Aziza Shad

Age, Thymopoiesis, and CD4+ T-Lymphocyte Regeneration after Intensive Chemotherapy

BACKGROUNDnInadequate reconstitution of CD4+ T lymphocytes is an important clinical problem complicating chemotherapy, human immunodeficiency virus infection, and bone marrow transplantation, but relatively little is known about how CD4+ T lymphocytes regenerate. There are two main possibilities: bone marrow-derived progenitors could reconstitute the lymphocyte population using a thymus-dependent pathway, or thymus-independent pathways could predominate. Previous studies have suggested that the CD45RA glycoprotein on CD4+ T lymphocytes is a marker for progeny generated by a thymus-dependent pathway.nnnMETHODSnWe studied 15 patients 1 to 24 years of age who had undergone intensive chemotherapy for cancer. The absolute numbers of CD4+ T lymphocytes in peripheral blood and the expression of CD45 isoforms (CD45RA and CD45RO) on these lymphocytes were studied serially during lymphocyte regeneration after the completion of therapy. Radiographic imaging of the thymus was performed concomitantly.nnnRESULTSnThere was an inverse relation between the patients ages and the CD4+ T-lymphocyte counts six months after therapy was completed (r = -0.92). The CD4+ recovery correlated quantitatively with the appearance of CD45RA+CD4+ T lymphocytes in the blood (r = 0.64). There was a higher proportion of CD45RA+CD4+ T lymphocytes in patients with thymic enlargement after chemotherapy than in patients without such enlargement (two-sided P = 0.015).nnnCONCLUSIONSnThymus-dependent regeneration of CD4+ T lymphocytes occurs primarily in children, whereas even young adults have deficiencies in this pathway. Our results suggest that rapid T-cell regeneration requires residual thymic function in patients receiving high-dose chemotherapy.

Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen.

PURPOSEnWe have used identical treatment protocols for adults and children with small non-cleaved-cell lymphoma (SNCL) for many years and report here the results of two successive treatment regimens in these age groups.nnnPATIENTS AND METHODSnSeventy-two patients (39 adults and 33 children) were treated with protocol 77-04 between 1977 and 1985. All patients, except those with resected abdominal disease, received 15 cycles of a combination of cyclophosphamide (CTX), doxorubicin (ADR), prednisone (PRED), vincristine (VCR), high-dose methotrexate (MTX), and intrathecal (IT) therapy. Forty-one patients (20 adults and 21 children) were treated with protocol 89-C-41, which has been used since 1989. High-risk patients received four alternating cycles (with a total duration of 12 to 15 weeks) of an intensified version of protocol 77-04 without PRED (CODOX-M), and a new drug combination consisting of ifosfamide, etoposide, high-dose cytarabine (ara-C), and IT MTX (IVAC). Low-risk patients received three cycles of the CODOX-M regimen. High-risk patients were randomized to either receive or not receive granulocyte-macrophage colony-stimulating factor (GM-CSF).nnnRESULTSnEvent-free survival (EFS) in protocol 77-04 was 56% at 2 years and beyond. EFS in protocol 89-C-41 was 92% at 2 years and beyond. GM-CSF was associated with increased thrombocytopenia.nnnCONCLUSIONnAdults and children with SNCL have a similar prognosis when treated with the same chemotherapy. EFS in high-risk patients has been markedly improved by including IVAC in protocol 89-C-41, and excellent results can be achieved with only four cycles of therapy. In protocol 89-C-41, GM-CSF was not beneficial.

Precursor B-lymphoblastic lymphoma presenting as a solitary bone tumor and mimicking Ewing's sarcoma. A report of four cases and review of the literature

Precursor B-lymphoblastic lymphoma (B-LBL) may present as a solitary bone tumor. Fewer than 10 cases with a proven precursor B-cell phenotype have been reported in the English literature. In this report, we describe four cases of B-lymphoblastic lymphoma presenting as a localized intraosseous mass, which clinically and histologically mimicked Ewings sarcoma. Three tumors occurred in the tibia and one in the humerus. In all four cases, the initial diagnosis was either Ewings sarcoma or consistent with Ewings sarcoma. All four patients were female. Three were children and one was an adult; mean age was 12.5 years (range, 4 to 31 years). All had extremity pain without significant constitutional symptoms. In three cases, the tumors were osteolytic on radiographic evaluation, and in one case, osteosclerotic. Immunohistochemical stains on paraffin-embedded tissue showed that the neoplastic cells expressed terminal deoxynucleotidyl transferase, CD43, vimentin, and CD99 (MIC2 gene product) in all cases. Three cases were negative for CD45. CD79a was positive in all four cases studied; however, CD20 (L26) was positive in only two of four cases. CD3 was negative in all cases. Two cases showed focal granular cytoplasmic staining for keratin. Two cases analyzed by polymerase chain reaction (PCR) revealed clonal rearrangement of the immunoglobulin heavy chain (IgH) gene. Follow-up revealed that the three pediatric patients, who received a high-dose multiagent chemotherapy regime for LBL, are disease free at follow-up intervals of more than 1, 11, and 12 years, respectively. The adult patient died two years after diagnosis with disseminated disease. Although rare, B-lymphoblastic lymphoma should be considered in the differential diagnosis of small round cell tumors of bone. A diagnosis of Ewings sarcoma should be made only after complete immunophenotyping and, if necessary, molecular diagnostic tests to exclude lymphoblastic lymphoma. A limited panel of antibodies can lead to an erroneous diagnosis; B-lymphoblastic lymphoma may be negative for CD45 and CD20 but positive for CD99 and even for keratin, mimicking Ewings sarcoma. Correct diagnosis is extremely important because LBL usually is curable in the pediatric age group with appropriate therapy.

Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas.

PURPOSEnTo evaluate long-term survivors of high-grade non-Hodgkins lymphomas (NHLs) for late effects and to attempt to assess the relative contributions of the primary treatment modalities to these late effects.nnnPATIENTS AND METHODSnOf 103 young survivors followed up for 1 to 20 years, 74 patients were interviewed and underwent various investigations, and an additional 12 patients were interviewed only. Of the 86 patients, 65 had previously suffered from small non-cleaved-cell lymphoma, 16 from lymphoblastic lymphoma, and five from large-cell lymphoma.nnnRESULTSnLeft ventricular dysfunction was identified in eight of 57 (14.0%) patients who had received doxorubicin (DOX) in doses greater than 200 mg/m2, of whom four were symptomatic and four were asymptomatic. A ninth patient required a pacemaker. Of the 86 patients, 23 (26.7%) reported pregnancies, 18 of whom had 30 children. Two of the 86 (2.3%) patients developed second cancers. Other major late effects included posttransfusion viral hepatitis, eight patients; CNS toxicity, two patients; endocrine impairment, 14 patients; vitamin B12 deficiency, two patients; esophageal stricture, one patient; urinary tract problems, two patients; and musculoskeletal defects, three patients. Major late effects occurred in 11 of 21 (52.4%) patients who had received radiation as well as chemotherapy, eight of 22 (36.4%) patients who had surgical resections as well as chemotherapy, and 17 of 74 (23.0%) patients who had received chemotherapy alone.nnnCONCLUSIONnThe predominant major late effects observed were late cardiac toxicity related to DOX therapy and hepatitis C virus infection that presumably resulted from blood product transfusions administered before the introduction of screening for the hepatitis C virus. Fertility was not greatly impaired, and second malignancies were uncommon. No patient had clinically significant impairment of growth. Radiation appeared to increase the likelihood of late effects.

Severe atypical neuropathy associated with administration of hematopoietic colony-stimulating factors and vincristine.

PURPOSEnWe have observed a severe atypical neuropathy (SAN) in patients with small non-cleaved-cell (SNCL) and large-cell lymphoma (LCL) treated with intensive chemotherapy and hematopoietic colony-stimulating factors (CSFs). The present analysis was undertaken in an attempt to identify factors associated with the development of this syndrome.nnnPATIENTS AND METHODSnFifty-four adult and pediatric patients consecutively treated according to the same chemotherapy protocol were included in the analysis. Low-risk patients received three cycles of cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate (CODOX-M) while in high-risk patients this drug combination was alternated with high-dose cytarabine (ara-C), etoposide, and ifosfamide (IVAC) for a total of four cycles. Twenty-eight patients received a CSF (granulocyte [G]- or granulocyte-macrophage [GM]-CSF), and 26 patients received no CSF. A statistical analysis, which included a logistic regression model, was undertaken to examine the importance of potential contributing factors to the development of SAN.nnnRESULTSnSAN, which consisted of excruciating foot pain, usually associated with marked motor weakness, was observed in 12 patients. There was a highly significant association between the occurrence of this syndrome and the administration of CSFs, and an independent association with the cumulative dose of vincristine given in the first cycle of chemotherapy. Furthermore, the analysis suggested a synergistic effect between administration of the CSFs and vincristine in the genesis of this neuropathy.nnnCONCLUSIONnOur results indicate that CSFs can precipitate SAN when given in conjunction with vincristine. The development of SAN was associated most strongly with the cumulative dose of vincristine -- the size of individual doses and the number of doses given in cycle 1 were important to the extent that they influenced the cumulative dose.

Non-Hodgkin’s Lymphoma

Pediatric lymphomas are the third most common group of malignancies in children and adolescents. Unlike lymphomas in adults, pediatric lymphomas are diffuse, aggressive neoplasms with a propensity for widespread dissemination. Intensification of conventional treatment approaches along with improvements in supportive care have resulted in dramatic improvement in event-free survival rates of close to 90% in patients with B-cell lymphomas and only slightly lower in patients with T-cell lymphomas. Lymphoid neoplasms arise because of genetic changes that result in altered growth and differential patterns of lymphoid cells. The characterization of these molecular abnormalities and an understanding of their consequences has led to new approaches to diagnosis and the detection of minimal residual disease and also provides the basis for the future development of novel treatment approaches targeted specifically to the neoplastic cells.

Role of tissue diagnosis in pulmonary involvement in pediatric human immunodeficiency virus infection

BACKGROUNDnPulmonary complications occur commonly during HIV infection. The aim of this study was to evaluate the clinical value of lung tissue examination in the diagnosis and treatment of pulmonary disorders in children with HIV infection.nnnMETHODSnThe medical records of 347 children enrolled between January, 1990, and April, 1994, into various antiretroviral therapy protocols were reviewed to identify patients who underwent a lung biopsy.nnnRESULTSnFourteen patients underwent diagnostic lung biopsies on 16 separate occasions. The most common radiologic findings were nodular infiltrates which were localized in 7 patients and diffuse in 6. Eight patients presented with fever and progressive respiratory distress unresponsive to empiric therapy, whereas the rest had progressive nodular infiltrates. The pathologic diagnoses included opportunistic infection in 7 patients, lymphocytic interstitial pneumonitis in 5, non-Hodgkins lymphoma in 3 and interstitial fibrosis in 1. The biopsy led to a major change in the treatment of 7 patients which resulted in a significant improvement of the pulmonary process in all of them. In an additional patient the excisional biopsy proved curative.nnnCONCLUSIONSnWhen patients are selected appropriately, lung biopsy might have a significant impact on therapy and outcome in HIV-infected children with pulmonary infiltrates.

A thirteen year old female with primary T-cell rich B-cell lymphoma of bone masquerading as chronic recurrent multifocal osteomyelitis

Primary lymphoma of the bone (PLB) accounts for 2% of all non-Hodgkins lymphomas, and until recently it had not been well characterized in literature. Most cases present in adulthood (average age 50), with localized painful lesions in the long bones, cranium, or axial skeleton. We describe a case of multifocal PLB in an adolescent female. In this case, the initial presentation, with migratory large joint polyarthralgias and bone pain, mimicked chronic recurrent multifocal osteomyelitis (CRMO). Had a biopsy not been performed the diagnosis would have been missed.

Cancer funding in developing countries: the next health-care crisis?

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Oncofertility and quality of life among adolescent and young adult survivors of childhood cancer.

222 Background: Although infertility risks due to childhood cancer treatment are well-documented, research on the psychosocial impact of treatment-associated infertility risks among adolescent and young adult (AYA) cancer survivors is limited. This study examined AYA pediatric cancer survivors perceptions of oncofertility and cancer treatment-associated infertility risks and associations with patient-reported quality of life (QoL).nnnMETHODSnPatients ages 12 to 25 (n= 70, M age 19.4, 74% white, 57% female, a majority leukemia/lymphoma survivors) were recruited from a pediatric hematology/oncology clinic and local pediatric cancer survivor support organizations. Patients reported knowledge and beliefs about treatment-related fertility risks and reproductive health, and oncofertility information and support needs, and completed the Pediatric Oncology Quality of Life (QoL) scale.nnnRESULTSnPatients knowledge about infertility risks and fertility preservation options was low (M 13.5, SD 8.6, range 0-42): patients attitudes indicated treatment-related infertility risks was important (M 21.7, SD 7.0, range 0-40), they perceived they were at-risk for infertility (M 3.8, SD 1.0 range 1-5), and expressed unmet needs for supportive resources on reproductive health (M 13.6, SD 4.8, range 1-24). Greater perceived risks of infertility (r = .34, p = .004) and importance of fertility risks (r = .34, p = .004) were associated with lower QoL. In a multivariable model adjusting for patient age and gender, beliefs that reproductive health was important was associated with lower QoL (B = .68, p = .041).nnnCONCLUSIONSnPopulation data demonstrate few AYA cancer survivors have opportunities to discuss fertility preservation with providers. Our findings indicate AYA cancer survivors perceive treatment-related infertility risks as important, associated with QoL, and with needs for more information about reproductive health and fertility preservation. Care models addressing AYA survivors infertility risks are needed as part of the diagnosis, treatment, and long-term follow-up of these patients.