bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibrutinib Selects for Cells with Elevated Reactive Oxygen Species and Downregulated Phosphatases
Authors: Camp Nathan , Garrett Meghan , Gopal Ajay K. , James Richard 
Published: November 2019

Signals from the B-cell receptor are inappropriately activated in B-cell malignancies, including Chronic lymphocytic leukemia (CLL), Mantle cell lymphoma (MCL), and Diffuse large B-cell lymphoma (DLBCL). In CLL, 90% of patients respond to treatment with ibrutinib, an inhibitor of Bruton's Tyrosine Kinase (BTK), with a mean three-year progression free survival rate of approximately 60%. Despite these promising numbers, patients who do not initially respond to ibrutinib have extremely poor outcomes, and nearly all patients eventually become resistant to ibrutinib due to mutations in BTK and its downstream effector Phospholipase C gamma 2 (PLCG2), with a median survival time of 23 months. In order to identify salvage therapies for ibrutinib-resistant patients, we employed several quantitative proteomic methods to identify signaling pathways and proteins that are essential in ibrutinib-resistant patient cells and cell lines. Total proteomic analysis of lymphoma cell lines selected with ibrutinib in vitro revealed that multiple mitochondrial proteins are increased in B cells exposed to ibrutinib. Next, we found that ibrutinib-treated B cells also exhibited increases in reactive oxygen species (ROS), which potently inhibit several protein phosphatases, including B cell receptor signaling regulators PTPN6 and INPP5D. We next looked at tyrosine phosphorylation in patient B cells collected at several time points during ibrutinib treatment and found decreased phosphorylation of both PTPN6 (Y536) and INPP5D (Y944 and Y865) during treatment. Furthermore, total levels of PTPN6 are decreased in patients within 3 months of initiating treatment, and disruption of PTPN6 in cell lines by CRISPR provided a selective advantage in ibrutinib-treated cell populations. Finally, we found that ibrutinib-treated and ibrutinib-naïve primary CLL cells are sensitive to compounds that prevent reactive oxygen species generation (SOD and PHOX inhibitors). Combined, we propose a mechanism by which ibrutinib treatment leads to increased levels of ROS and decreased phosphatase activity, ultimately leading to a growth advantage in the presence of ibrutinib without concomitant mutations in PLCG2 and BTK. We hypothesize that targeting proteins important for reactive oxygen species generation would also be useful in patients and could result in regained disease control and/or prevention of acquired resistance.

Disclosures
Gopal: Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria.
The Small Molecule IODVA1 Inhibits the Rac Guanine Nucleotide Exchange Factor Vav3 and Overcomes TKI-Resistance in Ph+(BCR-ABL1) B-ALL
Authors: Nassar Nicolas , Hegde Shailaja N , Gasilina Anjelika , Wunderlich Mark , Premnauth Gurdat , Merino Edward , Lin Yuan , Ahmadian Reza , Zheng Yi , Mizukawa Benjamin , Privette Vinnedge Lisa , Cancelas Jose A 
Published: November 2019

Aberrant activation of Rho guanine nucleotide exchange factors (RhoGEFs) is a chief mechanism driving abnormal activation of their RhoGTPase targets in cancer. Thus, small molecule inhibitor of RhoGEF activities can be used as a drug lead to treat leukemia and other malignancies. We have identified an active small molecule, IODVA1, in several xenograft mouse models of cancer including Ras-driven cancers. Here, we used cellular and mouse models of Ph+(BCR-ABL1) B-ALL to identify Vav3, the multi-domain tyrosine phosphorylation-dependent RacGEF as the target of the small molecule IODVA1.
IODVA1 specifically reduces the proliferation and survival of p190-BCR-ABL but not of empty vector expressing human CD34+ blood cells. IODVA1 binds tightly to recombinant Vav3 (Kd= 400 nM) but not to Rac1 or to the RhoGEF LARG. In Ba/F3 cells expressing p190-BCR-ABL, IODVA1 inhibits Rac activation and signaling within minutes of exposure. The decrease in Rac activity is not due to the activation of p50GAP or RhoGDI1 and is accompanied by a decrease in the activity of the pro-survival effectors PAK, JNK, and 4EBP and an increase in pro-apoptotic BAD activity. IODVA1prevents leukemia-related death and eliminates the leukemia burden in a BCR-ABL-induced murine model with no apparent toxicity. It eradicates leukemic propagating activity assessed by serial transplantation. Most importantly, IODVA1 increases the survival of a mouse model of TKI-resistant p210-BCR-ABL1(T315I) B-ALL better than ABL1-TKI imatinib and eliminates leukemic burden. p210-T315 leukemic mice survive 45 days after treatment has ended. Vav3- and Rac1/Rac2-deficient leukemic cells do not respond to IODVA1 in colony formation assay consistent with Vav3 being IODVA1's target. A mouse model of BCR-ABL leukemia deficient in Vav3 also does not respond to IODVA1. Cells from PDX models representing pediatric ALL patients including Ph+ (BCR-ABL(T315I) were found to be highly sensitive to IODVA1 ex vivo. Based on the described mechanism of action, we propose that IODVA1 is an allosteric inhibitor of Vav3 that holds promise as an anti-leukemic agent.

Disclosures
Cancelas: Hemanext: Consultancy, Research Funding; Fresenius-Kabi: Research Funding; Cerus Co.: Research Funding; TerumoBCT: Consultancy, Research Funding; Velico: Consultancy, Research Funding; Macopharma Inc: Research Funding; Cytosorbents: Research Funding; Cellphire: Research Funding.
Trend and Geographic Variations in the Incidence of Mantle Cell Lymphoma in the United States over 30 Years from 1975 to 2004.
Authors: Zhou Yuhong , Wang Haijun , Du Xin , Yi Qing , Zhang Yanxia , Romaguera Jorge , Wang Michael 
Published: November 2019

Abstract
Background: Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin’s lymphoma (NHL). To better understand the incidence and epidemiological features of MCL in the United States, we conducted a population-based study with 2635 patients (pts) of MCL identified from 9 Surveillance, Epidemiology, and End Results (SEER) tumor registries over 30 years.
Methods: From SEER public database, we identified 111 424 pts of all ages diagnosed with NHL between 1975 and 2004 in 9 SEER areas. Of these pts, 2635 had histologically confirmed MCL, accounting for 2.36% of NHL. The incidence with 95% confidence intervals were generated from SEER*Stat Software. Incidence was age-adjusted to the U.S. 2000 standard population. Annual percent change (APC) for the incidence was calculated and considered to be statistically significant if P<0.05. The crude 1-year survival rate was calculated as the ratio of the number of pts who survived over 1 year and the number of pts diagnosed with MCL.
Results: Of 2,635 pts with MCL, 68.1% were late-stages (stages III IV), 25.6% were early-stages (stages I–II), and 6.3% were unstaged. Median age at diagnosis for MCL was 68.0. Overall incidence was 0.41/100,000/year, which increased by age from 0.06 in pts aged <50 to 2.11 for 70–79 and 2.02 in pts aged 80 or older. The age-adjusted incidence increased from 0.08 in 1975 to 0.67 in 2004. APC was 4.64% (P<0.05). Incidence of MCL was higher in men (0.60) than in women (0.27) (P<0.05). Annual increase was greater in men (5.67%) than in women (2.93%). There were also substantial geographic variations (P<0.05) in the incidence of MCL. The age-adjusted incidence was highest in Seattle (0.49) and the lowest in Hawaii (0.33). The incidence appeared to be higher in Caucasians (0.44) than in African-Americans (0.25) and other races (0.25). Annual increase(from 1987–2004) was 8.68% in Caucasians, and 1.64% in African-Americans and other races.
Conclusions: The incidence of MCL increased progressively from 1975 to 2004, and was significantly higher in males and in Caucasians. There were substantial geographical variations in the incidence of MCL.
Distribution and Pathology Characteristics of Non Hodgkin Lymphoma in Peru: A Study of 1014 Cases Using WHO Classification of Lymphoid Neoplasm.
Authors: Beltran Brady , Morales Domingo , Quiñones Pilar , Salas R. , Carrasco-Yalan Antonio A. 
Published: November 2019

Abstract
BACKGROUND: The frequency of various subtypes of non-Hodgkin’s lymphoma (NHL) differs in various regions worldwide.
OBJECTIVE: To investigate the clinical and pathological features of non-Hodgkin’s lymphoma (NHL) and to evaluate the applicability of the new WHO classification of lymphoid neoplasms.
METHODS: According to the new WHO classification, a total of 1014 cases of non-Hodgkin’s lymphoma diagnosed during the period 2002–2006 were reviewed and reappraised with their morphological, immunological and clinical characteristics in one general hospital from Lima, Peru. All cases corresponded >18 years old.
RESULTS: There were 535 males and 479 females, mean age was 62.1 years (range 18 – 97 years) and the median was 64 years. B-cell neoplasms accounted for 763 cases (75.2%) and T/NK-cell neoplasms for 189 (18.6%). Sixty two cases (6.1%) were not classified. It was seen compared to that in the other Asian countries. Indolent lymphomas accounted for 17%, and aggressive ones for 83%. Among indolent lymphomas follicular grade I and II were the most common subset while MALT was second with low frequency. Among the aggressive lymphomas diffuse large cell lymphoma (DLCL) was the most common subtype, and accounted for 58.8% of all B cell lymphomas. Mantle and Burkitt lymphoma were very low incidence. Among the T cell lymphomas, peripheral T cell lymphomas, mycosis fungoides, Adult T Lymphoma/Leukemia (ATLL), T/NK nasal type Lymphoma were the most common subtypes. Nodal NHL occurred in 52% and extranodal in 48% of the cases. The more common extranodal presentation was stomach (14.1%), skin (8.1%), small intestine (2.9%) and nose (2.3%)
CONCLUSIONS: The high incidence of T cell lymphomas, extranodal presentation and reduced frequency of indolent lymphoma in the current study is comparable to that reported from Asian countries.
Posttransplant Lymphoproliferative Disorder in Adult Lung Transplant Recipients: A Report on Twenty-Seven Patients.
Authors: Stein Sophie D. , Misleh Jamal , Ahya Vivek , Kotloff Robert , Christie Jason , Tsai Donald E. 
Published: November 2019

Abstract
Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. We report a case series on the diagnosis, treatment and outcome of PTLD in lung transplant recipients. From 1991 to 2006, 27 (5%) of the 502 lung transplant recipients at our institution developed PTLD. The median age at transplant was 51.5 years (range 21–65 years) and the median time from transplant to PTLD diagnosis was 33.7 months (range 1–174 months). Most cases had an elevated LDH (86%) and were EBV-positive (85%). Of the cases tested (n=14), 64% were monoclonal. PTLD was most commonly diagnosed in the lung (56%) and gastrointestinal tract (26%). Three patients were diagnosed at autopsy, while the remaining 24 received therapy. Eight patients were initially treated with reduced immunosuppression (RI) alone, but only 3 (38%) obtained a complete response (CR). Rituxan (R) was used alone (n=3) or in combination with RI (n=3) as initial therapy in six patients, four of whom obtained a CR. Five patients utilized RI +/− surgical resection as a primary treatment modality, all of whom achieved a CR. However, all of them relapsed and required further treatment. Of these five patients initially treated with RI +/− surgical resection, a CR was reestablished in 3 using rituxan alone (1/3), combined rituxan and reduced immunosuppression (1/3) and radiation treatment alone (1/3). The remaining five patients from the 24 patients receiving induction therapy for PTLD were given other treatments. With an average follow-up of 28 months (range 1-130 months), 81% of patients have died. However, only 18% of deaths were directly related to progressive PTLD. The remaining 17 deaths were due to: infection unrelated to PTLD treatment (15%), multi-organ failure (7%), graft failure not due to RI (30%), stroke (4%), and renal failure (4%). Most deaths can be attributed to disease specific and posttransplant complications rather than PTLD. Although an unfortunate diagnosis, PTLD is responsive to therapy, particularly reduced immunosuppression and rituximab.
Clinical Profile of Patients with Primary Gastric Lymphoma: A Single Centre Experience.
Authors: Ambulkar Indumati B. , Goyle Sandeep , Borker Anupama , Tawde Bhairavi , Advani Suresh H. 
Published: November 2019

Abstract
BACKGROUND/AIMS: There are many controversies regarding the treatment for primary gastric non-Hodgkin’s lymphoma (PGL). We hypothesized that chemotherapy and local radiotherapy would improve patient survival in the treatment of with PGL.
METHODOLOGY: Between January 2003 and July 2007, retrospectively evaluated 15 patients with stage IE and IIE PGL. All patients clinical, biochemical, radiological and endoscopic features were evaluated. The histological diagnosis was established by endoscopic biopsies in all cases. All patients were treated with CHOP,RCHOP with or without radiotherapy. Patients with MALT as histopathology received H.pylori treatment. Upon the completion of chemotherapy, IFRT was given in the doses of 40.0 Gy. None of the patients underwent surgery. The response rates of chemotherapy and radiotherapy were analyzed.
RESULTS: We have treated 300 patients of non hodgkins lymphomas, extranodal NHLs were 80, GI lymphomas were 50,15 patients had PGL. The age rage was 39–71 years. Nine patients were males and 6 were females. The most common symptom was abdominal pain in 46.66% followed by abdominal mass in 33.33%,dyspepsia in 13.33% and weakess in 6.66% of patients. Duration of symptoms varied from 15 days to 6 months. Histological subtypes were diffuse large B-cell in 80% and marginal zone B-cell NHL of the mucosa-associated lymphoid tissue (MALT)-type in 20% of patients. Helicobacter pylori infection (HPI) was seen in all MALT type NHLs. Six patients(40%) received RCHOP with RT followed by RCHOP in 4(26.66%), CHOP in 3(20%) and R-CHOP with RT in 2 (13.33%) patients. Response was evaluated by repeat endoscopy after completion of 3 and 6 cycles. Fourteen (93.33%) patients showed complete response only after 3 cycles of chemotherapy. Only one (6.66%) relapsed who received CHOP alone. All patients are alive with a median follow-up of 30 months (range 2 to 54 months).
CONCLUSIONS: Primary chemotherapy with or without radiotherapy may produce complete remission in Stage IE-IIE PGL. The gastric function was well preserved with negligible stomach-related symptoms in all the patients. This organ-preserving combined treatment is highly effective and well tolerated for the patients with localized gastric DLBCL.
Results of a Nonrandomized, Open-Label, Phase II Study of Combined Gemcitabine, Mitoxantrone, and Rituximab in Relapsed or Refractory Mantle Cell Lymphoma.
Authors: Garbo Lawrence E. , Flynn Patrick J. , MacRae Margaret A. , Rauch Mary A. , Wang Yunfei , Kolibaba Kathryn S. 
Published: November 2019

Abstract
Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin’s lymphoma that usually presents as disseminated disease. Prognosis is poor, and responses to chemotherapy are less durable than those achieved in other types of lymphoma. New treatment options are desperately needed. Gemcitabine has shown activity in MCL as a single agent. In addition, the combination of mitoxantrone and rituximab has also been shown to be active in MCL. However, the use of these drugs in combination has not been evaluated in the treatment of MCL. The primary objective of this study was to determine the efficacy of gemcitabine+mitoxantrone+rituximab in relapsed or refractory MCL; secondary objectives were duration of response, survival at 1-year, progression-free survival (PFS), and toxicity, especially myelotoxicity. Sixteen patients were enrolled between April 2005 and December 2006, and only 15 were evaluable due to one patient’s withdrawal of consent. Patients received gemcitabine 900 mg/m2 IV (30–60 min infusion), mitoxantrone 10 mg/m2 IV (5–10 min infusion), and rituximab 375 mg/m2 IV on Day 1 (max 400 mg/hr). Patients also received gemcitabine 900 mg/m2 on Day 8 of the 21-day cycle. Medication was administered in the following order: gemcitabine→mitoxantrone→rituximab. Patients were to be treated for a maximum of 8 cycles or until the patient had evidence of a response, progressive disease, or intolerable toxicity. The median patient age was 74 years, 100% were white, and 69% were male. Of all patients, 86% had Stage IV MCL at baseline. Patients received a median of 6 cycles (range, 3 – 8). Efficacy results for the evaluable population are CR 13%, PR 27%, PD 13%, and SD 47%. Median PFS was 8.72 months (range, 1.84 – 23.49); median overall survival was 10.03 months (range, 2.50 – 23.49). Grade 3–4 treatment related toxicities reported in >1 patient were neutropenia (93%), leukopenia or thrombocytopenia (53% each), anemia (20%), and asthenia (13%). 60% of patients are currently alive as of July 2007; 9 patients discontinued study treatment due to disease progression (13%), toxicity (27%), MD request (7%), or withdrawal of consent (13%). 7 patients had normal study completion (44%). The study was closed early due to slow accrual owing to alternative treatment which became available at the time. The combination of gemcitabine, mitoxantrone, and rituximab in MCL was well-tolerated with manageable adverse events in spite of 93% neutropenia. Supplemented growth factor use was able to minimize neutropenia. No Grade 3–4 infection was reported. This regimen holds promise in patients with MCL and further studies are warranted. Updated data will be presented.
Phase II Study of RCHOP with Pegylated Liposomal Doxorubicin (DRCOP) for Patients > 60 Years Old with Untreated Diffuse Large B Cell Lymphoma (DLBCL).
Authors: Rodriguez Maria Alma , Fanale Michelle , Hagemeister Fredrick , McLaughlin Peter , Pro Barbara , Romaguera Jorge , Kwak Larry , Fayad Luis , Huang Xuelin , Durand Jean Bernard 
Published: November 2019

Abstract
Background: DLBCL is a common lymphoma of older adults, and a potentially curable disorder with the regimen RCHOP (Coiffier, et.al. NEJM,2002). Doxorubicin, a key drug in the regimen, has risk for cardiotoxicity, and thus of concern in older patients (pts) with higher incidence of cardiovascular (CV) disease. In breast cancer pts pegylated liposomal doxorubicin (D) has shown greater cardiac safety and similar efficacy to doxorubicin. We thus replaced doxorubicin with D in RCHOP (DRCOP).
Methods: The regimen is: Rituximab 375 mg/m2 IV day (d) 1; D 40 mg/m2 IV d 1; cyclophosphamide 750 mg/m2 IV d 1; vincristine 2 mg IV d 1 total dose; prednisone 100 mg/d p.o. d 1–5. Eligibility criteria are: > 60 years of age; untreated confirmed DLBCL (no discordant histology); Ann Arbor stage II-IV; baseline LVEF 50%. CV disease is permitted, if symptoms controlled, but consult at baseline by Cardiologist and at follow-up required. Growth factor support recommended (not required).
Results: 34 pts are evaluable for toxicity; 30 evaluable for response (1 pt off study after 1 cycle; 3 too early for response). Characteristics of pts: age 62–92 (median 75); 18 female; IPI 1=1pt; IPI 2 = 2 pts; IPI 3 = 16 pts; IPI >3 = 15 pts. Responses are: 28/30 (93%) CR; 2/30 (7%) PR. At this time, 3/30 failed: 1 progression; 1 death due to non-neutropenic pneumonia; 1 death due to disease. Grade 3–4 adverse events were: 1 drop in LVEF; 8 atrial arrhythmias (reversed); 1 hypotension (reversed); 1 chest pain (reversed); 17 neutropenia (13 febrile, with 5 infections); 3 hand-foot syndrome; 4 fatigue; 2 DVT; 2 neuropathy.
Conclusions: DRCOP has a high CR rate in this study of older pts with DLBCL, despite intermediate/high risk IPI. We’ve noted only one case of low LVEF ; more common are atrial arrythmias (8 pts), reversible. Neutropenia is the most common grade 3–4 adverse event (17 pts), and thus we strongly recommend growth factor support.
Treatment of Diffuse Large B-Cell Lymphoma of the Liver with Yttrium-90 Microsphere Embolization.
Authors: Benjamin Heather L. , Fenske Timothy S. , Kroft Steven H. , Hohenwalter Eric J. , Rilling William S. 
Published: November 2019

Abstract
We present a case of successful treatment of chemoresistant hepatic lymphoma using yttrium-90 micropheres. A 41 year-old male with a history of hepatitis C presented with fatigue, night sweats, right upper quadrant pain, a 20 pound weight loss, and hypercalcemia. CT scan of the abdomen revealed a 13.4 x 10.0 cm mass involving the right hepatic lobe, along with portohepatic, celiac, and retroperitoneal lymphadenopathy. Ultrasound-guided core biopsy of the portohepatic mass showed diffuse large B-cell lymphoma (DLBCL). The patient had a partial response to R-CHOP, and was subsequently treated with 3 additional chemotherapeutic regimens. Despite this extensive therapy, as well as surgical resection of hepatic lesions, he had residual lymphoma within the liver. Due to inadequate chemosensitivity, he was not a candidate for stem cell transplantation. Repeat biopsy showed loss of CD20 expression, eliminating radioimmunotherapy as an option. Because the residual lymphoma was confined to the liver, the patient was treated with yttrium-90 microspheres (TheraSphere®). The patient had a significant improvement in his abdominal pain. Furthermore, six weeks after treatment, a complete response in the hepatic lesions was documented by PET/CT scan. Although the patient later developed recurrent disease outside of the liver, the case clearly demonstrates the potential clinical utility of this approach in properly selected lymphoma patients. To our knowledge, this is the first reported case documenting clinical activity of yttrium-90 microspheres for lymphoma.
The Effect of Iodine-131-Rituximab on B Cell Lymphoma In Vitro and In Vivo.
Authors: Luo Rongcheng , Zuo Qiang , Wei Li , Liang Wangjun , Zhen Dayong , Luo Yuling , Yan Xiao , Yang Yang 
Published: November 2019

Abstract
The purpose of this study was to investigate the cell specific cytotoxic effect of Iodine-131 Rituximab on CD20-positive B cell lymphoma in vitro and on Raji cell tumors grown in vivo. Rituximab was labeled with Iodine -131 by the iodogen method. Cultured Raji cells or the nude mice bearing Raji tumors were treated with various concentrations of Iodine-131-Rituximab or Iodine-131 alone or Rituximab alone. The results showed that
The lethal effect was found on Raji cells treated with Iodine-131-Rituximab in a dose-dependent manner; The proliferation rate of Raji cells was significantly lower in cells treated with Iodine-131-Rituximab, as compared to the cells treated with Iodine-131or Rituximab alone (P<0.05); Tumor inhibition was found to be greatest in the mice treated with Iodine-131-Rituximab through intratumor injection, as compared with Iodine-131-Rituximab i.p. injection or Rituximab alone (p<0.05).
We conclude that Iodine-131-Rituximab specifically inhibits the growth of Raji tumor cells in vitro and in vivo. Iodine-131-Rituximab is a promising agent for radioimmunotherapy that targets CD20-positive B cell lymphoma.