bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacogenetics of Minimal Residual Disease Response in Children with Acute Lymphoblastic Leukemia (ALL).
Authors: Davies Stella M. , Borowitz Michael , Devidas Meenakshi , Winick Naomi , Martin Paul L. , Bowman Paul , Elliott James , Linda Stephen , Cook Edwin H. , Relling Mary V. 
Published: April 2020

Abstract
The presence of minimal residual disease (MRD) as a marker of antileukemic drug efficacy is being used to assess risk status and, in some cases, to adjust the intensity of therapy. Within known prognostic categories, the determinants of MRD are not yet known. Specific host germline pharmacogenetic polymorphisms have been linked to event-free survival in ALL in some studies, but their relationship to level of MRD after remission induction therapy has not been clearly elucidated. Herein, we determined whether the presence of MRD in bone marrow, measured by flow cytometry at day 8 and day 28 of remission induction therapy in over 1,000 children enrolled on Pediatric Oncology Group anti-metabolite based therapy protocols 9904, 9905, and 9906 was related to the following germline polymorphisms: MTHFR (A1298G, n=1413 and C677T, n=334), NQO1 (n=334), GSTP1 (n=334), TYMS (n=309), ADRB2 (n=715), RFC 80A/G (n=578), VDR (n=714), MDR1 C3435T (n=333), and MDR1 G2677T/A (n=328). We found that, after adjustment for ploidy, race and TEL-AML1 status (believed to influence blast clearance) the level of MRD at day 28 differed significantly by MTHFR A1298C genotype (p=0.005). MRD was detected in 31%, and 19% of those with A/A or A/C versus CC genotypes, respectively. Similarly, after adjustment for ploidy, race and TEL-AML1 status the level of MRD at day 28 differed by MDR1 2677 genotype (p=0.02). MRD was detected in 39% and 25% of those with GG versus other MDR1 2677 genotypes, respectively. MTHFR C677T, NQO1, GSTP1, TYMS, ADRB2, RFC, and MDR1 G2677T genotypes were not associated with presence of MRD. There was a trend towards an association between VDR genotype and presence of MRD. No significant associations were detected between any pharmacogenetic genotype and MRD at day 8.
Comment: These data indicate that presence of minimal residual disease at the end of induction, a known adverse risk factor in ALL, is importantly influenced by pharmacogenetic polymorphism. The strong association with MTHFR genotype, before the use of significant doses of methotrexate, illustrates the key role of folate in ALL blast metabolism. These data also indicate the value of an early endpoint such as MRD in identifying pharmacogenetic variables likely to influence outcome of specific therapeutic regimens, allowing prompt development of relevent mechanistic studies. Additional analyses will determine the impact of these polymorphisms on overall survival when the clinical outcome data from these studies is mature.
Induction Therapy Failures in Down Syndrome Patients with Acute Myelogenous Leukemia.
Authors: Loew Thomas W. , Gamis Alan , Smith Franklin O. , Massey Gita V. , Woods William G. , Hilden Joanne M. , Lange Beverly , Alonzo Todd A. , Chang Myron , Gerbing Robert B. 
Published: April 2020

Abstract
Down Syndrome (DS) is known to increase the risk of acute myelogenous leukemia. Recent cooperative group clinical trials, POG 9421 and CCG 2891, using standard timing and cytarabine/daunomycin based chemotherapy achieved induction rates of 95% and 91%, respectively. In 218 total patients (57 on 9421, 161 on standard timing arm of 2891), 17 induction failures occurred (3/57 on 9421, 14/161 on 2891). Analysis of the 17 induction failures demonstrated 6 died of toxicity/other causes (2 on 9421, 4 on 2891) and 11 failed to achieve complete remission (CR) with initial induction therapy (1 on 9421, 10 on 2891). Overall survival (OS) for patients not achieving CR with induction therapy was 9% (1 of 11). For the 10 who failed to achieve CR and subsequently died, median time to death was 10 months (range 3–59). Available data for these 11 patients indicate 10 underwent at least one attempt to induce a remission using other therapies with cytarabine in combination with asparaginase, anthracycline or etoposide being the most common regimen. The longest survivor was still alive 96 months post on-study after reinduction with mitoxantrone/cytarabine therapy. Three patients received bone marrow transplants (all allogeneic, 1 known matched sibling). One patient was transplanted still in relapse and died of progressive disease 10 months post on-study. One patient died of GvHD 59 months post on-study. While overall induction rates for patients with DS and AML are high (92% versus 78% for non-DS patients), survival rates for induction failures are dismal. Reevaluation of therapeutic approaches to DS patients failing induction chemotherapy is indicated.
Pulsing with Blast Cell Lysate or Blast-Derived Total RNA Reverses the Dendritic Cell-Mediated Increase in Cytotoxic Activity of Cytokine-Induced Killer Cells Against Human Allogeneic Acute Myelogenous Leukemia Cells.
Authors: Schottker Bjorn , Marten Angela , Ziske Carsten , Gorschluter Marcus , Schmidt-Wolf Ingo G.H. 
Published: April 2020

Abstract
Immunotherapeutic strategies may be a treatment option in patients with refractory acute myelogenous leukemia (AML) or, in cases of complete remission after conventional therapy regimens, may help to reduce disease recurrence or delay time to progression. Because evidence suggests a key role of dendritic cells (DCs) in cancer immunotherapy, we examined cytokine induced killer (CIK) cell responses in vitro after coincubation with autologous peripheral blood monocyte-derived DCs against three cell lines and allogeneic blasts from three patients with de novo AML. Although DCs were unable to enhance CIK cell effects against all three cell lines tested, the cytotoxic activity against the AML cells of the patients increased after coculture with mature DCs, which was significant in two of three patients. However, neither prior pulsing of the DCs with blast cell lysates nor with leukaemic cell-derived total RNA further enhanced the lytic capacity of the CIK cells. On the contrary, pulsing reduced the cytotoxic activity of the effector cells in a concentration-dependent manner. Because this decrease of allogeneic cytotoxicity was observed, we conclude that monocyte-derived DCs may be useful in autologous or allogeneic vaccine strategies for the treatment of AML or in priming donor lymphocytes in vitro, but unfractionated antigens as pulsing agents may have inhibitory effects on T cell efficiency and their employment in immunotherapeutic strategies for AML seems questionable.
Syncytial Variant of Nodular Sclerosing Hodgkin’s Disease.
Authors: Darabi Kamran , Tester William , Daskal Ierachmiel , Cohn Jeffrey 
Published: April 2020

Abstract
Background: Syncytial Variant is a subtype of nodular sclerosis Hodgkin’s disease (NSHD), reported to occur in younger patients (median age 25 years) who typically present with advanced disease and systemic symptoms.
Objectives: To evaluate the pretreatment characteristics and outcomes of NSHD patients diagnosed with syncytial variant (SV), compared to other NSHD patients without this histology (non-SV).
Methods: This is a retrospective medical chart review of all cases of NSHD seen at one institution over 2 decades. Pretreatment patient characteristics and outcomes data were analyzed.
Results: Of 63 patients with NSHD, 10 (16%) had SV histology. In contrast to previous reports, a trend for older age was observed for patients with SV (median 35 years), compared to patients with non-SV (median 27 years) (p=0.545). No differences in the distribution of B-symptoms or stage were observed between the two groups. Median recurrence-free survival was 37 months for SV cases, compared to 79 months for non-SV cases (p=0.046). Median overall survival was 38 months for SV, compared to 81 months for non-SV patients (p=0.05).
Conclusion: No significant differences were observed in pretreatment patient characteristics between SV and non-SV cases. However, we did observe a significantly worse recurrence-free and overall survival for SV patients, compared to non-SV cases. This is a limited retrospective study at a single institution and not all patients had received the same treatment. Therefore, further studies are needed to confirm these findings.
Analysis of Lymphocyte Monoclonality in Patients with Sjögren’s Syndrome Associated with Lymphoproliferative Disorder or Lymphoma.
Authors: Masaki Yasufumi , Dong Lingli , Kawabata Hiroshi , Hirose Yuko , Sugai Susumu 
Published: April 2020

Abstract
Purpose: Among 450 Sjögren’s syndrome (SS) patients in our hospital, we investigated 27 cases of malignant lymphoma (ML). In many reports, the risk of developing ML is higher, for example 43.8 times greater in patients with SS than in a comparable normal population in Kassan, et al, and 47.8 times greater in our Cases. Besides MALT lymphoma, other types of nodal lymphomas have been observed in patients with SS. To clarify the relationship between lymphocyte monoclonality and the development of the lymphomas in SS, we performed a clonality analysis of the tissues from salivary glands and lymphoproliferative organs.
Method. Clonality analysis was applied to lymphocytes in SS-related lymphoproliferative tissues from 3 patients who had lymphoproliferative disorder and were observed sequentially. We also compared the clonality between minor salivary gland and lymphoma tissues from 6 SS patients with nodal lymphoma. PCR amplification, cloning and sequencing were performed to identify immunoglobulin heavy chain complementarity-determining region 3 (IgH-CDR3) and T cell receptor-gamma (TCR-γ) gene rearrangement.
Results. In the 3 patients with sequential observation, B cell proliferation progressed from polyclonal or oligoclonal into monoclonal expansion in the salivary gland or extraglandular tissues. In one of these patients, lymphoma development was seen in the salivary gland. In all of the 6 SS patients with nodal lymphomas, the B cell clone in the salivary glands were different from those in the lymphoma tissues.
Conclusion. In patients with SS, there were two patterns of lymphoma progression. One was the multi-step process in which polyclonal B cell expansion evolves into monoclonal disease in extra-nodal lymphomas in salivary or lacrimal glands. The other was the independent clonality between salivary glands and lymphomas in patients with nodal lymphomas, and SS may play a role in the development of nodal lymphoma. Considering that the microenvironments of lymph nodes and salivary glands are different, the mechanism of the development of the extra-nodal lymphomas and the nodal lymphomas may be different.
Immunohistochemical Detection of CD95L (Fas Ligand) in Mantle Cell Lymphoma: A Prognostic Factor for Clinical Outcome.
Authors: Schrader Carsten , Meusers Peter , Brittinger Guenter , Janssen Dirk , Parwaresch Reza , Kneba Michael , Tiemann Markus 
Published: April 2020

Abstract
Mantle cell lymphoma is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. Proliferation indices are important prognostic factors in the clinical outcome. We investigated immunohistochemically the expression of the apoptotic marker CD95L (Fas Ligand) in relation to the clinical course. Biopsy specimen from 69 untreated patients enrolled in two multicenter prospective trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, CD95L. The CD95L expression was analyzed into three groups: negative, weak positive and strong positive. The expression was compared with the overall survival data analysed according to Kaplan and Meier. Patients with mantle cell lymphoma that had negative and weak positive CD95L expression had a median overall survival time of 32.0 months compared to 18.3 months for patients with a strong CD95L expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time between the patients with strong CD95L expression and the group of patients with negative or weak positive tumor cells (p&lt;0.0038). Based on these findings, the immunohistochemical detection of CD95L in mantle cell lymphoma is a prognostic factor.
Primary Cutaneous CD30+ Anaplastic Large Cell Lymphoma: Analysis of the Stanford Series Reveals Two Clinical Subsets of Patients.
Authors: Reddy Sunil A. , Liu Howard , Kohler Sabine , Hoppe Richard T. , Kim Youn H. 
Published: April 2020

Abstract
Primary cutaneous CD30+ anaplastic large cell lymphoma (PCALCL) represents the malignant end of the spectrum of CD30+ lymphoproliferative disorders. The management of PCALCL is markedly different than that of its primary nodal counterpart. The basis of this difference is due to the less aggressive nature of PCALCL. There is no evidence that chemotherapy is necessary or superior to the excellent results of local therapies such as radiation and/or excision for unilesional or local disease. Even patients with generalized disease have done well in some series. Here we review the characteristics and management of 40 cases of this rare cutaneous lymphoma. We have excluded Lymphomatoid Papulosis (LyP), the benign counterpart of PCALCL. In our series PCALCL was defined as CD30+ ALCL with disease limited to the skin as defined by a negative CT scan. Bone marrow biopsy was not necessary although it was always negative when done. Unilesional, local and extensive regional patients were generally treated with radiotherapy and/or excision, while chemotherapy and biologics were reserved for extensive regional and multifocal patients. The study included 30 men and 10 women with a mean age of 57.5 years (range 24–86). The estimated Kaplan-Meier disease specific survival (DSS) at 4 years for the entire group is 75.6%, with a median follow-up of 27.5 months (1–213). Twenty-six patients presented with unilesional or local disease, while there were 8 multifocal and 6 extensive regional patients (defined as 2 or more lesions beyond a 15 cm2 area apart but limited to 1 or 2 contiguous body regions). The unilesional/local patients had an estimated 4 year DSS of 93%. All but 2 of these patients are alive. The estimated Kaplan-Meier 4 year DSS of patients with either multifocal or extensive regional disease is 30%.
Estimated 4 year Kaplan-Meir survival of PCALCL by extent of skin involvement
unilesional/local 93% multifocal/extensive regional 30% P-value&lt;0.001
Seven deaths occurred in this series of which 6 were either directly or indirectly attributable to PCALCL. Of the deaths 3 were among the 6 patients with extensive regional disease and 2 were among the 8 patients with multifocal disease. Furthermore, 4 multifocal and 2 extensive regional patients have active disease at the time of last follow-up. Further followup will determine their eventual outcome. The 2 patients with unilesional disease who died, both developed rapid progression to extensive regional disease. Although most patients with PCALCL present with local disease and do quite well with local therapy, it appears that some PCALCL patients with multifocal disease, extensive regional disease, and rapidly progressive unilesional disease behave as high grade lymphomas refractory to standard chemotherapy.
Phase II Study of Arsenic Trioxide Plus Ascorbic Acid for Relapsed and Refractory Lymphoid Malignancies: A Wisconsin Oncology Network Study.
Authors: Kahl Brad S. , Ahuja Harish G. , Sanchez Federico A. , Rodrigues Gilberto A. , Voorhees Peter M. , Stevens Emily A. , Smith Jamie , Turman Nancy , Kim KyungMann , Bailey Howard H. 
Published: April 2020

Abstract
Introduction: Arsenic trioxide (AT) has impressive single agent activity in relapsed acute promyelocytic leukemia. It also has activity in myelodysplastic syndromes and multiple myeloma. In vitro data has suggested increased cytotoxicity when combined with agents that deplete intracellular glutathione, forming the rationale for combination studies. Ascorbic acid (AA) can deplete intracellular glutathione and may potentiate the cytotoxicity of AT. Upon this basis, we initiated a phase II study of arsenic trioxide plus ascorbic acid for relapsed/refracory lymphoid malignancies. Arsenic trioxide was administered at a dose of 0.25 mg/kg IV over one hour M-F for one week and then 2X/week for 5 weeks. Each arsenic infusion was followed by an infusion of 1000 mg ascorbic acid over 15 minutes. Each 6-week cycle was followed by a two-week rest period before repeating the cycle. Treatment was continued until best response plus two cycles or progressive disease.
Patient characteristics: Median age 70.5 (37–88). Gender 10M, 6F. Histologies CLL/SLL (4), Follicular (3), Mantle Cell (3), DLBCL (2), Burkitt (2), Marginal Zone (1), Hairy Cell (1). Median # Prior therapies 4 (2–13). Refractory to prior treatment 13/16. Median ECOG PS 1 (0–2). B symptoms 3/16. Elevated LDH 8/16. Elevated B2M 13/16.
Results: Median number of completed cycles 1 (0–4). Eight patients did not complete cycle #1, six due to progressive disease (PD) and 2 due to toxicity. Of the 2 patients coming off for toxicity, one patient with known coronary artery disease suffered a myocardial infarction on the 4th day of treatment and expired from congestive heart failure and the other experienced repeated grade 4 hyperglycemia. Six patients completed one cycle of therapy and were removed for PD. One patient completed 3 cycles of therapy before experiencing PD. One patient with mantle cell lymphoma received 4 cycles of therapy and achieved a CRu. The overall response rate was 6% (1/16). The responding patient’s treatment was stopped after 4 cycles for MD/patient preference and she experienced PD 5 months after completion of therapy. Grade 3 toxicities included thrombocytopenia (2 patients), anemia (3), neutropenia (1), stomatitis (1), anorexia (1), and elevated LFTs (1). Grade 4 toxicities included neutropenia (2) and hyperglycemia (1).
Conclusions: AT plus AA in this dosing schedule had modest toxicity but limited antitumor activity. The data should be interpreted in the context of our heavily treated, essentially refractory patient population. Our trial had a two-stage design, and was closed due to lack of activity at the first stage analysis. Other doses and schedules may prove to be more efficacious.
The MYOCAN Study. A Phase II Study of Cyclophosphamide, Oncovin, Myocet™, and Prednisone Plus Rituximab (R-COMP) in the Treatment of Elderly Patients with Diffuse Large B-Cell Non-Hodgkin Lymphoma (DLBCL).
Authors: Federico Massimo , Dyer Martin J.S. , Caballero Maria Dolores , Reilly Claire , Thiel Eckhard 
Published: April 2020

Abstract
BACKGROUND: For more than 20 years, CHOP has been the gold standard treatment for patients with aggressive NHL. The addition of rituximab to this regimen has been shown to improve outcomes in elderly patients with advanced (Coiffier et al NEJM2002; 346:235–42). However, CHOP is often poorly tolerated by elderly patients resulting in dose reductions and consequently lower response and cure rates compared to younger patients. Myocet™ (non-pegylated liposomal doxorubicin) has an improved pharmacokinetic profile with less myelosuppression and GI toxicity and has a reduced risk of cardiotoxicity at dose levels equivalent to standard formulations of doxorubicin.
METHODS: In this phase II, open label, 2-stage study, we replaced the conventional doxorubicin with Myocet™ to evaluate the response rate and safety of the R-COMP regimen (rituximab, cyclophosphamide, vincristine, Myocet™, prednisone). Previously untreated, elderly patients (≥60 yrs) with CD20+ newly diagnosed, advanced DLBCL were treated every 3 weeks with: Myocet™ 50mg/m2, cyclophosphamide 750mg/m2, vincristine 1.4 mg/m2 (max. 2mg), rituximab 375 mg/m2 (day 3 on cycle 1, day 1 thereafter) and prednisone 100mg/d d1–5 for 8 cycles. Response was assessed after 3 and 8 cycles.
RESULTS: Thirty patients were enrolled in stage 1 of the study with a median age of 72 (range 61–82). At baseline 17 (56%) patients had stage III–IV disease; 60% had an intermediate or high risk (2+) International Prognostic Index score and the median LVEF was 59% (range 50–75). A total of 198 cycles of chemotherapy were given, with a median of 8 cycles (range 1–8). Of the 198 cycles administered 15 (8%) were delayed by haematological or hepatic toxicity for a median of 7 days (range 0 to 25). The relative dose intensity for the regimen was 87%, for Myocet™ it was 84%. Toxicity was mainly haematological with grade 3 or 4 neutropenia in 29% of cycles and febrile neutropenia in 4%. There was no grade 3 or 4 vomiting and a low incidence of grade 1 or 2 vomiting (3%). At the last observation the median LVEF was 55% (range 40–76), 16 patients had no change or an improved LVEF and 13 patients had a reduced LVEF. In the cohort of 24 patients evaluable for response, 15 (63%) had a complete response and an additional 7 (29%) achieved a partial response.
CONCLUSIONS: These interim results suggest R-COMP is a well tolerated regimen with promising response rates in elderly patients with advanced DLBCL. Patient recruitment continues in stage 2 of the study with the aim of enrolling a total of 75 patients with a 2-year follow-up.
Long Term Results for Cladribine Induction and Interferon Maintenance Treatment in Previous Untreated Indolent Lymphoma.
Authors: Fridrik Michael A. ,   for the AGMT
Published: April 2020

Abstract
Indolent lymphoma in advanced stage is an incurable disease. The main treatment goal is palliation with low treatment related toxicity. In a multicenter setting we prospectively treated 91 previous untreated indolent lymphomas with intravenous cladribine 0.12 mg/kg body weight for 4 or 5 consecutive days every 4 weeks for 4 cycles. Following the cladribine induction treatment an interferon-2c maintenance therapy was started until progression. Median age was 59 years (range 25–79). All patients had stage 3 or 4 disease. Overall remission rate was 70% with 23% complete remissions. We found no significant difference in remission rate between the 4 or 5 day regimen. The remission rate was not different between follicular lymphoma, mantel-cell lymphoma, or Waldenstrom’s disease. Neither did the international prognostic index influence the rate of remission. Median observation was 60 months for living patients. Median time to progression and survival was 22 and 69 months respectively. At 5 years 23% and 57% were progression free and alive respectively. Transformation in a high-grade lymphoma occurred in 11/91 patients. A secondary cancer was observed in 4/91 patients. Toxicity was mainly hematologic for cladribine. Interferon maintenance was poorly tolerated, 27% of patients did not complete the therapy. Four months of cladribine seems to have similar results as conventional therapy with chlorambucil for 6 to 12 months.