes from these mice were transferred to lymphocyte-deficient, recombination activating gene-deficient (Rag(-/-)) mice bearing SL2 tumors and were tracked using bioluminescence imaging. Results: Two out of six Rag(-/-) mice rejected their tumors. There were no apparent differences in spatial distribution and proliferative intensity of adoptively-transferred CD8(+) T-lymphocytes between the two Rag(-/-) mice that rejected allogeneic SL2 tumors and the four Rag(-/-) mice that did not. Conclusion: The pattern of distribution in the mouse body and proliferative intensity of CD8(+) T-lymphocytes do not seem to be decisive factors influencing allogeneic tumor rejection.

Aim: To evaluate quantitative changes in B, NK and T lymphocyte subsets in peripheral blood of children with acute lymphoblastic leukemia (ALL) undergoing chemotherapy. Patients and Methods: Children with ALL were treated according to NOPHO ALL 2008 protocol. Levels of B lymphocytes (CD19⁺), NK cells (CD3⁻CD56⁺) and subsets of T lymphocytes (CD3⁺CD4⁺, CD4⁺CD25⁺Foxp3⁺, CD3⁺CD8⁺, CD3⁺CD8⁺CD57⁺, CD3⁺CD8⁺CD57⁻) in peripheral blood were analyzed by flow cytometry prior and during treatment with cytotoxic drugs. Results: Immunological analyses were performed in 25 children with ALL. Levels of B and NK lymphocytes decreased continuously during chemotherapy. In contrast, levels of most T lymphocyte subsets decreased only transiently and returned to pretreatment levels by days 78 to 85. The only T lymphocyte subset that did not return to the pretreatment level contained senescent CD3⁺CD8⁺CD57⁺ lymphocytes. Conclusion: Immunomodulating action of chemotherapy in children with ALL results in reduction of proportion of senescent CD8⁺ T lymphocytes.

The aim of the present study was to analyze the survival, spatial distribution and proliferation of adoptively transferred lymphocytes in allogeneic tumor rejection. Transgenic β-actin-luc mice that express luciferase were sensitized against SL2 tumors and were used as lymphocyte donors to study the anti-tumor effect in SL2 tumor-bearing lymphocyte-deficient RAG(-/-) mice. Whole-body bioluminescence images of recipient mice were obtained to track the adoptively transferred lymphocytes. Proliferation of lymphocytes was estimated by quantification of photon emission. T lymphocytes sensitized against allogeneic SL2 tumors cured the majority of SL2 tumor-bearing RAG(-/-) mice. Bioluminescence imaging showed that transferred T lymphocytes survived in the spleen and lymph nodes. Tumor rejection was associated with lymphocyte proliferation and migration to the tumor site. Sensitized T lymphocytes from transgenic β-actin-luc mice reject allogeneic SL2 tumors in RAG(-/-) mice and can be tracked in vivo using bioluminescence imaging.

Purpose of this study was to evaluate the lymphocyte populations’ distribution changes in peripheral blood of patients with primary Sjögren’s syndrome (pSS). Lymphocyte populations’ distribution changes in peripheral blood of pSS patients were investigated in 52 patients with pSS and in 28 healthy controls by flow cytometry. We found decreased absolute count of CD3⁺T cell population in pSS patients. Analysis of CD4⁺T cell population showed significant proportion and absolute count differences in pSS patient’s blood with SSA/SSB antibodies (Abs) in comparison to controls. No significant differences were observed analyzing CD4⁺and CD8⁺Treg subpopulation. Proportion and absolute counts of Th17 cells were significantly lower in pSS patient’s blood. Absolute counts of CD8⁺T cells were significantly lower in pSS patients in comparison to controls and also impaired proportion and absolute counts of CD8⁺subpopulations according to CD27⁺and CD57⁺were observed. Absolute counts of NKT and NK cells were decreased in pSS with Abs. B cells proportion was increased only in blood of pSS with Abs. Lymphocyte distribution impairment can be due to genetically determined lymphopenia or lymphocyte migration from periphery to inflammatory sites or/and increased susceptibility to apoptosis.

Prophylactic vaccination is arguably the most effective medical preventative method. After local inoculation, vaccines induce antigen-specific systemic immunity, protecting the whole body. Systemic antitumour immunity can cure advanced cancer, but will therapeutic vaccination suffice? A vaccine for castration-refractory prostate cancer (CRPC) was approved by regulatory authority, but its evidence is disputed. We critically reviewed the clinical efficacy of therapeutic cancer vaccines for prostate cancer, including the results of 31 clinical studies employing vaccines-only, and another 10 studies combining vaccines with immune co-stimulation. Vaccinations yielded immunological responses, but no study showed evidence for clinically relevant therapeutic improvement. Clinical failure of therapeutic vaccination is discussed in the light of immunological dogmas and mechanisms of antitumour therapies. We propose that cancer immunotherapy might be improved by immunological danger, i.e. disturbing tumour homeostasis by destroying the tumour tissue or inducing local inflammation. Such danger might override immunological tolerance, and thereby allow clinically relevant anticancer results.

Our aim is to evaluate the complement component C4 (C4) and its fragment C4d (C4d) levels, focusing on their associations with other markers of B cells’ activity in patients with primary Sjögren’s syndrome (pSS). Humoral factors C4, C4d, B cell-activating factor (BAFF), κ and λ free light chains (FLCs) and IgG (by immunoassay) were investigated in 58 patients with pSS and in 28 healthy controls. We observed significantly higher levels of BAFF, κ and λ FLC and IgG, and significantly lower level of C4 in pSS patients, while the level of C4d was similar in the both groups. Significantly higher levels of BAFF, κ and λ FLCs, IgG, and significantly lower C4 level were found in anti-SSA/SSB antibodies (Abs) seropositive pSS patients’ group comparing with healthy controls. Level of C4d was significantly lower in anti-SSA/SSB Abs seropositive pSS patients comparing with seronegative pSS patients and healthy controls. C4d correlated with C4, anti-SSB Abs level and κ/λ ratio. Significantly higher κ FLC and IgG levels were found in anti-SSA/SSB Abs seronegative pSS patients comparing with healthy controls. Anti-SSA/SSB seropositivity in pSS patients is associated with the decreased level of C4d. These results show that C4d can be an appropriate marker of antibody response and complement activation in pSS patients with Abs, and possibly may show the more severe condition—exhaustion of C4. Further studies are required to determine whether C4d assessment could be a relevant biomarker for the more severe condition and the worse prognosis of pSS.

Comparison of the therapeutic effect of treatment of non-muscle invasive bladder carcinoma (NMIBC) after intravesical Interleukin-2 (IL-2) instillations in the presence and absence of a marker tumour. Two pilot studies were performed in patients with NMIBC. The first study (10 patients) was performed in Krakow (Poland), the second (26 patients) in Vilnius (Lithuania). In Krakow the tumours were treated with incomplete transurethral resection (TUR) leaving a marker tumour of 0.5-1.0-cm followed by IL-2 instillations (3 × 10(6) IU IL-2) on five consecutive days. In Vilnius the tumours were treated with complete TUR, followed by IL-2 instillations (9 × 10(6) IU IL-2) on five consecutive days. During 30 months follow-up, the recurrence-free survival was 5/10 (50%) and 6/26 (23%) after incomplete and complete TUR, respectively. So, the ratio of the recurrence-free survival after incomplete/complete TUR of 50/23=2.2. The median of the recurrence-free survival is >20.5 months and 7 months after incomplete and complete TUR, respectively. So, this ratio was >20.5/7= >2.9. The hazard ratio which combines both the chance of the disease recurrence and its timing for both censored and uncensored cases was 0.53, again confirming the better outcome after incomplete TUR. A possible explanation for the better therapeutic effects after incomplete TUR compared with complete TUR is that the marker tumour has tumour-associated antigens (TAA) that could lead to an immune reaction that is stimulated by local application of IL-2. After complete TUR, no TAA are available to initiate and to stimulate an immune reaction; consequently, local IL-2 therapy is less effective after complete TUR. The results of these two pilot studies have led to the recent start of a randomised prospective clinical trial in which therapeutic effects of local IL-2 therapy after complete and incomplete TUR are compared.