BOREAS: a global, phase III study of the MDM2 inhibitor navtemadlin (KRT-232) in relapsed/refractory myelofibrosis.

Patients with myelofibrosis (MF) who discontinue ruxolitinib due to progression/resistance have poor prognoses. JAK inhibitors control symptoms and reduce spleen volumes with limited impact on underlying disease pathophysiology. Murine double minute 2 (MDM2), a negative regulator of p53, is overexpressed in circulating malignant CD34+ MF cells. The oral MDM2 inhibitor navtemadlin (KRT-232) restores p53 activity to drive apoptosis of wild-type TP53 tumor cells by inducing expression of pro-apoptotic Bcl-2 family proteins. Navtemadlin demonstrated promising clinical and disease-modifying activity and acceptable safety in a phase II study in patients with relapsed/refractory MF. The randomized phase III BOREAS study compares the efficacy and safety of navtemadlin to best available therapy in patients with MF that is relapsed/refractory to JAK inhibitor treatment.

Myelofibrosis (MF) is a rare blood cancer that disrupts normal blood cell production and causes fibrosis (tissue thickening/scarring) in bone marrow, reduced red blood cells in the circulation, and an enlarged spleen. Although currently approved treatments can help relieve some effects, they have limited impact on the underlying cause of the disease. Navtemadlin is a new therapy that inhibits a protein frequently overexpressed in cancer cells found in MF patients called murine double minute 2 (MDM2), which regulates a common tumor suppressor protein called p53. By inhibiting MDM2, navtemadlin restores normal p53 function and its ability to kill MF cancer cells. BOREAS is a large clinical study of navtemadlin for MF patients whose disease is not responding to current therapy.

Characteristics and outcomes of patients with multiple myeloma aged 21-40 years versus 41-60 years: a multi-institutional case-control study.

We compared the outcomes of multiple myeloma (MM) patients aged 21-40 and 41-60 years in the novel agent era. This case-control study included 1089 patients between 2000 and 2015. Cases and controls were matched for sex, International Staging System (ISS) stage and institution. There were 173 patients in the younger group and 916 patients in the older group. Younger patients presented with a higher incidence of lytic lesions (82% vs. 72%; P = 0·04) and high-risk cytogenetic abnormalities (83% vs. 68%; P = 0·007), but lower rate of elevated lactate dehydrogenase (21% vs. 44%; P < 0·001). Five- and 10-year overall survival (OS) in younger versus older patients was 83% vs. 67% and 56% vs. 39%, respectively (P < 0·001). Similar results were seen when studying the subset of 780 patients who underwent autologous transplantation. Younger patients with ISS stage 1 had a better OS than older patients (P < 0·001). There was no survival difference between younger and older patients with ISS stage 2 or 3. Younger MM patients, aged 21-40 years, treated in the era of novel agents have a better OS than their counterparts aged 41-60 years, but the survival advantage observed in younger patients was lost in more advanced stages of MM.

Altered plasma fibrin clot properties and fibrinolysis in patients with multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is associated with increased risk of venous and arterial thromboembolism. Formation of denser and poorly lysable fibrin clots is observed in patients with arterial and venous thromboembolism. We investigated fibrin clot properties and their determinants in MM patients. MATERIALS AND METHODS: Ex vivo plasma fibrin clot permeability, turbidity and susceptibility to lysis were evaluated in 106 MM patients at the time of diagnosis vs. 100 age- and sex-matched controls. MM patients had lower clot permeability (Ks ), compaction, indicating denser fibrin clots, impaired fibrin polymerization with longer lag phase and lower final turbidity (D-Dmax ), combined with hypofibrinolysis reflected by longer lysis time and slower rate of D-dimer release from fibrin clots (D-Drate ) compared with controls (all P < 0·001). RESULTS: Patients with IgG MM had lower Ks compared with IgA MM [5·9 (5·1-6·4) vs. 6·3 (5·9-7·2) 10(-9)  cm(2) ; P = 0·007] and longer lysis time compared with light-chain-disease patients [11·4 (10·9-12·3) vs. 10·7 (9·8-11·9) min; P = 0·022]. Of the fibrin variables, only Ks was significantly lower in patients with International Staging System (ISS) grade III than in those with ISS grade I and II [5·9 (4·9-6·6) vs. 6·2 (5·7-6·8) 10(-9)  cm(2) ; P = 0·015]. Multivariate analysis adjusted for age and fibrinogen showed that in MM patients elevated peak thrombin levels determine Ks and D-Dmax , while thrombin-activatable fibrinolysis inhibitor (TAFI) activity predicts Ks , t50% , D-Drate and lag phase. CONCLUSIONS: Our study demonstrates prothrombotic fibrin clot phenotype in patients with MM, with a significant impact of increased thrombin formation and TAFI activity.

rs2072135, a low-penetrance variant for chronic lymphocytic leukaemia?

Recent multi-stage genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are robustly associated with chronic lymphocytic leukaemia (CLL) risk. Given that most of these SNPs map to non-coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci (eQTL) data on lymphoblastoid cells lines (LCLs) we have globally demonstrated an association between GWAS P-values and eQTLs, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNPs for replication, we genotyped rs2072135 (GWAS P-value = 0·0024, eQTL P-value = 1·510(-19)) in five independent case-control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P-value = 1 × 10(-4)), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation.

The Real-World Evidence on the Fragility and Its Impact on the Choice of Treatment Regimen in Newly Diagnosed Patients with Multiple Myeloma over 75 Years of Age.

Fragility scales are intended to help in therapeutic decisions. Here, we asked if the fragility assessment in MM patients ≥ 75 years old qualified for treatment by the local physician correlates with the choice of treatment: a two- or three-drug regimens. Between 7/2018 and 12/2019, we prospectively enrolled 197 MM patients at the start of treatment from the 13 Polish Myeloma Group centers. The data to assess fragility were prospectively collected, but centrally assessed fragility was not disclosed to the local center. The activity of daily living (ADL) could be assessed in 192 (97.5%) and was independent in 158 (80.2%), moderately impaired in 23 (11.7%), and 11 (5.6%) in completely dependent. Patients with more than three comorbidities made up 26.9% (53 patients). Thus, according to the Palumbo calculator, 43 patients were in the intermediate fitness group (21.8%), and the rest belonged to the frailty group (153, 77.7%). Overall, 79.7% of patients (157) received three-drug regimens and 20.3% (40) received two-drug regimens. In each ECOG group, more than three out of four patients received three-drug regimens. According to the ADL scale, 82.3% of the independent 65.2% of moderately impaired, and 81.8% of the dependent received three-drug regimens. Out of 53 patients with at least four comorbidities, 71.7% received three-drug regimens, and the rest received two-drug regimens. Thirty-four patients from the intermediate fit group (79.0%), and 123 (79.9%) from the frail group received three-drug regimens. Early mortality occurred in 25 patients (12.7%). No one discontinued treatment due to toxicity. To conclude, MM patients over 75 are mainly treated with triple-drug regimens, not only in reduced doses, regardless of their frailty scores. However, the absence of prospective fragility assessment did not negatively affect early mortality and the number of treatment discontinuations, which brings into question the clinical utility of current fragility scales in everyday practice.

Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML.

PANTHER is a global, randomized phase 3 trial of pevonedistat+azacitidine (n = 227) vs azacitidine monotherapy (n = 227) in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS; n = 324), higher-risk chronic myelomonocytic leukemia (n = 27), or acute myeloid leukemia (AML) with 20% to 30% blasts (n = 103). The primary end point was event-free survival (EFS). In the intent-to-treat population, the median EFS was 17.7 months with pevonedistat+azacitidine vs 15.7 months with azacitidine (hazard ratio [HR], 0.968; 95% confidence interval [CI], 0.757-1.238; P = .557) and in the higher-risk MDS cohort, median EFS was 19.2 vs 15.6 months (HR, 0.887; 95% CI, 0.659-1.193; P = .431). Median overall survival (OS) in the higher-risk MDS cohort was 21.6 vs 17.5 months (HR, 0.785; P = .092), and in patients with AML with 20% to 30% blasts was 14.5 vs 14.7 months (HR, 1.107; P = .664). In a post hoc analysis, median OS in the higher-risk MDS cohort for patients receiving >3 cycles was 23.8 vs 20.6 months (P = .021) and for >6 cycles was 27.1 vs 22.5 months (P = .008). No new safety signals were identified, and the azacitidine dose intensity was maintained. Common hematologic grade ≥3 treatment emergent adverse events were anemia (33% vs 34%), neutropenia (31% vs 33%), and thrombocytopenia (30% vs 30%). These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of continuing therapy for >3 cycles. The trial was registered on clinicaltrials.gov as #NCT03268954.

Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma.

The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma.

Clinical characteristics of patients with chronic eosinophilic leukaemia (CEL) harbouring FIP1L1-PDGFRA fusion transcript--results of Polish multicentre study.

A small subgroup of patients with hypereosinophilic syndrome (HES) demonstrates imatinib-sensitive fusion transcript-the FIP1L1-PDGFRA (F/P+). These cases are currently diagnosed as chronic eosinophilic leukaemia (CEL). In this paper, we screened 77 patients to estimate the frequency of FIP1L1-PDGFRA transcript among patients with unexplained, long-term hypereosinophilia exceeding 1.5 x 10(9)/L and to analyse the clinical and serological features in F/P+ CEL population. The FIP1L1-PDGFRA chimeric protein was detectable in 16 (14 males and 2 females) out of 77 examined HES patients (20%) by RT-PCR. Two patients suffered from cough at diagnosis. Three out of 16 (18%) patients had no organ involvements, in 5-one organ was affected and in the remaining eight cases-at least two. Eosinophilic organ damage/dysfunction identified splenomegaly in the majority of studied patients. We compared clinical and serological features between CEL F/P+ (n = 16) and HES (n = 61) patients. F/P+ cases had significantly increased WBC and absolute eosinophil count (AEC) at diagnosis (p = 0.008 and 0.02), whereas platelet count was decreased in this population (p = 0.03). Serum B12 and tryptase levels were increased (p = 0.002 and 0.004) in CEL F/P+ patients when compared to HES cases whereas serum IL-5 levels were significantly increased in the latter group (p = 0.01). Male gender and splenomegaly occurred more frequent in CEL F/P+ population (p = 0.002 and 0.0007, respectively). Additionally, patients with F/P+ CEL (n = 16) were compared with F/P- CEL (n = 8). The latter group, was significantly older, had lower AEC and higher platelet count. In conclusion, significant clinical symptoms are infrequent present and splenomegaly remains the most common organ involvement in patients with CEL expressing F/P fusion transcript. Our study confirmed the long-term remission on imatinib in this patient population.

Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in adults with haematological malignancies: a phase 3, randomised, clinical trial and post-hoc efficacy analysis.

BACKGROUND: The adjuvanted recombinant zoster vaccine (Shingrix) can prevent herpes zoster in older adults and autologous haemopoietic stem cell transplant recipients. We evaluated the safety and immunogenicity of this vaccine in adults with haematological malignancies receiving immunosuppressive cancer treatments. METHODS: In this phase 3, randomised, observer-blind, placebo-controlled study, done at 77 centres worldwide, we randomly assigned (1:1) patients with haematological malignancies aged 18 years and older to receive two doses of the adjuvanted recombinant zoster vaccine or placebo 1-2 months apart during or after immunosuppressive cancer treatments, and stratified participants according to their underlying diseases. The co-primary objectives of the study were the evaluation of safety and reactogenicity of the adjuvanted recombinant zoster vaccine compared with placebo from the first vaccination up to 30 days after last vaccination in all participants; evaluation of the proportion of participants with a vaccine response in terms of anti-glycoprotein E humoral immune response to the adjuvanted recombinant zoster vaccine at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune responses to the vaccine compared with placebo at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. We assessed immunogenicity in the per-protocol cohort for immunogenicity and safety in the total vaccinated cohort. The study is registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical Trials Register, number 2012-003438-18. FINDINGS: Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286 participants to adjuvanted recombinant zoster vaccine and 283 to placebo. 283 in the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119 (80·4%, 95% CI 73·1-86·5) of 148 participants had a humoral vaccine response to adjuvanted recombinant zoster vaccine, compared with one (0·8%, 0·0-4·2) of 130 participants in the placebo group, and the adjusted geometric mean anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI 16 642·8-32 153·9) in the vaccine group and 777·6 mIU/mL (702·8-860·3) in the placebo group (adjusted geometric mean ratio 29·75, 21·09-41·96; p<0·0001) in all patients, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. Humoral and cell-mediated immune responses persisted above baseline until month 13 in all strata and, as expected, vaccine was more reactogenic than placebo (within 7 days after vaccination pain was reported by 221 [79·5%] of 278 vaccine group participants and 45 [16·4%] of 274 placebo group participants; fatigue was reported by 162 [58·3%] of 278 vaccine group participants and 102 [37·2%] of 274 placebo group participants). Incidences of unsolicited or serious adverse events, potential immune-mediated diseases, disease-related events, and fatal serious adverse events were similar between the groups. INTERPRETATION: The immunocompromised adult population with haematological malignancies is at high risk for herpes zoster. The adjuvanted recombinant zoster vaccine, which is currently licensed in certain countries for adults aged 50 years and older, is likely to benefit this population. FUNDING: GlaxoSmithKline Biologicals SA.

Efficacy and Safety of IQYMUNE®, a Ten Percent Intravenous Immunoglobulin in Adult Patients With Chronic, Primary Immune Thrombocytopenia.

BACKGROUND: Intravenous immunoglobulin (IVIG) IQYMUNE® is a highly purified 10% IVIG that was assessed using the new stringent definition of response described in the revised guideline on the clinical investigation of IVIG. The efficacy and the safety of IQYMUNE® were investigated in adult patients with chronic primary immune thrombocytopenia (ITP). METHODS: In this phase III multinational, multicentre, prospective, uncontrolled, open-label, single-arm study, adult patients with a baseline platelet count < 30 × 109/L were treated with IVIG 10% at a dose of 2 g/kg body weight administered over 2 consecutive days. The primary endpoint was Response over the study period and was defined according to the recent and most stringent European Medicines Agency guidelines (platelet count ≥ 30 × 109/L and a ≥ 2-fold increase from baseline, no new bleeding, and no concomitant treatment with drugs that affect platelet count and/or induce bleeding cessation). RESULTS: Thirty-eight patients were enrolled; 73 infusions were administered (38 on Day 1 and 35 on Day 2). Response was reached by 24 patients corresponding to 63.2% of patients in the full analysis set (95% CI: 46.0; 78.2) and 68.6% of patients in the per-protocol set (95% CI: 50.7; 83.1). The median time to Response was 1 day. The median duration of Response was 13.5 days. Reasons for non-response were failure to reach the required platelet count (n = 12), a new bleeding event (n = 1), and forbidden medication use (n = 1). Among the 23 patients with a baseline platelet count ≤ 20 × 109/L, 19 patients (82.6%) achieved a platelet count ≥ 50 × 109/L at least once before Day 5 (previous European Medicines Agency definition of response). Treatment was well tolerated even in patients with a high flow rate (≥ 6 mL/kg/h in 40% of patients). Headache (34.2%), pyrexia (15.8%), and creatinine renal clearance decrease, including one case of decrease in glomerular filtration rate (10.5%) were the most frequently reported drug-related adverse events. CONCLUSIONS: Administration of IQYMUNE® for 2 consecutive days at a dose of 2 g/kg was safe and efficacious. These results support the treatment of adult patients with chronic ITP with IQYMUNE®.

Obinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study.

GREEN (NCT01905943) is a non-randomized, open-label phase IIIb study investigating obinutuzumab alone or plus chemotherapy in chronic lymphocytic leukemia (CLL). We report a preplanned subgroup analysis of 158 previously untreated CLL patients receiving obinutuzumab-bendamustine (G-B). Patients received six 28-day cycles (C) of G-B: obinutuzumab day (D)1/D2 of C1 (25 mg D1/975 mg D2), 1000 mg D8 and D15 of C1, and D1 of C2-6; and bendamustine 70/90 mg/m2 D1 and D2 of C1-6. The primary endpoint was safety/tolerability. Grade ≥3 adverse events (AEs) occurred in 82.3% of patients, including neutropenia (49.4%), thrombocytopenia (12.0%) and febrile neutropenia (10.8%). Serious AEs included neutropenia (12.7%), febrile neutropenia (9.5%) and pneumonia (7.6%). Rates of grade ≥3 infections and infusion-related reactions were 20.3% and 17.1%, respectively. Due to tumor lysis syndrome (TLS; 8.2%), including two associated fatalities (one in another study cohort), additional risk-minimization measures were implemented. Overall response rate was 81.0%. After 32.8 months' median observation time, 2-year progression-free survival was 81.8%. Minimal residual disease was undetectable in 59.5% (94/158) and 27.8% (44/158) of patients for blood and bone marrow, respectively. Frontline G-B appears to have manageable toxicity with clinical activity in CLL. Careful TLS risk assessment, pretreatment and monitoring is required.

Gene polymorphisms of novel immunotolerant molecule BTLA: distribution of alleles, genotypes and haplotypes in Polish Caucasian population.

B and T lymphocyte attenuator (BTLA) is one of the members of immunoglobulin superfamily which, like CTLA-4 and PD-1, is involved in down regulation of immune response. Despite the important role of BTLA in maintaining immune homeostasis, relatively little studies were devoted to the relationship of polymorphisms in the gene encoding BTLA with susceptibility to autoimmune disease and cancer. Moreover, all published works were done in Asian populations. BTLA gene is located on chromosome 3 in q13.2 and consists of five exons. The aim of this study was to investigate the alleles, genotypes and haplotypes frequency of selected BTLA gene polymorphisms in Caucasian population originating from Poland. For this study, the single-nucleotide polymorphisms (SNPs) were chosen on the basis of literature data. Additionally, the tag dSNP under linkage equilibrium r (2) > 0.8 and available at the National Center for Biotechnology Information (NCBI) for Caucasian population of rare alleles at a frequency greater than 5 % have been chosen using the NCBI database. The ten BTLA SNPs investigated were: rs1844089, rs2705535, rs9288952, rs9288953, rs1982809, rs2633580, rs2705511, rs2705565, rs76844316, rs16859633. For all SNPs selected on the basis of literature data the significantly different distributions of genotypes between Asian and Caucasian populations were observed.

Induction therapy alters plasma fibrin clot properties in multiple myeloma patients: association with thromboembolic complications.

Induction therapy in patients with multiple myeloma increases the risk of thromboembolism. We have recently shown that multiple myeloma patients tend to form denser fibrin clots displaying poor lysability. We investigated the effect of induction therapy on fibrin clot properties in multiple myeloma patients. Ex-vivo plasma fibrin clot permeability, turbidity, susceptibility to lysis, thrombin generation, factor VIII and fibrinolytic proteins were compared in 48 multiple myeloma patients prior to and following 3 months of induction therapy, mainly with cyclophosphamide-thalidomide-dexamethasone regimen. Patients on thromboprophylaxis with aspirin or heparins were eligible. A 3-month induction therapy resulted in improved clot properties, that is higher clot permeability, compaction, shorter lag phase and higher final turbidity, along with shorter clot lysis time and higher rate of D-dimer release from fibrin clots than the baseline values. The therapy also resulted in lower thrombin generation, antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI), but elevated factor VIII. Progressive disease was associated with lower posttreatment clot permeability and lysability. Despite thromboprophylaxis, two patients developed ischemic stroke and 10 had venous thromboembolism. They were characterized by pretreatment lower clot permeability, prolonged clot lysis time, longer lag phase, higher peak thrombin generation, TAFI and plasminogen activator inhibitor -1. Formation of denser plasma fibrin clots with reduced lysability and increased thrombin generation at baseline could predispose to thrombotic complications during induction treatment in multiple myeloma patients. We observed improved fibrin clot properties and thrombin generation in multiple myeloma patients except those with progressive disease.

[Current principles of Wilson's disease--diagnosis and treatment]. / Aktualne zasady diagnostyki i leczenia choroby Wilsona.

Wilson's disease defined also as hepatolenticular degeneration is an important clinical problem of young adults still causing diagnostic difficulties. In the course of the last decade, genetic background of the disease has been definitely established and elucidated, confirming the variety of genetic mutations, responsible for its origin. The current scheme of the disease treatment has been elaborated and established. It aims to eliminate the excess of toxic copper ions from the organism as fast as possible. In the initial phase of the treatment, traditional and recently introduced chelating agents administration usually results in prompt tissue copper deposits excretion and copper metabolism balance maintenance. In the chronic therapy, zinc compounds, inducing intestinal and hepatic metallothionein synthesis, have been gaining more common application. Life-long, constant, pharmacological Wilson's disease therapy, administered after its early diagnosis, allows for long periods of patients survival, frequently comparable to the normal population.

Variations in suppressor molecule ctla-4 gene are related to susceptibility to multiple myeloma in a polish population.

Various phenotype and functional T-cell abnormalities are observed in multiple myeloma (MM) patients. The aim of this study was to investigate the association between polymorphisms in the gene encoding cytotoxic T-lymphocyte antigen-4 (CTLA-4), a negative regulator of the T-lymphocyte immune response and susceptibility to multiple myeloma in a Polish population. Two hundred MM patients and 380 healthy subjects were genotyped for the following polymorphisms: CTLA-4c.49A>G, CTLA-4g.319C>T, CTLA-4g.*642AT(8_33), CT60 (CTLA-4g.*6230G>A), Jo31 (CTLA-4g.*10223G>T). Our study is the largest and most comprehensive evaluation to date of the association between genetic polymorphisms in the CTLA-4 molecule and multiple myeloma. It was found that CTLA-4c.49A>G[G], CT60[G], and Jo31[G] alleles were more frequently observed in MM patients than in controls (0.50 vs. 0.44, p = 0.03, 0.65 vs. 0.58, p = 0.04, and 0.63 vs. 0.57, p = 0.03, respectively). Moreover, the haplotype CTLA-4c.49A>G[G], CTLA-4g.319C>T[C], CTLA-4g.*642AT(8_33) [8], CT60[G], Jo31[G] including all susceptibility alleles increases the risk of MM about fourfold (OR: 3.79, 95%CI: 2.08-6.89, p = 0.00001). These findings indicate that genetic variations in the CTLA-4 gene play role in susceptibility to multiple myeloma and warrant further investigation through replication studies.

ICOS gene polymorphisms in B-cell chronic lymphocytic leukemia in the Polish population.

There is strong evidence that altered immunological function entails an increased risk of B-cell chronic lymphocytic leukemia (B-CLL). The main mechanism of an anti-tumor response depends on T-cell activation. Unlike the constitutively expressed CD28, inducible costimulatory molecule (ICOS) is expressed on the T-cell surface after activation. ICOS enhances all the basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, the upregulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B cells. ICOS is essential for both efficient interaction between T and B cells and normal antibody responses to T cell-dependent antigens. It does not upregulate the production of interleukin-2, but superinduces the synthesis of interleukin-10. Our previous results indicated the ICOS gene has a role as a susceptibility locus to B-CLL. Therefore an extended study was undertaken to evaluate the association between four ICOS polymorphisms (which were recently described as functional ones) and susceptibility to B-CLL in the Polish population. A case-control study of 296 individuals, including 146 B-CLL patients, was conducted on four polymorphisms in the ICOS gene. Genotyping of the polymorphisms ICOS ISV1+173T>C (rs10932029), ICOSc.1624C>T (rs10932037), ICOSc.2373G>C (rs4675379), and ICOSc.602A>C (rs10183087) was carried out using allelic discrimination methods with the TaqMan SNP Genotyping Assay. There were no statistically significant differences in the allele, genotype, or haplotype distributions between B-CLL patients and healthy controls for any of the investigated polymorphic markers in the ICOS gene. However, we noted that patients carrying genotype ICOS ISV1+173T>C [TT], ICOSc.602A>C [AA], ICOSc.1624C>T [CC], and ICOSc.2373G>C [GG] have a decreased frequency of progression to a higher Rai stage during 60-month follow-up (21.35% vs. 40.8%, p = 0.013) compared to other individuals. This indicates that the investigated polymorphisms do not modulate the risk of B-CLL in the Polish population, but are associated with disease dynamics, in particular with the time to Rai stage progression.

Histopathological diagnosis of microscopic colitis.

A typical symptom of microscopic colitis (MC) is chronic watery diarrhea with normal endoscopic findings and characteristic inflammatory changes in histopathology. Treatment of the disease is mainly empiric. MC has two main subtypes: lymphocytic colitis and collagenous colitis. There are also untypical histopathological forms of MC: MC with giant cells, MC not otherwise specified (NOS) and cryptal lymphocytic coloproctitis. Some other histopathological changes in MC have been observed, especially Paneth cell hyperplasia or epithelial degeneration. Eosinophilic colitis, acute colitis, amyloidosis, ulcerative colitis and Crohn's disease should be taken into consideration in differential diagnosis. The most reliable biopsy material for histopathological examination are samples obtained from transverse colon. Some studies proved that treatment of MC makes it possible to reduce not only clinical, but also histopathological, manifestations.

Focal lesions in the ultrasonographic examination of the spleen as a symptom of various disease statuses: literature survey and case descriptions.

BACKGROUND: Ultrasonography (US) is an easy and non-invasive technique of visualizing spleen. Thanks to its repeatability, it plays an important role in the diagnostics of, among others, developmental anomalies, such as supernumerary or lobated spleens, as well as focal lesions. It is also used in monitoring the size of the spleen and it considerably facilitates diagnosis after certain injuries. Thanks to the application of the Doppler method, it also facilitates the diagnostics of pathologies within the spleen's vessels. CASE REPORT: This paper presents six different cases of focal lesions in the spleen, including lesions in the course of histiocytosis, in the course of sarcoidosis, as well as isolated abscesses of the spleen. The authors also present the case of a spleen with numerous metastatic lesions, the case of a near-splenic cyst, and the case of asymptomatic focal lesions of unknown origin. In all the presented cases, the lesions were accidentally revealed during ultrasonographic examination, which was the starting point for further diagnostics. CONCLUSIONS: Though rare, morphologic lesions in the spleen should always be taken into consideration when performing a routine ultrasonographic examination of the abdominal cavity, and the organ itself should not be ignored. US is a widely available, noninvasive, and useful method for diagnosing splenic abnormalities, including focal changes.

Expression of TGF beta1 genes and their receptor types I, II, and III in low- and high-grade malignancy non-Hodgkin's lymphomas.

BACKGROUND: Transforming growth factor beta (TGF ) is involved in a variety of important cellular functions. The lack of TGF -dependent cell-growth control might be related to oncogenesis, as it has been shown in lung, breast, and colon carcinomas. Current observations have revealed that TGF is rather an inhibiting, not a stimulating, factor as far as malignant tumor development is concerned. Recently, however, there has been a growing number of reports on increased expression of TGF genes in certain tumors. In patients with a diagnosis of non-small-cell lung carcinoma, the tumors expressing high levels of TGF were the ones that had a higher proliferation and metastasis capability, whereas more promising were the cases with lower levels of TGF expression. MATERIAL/METHODS: A pilot study of 14 patients was conducted comprising 8 patients with a low-grade lymphoma and 6 patients with a high-grade lymphoma. The QRT-PCR method was employed to assess the activity of TGF 1 and of its receptor types I, II, and III. RESULTS: The expression values for TGF 1 and its receptors I, II, and III were twice as high in the group of patients with a diagnosis of high-grade lymphomas as in the group of patients diagnosed with low-grade lymphomas. CONCLUSIONS: Results showed a clear difference in TGF 1 expression in patients with NHL depending on the subtype of the lymphoma, suggesting its significant role in the pathomechanism of this group of malignant diseases as well as its potential value as a prognostic factor.