bluuebunny/crossref_metadata_2025 huggingface dataset:
Intussusception in Childhood Acute T Cell Lymphoblastic Leukemia: An Unusual Complication - Report of 2 Cases.
Authors: Shah Jesika , Barlev Dan , Redner Arlene Sara , Shende Ashok , Karayalcin Gungor
Published: April 2020

Clinically significant gastrointestinal complications in children with acute lymphoblastic leukemia (ALL) have been reported. However, intussusception is a very rare complication. In one study of 286 children with ALL gastrointestinal complications occurred in 5.6% of patients with intussusception seen in only 0.3% of patients. We describe two cases of intussusception during chemotherapy for T-cell leukemia. Patient #1 was an 8 year old girl on chemotherapy for T-cell ALL. Around week 9 following POG 9404 protocol of consolidation chemotherapy, patient presented with severe abdominal pain and vomiting, and had marked, diffuse tenderness of the abdomen with guarding and hypo-active bowel sounds. Abdominal radiograph showed thickening of the descending colon; abdominal sonogram was normal; abdominal computed tomography (CT) scan however, revealed a soft tissue and fluid-filled mass extending from the cecum to the descending colon. These findings were consistent with a large bowel intussusception, which was successfully reduced with a barium enema. Patient #2 was a 15 year old male receiving chemotherapy for T-cell ALL following POG 9404 protocol. At week 14 of consolidation chemotherapy, patient presented with a 2 day history of nausea and colicky peri-umbilical and right lower quadrant abdominal pain. An abdominal CT scan revealed an ileocolic intussusception without bowel obstruction and mild wall thickening of the cecum. Barium enema resulted in successful reduction of the intussusception. Interestingly, both our patients were treated with high dose methotrexate 5gm/m2 during this time period and both experienced delayed excretion of methotrexate. To our knowledge, there is no known reported association between high dose methotrexate and intussusception. We speculate that the two could be related. The increased use of high dose methotrexate therapy in T-cell ALL may result in a higher incidence of intussusception in this population. Although, intussusception in ALL is a very rare complication, awareness of this entity and early recognition with radiological intervention may prevent unnecessary surgery and the associated morbidity and mortality in these patients.
Phenyhexyl Isothiocyanate, a Dual Inhibitor of Histone Deacetylation and Methylation, Inhibit Acute Lymphoblastic Leukemia Cells through Epigenetic Modulation.
Authors: Huang Yiqun , Ma Xudong , Chiao Dicky J.W. , Liu Delong
Published: April 2020

We have shown that phenyhexyl isothiocyanate(PHI) is a novel histone deacetylase inhibitor and can also modulate histone methylation. In this study we investigated the effect of PHI on human Acute Lymphoblastic leukemia cell line Molt-4 in vitro. The viability of Molt-4 cells was determined by MTT method. Apoptosis and cell cycle arrest were measured by flow cytometry. The expression of bcl-2, caspase-9, caspase-8, caspase-3, PRAP protein, acetylated H3 and H4, methylated H3K9 and H3K4 were detected by Western Blotting. The results showed that PHI inhibited the cell growth and decreased viability of Molt-4 cells. Cell cycle analysis indicated an arrest in G0/G1 phase. The expression of bcl-2, caspase-9, caspase-3, and PRAP was inhibited by PHI in a dose and time dependent manner. In contrast, there was no significant change in the expression of Caspase-8. PHI also significantly increased the level of acetylated histone H3 as well as H4. Interestingly, PHI increased the level of methylated H3k4, but decreased methylated H3K9. These data suggest that ALL cells are sensitive to the novel HDAC inhibitor, and PHI may become a novel agent in ALL therapy.
Laboratory Tumor Lysis Syndrome Complicating LBH589 Therapy in a Patient with Acute Myeloid Leukemia.
Authors: Kalff Anna , Shortt Jake , Farr Julia , McLennan Roger , Scott Jeffrey W. , Liu Angela , Spencer Andrew
Published: April 2020

LBH589 (Novartis) is a potent histone deacetylase inhibitor (HDACi) currently in early phase clinical development. Preliminary data suggests biological activity in a range of malignant hematological disorders including acute myeloid leukemia (AML). To-date, laboratory tumor lysis syndrome (LTLS) has not been described as a complication of LBH589 therapy. We report a case of a 60 year-old man who developed LTLS following treatment for AML with oral LBH589. The patient was diagnosed with refractory anemia with excess blasts (RAEB) in July 2005. Cytogenetic analysis demonstrated trisomy 8 and del(20q). He was initially treated with standard dose cytarabine and idarubicin (7 + 3). Post-induction bone marrow examination revealed ongoing dysplasia but no excess of myeloblasts. He subsequently received further cytarabine and idarubicin as consolidation. This was complicated by prolonged pancytopenia and subsequently by rapid progression to overt AML. Salvage therapy with fludarabine/cytarabine/G-CSF (FLAG) failed and he was referred to our institution for investigational therapy with LBH589. The patient was enrolled in a Phase IA/II trial of oral LBH589 for patients with advanced hematological malignancies and commenced intermittent oral LBH589 (30mg orally Monday, Wednesday and Friday on alternate weeks). He re-presented on day 14 with deteriorating renal function - creatinine 0.28mM/L (baseline 0.12mmol/L) and hyperleukocytosis (WBC 68 × 109/L). He recommenced LBH589 and was also commenced on hydroxyurea 1g bd, allopurinol and hydration. Within 24 hours, associated with a fall in his WBC to 9 × 109/L, he developed LTLS - corrected calcium 1.91mM/L (2.23 – 2.50), phosphate 2.99mM/L (0.70 – 1.30) and uric acid 0.8mM/L (0.15 – 0.50). He recovered uneventfully with the administration of rasburicase, intravenous fluid and electrolytes. Hydroxyurea was ceased and he continued LBH589 as per schedule. On day 28 with a WBC of 60 × 109/L and with prophylactic rasburicase and hyper-hydration, LTLS again recurred within 24 hours of LBH589 administration - WBC fell to 6 × 109/L accompanied by corrected calcium of 2.1 mM/L and serum phosphate of 1.91 mM/L. The patient again recovered uneventfully. This first reported case of LTLS with LBH589 therapy clearly demonstrates the potent anti-leukemic potential of LBH589 and mandates that caution be taken with LBH589 treatment of AML patients exhibiting highly proliferative and/or a high tumor burden disease.
Hematopoietc Stem Cell Targeted Neonatal Gene Therapy Cures oc/oc Mice from Osteopetrosis.
Authors: Richter Johan , Johansson Maria , de Vries Teun J. , Ehinger Mats , Everts Vince , Karlsson Stefan
Published: April 2020

Infantile malignant osteopeterosis (IMO) is a progressive, rare autosomal recessive disorder affecting osteoclast function. 50% of the affected children have a mutation in the Tcirg1 gene coding for one subunit of an osteoclast specific proton pump, OC116. The non-resorbed dense, sclerotic bones cause symptoms including pancytopenia and progressive visual loss and ultimately death. So far, the only curative treatment is hematopoietic stem cell (HSC) transplantation. The oc/oc mouse has a mutation in the gene homologous to Tcirg1 giving rise to similar symptoms as in patients leading to death of the mice at the age of 3–4 weeks. We have previously shown that the oc/oc mouse can be successfully treated with neonatal transplantation of normal HSC leading to prolonged survival and reversal of osteopetrosis (M. Johansson et al., Exp. Hematology34;242, 2006). In the current study we set out to develop HSC directed gene therapy for osteopetrosis in the oc/oc mouse model. As the bone marrow compartment is severely reduced in the oc/oc mouse fetal liver (FL) cells depleted of Ter119+ erythroid cells were used as a source of hematopoietic stem cells. We first established that wild type Ter119 depleted FL cells marked with a GFP vector and transplanted to newborn oc/oc mice i.p. could correct the osteopetrotic phenotype just as was shown for fresh bone marrow cells previously. Subsequently, Ter119 depleted FL cells from oc/oc mice were transduced with a retroviral vector expressing OC116 and GFP. In vitro transduction efficiency was 60–85%. One-day-old oc/oc mice were irradiated (400cGy) and transplanted i.p. with the transduced FL cells (1–3.5x106). 7 out of 14 mice survived past the expected lifespan and had 8–53% GFP+ cells in the peripheral blood at 3, 6 and 12 weeks. Analysis of bone structure with X-ray and histopathology showed an improvement at 8 weeks and an almost normal structure at 18 weeks, indicating induction of osteoclast activity. In vitro culture of osteoclasts from bone marrow from transplanted animals on bovine bone slices showed GFP marked osteoclasts and bone resorption, albeit at lower levels than for wild type cells. In the oc/oc mouse there is a block in B-lymphopoiesis leading to a reduced number of B-lymphocytes in the peripheral blood. In treated mice a reversal of this deficiency was observed.

In summary we have demonstrated that the osteoclast defect seen in oc/oc mice can be successfully corrected by neonatal transplantation of gene modified hematopoietic stem cells and that this can lead to long-term survival of treated mice. This represents a significant step towards the development of gene therapy for osteopetrosis.
The Effect of Combination of CDK Inhibitor (Roscovitine) and Derivatives of Tetracycline on Human Leukemic Cells.
Authors: Song Hairong , Hassan Zuzana
Published: April 2020

Roscovitine is a 2,6,9- trisubstituted aminopurine analogue that compete with ATP for binding to the active site of Cyclin-dependent kinases (CDKs). It inhibits CDK2/cyclinE, CDK7/cyclinH and CDK9/cyclinT. The cytotoxic effect of roscovitine and its analogues has been reported in several cancer cell lines in vitro and in animal models of cancer xenografts in vivo. The analogues of tetracycline (Doxycycline and Minocycline) possess anti-tumor, anti-metastatic and anti-angiogenesis properties with low toxicity besides acting as antibiotics. The effect of single agent is usually limited in cancer therapy and the use of single agent may mediate drug resistance. We have studied a cytotoxic effect of the CDK inhibitor roscovitine and tetracycline derivatives either alone or in combinations in human leukemia cells lines HL-60 (myeloid), Jurkat (lymphoblastic) and K562 (CML). HL-60, Jurkat and K562 cells were cultured in RPMI 1640 supplemented with 10% FBS. Cells were treated with roscovitine (0.5 – 100 μM), doxycyline (0.5 – 100 μg/ml) or minocycline (0.5 – 100 μg/ml) up to 48 hours alone or in combinations. The cells were examined for viability using AlarmaBlue assay, proliferation using 3H-thymidine incorporation assay, apoptosis using morphological criteria in Giemsa staining, cell cycle using propidium iodide and flow cytometry. Mitochondrial membrane permeabilization was assessed using tetramethylrhodamine ethyl ester. Specific proteins were detected by Western blotting. Incubation with roscovitine, doxycycline or minocycline decreased the cell viability in concentration-dependent manner in all three cell lines. Pretreatment of cells with doxycycline and minocycline for 24 hours followed by roscovitine for 24 hours have shown the additional decrease in cell viability. No such effect was observed when the drugs were used concomitantly. Roscovitine alone decreased proliferation in concentration- and time-dependent way in all three cell lines. Apoptotic morphology was firstly observed at 3 hrs after the treatment with roscovitine and markedly increased at 6 hrs in HL60 and Jurkat cells, but not in K562 cells. In HL60 and Jurkat cells, the cell cycle analysis has shown an increase in sub-G1 cells at 6 hours with maximum at 24h without preceding cell cycle arrest. In K562 cells sub-G1 peak increased subsequently to G2/M arrest. A marked loss of ΔΨm was observed at 2 hrs of exposure to 25uM of roscovitine in Jurkat and HL-60 cell lines, respectively. In HL60 and Jurkat cells, release of cytochrome c, AIF and Smac from mitochondria into cytosol were detected along with activation of caspases and PARP. However in K562, no caspase activation was detected at studied time points. Thus, all three agents have a cytotoxic effect in different types of leukemic cells, however, the additional cytotoxic effect of combination of Roscovitine and derivatives of tetracycline might be a potent therapeutic approach in treatment of leukemia.
Treatment of Acute Myeloid Leukemia in a Community Hospital.
Authors: Dhami Mandeep S. , Bulgaru Anca , Jagathambal Kandhasamy , Kapur Dinesh , Slater Dennis E. , Maderazo Eufronio G. , Bauer Frank A.
Published: April 2020

Optimal management of patients with acute myeloid leukemia requires an accurate diagnosis along with cytogenetics and an intensive systemic chemotherapy regimen administered by a multidisciplinary team of experienced physicians, nurses and other support staff. It has been suggested that such complex patients should be treated only at tertiary care centers. However, it is often difficult for patients and families to receive care at teratiary care center which may be at a great distance from their home. Here we present a retrospective review of all patients diagnosed and treated for acute myeloid leukemia at William W Backus Hospital, a 213 bed acute care hospital serving a community of 70,000 in Norwich, Connecticut between the years 2000 and 2005. A total of 44 patients were treated during this period. There were 22 males and 22 females. The median age was 67.5 years. Bone Marrow samples were evaluated by a hematopathologist (histopathology, flowcytometry and cytogenetics) at a near-by tertiary care center. FAB subgroups and cytogenetics were similar to other published studies. APML patients are not included in this analysis. The median survival for the entire group was 14.7 months ranging from 2 days to 113 months. Fourteen patients were alive, all in continued clinical remission except one with relapsed disease and one patient remains transfusion dependent. Median survival was 15.2 months for men compared to 13.2 months for women. Four patients were referred for bone marrow/stem cell transplant after induction therapy.

The limitation of this study is the relatively small number of patients as one would expect from a study done at a small community hospital. Nevertheless, it appears that the median survival of our patients is similar to a pooled analysis of five SWOG trials published by Gundacker et al. We conclude that most patients with acute myeloid leukemia can be managed in a community hospital with commitment and experience to treat such patients.

Treatment outcomes (median survival) Study Number of Patients Under 55 55 – 65 65 – 75 Over 75 *Gundacker et al. Blood, 1 May 2006, volume 107, 3481–3485 Current study 44 17.1 m 18 m 11.7 m 5.7 m Gundacker et al* 968 18.8 m 9.0 m 6.9 m 3.5 m
Long-Term Abnormalities of Patient-Reported Outcomes after Recovery from Thrombotic Thrombocytopenic Purpura (TTP) Using Health Related Quality-of-Life (QOL) Measurements.
Authors: Lewis Qurana , Terrell Deirdra R. , Vesely Sara K. , George James N.
Published: April 2020

Patients who survive an acute episode of TTP are expected to have complete recovery. The only currently appreciated risk is the possibility of a recurrent acute episode. However, survivors often describe problems that interfere with daily activities such as decreased energy and poor concentration and memory in spite of normal physical examination and laboratory data. The Oklahoma TTP-HUS Registry has complete follow up data on 333 of 335 consecutive patients with clinically diagnosed TTP or HUS in central-western Oklahoma from January 1, 1989 through December 2005. Since February 1998 we have collected QOL data annually, beginning one year after the initial episode, using the Medical Outcomes Study Short Form-36 (SF-36) to assess eight domains of physical and mental health. We compared our patients to US population norms that have been determined from the total, non-institutionalized US population. Results are reported as the percent of our patients who were within the top 75 percent of the US population values. The parameter of the top 75 percent of the US population was selected to approximate a range of normal function.

Percent of TTP patients in the top 75% of the US Population for all SF-36 domains Data for all TTP patients who had their first QOL less than two years from the time of their initial episode and who did not relapse in that interval SF-36 Domain TTP Patients (n=76) P Vitality 43% <0.01 Role physical 46% <0.01 Physical functioning 44% <0.01 Bodily pain 63% 0.17 General health 33% <0.01 Social functioning 55% <0.01 Role Emotional 62% 0.01 Mental health 61% 0.05 Percent of TTP patients, by clinical category, in the top 75% of the US population for the SF-36 general health domain1 1Data for the general health domain, to compare patients designated in different clinical categories of TTP (n=122) 2Patients with ADAMTS13 deficiency are reported separately, not with their clinical category: 16 were idiopathic, 2 were pregnant, 1 had bloody diarrhea Clinical Category N TTP Patients (n=122) P Idiopathic 57 40% <0.01 Quinine-induced 15 33% <0.01 Preganancy-associated 18 44% <0.01 Bloody diarrhea prodrome 13 38% <0.01 ADAMTS13 <10%2 19 32% <0.01

Patients who have recovered from TTP performed significantly worse than the US population for all domains of the SF-36 except for bodily pain. For the general health domain, patients in all categories were significantly worse than the US population. Thirty-two patients had ≥ 4 QOLs: there was a significant trend for improvement across time in the role physical domain (p<.01); the other 7 domains had no significant trend across time.

CONCLUSIONS: Following an acute episode of TTP, the QOL of patients is worse than the US population, suggesting that the ischemia of TTP may cause persistent physical and cognitive abnormalities.
Deep Venous Thromboses Associated with Peripherally Inserted Central Catheters in Patients with Hematological Malignancies.
Authors: Tran Ha , Chamsuddin Abbas , Winton Elliott F. , Heffner Leonard , Langston Amelia , Waller Ned , Arellano Martha , Khoury H. Jean
Published: April 2020

Deep venous thromboses (DVTs) complicating peripherally inserted central catheters (PICCs) placed for antibiotic administration were observed in 1.4% of patients in the largest study to date that included more than 2000 patients (Clinical Infectious Diseases, 34:1179–1183). The incidence of DVTs associated with PICCs in patients with hematological malignancies is unknown. We designed this retrospective analysis to better determine the incidence, characteristics, and outcomes of PICC-related DVTs on a Leukemia Unit at a large academic institution. Between April 2001 and February 2006, a total of 899 PICCs were placed in 568 patients with hematological malignancies. Ultrasound documented deep venous thromboses occurred in 38 patients (6.69%), a median of 26 days (2–172) after PICC placement. Patient’s characteristics were as follows: median age at the time of PICC insertion 45.5 yrs; 61% male; 37% black and 58% white. At the time of PICC placement 22 (58%) patients had newly diagnosed AML (46%), ALL (36%), lymphoma (13%), or CML (5%). Median platelet count at the time of DVT diagnosis was 106 ×10E3/μL. DVT management included removal of the PICC (71%), thrombectomies/thrombolysis/PTCA (13%), and anticoagulation with heparin (76%), or warfarin (24%). Anticoagulation was subsequently intermittently discontinued due to chemotherapy-induced thrombocytopenias. With a median follow up of 601 days, there were no documented pulmonary emboli or hemorrhages; 50% were in remission, 8% had relapsed disease, and 39% were deceased. In summary, patients with hematological malignancies appear to have a higher incidence of PICC-associated DVTs compared to patients without malignant hematological disorders with PICCs inserted for antibiotic administration. Risk factor analysis is in progress.
Inhibition of Signal Transducer and Activator of Transcription 6 Activity in the Hodgkin Lymphoma Cell Line L1236 Induces Growth Inhibition and Apoptosis.
Authors: Liu Cheng , Andersson Margareta , Xu Dawei , Claesson Hans-Erik , Bjorkholm Magnus , Sjoberg Jan
Published: April 2020

Signal transducer and activator of transcription 6 (STAT6) plays a central role in interleukin (IL)-4 and -13 signaling. Upon binding of the cognate receptors by these cytokines, STAT6 becomes phosphorylated by Jak family kinases and subsequently translocates to the nucleus where transcription of its target genes is regulated. Expression of IL-13 and its receptor are common features of Hodgkin lymphoma (HL) tumor cells, the so-called Hodgkin Reed-Sternberg (H-RS) cells, in which this cytokine has been shown to act as an autocrine growth factor. Consequently, constitutively phosphorylated STAT6 with a nuclear localization is a common and distinctive feature of H-RS cells in classical HL. We knocked down STAT6 expression in the HL cell line L1236 with small interfering RNA (siRNA) and found that inhibition of STAT6 activity results in cell growth inhibition, decreased viability and increased apoptosis. The results depict a central role of STAT6 in the growth of H-RS cells and indicate that STAT6 could be a potential target for therapeutic intervention in HL. Moreover, in order to identify the target genes of this transcription factor in H-RS cells, a combined approach of RNA interference and microarray is performed and the results will be presented.
Female Gonadal Toxicities after Treatment of Primary Hodgkin Lymphoma (HL). Analysis of the LENT-SOMA Questionnaire Registered in the Database of the German Hodgkin Study Group (GHSG).
Authors: Behringer Karolin , Gilman Elena , Borchmann Peter , Heuser Eva , Pfistner Beate , Diehl Volker , Engert Andreas
Published: April 2020

Introduction:

As a consequence of the impressive long-term remission rates in Hodgkin Lymphoma (HL), the reduction of treatment-related complications is becoming increasingly important. The most important treatment-related toxicities are secondary malignancies, infertility, pulmonary, cardiac, and thyroid dysfunction. Here, we report results of the prospectively planned LENT-SOMA questionnaire to determine female gonadal toxicities in women successfully treated for HL.

Patients and methods:

Between 1998 and 2002, the GHSG has conducted the fourth generation of clinical trials for the treatment of early, intermediate and advanced stage HL (HD 10–12) involving a total of approximately 4000 evaluable patients. The LENT-SOMA questionnaire was sent out to the participating centers 2, 5 and 10 years after a patient’s randomisation to evaluate cardiac, pulmonary, and gonadal dysfunction after HL treatment. To focus on female gonadal toxicities, questions referred to the menstrual cycle, infertility, and osteoporosis.

Results:

Overall, approximately 1.900 (50%) LENT-SOMA questionnaire after 2 years were identified. A total of 568 questionnaire were evaluable for the question of menstrual cycle after therapy. Amenorrhea was most frequent in women with advanced stage after treatment with 8 cycles of escalated BEACOPP compared to treatment consisting of 4 cycles of escalated BEACOPP plus 4 cycles of BEACOPP baseline (45% vs. 19%, p<0.0001). A regular cycle was most commonly reported in women treated with two or four cycles of ABVD (98.8% and 95.9%). The frequency of gonadal dysfunction will be evaluated according to treatment modality (chemotherapy, chemo- and radiotherapy) and it will be analysed with respect to age.

Conclusion:

Female gonadal toxicities after HL treatment include amenorrhea, infertility and osteoporosis. The first analysis of the LENT-SOMA questionnaire focussing on female gonadal dysfunction will be presented.
High Grade Transformation in Splenic Marginal Zone Lymphoma: A Description of a Series of 8 Cases.
Authors: Dungarwalla Moez R. , Wotherspoon Andrew , Morgan Gareth , Catovsky Daniel , Dearden Claire E. , Matutes Estella
Published: April 2020

Splenic marginal zone lymphoma (SMZL) without or with villous lymphocytes (SLVL) is a low grade B cell non-Hodgkin’s lymphoma that comprises <1% of lymphoid malignancies. SLVL is indistinguishable histologically from SMZL and it is believed that the 2 entities represent different phases of the same process in the spleen and the bone marrow. Characteristic features of SMZL are splenomegaly, moderate lymphocytosis, immunophenotype with a CLL score < 2 and nodular/intrasinusoidal pattern of bone marrow infiltration. Despite its slow clinical course, and response to splenectomy, approximately 50% of deaths in patients with SMZL are caused by progressive disease. As in other low grade lymphoproliferative disorders, SMZL may undergo high grade transformation. We describe 8 cases of SMZL that showed clinical, morphological and histological features of progression to large B cell lymphoma. These 8 cases represent 19% of our series of 41 SMZL patients followed up between 1996 and 2006. Patients were aged between 44 and 76 years, and there were 4 men and 4 women. Progression to high grade B cell lymphoma occurred between 1 and 48 months from diagnosis. The cases can be divided into 2 distinct groups on the basis of the site of transformation. Those cases with high grade transformation in the bone marrow had a median overall survival of 10 months, although 1 patient did attain a complete remission with combination chemotherapy (R-CHOP) and is alive at 12 months. In contrast, there were 3 cases of transformation in peripheral lymph nodes with a median overall survival of 60 months. Large B cell lymphoma was also diagnosed in the spleen in the initial stages of the disease in 1 case. This patient achieved a complete remission with R-CHOP post splenectomy, and is still alive at 36 months follow up. In a previous report of transformation to large B cell lymphoma in SMZL (Camacho et al, Am J Surg Pathol 2001) a 13% incidence was reported. In our series of 8 cases the incidence of transformation is 19%. Hence it appears that while the incidence of large B cell transformation seems to be higher than in CLL (1–10%) it is lower than that reported in follicular lymphoma (25–60%). Two of the 4 cases of high grade transformation in the bone marrow had previously been treated with fludarabine in the year prior to their progression to large B cell lymphoma. In 1 of these cases Epstein Barr Virus encoded RNA was detected in the malignant cells at the time of transformation. This may suggest that EBV is involved in the pathology of SMZL transformation, and treatment with immunosuppressive agents such as the purine analogues, may increase this risk. In our series of 41 patients, 6 have received fludarabine therapy and the risk of high grade transformation in this small group is significantly higher at 33% (2/6).
The Prevalence of Second Malignancies and Autoimmune Diseases in Patients with Lymphoproliferative Disorders.
Authors: Seery Tara E. , Sycheva Tatyana , Oo Thein H.
Published: April 2020

BACKGROUND: The incidence and prevalence of second malignancies and autoimmune diseases are high in patients with lymphoproliferative disorders (LPD). However, there is lack of specific data and the relative risks compared to general population are unknown.

METHODS: We performed retrospective chart analysis of 185 patients with LPD in a tertiary hospital from 2000 to 2006. The data was based on available chart reviews and interdepartmental charge codes. All second malignancies and autoimmune diseases were documented irrespective of time of onset.

FINDINGS: M:F ratio = 1.1: 1.0 (97M, 88F). Median age 56. Cases consisted of: CLL/SLL 52(28.1%), multiple myeloma 28(15.135%), unspecified Non-Hodgkin’s Lymphoma 40(21.62%), large cell 24(12.97%), follicular 16(8.64%), marginal zone 11(5.94%), mantle 4(2.16%), T-cell 1(0.54%), and Hodgkin’s 9(4.86%). 37 second malignancies were documented. The prevalence was as follows: prostate 14(7.56%), breast 7(3.783%), kidney 3(1.621%), skin 3(1.621%), colon 2(1.081%), lung 3(1.621%), CMML 1(0.54%), AML 1(0.54%), larynx 1(0.54%), vulva 1(0.54%), pituitary 1(0.54%). The US prevalence of cancers as of January 2003 (population 299,259,581) based on the SEER ( Surveillance, Epidemiology and End Results) data is as follows: all cancers 3.5073%, prostate 0.648%, breast 0.792%, colon 0.357%, kidney 0.077%, lung 0.119%, larynx 0.033%.

Relative risks for second malignancies in LPD patients were calculated (see table). 55 (29.7%) autoimmune diseases were also documented: hypothyroidism 34(18.378%), ITP 10(5.405%), rheumatoid arthritis (RA) 6 (3.243%), hemolytic anemia 3(1.621%), Sjogren’s 1(0.54%), cryoglobulinemia 1(0.54%). The prevalence of autoimmune diseases in the USA is 3.21%. The prevalence of specific autoimmune diseases except RA is unknown in the available literature. The relative risk of autoimmune disorders in LPD patients is 9.25 folds.

DISCUSSION: Our data shows that the prevalence of some second malignancies (renal, prostate, lung, laryngeal, breast, colon) and autoimmune disorders are very high in LPD patients. Due to lack of SEER data, we were unable to calculate the relative risks of other cancers and autoimmune diseases. The relative risk of a second malignancy is increased up to 5-fold (up to 21-fold with renal cancer) and autoimmune diseases up to 9.25-fold. This study has limitations in terms of the sample size and unavailability of some SEER data. However, the results are provoking and need to be validated in larger studies.

Relative Risk of Second Malignancy Cancer Types Lymphoproliferative Disorders n=184 General Population n=299,259,581 Relative Risk All Cancers 20.0% (37) 3.507% 5.702 Prostate Cancer 7.567% (14) 0.648% 11.677 Breast Cancer 3.783% (7) 0.0792% 4.776 Renal Cell Cancer 1.621% (3) 0.077% 21.05 Lung Cancer 1.621% (3) 0.119% 13.621 Colon Cancer 1.081% (2) 0.357% 3.028 Laryngeal Cancer 0.540% (1) 0.033% 16.363
Gender and Regional Differences in In-Hospital Mortality in Patients with Sickle Cell Anemia (SCA) in the United States: Results from the Nationwide Inpatient Sample (NIS) 1993-2003.
Authors: Haywood Carlton , Lanzkron Sophie
Published: April 2020

Background: The purpose of this study was to use the NIS to describe hospital utilization and in-hospital mortality among adults with SCA in the US between 1993-2003.

Methods: The NIS is designed to approximate a 20% stratified sample of U.S. community hospitals. We restricted our analyses to discharge records with ICD-9-CM diagnosis codes 28261 or 28262 (SCA without/with crisis), and where the age was listed as 18 or older. Analyses were conducted using tests of linear combinations of coefficients, χ2, and linear and logistic regression.

Results: There were an estimated 705,080 hospitalizations over the time period (mean of 64,098 hospitalizations/year). 54% of all hospitalizations were for females. 50% of the hospitalizations were expected to be paid for by Medicaid. The mean patient age over the time period was 31.3 yrs. The mean patient age increased from 30.3 in 1993 to 32.1 in 2003 (p < 0.001). Mean age over time increased even after adjusting for the gender makeup and hospital region (β=0.162, p < 0.001). There were no gender differences in the median age (30) of patients. Mean length of stay (LOS) was 6.5 days for the time period. LOS decreased from 7.5 days in 1993 to 6.4 days in 2003 (p=0.001). Adult women experienced longer LOS than adult men (6.8 days vs. 6.3 days, p <0.001). This difference remained significant even after controlling for age, time, insurance status, and hospital region (β = 0.49, p<0.001). Mean charges/discharge increased from $16,799 in 1993 to $22,281 in 2003, even after adjusting for inflation (p < 0.001). There were an estimated 4497 in-hospital deaths during the time period (0.64% of hospitalizations). The median age at death was 38. The median age at death increased from 35 in 1993 to 42 in 2003 (p = 0.0061). This was due to an increase in age of death (39) for women (p=0.0052). In men the median age of death (37) did not change over time(p=0.4352). In bivariate analyses of median age at death, women were older than men (39 vs. 37 p=0.0056). A simple logistic regression of deaths over time found no significant trends in the odds of an in-hospital death over the time period. In a multivariate model of death over time patients in the South and the West experienced higher odds of an in-hospital death than patients in the Northeast and Midwest.

Conclusions: Our analysis shows that women with SCA have longer in-hospital LOS than men, and are older in age at death than men. While the median age at death among persons hospitalized with SCA has been increasing since 1993, this increase is seen exclusively in women. There has been no change in longevity in men hospitalized with SCA over the time period studied.
Human Herpesvirus (HHV) 8 K1 Suppresses Fas-Mediated Apoptosis and Binds to the Fas Complex.
Authors: Maeng Hoyoung , Wang Shu , Wang Suizhao , Young Daniel , Samaniego Felipe
Published: April 2020

Kaposi’s sarcoma-associated herpesvirus (KSHV or HHV-8) is associated with multicentric Castleman’s disease, primary effusion lymphoma (PEL), and Kaposi’s sarcoma. Malignant tumors are frequently associated with resistance to Fas-mediated apoptosis, which is a common obstacle to the successful treatment of many different types of cancers. Oncoprotein K1 encoded by HHV-8 is a transmembrane protein with an immunoreceptor tyrosine-based activation motif (ITAM) sequence in its short cytoplasmic domain, which is constitutively phosphorylated (J Natl Cancer Inst Monogr. 28; 15–23, 2001). We have found that K1-expressing cells are resistant to apoptosis and K1 directly binds Fas to inhibit apoptosis. K1-transfected BJAB cells were resistant to Fas-induced apoptosis, but not to other stimuli including tumor necrosis-related apoptosis-inducing ligand or radiation. K1 transgenic mice showed lymph node hyperplasia and large spleens. Nine out of 12 K1 transgenic mice survived injection of 0.3 mg/gram activating anti-Fas (Jo2) antibody whereas 13 out of 22 control mice died with hepatocyte apoptosis (p=0.03). We prepared deletion and point mutants of K1 and Fas to map their respective binding sites.

Immunoprecipitation-immunoblotting analysis of the transfectant cell lysates showed that binding occurred through the extracellular domains of K1 and Fas. Also, we have found that preligand assembly domain-deleted Fas mutants (amino acids 1-66 deleted) still bind to K1. The deletion mutants encompassing cysteine-rich domains 1, 2, and 3 of the extracellular domain of Fas are currently being tested for mediating binding to K1. These results support the presence of an apoptosis regulatory system based on Fas-protein interactions. By characterizing this mechanism, we will lay the foundation of an apoptosis regulatory pathway that may explain apoptosis resistance of many cancers.
Evaluation of Microsatellite Instability in Gastric MALT Lymphomas.
Authors: Siakantaris Marina P. , Angelopoulou Maria K. , Lilakos Konstantinos , Metaxas Yannis , Moschoyianni Maria , Gamaletsou Maria , Vassilakopoulos Theodoros P. , Kyrtsonis Marie-Christine , Korkolopoulou Penelope , Panayiotidis Panayiotis , Pangalis Gerassimos A.
Published: April 2020

BACKGROUND: Microsatellite instability (MSI) is a major mechanism of carcinogenesis in hereditary nonpolyposis colorectal cancer, sporadic colon cancer, as well as other solid tumors. It is also encountered in gastritis and other chronic inflammatory conditions. Gastric MALT lymphomas are associated with chronic antigenic stimulation due to Helicobacter pylori (H.P) infection, leading to chronic gastritis, before converting to overt lymphoma.

AIM: The evaluation of the presence of MSI in gastric MALT lymphoma lesions at diagnosis and during follow-up, after H.P eradication and/or chemotherapy.

METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded MALT lymphoma gastric biopsies. Blood genomic DNA was used as control. A pentaplex PCR was performed using primers for 5 different mononucleotide loci (NR21, NR24, NR27, BAT25 and BAT26). Sense oligonucleotides were labeled with WellRead fluorophores and products were run on a CEQ8000 apparatus (Beckman Coulter). Allele scoring was performed using the specific software. For the definition of MSI, 2/5 loci had to show banding shifts or gains outside the quasimonomorphic area for each marker.

RESULTS: 10 MALT lymphoma patients at diagnosis were studied and peaks were compared between stomach and blood samples. All 5 markers studied did not reveal any additional peaks when blood and gastric DNA were compared. In 4 patients follow-up gastric biopsies were available, after H.P eradication, as well as after chemotherapy treatment. There was no evidence of MSI in the serial gastric biopsies of these patients.

CONCLUSIONS: MSI was not detected in any gastric biopsies of this small group of MALT patients, either at diagnosis, or after treatment. The role of MSI in the lymphomagenesis of this distinct type of lymphoma needs to be further evaluated in serial specimens in a larger series of patients.
Rearrangement Patterns of Igs and bcl2/IgH and Clinical Significance in Follicular Lymphoma.
Authors: Martinez-Lopez J. , Rivero A. , Montalban C. , de la Serna J. , Fernandez-Sevilla A. , Paz J. , Canales M. , Ona R. , Sanchez-Godoy P. , Martinez R. , Grande S. , Martinez-Sanchez P. , Ayala R. , Tomas Jose F.
Published: April 2020

Objectives: To identify a clonal population by molecular techniques in patients treated with Fluradabine, Cyclophosphamide, Rituximab (CF+R) and included in the LNF-03 clinical trial. To relate these alterations to the clinical variables at diagnosis and response to treatment.

Patients and Methods: Patients: 71 patients from the LNF-03 clinical trial. Their treatment consisted of CF+ Rx6 and posterior maintenance with Rituximab. Peripheral Blood (PB) and Bone Marrow (BM) were studied at diagnosis.

Methods: bcl2/IgH rearrangements were studied by real-time PCR (Olsson et al, Mod Pathol 1999). Ig rearrangement of VDJ IgH, Igs IgL KVJ, Kdel and LVJ was studied according to BIOMED II protocols.

Results: 43 of the 71 patients (60.56%) presented some molecular alteration in PB or BM. 33% of the patients in the study presented t(14;18) in some of its majority forms, bcl2/IgH mayor 19 (26.4%) and minor 3 (4.22%). 13 patients were positive for bcl-2/IgH, both in BM and in PB. The median amount of blc2/IgH in BM was 8.315% (62.9–0.04), Whereas in pb it was 4.775% (92.6–0.06), with no significant differences observed. Nevertheless, monoclonality was detected in BM in eight cases but not in PB, and to the inverse, one it happened in three patients.

Of 71 patients, 38 (53.52%), presented displayed monoclonality in at least one of the Ig genes. Of these patients, 38% presented the clonal rearrangement in IG-L KVJ, 26% in IG-H CDR1, 23% in IG-L KDEL, and 13% rearranged in IG-L LAMBDA. There were 57 patients whose BM was available. 28 of them presented pathological infiltration, and monoclonality was detected in 23 cases; in 29 patients who were not pathologically infiltrated, monoclonality was detected in 12 cases. 83% (6/37) of the patients presented a complete response (CR), 8.1% (3/37) uncertain CR (uCR) and 8.1% (3/37) partial response (PR), after the induction treatment.

No relation was found between the presence of molecular alterations in BM/PB and the achievement of a CR.

Conclusions: The study of the rearrangements of Ig and bcl2/IgH is a good strategy for identifying lymphomatosus disease at diagnosis; bone marrow is more informative than peripheral blood. The presence of molecular alterations in PB and/or BM is not related to a poorer answer to induction treatment. Partially funded by Roche Farma SA.
CD40L Modulates TRAIL-Induced Apoptosis in Germinal Center Derived B Cell Lymphomas.
Authors: Travert Marion , Ame-Thomas Patricia , Fest Thierry , Pangault Céline , Semana Gilbert , Lamy Thierry , Tarte Karin , Guillaudeux Thierry
Published: April 2020

Follicular lymphoma are characterized by the rearrangement of the bcl-2 gene, present in more than 90% of patients. Over-expression of the bcl-2 protein resulting from this translocation is associated with the inability to eradicate the lymphoma, by inhibiting apoptosis. Despite the median survival ranges from 8 to 15 years, leading to the designation of indolent lymphoma, patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. Numerous reports have shown that Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in a wide variety of transformed cell lines of diverse lineage, but does not appear to kill normal cells, even though TRAIL mRNA is expressed at significant levels in most normal tissues. As cell death induced by TRAIL occurs almost exclusively in tumor cells, it suggests that this drug is safe to use as an antitumor therapy. We therefore investigated the efficiency of this cytokine to induce apoptosis in germinal center derived B cell lymphoma, despite bcl-2 over-expression. Our study was also designed to evaluate the role of CD40L, one of the main differentiation signal involved in B cell maturation during the germinal center reaction, on the regulation of TRAIL-induced apoptosis. This study was performed on three germinal center derived tumor cell lines (BL2, VAL and RL), and on normal and tumor primary cells obtained from human tonsils and lymph nodes. Our data show that normal B lymphocytes obtained from tonsil biopsies are resistant to TRAIL-mediated apoptosis, when B lymphoma cells issued from lymph node of numerous patients are significantly sensitive to the cytokine. When we treat these lymphoma cells with trimeric huCD40L, we partly rescue these cells from spontaneous apoptosis which naturally occurs after few days of culture, and reverse by 50% TRAIL-mediated apoptosis when cells were co-treated with huCD40L for 16 hours. Similar results were reproduced on some germinal center derived cell lines. BL2 was indeed found highly sensitive to TRAIL-induced apoptosis following a 24 hour exposure. On the opposite, VAL and RL were almost insensitive. We have demonstrate that apoptosis is exclusively mediated by TRAIL-R1 in BL2. Analysis of signalling pathways revealed that the protection to TRAIL-induced apoptosis by CD40L is due to some specific anti-apoptotic molecules that will be described. Genes encoding these molecules are targets of the NFκB signalling pathway activated by CD40L. Our results suggest that activation of NFκB and induction of anti-apoptotic molecules by CD40L play an important role in the protection of germinal center derived B cell lymphomas against apoptosis. Then, NFκB inhibitors may be wise to use in clinical trials in conjunction with TRAIL against follicular lymphomas.
Distinct Cytogenetic Aberrations during the Course of Mantle Cell Lymphoma (MCL).
Authors: Papadhimitriou Stephanos I. , Davea Ageliki , Savvidou Ioanna , Paterakis George , Goumakou Helen , Griva-Kritikou Elpi , Androutsos George , Pavlidis Dimitris , Marinakis Theodoros , Anagnostopoulos Nikolaos I. , Georgiakaki Maria
Published: April 2020

BACKGROUND: Apart from t(11;14)(q13;q32), MCL is also characterized by other nonrandom cytogenetic findings. These additional aberrations are well studied at diagnosis and believed to represent clonal evolution during lymphomagenesis, but little is known about karyotypic changes during the course of the disease.

METHODS: The study included 33 patients with MCL. In all cases, an interphase FISH assay was performed at diagnosis on lymphoma cells from peripheral blood, bone marrow or touch imprints of involved sites. Commercial probes were employed for the detection of t(11;14), +12, 13q−, and abnormalities of ATM, p53, p16, TEL, c-MYC and BCL6 genes. In 14 cases, the same FISH screening was repeated at least once (up to four times) during the course of the disease, at relapse or in the context of partial or no response.

RESULTS: The most frequent additional findings at diagnosis were ATM deletion in 15 cases (45.5%) and 13q− in 12 cases (36.4%), followed by p16 deletion (3 cases; 1 homozygous), p53 deletion (2 cases), and +12, duplication of the CCND1/IGH fusion gene and BCL6 triplication, in one case each. 11 of the 14 cases studied at follow-up showed karyotypic evolution, with acquisition of p16 deletion (6 cases; 4 homozygous), TEL deletion (5 cases; 2 on the basis of monosomy 12), duplication of the CCND1/IGH fusion (3 cases), p53 deletion (2 cases), and c-MYC amplification (1 case). There was no case with acquisition of ATM deletion, 13q− or +12, but in two cases with 13q− in a minor subclone at diagnosis the aberration was estimated to involve the total of the lymphoma cells at relapse. Interestingly, new BCL6 aberrations were seen in 3 cases (triplication in one and amplification in the other two, including the case with gene triplication at diagnosis) and were detected at the third or the fourth repetition of the screening. The longest survival after detection of these aberrations was 3 months.

CONCLUSIONS: Our data suggest that in most cases of MCL clonal evolution also occurs during the course of the disease, with the acquisition of multiple additional chromosomal lesions. Despite the small number of patients in our series, it seems that some of the aberrations (like ATM deletion or 13q−) are most commonly already present at diagnosis, while others (such as monosomy 12 and/or TEL deletion) appear more often or even exclusively on follow-up. From the clinical point of view, we found that the most informative finding is the overrepresentation of the BCL6 gene, apparently associated with aggressive behavior and perhaps the terminal stage of MCL.
Expression of Coxsackie Adenovirus Receptor in Cutaneous T-Cell Lymphoma: Potential for Skin Targeted Gene Therapy.
Authors: Ledet Johnathan , May Joshua , Billelo Seth , Friday Ellen , Nordberg Mary , Turturro Francesco
Published: April 2020

Cutaneous T-cell lymphoma (CTCL) represents a spectrum of diseases characterized by the accumulation of clonal lymphocytes in the skin. It has been well established that primary cutaneous lymphomas of T-cell lineage have shown ALK protein expression. Furthermore, we have previously shown that ALK-ALCL cell lines highly express the coxsackie-adenovirus receptor (CAR), primary receptor for recombinant wild type-fiber adenovirus-derived vectors for gene therapy. Since skin-directed therapies are the preferred first-line treatment the presence of CAR in CTCL may be helpful in developing therapeutic modalities such gene or targeted molecular therapy. By using ALK-immunostaining, we analyzed retrospectively a series of human tissue primarily diagnosed as CTCL [5 mycosis fungoides (MF), 4 (ALCL)] or peripheral T cell lymphoma (1 PTCL) in order to establish the level of CAR expression in primary CTCL tissue. Fluorescence in situ hybridization (FISH) analyses were also performed on these cases using a locus specific DNA probe for the ALK/p2 locus. We used ALK identification because at the time when the primary diagnosis was placed, the samples were not tested for ALK expression. Patients ranged in age from 32–73 years old with a median age of 58. Normal skin biopsies from 8 patients were used as controls. The results of our analysis are illustrated in Table 1.

TABLE 1. DIAGNOSIS SPECIMEN CAR INTENSITY/% ALK INTENSITY/% FISH CD30 ALCL RT ANKLE MASS 0 / 0 N/A N/A POS ALCL RT FLANK MASS 1+/ 80 1+ / 80 32% B-ANEUPLOID ALCL SKIN, LOWER RIGHT EXTREMITY 0 / 0 2+/ 10 NL POS PTCL SKIN, RT ARM 3+ / 95 3 +/ 70 MF SKIN, RT AXILLA 1 + / 5 3+ / 5 ALK POS MF SKIN 1+ / 5 3+ / 5 NL 21% ANEUPLOID MF SKIN, ARM 0 / 0 3+ / 90 NL (18% ANEUPLOID) POS (RARE) MF SKIN, LEFT BACK 2+ / 40 3+ / 95 NL MF SKIN, RT FOREARM 2+ / 30 1 + / 30

In this study, we show that the immunostaining of CAR in combination with classic ALK-immuno or ALK-FISH is feasible and helps in identifying CTCL cases candidate for skin targeted adenoviral-mediated gene therapy.