bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNTO 328, an Anti-Interleukin (IL)-6 Monoclonal Antibody (mAb) - Preliminary Results of Subjects with Castleman’s Disease from a Phase 1 Study in Selected Hematological Malignancies.
Authors: VanRhee Frits , Fayad Luis , Borghaei Hossein , Voorhees Peter M. , Orlowski Robert Z. , Furman Richard R. , Zaki Mohamed , Prabhakar Uma , Jiao Trina , Lihou Christine , Garay Carlos A. , Kurzrock Razelle 
Published: October 2019

Abstract
Background: IL-6 is a pleiotropic cytokine, the dysregulation of which plays an etiological role in many diseases. Multicentric Castleman’s disease (CD) is a polyclonal lymphoproliferative disorder in which IL-6, overproduced by enlarged lymph nodes, is responsible for B-cell proliferation, auto-immune phenomena, systemic inflammatory manifestations (eg, fever, fatigue, and weight loss) and abnormal laboratory findings, including anemia, hyper-γ-globulinemia, hypoalbuminemia, thrombocytosis and increases in acute-phase proteins (eg, CRP, ESR and fibrinogen). The inflammatory syndrome can be severe and refractory to steroids, chemotherapy and even autologous stem cell transplantation. CNTO 328 is a chimeric mAb that specifically binds and neutralizes human IL-6 with high affinity. A phase I trial is being conducted to assess the safety and PK of CNTO 328 in subjects with CD and other hematological diseases.
Methods: This trial enrolls subjects with non Hodgkin’s B-cell lymphoma, multiple myeloma, or CD in cohorts exploring doses ranging from 3 to 12mg/kg given intravenously repeated either weekly, or every 2, or 3 weeks. Dose limiting toxicity (DLT) is defined as a ≥Grade 3 event (excluding hematologic toxicity), or ≥Grade 2 allergic reaction/hypersensitivity by NCI CTCAE attributed to CNTO 328 after the first administration. Clinical benefit assessment is based on improvements in Hb, fatigue, anorexia, fever/night sweats, weight, and size of target lymph node.
Results: Results from the first 7 CD subjects enrolled in Cohorts 1 (n=1, CNTO 328 3mg/kg q 2 weeks), 2 (n=2, CNTO 328 6mg/kg q 2 weeks) and 3 (n=4, CNTO 328 12mg/kg q 3 weeks) are currently available. At present time, subjects have received a median number of 4 (range 3 to 21) doses. CNTO 328 alone was well tolerated and no DLTs were observed. Non-related to CNTO 328 Grade 3 AEs such as anemia, thrombocytosis, fatigue and one possibly-related AE (ie, vomiting, grade 3) were observed. In addition, 3 subjects experienced Grade 3 SAEs that were deemed either unrelated or unlikely related to CNTO 328. Six evaluable subjects with CD showed a response by clinical benefit assessment including improvement in Hb and in severe thrombocytosis, and fatigue, reduction of fever, resolution of rash, improvement in skin tumors, or decrease in lymphadenopathy. PK and PD analysis from these subjects is currently ongoing and data from these analyses will be presented.
Conclusions: Treatment with CNTO 328 has been well tolerated in CD subjects at doses up to 12mg/kg q 3 weeks, and no allergic reactions have been observed after repeated dosing. Preliminary results suggest that CNTO 328 can abrogate the effects of IL-6 and induce both clinical and biochemical responses in CD.
Outcome in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with CHOP-R Can Be Predicted by Stage and Serum Lactate Dehydrogenase (LDH) Level.
Authors: Sehn Laurie H. , Chhanabhai Mukesh , Gill Karamjit , Hoskins Paul , Klasa Richard , Savage Kerry J. , Shenkier Tamara , Sutherland Judy , Gascoyne Randy D. , Connors Joseph M. 
Published: October 2019

Abstract
Background: DLBCL is a heterogeneous entity with patients exhibiting a wide range of clinical outcomes. A reliable prediction tool is vital for optimizing patient care. We have previously demonstrated that a revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI following treatment with rituximab and CHOP (CHOP-R). (Sehn, ASH 2005). Further exploration of clinical prognostic factors in an expanded cohort of patients yields a simplified prediction model based on stage and LDH alone.
Methods: We performed a retrospective analysis to assess the predictive value of recognized clinical prognostic factors in an unselected population of patients with DLBCL treated with CHOP-R. Patients were identified using the Lymphoid Cancer Database of the British Columbia (BC) Cancer Agency and included all patients >16 y of age who were newly diagnosed with DLBCL prior to Jan 15, 2006, treated in BC with a CHOP-R protocol. Patients were excluded if they were HIV positive, had evidence of an active second malignancy or an underlying indolent NHL.
Results: 523 patients were identified with the following characteristics: median age 61 y (16–93); male, 60%; stage III/IV, 55%; elevated LDH, 53%; performance status (PS) ≥2, 41%; ≥2 extranodal sites, 29%. Patients with advanced stage lymphoma (stage III/IV, B symptoms or bulky disease) or patients who were not candidates for radiation therapy were treated with 6–8 cycles of CHOP-R (91%) while those with limited stage were treated with CHOP-Rx3 and involved field radiation therapy (9%). Median follow-up for living patients is 24 months. On univariate analysis, stage, PS and LDH remain predictive for both PFS and OS. Number of extranodal sites is a borderline predictor of PFS (p=0.05) and no longer predictive of OS (p=0.276). Although age no longer predicts for PFS (p=0.17), it remains predictive of OS (p=0.001) since elderly patients are less likely to be treated successfully with secondary therapy and more likely to die from unrelated causes. On multivariate analysis, only stage (p<0.001) and LDH (p<0.001) remain significant predictors of PFS with similar predictive capacity (relative risk 2.7 and 3.0 respectively). A prediction model based on these two factors alone can predict outcome (see Table) as effectively as the full 5-factor IPI.
Conclusions: A prediction model based on stage of disease and serum LDH level at presentation provides an accurate estimate of outcome following primary therapy with CHOP-R for patients with DLBCL.
Breakthrough Fungal Infections after Allogeneic Hematopoietic Stem Cell Transplantation in Patients on Prophylactic Voriconazole.
Authors: Trifilio Steve , Singhal Seema , Williams Stephanie , Winter Jane , Tallman Martin , Gordon Leo , Frankfurt Olga , Evens Andrew , Mehta Jayesh 
Published: October 2019

Abstract
Voriconazole is a triazole anti-fungal agent with excellent activity against Aspergillus spp. We use liquid itraconazole 200 mg PO twice daily from day 0 to a month beyond discontinuation of all immunosuppression as standard anti-fungal prophylaxis after allogeneic HSCT in patients with no prior history of aspergillosis. This is changed to PO voriconazole 200 mg twice daily if corticosteroid therapy is started for GVHD. Voriconazole is continued even after steroid therapy is discontinued. Patients with a past history of aspergillosis get voriconazole from day 0. 71 allograft recipients who received voriconazole, and in whom complete clinical, microbiologic, and pharmacokinetic data were available were studied to determine the efficacy of voriconazole in preventing invasive fungal infections (IFI). 17 patients had not received itraconazole previously. The remainder had received itraconazole for 1–161 days (median 14). The length of voriconazole therapy was 6–956 days (median 133). The total number of patient-days on voriconazole was 13805 (~38 years). A total of 10 IFIs were seen in patients on voriconazole: Candida glabrata (n=5), Candida krusei (n=1), Cunninghamella (n=1), Rhizopus (n=2), and Mucor (n=1). The figure below shows the actuarial probability of IFI − 18% at 1 year.
Figure 1 Figure 1.
It is noteworthy that while 4 cases of zygomycosis were seen, no case of Aspergillus infection was seen. The figure below shows the actuarial probability of zygomycosis − 7% at 1 year.
Zygomycetes are generally not susceptible to voriconazole, and thus breakthrough infections are not surprising. However, C. glabrata and C. krusei are often susceptible to voriconazole with MICs of <2 μ g/mL (Spellberg et al. Clin Infect Dis2006;42:244–251). In that context, it is interesting that plasma steady-state trough voriconazole levels around the time the infection occurred were <0.2, <0.2, 0.33, 0.55, 0.63, and 1.78 μ g/mL in the 6 candidiasis cases. Excluding the 4 zygomycosis cases, all 6 candidiasis cases were seen amongst the 43 patients with voriconazole levels of ≤ 2 μ g/mL and none amongst the 24 with levels of >2 μ g/mL (P=0.061; Fisher’s exact test). This observation is in keeping with a recent report that showed correlation between voriconazole levels and therapeutic success in aspergillosis (Smith et al. Antimicrob Agents Chemother2006;50:1570–1572). We conclude that (1) voriconazole is extremely effective at preventing aspergillus infections, (2) zygomycosis is a concern in voriconazole-treated patients although the incidence appears low, and (3) therapeutic drug monitoring with dose adjustment may be indicated in patients on voriconazole to avoid breakthrough infections with fungi that are otherwise susceptible to the drug.
Figure 2 Figure 2.
Autologous Serum Containing Platelet Derived Growth Factors (PDGFs) as Topical Treatment for “Sicca Syndrome” Associated with Chronic GvHD.
Authors: Claudia Del Fante , Cesare Perotti , Gianluca Viarengo , Andrea Marchesi , Cristina Parisi , Paola Bergamaschi , Laura Salvaneschi 
Published: October 2019

Abstract
Introduction: Severe “sicca syndrome” after haemopoietic stem cell transplantation impairs the quality of life of transplanted patients and no valid therapeutic options are available. Autologous serum enriched with PDGFs is a new therapeutic option because of its high content in different growth factors and fibronectin able to restore the epithelial integrity of cornea and conjunctive.
Herein we present our experience on 16 allotransplanted patients (pts) undergoing extracorporeal photochemotherapy treatment for drug resistant chronic GvHD associated with severe eye dryness. All pts were treated with autologous serum eye drops prepared in our laboratory under gmp conditions.
Material and Methods: A peripheral blood sample of 30 ml was obtained from each pt in sterile conditions and centrifuged at 1500 rpm per 15 min. Serum was diluted with sterile saline to obtain a final concentration of 30%. No antibiotic was added. The solution was aliquoted in 1 ml plastic tubes (with the purpose of single use) and freezed at −20°C. The maximum storage time allowed was 30 days. At time of preparation PDGFs (PDGF, TGF b1, VEGF, EGF, IGF) content was assessed by ELISA technique and bacterial and fungal contamination was tested.
16 pts (11 M, 5 F), median age 41 yrs (range: 14–61), median plt count 170x103/mL (range: 110–530), median Hct% 36 (32–46) were enrolled and instructed to instill two autologous serum eye drops per eye four times/day. A written informed consent was always obtained. Schirmer’s test was performed immediately before treatment and bi-monthly. The median follow up was 12,5 months (4–16).
Results: 14/16 pts experienced a significative dry eye improvement that was mantained during the course of treatment. The need of topical therapy diminished progressively till two drops per eye once a day. The mean Schirmer’s test value improved from 1.5 to 4.6 mm/5 mins during the follow up.
Neither microbial contamination on the samples tested nor oftalmic infectious episodes were documented.
Conclusions: Autologous serum eye drops demonstrated to be a valid, safe and low cost new therapeutic option for treatment of “sicca syndrome” associated with chronic GVHD. Preparation under gmp conditions, storage in single use vials and detailed instructions to the patient demonstrated to be an effective approach to avoid the addition of antibiotic and microbial contamination of the solution.
Predicting Steroid Refractroy Acute Gastrointestinal (GI) Acute Graft Versus Host Disease (AGVHD) by Assessment of Crypt Loss at Diagnosis.
Authors: Melson Joshua , Keshavarzian Ali , Jakate Shriram , Arai Sally , Gregory Stephanie A. , Fung Henry C. 
Published: October 2019

Abstract
Acute graft versus host disease accounts for most of the treatment failures after an allogeneic stem cell transplantation. The prognosis of patients with steroid refractory acute graft versus host disease is poor with conventional treatment. Early identification of patients with steroid refractory acute graft versus host disease may improve the transplant outcomes. Crypt loss has been associated with the severity of disease in patients with inflammatory bowel disease. It is also found in patients with acute gastrointestinal graft versus host disease with unknown clinical significance. In an attempt to evaluate the significance of crypt loss in patients with acute gastrointestinal graft versus host disease, we conducted a retrospective study on 22 consecutive post allogeneic stem cell transplant patients in our institution that underwent colonoscopy and colonic biopsy. In this study, crypt loss was graded and correlated with clinical parameters of disease severity including stool volume, endoscopic appearance, response to graft versus host disease treatment and one year mortality attributed to graft versus host disease. All the biopsies were reviewed by one of the co-authors (Shriram Jakate, M.D.). Twenty two consecutive patients who were treated for gastrointestinal graft versus host disease following stem cell transplantation were studied. Crypt loss was present in 16/22 cases and in 10/22 cases crypt loss was determined to be severe by the presence of contiguous areas of crypt loss. In those with severe crypt loss 9/10 patients had daily stool volumes in excess of 1000 ml/day while only 3/6 in those with minimal crypt loss had this level of severe diarrhea. Patients with severe crypt loss were more likely to have a pathologic appearance at endoscopy and to require second-line therapy (i.e. steroid refractory acute graft versus host disease). The diarrhea of those with severe crypt loss was less likely to resolve even though it was more aggressively treated. Of the 10 patients with severe crypt loss, 5 (50%) died of graft versus host disease related causes. Conversely, only one of 12 patients (8%) with mild or no crypt loss had a death attributable to acute graft versus host disease. Our study shows that severe crypt loss predicts for severity of acute gastrointestinal graft versus host disease, response to treatment and more importantly steroid refractoriness. In addition, crypt loss severity is associated with an increased risk of death related to acute graft versus host disease. We conclude that the assessment of crypt loss at diagnosis may serve as a tool to identify patients with steroid refractory acute gastrointestinal graft versus host disease and could be used to select patients for therapeutic trial in acute graft versus host disease.
DNA-Microarray for Simultaneous Detection of Herpesviruses and Adenovirus in Patients Undergoing Allogeneic Stem Cell Transplantation.
Authors: Ditzen Anette K. , Rutzka Anke , Stichling Markus , Mueller Rene , Ehricht Ralf , Illmer Thomas , Bornhaeuser Martin , Jacobs Enno , Rohayem Jacques 
Published: October 2019

Abstract
Herpesviruses and adenovirus are an important cause of end-organ disease (EOD) and are associated with graft versus host disease (GVHD) in patients undergoing allogeneic stem cell transplantation (SCT). Detection and monitoring of those viruses is routinely performed by simplex quantitative real-time PCR. Since more than one herpes- or adenovirus are reported to be present shortly after transplantation, detection of all possible (sub-)clinical viral infections is still time-consuming and cost-intense. We therefore designed a DNA-microarray for the simultaneous detection of herpes-simplex-virus-1 and -2 (HSV-1/2), cytomegalovirus (CMV), varicella-zoster-virus (VZV), Epstein-Barr-virus (EBV), human herpesvirus-6 (HHV-6) and adenovirus. The DNA-microarray was validated in comparison to simplex quantitative PCR routinely used in our diagnostic laboratory. We retrospectively screened 608 samples of 35 patients undergoing allogeneic SCT on a regular basis until day 100 post-transplantation. The detection limit of the DNA-microarray is 10 genome equivalents (GE)/ml. We detected one or more viruses in 367 samples (60,2%). Of the positive samples, CMV was detected in 272 (74,1%), EBV in 103 (28,1%), HHV-6 in 81 (22,1%), adenovirus in 35 (9,5%), HSV-1/2 in 21 (5,7%) and VZV in 14 samples (5,2%), respectively. Of the samples containing two viruses (n=62), we detected CMV/EBV in 19 (30,6%), CMV/HHV-6 in 27 (43,6%) and HHV-6/EBV in 7 (11,3%) samples, respectively. CMV/EBV/HHV-6 was detected in 4 (36,4%) of the samples containing 3 viruses (n=11). Results of the DNA-microarray showed good overall agreement in comparison to the simplex quantitative PCR. We conclude that the DNA-microarray is a highly sensitive and specific method for the simultaneous detection of up to six viruses in a single sample. By screening and monitoring SCT-patients for viruses known to be associated with EOD or GVHD we herewith introduce an innovative molecular technique that can simultaneously detect multiple viral infections on a large scale. The assay is currently used to determine the impact of multi-virus detection on clinical end-points like GVHD and infectious complications in patients undergoing allogeneic stem cell transplantation.
Oral Busulfan and Cyclophosphamide or IV Busulfan and Fludarabine for Allogeneic HSCT in Hematologic Malignancies?.
Authors: Altman J. , Venepalli N. , Monreal J. , Rashid K. , Gordon L. , Winter J. , Williams S. , Tallman M. , Frankfurt O. , Evens A. , Singhal S. , Mehta J. 
Published: October 2019

Abstract
Pharmacokinetic properties of IV busulfan are more predictable than those of oral. While this results in lower toxicity, it is unclear if clinical results are superior. 55 consecutive patients with hematologic malignancies (35 AML/MDS, 10 lymphoma/CLL, 7 CML/MPD, 3 ALL) allografted after oral busulfan (14 mg/kg) with cyclophosphamide (120 mg/kg) (BuCy; n=24; cyclosporine-MTX) or IV busulfan (520 mg/m2) with fludarabine (160 mg/m2) (BuFlu; n=31; tacrolimus-MTX) were studied. The donors were HLA-identical sibs (n=41), 10/10 allele-matched unrelated (n=10), or 9/10 allele-matched individuals (n=4; 2 unrelated). Busulfan levels were not monitored. G/GM-CSF were not given routinely. Supportive care was uniform. 11 patients died of transplant-related causes, 21 relapsed (12 dead), and 32 were alive at the last follow-up (23 in continuous CR). The actuarial 2-y overall (OS) and event-free (EFS) survival was 50% (95% CI: 34–67%) and 34% (95% CI: 19–49%). The following pre-HSCT prognostic factors affected OS adversely in univariate analysis: refractory disease, ECOG performance status (PS) 2/3, elevated LDH, albumin <3, CD34+ cell dose ≤6 × 106/kg, HLA mismatch, and platelets <100 × 109/L. The table shows comparison of the BuCy and BuFlu by patient and donor age, type of donors, and the factors found to influence survival. The two groups were comparable.
In a Cox model that included the conditioning regimen and the above variables, low platelets (RR 0.285; P=0.013) and poor PS (RR 0.244; P=0.023) affected OS adversely. EFS was adversely affected by poor PS (RR=0.304; P=0.032), with borderline effect of low platelets (RR=0.451; P=0.062) and refractory disease (RR=0.502; P=0.095). The figure below shows OS by the presence or absence of the 2 adverse variables.
The figure below shows OS by the conditioning regimen. These curves have been generated from the Cox model and have been adjusted for the other variables in the model. While the difference is not statistically significant, BuFlu appears superior. However, similarly generated EFS curves for BuCy and BuFlu are superimposable.
We conclude that with limited patient numbers and follow-up, BuCy and BuFlu appear identical in efficacy although the appearance of the OS curves suggest that differences may emerge with loner follow-up and bigger patient numbers.
Figure Figure Figure Figure Characteristic BuCy BuFlu P Patient age 44 (27–62) 40 (20–61) 0.23 Donor age 46 (25–65) 39 (25–66) 0.25 MSD 22/24 (92%) 19/31 (61%) 0.013 Refractory disease 12/24 (50%) 16/31 (52%) 0.91 ECOG PS 2/3 6/24 (25%) 4/31 (13%) 0.30 Elevated LDH 6/24 (25%) 4/31 (13%) 0.30 Albumin < 3 7/24 (29%) 8/31 (26%) 0.78 CD34+ cell dose ≤6 × 106/kg 21/24 (88%) 21/31 (68%) 0..12 HLA mismatch 1/24 (4%) 3/31 (10%) 0.62 Platelets <100 × 109/L 9/24 (38%) 14/31 (45%) 0.57
Systematic Review of Controlled Clinical Trials on the Use of Ursodeoxycholic Acid for the Prevention of Hepatic Sinusoidal Obstruction Syndrome in Hematopoietic Stem Cell Transplantation.
Authors: Tay Jason , Tinmouth Alan T. , Fergusson Dean , Huebsch Lothar B. , Allan David S. 
Published: October 2019

Abstract
Background: Hepatic sinusoidal obstruction syndrome (HSOS) is a serious life-threatening complication of hematopoietic stem cell transplantation (HSCT). Currently, there is no optimal therapeutic strategy and preventive measures are ill-defined. Ursodeoxycholic acid (UA) is well-tolerated, inexpensive oral medication that has been associated with possible benefit as a prophylactic agent. We sought to summarize and quantify the clinical effects of prophylactic ursodeoxycholic acid in the context of HSCT. We undertook a systematic review of studies addressing the use of UA as monotherapy or in combination with other agents in patients undergoing HSCT.
Methods: The Search Strategy included MEDLINE (1966 to 4th week of March 2006), EMBASE (1980 to 4th week of March 2006), all EBM Reviews (4th quarter of 2005), Ovid Healthstar (1966 to 4th week of March 2006) and Google Scholar on March 20/2006. A random effects model was used to summarize outcome data.
Results: Six studies representing 824 patients were included in the review; 4 randomized clinical trials and 2 historical controlled studies. Three randomized clinical trials comparing prophylactic UA to no treatment demonstrated reduced proportion of HSOS (Relative Risk (RR) 0.34; 95% CI 0.17–0.66). When limited to higher quality studies, the effects remain (RR 0.36; 95%CI 0.15–0.90). Transplant related mortality also appears to be reduced (RR 0.58; 95% CI 0.35–0.95. However, UA did not significantly improve the outcomes of acute graft versus host disease (RR 0.76; 95% CI 0.53–1.09), relapse (RR 0.77; 95% CI 0.46–1.31) or overall survival (RR 1.22; 95 % CI 0.96–1.54).
Conclusion: UA is effective for HSOS prophylaxis in patients undergoing HSCT. HSCT centers should consider UA as standard therapy and controlled trials of novel treatments for HSOS should consider the use of UA as a comparator.