bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1 Clinical Trial of a Novel Proteasome Inhibitor (NPI-0052) in Patients with Lymphomas and Solid Tumors.
Authors: Kurzrock Razelle , Hamlin Paul , Younes Anas , Hong David , Gordon Michael , Spear Matthew A. , Palladino Michael A. , Lloyd G. Kenneth , Longenecker Angie M. , Neuteboom Saskia T.C. , Cropp Gillian F. , Hannah Alison , Aghajanian Carol 
Published: October 2019

Abstract
NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with activity in multiple myeloma, lymphoma, leukemia and solid tumor models. Phase 1 dose escalation studies are ongoing in patients with myeloma, lymphomas and solid tumors. Data from the Phase 1 study in patients with lymphomas or solid tumors are presented herein to examine the endpoints of pharmacodynamics (proteasome inhibition), pharmacokinetics and safety at doses below the MTD. Patients in this study were treated with NPI-0052 administered as a weekly IV bolus, for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. In addition to weekly safety monitoring, proteasome inhibition and pharmacokinetics were assayed after the 1st and 3rd dose and with intrapatient dose escalations. Sixteen patients have been treated at doses ranging from 0.0125 mg/m2 to 0.112 mg/m2 for up to 7 cycles without reaching an MTD. Although, one SAE of MRSA sepsis and renal failure was reported at a dose of 0.1 mg/m2, drug related adverse events have not been reported at 0.112 mg/m2. Proteasome inhibition in whole blood has been assayed from 0.0125 mg/m2 through 0.075 mg/m2, with results ranging from no inhibition to 63% inhibition of CT-L activity and indication of a correlation of inhibition with dose, inclusive of intrapatient dose increases. Preliminary pharmacokinetic data demonstrate a rapid elimination half-life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L. No responses have been confirmed, however, 4 patients have had stable disease for 4 or more months, including patients with hepatocellular carcinoma (6 months), adenoid cystic carcinoma (4 months and 4 months), and cervical carcinoma [7 months with investigator reported complete resolution of target (lymph node) lesion(s) to palpation]. These data suggest that NPI-0052 is affecting parameters relevant to pharmacodynamics, pharmacokinetics and potentially clinical benefit at doses below the MTD. Dose escalation continues to define a recommended phase 2 dose and further investigate the relevance of these outcomes in larger Recommended Phase 2 Dose Cohorts.
Prognostic Significance of Molecular Cytogenetics in Chinese Patients with Chronic Lymphocytic Leukemia: A Prospective Unicentric Analysis.
Authors: Xu Wei , Li Jianyong , Li Li , Wu Yujie , Yu Hui , Qiu Hongxia , Fan Lei , Ruan Changgeng 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western countries, however, infrequent in the Eastern. It is characterized by a highly variable clinical course; some patients survive more than 20 years, whereas others die within a few months of diagnosis. The characteristics of Chinese patients with CLL compared with the Western countries have not yet been clarified. The aim of this study was to prospectively explore characteristics and prognostic significance of molecular cytogenetic aberrations in Chinese patients with CLL. Interphase fluorescence in situ hybridization (FISH) and a panel of probes (LSI D13S319,LSI p53,LSI ATM,CEP 12,LSI MYB,LSI IGHC/IGHV) were used to detect cytogenetics abnormalities in 95 patients with CLL. Cytogenetics aberrations and their association with some other prognostic factors were analyzed. Kaplan-Meier was used for survival time. Out of the 95 CLL patients, molecular cytogenetic aberrations were found in 69 (72.6%) cases and 25 (26.3%) patients showed more than two kinds of abnormalities. The most frequent abnormalities detected were del(13q14) in 46 cases (48.4%), followed by trisomy of chromosome 12 in 22 patients (23.2%), 14q32 rearrangement in 21 patients (22.1%), del(17p13) in 16 patients (16.8%), del(11q22) in 9 patients (9.5%) and del(6q23) in 5 patients (5.3%). There were no significant differences of molecular cytogenetic aberrations in sex, age, Binet stages, peripheral lymphocyte count, and the levels of lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), and ZAP-70. The TP53 and ATM gene deletion rates were higher in the group of CD38 high expression than that in the group of low expression (P=0.047 and P=0.001). No patient with TP53 and ATM gene deletion achieved complete response (CR) among 41 patients received treatment with fludarabine. The survival time was shorter in patients with high levels of LDH (P=0.028), β2-MG (P=0.012), and CD38 (P=0.000), and with TP53 gene deletion (P=0.000). Patients with sole del(13q14) had longer survival time than those with other abnormalities (P=0.044). It was showed that panel FISH has greatly increased the sensitivity of cytogenetic analyses and del(13q14) was the most frequent abnormality in CLL. Detection of molecular cytogenetic aberrations with FISH had important prognostic significance in CLL. The patients with sole del(13q14) had favorable outcome, and with del(17p13) had poor outcome.
Alemtuzumab (ALZ) Is an Effective Treatment for Both Primary and Relapsed Severe Paraneoplastic Pemphigus (PNP) Associated to B-Cell Chronic Lymphocytic Leukemia (CLL).
Authors: Bech Rikke , Baumgartner-Nielsen Jane , Peterslund N.A. , Steiniche Torben , Bang Karen , Deleuran Mette , d’Amore Francesco 
Published: October 2019

Abstract
ALZ is a monoclonal antibody used in the treatment of a variety of lymphoproliferative diseases, primarily CLL. PNP is a severe mucocutaneous disease often associated with B-cell malignancies. Besides distinct clinical and histopathological features, a correct PNP diagnosis relies on the demonstration by direct immunofluorescence of intercellular and basement membrane IgG deposits in the affected tissue. PNP is often refractory to immunosuppressive drugs and has frequently a fatal outcome. We report three cases, where sustained remissions of both PNP and CLL were induced by ALZ. In two of these cases, ALZ was able to reinduce a sustained PNP remission at the reappearence of the disorder years after the primary treatment. In all cases, the PNP diagnosis was confirmed by immunofluorescence. A 68-year old male with a 4-year CLL history developed blisters and ulcers on the extremities and trunk and severe stomatitis. Despite immunosuppression with steroids, fludarabine, cyclophosphamide, ciclosporin A, and azathioprin, PNP exacerbated. A standard 12-weeks ALZ schedule was initiated. PNP lesions started to regress under the last weeks of treatment and resolved completely within a few further weeks. A bone marrow biopsy showed a morphological and flowcytometric CLL remission. Now, 30 months after ALZ, the patient is still in remission without evidence of either PNP or CLL activity. Almost a year after this first case, a 77-year old male with a 3-year CLL history, presented with severe mucocutaneous lesions of the lips, oro-esophageal cavity, penis and extremities. PNP was diagnosed and a standard 12-weeks ALZ schedule was initiated. As in the first case, the lesions began to regress during the last weeks of treatment and normalized within the subsequent 8 weeks. At present, 1½ year after ALZ, the patient is well displaying only discrete residual PNP activity (left tongue margin, and praeputium). In the third case, a 80-year old woman with a B-CLL diagnosed 4 years previously, a severe PNP involving skin (upper trunk and extremities) and mucosae (anal and vagina) developed in association with marked CLL progression. After some unsuccessful immunosuppressive attempts, alemtuzumab treatment was initiated. All PNP lesions disappeared within a few weeks.
Conclusion: ALZ should be considered as a treatment option in severe CLL-associated PNP.
Prognostic Impact of Cancer Testis Antigens Expression in Advanced Stage Multiple Myeloma Patients.
Authors: Andrade Valéria C.C. , Vettore André L. , Almeida Manuella S.S. , Oliveira José S.R. , Chauffaille Maria de Lourdes L.F. , Yamamoto Mihoko , Andriolo Adagmar , Felix Roberta S. , Carvalho Fabrício , Caballero Otávia L. , Araujo Amélia G. , Panepucci Rodrigo A. , Zago Marco A. , Colleoni Gisele W.B. 
Published: October 2019

Abstract
Background: Cancer testis antigens have become the most extensively studied antigen group in the field of tumor immunology.
Aims: This study aims to analyze global expression of 14 CT (cancer/testis) antigens in MM to identify possible prognostic markers and therapeutic targets.
Patients and Methods: The expression of MAGEA1, MAGEA2, MAGEA3/6, MAGEA4, MAGEA10, MAGEA12, BAGE1, MAGEC1/CT7, GAGE family, LAGE-1, PRAME, NY-ESO-1, SPA17 and SSX1 was studied by RT-PCR in: 15 normal tissues, one pool of 10 normal bone marrow samples, three normal tonsils and bone marrow aspirates from six normal donors, three monoclonal gammophaties of undetermined significance (MGUS), five solitary plasmacytomas, 39 MM samples (95% advanced stage) and MM cell line U266. CodeLink Human UniSet I Bioarrays 10,000 genes was used for arrays analyses.
Results: SPA17 was positive in all normal tissues and was excluded for further analyses. MAGEC1/CT7 was positive in bone marrow aspirates from one MGUS and in one plasmacytoma. U266 cell line was positive for all CT antigens, except SSX1. The frequencies of CT antigens expression in MM patients were: MAGEC1/CT7 = 30/39 (77%); LAGE-1 = 19/39 (49%); MAGEA3/6 = 16/39 (41%); MAGEA2 = 14/39 (36%); GAGE family = 13/39 (33%); NY-ESO-1 = 13/39 (33%); BAGE-1 = 12/39 (28%); MAGEA1 = 10/39 (26%); PRAME = 9/39 (23%); SSX-1 = 10/39 (26%); MAGEA12 = 8/39 (20.5%); MAGEA4 and MAGEA10 = 0%. Cox’s regression model showed that GAGE family positivity and number of positive CT antigens > 6 were independent prognostic factors when all patients were analyzed. However, MAGEC1/CT7 expression was the only independent prognostic factor when non-transplanted patients where analyzed. Three samples predominantly positive (> 6) and three samples predominantly negative (0 or 1) for the 13 analyzed CT antigens were submitted to microarrays analyses. 147 genes were overexpressed in predominantly positive CT antigens samples.
Conclusions: Based on our findings, MAGEC1/CT7, MAGEA3/6 and LAGE-1 seem good candidates for immunotherapy, since together they are overexpressed in 85% of our MM cases. Besides, GAGE family expression, number of CT antigens > 6 and MAGEC1/CT7 seem to have impact on MM prognosis. Also, the results of arrays analyses corroborate the hypothesis that MM can be separate in two groups: predominantly positive and predominantly negative for CT antigens, meaning that these antigens may have important role for MM biology.
Therapy Response by Decrease of Free Light Chain Concentration in Multiple Myeloma Patients Treated with Bortezomib/Doxorubicin/Dexamethasone as First-Line Therapy.
Authors: Zinke-Cerwenka Wilma , Stojakovic Tatjana , Scharnagl Hubert , Wassertheurer Sabine , Linkesch Werner 
Published: October 2019

Abstract
Incorporation of new drugs such as the proteasome inhibitor bortezomib in the treatment of multiple myeloma (MM) has increased response rates. However, the challenge is to find the optimal combination of drugs and to change therapy as early as possible in case of suboptimal response. Therefore, we analyzed retrospectively the concentrations of serum free light chains (FLC) before, during and after therapy with bortezomib/doxorubicin/dexamethasone. In order to evaluate their prognostic value we compared the FLC kinetics to therapy response according to the International Uniform Response Criteria. Sixteen patients with newly diagnosed symptomatic MM (IgG/kappa: 9, IgG/lambda: 2, IgA/lambda: 1, IgA/kappa: 1, IgD/lambda: 1, IgD/kappa: 1, light chain kappa: 1) who received 4 cycles of bortezomib/doxorubicin and dexamethasone as initial therapy from November 2005 to June 2007 were analyzed. All patients showed a decrease in the FLC and/or a change of the quotient kappa/lambda towards the normal value after therapy. Reduction of FLC concentration ranged from 2.4- to 840-fold. Marked reduction could be observed after the first cycle of therapy. Seven patients revealed good response (sCR, CR or VGPR). In six of them, the decrease in FLC concentration was at least 20-fold, in one patient 2.9-fold. This patient had only a moderate increase of FLC concentration before therapy (below four times upper limit of normal). Two patients did not achieve good response (SD: 1, PD: 1); they had only a slight reduction in FLC (2.4- and 2.5-fold, respectively) although their initial FLC concentration was high. In parallel to the reduction of FLC, the serum concentration of immunoglobulins decreased. However, lowering of FLC occurred earlier and was more pronounced. Measurement of FLC concentration provides more rapid information for treatment monitoring than immunoglobulins and thus may be helpful to change therapy as early as possible in case of suboptimal response.
Preliminary Results of the Combination Rituximab, Fludarabine, Cyclophosphamide and Mitoxantrone (R-FCM) Followed by Rituximab Maintenance in Previously Untreated Chronic Lymphocytic Leukemia (CLL).
Authors: Bosch Francesc , Muntañola Ana , Villamor Neus , Terol Maria Jose , Gonzalez-Barca Elena , Ribera Josep Maria , Gonzalez Marcos , Abella Eugenia , Delgado Julio , Carbonell Felix , Garcia-Marco Jose A. , Escoda Lourdes , Ferrer Secundino , Monzo E. , Gonzalez Yolanda , Abrisqueta Pau , Salamero Olga , Gine Eva , Montserrat Emili 
Published: October 2019

Abstract
Immuno-chemotherapy (rituximab + combination chemotherapy) is emerging as the new gold standard for CLL treatment. However, the best combination chemotherapy to be given along with rituximab has not yet been determined. In addition, there is some indication that rituximab maintenance could be of benefit in CLL, as it has already been demonstrated in follicular lymphoma. In patients with previously untreated CLL, FCM results in a response rate of 90%, including a high proportion of MRD-negative CRs. These results suggested that FCM could be an ideal companion for rituximab in CLL therapy. Against this background, we have recently conducted a prospective clinical trial in which patients with untreated CLL receive R-FCM followed by maintenance with rituximab. Patients are eligible for therapy if they are younger than 70 yrs, have active disease (NCI-WG criteria), and adequate performance status. R-FCM consists of rituximab 500 mg/m2 on day 1 (375 mg/m2 the first cycle), fludarabine 25 mg/m2 i.v. on days 1 to 3, cyclophosphamide 200 mg/m2 on days 1 to 3, and mitoxantrone 6 mg/m2 i.v. on day 1, given at a 4-week intervals up to six courses. All patients receive G-CSF and cotrimoxazole. Patients achieving response (CR or PR) are subsequently treated with rituximab 375 mg/m2 every three months up to two years. Response is assessed three months after R-FCM treatment and includes MRD evaluation by four-color flow cytometry. Out of 69 patients included in the study, 38 (74% male, median age. 59 years) are evaluable for response to the first part of the treatment (R-FCM induction therapy). At study entry, 83% of the patients were in advanced (B and C) Binet’s clinical stage and 64% had increased (>20%) ZAP-70 expression. Ninety per cent of the patients have received the entire planed treatment. Overall response rate is 92%. MRD-negative CR is 36%, MRD-positive CR 41% (CR rate, 77%), nPR 7%, and PR 8%. Two out of 4 PR cases are MRD-negative. Toxicity has been manageable, with grade III–IV neutropenia being observed in 8% of the cases. Six serious adverse events have been documented (4 infections, 1 coronary disease, 1 CMV reactivation), two of them unrelated to the treatment. In conclusion, R-FCM is a well tolerated regimen that induces a high CR rate, including an important proportion of MRD-negative CRs. Whether these already extremely promising results are improved by maintenance therapy with rituximab remains to be seen.
Interim Results of a Phase I/II Study of Ocrelizumab, a New Humanised Anti-CD20 Antibody in Patients with Relapsed/Refractory Follicular Non-Hodgkin’s Lymphoma.
Authors: Morschhauser Franck , Marlton Paula , Vitolo Umberto , Linden Ola , Seymour John , Crump Michael , Coiffier Bertrand , Pulsoni Alessandro , Belch Andrew , Lerch Erika , Kimby Eva , Arnljots Kristina , Wassner Elisabeth , Mendila Myriam 
Published: October 2019

Abstract
Background: Ocrelizumab is a new humanised anti-CD20 antibody with the potential for enhanced efficacy in non-Hodgkin’s lymphoma (NHL) compared with rituximab due to increased binding affinity for the low-affinity variants of the FcγRIIIa receptor. An open-label, multicentre, dose-escalation study was conducted to evaluate the safety, efficacy, pharmacokinetics and pharmacogenetics of ocrelizumab in patients (pts) with relapsed/refractory follicular NHL following prior rituximab-containing therapy.
Methods: A total of 47 pts with a response (complete response [CR], unconfirmed CR [CRu], partial response [PR]) or stable disease (SD) of ≥6 months’ duration following prior rituximab-containing treatment were enrolled into 3 sequential dose cohorts. Pts received infusions of ocrelizumab q3w at 200 mg/m2 (cohort A), 375 mg/m2 (cohort B) and 750 mg/m2 (cohort C) for up to 8 doses. Response was assessed after 4 doses and after the end of treatment.
Results: Fifteen pts were enrolled in cohort A, 16 in cohort B and 16 in cohort C; 60% were male; mean age was 57 years; 78% had stage III/IV disease. At study entry 30%, 50% and 67% had intermediate or high FLIPI score in cohorts A, B and C, respectively. Median number of prior therapies was 2 (range 1–7); time to progression after last rituximab-containing therapy of <12 months: 47% (cohort A), 31% (cohort B) and 62% (cohort C) of pts. The majority of pts reported ≥1 adverse event (AE) [80–100%, cohorts A-C]; most of these were grade 1/2, with only 6 pts experiencing a grade 3 AE and no grade 4 AEs observed. The most common AEs were infusion-related reactions (IRR; 73%, 75% and 69% in cohorts A, B and C, respectively); only one was grade 3. Two pts discontinued treatment due to toxicity (dyspnoea, IRR). A total of 17 pts responded to ocrelizumab for a response rate (RR) of 36% (13% CR/CRu) across all cohorts. RR by cohort was 27% (13% CR/CRu) for A, 50% (25% CR/CRu) for B and 31% (no CR/CRu) for C. In pts relapsing after prior response (CR/PR) to rituximab-containing therapy (n=40), RRs were 23% (15% CR/CRu), 62% (31% CR/CRu) and 33% (no CR/CRu) in cohorts A, B and C, respectively. Of 6 pts with SD after prior rituximab-containing therapy, 1 pt had a PR, 4 pts had SD and 1 pt progressed.
Conclusion: Ocrelizumab is well tolerated at doses up to 750 mg/m2 given q3w; AEs consist mainly of grade 1/2 IRRs. Severe IRRs (grade 3/4) following ocrelizumab occur less frequently than with rituximab. In this heavily and rituximab-pretreated pt population, the RR of 36% is encouraging.
Ratio of Mutant JAK2-V617F to Wild Type Jak2 Determines the MPD Phenotypes in Transgenic Mice.
Authors: Tiedt Ralph , Hao-Shen Hui , Sobas Marta A. , Looser Renate , Dirnhofer Stephan , Schwaller Jürg , Skoda Radek C. 
Published: October 2019

Abstract
The reason why the JAK2-V617F mutation is associated with several phenotypic manifestations of human myeloproliferative disorders (MPD), i.e. polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), is currently unknown. We established an inducible transgenic mouse model for MPD using a bacterial artificial chromosome (BAC) containing the human JAK2-V617F gene under the control of the JAK2 promoter. The sequences encoding the kinase domain were placed in the inverse orientation and flanked with antiparallel loxP sites to make the construct inducible by Cre-recombinase. A transgenic strain (FF1) containing 9 copies of the JAK2-V617F transgene was analyzed in detail. In this strain, Cre activity can lead to activation and/or excision of the multiple transgene copies. Depending on the number of actively rearranged transgene copies, we observed graded levels of expression of the JAK2-V617F mRNA and different MPD phenotypes. Crossing FF1 mice with transgenic mice expressing Cre-recombinase under the control of the hematopoiesis specific Vav promoter (VavCre) led to reduction of the FF1 copy number and low levels of JAK2-V617F expression (approximately 40% of endogenous wild type Jak2). These FF1;VavCre mice developed a phenotype resembling ET with strongly elevated platelet counts and moderate neutrophilia (Figure 1A). In contrast, induction of the JAK2-V617F transgene with the interferon-inducible MxCre resulted in less excision and higher JAK2-V617F transgene expression (approximately equal to wild type Jak2). These MxCre;FF1 mice displayed a PV phenotype with increased hemoglobin, thrombocytosis and neutrophilia (Figure 1B). The highest expression levels of JAK2-V617F were achieved by retroviral transduction (approximately 300% of wild type Jak2). Transplantation of these bone marrow cells into irradiated recipients caused a PV-like phenotype without thrombocytosis. Thus, the phenotype correlated with the ratio of mutant to wild type JAK2 mRNA. In patients with MPD, we found a similar correlation between the ratio of mutant to wild type JAK2 mRNA and the ET, PV and PMF phenotypes. In contrast to our transgenic mice, which display graded levels of JAK2-V617F with wild type JAK2 being present in every cell, each individual blood cell from patients with MPD can only be homozygous or heterozygous for the mutation, or normal. Therefore, the molecular mechanism determining the phenotype in humans may be more complex than in our mouse model and appears to be linked to the transition of the JAK2-V617F mutation to homozygosity.
Figure Figure