bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Integrin-Linked Kinase (ILK) Inhibitor QLT0267 on Multiple Myeloma Cells and Evaluation of ILK as a Therapeutic Target in Multiple Myeloma.
Authors: Stühmer Thorsten , Steinbrunn Torsten , Grella Evelyn , Bargou Ralf C. 
Published: October 2019

Abstract
Multiple myeloma (MM) is a fatal plasma cell tumor that accounts for about 1% of cancers. A hallmark of the disease is its location in the bone marrow where the tumor cells receive prosurvival support from the microenvironment and cause extensive osteolytic damage. Novel drugs are currently being developed into a range of new treatment options. However, because the problems of cancer relapse and eventual selection of therapy-resistant offspring remain, additional therapeutic targets should still be investigated. ILK is a multifunctional protein that, as an adaptor and/or as a kinase, may relay adhesion- and growth factor receptor-mediated signals to downstream signaling cascades that promote growth and survival. We have analysed the expression of ILK in MM cells and have tested the effects of a novel small molecule ILK-inhibitor (QLT0267; QLT Inc., Vancouver, Canada) in MM cell lines, primary MM tumor cells and healthy cells, respectively. ILK expression at either cDNA or protein level was detectable in virtually every MM sample tested. Treatment with QLT0267 for up to 3 days resulted in extensive apoptotic death in MM cell lines (EC50 values below 10 microM in 8/9 MM cell lines tested) and in a majority of primary (anti-CD138-purified) MM samples (EC50 values below 10 microM in 8/14 primary MM samples tested). Drug treatment led to rapid decreases in the levels of phospho-STAT3, phospho-GSK3beta and total Akt protein, whereas levels of ILK and of phospho-ERK were unaffected or, in the latter case, showed a slight increase. Similar to other current pharmacologic approaches, targeting ILK may have several detrimental impacts on the signaling network that sustains MM cells. Such pleiotropic effects could prove valuable for combination treatments. The survival of peripheral blood mononuclear cells and of bone marrow stromal cells (BMSCs) at 20 microM QLT0267 was just slightly affected, indicating that the scope for establishment of a therapeutic window in MM might exist. High (20 microM) concentrations of QLT0267 gradually (and reversibly) promoted detachment of BMSCs from the culture dish, indicating that the drug might be useful to temporarily impair their effectiveness to support myeloma cells. Taken together, these experiments provide a rationale to further explore the utility of ILK-inhibition for the treatment of MM.
AT9283, a Potent Inhibitor of JAK2, Is Active in JAK2 V617F Myeloproliferative Disease Models.
Authors: Squires Matthew S. , Curry Jayne E. , Dawson Mark A. , Scott Mike A. , Barber Kelly , Reule Matthias , Smyth Tomoko , Wallis Nicola , Yule Murray , Thompson Neil T. , Lyons John F. , Green Anthony R. 
Published: October 2019

Abstract
AT9283 is a potent inhibitor of JAK2, JAK3, mutant Abl kinase (T315IAbl) and Aurora kinases A and B all of which have an IC50 <5nM. The compound is currently in early phase clinical development for hematological malignancies. Multitargeted kinase inhibitors may be of particular value as anti-proliferative agents as a consequence of their ability to inhibit several signalling pathways simultaneously. Many of the kinases targeted by AT9283 lie in signalling pathways activated by oncogenes and may contribute in a positive way to the anti-tumour action of the compound. Here we describe the characterisation of the anti-tumour effects of AT9283 in models of JAK2-dependent disease The JAK2 V617F mutation has been identified in more than 95% of patients with Polycythemia vera and in 50 to 60% of patients with Essential Thrombocythemia and myelofibrosis. JAK2 is a key modulator of cytokine signalling, transducing signals from cell surface receptors via the JAK/STAT pathway. The point mutation renders the kinase constitutively active and induces cytokine-independent proliferation of cell lines harboring mutated JAK2. AT9283 was profiled against two cell lines harboring JAK2 V617F (HEL, SET-2) as well as two lines with a dependence on cytokine signalling through wild type endogenous JAK2 for survival (BA/F3 wt, TF-1, stimulated with IL3). These lines were compared with two additional leukaemia cell lines not dependent upon JAK signalling for survival, K562 (Ph+CML) and HL60 (N-Ras PML). In each case the dominant effect of the compound is to inhibit cell growth through JAK inhibition where the survival of the cell line depends on signalling through the JAK2 pathway. In contrast the cell lines less dependent on JAK2 for survival show a polyploid phenotype indicative of Aurora kinase inhibition. In HEL cells AT9283 inhibits phosphorylation of JAK2 pathway markers such as phospho-STAT5 (Tyr694) at 100nM, a dose consistent with concentrations required to inhibit the proliferation of these cells. Consequently, the cell cycle profiles generated when either K562 or HL60 cells are treated with AT9283 suggest that endoreduplication derived from Aurora inhibition is the dominant phenotype. In a JAK driven system the dominant phenotype observed is induction of apoptosis via inhibition of JAK. In an in vivo model, administration of a single dose of AT9283 to the JAK-dependent HEL xenograft, inhibited phosphorylation of STAT5 indicating JAK2 inhibition in the tumour tissue and an efficacy study demonstrated growth inhibitory effects of 9283 in this model. Finally the activity of AT9283 was tested in primary assays using cells taken either from healthy volunteers or patients diagnosed with MPD. These data together support further clinical investigation of the compound in patients with a myeloproliferative disorder.
The Presence of the JAK2V617F Mutation in Primary Myelofibrosis and Its Allele Burden in Polycythemia Vera Predict Chemosensitivity to Hydroxyurea.
Authors: Sirhan Shireen , Huang Jocelin , Li Chin-Yang , Tefferi Ayalew 
Published: October 2019

Abstract
Background: Almost all cases of polycythemia vera (PV) and more than half of those with either essential thrombocythemia (ET) or primary myelofibrosis (PMF) harbor JAK2V617F. It has been previously shown that V617F-positive ET patients, as opposed to their mutation-negative counterparts, require lower doses of hydroxyurea (HU) for control of their platelet count. In the current study we looked for a similar scenario in PMF and PV.
Methods: Study patients were identified by database inquiry based on the presence of treatment history with HU and adequate follow-up. Qualitative (PMF) and quantitative (PV) analysis of JAK2V617F was performed according to previously published allele specific PCR-based methods. Mutation analysis was performed on bone marrow samples collected at time of initial diagnosis or within one year of diagnosis. HU treatment response assignment was according to criteria set by the International Working Group for Myelofibrosis Research and Treatment. In PV, a complete response (CR) required normalization of blood counts associated with a more than 50% benefit in both phlebotomy requirement and splenomegaly. Partial response (PR) required either becoming phlebotomy independent or normalization of blood counts or a greater than 50% improvement in splenomegaly.
Results: The study cohort consisted of 69 patients with PMF (median age 62 years; 36% females) and 56 patients with PV (median age 67 years; 45% females). In PMF, by univariate analysis, HU response was associated with a shorter disease duration (p=0.008), absence of previous therapy (p=0.01), older age at diagnosis (p=0.009), and presence of V617F (p=0.02). On multivariable analysis, only the latter retained its significance; HU response rate was 48% in V617F-positive patients (11/21 patients) and 8% in mutation-negative cases (1/12 patients). In PV, V617F allele burden correlated directly with HU response (p=0.05) and, in responding patients, inversely with HU dose (p=0.01; Figure). All 9 patients with upper quartile V617F allele burden responded (8 with CR) whereas 6 of the 11 (55%) HU non-responders displayed V617F allele burden in the lower quartile range. Among the 45 HU responders, the maximum daily dose of HU employed in all 9 patients in the upper quartile allele burden range and 4 of the 5 in the middle quartiles range was below 1500 mg. In contrast, 8 of the 31 patients (26%) in the lower allele burden quartile range required doses at 1.5 gm or more per day.
Conclusion: The current study suggests that response to HU therapy in both PMF and PV is more robust in the presence of JAK2V617F; the particular information is useful in identifying PMF patients who are likely to benefit from HU therapy and in individualizing HU starting dose in PV patients.
Figure Figure
Comparison of Immunohystochemical (IHC) Expression Profile and Prognosis in 98 Patients with Diffuse Large B Cell Non-Hodgkin’s Lymphoma (DLBCL) with and without Human Immunodeficiency Virus (HIV) Infection.
Authors: Xicoy Blanca , Ribera Josep-Maria , Morgades Mireia , Mate Jose-Luis , Tapia Gustavo , Navarro Jose-Tomas , Ruiz Tatiana , Ariza Aurelio , Feliu Evarist 
Published: October 2019

Abstract
In some studies DLBCL germinal center (GC) phenotype has better prognosis than non-germinal center (non-GC) according to IHC expression profile by tissue microarrays (TMA), but the frequency and prognostic significance of ICH expression profile in HIV-related DLBCL is not well known. The objectives of this study were to characterize the IHC expression pattern in 98 pts with DLBCL, of which 34 were HIV positive, and to evaluate its prognostic significance. From August 1991 to February 2006, 98 consecutive pts with DLBCL from a single institution were retrospectively studied. Group A: HIV-negative DLBCL pts, n=64; group B: HIV-related DLBCL pts, n=34. TMA was constructed containing sections of paraffin-embedded tissue samples and cases were assessed for IHC study (expression of CD10, BCL-6, MUM-1). Patients were classified as CG pattern (CD10+ or CD10−/BCL-6+/MUM1−) and non-GC pattern (any other combination of these markers). Clinical and biological characteristics as well as overall survival (OS) and disease-free survival (DFS) were analyzed comparing: 1-GC vs non-GC pattern within groups A and B; 2-GC pattern from groups A vs B; 3-Non-GC pattern from groups A vs B; 4-non-GC pts from group A vs non-GC pts from group B, considering only the pts treated with highly active antiretroviral therapy (HAART) (n=13/32, 41%). There were no differences in clinico-biological parameters according to IHC pattern within each group. The only differences in OS and DFS between subgroups were observed in HIV-related DLBCL with non-GC pattern, whose survival was poorer than non-HIV related pts. Whithin the former group, only those pts not receiving HAART retained their bad prognosis. 5-year OS (95% CI) and 5-year DFS (95%CI) are summarized in the table. In our series the frequency of GC and non-GC subtypes was not significantly different in HIV positive and negative pts with DLBCL. Only those pts with HIV-related DLBCL with non-GC expression pattern not receiving HAART had a significantly inferior survival.
The Efficacy of R-ICE Therapy as a Salvage Treatment for Relapse and Refractory Diffuse Large B-Cell Lymphoma.
Authors: Kodaira Makoto , Yokoyama Masahiro , Asai Hiroaki , Yamada Shuhei , Ueda Kyoko , Myojo Tomohiro , Nishimura Tomoko , Mishima Yuko , Sakajiri Sakura , Takeuchi Kengo , Saotome Takashi , Terui Yasuhito , Takahashi Shunji , Hatake Kiyohiko 
Published: October 2019

Abstract
<Background> Patients with relapsed and refractory diffuse large B-cell lymphoma are usually treated with platinum-based salvage chemotherapy. We retrospectively analyzed the efficacy of adding rituximab with ICE as a salvage treatment for relapsed and refractory diffuse large B-cell lymphoma.
<Method>From November 2003 to December 2006, patients with relapsed or refractory de novo diffuse large B-cell lymphoma represented CD20 positivty who received R-ICE (rituximab375mg/m2, Ifosfamide 1200mg/m2, calboplatin 400mg/m2 and etopside100mg/m2 ), were analyzed retrospectively.
<Result>23 patients (19 relapse and 4 reflactory) (M:F=14:9) (median age 69, 28–77) were included. At starting treatment, twelve patients received rituximab and 11 patients were rituximab naive. In all 23 patients, responses were 11 Complete remission (CR), and 6 partial response (PR), resulting in overall response (ORR) was 74.9%. With median follow up of 10.5 months, estimated 1yr-progression free survival (PFS) was 49% and 1yr-overall survival (OS) was 70%.In patients received rituximab, ORR was 66.7% and 5 patiets achieved CR (41.7%).In the without rituximab, ORR was 90.9% and 7 patiets achieved CR (63.6%). No statistical differences were observed in response even with retuximab pretreatment. Estimated 1yr-PFS was 23% and 70% (p=0.0752) and 1yr-OS was 59% and83% (P=0.0049),respectively. NCI-CTC grade 3/4 neutropenia and thrombocytopenia were reported 100% and 91%, For non-hematological adverse event, there were grade 3 liver dysfunction (2/23) and grade 3 arrythmia (1/23). No toxic death was reported in this study.
<Conclusion> R-ICE showed promising efficacy with tolelable toxicity. Available date suggested adding rituximab to ICE is more effective for patients not received rituximab in the pretreament.
R-COMP 21 (Prednisone, Cyclophosphamide, Vincristine, Myocettm and Rituximab) for Frail and Elderly Patients with Aggressive B-Cell Non-Hodgkin Lymphoma: A Pilot Study.
Authors: Isidori Alessandro , Ferrara Felicetto , Alesiani Francesco , Ronconi Sonia , Catarini Massimo , D’Adamo Francesca , Guiducci Barbara , Bernardi Daniele , Visani Giuseppe 
Published: October 2019

Abstract
CHOP chemotherapy is the gold standard treatment for patients with indolent and aggressive non-Hodgkin Lymphomas. However, CHOP is frequently poorly tolerated by frail and elderly patients resulting in dose reductions and consequently lower response and cure rates compared to younger patients. The toxicity and efficacy of nonpegylated liposomal doxorubicin (Myocet™) when substituted for conventional doxorubicin in the CHOP 21 regimen (Doxorubicin, Cyclophosphamide, Vincristine, Prednisone given every 3 weeks) were evaluated in the treatment of frail elderly patients with aggressive non-Hodgkin’s lymphoma. Twenty patients (median age: 73 years, range 61–82) with diffuse large B cell non-Hodgkin lymphoma, either at diagnosis (15 patients) or relapsing (5 patients), were enrolled in the study. At baseline 14/20 (72%) patients had stage III–IV disease. All patients had one or more comorbidity. Eighteen out of 20 patients (90%) had an intermediate or high risk International Prognostic Index score. The median left ventricular ejection fraction (LVEF) before starting chemotherapy was 62% (range 43–73). A total of 111 chemotherapy cycles were administered, with a median of 6 cycles (range 1–8). Of the cycles administered, 19 (17%) were delayed by haematological toxicity. The relative dose intensity for the regimen was 83%. Toxicity was mainly haematological with grade 3 or 4 neutropenia in 16% of cycles and febrile neutropenia in 5%. However, 3/20 patients presented a grade III–IV WHO toxicity (one fatal pulmonary embolism, one congestive heart failure, one ischemic heart failure) while receiving R-COMP chemotherapy. All but one patient were evaluable for response. 13 out of 19 (68%) had a complete response and an additional 5 patients (26%) achieved a partial response. Of the evaluable patients, only 1/19 (5%) did not respond at all to chemotherapy and rapidly died due to progressive disease. With a median follow-up of 14 months (range 7–18) as of July 2007, 15/18 responding patients (83%) are alive and disease free, as well as 3/18 are alive with active disease. In conclusion, the R-COMP 21 is a very effective regimen with promising response rates in frail and elderly patients with high risk aggressive non-Hodgkin lymphoma. Further studies with a larger cohort of patients are warranted to better define the impact of non pegylated liposomal doxorubicin on overall survival of this setting of elderly and particularly frail patients.
Development of Pulmonary Sarcoidosis during Lymphoma Treatment: A Diagnostic Dilemma.
Authors: Campos-Gines Angel F. , Antony Suresh J. , Arango Carmen P. , Landeros Mark M. , Herrada Juan 
Published: October 2019

Abstract
Background: Although the association of sarcoidosis and malignancy has long been described (Brincker, Br J Cancer 1972), so far only 3 patients (pts) have been documented to have developed sarcoidosis during or immediately after chemotherapy for non-Hodgkin lymphoma (NHL) (Kornacker et al. Ann Hematol 2002; Hollister et al. J Clin Oncol 2005).
Methods: Case report. Results: A 50 year-old male with 2-month history of back pain and 20 pound weight loss had a soft tissue mass in the lumbar area biopsied. The pathology revealed a diffuse large B-cell lymphoma. Bone marrow biopsy showed no abnormalities. Computed tomography (CT) and [18F] fluorodioxyglucose positron emission tomography (PET) revealed large bilateral pulmonary masses and extensive periaortic lymphadenopathy. Treatment consisted of chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab every 21 days. 11 days after completion of the 4th cycle, the pt was hospitalized with febrile neutropenia, and received intravenous cefepime and vancomycin with growth-factor support. Pt was released from the hospital on day 20th of the cycle with a white cell count of 15 thousand / uL, mostly neutrophils, and negative blood, sputum, and urine cultures. Because of persistent fever (38.5 °C) and non-productive cough 3 weeks after discharge, CT studies were obtained. In the chest there was no evidence of the previously noted lung masses, and there was the presence of new bilateral diffuse pulmonary infiltrates. Abdominal CT demonstrated near complete resolution of the periaortic lymphadenopathy. A transbronchial biopsy and a bronchoalveolar lavage were obtained, revealing the presence of non-caseating granulomas, and no evidence of malignancy, mycobacteria, or fungal micro-organisms. The serum level of angiotensin-converting enzyme was markedly elevated (112; normal range 9–67). At this point the pt was diagnosed with symptomatic pulmonary sarcoidosis and he was treated with oral prednisone. Follow-up CT evidenced a complete resolution of the pulmonary infiltrates. No further chemotherapy was administered. After a subsequent follow-up of 14 months, the pt remains in complete remission by clinical, serological, and radiographic (CT and PET) criteria.
Conclusions: The diagnosis of new radiographic changes in pts with NHL receiving chemotherapy needs to be histologically confirmed.
A Prospective Multivariate Analysis of Risk Factors Associated with Occurrence of Febrile Neutropenia in Any Cycle in NHL Patients Receiving Chemotherapy.
Authors: Pettengell Ruth , Bosly Andre , Szucs Thomas D. , Jackisch Christian , Leonard Robert , Paridaens Robert , Constenla Manuel , Schwenkglenks Matthias 
Published: October 2019

Abstract
Febrile neutropenia (FN) following chemotherapy often results in hospitalisation and chemotherapy dose delays or reductions in subsequent cycles. Although current guidelines highlight non-Hodgkin lymphoma (NHL) patients receiving standard regimens as having a significant risk of FN, the contribution of additional factors to the overall risk of FN is not fully understood. We present a logistic regression model describing the relationship of various clinical factors with FN occurrence in NHL. Predictors were chosen based on their clinical and statistical significance (5% level) and to allow comparison with other models. Data were obtained from the INC-EU Prospective Observational European Neutropenia Study, which aimed to assess the incidence and predictors of neutropenia, FN and chemotherapy dose limitations in breast cancer and lymphoma. 240 NHL patients were recruited from 37 centres in Belgium, France, Germany, Spain, and the UK. Ann Arbor stages were distributed: I 18%; II 26%; III 17%; IV 40%. Chemotherapy regimens received were 3-weekly CHOP-like (74%), 2-weekly CHOP-like (17%), ACVBP-like (4%) and other regimens (5%). Overall colony stimulating factor (CSF) prophylaxis in patients who had not previously experienced FN was 50%. FN incidence in any cycle was 22%. The resulting logistic regression model of any FN occurrence is shown in the table. Replacing GFR and height with the closely related parameters of age and weight slightly affected predictive ability but did not affect model stability. The area under the receiver operating characteristic curve was 0.84. Using the optimal probability cut-off, model test characteristics were 75% sensitivity and 76% specificity; corresponding to positive and negative predictive values of 48% and 91%, respectively. Low absolute neutrophil or white blood cell count (ANC, WBC), high baseline alkaline phosphatase, low GFR (or high age), low height (or low weight), cardiac comorbidity, recent infection, and high planned chemotherapy dose appeared to increase the risk of FN occurrence. Although chemotherapy dose reduction or delay protected against FN, these are associated with reduced survival in patients receiving CHOP-like regimens. CSF use was a protective factor. These results complement risk factors highlighted in current guidelines.