bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bisphosphonate Related Osteonecrosis (BRON) of the Jaw: Single Institutional Update.
Authors: Mehrotra Bhoomi , Ruggiero Salvatore L. 
Published: April 2020

Abstract
BACKGROUND: Bisphosphonate therapy is indicated in the treatment of patients with symptomatic bony disease secondary to multiple myeloma, solid tumors and in the chronic management of osteoporosis. We have previously reported our early experience with bisphosphonate related osteonecrosis of the jaw (J Oral Maxillofac Surg2004; 62:527–534). This entity is now being recognized more commonly by treating hematologists/ oncologists and dental medicine community and the incidence of this complication has been reported between 4–10% among those patients receiving chronic intravenous bisphosphonate therapy. BRON is associated with significant morbidity in cancer patients and often requires symptomatic management for local palliation. The purpose of our current study is to update our previously reported experience at our institution and to review preventative and symptomatic management of this entity.
METHODS: We performed a retrospective analysis of patient records identified to have BRON at our institution. Institutional Review Board approval was obtained for this study. Information regarding age, gender, indication for bisphosphonate treatment, type of bisphosphonate agent used, clinical manifestation and management of osteonecrosis were recorded.
RESULTS: One hundred and two patients with BRON were identified at our institution. Median age was 67 years (range 40–89); Males: n=31; Females: n=71; Indications for bisphosphonate therapy: Multiple myeloma (n=40); Breast cancer (n=39), Prostate cancer (n=6), Uterine sarcoma (n=1), Connective tissue disorders (n=2), osteoporosis (n=14). Prior bisphosphosphonate therapy included: Pamidronate (n=28); Zoledronate (n=29); Pamidronate and Zoledronate therapy (n=31), and oral bisphosphonates (n=14). 24 of 102 patients had also received steroid therapy at some time during their clinical course. Most common presentation was a non healing extraction socket. Forty of 102 patients presented after surgical trauma to the jaw bone. Biopsies, when performed, confirmed the presence of osteonecrosis. No patients in this series had received radiation therapy to the jaw or had evidence of metastatic disease to the jaw bone. Surgical debridement was neccessary in 28 of 102 patients for local control of symptoms. Other patients were managed conservatively with antibiotics and local irrigation.
CONCLUSION: Long term intravenous and oral bisphosphonate therapy is associated with osteonecrosis of the jaw bone. Surgical trauma to the jaw bone may be associated with poor post-operative healing in these patients. Physicians and patients need to be aware of this significant potential complication of this therapy which may result in significant morbidity and impaired quality of life for these patients. Most patients can be managed conservatively, however, a significant fraction require surgical debridement for local palliation.
Boosts with Highly Purified Stem Cells Can Improve Hematopoietic Regeneration after Allogeneic Transplantation from Alternative Donors.
Authors: Lang Peter , Greil Johann , Koch Markus , Bader Peter , Pfeiffer Matthias , Berger Rebecca , Klingebiel Thomas , Wernet Dorothee , Niethammer Dietrich , Handgretinger Rupert 
Published: April 2020

Abstract
In allogeneic transplantation it is a major goal to maintain a stable long term engraftment. However, several factors like viral infections, drug toxicity or low stem cell numbers may hamper hematopoietic recovery or may even cause a late graft failure after successful initial engraftment. Hematopoietic growth factors or additional stem cell donations (boosts) may help to overcome this problem. In this retrospective analysis, the efficacy of boosts with highly purified peripheral stem cells either from closely matched unrelated or from haploidentical related donors was evaluated in pediatric patients with stagnant hematopoiesis (&lt;1500 leucocytes or &lt;50 000 platelets between 30–90 days posttransplant, n=11) or with initially increasing and then decreasing hematopoiesis (n=3). Patients with Graft rejection or hemophagocytosis were excluded. Diagnoses were: acute leukemias (n=10), nonmalignatn diseases (n=4). Most boosts were taken from the original graft: if the grafts contained &gt;10x106 (unrelated donors) or &gt;20x106/kg BW CD34+ cells, surplus stem cells were purified with an immunomagnetic selection method using antiCD34 or antiCD133 coated microbeads and cryopreserved. Three haploidentical donors were asked for a second donation. Our aim was to maintain stable and complete hematopoiesis after transplantation without inducing acute or chronic GvHD.
A total of 18 boosts were given between 30 and 290 days after transplantation with a median number of 5 (0.6–34) x 106 CD34+/CD133+ progenitor cells/kg and only 2200 (100–25000) residual T-cells/kg. All patients had a complete donor chimerism and no reconditioning or posttransplant pharmacological immunosuppression was administered. Patients who received G-CSF were excluded. Due to the low number of T cells, acute GvHD &gt;grade I and also chronic GvHD could be completely avoided even in haploidentical donors.
Leukocyte counts, neutrophile counts, lymphocyte counts (and platelet counts in patients with thrombocytopenia) within the week before infusion of the boosts were compared with cell counts 4 and 8 weeks after infusion, using the paired T-test. A significant increase of all cell counts was observed (medina numbers pre boosting: 900/μl, 312/μl, 142/μl; 4 weeks post boosting: 2065/μl, 1264/μl, 317/μl; 8 weeks post boosting:2570/μl, 1780/μl, 385/μl; p&lt;0.05 for all comparisons). Furthermore, independence from platelet transfusion could be achieved.
Conclusions: Boosts with purified stem cells and low T-cell contamination (&lt;10000 T-cells/kg) can be administered after transplantation without the risk of inducing GvHD, even in mismatched donors. No pharmacological immunosuppression was necessary. Thus, the method represents a safe tool and can improve donor derived hematopoiesis.
Quality of Reporting of Harms in the NCI Sponsored Phase III Hematological Malignancies Trials.
Authors: Soares Heloisa P. , Kumar Ambuj , Djulbegovic Benjamin 
Published: April 2020

Abstract
Background: To make informed decisions, patients and physicians need accurate information both on treatment benefits and harms. However, reports of clinical trials typically focus on description of benefits only. Research supported by the NCI account almost for 100% of all publicly sponsored phase III trials in the US, and is widely considered as the most important for advancement of treatment against cancer. Therefore, it is important to assess the quality of reporting of treatment-related mortality (TRM) and morbidity (TRMorb) in this setting.
Methods: We evaluated all randomized controlled trials (RCTs) that have been conducted by six NCI sponsored cooperative oncology groups (COGs). We included all trials that were completed by 2002. Here we focus on hematological malignancy trials. Data related to TRM and TRMorb were extracted from publications that reported benefits (i.e. survival or event-free survival). Data were pooled using meta-analytic techniques to assess if the harms were worse in experimental vs. standard treatments.
Results: We evaluated,114 hematological-malignancy trials. Seventy-nine trials studied leukemias, 32 lymphomas and 3 either multiple myeloma or myelodysplastic syndrome. Quality of reporting for the most important methodological domains (such as randomization methodology, power calculation, drop-out rates, use of intention-to-treat analysis) was high. Data related to TRM were extractable from 41 trials (36%) only. Overall, TRM accounted for less than 5% of all deaths and was shown to be significantly higher in patients allocated to innovative treatments [Odds ratio 1.93: 99%CI (1.11–1.76)]. TRM was similar according to the type of hematological malignancy or COG. Treatment-related morbidity data were reported in different non-standardized formats; therefore, it was not possible to perform a meta-analysis to give an accurate assessment of TRMorb in experimental and conventional treatment arms.
Conclusion: Treatment-related harms have been inadequately reported even in the currently best available research. Given the fact, that the users of research evidence can only rely on the available published reports, the NCI should urgently improve the requirment for the standards of reporting of clinical trials it funds.
Long-Term Survival Is Comparable between Palifermin-Treated and Placebo-Treated Patients (Pts) with Hematologic Malignancies (HM) Undergoing High-Dose Chemotherapy and Total Body Irradiation Followed by Autologous Hematopoietic Stem Cell Transplantation (HSCT).
Authors: Spielberger Ricardo , Emmanouilides Christos , Bensinger William , Rong Alan , Cesano Alessandra , Stiff Patrick 
Published: April 2020

Abstract
Oral mucositis (OM) is a severely debilitating side effect of chemoradiotherapy that often causes significant pain, diminished quality of life, and increased risk of infections. Palifermin decreases the incidence and duration of severe OM in HM pts receiving myelotoxic therapy and HSCT. Palifermin safety and efficacy have not been established in the non-HM setting. Since the rHuKGF receptor is not expressed by HM, palifermin is not expected to interfere with long-term disease outcomes in this pt population.
Aim: We assessed palifermin’s effects on the long-term disease outcomes (survival, disease progression, secondary malignancies) in pts with HM.
Methods: Long-term follow-up data were pooled from a 1998 phase 2, double-blind, placebo-controlled study (n=86) and a 2000 double-blind, placebo-controlled phase 3 study (n=212). The analysis included 152 pts treated with palifermin and 146 pts treated with placebo. Pts were assessed at 6-month intervals during the first year and annually thereafter until death or loss to follow-up. The Kaplan-Meier (K–M) method provided estimates of the safety endpoints. Data reported here are as of August 2004.
Results: There were 298 pts (152 palifermin: 146 placebo) monitored for long-term follow-up. The median follow-up period was 23.3 months for palifermin and 23.5 months for placebo. The overall survival and progression-free survival curves (p=0.474 and p=0.253, respectively) are similar between the palifermin and placebo groups. Secondary malignancies occurred in only 6 of 152 (3%) palifermin and 5 of 146 (4%) placebo pts. All secondary malignancies were myelodysplastic syndromes: 9 patients with diagnoses of Non-Hodgkin’s lymphoma and 2 patients of Hodgkin’s Disease. The number of deaths was similar between the groups (30% palifermin; 27% placebo); most deaths occurred within 12 months of randomization and were attributable to the underlying HM disease.
Conclusion: Use of palifermin for the prevention of severe OM has shown no negative impact on long-term disease outcomes, including survival, in the HSCT setting for patients with HM.
Graft Versus Host Disease-Like Syndrome after Autologous Stem Cell Transplantation in CLL Patients Treated with a TBI/Cy/Alemtuzumab (CAMPATH-1H) High-Dose Regimen.
Authors: Zenz Thorsten , Dreger Peter , Kröber Alexander , Ritgen Matthias , Bunjes Donald , Döhner Hartmut , Stilgenbauer Stephan 
Published: April 2020

Abstract
Introduction: A high incidence of unexplained skin rashes after an alemtuzumab containing high-dose regimen led us to retrospectively review CLL patients who underwent autografting within the CLL3C/CLL3 trials of the German CLL Study Group (GCLLSG) at a single center (University of Ulm).
Patients and Methods: CLL patients who received an autologous SCT after high-dose regimens with TBI (12Gy) / Cyclophosphamide (120mg/kg) without (CLL3: TBI/Cy) or with alemtuzumab (103mg i.v.) (CLL3C: TBI/Cy/A) between 2000 and 2004. Before SCT the patients received cytoreduction with FC and PBSC graft mobilization with Dexa-BEAM + G-CSF.
Results: 27 CLL patients received an autologous SCT after high-dose regimens with TBI/CY (n=11, age 34–61) or TBI/Cy/A (n=16, age 34–65). A mean of 6.0 (±2.8) (TBI/Cy) and 7.6 (±6.1) (TBI/Cy/A) x10-6 CD34+ cells/kg were transfused. At a median follow up of 24 months, overall survival was not different in the two groups (TBI/Cy: 91%; TBI/Cy/A: 81%). Twelve of 16 (75%) patients (TBI/Cy/A) developed a skin rash 43–601 days after transplantation (not including immediate alemtuzumab side effects) and 7 (44%) were classified as acute GvHD (skin grade 1–3). Concurrent symptoms included conjunctivitis (n=4), sicca syndrome(n=5), and cholestasis (n=4). The incidence of GvHD among patients alive at 1 year was 58% (TBI/Cy/A) vs. 0% (TBI/Cy) (log rank p=0.0048). On skin biopsy, the findings were compatible with GvHD grade 1–2 in 5/5 patients. All patients with GvHD were treated with steroids and in two patients GvHD was severe enough to lead to further immunosuppression with cyclosporine, MMF or FK506. In 3 patients signs and symptoms resolved and 4 patients improved but continued to have mild skin rashes and symptoms. Immune reconstitution showed that the CD4/CD8 ratio was more than 12 times higher in the TBI/Cy/A group (8.0 vs 0.6). When comparing the patients with GvHD with patients not developing a skin rash in the TBI/Cy/A group, the difference was statistically significant (ratio 20.3 (95%CI 4.8–35.7) vs 1 (95%CI0.7–1.3), Mann-Whitney: p=0.00001). The high ratio was due to an extreme depletion of CD8 positive T cells.
Conclusion: The incorporation of alemtuzumab into the high-dose regimen prior to autologous SCT in CLL led to a high incidence of a GvHD-like syndrome primarily of the skin. The remarkable incidence of GvHD went along with the severe depletion of CD8+ T-cells leading to an abnormally high CD4/CD8 ratio. The further investigation of the underlying mechanisms may lead to a better understanding of the development of GvHD and autoimmune disease and serve as a model system of these disorders.
Non-Myeloablative Autologous Hematopoietic Stem Cell Transplantation (HSCT) for Relapsing-Remitting Multiple Sclerosis.
Authors: Burt Richard K. , Oyama Yu , Statkute Laisvyde , Quigley Kathleen , Weppner Catherine , Verda Larissa 
Published: April 2020

Abstract
We have previously reported that autologous HSCT using a cancer-specific myeloablative regimen (cyclophosphamide and total body irradiation) did not improve the neurologic disability (EDSS) score or even forestall progressive neurologic decline in patients with secondary progressive (axonal degenerative) multiple sclerosis. We, therefore, redesigned our approach to use a non-myeloablative regimen composed of agents specifically used to treat multiple sclerosis (cyclophosphamide and CAMPATH-1H) with infusion of cyclophosphamide / G-CSF mobilized autologous peripheral blood stem cells (PBSC) in patients with relapsing-remitting (inflammatory) multiple sclerosis. This regimen was designed for lymphoablation without myeloablation. Nineteen patients were treated. The regimen was well tolerated. No patient had either an early or late infectious events, 50% of patients never had a neutropenic fever. Of those who developed fever during transplant, fever lasted less than 24 hours and was related to CAMPATH-1H or stem cell infusion. One-half of the patients never required a RBC transfusion and one quarter never required a platelet transfusion. The mean day of WBC engraftment was day +8. The mean day of hospital discharge was day +10. CD4 recovery occurred by 6 months. The EDSS neurologic rating scale that varies from 0 (normal) to 10 (dead from neurologic disease) is evaluated every 6 months for 1 year then yearly. In fifteen patients with 6 or more months of follow-up, the EDSS has improved by at least one point in the majority (8 patients), remained unchanged in six and deteriorated in only one. A randomized multicenter trial, the Multiple Sclerosis International Stem Cell Transplant (MIST) trial comparing this approach to continued standard therapy for relapsing-remitting MS in patients with an enrollment EDSS of 2.0 to 6.0 is currently registering patients.
Dose Intensive Induction Chemotherapy Does Not Decrease Tumor Contamination of Autograft or Improve Survival for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant.
Authors: Sayani Farzana A. , Bahlis Nizar J. , Faris Peter , Savoie Mary Lynn , Chaudhry Ahsan , Jeje Oluyemi , Brown Christopher B. , Russell James A. , Stewart Douglas A. 
Published: April 2020

Abstract
Multiple dose intensive chemotherapy regimens have been used for induction/mobilization of stem cells for autologous stem cell transplantation (ASCT) in multiple myeloma. However, the exact role and regimens of such dose intensive chemotherapy has not been clearly defined. We therefore did a retrospective study to determine if dose intensive cyclophosphamide (Cyclo) 5.25 g/m2, etoposide 1.05 g/m2 and cisplatin 105 mg/m2 (DICEP) results in improved relapse rate and survival compared to standard mobilization with only Cyclo 2 g/m2. Between January 1998 and March 2004, a consecutive series of 57 newly diagnosed multiple myeloma patients receiving DICEP (38) or Cyclo (19) for in-vivo purging/mobilization were analyzed. Both groups were similar in regards to age and sex. There were no significant differences in IPI score, Durie-Salmon stage, B2 microglobulin, calcium, creatinine and albumin levels between treatment groups. Outcomes included time to relapse and time to death. Median follow up time was 799 days. Kaplan-Meier plots for time to relapse showed no significant difference (p=0.0992). Median relapse time in the DICEP group was 905 days (95% CI 580–1604) compared to 1112 days (95% CI 742-infinity) in the Cyclo group. Kaplan-Meier plots for overall survival showed no significant difference between both groups (p=0.8664). The median survival times have not yet been reached in either group and are not reported. Analysis revealed no discernable confounding risk factors. Effects of treatment on outcomes were not altered after adjusting for IPI score and Durie-Salmon staging using the stratified log-rank test. Small sample size and short duration of followup are potential limiting factors for this study, however, preliminary analysis of a larger sample of 91 multiple myeloma patients receiving either DICEP or a less intense induction/mobilization regimen, also revealed no significant difference in disease free or overall survival. Monoclonal plasma cell contamination of stem cell products was not significantly different between both groups (DICEP 42.9%, Cyclo 56.3%, p=0.5573). This study therefore suggests that the very intense DICEP induction/mobilization regimen results in no significant difference in survival outcomes. The more intense regimen does not significantly decrease tumor contamination of autograft stem cells. Overall, our experience suggests that novel induction therapies such as bortezomib, lenolidomide etc. should be pursued in preference to any further study of high dose cytotoxic chemotherapy induction.
Figure Figure
Tymic Output after Autologous Bone Marrow Transplantation (ASCT) HIV-Related Lymphoma.
Authors: Simonelli Cecilia , Spina Michele , Pratesi Chiara , Tedeschi Rosamaria , Rupolo Maurizio , Bortolin Maria Teresa , Zanussi Stefania , Michieli Mariagrazia , De Paoli Paolo , Tirelli Umberto 
Published: April 2020

Abstract
Background: One of the major concern for ASCT in HIV-positive patients (pts) is that post-transplant immunosuppression might worsen the immunosuppression and enhance the HIV replication. Therefore we analyzed whether the immune system of HIV-positive pts might support an immune recovery similar to the HIV-negative pts who underwent the same ASCT program.
Methods: The kinetics and the extent of immunereconstitution were assessed by measuring: TCR excision circles (TRECs), CD4, CD8, CD56, CD4, CD45RA, CD19 cells, and HIV pro and viraemia
Results: 15 HIV-positive and 7 HIV-negative pts with relapsed DBCL underwent ASCT. Before the induction therapy TRECs/106 PBMC mean value was 962±2183 and 2948±5485 in HIV-positive and HIV-negative pts respectively. The nadir was reached before ASCT (150±11 vs 927±1842). At one year the mean value of TRECs/106 PBMC returned to the baseline in HIV-negative pts, while in HIV-positive pts largely overcame the baseline (2440±2799). Before the induction therapy, HIV-positive pts showed a significant lower CD4 (174±110 vs 386±200) CD56 (86±129 vs 144±92) and CD4/CD8 ratio in comparison with HIV-negative pts. CD4 count nadir was reached during aplastic period in both groups. No differences were present in the dynamics of CD4, CD45RA, CD8 and CD56 recovery between the two groups. At one year CD4 count returned to the baseline value in HIV-negative pts while in HIV-positive pts overcame 70% the baseline value. Before ASCT, all HIV-positive pts were on HAART and HIV-viraemia was &lt;50cp/ml in 10/15; 6 pts discontinued HAART, but HIV viraemia and proviraemia did not increase significantly during the overall observational period.
Conclusions: The dynamics of the immunereconstitution was similar in HIV-positive and HIV-negative pts, but the tymic output unexpectedly seemed to be enhanced in HIV-positive pts. Supported by ISS grants.
B-Cell Scaffold Protein with Ankyrin Repeats (BANK1) Is Differentially Expressed in ZAP-70 Negative Compared to ZAP-70 Positive Chronic Lymphocytic Leukemia Cells.
Authors: Dicker Frank , Schnittger Susanne , Schoch Claudia , Kohlmann Alexander , Liu Wei-Min , Kern Wolfgang , Prof Torsten Haferlach 
Published: April 2020

Abstract
The lack of somatic mutations of the immunoglobulin variable heavy chain (IgVH) gene has been established as poor prognostic marker for chronic lymphocytic leukemia (CLL) patients at early stage disease. Expression of the non receptor tyrosine kinase zeta chain associated protein (ZAP-70) was proposed as a surrogate marker for an unmutated IgVH, however, up to 30% discordant samples have been reported depending on the respective study. B cell receptor (BCR) mediated signaling is enhanced by ZAP-70 expression in CLL cells in vitro and ZAP-70 expression also tends to decrease the time from diagnosis to treatment irrespective of the IgVH status. Therefore, we wanted to identify differentially expressed genes between the ZAP-70 positive and negative CLLs by gene expression profiling of peripheral blood mononuclear cells (PBMCs) using Affymetrix microarrays (HG-U133 Plus 2.0). ZAP-70 expression was analyzed by quantitative real time PCR of CD19 purified (purity &gt; 99%) PBMCs (n=62) using a LightCycler instrument. Expression of ZAP-70 mRNA was normalized against the housekeeping gene ABL and a relative quantitation against Jurkat T cells as a calibrator was performed. Results are expressed as normalized ratio and a cut-off of 0.5 normalized ratio gave the best correlation to the IgVH status with 77% concordant samples between ZAP-70 expression and the IgVH status. The discordant samples consisted of 5 unmutated IgVHs in the ZAP-70 negative group and 9 mutated in the ZAP-70 positive group. In a second step PBMCs of the same samples were analyzed by gene expression profiling and differentially expressed genes were identified by t-test. Among the two best genes that could be used in a classification algorithm (SVM) to distinguish between the 2 subsets with 92% accuracy were ZAP-70 and B cell scaffold protein with ankyrin repeats (BANK1). The expression of BANK1 was increased 3–4-fold in the ZAP-70 negative compared to the ZAP-70 positive CLL subset (P = 0,001). In the literature, BANK1 has been identified in human BCR expressing B cells and seems to be B cell restricted. In B cells the scaffolding protein BANK1 enhances BCR-mediated Ca2+-signaling, a signaling pathway that is also enhanced by ZAP-70 expression in CLL B cells. Based on these data we show that increased BANK1 expression correlates with a ZAP-70 negative status in CLL B cells. The functional consequences of BANK1 expression in the ZAP-70 negative subset of CLL B cells, which are usually associated with a more favorable prognosis, still need to be established further.