Prevalence of malnutrition and deficiency of vitamin d in patients with lymphoproliferative diseases and their influence on disease outcome

Uvod: Pothranjenost je česta prilikom dijagnoze malignih bolesti, uključujući i limfoproliferativne bolesti (LPB). Serumska vrednost vitamina D je niska kod većine bolesnika sa malignim i hroničnim bolestima. Ova dva parametra mogu da utiču na ishod lečenja limfoproliferativnih bolesti i preživljavanje. Cilj: Određivanje učestalosti pothranjenosti i nedostatka vitamina D kod bolesnika sa LPB i njihov uticaj na terapijski odgovor i preživljavanje unutar jedne godine. Metodologija: Istraživanje je obuhvatilo 153 bolesnika sa LPB lečenih na Klinici za hematologiju Kliničkog centra Srbije u periodu od januara 2014. do septembra 2016. Uključeno je 70 (45,8%) bolesnika sa difuznim B krupnoćelijskim limfomom (DBKL), 20 (13,1%) sa folikularnim limfomom (FL), 21(13,7%) sa hroničnom limfocitnom leukemijom (HLL), 22 (14,4%) sa Hodgkinovim limfomom (HL) i 20 (13,1%) sa multiplim mijelomom (MM). Isključeni su bolesnici koji su imali loše funkcionalno stanje po Eastern Cooperative Oncology group scale - ECOG ˃3. Opšti podaci su dobijeni iz istorija bolesti, uključujući podatke o telesnoj težini, visini i gubitku u telesnoj težini pre lečenja i komorbiditetima. Komorbiditetni indeks je procenjivan na osnovu kumulativnog komorbiditetinog indeksa (CIRS) i Karlsonovog komorbiditetnog indeksa (CCI). Pothranjenost je određena prema tri upitnika Nutritional risk screening 2002 (NRS 2002), Mini nutritional assessment (MNA) i indeksa telesne mase (ITM). U okviru rutinskih biohemjskih analiza rađena je vrednost serumske laktat dehidrogenaze (LDH). Vrednost serumskog 25(OH) vitamina D određivana je do 5 dana pre započinjanja lečenja, hemiluminiscentnom metodom na imunoanalizatoru Beckman Access 2, pomoću paramegnetnih partikula. Na završetku lečenja rađena je evaluacija terapijskog odgovora. Povoljan terapijski odgovor (PTO) podrazumevao je kompletnu ili parcijalnu remisiju a nepovoljan stabilnu ili progresivnu bolest (NTO). Pod progresijom se podrazumeva relaps bolesti ili smrtni ishod. Medijana praćenja bolesnika je iznosila 38 (2-53) meseci. Rezultati: Uključeno je 69 (45,1%) žena i 84 (54,9%) muškaraca, prosečne starosti 57,2± 15,6 godina...Malnutrition is frequent in malignant diseases, including lymphoproliferative diseases (LPD). Vitamin D deficiency is also frequent in many chronic and malignant diseases. These to parameters can influence terapeutic response and survival. Aim: To assess frequency of malnutrition and 25(OH) vitamin D deficiency in lymphoproliferative disorders (LPD) and their influence on terapeutic responce and survival within one year. Methdology: This study has included 153 patients treated at Clinic for hematology, Clinical center of Serbia between january 2014. and september 2016. It included 70 (45,8%) patients with diffuse large B cell lymphoma (DLBCL), 20 (13,1%) with follicular lymphoma (FL), 21(13,7%) with chronic lymphocitic leukemia (CLL), 22 (14,4%) with Hodgkin lymphoma (HL) and 20 (13,1%) with multiple myeloma (MM). Patients with worse performance status according Eastern Cooperative Oncology group scale - ECOG ˃3 were excluded from the study. General data were taken from medical hystories, including body weight and height, weight loss befor treatment and comorbidities. Comorbidity was assessed using cumulative index for comorbidities (CIRS) and Carlson comorbidity index (CCI). Malnutrition was assessed using: Nutritional risk screening 2002 (NRS 2002), Mini nutritional assessment (MNA) and body mass index (BMI). Serum lactat dehydrogenese (LDH) value was rutinely assessed in context of biochemical analyses. The value of serum 25(OH) vitamina D was assesed until 5 days before treatment using chemiluminiscent method at the Beckman immunoassay Access 2 analyser, with paramagnetic particules. At the end of treatment terapy response was evaluated. Favourable response (FR) was assigned to patients who have achieved complete or partial remission, and unfavourable response (UR) to patients with stable and progressive disease, relaps or death. Median follow up was 38 (2-53) months..

Brza progresija hronične limfocitne leukemije u Rihterov sindrom kod bolesnika sa kariotipom blizu triploidnog broja hromozom

Introduction. The presence of aneuploidy in patients diagnosed with chronic lymphocytic leukemia (CLL), except trisomy 12, is considered quite uncommon. Hyperdiploidy or near-tetraploidy (occurring in 1–3% of all CLL patients) usually confer a poor prognosis. Case report. We report a patient in a progressive phase of CLL with near–triploid karyotype. The prognosis of the disease was more precisely determined by applying the cytogenetic analysis of the karyotype and was complemented with molecular methods and pathohistological examination. The complex karyotype was accompanied by the TP53, C-MYC, and IGH gene disruptions, the most probable cause of rapid evolution into Richter’s syndrome. Conclusion. The use of comprehensive contemporary diagnostic techniques is highly recommended in patients who are in the progressive phase of CLL, primarily for the adequate choice of management strategy. The presented case confirms that aneuploidy in CLL patients indicates poor prognosis, which is in accordance with previous publications reporting on cases of CLL patients with aneuploidy.Uvod. Prisustvo aneuploidije kod bolesnika sa dijagnozom hronične limfocitne leukemije (HLL), sa izuzetkom trizomije 12, smatra se retkom pojavom. Pojava hiperdiploidnog ili kariotipa blizu tetraploidnog broja hromozoma (koji se javlja kod 1–3% svih bolesnika sa HLL) smatra se lošim prognostičkim parametrom. Prikaz bolesnika. Prikazan je bolesnik u uznapredovaloj fazi HLL sa kariotipom blizu triploidnog broja hromozoma. Prognoza bolesti je preciznije određena citogenetičkom analizom kariotipa bolesnika, i dopunjena molekularnim metodama i patohistološkom analizom. Otkriveno je prisustvo kompleksnog kariotipa udruženog sa poremećajima u genima TP53, C-MYC i IGH, što je najverovatnije bio uzrok brze progresije u Rihterov sindrom. Zaključak. Primena savremenih dijagnostičkih metoda veoma je značajna kod bolesnika u uznapredovaloj fazi HLL, prvenstveno zbog adekvatnog terapijskog pristupa. Prikazani slučaj ukazuje da je prisustvo aneuploidije kod bolesnika sa HLL loš prognostički znak, što je u saglasnosti sa prethodno publikovanim prikazima bolesnika sa HLL i sa aneuploidijom u kariotipu

Comparative analysis of International Prognostic Index for chronic lymphocytic leukemia, progression-risk score, and MD Anderson Cancer Center 2011 score: A single center experience

Uvod/Cilj Prognoza hronične limfocitne leukemije (HLL) značajno je unapređena u poslednje vreme. Među nekoliko prognostičkih modela čiji je cilj predviđanje vremena do prve terapije (eng. TTFT) izdvajaju se skor rizika od progresije (eng. PRS) i skor Centra za rak MD Anderson iz 2011. God. (eng. MDACC 2011), dok se internacionalni prognostički indeks za HLL (eng. CLL-IPI), iako primarno ustanovljen za predikciju ukupnog preživljavanja (eng. OS), dobro pokazao i u predikciji TTFT. Cilj ovog rada je da se ispita značaj pomenutih prognostičkih modela u pogledu predviđanja TTFT i OS. Metode Analizirana kohorta je obuhvatila 57 neselektovanih bolesnika sa HLL Univerzitetskog kliničkog centra Srbije sa prosečno agresivnijim profilom bolesti u odnosu na opštu populaciju de novo bolesnika sa HLL. Bolesnici su ocenjivani prema navedenim skorovima uz analizu TTFT i OS. Rezultati Bolesnici sa višim vrednostima CLL-IPI, PRS i MDACC 2011 primili su prvu terapiju značajno ranije u poređenju sa bolesnicima sa nižim vrednostima ovih skorova (p = 0,002, p = 0,019 i p lt 0,001, redom). U multivarijantnoj analizi, MDACC 2011 i CLL-IPI su zadržali prognostički značaj u predikciji TTFT (p = 0,001, odnosno p = 0,018), dok je PRS ovaj značaj izgubio. CLL-IPI je bio jedini značajan prediktor OS u univarijantnoj (p = 0,005) i u multivarijantnoj analizi (p = 0,013). Zaključak CLL-IPI, PRS i naročito MDACC 2011 su dobri prediktori TTFT čak i u kohortama bolesnika sa agresivnijom bolešću, dok je za predikciju OS od ova tri prognostička modela CLL-IPI jedini primenljiv. Ovi rezultati pokazuju da bi prognostičke modele trebalo ispitati na bolesnicima sa HLL u različitim fazama bolesti, kakvi se sreću u realnoj kliničkoj praksi.Introduction/Objective Prognostication of chronic lymphocytic leukemia (CLL) has been substantially improved in recent times. Among several prognostic models (PMs) focused on the prediction of time to first treatment (TTFT), progression-risk score (PRS), and MD Anderson Cancer Center score 2011 (MDACC 2011) are the most relevant, while CLL-International Prognostic Index (CLL-IPI), although originally developed to predict overall survival (OS), is also being used to estimate TTFT. The aim of this study was to investigate CLL-IPI, PRS, and MDACC 2011 prognostic values regarding TTFT and OS. Methods The analyzed cohort included 57 unselected Serbian CLL patients from a single institution, with the basic characteristics reflecting more aggressive disease than in the general de novo CLL population. The eligible patients were assigned investigated PMs, and TTFT and OS analyses were performed. Results Patients with higher risk scores according to CLL-IPI, PRS, and MDACC 2011 underwent treatment significantly earlier than patients with lower risk scores (p = 0.002, p = 0.019, and p lt 0.001, respectively). In multivariate analysis, MDACC 2011 and CLL-IPI retained their significance regarding TTFT (p = 0.001 and p = 0.018, respectively), while PRS did not. CLL-IPI was the only significant predictor of OS both at the univariate (p = 0.005) and multivariate (p = 0.013) levels. Conclusion CLL-IPI, PRS, and particularly MDACC 2011 are able to predict TTFT even in cohorts with more advanced-disease patients, while for prediction of OS, CLL-IPI is the only applicable among the three PMs. These results imply that PMs should be investigated in more diverse CLL populations, as it is in real-life setting

Increased oxidative stress in diffuse large B-cell lymphoma

Background: Oxidative stress is caused by imbalance between excessive production of reactive oxygen species and decreased capabilities of antioxidant system, and it is recognized as a feature in cancerogenesis, as well in hematologic malignancies. Previous studies have shown increasing expression of oxidative stress markers and antioxidant enzymes in lymph nodes progressing to aggressive lymphomas. Aims: The aim of our study was to assess the clinical and prognostic significance of oxidative stress markers in patients with untreated diffuse large B-cell lymphoma (DLBCL). Methods: We analysed 64 patients diagnosed with DLBLC during 2018 and 2019, while 27 healthy volunteers (51.9% males) served as a control group. The plasma sample and laboratory analyses were obtained prior to initiation of specific hematologic treatment. After completion of the therapy, the patients were followed up for up to 4 years and for each of them progression free survival (PFS) and overall survival (OS) were calculated. Malondialdehyde (MDA) and protein carbonyl (PC) were used as markers of oxidative stress in plasma of patients and volunteers, while catalase is used as an antioxidant marker. Results: The mean patients’ age was 56.2 years (range, 20–87); 51.6% were males. Majority of patients were analysed before 1L therapy (n=61; 95,3%), and had following clinical stages: Ann Arbor stage I 23.4%, stage II 37.5%, stage III 15.6% and stage IV 23.4%. Majority of the patients had satisfactory performance status (73.5% had ECOG PS ≥1), bulky tumorous mass was present in 34.4% of patients, whereas 70.3% had extranodal localisation of lymphoma. MDA (6.66±2.7 nmol/ml) was significantly increased (p<0.001, 2.6-fold), while PC (4.29±2.7 nmol/mg) was also significantly increased (p=0.0027, 5-fold) in patients with DLBCL compared to healthy volunteers. In opposite, antioxidant catalase (0.194±0.06 IU/ml) was significantly reduced (p=0.0034, 1.9-fold) in patients with DLBCL. MDA was in significant (p<0.05) negative correlation with hemoglobin (r2=0.586) and LDH (r2=0.59) levels before chemotherapy. MDA was in significant (p<0.01) positive correlation with the age (r2=0.769) of patients with DLBCL at diagnosis. Moreover, MDA was in significant positive correlation with overall survival (p<0.01, r2=0.736) and progression-free survival (p<0.01, r2=0.736) of patients with DLBCL. PC was in negative correlation with the clinical stage (r2=0.103, p=0.146) and therapy response (r2=0.136, p=0.091) of DLBCL but did not reach significance. Summary/Conclusion: The elevated oxidative markers and reduced antioxidant support oxidative stress in patients with DLBCL, while MDA can be a prognostic marker of overall survival

Follicular lymphoma patients with a high FLIPI score and a high tumor burden: A risk stratification model

Background/Aim. The widely accepted Follicular Lymphoma International Prognostic Index (FLIPI) divides patients into three risk groups based on the score of adverse prognostic factors. The estimated 5-year survival in patients with a high FLIPI score is around 50%. The aim of this study was to analyse the prognostic value of clinical and laboratory parameters that are not included in the FLIPI and the New Prognostic Index for Follicular Lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project (FLIPI2) indices, in follicular lymphoma (FL) patients with a high FLIPI score and high tumor burden. Methods. The retrospective analysis included 57 newly diagnosed patients with FL, a high FLIPI score and a high tumor burden. All the patients were diagnosed and treated between April 2000 and June 2007 at the Clinic for Hematology, Clinical Center of Serbia, Belgrade. Results. The patients with a histological grade > 1, erythrocyte sedimentation rate (ESR) ± 45 mm/h and hypoalbuminemia had a significantly worse overall survival (p = 0.015; p = 0.001; p = 0.008, respectively), while there was a tendency toward worse overall survival in the patients with an Eastern Cooperative Oncology Group (ECOG) > 1 (p = 0.075). Multivariate Cox regression analysis identified a histological grade > 1, ESR ± 45 mm/h and hypoalbuminemia as independent risk factors for a poor outcome. Based on a cumulative score of unfavourable prognostic factors, patients who had 0 or 1 unfavourable factors had a significantly better 5-year overall survival compared to patients with 2 or 3 risk factors (75% vs 24.1%, p = 0.000). Conclusion. The obtained results suggest that from the examined prognostic parameters histological grade > 1, ESR ± 45 mm/h and hypoalbuminemia can contribute in defining patients who need more aggressive initial treatment approach, if two or three of these parameters are present on presentation

Prognostic significance of cellular vascular endothelial growth factor (VEGF) expression in the course of chronic myeloid leukaemia

Introduction. Increased angiogenesis in bone marrow is one of the characteristics of chronic myeloid leukaemia (CML), a clonal myeloproliferative disorder that expresses a chimeric bcr/abl protein. Vascular endothelial growth factor (VEGF) is one of the most potent and a specific regulator of angiogenesis which principally targets endothelial cells and regulates several of their functions, including mitogenesis, permeability and migration. The impact of elevated VEGF expression on the course of chronic myeloid leukaemia is unknown. Objective. The aim of this study was the follow-up of VEGF expression during the course of CML. Methods. We studied VEGF expression of 85 CML patients (median age 50 years, range 16-75 years). At the commencement of the study, 29 patients were in chronic phase (CP), 25 in an accelerated phase (AP), and 31 in the blast crisis (BC). The temporal expression (percentage positivity per 1000 analysed cells) VEGF proteins over the course of CML were studied using the immunohistochemical technique utilizing relevant monoclonal antibodies. It was correlated with the laboratory (Hb, WBC and platelet counts, and the percentage of blasts) and clinical parameters (organomegaly, duration of CP, AP, and BC) of disease progression. Results. The expression of VEGF protein was most pronounced in AP (ANOVA, p=0.033). The level of VEGF expression correlated inversely with the degree of splenomegaly (Pearson, r=-0.400, p=0.011). High expression of VEGF correlated with a shorter overall survival (log rank, p=0.042). Conclusion. Immunohistochemically confirmed significance of the expression of VEGF in dependence of the CML stage could be of clinical importance in deciding on the timing therapy. These data suggest that VEGF plays a role in the biology of CML and that VEGF inhibitors should be investigated in CML

Diagnosis and the treatment of primary amyloidosis

Backgraund. Primary amyloidosis belongs to a group of monoclonal plasma cell disorders, characterized by extracellular deposition of immunoglobulin light chain fibrils in various tissues and subsequent multiorgan dysfunction. Case report. We present a 51-year-old female with 2-years history of fatigue on exertion, oedema of face, abdomen and legs, bone pain and obstipation. After diagnostic procedures such as electrophoresis and immunoelectrophoresis of serum and urine proteins, immunohistohemical staining of bone marrow biopsy specimens and Congo red staining of rectal biopsy specimens, the patient received misdiagnosis of multiple myeloma and was referred to our hospital for further treatment. We reevaluated and complemented diagnostic procedures (ehocardiosonography and biopsy of subcutaneaus tissue with Congo red staining), and established diagnosis of primary amyloidosis. The therapy had started with intravenous (iv) melphalan and dexamethasone (totally eight cycles) and continued with peroral melphalan and iv dexamethasone. Stabilization of the disease was achieved after 35 months of the treatment. Conclusion. The case of this rare and often fatal disease emphasizes significance of early diagnosis and, consequently, initiation of specific therapies which are indispensable to improve the disease prognosis

Association of SLC28A3 Gene Expression and CYP2B6*6 Allele with the Response to Fludarabine Plus Cyclophosphamide in Chronic Lymphocytic Leukemia Patients

Fludarabine plus cyclophosphamide (FC) chemotherapy is the basis of treatment protocols used in management of chronic lymphocytic leukemia (CLL). In some patients, response to therapy may be affected by aberrant function of genes involved in pharmacokinetics and pharmacodynamics of the drugs. The aim of this research was to assess the impact of pharmacogenetic variability, namely expression of SLC28A3 gene and the presence of CYP2B6*6 variant allele, on the FC treatment efficacy. Forty-four CLL patients with functional TP53 gene at the time of FC initiation were enrolled in this study. CYP2B6 genotyping was performed by polymerase chain reaction and direct sequencing. SLC28A3 expression was measured by quantitative reverse-transcriptase polymerase chain reaction. Significantly higher pretreatment levels of SLC28A3 mRNA were detected in patients who failed to respond to FC in comparison to patients who achieved complete and partial response (p = 0.01). SLC28A3 high-expressing cases were almost ten times more likely not to respond to FC than low-expressing cases (OR = 9.8; p = 0.046). However, association of SLC28A3 expression with progression-free survival (PFS) and overall survival (OS) was not observed. CYP2B6*6 allele, detected in 24 patients (54.6%), exerted no association with the attainment of response to FC, as well as with PFS and OS. The results of this study demonstrate that SLC28A3 expression is a significant predictor of FC efficacy in CLL patients with intact TP53. Elevated SLC28A3 mRNA levels are associated with inferior short-term response to FC, suggesting that, if validated on larger cohorts, SLC28A3 expression may become a biomarker useful for pretreatment stratification of patients