bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erythropoietic (Congenital) Porphyria: A Rare Abnormality of the Normoblasts
Authors: SCHMID RUDI , SCHWARTZ SAMUEL , SUNDBERG R. DOROTHY 
Published: October 2019

Abstract
1. In 5 patients with erythropoietic (congenital) porphyria, unstained bone marrow preparations were studied and photographed by fluorescence and absorption microscopy. The same marrow slides were also studied after ordinary staining.
2. Two morphologically different varieties of normoblasts were observed, which were designated as normal and abnormal cells. Normoblasts of the abnormal variety exhibited nuclear inclusion bodies containing hemoglobin.
3. Red fluorescence, indicative of porphyrin, was found only in normoblasts belonging to the abnormal cell variety. Normal normoblasts failed to exhibit red fluorescence.
4. The red fluorescence originated predominantly from the normoblastic nucleus. The fluorescence intensity of the cytoplasm was usually very low. Polychromatophilic erythrocytes also exhibited only weak fluorescence.
5. These findings indicate the coexistence of two different lines of normoblasts. The nuclei of cells belonging to the abnormal line probably form excessive amounts of porphyrins and may release them into the plasma in the course of cellular maturation. It is believed that these cells carry the abnormal trait representing the "inborn error of metabolism."
6. A critical review of all cases of porphyria, reported as "congenital," has shown that on the basis of the presented data, it was possible to establish the diagnosis of erythropoietic (congenital) porphyria beyond reasonable doubt in but 34 instances. Nineteen of the patients were female, fourteen were male. In a few families, more than one case was observed in the same generation, but in no instance was the disease recognized in subsequent generations.
7. Erythropoietic porphyria is a congenital disease, entirely distinct from hepatic photosensitive ("cutanea tarda") porphyria. No evidence has been found of a genetic mixture of these two forms of porphyria.
Splenic Aspiration Biopsy in the Dog
Authors: SWISHER SCOTT N. , DALE W. ANDREW 
Published: October 2019

Abstract
A method of partial marsupialization of the dog spleen which permits repeated aspiration biopsies of the spleen has been developed. Needle-core or open surgical biopsies may also be carried out on these dogs. The cytologic picture found in material from aspiration biopsies of dog spleens is described. Percutaneous splenic-portal venography or injection into the portal circulation may also be carried out by injecting directly into the marsupialized spleen.
Long-Term Tissue Culture of Human Bone Marrow
Authors: BERMAN LAWRENCE , STULBERG CYRIL S. , RUDDLE FRANK H. , CUNNINGHAM NANCY 
Published: October 2019

Abstract
Using methods described, long-term tissue cultures of human bone marrow pass through three typical growth phases : (1) a myeloid phase during which myeloid cells can be recognized; (2) a round-cell phase during which histioid and monocytoid cells predominate; and (3) a fibroblastic phase which can be maintained thereafter. The three phases are of variable onset and duration.
In a culture from a patient with carcinoma of the lung, isolated colonies of polygonal cells appeared on the 51st day of continuous cultivation. These were removed and subcultured. By means of trypsinization, the sheets of polygonal cells were transferred and subcultured in bulk and in a manner making it possible to obtain replicate cultures. The morphologic characteristics and growth behavior of the strain of cells (Detroit-6 strain) are similar to those observed for HeLa cells. The pattern of growth of the Detroit-6 strain is that of epithelial cells, presumably of metastatic origin from a carcinoma of the lung.
The susceptibilities of the Detroit-6 strain to infection with various viruses (poliomyelitis, Coxsackie, herpes simplex, and influenza) are similar to those observed in the HeLa strain of human malignant epithelial cells originating from a carcinoma of the cervix.
The possible values of long-term tissue culture of human bone marrow have been discussed.
Late Consolidation for Patients with Standard Risk AML up to 60 Years: Results of a Prospective Randomized Comparison of High Dose AraC and Autologous PBSCT.
Authors: Ganser Arnold , Krauter Jürgen , Hoelzer Dieter , Ottmann Oliver , Martin Hans , Lübbert Michael , Finke Jürgen , Heit Wolf , Fiedler Walter , Hossfeld Dieter , Kanz Lothar , Schlimok Günter , Kirchner Hartmut , Raghavachar Aruna , Brugger Wolfram , Heil Gerhard 
Published: October 2019

Abstract
421 patients (pts.) up to 60 years with de novo (n=328) or secondary (n=93) AML were treated with risk-adapted therapy. Pts. with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (up to 5% blasts in day 15 BM) were considered standard risk (SR), all others as high risk (HR). Induction I consisted of standard dose araC, idarubicine and VP16 (IVA-I). Pts. with GR to IVA-I continued with IVA-II on day 21. In pts. with bad response, the second cycle consisted of either IVA-II or FlAG/Ida. Double induction was followed by early consolidation with intermediate dose araC. As late consolidation, SR patients were randomized between high dose (HD) araC (12 x 3g/m2)/daunorubicine (3 x 45mg/m2) or an autologous PBSCT with PBSC mobilized after early consolidation except SR pts. with normal karyotype and an HLA-matched sibling who were allotransplanted. 214 pts. were classified as SR and 199 as HR. 91% of the SR and 59% of the HR pts. achieved CR (overall CR rate 75%) and 1% of the SR pts. died during induction. After 55 months, overall survival was significantly better for SR (49%) than for HR pts. (25%). Within the SR group, relapse free survival at 46 months was 63% for 21 pts. with inv(16), 58% for 25 pts. with t(8;21), and 37% for 148 pts. with normal karyotype (p = 0.13). Overall survival at 48 months was significantly better (p=0.014) for pts. with inv(16) (93%) than for those with t(8;21) (60%) or normal karyotype (44%). 48 SR pts. (12 with CBF leukemia) were randomized to receive HDaraC and 53 (14 with CBF leukemia) to undergo autoPBSCT. At 55 months, the overall survival was 52% for the autotransplanted pts. and 65% for those receiving HDaraC (p=0.71, intent-to-treat analysis). Median duration of neutropenia (<500/ μl) was 8 days for autoPBSCT and 19 days for HDaraC. Eleven pts. died in the HDaraC group (4 in CR and 7 from relapse) and 12 autotransplanted pts. died (1 in CR and 11 from relaspe). In pts. with normal karyotype, overall survival at 55 months for the allotransplanted SR pts. (n = 29) was 58% with no significant difference to HDaraC (62%) or autoPBSCT (43%). Relapse free survival for SR pts. with normal karyotype was 56% after allotransplantation, and 36% after autoPBSCT and HDaraC respectively (p = n.s.). In conclusion, overall survival is similar in SR AML pts. after autoPBSCT, HDaraC or allotransplantation. In SR pts. without an HLA-identical sibling donor, the reduced treatment related toxicity recommends autoPBSCT as late consolidation. In standard risk pts. with normal karyotype, allotransplantation from an HLA-identical sibling seems to have the highest antileukemic activity.
HoxA9 Activates Transcription of the Gene Encoding Gp91phox, a Respiratory Burst Oxidase Protein, during Myeloid Differentiation.
Authors: Eklund Elizabeth A. , Bei Ling , Lu YuFeng 
Published: October 2019

Abstract
Transcription of the CYBB gene, which encodes the respiratory burst oxidase protein, gp91phox, is restricted to phagocytic cells, differentiated beyond the promyelocyte stage. Regulation of CYBB transcription involves several repressor cis elements in the promoter. These repressor elements are homologous to the derived consensus sequence for DNA-binding of HoxA10 as a hetero-dimer with Pbx1a. The HoxA10/Pbx1 complex recruits histone deacetylase 2 and represses CYBB transcription in undifferentiated cells. During myeloid differentiation, HoxA10 is tyrosine phosphorylated, which decreases DNA-binding affinity for the CYBB repressor element. In our previous investigations, we found this decreased binding affinity requires phosphorylation of two tyrosine residues in the DNA-binding homeodomain. These residues are highly conserved with other HoxA proteins. However, we also found decreased DNA-binding requires interaction of these homeodomain tyrosines with a non-conserved domain, amino terminal in HoxA10. In previous investigations, we determined these CYBB repressor cis elements function as positive cis elements in differentiated myeloid cells, and interact with an unidentified protein complex. In these studies, we investigate the proteins involved in transcriptional activation of the CYBB gene, via these promoter sequences. We find this cis element is activated by HoxA9 and Pbx1a, in differentiating myeloid cells. Consistent with this, we find increased binding of HoxA9 to this CYBB cis element, during myeloid differentiation, in vitro and in vivo. Consistent with our results with HoxA10, we find HoxA9 is tyrosine phosphorylated during myeloid differentiation. However, in contrast to HoxA10, we find tyrosine phosphorylation of the conserved residues in the HoxA9 DNA-binding homeodomain increases binding to the CYBB cis element. Therefore, we conclude HoxA10 and HoxA9 have opposing functions, for myeloid specific gene transcription, during differentiation. We also find these functions are regulated by post translational modification of conserved tyrosine residues in the homeodomain regions of these proteins. Additionally, our results suggest differences in the effect of phosphorylation of these residues on DNA-binding is likely due to interaction with non-conserved domains in HoxA9 and HoxA10.
Associations of DNA Repair Gene Polymorphisms in XRCC1 and ERCC2 with Clinical Outcome in ECOG Trial E9486.
Authors: Van Ness Brian , Blood Emily , Greipp Philip , Kay Neil , Rajkumar Vincent , Kyle Robert , Oken Martin , Fonseca Rafael , Zhao Fangyi 
Published: October 2019

Abstract
Although multiple myeloma is clinically defined as the accumulation of clonal, malignant plasma cells in the bone marrow, the disease shows significant heterogeneity with regard to morphology, progression and therapeutic response. Our hypothesis is that this heterogeneity likely is due, in part, to germline genetic polymorphisms that contribute significantly to an individual’s disease course and response. In particular, individuals deficient in the repair of DNA damage are not only at high risk for developing cancer, but also could show DNA repair dependent responses associated with DNA damaging therapeutic agents. In this study we examined the association of functional genetic polymorphisms in the DNA repair genes, XRCC1 (SNP positions 280, 399) and ERCC2 (SNP positions 312, 751), with toxicities and clinical outcomes in the ECOG, 3 arm chemotherapeutic trial, E9486 [A-VBMCP, B-VBMCP+Cylophosphamide, C- VBMCP+interferon]. DNA from 359 patients was genotyped and examined for association with response, toxicities, blood counts, bone pathology, and survival parameters. Notably, in the interferon arm of the trial significant associations were observed in progression free survival and polymorphisms of XRCC399 (AA median survival 51 months versus AG/GG median survival of 33 months; p=,008), ERCC751 (AA/AC median survival 33 months versus CC median survival of 48 months; p=.05), and ERCC312 (AA median survival 49 months versus AG/GG median survival of 34 months; p=.02). Hazard ratios ranged form 1.7 to 2.05 for survival differences associated with DNA repair genes in this arm. Interestingly, T cell counts are known to be impacted by interferon; and DNA repair polymorphisms in this arm were also associated with CD8+ T cell counts. While this represents a single arm of one clinical trial, it is intriguing to consider the impact of genetic polymorphisms on DNA repair in light of chemotherapeutic agents that may affect cells of the immune system. Previous studies from the ECOG Myeloma Committee of the E9486 trial show highly significant associations of survival and immune status in myeloma patients. Our results suggest genetic polymorphisms in DNA repair genes may influence clinical outcome in certain therapeutic regimens. Genetic polymorphisms in these DNA repair genes are currently being completed in 800 patients of the SW9321 SWOG/ECOG intergroup trial and additional association studies will be included in the presentation.
Marked Activity of Velcade Plus Thalidomide (V+T) in Advanced and Refractory Multiple Myeloma (MM).
Authors: Zangari Maurizio , Barlogie Bart , Hollmig Klaus , Fassas Athanasios , Rasmussen Erik , Thertulien Raymond , Talamo Giampaolo , Lee Choon-Kee , Tricot Guido 
Published: October 2019

Abstract
Based on an index patient who responded to V 1.0 mg/m2 + T 100 mg upon progression on V alone and documented prior resistance to T, a phase 1–2 trial was initiated of the V+T combination in patients with advanced and refractory MM, 79% with a history of cytogenetic abnormalities (CA) including 57% pre-V, 81% with one and 52% with 2 prior transplants (n=79). Due to concerns for synergistic neurotoxicity, V was initially given at a dose of 1.0 mg/m2 on days 1, 4, 8 and 11; with the second cycle on day 21, T was introduced at incremental doses, per cohorts of at least 10 patients, at 50, 100, 150 and 200 mg daily. In the absence of grade 3 neurotoxicity, V was then increased to 1.3 mg/m2 and the same T dose escalation scheme was applied. Accrual to the 7th cohort with V 1.3 mg/m2 + T 150 mg has been completed. Distribution of cohorts is as depicted in the attached table per V and T dose along with overall characteristics. First cycle PR to V alone was 25% including 10% achieving n-CR; maximum response was noted after completion of 2 additional cycles with combined V + T: 40% achieved PR and ~ 20% n-CR, 60% had ≥ 25% M protein reduction. Analysis of response rates by V and T cohorts (V 1.0 mg/m2, n=45; V 1.3 mg/m2, n=34) and T dose (T ≤ 100 mg, n=42; > 100 mg, n=37) revealed no significant differences in response rates: median EFS for all 79 patients is 7 mos and median OS 21 (at 12 mo 67% alive). On multivariate analysis of 17 potentially relevant prognostic markers, prior therapy > 5 yrs (36% of patients) was associated with improved survival (HR 0.4, p=.03) whereas prior T (78% of patients) was associated with inferior post-V+T survival (HR 4.1, p=.05). In addition, V 1.3 mg/m2 reduced the risk of events (HR 0.6, p=.07) and of death (HR 0.3, p=.02).
Bortezomib (VELCADE®) Plus Dexamethasone as Induction Treatment Prior to Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: Preliminary Results of an IFM Phase II Study.
Authors: Harousseau Jean-Luc , Attal Michel , Leleu Xavier , Gressin Remy , Hulin Cyrille , Fuzibet Jean-Gabriel , Troncy Jacques 
Published: October 2019

Abstract
When patients (pts) with newly diagnosed multiple myeloma (MM) are treated with autologous stem cell transplantation (ASCT), the standard induction therapy is a dexamethasone (Dex) based regimen. Currently, the use of VAD or Dex alone results in a complete remission (CR) rate of <10%. In an ongoing ECOG trial comparing Dex alone to the combination thalidomide plus Dex, preliminary results did not show a clear advantage of the combination (Rajkumar ASCO 2004). Since achievement of CR is a major objective in the treatment of MM, better therapeutic regimens are being investigated.
Bortezomib is currently approved in the US and in the EU for the treatment of relapsed/refractory MM. Both in vitro studies and preliminary clinical experience in relapsed/refractory pts have suggested that the combination of bortezomib and Dex could further improve the results achieved with bortezomib alone.
The IFM group initiated a Phase II open trial assessing the combination of bortezomib and Dex in pts with previously untreated MM and who are candidates for ASCT. The regimen consisted of bortezomib 1.3mg/m² iv on days 1, 4, 8, 11 and Dex 40 mg per os days 1–4, 9–12 (for the first 2 cycles, days 1–4 only for the last 2 cycles), administered on 4 consecutive 21 days cycles. Stem cell collection was performed just before cycle 4 after G-CSF priming. The primary objective of the study was CR rate after 4 cycles. As of August 1, 47 pts have been recruited and data is available for the first 18 pts. The median age is 53 years (38–63) Sixteen / 18 pts received 4 cycles: 1 patient progressed after 3 cycles and in one case the last two injections of bortezomib were not performed because of grade 3 neuropathy. The overall results were as follows: CR (negative electrophoresis) 3; very good partial remission (90% reduction of M component) 2; partial remission (50% reduction of the serum M component or 90% reduction of the urine M component) 10; failure (stable disease or progression ) 3. The overall response rate was 83% and the CR rate was 17%. Side effect were usually mild (grade 1/2); only one grade 3 neuropathy was recorded. In all cases stem cells could be adequately collected. These preliminary results appear to be very encouraging and the bortezomib / Dex combination appears effective and well tolerated in pts with newly diagnosed MM. The results will be updated at time of presentation. If updated analysis confirms currently available data, the IFM will start a large randomized phase III trial comparing VAD and bortezomib / Dex as induction treatment prior to ASCT in pts with newly diagnosed MM up to the age of 65.
Rare Concomitance of Primary Systemic Amyloidosis with Immunoglobulin M Monoclonal Gammopathy or Waldenstrom Macroglobulinemia.
Authors: Hecksel Kathleen A. , Lacy Martha Q. , Dispenzieri Angela , Gertz Morie A. 
Published: October 2019

Abstract
Introduction: Primary systemic amyloidosis occurs when a clonal plasma cell population secretes light chains (or light chain fragments) that deposit in tissues as amyloid and cause organ failure and ultimately patient death. Primary systemic amyloidosis generally results from non-proliferative small populations of plasma cells. While it is known that IgG, IgA and light chain producing plasma cells can secrete amyloid in association with myeloma, fewer medical professionals recognize that IgM-secreting lymphoplasmacytic cells can produce amyloid proteins. When monoclonal IgM secreting marrow lymphocytes are present, amyloidosis can result with or without overt Waldenstrom Macroglobulinemia.
Patients and Methods: All patients seen at the Mayo Clinic between January 1968 and August 2000 with both a serum IgM monoclonal protein and biopsy-proven amyloidosis were analyzed. The Mayo Clinic Dysproteinemia Database recognized 128 patients (42 female, 86 male) with a median age of 65 years.
Results: Seventy-two percent (n=92) of the patients have died with a median survival of 1.72 years following biopsy proven amyloidosis (figure 1). Median serum IgM monoclonal spike was 1.38 g/dL. In addition, serum IgM kappa to lambda light chain ratios (1:3) were found to be reversed in patients with IgM gammopathy when amyloid was present (compared to the reverse ratio (3:1) in patients with Waldenstrom macroglobulinemia in the absence of amyloidosis). Subcutaneous fat, rectum and bone marrow revealed amyloid in 72%, 69% and 70%, respectively, providing non-invasive techniques for amyloidosis diagnosis without the risks of bleeding associated with renal or hepatic percutaneous biopsy. Variables not shown to affect survival included the following: age, gender, serum M spike, urine protein, alkaline phosphatase, creatinine, light chain isotype, ejection fraction, and percent marrow plasma cells. The presence of amyloid cardiomyopathy (defined as a cardiac interventricular septal thickness greater than 12 mm.) was the only variable to adversely affect survival. Of the patients with echocardiographic evidence of cardiomyopathy, the median survival was 10.8 months. In contrast, the patients without echocardiographic evidence of cardiomyopathy at diagnosis had a median survival of 39 months (figure 2).
Conclusion: Amyloidosis is underappreciated and should be considered in the differential diagnosis of all patients presenting with IgM gammopathy. Patients found to have amyloidosis in this setting should be tested for amyloid cardiomyopathy, as its presence predicts poor outcome. Lambda light chain in serum IgM samples should increase the index of suspicion for the presence of amyloid since IgM lambda is present in only 25% of IgM MGUS or Macroglobulinemia patients but is seen in 75% of IgM amyloidosis patients.
Figure Figure
Anagrelide-Associated Cardiomyopathy in Polycythemia Vera and Essential Thrombocythemia.
Authors: Jurgens Donald J. , Moreno-Aspitia Alvaro , Tefferi Ayalew 
Published: October 2019

Abstract
Introduction : Anecdotal reports of “idiopathic” cardiomyopathy (ICM) in patients receiving anagrelide therapy have surfaced but not formally studied. We undertook a tertiary-center comprehensive study of ICM that was diagnosed in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET).
Methods : Standard criteria were used for the diagnosis of both ET and PV. A diagnosis of ICM required echocardiogram documentation of a reduced left ventricular systolic ejection fraction (EF < 50%) as well as the absence of both coronary artery disease and other causes of cardiomyopathy. In order to avoid specific drug selection bias, we queried the entire Mayo Clinic Rochester database first for the diagnosis of ‘polycythemia’, ‘thrombocytosis’, or ‘thrombocythemia’ and subsequently cross-referenced the results with the diagnosis of either ‘cardiomyopathy’ or ‘heart failure’.
Results : Initial data inquiry yielded a total of 434 patients whose medical histories were thoroughly reviewed for the presence of an echocardiogram-documented ICM that post-dated a diagnosis of either ET or PV. Nine such patients (7 females; age range 46–78 years) were identified. Anagrelide therapy, at standard doses (median 2 mg/day), was temporally associated with ICM in 4 of the 9 patients while treatment in the remaining 5 patients consisted of either phlebotomy alone (3 patients) or other cytoreductive agents (2 patients). A similar database inquiry at Mayo Clinic Jacksonville identified 2 more patients with ICM that was temporally associated with anagrelide treatment. A normal echocardiogram was documented in 3 of the 6 patients with anagrelide-associated ICM at 2, 15, and 39 months prior to treatment (table 1).
Interval (months) Ejection fraction (%) Sex Diagnosis Diagnosis to ICM Anagrelide treatment to ICM Pre-treatment At ICM diagnosis Off-anagrelide therapy for 0.2–16 months F PV 66 60 69 30 and then 18 with continued anagrelide therapy 28 F ET 8 6 N/A 30 N/A F PV 120 36 N/A 20 66 F PV 156 13 73 35 55 F ET 108 10 N/A 35 44 F ET 108 11 58 10 34
Anagrelide therapy was immediately discontinued when ICM was diagnosed in 5 of the 6 patients and after further worsening of EF on continued anagrelide therapy in the sixth patient (first patient in table 1). All 6 patients with anagrelide-associated ICM experienced symptomatic improvement after drug discontinuation but the corresponding improvement in EF, after a period of 0.2–16 months, was often suboptimal (table 1). In contrast, ICM not associated with anagrelide therapy remained unchanged both in terms of symptoms and EF in all 5 cases.
Conclusion : Anagrelide-induced cardiomyopathy might occur in some patients with either PV or ET. Prompt recognition and drug discontinuation has the potential to adequately reverse the situation in some but not all patients.