Background : High dose chemotherapy has an established, albeit limited role, in the management of non-Hodgkin lymphoma (NHL). In fact, because of its toxicity, in particular mucositis, neutropenia and thrombocytopenia, myeloablative regimens with autologous stem cell support can be safely delivered only to clinically fit and younger pts, require prolonged hospitalization, and have a restricted impact in the therapy of NHL. With the primary aim of widening the applicability of myeloablative regimens, we designed a pilot study using high-dose Zevalin with tandem stem-cell support in a prospective cohort of 13 refractory or relapsed NHL patients, unable to safely undergo a BEAM chemotherapy course. Methods : Prior to Zevalin, all pts received one cycle of high-dose cyclophosphamide plus rituximab, and one cycle of high-dose cytarabine and rituximab, at patient-adapted doses. Hematopoietic stem cells were harvested from the peripheral blood during the post-cyclophosphamide and/or the post-cytarabine recovery phase, and tested for MRD. Zevalin was administered at twice the MTD (0.8 mCi/kg), and followed by tandem autografting of a small amount of CD34+ (0.8–2 x 106/kg) on day +7, and an optimal amount (>=5 x 106 CD34+ cells/kg) on day +14, respectively. The former reinfusion (supportive autografting) was done still in the presence of potentially myelotoxic doses of circulating radioactivity, and its aim was solely to achieve an immediate albeit transient hematopoietic recovery. At the time of the second reinfusion (reconstituting autografting) the calculated radiation dose to the reinfused stem cells was less than 5 cGy, in order to ensure a complete and long lasting hematopoietic reconstitution. Results: From July 2004 through March 2005, 13 overall NHL patients entered into the study (DLBCL 5, follicular 3, mantle cell 2, marginal zone nodal 1, small lymphocytic 1, lymphoplasmacytoid 1). Median age was 60 yrs (29–69). The number of prior chemotherapy regimes was 1 (4 pts), 2 (5 pts), 3 (3 pts) and 4 (1 pt), respectively. Neutropenia grade 1 or higher was documented in all but 1 patient, and lasted a median of 7 days (1–15), while grade 4 neutropenia was observed in 8 pts, in which lasted a median of 3.5 days only (1–10). Grade >=1 thrombocytopenia was observed in all patients (median 16 days, range 7–30), while grade 4 thrombocytopenia occurred in 10 pts for a median duration (in the thrombocytopenic pts) of 6 days (1–13). Eight patients required platelet transfusions (median 2, range 1–6), and 9 pts received 1 RBC transfusion each. No extra-hematologic toxicity was observed, and all but 4 patients were cared for as outpatients. The 4 hospital admissions lasted 2 (2 pts) and 4 days (2 pts) respectively, and were required for FUO that rapidly resolved upon antibiotic administration. After a median follow-up of 6 months (1–11), 11 pts are alive, of which 10 in continuous CR. Conclusions : High-dose Zevalin with tandem stem-cell transplantation was minimally toxic in this heavily pretreated patient population, and fully applicable in an outpatient setting. Its administration at 0.8 mCi/kg (and possibly up to 1.2 mCi/kg) as a final consolidation step, warrants prospective comparison with conventional-dose regimens in a minimally selected NHL patient population.
Background Musculoskeletal pain is a frequent complaint in pediatrics in both tertiary and primary care. Although musculoskeletal symptoms are not usually related to severe disease, they can represent the first manifestation of an occult malignancy. When these complaints predominate in the clinical presentation, they lead the diagnosis towards nonmalignant conditions, that are most common cause of such symptoms in children, like injuries, nonspecific reactive arthritis or inflammatory connective tissue diseases. However, in acute lymphoblastic leukaemia, the most prevalent childhood malignancy, bone and joint pains are present early in 40-60% of cases and they frequently anticipate any abnormalities in complete blood counts. Objectives To describe the clinical manifestations and complementary findings of the patients referred to a pediatric rheumatology unit with a final diagnosis of malignancy. Methods Retrospective analysis of medical records from patients with final diagnosis of neoplasia attended at the Pediatric Rheumatology Unit of the Federico II University of Naples, Italy, between January 1990 and December 2010. Data on musculoskeletal complaints, clinical examination, laboratory tests, radiological studies and diagnostic procedures were obtained. Results Of 2,675 patients referred, 15 had a final diagnosis of neoplasia (0.56%) (8 M, 7 F, mean age 8 years, range: 4 - 15 years). Seven children were diagnosed with acute lymphoblastic leukemia, two with neuroblastoma, two with lymphoma, one with histiocytosis, one with Ewing’s sarcoma, one with osteosarcoma and one with cerebral tumor. The most frequent symptoms were arthralgias (12/15, 80%), 4/15 children presented back pain, 2/15 patients presented polyarthritis, 1 child had myalgia. Nine children received a provisional diagnosis (60%): Juvenile idiopathic arthritis (JIA) was the most frequent (4/9), 3 children were diagnosed with rheumatic fever, 1 with Familial Mediterranean Fever, 1 with Systemic Lupus Erythematosus. The mean time between disease onset and final diagnosis was 3 months (range 1 – 12 months). Laboratory studies revealed anemia and a significant increase in sedimentation rate, lactate dehydrogenase and serum ferritin values; white blood cell and platelet changes were less frequent. Imaging studies contributed significantly to the diagnosis in 8 patients. The diagnosis was confirmed by bone marrow aspirate in 7 children with leukemia and by biopsies in those with bone tumor, lymphoma and histiocytosis. Conclusions Malignancies should be considered in the differential diagnosis of children with musculoskeletal pain, because they are common at the onset of neoplasia, especially for acute lymphoid leukemia, and this possibility should be considered in the differential diagnosis of rheumatic diseases especially in the presence of abnormal laboratory (lactate dehydrogenase and serum ferritin) or imaging studies. The detection and resolution of mimicking symptoms require knowledge, skills, and a problem-solving attitude for musculoskeletal d...
Background: Because of severe toxicity, in particular mucositis, neutropenia and thrombocytopenia, myeloablative regimens with stem cell support can be safely delivered only to clinically fit and younger pts, require prolonged hospitalization, and have a limited impact in the therapy of NHL. With the aim of rendering high-dose chemotherapy a well tolerated and widely applicable regimen, we carried out a pilot study using high-dose Zevalin with tandem stem-cell support in a prospective cohort of refractory or relapsed NHL patients. Methods: From June 2004 through June 2006, 29 overall NHL patients entered into the study (DLBCL, n=11; follicular, n=10; mantle cell, n=3; small lymphocytic, n=4; Richter syndrome, n=1). Median age was 62 yrs (29–76). The median number of prior chemotherapy regimes was 2 (1–4). Prior to Zevalin, all patients received 3 cycles of standard-dose salvage chemotherapy (DHAP or CHOP, as appropriate), followed by one cycle of high-dose cyclophosphamide plus rituximab, and one cycle of high-dose cytarabine and rituximab, at patient-adapted doses. Hematopoietic stem cells were harvested from the peripheral blood during the post-cyclophosphamide and/or the post-cytarabine recovery phase, and tested for MRD. Zevalin was administered at 0.8 mCi/kg (n=13 pts) or 1.2 mCi/kg (n=16 pts), respectively, and followed by tandem autografting of CD34+ on day +7 and an on day +14, respectively. The latter procedure was performed late, when the radiation absorbed dose to the reinfused stem cells was estimated to be less than 5cGy. In addition, all patients received on day +7 a limited amount (0.8–4.3 x 106/kg) of CD34+ cells. The aim of this early reinfusion, performed in the presence of myelotoxic levels of body radioactivity, was to foster a rapid albeit transient hematopoietic recovery, thus reducing the extend and duration of severe post-Zevalin pancytopenia. Results: Grade 4 neutropenia was observed in 13 pts (45%), and lasted a median of 4 days only (1–14). Grade 4 thrombocytopenia occurred in 19 pts (65%) for a median duration of 5 days (1–14). Fifteen patients (52%) required platelet transfusions (median 2, range 1–6), and 14 pts (48%) received 1 RBC transfusion each. No extra-hematologic toxicity was observed except for mild nausea in 17% of the patients, and all but 3 patients were cared for as outpatients. The 3 hospital admissions lasted 2, 4 and 11 days respectively, and were required for FUO that resolved upon antibiotic administration. Bone marrow analysis performed at 6 (n=5 pts) and 12 months (n=10 pts) showed in all a normal karyotype and a colony growth comparable to controls (NHL pts autografted following BEAM chemotherapy). After a median follow-up of 12 months, the 2-yr OS rate was 87% for indolent and 85% for aggressive lymphoma pts, respectively, while the EFS rate was 55% and 77%, respectively. Conclusions: High-dose Zevalin with tandem stem-cell transplantation was minimally toxic in this pretreated and elderly patient population, proved fully applicable in an outpatient setting, and showed promising activity. Its upfront inclusion as consolidation step after induction chemotherapy warrants a prospective comparison with R-CHOP, in particular in elderly pts with aggressive NHL.
A pituitary adenoma was discovered in a 9-year-old boy 4 years after he underwent a bilateral adrenalectomy for Cushing’s syndrome.
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