bluuebunny/crossref_metadata_2025 huggingface dataset:
Subclincal Atherosclerosis as Measured by CIMT Is Present in Patients with Hodgkin’s Disease.
Authors: Levine Jennifer M. , Weiner Michael A. , Rundek Tatjana , Elkind Mitchell S.V. , Hughes Deborah , Ramas Romel , Cheung Ken , Kelly Kara M.
Published: October 2019

Cardiovascular disease is a well-described late effect of treatment for Hodgkin’s Disease (HD), generally attributed to high dose radiation therapy (RT) to the mediastinum and neck. Increased carotid artery intima-media thickness (CIMT), measured by ultrasound, is a valid marker of subclinical atherosclerosis and is associated with an increased risk of future vascular disease. We evaluated CIMT in 31 patients with HD, (22 males, 9 females), mean age 21 (range 9–39) years, between 2 and 241 months from diagnosis. Thirty patients received chemotherapy, including anthracyclines. Sixteen patients were treated with RT to the bilateral neck and mediastinum; 4 received high dose (36Gy) RT and 12 received lower dose (21–25Gy) RT. One patient received lower dose RT only to the bilateral neck. Fourteen patients were treated with chemotherapy alone. CIMT was assessed using a standardized scanning and reading protocol. The CIMT was calculated as the mean of the maximum measurement at 12 sites; near and far walls of the common carotid, bifurcation and internal carotid arteries bilaterally. The mean CIMT for the total cohort was 0.757mm. Among 5 patients (mean age 13, range 9–16 years), evaluated while actively receiving therapy or within one year from completion of therapy, mean CIMT was 0.715, equivalent to the mean CIMT found in healthy 30 year old adults (Stein, Stroke 2004). In a multivariate linear regression analysis CIMT was significantly associated with increasing time since diagnosis (p=0.035), age (p=0.016), and male gender (p=0.014). There was no difference in CIMT between those patients treated with chemotherapy alone vs. chemotherapy and radiation therapy. Subclinical atherosclerosis in patients with HD may evolve early in the course of treatment and survivorship and then increase with age and time from diagnosis. Type of treatment was not a significant predictor of CIMT in our cohort suggesting that factors other than RT play a role in the development of subclinical atherosclerosis. Further studies are needed to better elucidate the etiology of atherosclerotic disease in HD survivors. Screening with CIMT may detect subclinical atherosclerosis and allow for earlier intervention to prevent cardiovascular disease in this population.
Analysis of Clinical Characteristics and Prognostic Variables of Hodgkin’s Lymphoma: A Single Center Experience.
Authors: ALshemmari Salem H. , Bhat Ganapathi M. , Ameen Reem M. , Sajinani Kamlesh P. , Gyarfas Jan
Published: October 2019

Background: Hodgkin’s disease is a curable malignant disease. Despite advances in the management of this disease entity, there are groups of patients who suffer relapse and identification of prognostic variables and adaptation of treatment to individual risk remains a major challenge. Emphasized in this study are the clinicopathological characteristics and outcome of Hodgkin’s lymphomas.

Materials and Methods: A retrospective analysis of 245 adult patients treated for Hodgkin’s lymphoma between October 1990 and Dec 2004 was done. An analysis of the most important variables was made in terms of both disease free and overall survival. Spectrums of pretreatment factors were evaluated including International Prognostic Factors, extranodal disease symptoms, histology, and bulky disease. Patients were treated with chemotherapy, radiotherapy either alone or in combinations at the beginning and relapses was treated with various salvage regimes combined with radiotherapy and stem cell transplant.

Results: The median age in this study group was 32 years (14–72) and 156(63.67%) were male. Distribution by stages were: stage I-43, stage II-113, stage III-44, and stage IV-45.Pathological subtypes were Nodular sclerosis-128, Mixed cellularity-56,Lymphocyte rich classical-13,Lymphocyte depletion-7,and nodular lymphocyte predominance-29,not specified in 12.B symptoms observed in 95,bulky in 72 and Extra nodal involvement in 63 patients. Complete remission was achieved in 226 patients with first line management (92.24%).Primary chemo refractory (19) and relapses were observed in 72 patients, and subsequent salvage chemotherapy including stem cell transplant (28 patients) resulted CR in 41.With the median follow up of 41months (1-374), OS was 95% and DFS was 87%.Twelve patients died out of which 8 due to disease recurrence or progression.

Conclusions: Achieving a complete remission shows a favorable prognosis for prolonged DFS. StageIV, bulky disease,B symptoms, extra nodal involvement and NS histology were associated with inferior OS and DFS. Additional factors for poor DFS were male sex, hypoalbumenemia and anemia. Age and leucocytosis did not affect the outcome. Identifying the pretreatment risk factors may be useful in designing clinical trials for the treatment of relapsed and refractory Hodgkin’s disease and in making individual therapeutic decisions.
Flow Cytometry and Fluorescence In Situ Hybridization Are Methods of Choice for Routine Diagnosis of Mantle Cell Lymphoma.
Authors: Rymkiewicz Grzegorz , Woroniecka Renata , Blachnio Katarzyna , Pienkowska-Grela Barbara , Walewski Jan
Published: October 2019

Mantle cell lymphoma (MCL) is a distinct clinicopathologic entity, characterized by expansion of lymphocytes with co-expression of CD5 and CD20 and frequent t(11;14) translocation. MCL and its morphological variants are frequently confused with other lymphoma subtypes. The aim of this study was to analyze a contribution of histopathology (HP), immunohistochemistry (IHC), flow cytometry (FCM) and cytogenetic analysis with fluorescence in situ hybridization (FISH) to ultimate diagnosis of MCL. We identified 66 pts diagnosed with MCL either by use of HP/IHC or/and FCM. Initial diagnosis was based on HP/IHC only, and was validated in 55 of 66 patients by combined use of HP/IH, FCM, and FISH. We examined paraffin sections IHC panel consisting of antibodies to CD3, CD5, CD20, CD23, CD43, and cyclin D1. FCM analysis was done by 3-colour direct immunofluorescence with extended panel of antibodies to CD5, CD10, CD11c, CD19, CD20, CD22, CD23, CD25, CD38, CD45, HLADR, FMC7, light and heavy chains. We used FISH to detect the t(11;14) in interphase cells of 24 cases of MCL. All 55 cases of MCL were CD20 positive and CD23 negative on IHC, 32 of 51 (63%) and 46 of 52 (88%) cases coexpressed the CD5 and CD43 antigens, respectively. Cyclin-D1 staining revealed nuclear positivity in 38 of 52 (73%) pts. Dual expression of CD5 and cyclin D1 - a finding highly reliable for MCL diagnosis on IHC, was seen in 49% (27/55) of pts. All MCL cases were CD20 (51/51) and CD19 (55/55) positive by FCM with higher intensity of CD20 expression compared to CD19 in 100% (51/51) of cases. CD5 and CD25 were coexpressed in 54 of 55 (98%) and in 43 of 49 (88%) pts respectively. CD22 (45/45) and HLADR (55/55) were positive in all cases. FMC7 and CD38 were found in 22 of 23 (96%) and in 19 of 23 (83%) patients, respectively. CD10, CD11c, CD23 were only seen on a subpopulation of cells with weak intensity in 15%(7/48), 13% (6/45), and 11% (5/46) pts., respectively. MCL cells expressed moderate intensity monoclonal surface light chains in 47 of 52 (90%) pts with L light chain predominance and IgM+/IgD+ in 16 of 17 (94%) pts. False or incomplete initial diagnosis based mainly on lymph node HP/IHC was found in 35 of 66 (53%) cases. False FCM diagnosis of MCL was found in 2 of 66 (3%) cases. Results of FCM and FISH were consistent with the MCL diagnosis in 92% (22/24) of patients, in our hands. Our data indicate that the phenotypic pattern of MCL by FCM is remarkably constant among patients. As MCL represents a frequent diagnostic challenge, a combined use of FCM and FISH may provide an optimum solution.
Gastrointestinal Involvement in Mantle Cell Lymphoma (MCL). A Prospective Clinical, Endoscopical, Pathological and Molecular Study.
Authors: Salar Antonio , Juanpere Nuria , Gonzalez-Barca Eva , Bellosillo Beatriz , Espinet Blanca , Seoane Agustin , Panadés Agustin , Romagosa Vicente , Pedro Carmen , Nieto Miguel , Abella Eugenia , Domingo-Domenech Eva , Sole Francesc , Fernandez-Sevilla Alberto , Besses Carlos , Serrano Sergio
Published: October 2019

Objective: to investigate the clinical, endoscopical, microscopical and molecular involvement of the GI tract in a prospective series of MCL.

Methods: 13 patients with MCL have been prospectively and consecutively entered in a staging workup that included upper and lower endoscopy of the GI tract. Multiple biopsies of the stomach and colon were taken from pathologic mucosa and also from macroscopically normal mucosa. Specimens were assessed with immunohistochemistry (IHC), FISH and PCR.

Results: Only 1 patient presented with GI symptoms at diagnosis. Endoscopy: Upper GI: abnormal mucosa in 5 cases (38%); Lower GI: abnormal mucosa in 6 cases (45%): mild colitis in 1, multiple micropolyps in 3, a large polyp and multiple micropolyps in 1 and three large polyps with normal mucosa in 1. As a whole, 9 patients (70%) had upper or lower endoscopic findings.

Pathology: 10 cases (77%) had microscopic infiltration by MCL of the upper GI tract and 10 cases (77%) of the lower GI tract. As a whole, all but one patient (92%) were found to have microscopic infiltration of the GI tract. All positive cases for CD20 and CD5 were positive for cyclin D1. The PCR product showed a clear monoclonal peak in 12 out of 19 samples, giving a sensitivity of 63.5% compared with IHC. FISH was positive in 7 out of 11 samples (sensitivity of 64% compared with IHC). All but one case with endoscopic abnormalities had GI microscopic infiltration by MCL and 67% of cases with normal endoscopy were found to have GI tract infiltration by MCL.

Conclusions: In our series, GI involvement by MCL was detected in almost all patients. All patients with endoscopic abnormalities had infiltration by MCL at the microscopic level. In 2/3 of the patients with normal endoscopy, GI tract involvement could be demonstrated at the microscopic level. IHC with cyclin D1 was more efficient than FISH and PCR as a diagnostic tool in this setting.
Analysis of Prognosis in Follicular Lymphoma According to the FLIPI.
Authors: Hashimoto Chizuko , Kanamori Heiwa , Tomita Naoto , Takabayashi Maki , Yamazaki Etsuko , Ogawa Koji , Hattori Michiko , Fujita Hiroyuki , Fujisawa Shin , Motomura Shigeki , Kodama Fumio , Ishigatsubo Yoshiaki
Published: October 2019

By the new treatment approaches, such as rituximab, anti-CD20 radioimmunotherapy, high-dose therapy, transplantation, the outcome of treatment for follicular lymphoma has been improved. However, there are wide alternatives in a treatment of follicular lymphoma to stemcell transplantation from watchful waiting, and analysis of prognosis is important in choice of a therapy. The international non-Hodgkin’s lymphoma prognostic index (IPI) has been used for follicular lymphoma. Recently, a new method of the follicular lymphoma international prognostic index (FLIPI) is reported and attracts attention. We apply these two prognostic models for newly diagnosed follicular lymphoma, and reviewed its availability. 5 factors were used, The IPI (age>60, EN≥2, LDH>N, PS≥2, CS≥3), and the FLIPI (age>60, Hb<12.0g/dl, LDH>N, CS≥3, nodal sites>4), respectively. Between 1988 and 2001, 107 patients of newly diagnosed follicular lymphoma (grade I-III) were analyzed. Response rate, overall survival (OS), and progression free survival (PFS) were calculated for each prognostic model. Patients characteristics were male/female 49/58, median age 54yr. (range 21–87yr.), and histological grade I, II/III 103/4. The median follow-up of our series was 84 months (range 40–206 months). CR, PR was 60.7%, 31.8%, and response rate was 92.5%. Median OS at 10 years was 64.4%, and median PFS at 10 years was 28.5%. Patient distribution by the IPI and the FLIPI were the followings; the IPI (L/LI/HI/H 49/41/15/2), the FLIPI (L/I/H 41/29/37). There were few patients equivalent to high risk group in IPI, and it was the patient distribution which was more equal in FLIPI in comparison with IPI.

OS by the IPI and the FLIPI risk group at 10 year were L: 85%, LI: 54%, HI: 44%, H: 50% (p=0.0088), and L: 87%, I: 66%, H: 47% (p<0.0001). PFS by the IPI and the FLIPI risk group at 10 year were L: 36%, LI: 23%, HI: 27%, H: 0% (p=0.0679), and L: 43%, I: 25%, H: 16% (p=0.0003). Correlation with a survival was recognized in FLIPI on OS, PFS more by significantly. As a conclusion, the FLIPI is a promising consequence prediction model. A standard treatment for follicular lymphoma is not established, and the examination that a treatment on the basis of prognosticator is strategic is necessary in future. As for grade 3, there was a little number of patients in this study, but further examination is necessary for adaptation of the FLIPI about this group.
G-CSF Supported CHOP-14 with Rituximab in Patients <60 Years with High-Risk Diffuse Large B Cell Lymphoma (DLBCL).
Authors: Bernell Per , Hedlund Anette , Bjorkholm Magnus
Published: October 2019

Introduction: During recent years studies have shown that elderly patients with aggressive lymphoma may benefit from dose-intensified chemotherapy (CHOP-14). In addition, the addition of rituximab (R) to CHOP-21, seems to improve response rates and survival in elderly patients and younger patients with low and low/intermediate risk factors. Given these promising results we early decided to use G-CSF supported R-CHOP-14 in patients < 60 years with previously untreated DLBCL and risk factors.

Patients and methods: Between March 2000 and June 2003, 25 consecutive and previously untreated patients with CD20+, stage II–IV DLBCL and ≥ 1 risk factor (IPI) were included. HIV+ patients and patients with CNS involvement were not eligible. The median age was 56 years (range 27–60). The CHOP regimen (6–8 cycles) was delivered every 14 days with R (375mg/m2) iv on day 1. G-CSF (300ug/day) was given sc from day 5 to day 13 or until an absolute granulocyte count >4.0x109/l. Re-staging studies were routinely performed every two cycles. Non-responding patients were planned to receive MIME chemotherapy followed by high-dose therapy and autologous stem cell support (ASCS). Four patients were given local radiotherapy to previous bulky disease.

Results: Seven (28%) patients had an IPI score of 1 and 72% IPI 2 or 3. 23/25 (91%) had elevated S-LDH, 12/25 (48%) had bulky disease and 14/25 (56%) had an extranodal lymphoma manifestation. 17/25 (68%) of tumors were positive for bcl-2 (immunohistochemistry). 22/25 (88%) patients achieved a CR. One SD patient (IPI 3) died from progressive disease and two patients with PR and SD after 4 courses received dose-escalated MIME chemotherapy and BEAM high-dose therapy with ACSC and remain in CR. After a median observation time of 32 months (range 21–37 months) 4 (3 with IPI 3) of 22 CR patients have relapsed following R-CHOP. Two (both IPI 3) of relapsing patients died from lymphoma. R-CHOP was delivered on day 15 in 83% of cycles. Grade 3–4 neutropenia and thrombocytopenia were observed in 80% and 16% of patients, respectively. Five patients developed neutropenic fever and pneumonia was diagnosed in additional 3 patients. Non-hematological toxicity was in general mild. Grade 3 or 4 adverse events related to the infusion of R were not observed.

Conclusion: G-CSF supported R-CHOP-14 immunochemotherapy is feasible, safe and effective in young patients with advanced aggressive DLBCL and risk features. Innovative treatment approaches are needed for non-responding and relapsing patients.
Rituximab Plus Dose Enhancement and Biweekly Administration of CHOP for Newly-Diagnosed Patients with Diffuse Large-B-Cell Lymphoma.
Authors: Javier Francisco , Ríos E. , Almagro M. , Durán-Cabral J.M. , Rodríguez J.N. , Durán-Nieto S. , Bergua J. , Martino L. , Romero A. , Martín-Reina M.V. , Gil J.L.
Published: October 2019

Introduction: Rituximab plus CHOP every 3 weeks is associated with a increase in the survival of elderly patients. Dose intensification and dose compression with G-CSF support may provide an advantage compared with standard-dose CHOP.

Purpose: To evaluate the efficacy and safety of Rituximab plus CHOP with increased dose of cyclophosphamide and shortened intervals between chemotherapy courses in newly-diagnosed patients with diffuse large-B-cell lymphoma.

Therapeutic scheme: Rituximab 375 mg/m2 (d1), cyclophosphamide 1.500 mg/m2 (d1), vincristine 1.4 mg/m2 maximum 2 mg (d1), adriamycin 50 mg/m2 (d1) and prednisone were given. G-CSF (5–10 μg/kg) was added on days 3 to 11 in each course. Six to 8 courses were applied at 14-day intervals.

Results: Between january 2002 and may 2005 twenty eight patients, from seven institutions, were included in this study and received 187 courses. Their median age was 48 years (19 to 59 years). The four last patients have not yet finished their treatment and were not evaluable for response. All patients exhibited alopecia and acceptable myelosupression. Thirteen episodes of fever were reported. Among 24 evaluable patients ORR was 83.3% (70.8% CR and 12.5% PR). With a median follow-up of 11 months (range 4–42) the OS and EFS at 30 months is 83% and 75%, respectively.

Conclusions: The administration of Rituximab plus CHOP every 14 days with enhanced dose of cyclophosphamide is safe. The toxicity is mainly hematological, but can be surmounted with the use of G-CSF and EPO. Recruitment of more patients and longer follow-up are required to confirm these results.
Primary Bone Lymphoma. A Single Center Experience.
Authors: Bouzani Maria , Gigantes Stavros , Rontogianni Dimitra , Violaki Vasiliki , Karmiris Themis , Apostolidis John , Mpakiri Maria , Sotiropoulou Anastasia , Nikiforakis Emmanuel
Published: October 2019

Introduction. Primary Bone Lymphomas [PBL] are rare extranodal non Hodgkin’s Lymphomas [NHL] constituting about 5% of all extranodal NHL. In this study we present our experience from a retrospective analysis of patients with PBL; we have assessed the patient characteristics, response to therapy and outcome.

Patients - Methods. From a population of 600 newly diagnosed patients with NHL who have been registered to our Unit between 1990 and 2004, 18 [ 3% ] have been classified as PBL. Apart from patient characteristics and clinical course, 12 cases were studied with immunohistochemistry for expression of antigens associated with different stages of B-cell differentiation. The median age of the patients [12 men, 6 women, M/F ratio 2/1] was 54 years (range 32 – 83). The stage of the disease was evaluated as I in 12 patients (66 %), II in one (6%), and IV in five patients (28%). The histology was that of a diffuse large -B-cell lymphoma in 17 cases [94%] while one patient [6%] had lymphoplasmacytoid lymphoma. The most common site of involvement was the axial skeleton (13/18, 72%), followed by the long bones of the extremities (5/18, 27%). All studied tumors revealed a germinal center [ G-C] immunophenotype signature [bcl−6 +], but only 4 of 12 [33%] confirmed their G-C origin [bcl-6+CD10+].

Results: Sixteen patients were treated with an anthracycline based chemotherapy regimen with [14] or without [2] radiotherapy [RT]. Only one patient was treated with RT alone, while one patient denied treatment. Fifteen patients (88%) achieved complete remission, one (6%) partial remission, and one patient (6%) had progressive disease to first line therapy with a CHOP-like regimen. Five patients (30%) experienced relapse; in three cases the relapses involved the CNS. Finally, 16 patients remain alive: 14 in CR [10 (60%) in 1st, 4 (23%) in 2nd CR], and one (6%) with active disease. Two patients (11%) have died, both with CNS disease. One patient survives without recieving treatment. With a median follow-up time of 47 months (range 8– 150), the 6 year actuarial overall and disease free survival was 72% and 52% respectively.

Conclusions: PBL are rare extranodal NHL. They mostly involve the bones of the axial skeleton. The vast majority of them present with a germinal center immunophenotypic profile. The response rate is high (88%). However, the disease recurs in one third of the cases, most often in the CNS.
A Phase II Study of the Combination of Topotecan, Ara-C, Cisplatin and Prednisolone (Toposhap) for Slavage of Primary Refractory and Relapsed Patients with Lymphoid Malignancies.
Authors: Giglio Auro del , Dantas André A.P.H. , Burgos Ana Rita M.
Published: October 2019

Introduction: Topotecan has activity in several hematological malignancies. We have previosuly described a phase I trial of the combination of Topotecan, Cisplatin, Ara-C and Prednisolone (TOPOSHAP) (Acta Haematol. 2004;112(3):121–5). In this phase I study the recomended doses were Topotecan 1,0 mg/m2/d, IV, given on days 1 to 3, Cisplatin 25 mg/m2/d, IV, on days 1 to 3, Ara-c 500 mg/m2, IV, on day 4, prednisolone 250 mg, IV, on days 1 to 4.

Patients and Methods: We treated 22 patients (19 to 73 years old) with primary refractory or relapsed Acute lymphoblastic leukemia (ALL), Non-Hodgkin’s Lymphoma (NHL) or Hodgkin’s disease (HD), with measurable disease, with the TOPOSHAP regimen in the aforementioned doses. Tumor reponse was evaluated after the second cycle of this regimen.

Results: Fifty four cycles of chemotherapy were given, ranging from 2 to 6 per patient. One patient died before completing the second cycle of chemotherapy. In the 19 evaluable patients we observed a response rate of 53% (5 CR and 6 PR). All patients had grade IV myelotoxicity and 8 required dose reduction. Seven patients had febrile neutropenia and 3 had mucositis, 2 had diarrhea and 1 had WHO grade 1 renal insuficiency.

Conclusion: We conclude that the TOPOSHAP regimen is an active regimen for the salvage of refractory or relapsed patients with hematological lymphoid malignancies.
Randomized Comparison of Cladribine Containing Regimens and COP in Previously Untreated Patients with Small Lymphocytic, Marginal Zone and Follicular Lymphoma.
Authors: Kalinka Ewa , Wajs Jaroslaw , Sulek Kazimierz , Robak Tadeusz , Blasinska-Morawiec Maria , Sawczuk-Chabin Joanna , Ceglarek Bernadetta , Konopka Lech , Centkowski Piotr , Seferynska Ilona , Warzocha Krzysztof
Published: October 2019

The aim of the study was to comparatively assess first-line treatment with cladribine alone or in combination with cyclophosphamide (CCR, cladribine-containing regimens) and COP (cyclophosphamide, vincristine, prednisone) in different subtypes of low-grade lymphoma. End points were complete remission (CR), overall response rate (ORR), incidence of chemotherapy-related side effects as well as freedom from progression (FFP) and overall survival (OS). From June’2000 to June’2005, 178 previously untreated patients (pts) were randomly allocated to receive 6 monthly courses of either CCR or COP in 17 centers in Poland. This analysis included 107 pts who have completed scheduled chemotherapy, including 45 pts with small lymphocytic (SLL, median age=64 years), 26 marginal zone (MZL, median age=58 years) and 36 follicular (FL, median age=65 years) lymphoma. Compared to COP, CCR induced higher CR rates in all treated groups (65% vs 15%, p=.005; 57% vs 10%, p=.02; 58% vs 12%, p=.03, respectively) but differences in ORR were not significant (92% vs 69%; 92% vs 60%; 79% vs 62%, respectively). Incidence of side effects did not differ significantly in CCR- as compared to COP-treated pts, e.i. infections (10% vs 7%; 14% vs 20%; 15% vs 0%, respectively), myelosuppression (31% vs 7%; 21% vs 20%; 30% vs 0%, respectively), and non-hematological adverse events (10% vs 14%; 7% vs 30%; 7% vs 22%, respectively). With a median follow-up of 12 months, median FFP was superior in CCR- as compared to COP-treated treated pts with SLL (43 vs 12 months, log-rank p<.03) or MZL (37 vs 7 months, log-rank p<.03) but not with FL (17 vs 22 months). Although the median OS has not been reached in any of the histological group so far, no difference in its duration is detected between CCR- or COP-treated pts. In summary, for pts with SLL, MZL and FL, first-line CCR regimens provided better CR and similar toxicity rates as compared to COP, which translated into longer FFP in SLL and MZL but not in FL pts. Although these results warrant larger number of pts and longer follow-up, they might suggest the choice of different front-line chemotherapy with or without immunotherapy in particular histological subtypes of low-grade lymphoma.
A Phase 2 Study of Bortezomib in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: de Vos Sven , Fernando Donna , Schenkein David P. , Rosen Peter J.
Published: October 2019

The novel proteasome inhibitor bortezomib (Velcade®) is approved for the treatment of multiple myeloma following at least one prior therapy. Recently, bortezomib was shown to be active in relapsed mantle cell lymphoma and some low grade B-cell non-Hodgkin’s lymphomas. We conducted a phase 2 trial to evaluate the overall response rate (ORR) following treatment with single agent bortezomib in patients with relapsed DLBCL. Non-hospitalized patients with measurable disease, and a Karnofsky Performance Score > 60%, were eligible for the trial if they had relapsed after or were refractory to their most recent chemotherapy. Patients had to be either not eligible for high dose chemotherapy with stem cell support or had already received a stem cell transplantation. The treatment schedule was: bortezomib 1.3 mg/m2 via intravenous bolus on days 1, 4, 8, and 11 of a 21-day cycle for up to 8 cycles. Responses were assessed using the International Workshop criteria (J Clin Oncol. 1999;17:1244). Ten patients were enrolled in this trial with one screen failure. The mean age was 60 years (range 22 to 83). The study population was heavily pretreated with a mean of 4.6 (range 2 to 7) prior chemotherapy regimens. Three patients (33.3 %) had received high dose chemotherapy with stem cell transplantation. The mean number of treatment cycles received was 2.33 (range 1 to 8). One of nine patients had stable disease (SD) and completed all 8 treatment cycles whereas all other patients progressed while on study drug (PD). The treatment was well tolerated. Grade ≥ 3 AEs included thrombocytopenia, neutropenia, hyponatremia, and hyperkalemia. In summary, single agent bortezomib is not an active drug in heavily pretreated patients with relapsed/refractory DLBCL. Bortezomib has clinical activity as single agent in other lymphoma subtypes and there is at least additive preclinical and clinical activity in combination with other agents. Therefore, investigation of bortezomib-containing combination therapies might be considered in less heavily pretreated DLBCL patients.
Development of Dendritic Cell Vaccine Against Measles for Patients Following Hematopoietic Cell Transplantation.
Authors: Kumamoto Tadashi , Nashida Yuji , Hirayama Masahiro , Azuma Eiichi , Komada Yoshihiro
Published: October 2019

Measles virus (MV) remains one of the serious pathogens among patients following hematopoietic cell transplantation (HCT). According to our questionnaires reported in Japan Society for Pediatric Hematology from 170 institutes in 2001, 37 patients from 21 institutes were affected with measles after HCT and 3 out of these patients died. This high mortality rate is mainly due to secondary infection, which developed on the basis of immune suppression induced by MV infection. However, only 29 of 170 institutions performed measles vaccination after HCT. It is speculated that the potential of immune suppression by vaccine strain of MV is one of the major reasons for hesitating vaccination following HCT. MV-producing glycoproteins expressed in MV-infected cells play important roles in the induction of immune suppression. MV-infected DCs express measles glycoprotein complexes consisted of fusion (F) and hemagglutinin (HA) protein. During DC-T cell interaction, the signal transmitted from F-HA complex interferes with Jak/STAT and PI3-k/Akt kinase pathways, and eventually inhibits the survival and proliferation of T cells. Here, we produced a DC-based vaccine against MV by loading DCs with MV-infected autologous DCs. MV in the infected DC was inactivated using ultraviolet-B before loaded. The DC-based vaccine neither expressed HA nor inhibited allogeneic T cell proliferation, while induced the production of interferon (IFN)-gamma by autologous CD4+ and CD8+ naive T cells. Importantly, 19 out of 20 DC-vaccines effectively induced IFN-gamma producing cells in vitro, even when prepared from patients who suffered from acute or chronic GvHD, and were taking immunosuppressives. Surprisingly, IFN-gamma producing cells were induced in all 8 patients who had undergone HCT within a year (2 patients in 1 month, 2 in 2 months, 1 in 6 months, 2 in 7 months, and 1 in 10 months). These findings indicate that our DC-based MV vaccine induces MV-specific immunity even in post-HCT patients without immune suppression, and enable early immunization safely following HCT.
Delayed Hepatitis B Active Viral Replications without Active Viral Biochemical Hepatitis Two Months after Cessation of Pre-Emptive Adefovir Therapy in a Patient with Waldenstrom Macroglobulinemia Treated with Rituximab and Fludarabine Chemotherapy.
Authors: Hanbali Amr S. , Khaled Yasser
Published: October 2019

Introduction:

Reactivation of HBV is a well-known complication in patients receiving cytotoxic therapy for malignancy. The incidence of hepatitis directly resulting from reactivation of HBV has been reported as 49% in HBs antigen-positive-patients with lymphoma. Preemptive use of lamivudine has successfully reduced the fatal complication of HBV reactivation after chemotherapy. The Optimal duration of Lamivudine adminstration has not yet been defined, although additional 1–2 months of therapy after chemotherapy cessation is recommended according to some studies.

The efficacy and duration of therapy with Adefovir has not been established in the same circumstances.

Method:

A 32-year-old Fillipino female, who presented in September 2004 with Waldenstrom Macroglobulinemia. She was found to have Hepatitis B surface antigen positive. Other Hepatitis B related laboratory testing revealed negative hepatitis B Delta antibody, negative hepatitis BE antigen negative hepatitis B core antibody IgM and positive hepatitis BE antibody.

Hepatitis B DNA less than 500 copies/ML. Patient was started on pre-emptive Adefovir during her treatment with 4 cycles of Fludrabine followed by four weekly treatment with rituximab. She achieved partial response and Adefovir was discontinued two months after completion of chemotherapy and Rituximab. Prior to proceeding with high dose chemotherapy with stem cell support four months after discontinuation of Adefovir, repeat hepatitis B DNA revealed more than 10 millon copies with normal biochemical profile.

Conclusion:

Use of adefovir for during and for 2 months after Rituximab containing chemotherapy was not successful in preventing reactivation of hepatitis B virus, and extreme caution should be practiced when treating a patient with a positive HBs antigen with Rituximab containing chemotherapy. Also the optimal duration for continuing HBV prophylaxis is not known, but clearly 2 months is a suboptimal duration. It is unknown if adefovir is as effective as lamivudine in preventing reactivation of HBV with Rituximab. The lag of HBV related hepatitis despite active viral replication cholud be related to prior immune-suppression by Rituximab and Fludarabine.
Accelerated Delivery of Rituximab Is Safe on an Out-Patient Basis.
Authors: Middleton Helen J. , Mollee Peter , Bird Robert , Mills Anthony K. , Marlton Paula , Gill Devinder
Published: October 2019

Aim

A prospective study to determine the safety of the accelerated delivery of rituximab.

Methods

A pilot study investigating the safety of the accelerated delivery of rituximab was commenced in September 2004. First doses of rituximab were delivered as per prescribing guidelines. Patients without infusion related toxicity were eligible for accelerated rituximab in second or subsequent infusions. In the first 4 patients the infusion was administered at 100mg/hr, increasing to 400mg/hr after 15 minutes in the absence of a reaction. All subsequent patients commenced the infusion at 400mg/hr. All patients received premedication with paracetamol, promethazine and hydrocortisone unless contra-indicated. Patients with a previous grade III/IV infusion related toxicity were excluded.

Results

23 patients have been enrolled to date. Data is available for 62 infusions - median 3 infusions per patient (range: 1–6). Median age was 64 years (range: 28–85). 65% of patients were male. Diagnoses included non-Hodgkin’s Lymphoma - 20 patients (Diffuse Large Cell Lymphoma - 8, Follicular Lymphoma - 9, Mantle Cell Lymphoma - 1, Lymphoplasmacytic Lymphoma - 2), Immune Thrombocytopenic Purpura - 2 and Dermatomyositis-1. 44% of patients received single agent rituximab and 56% received it in combination with chemotherapy. The median dose of rituximab was 700mg (range: 600–800mg). There were 2 adverse events with no grade III/IV infusion related toxicity. One patient experienced grade I hypothermia. A second patient experienced grade II fevers and rigors which required interruption of the infusion. The patient was subsequently found to have pneumonia. The infusion was completed without further incident. Excluding data from the latter patient, median infusion time was 1 hour and 55 minutes and 76% of infusions were completed within 2 hours.

Conclusion

For second or subsequent infusions, the accelerated delivery of rituximab is safe and well tolerated allowing shorter outpatient stays and improving the efficiency of resource utilisation. The study has been extended to include patients with bulky lymphoma and Chronic Lymphocytic Leukaemia.
CD30+ Lymphoproliferative Disorder/Lymphomatoid Papulosis - A Regression Caused by Mistletoe Therapy.
Authors: Seifert Georg , Tautz Christoph , Seeger Karl , Henze Guenter , Laengler Alfred
Published: October 2019

Lymphomatoid papulosis (LyP) is a CD30+ cutaneous lymphoma according to the WHO classifications and regarded as a condition of uncertain malignant potential. The incidence of LyP in children is relatively low compared to that in adults. It is correlated with malignant lymphomas in 5–20% of adult LyP-patients. In children, an increased risk for the development of a malignant lymphoma is observed. The clinical course is often chronic. Most common treatment for LyP is topical steroids, antibiotics, phototherapy and low-dose methotrexate. Prognosis is excellent with a survival of 100% even for patients with malignant lymphomas. Case-report: An 8-years old boy suffered from reddish nodules (maximum 7 cm in diameter) on his right forearm and his left leg. Immunohistochemical analysis identified a CD30+large-T-cell-type-NHL of the skin. Topic steroids were effective but six months later he showed axillar lymph-node swelling. Immunohistochemically it was classified as anaplastic large cell T-type-lymphoma (ALCL) without signs of systemic involvement. Combination chemotherapy according to the European ALCL-trial (high-risk-group) was given for six months. All nodules (cutaneous and lympoid/axilla) resolved within a few weeks. Two months after cessation of chemotherapy a new skin-nodule on the left forearm appeared. The immunohistochemical diagnosis was now LyP. No specific therapy was given. In the following two months he developed two further solid and painful skin-lesions. In this situation we decided to start a therapeutic approach with subcutaneous mistleote (MT), which was injected close to one of these lesions. The skin-nodules decreased after the first dose and MT injections into all nodules were continued. Within the following two weeks the skin-lesions resolved completely and subcutaneous MT therapy was continued. Two months later, he developed two new nodules responding within a few days to increased dose of MT. While continuation therapy with MT the boy was without clinical signs both of the LvP and ALCL for nearly two years. Subsequently MT therapy was terminated. Three weeks after cessation the cutaneus LyP generally reactivated all over the body with typical nodules (maximum 1 cm in diameter). Subcutaneus MT therapy was restarted and the cutnaneus LyP regressed within 2 weeks completely without additional therapy.
Copper Deficiency Secondary to Bariatric Surgery Mimicking Myelodysplasia.
Authors: Doshi Vaishali R. , Thertulien Raymond
Published: October 2019

Introduction: Bariatric Surgery is promoted as a successful method for weight loss and is performed with increasing frequency. The benefits and the short term risks of the surgical procedure are well understood. However, its long term pathophysiological consequences are still for the most part unknown. They may include metabolic changes that result in malnourishment and malabsorption. Deficiency disorders of iron, B-12 and folate are commonly encountered. However hematological problems from copper deficiency due to malabsorption have not been well studied.

Background: Copper and Iron are essential trace elements through their functions as co-factors in numerous biochemical reactions. Hephaestin, a transmembrane copper-dependent ferroxidase, is necessary for effective iron transport from intestinal enterocyte into the circulation. Copper is hence required for iron absorption. Copper enzymes such as superoxide dismutase and cytochrome oxidase have an essential role in red cell development and heme maturation.

Patients and Method: We present data on five patients referred for treatment of myelodysplasia whose evaluation revealed copper deficiency and low ceruloplasmin level. All five patients were female and had undergone gastric bypass surgery for weight reduction. The hematological features included pancytopenia, erythroid hyperplasia and dysplasia with increased blasts mimicking erythroleukemia, multilineage dysplasia with ring sideroblasts, bilineage megakaryocytic and erythroid dysplasia. One patient presented with neutropenia and anemia with a normal bone marrow; she was found to have copper deficiency. No cytogenetic abnormalities were observed and the patients had normal B-12 and folate. Copper gluconate was started at 20 mg/day by mouth, with weekly monitoring, till normal levels were reached. Patients were subsequently maintained at 5–10 mg/day with regular monitoring. Upon repletion of copper, all the patients recovered with normalization of the bone marrow and peripheral counts.

Discussion: We conclude that Gastric bypass especially Roux-en-Y gives rise to copper deficiency due to malabsorption in the duodenum and can present as pseudomyelodysplasia. We consider measurement of copper and ceruloplasmin levels an important component of the evaluation of patients presenting with myelodysplasia with normal cytogenetics, especially after gastric bypass.
Chronic Lymphocytic Leukaemia Patients with a Biallelic Deletion of 13q14 Have a More Favourable Profile of Prognostic Factors Compared with Cases That Have a Monoallelic 13q14 Deletion.
Authors: Pettitt Andrew R. , Emmens Chloe J. , Lin Ke , Harris Robert J.
Published: October 2019

Deletion of 13q14 is a common finding in CLL and is associated with a good prognosis when it occurs in the absence of del 17p13, del 11q23 and trisomy 12. In contrast, the latter chromosomal abnormalities, together with unmutated IgVH genes, CD38 expression and p53 dysfunction, are associated with an adverse clinical outcome. Unlike del 17p13 and del 11q23, which usually affect only one allele, del 13q14 can affect one or both alleles in a given case. It was therefore of interest to compare cases of CLL harbouring a monoallelic 13q deletion (13q+/−) with those cases harbouring a biallelic 13q deletion (13q−/−). FISH data including 13q14 status were available for 103 newly diagnosed cases of CLL presenting to the Royal Liverpool University Hospital between March 2002 and June 2005. 18 cases had a biallelic 13q deletion and 32 had a monoallelic 13q deletion, while 53 cases had no 13q deletion (13q+/+). As compared with 13q+/− and 13q+/+ cases, 13q−/− cases had a lower frequency of unmutated IgVH genes (8% v 32% and 46% respectively), CD38 positivity (14% v 32% and 29%), p53 dysfunction (13% v 34% and 30%), deletion of 17p13 (0% v 9% and 8%), deletion of 11q23 (0% v 13% and 6%) and trisomy 12 (0% v 13% and 23%). The combined frequency of 17p deletion, 11q deletion and trisomy 12 among cases with 13q−/−, 13q+/− and 13q+/+ was 0%, 31% and 35% respectively (P = 0.0085). At least one of the above adverse prognostic factors was found in 33% of 13q−/− cases, 82% of 13q+/− cases and 80% of 13q+/+ cases (P = 0.0084). There was no difference in sex or clinical stage between the 3 groups, although patients with 13q−/− tended to be older than those with 13q+/− (68.1 v 61.3 years, P = 0.0720). After a median follow-up of 18 months (range 1–39 months), no difference in treatment-free or overall survival was observed between the 3 groups but only 7 of the 50 evaluable patients had received treatment and only 3 had died. In conclusion, CLL patients with biallelic deletion of 13q14 appear to have a more benign form of the disease than do patients with a monoallelic 13q deletion. The latter have a profile of prognostic factors indistinguishable from that of patients with no 13q deletion. This suggests that the overall favourable prognosis associated with 13q deletion is probably attributable to the subset of cases in which both alleles are deleted.
Identification and Purification of Hodgkin Cells from Lymph Nodes Involved by Classical Hodgkin Lymphoma by Flow Cytometry and Flow Cytometric Cell Sorting.
Authors: Fromm Jonathan R. , Kussick Steven J. , Wood Brent L.
Published: October 2019

The diagnosis of classical Hodgkin lymphoma (CHL) has historically been made in tissue sections, as attempts to identify the neoplastic Hodgkin and Reed-Sternberg (HRS) cells of CHL by flow cytometry (FC) have been largely unsuccessful. As HRS cells are known to be ringed (“rosetted”) by benign/reactive T cells, we hypothesized that in cell suspensions the HRS will be bound to T cells (forming T cell rosettes), and that consequently the rosettes would have a composite T-cell/HRS immunophenotype by FC (CD3+/CD15+/CD20−/CD30+/CD45+). We further hypothesized that specific antibodies to the adhesion molecules known to be involved in T cell/HRS cell binding (CD2 and LFA-1 on the T cell, and CD54 and CD58 on the HRS cell) might result in “naked” (unbound) HRS cells, enabling us to use FC to identify HRS cells with the expected immunophenotype (CD3−/CD15+/CD20−/CD30+/CD45−). Our initial FC studies of the HRS cell line L1236 demonstrated that CD15, CD30, CD40, CD71, CD86, CD95, and HLA-DR, but not CD3 or CD20, were brightly expressed on these cells and may be useful in identification of HRS in authentic cases of CHL involving lymph nodes. In mixing experiments, L1236 cells spontaneously bound normal T cells, analogous to T cell rosetting of HRS cells in CHL; these interactions could be blocked specifically using a cocktail of unlabeled antibodies to CD2, LFA-1, CD54, and CD58. Among 27 lymph nodes involved by CHL, this novel FC method, in which 250,000 to 500,000 total lymph node cells were evaluated, and in which up to ten cellular antigens were assessed simultaneously, enabled HRS cells to be identified in 89% of cases. 82% of these cases demonstrated interactions between HRS cells and T cells that could be disrupted with blocking antibodies. None of 29 non-CHL neoplasms, and none of 23 reactive lymph nodes, demonstrated HRS populations by FC. The proportions of cases where the HRS population showed expression of CD15, CD30, CD40, CD71, CD86, CD95, and HLA-DR, and absence of CD3 and CD20 was similar to that described previously in tissue sections by immunohistochemistry. Interestingly, in contrast to the findings in tissue sections, by FC the non-rosetted HRS cells of most CHL cases (73%) demonstrated detectable expression of CD45, usually at a low level. Finally, cell sorting experiments confirmed that (1) populations identified by FC have the cytomorphology of HRS cells, (2) HRS/T cell rosettes can be detected by FC, and (3) these rosettes can disrupted by the blocking antibody cocktail. This FC technique offers a potential alternative to immunohistochemistry in confirming the diagnosis of CHL and, through cell sorting, provides a means of rapidly purifying HRS cells.
53BP1 Is Targeted to Sites of DNA Breaks within the Immunoglobulin Heavy Chain Locus and Promotes Class Switch Recombination.
Authors: Manis John , Walsh Nicole , Carpenter Phil , Dutt Shilpee
Published: October 2019

The maintenance of genomic integrity relies on the cellular response to chromosomal damage from both exogenous (e.g. ionizing radiation) and endogenous (e.g. oxidative stress) sources. Various members of the DNA damage-sensing pathway including ATM, H2AX, 53BP1, and MDC1 are necessary to orchestrate the repair of DNA breaks. B cells undergo several programmed DNA alterations during their development: V(D)J recombination, Somatic Hypermutation (SHM), and Class Switch Recombination (CSR). We have previously shown that 53BP1 is relatively dispensable for V(D)J recombination and SHM. In contrast, class switch recombination is largely blocked to all isotypes indicating that regulated DNA breaks in B cells are regarded differentially by the DNA damage response machinery. 53BP1 is thought to promote the joining of DNA ends during CSR thus preventing translocations that could potentially lead to lymphoma. To better understand the damage response to CSR induced DNA breaks, a chromatin immunoprecipitation strategy and a combined immunofluorescence/FISH method was used to examine the components that assemble at IgH switch (S) regions during CSR. H2AX was found at S regions specifically targeted to undergo CSR after in vitro stimulation of B cells, and to a lesser degree, at adjacent S regions that were not activated for a switch event. H2AX was also found at S regions in switch activated 53BP1-deficient B cells. In contrast, 53BP1 was found primarily at S regions specifically targeted for CSR, and not at the adjacent S regions. Moreover, the localization of 53BP1 to S regions appeared to be in part, independent of DNA breaks, and potentially reliant on specialized DNA structures that are generated during CSR. These findings support a differential role for the various components of the DNA damage response program during CSR and have implications for understanding mechanisms of lymphomagenesis.