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We examined the cognitive flexibility performance of young autistic children and a group of neurotypical peers. Thirty-six autistic children (72-83 months) and 200 age-matched typically-developing children were assessed on the Children's Color Trails Test (CCTT), a semantic and a phonemic verbal fluency task. The results showed that the autistic children performed worse than their neurotypical peers in the switching component of the CCTT. In the fluency tests, the autistic group generated overall fewer word items than their neurotypical peers, however, their poorer performance was driven by specific linguistic stimuli in the fluency tasks. The findings suggest that cognitive flexibility for the autistic children was affected in the nonverbal CCTT only, while poor performance in semantic and phonemic fluency seemed to be inherent to the language properties of the verbal fluency tasks.

Clinical Practice Points • Progressive multifocal leukoencephalopathy (PML) is a rare but fatal demyelinating disease caused by John Cunningham polyomavirus, mainly affecting immunosuppressed patients. It sporadically complicates hematological malignancies and has been reported after monoclonal antibody treatment, predominantly rituximab. In recent years, obinutuzumab, a third-generation type II anti-CD20+ monoclonal antibody, has been widely used for chronic lymphocytic leukemia and follicular lymphoma. • We present the case of a patient with relapsing follicular lymphoma who developed PML after obinutuzumab therapy and is, to our knowledge, the first case to be thoroughly presented in the literature. • Although PML is very rare in everyday clinical practice, this report highlights the importance of suspecting PML in any lymphoma patient undergoing novel treatments and presenting focal neurologic deficits, in an effort to avoid unnecessary invasive procedures and delay in diagnosis.

Background/Aim: Primary mediastinal large B-cell lymphoma (PMLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL), whose prognosis has greatly improved since the incorporation of the anti-CD20 monoclonal antibody rituximab into current therapeutic regimens. Evidence, however, on the optimal time interval between consecutive chemoimmunotherapy (CIT) cycles is still scarce. This study aimed to evaluate the efficacy outcomes of the more commonly administered 3-weekly regimens to the biweekly ones in a PMLBCL patients’ population, who were mostly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP-21) or R-CHOP-14. Patients and Methods: We retrospectively studied our cohort of consecutively treated PMLBCL patients, focusing on their treatment density, in order to determine possible differences in treatment outcomes. Results: CIT, in the form of both R-CHOP-21 as well as R-CHOP-14 (or similar regimens), is highly active in PMLBCL, with low rates of early treatment failure. In our cohort of patients, R-CHOP-14 did not result in a meaningful improvement of freedom from progression (FFP) or overall survival (OS). Conclusion: Both R-CHOP-14 and R-CHOP-21 are probably equally effective in PMLBCL, yet further, prospective, randomized studies are warranted to clarify whether dose-dense regimens can be associated with better disease control and long-term results.

There are limited data on the prevalence and determinants of COVID-19 vaccination coverage among physicians. A cross-sectional, questionnaire-based, online study was conducted among the members of the Athens Medical Association (I.S.A.) over the period 25 February to 13 March 2021. All members of I.S.A. were invited to participate in the anonymous online survey. A structured, anonymous questionnaire was used. Overall, 1993 physicians participated in the survey. The reported vaccination coverage was 85.3%. The main reasons of no vaccination were pending vaccination appointment followed by safety concerns. Participants being informed about the COVID-19 vaccines by social media resulted in lower COVID-19 vaccination coverage than health workers being informed by other sources. Logistic regression analysis demonstrated that no fear over COVID-19 vaccination-related side effects, history of influenza vaccination for flu season 2020–2021, and the perception that the information on COVID-19 vaccination from the national public health authorities is reliable, were independent factors of reported COVID-19 vaccination coverage. Our results demonstrate a considerable improvement of the COVID-19 vaccination uptake among Greek physicians. The finding that participants reported high reliability of the information related to COVID-19 vaccination provided by the Greek public health authorities is an opportunity which should be broadly exploited by policymakers in order to combat vaccination hesitancy, and further improve COVID-19 vaccination uptake and coverage among physicians/HCWs, and the general population.

The aim of the present study was to provide normative data in Greek, regarding sequential motion rate (SMR) and oral reading rate (ORR), and to show the sensitivity of both tasks to predict Parkinson's disease (PD).The speech rate of sixty-five healthy control participants was recorded and analyzed using speech acoustics. The speech rate of a subsample of 20 healthy control participants was compared to the speech rate of 20 pair-matched dysarthric parkinsonian participants. All participants produced the syllables /pataka/ (SMR task) as quickly as possible and read aloud a standard Greek passage (ORR task).In normative data, the mean score for the SMR variable was 4.91 syllables per second (SD = 0.73) and for the ORR variable was 4.42 syllables per second (SDThis study provided Greek normative data in SMR and ORR tasks. Both tasks showed high sensitivity and specificity to predict PD in the Greek sample of participants.

Summary The aim of the present study was to examine whether the exercise intensity corresponding to the lactate threshold may be predicted by the Maximum Phonation Time task (MPT). Ten Greek amateur football players (age: 18.4 ± 1.0 years), performed a graded cycling exercise test to exhaustion in order to determine lactate threshold. A number of physiological variables were measured including perceived exertion, cardiopulmonary values and blood lactate. The MPT variable was correlated with all of the physiological variables. Also, a binary logistic regression analysis was used to investigate whether MPT could predict lactate threshold. The ROC analysis showed specificity to be 0.90 and sensitivity to be 0.70 (optimal screening cutoff point for MPT 9.5 seconds). The results showed an odds ratio of 1.45 indicating a 45% increase in the probability of passing the threshold for every second there was a reduction in voice duration. MPT may be used as a simple, non-invasive, inexpensive method for monitoring exercise intensity during physical exercise. Further research is needed to measure its efficacy in bigger samples and in different sports.

Transplant-ineligible relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADG), with bendamustine- rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real-life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola-(B)R mainly within a compassionate use program. Treatment was given for up to six 21-day cycles. Bendamustine was omitted in three cases due to previous short-lived responses. Fourty-nine rrDLBCL(efficacy cohort-EC) and 58 rr aggressive B-NHL (safety cohort-SC) patients received at least 1 Pola-BR cycle. Twenty-one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression-free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% of patients experienced a grade ≥3 adverse event, mainly hematologic. Treatment discontinuations and death during treatment were mainly due to disease progression. Twenty-two (41%) patients received further treatment; 11/22 are still alive, including one after CAR-T cells, and two after stem cell transplantation. Our data confirm that Pola-BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity. Pola-BR could be used as bridging therapy before further consolidative treatments.

End-of-treatment (EoT) PET/CT is used as a guide to omit radiotherapy (RT) patients with primary mediastinal large B-cell lymphoma (PMBCL). We present the mature and extended results of a retrospective study evaluating the prognostic significance of EoT-PET/CT after adequate response to R-CHOP. Among 231 consecutive PMLBCL patients, 182 underwent EoT-PET/CT and were evaluated according to the Deauville 5-point scale (D5PS) criteria. Freedom from progression (FFP) was measured from the time of PET/CT examination. Among 182 patients, 72 (40%) had D5PS score 1 (D5PSS-1), 33 (18%) had 2, 28 (15%) had 3, 29 (16%) had 4, and 20 (11%) had 5. The 5-year FFP was 97, 94, 92, 82, and 44% for D5PSS-1, D5PSS-2, D5PSS-3, D5PSS-4, and D5PSS-5, respectively. Among 105 patients with unequivocally negative PET/CT (D5PSS-1/D5PSS-2), 49 (47%) received RT (median dose 3420 cGy) and 56 (53%) did not with relapses in 0/49 vs. 4/56 patients (2 mediastinum and 2 isolated CNS relapses).The 5-year FFP for those who received RT or not was 100% versus 96%, when isolated CNS relapses were censored (p = 0.159). Among D5PSS-3 patients (27/28 irradiated-median dose 3600 cGy), the 5-year FFP was 92%. The 5-year FFP for D5PSS-4 and D5PSS-5 was 82 and 44%; 44/49 patients received RT (median dose 4000 and 4400 cGy for D5PSS-4 and D5PSS-5). Our study supports the omission of RT in a sizeable fraction of PET/CT-negative patients and definitely discourages salvage chemotherapy and ASCT in patients with PMLBCL who conventionally respond to R-CHOP, solely based on PET/CT positivity in the absence of documented progressive or multifocal disease. The persistence of positive PET/CT with D5PSS < 5 after consolidative RT should not trigger the initiation of further salvage chemotherapy in the absence of conventionally defined PD.

End-of-treatment (EoT) PET/CT is used as a guide to omit radiotherapy (RT) patients with primary mediastinal large B-cell lymphoma (PMBCL). We present the mature and extended results of a retrospective study evaluating the prognostic significance of EoT-PET/CT after adequate response to R-CHOP. Among 231 consecutive PMLBCL patients, 182 underwent EoT-PET/CT and were evaluated according to the Deauville 5-point scale (D5PS) criteria. Freedom from progression (FFP) was measured from the time of PET/CT examination. Among 182 patients, 72 (40%) had D5PS score 1 (D5PSS-1), 33 (18%) had 2, 28 (15%) had 3, 29 (16%) had 4, and 20 (11%) had 5. The 5-year FFP was 97, 94, 92, 82, and 44% for D5PSS-1, D5PSS-2, D5PSS-3, D5PSS-4, and D5PSS-5, respectively. Among 105 patients with unequivocally negative PET/CT (D5PSS-1/D5PSS-2), 49 (47%) received RT (median dose 3420 cGy) and 56 (53%) did not with relapses in 0/49 vs. 4/56 patients (2 mediastinum and 2 isolated CNS relapses).The 5-year FFP for those who received RT or not was 100% versus 96%, when isolated CNS relapses were censored (p = 0.159). Among D5PSS-3 patients (27/28 irradiated-median dose 3600 cGy), the 5-year FFP was 92%. The 5-year FFP for D5PSS-4 and D5PSS-5 was 82 and 44%; 44/49 patients received RT (median dose 4000 and 4400 cGy for D5PSS-4 and D5PSS-5). Our study supports the omission of RT in a sizeable fraction of PET/CT-negative patients and definitely discourages salvage chemotherapy and ASCT in patients with PMLBCL who conventionally respond to R-CHOP, solely based on PET/CT positivity in the absence of documented progressive or multifocal disease. The persistence of positive PET/CT with D5PSS5 after consolidative RT should not trigger the initiation of further salvage chemotherapy in the absence of conventionally defined PD.

Hypoxia-Inducible Factor-1α (HIF-1α) expression is upregulated in Sickle Cell Disease (SCD) and correlates with various laboratory markers of disease severity. Nitric Oxide plays a pivotal role in SCD pathophysiology and endothelial Nitric Oxide Synthase (NOS3) polymorphisms affect prognosis and laboratory parameters. This study questions the effect of NOS3 G894T and T786C polymorphisms on HIF-1α expression in SCD. We show that G894T polymorphism is a significant predictor of HIF-1α expression. Its effect is exerted independently of hemolysis/hemoglobin fragment concentrations, as shown in multiple regression analysis. Our results establish a novel modulator of HIF-1α expression on the mRNA level and indirectly support the role of nitric oxide in the pathophysiology of SCD.

Background R-CHOP can cure approximately 75% of patients with primary mediastinal large B-cell lymphoma (PMLBCL), but prognostic factors have not been sufficiently evaluated yet. R-da- EPOCH is potentially more effective but also more toxic than R-CHOP. Reliable prognostic classification is needed to guide treatment decisions. Materials and Methods We analyzed the impact of clinical prognostic factors on the outcome of 332 PMLBCL patients ≤65 years treated with R-CHOP ± radiotherapy in a multicenter setting in Greece and Cyprus. Results With a median follow-up of 69 months, 5-year freedom from progression (FFP) was 78% and 5-year lymphoma specific survival (LSS) was 89%. On multivariate analysis, extranodal involvement (E/IV) and lactate dehydrogenase (LDH) ≥2 times upper limit of normal (model A) were significantly associated with FFP; E/IV and bulky disease (model B) were associated with LSS. Both models performed better than the International Prognostic Index (IPI) and the age-adjusted IPI by Harrel's C rank parameter and Akaike information criterion. Both models A and B defined high-risk subgroups (13%–27% of patients [pts]) with approximately 19%–23% lymphoma-related mortality. They also defined subgroups composing approximately one-fourth or one-half of the patients, with 11% risk of failure and only 1% or 4% 5-year lymphoma-related mortality. Conclusion The combination of E/IV with either bulky disease or LDH ≥2 times upper limit of normal defined high-risk but not very-high-risk subgroups. More importantly, their absence defined subgroups comprising approximately one-fourth or one-half of the pts, with 11% risk of failure and minimal lymphoma-related mortality, who may not need more intensive treatment such as R-da-EPOCH. Implications for Practice By analyzing the impact of baseline clinical characteristics on outcomes of a large cohort of patients with primary mediastinal large B-cell lymphoma homogeneously treated with R-CHOP with or without radiotherapy, we developed novel prognostic indices which can aid in deciding which patients can be adequately treated with R-CHOP and do not need more intensive regimens such as R-da-EPOCH. The new indices consist of objectively determined characteristics (extranodal disease or stage IV, bulky disease, and markedly elevated serum lactate dehydrogenase), which are readily available from standard initial staging procedures and offer better discrimination compared with established risk scores (International Prognostic Index [IPI] and age-adjusted IPI).

Introduction Venous blood (VB) sampling for complete blood count (CBC) via venipuncture is the basic method for the daily evaluation of hematological patients. However, several issues during this process, such as venipuncture difficulty and repetitive attempts, may cause pain, phlebitis, hematomas, inadequate sampling, and patient discomfort. Capillary blood (CB) sampling could be an alternative and less painful solution for the patient. The purpose of this study was the comparative evaluation of basic CBC parameters, as counted from venous and capillary blood samples. Methods During the period 06/2016-06/2019 in which the study was conducted, 1634 automated counts of VB or CB were performed, derived from 425 hematological hospitalized patients. Bland-Altman plots were performed to show the agreement of VB and CB counts of common hematological parameters (Hb, Hct, WBC, absolute neutrophil count-[ANC], RBC, Plt, MCV, MCH), using two different hematology analyzers (Mindray BC-3000 Plus Auto and Sysmex XE-5000). Clinical significance of CB sampling was assessed by applying specific clinically significant cutoffs for Hb, ANC, and Plt. Results All measured parameters revealed a significant correlation (r > .9) between CB and VB samples, irrelatively of the hematology analyzer used. CB measurements of Hb, ANC, and Plt, at different clinically important cutoff levels, showed excellent sensitivity (87%-100%), specificity (95%-100%), positive predictive value, and negative predictive value (87%-100% and 90%-100%, respectively). Conclusion Capillary blood and VB counts in hematological patients were equivalent for most basic hematological parameters. Hb, ANC, and Plt CB counts revealed clinically significant performance, indicating that they can reliably substitute VB sampling in the day work.

Speech and voice symptomatology (dysarthrophonia) are often reported by patients with myasthenia gravis (MG). However, they have been poorly investigated despite their significant impact on quality of life. Quantitative methods for the assessment of dysarthrοphonia could facilitate the evaluation of these common MG symptoms. The goal of this study was to investigate the phonatory (sustained phonation and reading) and speech (diadochokinesis) function in MG patients using quantitative measures. The voice/speech of 12 MG patients (7 with anti-AchR and 5 with anti-MuSK antibodies) and 24 age-matched healthy controls was recorded and analyzed using electroglottography (EGG) and speech acoustics. For the analysis of voice, the variables that were found to distinguish MG patients compared to healthy controls were a higher average fundamental frequency (P0.05), a higher standard deviation of the average fundamental frequency (P0.001), a higher mean fundamental frequency of the vibrating vocal folds (P0.005) and a higher fundamental frequency range (P0.005). The analysis of diadochokinesis showed that MG patients had a higher mean duration of the silent interval between a series of repetitive /pa/ syllables (P0.05), of the sound /t/ (P=0.05) and of the silent interval between a series of repetitive /ka/syllables (P0.05). No statistical differences were found in any of these variables between the MG subgroups with anti-AchR or anti-MuSK antibodies. This study demonstrates that non-invasive physiological methods (EGG and speech acoustics) offer essential tools for the assessment of dysarthrophonia in MG patients.

Although classical Hodgkin lymphoma (cHL) is usually curable, 20−30% of the patients experience treatment failure and most of them are typically treated with salvage chemotherapy and autologous stem cell transplantation (autoSCT). However, 45−55% of that subset further relapse or progress despite intensive treatment. At the advanced stage of the disease course, recently developed immunotherapeutic approaches have provided very promising results with prolonged remissions or disease stabilization in many patients. Brentuximab vedotin (BV) has been approved for patients with relapsed/refractory cHL (rr-cHL) who have failed autoSCT, as a consolidation after autoSCT in high-risk patients, as well as for patients who are ineligible for autoSCT or multiagent chemotherapy who have failed ≥ two treatment lines. However, except of the consolidation setting, 90−95% of the patients will progress and require further treatment. In this clinical setting, immune checkpoint inhibitors (CPIs) have produced impressive results. Both nivolumab and pembrolizumab have been approved for rr-cHL after autoSCT and BV failure, while pembrolizumab has also been licensed for transplant ineligible patients after BV failure. Other CPIs, sintilimab and tislelizumab, have been successfully tested in China, albeit in less heavily pretreated populations. Recent data suggest that the efficacy of CPIs may be augmented by hypomethylating agents, such as decitabine. As a result of their success in heavily pretreated disease, BV and CPIs are moving to earlier lines of treatment. BV was recently licensed by the FDA for the first-line treatment of stage III/IV Hodgkin lymphoma (HL) in combination with AVD (only stage IV according to the European Medicines Agency (EMA)). CPIs are currently being evaluated in combination with AVD in phase II trials of first-line treatment. The impact of BV and CPIs was also investigated in the setting of second-line salvage therapy. Finally, combinations of targeted therapies are under evaluation. Based on these exciting results, it appears reasonable to predict that an improvement in survival and a potential increase in the cure rates of cHL will soon become evident.

Sickle cell disease (SCD), a hereditary form of chronic hemolytic anemia, is characterized by acute vascular occlusion and chronic complications as pulmonary hypertension (PH), a hallmark of higher mortality. This study aimed to determine peripheral blood expression of superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme in SCD patients on the mRNA level and compared it with SOD2 expression in healthy individuals. It also aimed to detect possible differences in SOD2 expression among patients with/without specific SCD complications and to detect possible correlations with patient laboratory parameters. SOD2 mRNA levels were significantly lower in SCD patients in comparison with controls and correlated with red blood cell count, reticulocyte count, platelet count, C-reactive protein, ferritin, and brain natriuretic peptide values. SCD patients with echocardiographic indications of PH featured significantly reduced SOD2 expression in comparison with patients without such indications. Consequently, SOD2 expression emerges as a potential biomarker of PH in SCD being a link among hemolysis, inflammation, iron overload, oxidative stress, and SCD cardiopathy.

The outcome of patients with relapsed/refractory classical Hodgkin lymphoma (rr-cHL) has improved considerably in recent years owing to the approval of highly active novel agents such as brentuximab vedotin and Programmed Death-1 (PD-1) inhibitors. Although no randomized trials have been conducted to provide formal proof, it is almost undisputable that the survival of these patients has been prolonged. As autologous stem-cell transplantation (SCT) remains the standard of care for second-line therapy of most patients with rr-cHL, optimization of second-line regimens with the use of brentuximab vedotin, or, in the future, checkpoint inhibitors, is promising to increase both the eligibility rate for transplant and the final outcome. The need for subsequent therapy, and especially allogeneic SCT, can be reduced with brentuximab vedotin consolidation for 1 year, while pembrolizumab is also being tested in this setting. Several other drug categories appear to be active in rr-cHL, but their development has been delayed by the appearance of brentuximab vedotin, nivolumab and pembrolizumab, which have dominated the field of rr-cHL treatment in the last 5 years. Combinations of active drugs in chemo-free approaches may further increase efficacy and hopefully reduce toxicity in rr-cHL, but are still under development.

Dysarthrophonia is a predominant symptom in many neurological diseases, affecting the quality of life of the patients. In this study, we produced a discriminant function equation that can differentiate MS patients from healthy controls, using electroglottographic variables not analyzed in a previous study. We applied stepwise linear discriminant function analysis in order to produce a function and score derived from electroglottographic variables extracted from a previous study. The derived discriminant function’s statistical significance was determined via Wilk’s λ test (and the associated p value). Finally, a 2 × 2 confusion matrix was used to determine the function’s predictive accuracy, whereas the cross-validated predictive accuracy is estimated via the “leave-one-out” classification process. Discriminant function analysis (DFA) was used to create a linear function of continuous predictors. DFA produced the following model (Wilk’s λ = 0.043, χ2 = 388.588, p

Positron emission tomography with integrated computed tomography (PET/CT) is increasingly used for the initial staging, final or even interim (mid-treatment) response assessment in malignant lymphomas. Extensive clinical experience has been gained with Hodgkin lymphoma (HL) and aggressive B-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMLBCL) and other subtypes, which are the subject of the present review. The use of PET/CT is now considered mandatory for baseline staging in these entities, providing more accurate information and obviating the need of bone marrow biopsy (BMB) at least in HL. PET/CT has been the long-standing “gold standard” for final response assessment. Furthermore, early interim PET evaluation provides valuable prognostic information in HL and DLBCL. In HL, it appears that treatment intensification with Bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP)-escalated can improve disease control in patients with persistent PET positivity after two cycles of ABVD. However, there is no randomized evidence of survival benefit as yet. In contrast, regimens effective in overcoming the adverse impact of persistent PET positivity have not been yet described in DLBCL. The 2014 recommendations suggest the use of PET/CT for baseline staging and final response assessment in all [18F]fluorodeoxyglucose (FDG)-avid lymphoma subtypes, including the above named ones. The use of interim evaluation is not considered fully documented yet. The exact role of PET/CT in guiding treatment decisions has to be defined by ongoing and future randomized trials and evidence-based approaches are expected to become available in the near future.

AIM To examine the real-life impact of baseline positron-emission tomography/computed tomography (PET/CT) in Hodgkin lymphoma (HL). PATIENTS AND METHODS A total of 162 consecutive patients with HL were retrospectively studied. RESULTS Disease was up-staged in 26 patients (16%) and down-staged in 9 (6%). However, treatment strategy was modified in only 10 patients (6% of total). Involved field radiotherapy was delineated according to PET/CT in 36/66 patients (59%). These treatment modifications did not significantly affect outcome. Moreover, three potent prognostic parameters were identified: the number of involved sites, maximum standardized uptake value (SUVmax), and the product of SUVmax and maximal largest lesion diameter, as a surrogate of total lesion glycolysis. All three significantly correlated with 5-year freedom from disease progression p=0.004, p=0.009 and p=0.04, respectively). CONCLUSION Baseline PET/CT findings may lead to treatment modification in

Objectives To evaluate the prognostic impact of hypercalcemia in newly diagnosed patients with symptomatic multiple myeloma (MM), especially after the incorporation of new agents. Methods we analyzed the outcomes of newly diagnosed patients with symptomatic myeloma included in the database of the Greek Myeloma Study Group for the prognostic effect of the presence of hypercalcemia (defined as corrected serum calcium ≥11 mg/dl) at diagnosis. Results Among 2129 consecutive patients with symptomatic MM, 19.5% presented with hypercalcemia at the time of diagnosis. The presence of hypercalcemia was associated with anemia, thrombocytopenia, lower eGFR, advanced ISS stage and presence of lytic lesions. Hypercalcemia was more common in patients with high risk cytogenetics and was associated with inferior survival across different time periods, age groups and primary treatments. Hypercalcemia was also associated with a two-fold increase in the risk of early death. In patients with available FISH, hypercalcemia could substitute for the presence of high risk cytogenetics and identify patients with worse prognosis along with ISS stage and elevated serum LDH. Conclusion hypercalcemia remains a poor prognostic feature in the era of novel agents despite the improvement in the outcomes of patients who present with elevated calcium. This article is protected by copyright. All rights reserved.

Objective. Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder with variable onset, rate of progression, and phenotypic expression. Later-onset, more slowly progressive PKAN often presents with neuropsychiatric as well as motor manifestations that include speech difficulties, progressive dystonia, rigidity, and parkinsonism. PKAN is caused by biallelic PANK2 mutations, a gene that encodes pantothenate kinase 2, a regulatory enzyme in coenzyme A biosynthesis. Current therapeutic strategies rely on symptomatic relief. We describe the treatment of the first, later-onset PKAN patient with oral fosmetpantotenate (previously known as RE-024), a novel replacement therapy developed to bypass the enzymatic defect. Methods. This was an open-label, uncontrolled, 12-month treatment with fosmetpantotenate of a single patient with a later-onset, moderately severe, and slowly progressive form of PKAN. Results. The patient showed improvement in all clinical parameters including the Unified Parkinson’s Disease Rating Scale (UPDRS), Barry-Albright Dystonia Scale, the EuroQol five-dimensional three-level (EQ-5D-3L) scale, timed 25-foot walk test, and electroglottographic speech analysis. Fosmetpantotenate was well-tolerated with only transient liver enzyme elevation which normalized after dose reduction and did not recur after subsequent dose increases. Conclusions. Fosmetpantotenate showed promising results in a single PKAN patient and should be further studied in controlled trials.

Introduction A novel approach that can cover the therapeutic gap in NHL treatment are the autologous T cells, expressing Chimeric Antigen Receptors (CAR-T cells) against tumor markers. Such clinical-grade products based on Lenti (LV) or Retro- vectors have hit the market. An alternative vector system for CAR gene transfer in T-cells are Foamy Viruses (FV). To evaluate the potential of FV vectors in CAR-T cell development, we synthesized an antiCD19 scFv cDNA and cloned it in both an FV and an LV backbone; both vectors were tested in paired experiments Material and Methods The anti-CD19 CAR was under the control of the EF1a promoter; EGFP expression was under the control of an IRES2 element. The anti-CD19 CAR sequence was deduced from published data. FV vectors were made with a 4-plasmid vector system in 293T cells. 2nd generation LV vectors were purchased from Addgene. Cord blood (CB), healthy donor peripheral blood (PB) and CLL patients' PB was used as a source for CD3+ cells using immunomagnetic enrichment. Informed consent has been obtained in all cases of human sample use. T cells were activated by antiCD3/CD28 beads and transduced with antiCD19 LV or FV vectors. Transduction efficiency was assayed by flow cytometry (FCM) using a PE-conjugated anti-mouse Fab antibody. FV and LV CAR-T cells were expanded with Rapid Expansion Protocol (REP) and their cytotoxicity assays was evaluated against the CD19+ cell lines Raji and Daudi. The CLL patient derived CAR-Ts were evaluated against autologous B cells. Cytotoxicity was evaluated with an FCM protocol using CFSE-stained target cells vs unstained effector CARTs in different ratios. At the end of the incubation cells were stained with 7AAD to discriminate against live/dead cells. CAR-T cell activation was also assayed by INF-γ ELISA, following cocultures with target cells at a ratio of 1:1 for 24h. Results Vector titers: LV vector titers were between 3-5x10^5 TU/ml for both LV vectors (with or without EGFP cassette). FV vector titers were between 2-4x10^5 TU/ml regardless of the presence of the EGFP cassette. Tx efficiency: FV can mediate efficient gene transfer on T cells in the presence of heparin at an effective dose of 20-40 U/ml using a spinoculation technique. Transduction efficiency ranged from 40-65% at MOI=3-5, and was comparable to the transduction efficiency of LV vectors at a much higher MOI (10 to 30). Cytotoxicity data on lines: Following REP, the cell population consisted mostly (close to 96% purity) of CAR-T cells regardless of the vector used or of the T cell source. Effector cells were cocultured with the CD19+ cell lines, Daudi and Raji at varying ratios. With cord blood derived FV-CAR-T cells, at 4h post coculture we observed a 39.4% cell lysis at a ratio of 10:1 effector to target (n=1). Similar results were obtained for LV vectors. Peripheral blood derived CAR-T cells at THE same ratio (10:1), demonstrated 83.9% and 93.1% cell lysis for FV-CART and LV-CART cells respectively (n=2). Cytotoxicity data on CLL cells: T-cells from peripheral blood of CLL patients were used to generate LV- and FV-CAR-T cells. At the ratio of 10:1, we observed 73.1% and 69,8% cytotoxicity for FV-CAR-Ts and 70.1% and 70.7% with LV-CAR-Ts, in 2 independent paired experiments. IFN as activation marker: In two paired activation experiments, CB-derived FV-CAR-T cells secrete 560 and 437pg/ml of IFN-γ; similarly, LV-CAR-Ts secrete 534 and 554pg/ml IFN-γ. Untransduced control cells, produced 68pg/ml and 12pg/ml for FV-CAR-T and LV-CAR-T experimental arm respectively. Conclusion In the current work, we developed and tested FV vectors for anti- CD19 CAR-T cell production. We proved that FV viral vectors are capable of mediating efficient gene transfer to human T cells. We developed a method to efficiently transfer FV vectors into T-cells, using a clinically relevant protocol with heparin. The FV-derived CAR T cells demonstrate the same cytotoxic properties in vitro as their LV-derived counterpart and the same activation levels in the presence of CD19 expressing target cells as measured by IFN-γ secretion. FV CARTs derived from PB of CLL patients were capable of mediating comparable cytotoxicity levels as their LV-derived counterparts. Overall, we provide a proof of concept that FVs could be a safe and efficient alternative to LV derived vectors for CAR-T cells. Disclosures No relevant conflicts of interest to declare.

Prayer marks (PMs) are commonly occurring dermatologic changes in muslims who pray and develop over a long period of time as a consequence of repeated and extended pressure. PMs need careful examination especially for patients with diabetes, who are more vulnerable due to predisposing factors such as venous insufficiency and peripheral neuropathy. A total of 166 patients with diabetes (150 males, 16 females) and 65 normal subjects from Bangladesh were examined for the appearance of PMs. Twenty-eight patients (16.9 %) and one normal subject (1.5 %) had PMs. The marks were not itchy or painful and they were observed on the dorsal aspect of the left foot, which was attributed to a more typical prayer position that placed pressure on the left foot. PMs are not a rare clinical entity among muslim patients with diabetes and most clinicians should be aware of it as it can be the predominant cause of an ulcer.

Endothelial Nitric Oxide Synthase (eNOS) is crucial for vascular homeostasis. Polymorphisms T786C and G894T affect eNOS regulation and have been related to various diseases. Sickle Cell Disease (SCD), a clinically diverse chronic hemolytic anemia, implies impaired nitric oxide bioavailability. Our aim was to determine eNOS genotype for T786C and G894T polymorphisms in Greek patients with SCD and to elucidate its consequences and effects if any on clinical phenotype. Seventy nine steady state cases, mostly compound heterozygous for Sickle Cell anemia/beta thalassemia and 48 controls were measured. Peripheral blood DNA was extracted and genotyped with PCR-RFLPs and Sanger sequencing. Total RNA was extracted from 18 patients and 9 controls and eNOS mRNA levels were determined by real-time PCR. Genotypes, allele distribution and eNOS mRNA levels did not differ between patients and controls, or among patients with different beta globin gene mutations. The 786CC genotype was more common in S/S and β0/S patients with retinopathy. Moreover, 894TT S/S and β0/S patients tended to have a higher hematocrit than 894GG and GT ones. However, the T786C eNOS genotype does not seem to affect peripheral blood cell-derived eNOS mRNA levels, at least in steady state conditions. This work is the first one describing the effects of eNOS polymorphisms on different forms of SCD, the first enrolling SCD patients of Caucasian origin and the first determining eNOS mRNA levels in peripheral blood from steady-state SCD patients.

The Montreal Cognitive Assessment (MoCA) is a brief cognitive instrument for the measurement of dementia. The aim of the present study is to provide normative data for the MoCA test in the Greek speaking population and to measure its validity in a clinical group of parkinsonian dementia participants. A total of 710 healthy Greek speaking participants and 19 parkinsonian dementia participants took part in the study. Both, the MoCA test and a neuropsychological test battery (digit span, semantic verbal fluency, phonemic verbal fluency, Color Trails Test) were administered to the normative and clinical samples. The test was found to correlate with all neuropsychological tests used in the test battery and it showed high discriminant validity (optimal screening cutoff point = 21, sensitivity = 0.82, specificity = 0.90) in the parkinsonian dementia participants. Further research is needed to use it in larger clinical samples and in different neurological diseases.

The Color Trails Test (CTT) is a neuropsychological test that measures perceptual tracking and sustained and divided attention. Recently, its use has been increased in neurological diseases such as Alzheimer's disease, brain injury, and subclinical infarction. The aim of the present study was to provide normative data for the CTT in the Greek population. A total of 321 native Greek speakers with various professional backgrounds took part in the study. Exclusion criteria involved the existence of neurological and psychiatric diseases, history of alcohol and/or drug dependence, traumatic brain injury, and a Mini-Mental State Examination score below 27. Our results showed that age and education are important factors to consider for the interpretation of scores in all CTT variables. Older participants took more time and exhibited more errors, more near-misses, and more prompts compared with younger participants. Also, more-educated participants took less time, made fewer errors, had fewer near-misses, and rewired fewer prompts compared with less educated participants. CTT is a promising tool for the measurement of attention in the Greek population. Further research is needed to use this test in Greek patients with various neurological diseases.