The Usefulness of High Dose (7-10mci) Gallium (67Ga) Scanning to Diagnose Richter's Transformation

Gallium (⁶⁷Ga) scan was performed in 29 CLL patients with chronic lymphocytic leukemia who were suspected on clinical grounds to have Richter's transformation (RT). Of 29 patients, nine had a positive ⁶⁷Ga scan; seven of these had a subsequent biopsy that verified large-cell lymphoma or Hodgkin's disease. The other two patients underwent biopsies that revealed fungal infections, a known cause of ⁶⁷Ga uptake. Two patients had biopsies that were consistent with RT but showed no affinity to ⁶⁷Ga. One false negative resulted five days after chemotherapy, a known cause of diminished ⁶⁷Ga uptake. The other occurred within a small infraorbital mass, containing onl 10% centroblasts, which is below the level of detection for ⁶⁷Ga scanning. Subsequent ⁶⁷Ga scans in both patients revealed ⁶⁷Ga avid lesions, which demonstrated RT upon biopsy. This technique was more strongly predictive of RT than was measurement of serum B-2 microglobulin or serum lactate dehydrogenase levels.⁶⁷Ga scanning is very useful in localizing an optimal site for biopsy to document RT; it may also have the potential to help assess response to treatment, predict recurrence, and contribute to long-term follow-up in this subset of patients.     

Hodgkin's Disease Variant of Richter's Syndrome: Experience at a Single Institution

Patients developing Hodgkin's disease (HD) after a diagnosis of chronic lymphocytic leukemia (CLL), are frequently included in a series of patients with Richter's syndrome (RS). We sought to determine the natural history of the association of CLL and HD. Over a 21 year period, 1374 patients with CLL have been registered in our computer data base. Seven cases of CLL and HD have been documented and confirmed. The median age of these patients was 71 years (range 44-77) and clinical features included male gender (86%), B symptomatology (86%), rapidly progressive lymphadenopathy (71%), prior CLL therapy (71%), advanced Ann Arbor stage (86%), marrow involvement with HD (43%), and autoimmune hemolytic anemia (29%). HD was documented by excisional lymph node biopsy in six cases and splenectomy in one. Mixed cellularity HD was shown in six and nodular sclerosis in one. Five of the biopsies revealed intervening areas consistent with small lymphocytic lymphoma. The Sternberg-Reed (SR) cells were CD15+ in 6/7 cases, and Ki-1+ in the 6 patients tested. CD45 and CD20 staining of the SR cells was nonreactive. The median time to development of HD was 45 months (range 0 to 96). The overall responses to different chemotherapy regimens was approximately 25% with only one CR. Six patients have died at 3,9,10,13,15 and 36 months and one patient is alive with progressive disease at 11 months. Our data suggests that CLL patients have a heightened risk for HD, features of advanced HD on presentation, and a poor response rate with short survival.     

Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) Reduces Pancytopenia After Rescue Therapy in a Patient with Hodgkin's Lymphoma

After several relapses, a stage IV lymphocyte depletion Hodgkin Lymphoma patient, with a bone marrow progenitor compartment depleted by several courses of chemotherapy, received further combination chemotherapy which caused severe and long-lasting pancytopenia. Because of an objective degree of tumor regression, a second identical course was administered, followed by Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) in an attempt to accelerate bone marrow recovery. This led to a significantly shorter period of neutropenia and thrombocytopenia with no additional red blood cell and platelet transfusion requirements. Furthermore, the neutropenic phase was not accompanied by septic complications. It is suggested that patients with solid tumors, even with a severely compromised bone marrow after several chemotherapy courses, may benefit from GM-CSF administration after rescue chemotherapy.     

Granulocyte colony-stimulating factor receptors on CD34++ cells in patients with myelodysplastic syndrome (MDS) and MDS-acute myeloid leukemia

We studied surface expression of granulocyte colony-stimulating factor receptor (G-CSFR) on CD34⁺⁺ progenitor cells of myelodysplastic patients. Late stages of disease showed a higher proportion of high or low G-CSFR expression than early stages. Most of the patients with the low expression had neutropenia. Neutropenia was relatively less present in the normal group, but it reappeared in the high group. All the neutropenic patients in the high group showed response to G-CSF, while response in the normal group was minor. These findings suggest that lowered expression of G-CSFR leads to neutropenia in myelodysplastic patients. This article reviewed the knowledge of the G-CSFR and its role in the disorders of granulopoiesis, including myelodysplastic syndrome (MDS).     

Granulocyte Colony Stimulating Factor Increases Drug Resistance of Leukaemic Blast Cells to Daunorubicin

Acute leukaemia is known as the most common cancer in childhood. Febrile neutropenia is a common serious side effect of the cytostatic treatment of malignancies. The clinical use of Granulocyte Colony Stimulating Factor (G-CSF) has become widespread to minimize chemotherapy-induced myelosuppression and febrile neutropenia in childhood solid tumors, acute lymphoid leukaemia (ALL) and in several trials with AML. In case of ALL this seems to be reasonable because, due to the absence of G-CSF receptor (G-CSFR) on the surface of normal lymphoid cells, G-CSF does not have any influence on the pathways of proliferation and differentiation of lymphoid lineage cells. It has been suggested, however, that ALL blasts with B or T cell surface antigens as well as biphenotypic leukaemia cells express G-CSFR, and they are able to respond to exogenously added G-CSF with proliferation. In this study we investigated how G-CSF might influence the sensitivity of leukemic cells to daunorubicin induced cell death using MTT assay, flow cytometry and Western blot analysis. After pretreatment of KG-1 leukaemic cells with G-CSF a moderate increase in the resistance of these cells to daunorubicin could be observed. These results draw attention to the risk of G-CSF application as an adjuvant therapy of childhood ALL. In addition, adjuvant treatment of AML patients with G-CSF in order to prevent neutropenia, or its use in priming regimens might result resistance to daunorubicin.     

Bone Marrow Findings in Malignant Histiocytosis and/or Malignant Lymphoma with Concurrent Hemophagocytic Syndrome

We examined bone marrow specimens from 19 patients with malignant histiocytosis (MH) and/or malignant lymphoma (ML) with concurrent hemophagocytic syndrome (HS) who suffered from high fever, hepatosplenomegaly, liver dysfunction, profound cytopenia, and erythrophagocytosis. There was little lymph-node enlargement or no tumor formation. The neoplastic cells in 3 patients exhibited histiocytes/macrophages phenotype with positive reactions for fluoride-sensitive nonspecific esterase, lysozyme and CD68 (KP1). Twelve other patients showed a T-cell (CD3) phenotype, in which 5 patients expressed CD30 (BerH2) as well. B-cell characteristics with CD20 (L26), CIg. νλ and γκ were manifest in 2 patients, but indeterminate markers were found in the 2 remaining patients. Eighteen patients showed an infiltration of large neoplastic cells mainly with noncohesive interstitial growth pattern, ranging from 1.7% to 74.2% of the nucleated cells in the bone marrow. A large number of histiocytes/macrophages and dendritic cells was diffusely observed in 15 patients. Severely decreased hematopoiesis in all three series of hematopoietic cells was found in 16 patients.

Bone marrow infiltration by the neoplastic cells and numerous reactive cells with erythrophagocytosis appears be an important factor of profound cytopenia in patients of MH and/ or ML with HS. The infiltrating pattern of the neoplastic and reactive cells in the bone marrow of MH and/or ML with HS was different from that of other types of peripheral T-cell ML, B-cell ML in high grade malignancy, and Hodgkin's disease. Cell characteristics and lineage of the neoplastic cells in MH and/or ML with HS are also discussed in this study.     

Unmasking Cryptococcal Meningitis Immune Reconstitution Inflammatory Syndrome due to Granulocyte Colony-Stimulating Factor Use in a Patient with a Poorly Differentiated Germ Cell Neoplasm

Cryptococcal meningitis immune reconstitution inflammatory syndrome (IRIS) is frequently seen in patients with HIV and less frequently in patients on immune suppressive medications for other conditions. Here, we describe the first reported case of unmasking cryptococcal IRIS due to granulocyte colony-stimulating factor used in an HIV-negative patient with chemotherapy-induced neutropenia.Key words: Cryptococcal meningitis, Immune reconstitution inflammatory syndrome, Granulocyte colony-stimulating factor, Immunosuppressed host, Chemotherapy     

PEG-rhG-CSF与G-CSF预防及治疗化疗后中性粒细胞缺乏的效果比较

目的:回顾性分析PEG-rhG-CSF与G-CSF在淋巴瘤化疗后中性粒细胞缺乏预防中的作用,及其不良反应对比.方法:回顾性选取诊断明确的淋巴瘤患者共78例,其中在淋巴瘤化疗后立即给予PEG-rhG-CSF预防中性粒细胞缺乏的患者42例(实验组),另外36例患者则是在出现中性粒细胞缺乏后给予G-CSF治疗(对照组),直至...     

应用GM-CSF治疗恶性肿瘤化疗后白细胞减少的临床研究

本文研究总结了北医联合生物工程公司研制的GM-CSF，应用于恶性肿瘤化疗引起的白细胞减少12例，其白细胞减少时间较对照组缩短5天。对合并感染的病人有较明显的抗感染作用，降低了抗生素的作用时间，临床应用常规剂量未发生明显副作用。是肿瘤根治性化疗的抢救、保驾药品。     

Effects of the in vivo Administration of Recombinant Human Granulocyte Colony-stimulating Factor Following Cytotoxic Chemotherapy on Granulocytic Precursors in Patients with Malignant Lymphoma1

We examined the effects of the in vivo administration of recombinant granulocytc colony-stimulating factor (rhG-CSF) on granulocytic precursors in the bone marrow of 4 patients with malignant lymphoma who received chemotherapy. Patients were treated with rhG-CSF at doses of 100–800 μg/ m²/day intravenously for 14 days only in the first course of chemotherapy (G-CSF course) followed by the second course of chemotherapy without rhG-CSF which was used as a control course. In the G-CSF course, white blood cell counts (WBCs) demonstrated a biphasic response consisting of a first peak observed within a few days after the initiation of rhG-CSF administration, and a second peak observed on the last day of rhG-CSF injection or the day after. In the second peak, the incidence of granulocyte-macrophage colony-forming units (CFU-GM) in mononucleated bone marrow cells did not change significantly after treatment with rhG-CSF as compared with a control. However, since the number of nucleated cells in the bone marrow increased, the absolute number of CFU-GM in the bone marrow increased. The number of mature and immature granulocytes in the bone marrow increased. These findings suggest that G-CSF stimulates the proliferation and differentiation of granulocytic precursors in the bone marrow in granulocytopenic patients who received cytotoxic drugs and causes mature granulocytes to be released from the bone marrow.     

The Possible Role of G-CSF in the Pathogenesis of Sweet's Syndrome

Sweet's syndrome (SS) is characterized by the clinical features of fever, leucocytosis, neutrophilia and the sudden onset of asymmetric, often very painful skin lesions and dense dermal infiltrates of mature neutrophils without signs of vasculitis. Apart from idiopathic cases the disease is frequently associated with hematological malignancies, but it may also be observed in patients with solid tumors, mainly tumors of the genito-urinary tract. In the past, numerous theories have been proposed to explain the pathogenesis of this rare disease. SS has been interpreted as a direct response to mechanical and chemical irritants, an infectious disease or a disorder of neutrophilic chemotaxis and/or phagocytosis, but most often it has been described as a hypersensitivity reaction. Each of these theories can account for particular symptoms, but none of them reconciles the dominating clinical and laboratory features of the disease. Furthermore recently published casuistic observations suggest the involvement of certain cytokines in particular G-CSF and 11-6 in the pathogenesis of the disease, which might explain many of the observed clinical and laboratory findings. The following article summarizes these data and gives a review of the current literature.     

Effects of rhG-CSF on Infection Complications and Impaired Function of Neutrophils Secondary to Chemotherapy for Non-Hodgkin's Lymphoma

It has been previously demonstrated that the administration of recombinant human granulocyte-colony stimulating factor (rhG-CSF) ameliorates the decrease of the polymorphonuclear neutrophils (PMNs) count after the cytotoxic chemotherapies, thereby reducing the infection complications associated with neutropenia. In this multi-center study, we studied the prophylaxtic effect of rhG-CSF administration on infection complications in patients with non-Hodgkin malignant lymphoma, who received cytotoxic chemotherapies (CHOP or ProMACE/CytaBOM). rhG-CSF administration reduced the frequency of infection complications, and there was no obvious difference in it's frequency between the CHOP-treated and the ProMACE/CytaBOM-treated groups when administered with rhG-CSF, thereby indicating that third generation therapy for NHL may be safely completed in Japanese in combination with rhG-CSF administration. Furthermore, we investigated both the in vitro and the in vivo effects of rhG-CSF on the function of PMNs in patients with NHL and healthy donors, and revealed that the administration of rhG-CSF for NHL patients receiving cytotoxic chemotherapy brought on an improvement of the production of active oxygen but did not affect serum levels of IFNs, IL-1 -(J, and IL-6, inspite of a slight elevation of TNF-a. Consistent with these results, in vitro treatment of PMNs with rhG-CSF induced no significant production of these inflammatory cytokines and their mRNA expressions. Furthermore, rhG-CSF administration showed no significant effects in vivo on the expression of CD1 la, CD1 lb and LECAM-1 on PMNs and integrins on platelets.     

Origin of High-Grade Lymphomas in Richter Syndrome

Patients with B cell chronic lymphocytic leukemia (CLL) occasionally develop high-grade B cell lymphomas that are associated with constitutional symptoms, rapidly progressive lymphadenopathy, and swift clinical deterioration. Now known as Richter syndrome, this symptom complex develops in approximately 5% of all patients with CLL. Structural and molecular analysis of the immunoglobulin (Ig) genes have allowed investigators to define the clonal relationship between the leukemia and lymphoma cells of a given patient. In most cases the aggressive lymphoma evolves from the original leukemia cell clone. However, in some cases the lymphoma apparently represents a second malignancy. Differentiation between these two types of lymphoma may have clinical significance. Further investigation is required to allow for identification of CLL patients who are at risk for developing Richter syndrome and to understand factors involved in its etiopathogenesis.     

A Phase II Study of Recombinant Granulocyte Macrophage Colony Stimulating Factor in Patients with Non-Hodgkin's Lymphoma

Myelosuppression is often the major limiting factor that prevents timely administration of cytotoxic chemotherapeutic agents, particularly in chemoresponsive malignancies. A study was designed to assess the role of GM-CSF in preventing myelosuppression in patients with intermediate-grade non-Hodgkin's lymphoma receiving combination chemotherapy (Cyclophosphamide, Vincristine, Prednisone and Epirubicin or Mitozantrone, ± Bleomycin). A total of 24 patients were entered and data collated from 20 of them are amenable to analysis.

All patients received the first chemotherapy cycle without GM-CSF and the second with GM-CSF (250 mg/m² subcutaneously twice daily for 5 days commencing on the 5th day following chemotherapy). By entering only those patients who had suffered myelosuppression following chemotherapy, an internal control was established. GM-CSF administration significantly reduced the degree of neutropenia and leucopenia. The mean nadir white blood cell (WBC) and absolute neutrophil counts (ANC) were 2.88 × 10⁹/L and 0.97 × 10⁹/L in cycle 1 as compared to 5.95 × 10⁹/L and 2.92 × 10⁹/L respectively, in cycle 2 (p = 0.05 and 0.02, respectively). Eight patients (40%) had febrile neutropenias and 13 patients (65%) experienced a treatment delay by a median of 8 days during cycle 1. Six patients (30%) had febrile neutropenias and 2 patients (10%) had a treatment delay of 3 days during cycle 2. Reversible toxicity was seen in the majority of patients: bone pains (60%), skin rashes (35%), arthralgias (25%), and altered taste sensation (10%). No patient developed the capillary leak syndrome. This study demonstrates the efficacy of GM-CSF in preventing chemotherapy-induced myelosuppression.     

大剂量多西他塞联合粒细胞集落刺激因子用于恶性实体瘤外周血造血干/祖细胞动员

目的观察大剂量多西他塞联合粒细胞集落刺激因子(G-CSF)在恶性实体瘤患者动员采集自体外周血造血干/祖细胞的有效性和安全性。方法30例恶性实体瘤患者入组,第一天采用多西他塞120mg/m2经静脉持续滴注3小时,在白细胞1.0×109/L左右时每天给予G-CSF5μg/kg,分早晚两次皮下注射,直至采集结束。结果在给予多西他塞后平均第(6.47±1.01)天白细胞降至1.0×109/L,皮下注射G-CSF平均(3.50±1.01)天即多西他塞动员后平均第(9.97±1.03)天开始外周血造血干/组细胞单采,每人每天采集一次,采集两天,共获CD34+细胞中位数3.49×106/kg(1.71×106～16.69×106/kg),其中CD34+细胞>2.0×106/kg的患者25例。不同采集时间获CD34+细胞数差异无统计学意义(P=0.651)。6例发生关节轻度疼痛,3例轻度腹泻,1例口腔粘膜炎。结论多西他塞120mg/m2联合G-CSF5μg/kg是恶性实体瘤患者动员采集自体干/祖细胞的有效安全方案。     

G（M）-CSF治疗放化疗引起的口腔黏膜炎的临床观察

目的：观察因接受同步放化疗而出现白细胞低下并同时伴有口腔黏膜炎的局部晚期头颈部肿瘤患者，在接受G（M）CSF治疗以提升白细胞的同时，G（M）CSF对口腔黏膜炎的治疗作用。方法： 15例局部晚期头颈部肿瘤病人在接受同步放化疗中，当白细胞≤1.5×109/L并同时伴有Ⅲ~Ⅳ度口腔黏膜炎时，给予GCSF（惠尔血）150~300 μg/日或G（M）CSF（生白能）200~300 μg/日，皮下注射，连用5～10 d。结果： 所有病人的白细胞均提升至5.0×109/L以上，口腔黏膜炎1例痊愈（CR），8例好转（PR），6例稳定（NC），无1例进展（PD），总有效率（CR+PR）为60%。结论： G（M）CSF在有效提升白细胞的同时，对同时伴有的口腔黏膜炎有明显的治疗作用。     

Distribution of lymphoma subtypes in Ukraine according to the WHO 2016 classification

The Ukrainian Lymphoma Registry (ULR) was established in 2019 with the aim of monitoring the quality of diagnosis, staging, and treatment of lymphoma in Ukraine. Between September 2019 and October 2021, 546 patients with newly diagnosed lymphoma were prospectively registered. All cases were diagnosed according to the 2016 updated WHO lymphoma classification. The male-to-female ratio (M/F) for the whole population was 0.7, with a median age of 46 years (range 18–95). The adoption of the 2016 WHO classification resulted in the identification of 36 different lymphoma subtypes, with 132 cases (24.2%) classified differently compared to the 2008 WHO classification. Only 12 cases (2.8%) were true new entities, including seven cases of high-grade B-cell lymphoma NOS, three of anaplastic large B-cell lymphoma, ALK-negative, 1 case of HHV8+ DLBCL NOS, and 1 of high-grade B-cell lymphoma with C-MYC and BCL2/BCL6 rearrangement. Moreover, 55 (61.1%) entities, including 37 defined by WHO 2008 and 18 defined by WHO 2016, were not represented at all. The analysis of cases registered in the ULR provides a comprehensive breakdown of the subtypes, stage distribution, and treatment of malignant lymphomas (ML) in Ukraine, supporting the usefulness of prospective data collection and timely reporting. We believe that this study is the first step toward a better understanding of the real-life outcomes of patients with ML.     

Granulocyte colony-stimulating factor receptor signalling via Janus kinase 2/signal transducer and activator of transcription 3 in ovarian cancer

Background:

Ovarian cancer remains a major cause of cancer mortality in women, with only limited understanding of disease aetiology at the molecular level. Granulocyte colony-stimulating factor (G-CSF) is a key regulator of both normal and emergency haematopoiesis, and is used clinically to aid haematopoietic recovery following ablative therapies for a variety of solid tumours including ovarian cancer.

Methods:

The expression of G-CSF and its receptor, G-CSFR, was examined in primary ovarian cancer samples and a panel of ovarian cancer cell lines, and the effects of G-CSF treatment on proliferation, migration and survival were determined.

Results:

G-CSFR was predominantly expressed in high-grade serous ovarian epithelial tumour samples and a subset of ovarian cancer cell lines. Stimulation of G-CSFR-expressing ovarian epithelial cancer cells with G-CSF led to increased migration and survival, including against chemotherapy-induced apoptosis. The effects of G-CSF were mediated by signalling via the downstream JAK2/STAT3 pathway.

Conclusion:

This study suggests that G-CSF has the potential to impact on ovarian cancer pathogenesis, and that G-CSFR expression status should be considered in determining appropriate therapy.