Proinflammatory chemokine gene expression influences survival of patients with non-Hodgkin’s lymphoma

Patients with multiple myeloma (MM) treated with conventional chemotherapy have an averagesurvival of approximately three years. High dose chemotherapy followed by autologous stem cell transplantation(ASCT), first introduced in the mid-1980s, is now considered the standard therapy for almost all patientswith multiple myeloma, because it prolongs overall survival and disease free survival. Between November 1997and October 2006, 122 patients with MM (58 females, 64 males, median age 51.0 years [± 7.98] range: 30–66years) were transplanted in the Department of Hematooncology and Bone Marrow Transplantation at the MedicalUniversity of Lublin: 47 patients were in complete remission or in unconfirmed complete remission,66 patients were in partial remission, and nine had stable disease. Of these, there were 95 patients with IgG myeloma,16 with IgA myeloma, one with IgG/IgA, one with IgM myeloma, five with non secretory type, two withsolitary tumor and two with LCD myeloma. According to Durie-Salmon, 62 patients had stage III of the disease,46 had stage II and four had stage I. Most patients (69/122) were transplanted after two or more cycles ofchemotherapy, 48 patients were transplanted after one cycle of chemotherapy, one patient after surgery and rtg--therapy and four patients had not been treated. In mobilisation procedure, the patients received a single infusionof cyclophosphamide (4–6 g/m2) or etoposide 1.6 g/m2 followed by daily administration of G-CSF until theperipheral stem cells harvest. The number of median harvest sessions was 2.0 (± 0.89) (range: 1–5). An averageof 7.09 (± 33.28) × 106 CD34+ cells/kg were collected from each patient (range: 1.8–111.0 × 106/kg). Conditioningregimen consisted of high dose melphalan 60–210 mg/m2 without TBI. An average of 3.04 (± 11.59) × 106CD34+ cells/kg were transplanted to each patient. Fatal complications occured in four patients (treatment--related mortality = 3.2%). In all patients there was regeneration of hematopoiesis. The median number of daysfor recovery to ANC > 0.5 × 109/l was 13 (± 4.69) (range: 10–38) and platelets recovery to > 50 × 109/l was 25days (± 11.65) (range: 12–45). Median time of hospitalization was 22 days (± 7.14) (range: 14–50). Patientswere evaluated on day 100 after transplantation: 74.9% achieved CR and nCR, 14.3% were in PR, 5.4% had SDand 5.4% had progressed. Median of OS was 45 months (± 30.67). OS at 3-years was 84% and at 7-years 59%.Median PFS was 25 months (± 26.13). PFS at 3-years was 68%, and at 7-years was 43%. At present (November2009) 52 patients (42%) are still alive. High-dose chemotherapy followed by autologous stem cell transplantationis a valuable, well tolerated method of treatment for patients with MM that allows the achievement of long--lasting survival

Proinflammatory chemokine gene expression influences survival of patients with non-Hodgkin’s lymphoma

The migration, survival and proliferation of cells is the basis for all physiologic and pathologic processes in the human body. All these reactions are regulated by a complex chemokine network that guides lymphocytes homing, chemotaxis, adhesion and interplay between immunologic system response cells. Chemokines are also responsible for metastatic dissemination of cancers, including Hodgkin&#8217;s and non-Hodgkin&#8217;s lymphomas. The purpose of this study was to determine chemokine gene expression (CXCL8, CXCL10, CCL2, CCL3, CCL4 and CCL5) in lymphoma lymph nodes compared to their expression in reactive lymph nodes. We also analyzed the influence of chemokine gene expression on the survival of lymphoma patients. Chemokine gene expression was evaluated in 37 lymphoma lymph nodes and in 25 samples of reactive lymph nodes. Gene expression of chemokines CXCL8, CXCL10, CCL2, CCL3, CCL4 and CCL5 was measured using the PCR method. Statistical analysis was performed using CSS Statistica for Windows (version 7.0) software. Probability values < < 0.05 were considered statistically significant and those between 0.05 and 0.1 as indicative of a trend. We found lower CXCL8 and CXCL10 gene expression in lymphoma lymph nodes compared to reactive lymph nodes. In the cases of CCL2 and CCL3, expression in lymphomas was higher than in reactive lymph nodes. Patients with high expression of CCL2 and CXCL10 had shorter survival. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 2, pp. 240&#8211;247

A Threefold Dose Intensity Treatment With Ifosfamide, Carboplatin, and Etoposide for Patients With Small Cell Lung Cancer: A Randomized Trial

Background The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). Methods Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/m2, paclitaxel at 175 mg/m2, and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. Results Median relative dose intensity in the High-ICE arm was 293% (range = 174%-392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% CI = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% CI = 67% to 87%] and n = 48 [68%, 95% CI = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High-ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade ≥ 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High-ICE treatment was predictably associated with severe myelosuppression, and five patients (8%) died from toxicity. Conclusions The long-term outcome of SCLC was not improved by raising the dose intensity of ICE chemotherapy by threefol

Diagnostyka i leczenie raka tarczycy - rekomendacje polskie

Obecna edycja Polskich Rekomendacji Diagnostyki i Leczenia Raka Tarczycy została przygotowana i zaakceptowana łącznie przez wszystkie wymienione w tytule towarzystwa naukowe z uwzględnieniem zasad EBM, poprzez porównanie najnowszych rekomendacji międzynarodowych i dostosowanie ich do polskich warunków. Biopsja aspiracyjna cienkoigłowa (BAC) była i pozostaje najważniejszym sposobem oceny ryzyka złośliwości w guzku tarczycy. Obecne rekomendacje zmieniają jednak kryteria wyboru miejsca do BAC. W zgodzie z poprzednimi wersjami rekomendacji zaleca się wykonanie BAC pod kontrolą USG, ale wielkość guza przestaje być jedynym i najważniejszym kryterium wyboru miejsca do BAC. Znacznie istotniejsza jest obecność cech ryzyka ultrasonograficznego, które powinny stanowić nadrzędne kryterium przy wyborze miejsca do BAC. Guzki mniejsze od 0,5 cm we wszystkich wymiarach mogą podlegać obserwacji bez BAC, o ile nie ma klinicznych cech wzmożonego ryzyka złośliwości. W przypadku wielu guzków, liczba i siła predykcyjna ultrasonograficznych cech ryzyka decyduje o kolejności BAC. Przy spełnieniu tych warunków uzyskanie wyniku łagodnego z 3 zmian o najwyższym ryzyku stanowi wystarczające wykluczenie złośliwości wola. Drugą nową decyzją w niniejszych rekomendacjach jest przyjęcie sześciostopniowego podziału wyników badania cytologicznego BAC. Zgodnie z propozycją NCI, wynik łagodny (przy spełnionych kryteriach wiarygodności badania) obciążony jest zaledwie 1-procentowym ryzykiem wyniku fałszywie ujemnego, nie wymaga więc powtarzania, o ile nie wystąpi znaczący klinicznie wzrost guza lub pojawienie się nowych ultrasonograficznych cech ryzyka. Z drugiej strony, oprócz kategorii "guz złośliwy" wprowadzono kategorię "podejrzenie złośliwości" obciążoną 50-75-procentowym ryzykiem potwierdzenia w badaniu histopatologicznym. Dawne rozpoznanie "guzek pęcherzykowy" lub "guzek oksyfilny" zostało zastąpione bardziej dokładnym rozpoznaniem "podejrzenie nowotworu pęcherzykowego". Należy podkreślić, że to rozpoznanie (sugerujemy także używanie skrótu PNP) nie oznacza, że patolog nie jest pewny, że guz należy do tej kategorii. Określenie "podejrzenie NP" odnosi się jedynie do faktu, że jednoznaczne stwierdzenie nowotworu pęcherzykowego (zarówno gruczolaka, jak i raka) nie jest możliwe w badaniu cytologicznym. Dlatego chorzy z tym rozpoznaniem są kandydatami do leczenia chirurgicznego, ale w przypadku zmian małych, poniżej 2&#8211;3 cm średnicy, i braku klinicznych cech złośliwości rekomendacje dopuszczają tu strategię zachowawczą - głównie uważną obserwację. Wynika to z faktu, że guzy tarczycy z rozpoznaniem PNP są w Polsce obciążone zaledwie 5-10-procentowym ryzykiem ujawnienia złośliwości w pooperacyjnym badaniu histopatologicznym, w przeciwieństwie do krajów anglosaskich, w których wobec braku historii niedoboru jodu, to ryzyko jest większe. Jeżeli patolog nie jest pewny czy obserwowana zmiana spełnia kryteria kategorii "podejrzenie nowotworu pęcherzykowego", powinien postawić rozpoznanie "zmiany pęcherzykowej bliżej nieokreślonej". Po takim rozpoznaniu wskazane jest wykonanie kolejnej BAC, na ogół po 3-6 miesiącach, jeżeli nie ma cech klinicznych wysokiego ryzyka złośliwości. Należy podkreślić, że jeżeli materiał pobrany cytologicznie nie spełnia kryteriów wiarygodności, patolog powinien wyraźnie stwierdzić, że biopsja jest niediagnostyczna. Leczenie raka tarczycy opiera się na całkowitym wycięciu tarczycy i odpowiednim do zaawansowania zakresie operacji węzłów chłonnych. Tylko w raku brodawkowatym, w którym ognisko raka jest mniejsze od 1 cm w badaniu histopatologicznym, można zaakceptować operację o mniejszym zakresie i nie ma wskazań do leczenia jodem radioaktywnym. Leczenie to przeprowadza się natomiast we wszystkich przypadkach raka tarczycy o zaawansowaniu T3-T4 lub N1 lub M1. Wskazania do leczenia radiojodem przy zaawansowaniu T2N0M0 są mniej jednoznacznie, niemniej rekomendacje polskie podkreślają dobre doświadczenie ośrodków polskich w zapobieganiu wznowie w ten sposób. Po leczeniu konieczne jest podanie L-tyroksyny, której dawkę ustala się w zależności od zaawansowania raka. Odstępuje się jednak od stosowania dawek supresyjnych u chorych w remisji. Także częstość i zakres dalszego monitorowania choroby są zależne od jej zaawansowania i wyników dotychczasowego leczenia. (Endokrynol Pol 2010; 61 (5): 518-568

Badanie wieloośrodkowe rozpoznań raka tarczycy

Introduction: In the front of the problems related to the differentiation between benign and malignant thyroid tumors we decided to perform a multicentre study in order to validate diagnoses of malignant thyroid tumors and assess the inter-observer variability. Material and methods: Material included 690 cases of malignant and benign thyroid lesions with primary histopathology established in 1985-1999. These cases were selected to multicentre study. The studies were sent from centres which agreed to participate in the project and than coded in the independent centre - Department of Nuclear Medicine and Endocrine Oncology. 40 pathologists from 25 centres provided their diagnoses which were compared with the reference ones. Results: 10 547 diagnoses were evaluated, both on their accuracy of the distinction between malignant and benign lesions and on their accuracy of cancer histotype definition. The reference diagnosis was made by an agreement between four expert pathologists (D.L., S.S., J.S. and A.K.). The participants diagnosed 21% of cases differently than experts. Concerning the diagnosis of cancer histotype, the difference between participants diagnosis and the reference one was even higher. The best concordance was achieved in the diagnosis of papillary thyroid cancer, however, on the cost of cancer overdiagnosis by some participants. Follicular cancer was diagnosed accurately only in 75.4% of cases. Conclusion: The study documents a high inter-observer variability of thyroid cancer diagnosis and confirms the lesser accuracy of diagnosis of follicular cancer.Wstęp: Histopatologia guzów tarczycy należy do jednych z trudniejszych działów patomorfologii. Wzrostowi liczby badań towarzyszy wiele problemów diagnostycznych, w tym najistotniejszych dotyczących różnicowania zmian łagodnych od złośliwych. Uważa się, że powtarzalność rozpoznania histopatologicznego w rakach tarczycy jest zdecydowanie niższa od spodziewanej. To stanowiło podstawę dla zaplanowania i realizacji wieloośrodkowego badania w celu sprawdzenia powtarzalności, wiarygodności i stopnia niezgodności histopatologicznej diagnostyki raków tarczycy. Materiał i metoda: Materiał stanowiły 690 rozpoznania pierwotne nadesłanych przypadków, rozpoznania referencyjne ustalone przez 4 ekspertów oraz rozpoznania uczestników prowadzonego w latach 2000-2002 badania wieloośrodkowego. Preparaty dostarczone z ośrodków, które wyraziły chęć uczestniczenia w grancie zostały zakodowane w ośrodku niezależnym - Zakładzie Medycyny Nuklearnej i Endokrynologii I.O. w Gliwicach. Preparaty po zakodowaniu były sukcesywnie rozsyłane do ośrodków uczestniczących w badaniu i oceniane przez uczestników badania jak i niezależnie przez czterech ekspertów. Na podstawie tych ostatnich rozpoznań było możliwe ustalenie puli rozpoznań referencyjnych bez konieczności powtórnej analizy preparatów. Rozpoznania te stanowiły "złoty standard", do którego odnoszono rozpoznania uczestników. Wyniki: 40 uczestników grantu postawiło łącznie 10 547 rozpoznań, diagnozując przeciętnie 264 przypadki. Rozpoznań niezgodnych co do złośliwości zmiany było 2262, co stanowi 21,44%. Sześciu z uczestników wykazało ponad 33% rozpoznań niezgodnych z rozpoznaniem referencyjnym. Odsetek rozpoznań niezgodnych wzrósł znacznie, gdy w analizie uwzględniono szczegółowy typ histologiczny raka i w tym przypadku co trzeci uczestnik nie zgadzał się z rozpoznaniem referencyjnym. Najwyższą zgodność rozpoznań, sięgającą 90%, odnotowano w ocenie raków brodawkowatych Uczestnicy stawiający rozpoznanie raka zgodne w wysokim procencie z rozpoznaniami referencyjnymi zdecydowanie rzadziej diagnozowali zgodnie z ekspertami zmiany łagodne. Rak pęcherzykowy zgodnie oceniono w 75,4% jednak aż 1/5 uczestników diagnozowała ponad 40% przypadków inaczej niż eksperci. Wniosek: Porównanie zgodności rozpoznań raka tarczycy między poszczególnymi patologami pozwala uściślić źródła błędów diagnostycznych oraz wyznaczyć kryteria dla poprawnej diagnostyki, które różnią się w zależności od typu raka

Recommendations for the management of tuberculosis in children — KOMPASS TB. Part 1: Tuberculosis prevention

Since the second half of the 20th century the incidence of tuberculosis has been declining in Poland. Despite this, current epidemiological data still support the need for the continued mass BCG vaccination in Poland in the near future. Apart from the protection against severe hematogenous forms of tuberculosis, vaccination lowers the risk of infection with Mycobacterium tuberculosis. Primary and acquired immunodeficiency, including immunity disorders associated with an ongoing treatment, are contraindications to BCG vaccination. The most common adverse effects following BCG vaccination are reactions at the site of injection and in regional lymph nodes, which usually does not require treatment. Methods of tuberculosis prevention, particularly recommended in low-incidence countries, include: diagnostic investigations of patients who had contacts with pulmonary tuberculosis as well as an active detection and treatment of latent Mycobacterium tuberculosis infection. Latent tuberculosis infection can be identified on the basis of positive results of the tuberculin skin test or interferon-gamma release assays after the active disease has been ruled out. This condition does require prophylactic treatment

Role of Donor Activating KIR–HLA Ligand–Mediated NK Cell Education Status in Control of Malignancy in Hematopoietic Cell Transplant Recipients

AbstractSome cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I–dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P = .020, Pcorr = .039; HR, 1.51; P = .020, Pcorr = .040; and for TTP: HR, 1.82; P = .049, Pcorr = .096; HR, 1.72; P = .096, Pcorr = .18; and HR, 1.65; P = .11, Pcorr = .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P = .00031, Pcorr = .00062; and HR, 1.43; P = .019, Pcorr = .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P = .00022, Pcorr = .00045; and HR, 3.82; P = .027, Pcorr = .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable

Accelerated Cosmological Models in First-Order Non-Linear Gravity

The evidence of the acceleration of universe at present time has lead to investigate modified theories of gravity and alternative theories of gravity, which are able to explain acceleration from a theoretical viewpoint without the need of introducing dark energy. In this paper we study alternative gravitational theories defined by Lagrangians which depend on general functions of the Ricci scalar invariant in minimal interaction with matter, in view of their possible cosmological applications. Structural equations for the spacetimes described by such theories are solved and the corresponding field equations are investigated in the Palatini formalism, which prevents instability problems. Particular examples of these theories are also shown to provide, under suitable hypotheses, a coherent theoretical explanation of earlier results concerning the present acceleration of the universe and cosmological inflation. We suggest moreover a new possible Lagrangian, depending on the inverse of sinh(R), which gives an explanation to the present acceleration of the universe.Comment: 23 pages, Revtex4 fil

Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1

Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analyzed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV)

The ESCAPE project : Energy-efficient Scalable Algorithms for Weather Prediction at Exascale

In the simulation of complex multi-scale flows arising in weather and climate modelling, one of the biggest challenges is to satisfy strict service requirements in terms of time to solution and to satisfy budgetary constraints in terms of energy to solution, without compromising the accuracy and stability of the application. These simulations require algorithms that minimise the energy footprint along with the time required to produce a solution, maintain the physically required level of accuracy, are numerically stable, and are resilient in case of hardware failure. The European Centre for Medium-Range Weather Forecasts (ECMWF) led the ESCAPE (Energy-efficient Scalable Algorithms for Weather Prediction at Exascale) project, funded by Horizon 2020 (H2020) under the FET-HPC (Future and Emerging Technologies in High Performance Computing) initiative. The goal of ESCAPE was to develop a sustainable strategy to evolve weather and climate prediction models to next-generation computing technologies. The project partners incorporate the expertise of leading European regional forecasting consortia, university research, experienced high-performance computing centres, and hardware vendors. This paper presents an overview of the ESCAPE strategy: (i) identify domain-specific key algorithmic motifs in weather prediction and climate models (which we term Weather & Climate Dwarfs), (ii) categorise them in terms of computational and communication patterns while (iii) adapting them to different hardware architectures with alternative programming models, (iv) analyse the challenges in optimising, and (v) find alternative algorithms for the same scheme. The participating weather prediction models are the following: IFS (Integrated Forecasting System); ALARO, a combination of AROME (Application de la Recherche a l'Operationnel a Meso-Echelle) and ALADIN (Aire Limitee Adaptation Dynamique Developpement International); and COSMO-EULAG, a combination of COSMO (Consortium for Small-scale Modeling) and EULAG (Eulerian and semi-Lagrangian fluid solver). For many of the weather and climate dwarfs ESCAPE provides prototype implementations on different hardware architectures (mainly Intel Skylake CPUs, NVIDIA GPUs, Intel Xeon Phi, Optalysys optical processor) with different programming models. The spectral transform dwarf represents a detailed example of the co-design cycle of an ESCAPE dwarf. The dwarf concept has proven to be extremely useful for the rapid prototyping of alternative algorithms and their interaction with hardware; e.g. the use of a domain-specific language (DSL). Manual adaptations have led to substantial accelerations of key algorithms in numerical weather prediction (NWP) but are not a general recipe for the performance portability of complex NWP models. Existing DSLs are found to require further evolution but are promising tools for achieving the latter. Measurements of energy and time to solution suggest that a future focus needs to be on exploiting the simultaneous use of all available resources in hybrid CPU-GPU arrangements