Expectations and outcomes of varying treatment strategies for CML presenting during pregnancy.

Diagnosing chronic myeloid leukaemia (CML) during pregnancy is rare. Tyrosine kinase inhibitors (TKIs) have traditionally been contraindicated owing to their teratogenicity. Management decisions should consider the risks to mother and foetus of uncontrolled disease and teratogenic medications. Further cases are required to build upon the paucity of current literature. We report 22 cases of CML diagnosed during pregnancy from 2002 to date. Twenty-one pregnancies resulted in healthy babies and one patient miscarried. Some patients remained untreated throughout pregnancy but the majority received one or both of interferon-α and leucapheresis. One patient was started on imatinib at Week 26, and one on hydroxycarbamide in the third trimester. We report haematological parameters during pregnancy to provide clinicians with realistic expectations of management. There were no fetal abnormalities related to treatment during pregnancy. Seventeen patients achieved at least major molecular response on first-line TKI. A diagnosis of CML during pregnancy can be managed without significant consequences for mother or child. Leucapheresis and interferon-α are generally safe throughout pregnancy. Despite having been avoided previously, there is growing evidence that certain TKIs may be used in particular circumstances during the later stages of pregnancy. Future work should aim to further elucidate this safety profile.

Extramedullary myeloma representing as a pericardial effusion with tamponade: two case reports and a further review of 19 cases in the literature.

Two rare cases of extramedullary pericardial myeloma presenting after initial diagnosis of multiple myeloma are described. A systematic search using PubMed (National Library of Medicine) identified a further 19 cases in the literature. The characteristics of presentation, duration of survival and optimal management of patients with pericardial myelomatous involvement are discussed.

T helper and T suppressor cells are restricted by the A and E molecules, respectively, in the F antigen system.

The role of the A and E molecules as restriction elements was examined in the F antigen system. In the mouse the only responder haplotype known to date is k, and blocking studies with a monoclonal antibody show that in vitro T-cell proliferation is restricted by the Ak molecule. The (CBA X DBA/2)F1 hybrid, which is a responder X nonresponder cross, is itself a nonresponder in terms of F-specific antibody production. Up to 10 days after priming, (CBA X DBA/2)F1 T cells exhibited an F-specific proliferative response, but this diminished rapidly at later times. This diminution could be blocked with an E-specific monoclonal antibody, suggesting that suppression is restricted by the E molecule.

Acute myeloblastic leukaemias of FAB types M6 and M4, with cryptic PML/RARalpha fusion gene formation, relapsing as acute promyelocytic leukaemia M3.

Demonstration of either the translocation t(15;17)(q22;q21) or the fusion of PML and RARalpha genes is regarded as diagnostic for acute myeloid leukaemia (AML) of FAB type M3, but has occasionally been seen in other FAB types. We present two such cases. Case 1 presented with FAB type M6 and a complex karyotype involving chromosomes 1, 2, 11 and 17. Bone marrow relapse of FAB type M3 followed autologous bone marrow transplantation. Subsequent marrow dysplasia and an M6 relapse were accompanied by a new cytogenetic clone involving chromosomes X, 2, 4, 6, 7 and 16. Fluorescence in situ hybridization (FISH) of metaphase chromosomes at diagnosis showed insertion of material from chromosome 17 into a 'normal' 15 with juxtaposition of PML and RARalpha. Case 2 presented as AML M4 and relapsed as M3. Cytogenetic analysis at diagnosis and in relapse showed 46,XY,t(15;17)(q22;q11),del(16)(q22). FISH analysis showed this to be a three-way translocation involving chromosomes 15, 16 and 17 again with juxtaposition of PML and RARalpha. Reverse transcription-polymerase chain reaction (RT-PCR) revealed PML/RARalpha fusion at diagnosis, in remission and in first relapse. These examples strengthen the case for RT-PCR screening of all AML patients for these fusion genes.

Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation.

Ligation of the cell-surface Fas molecule by its ligand (Fas-L) or agonistic anti-Fas monoclonal antibodies results in the cleavage and activation of the cysteine protease procaspase 8 followed by the activation of procaspase 3 and by apoptosis. In some leukemia cell lines, cytotoxic drugs induce expression of Fas-L, which may contribute to cell killing through the ligation of Fas. The involvement of Fas, Fas-L, and caspase 8 was studied in the killing of B-cell chronic lymphocytic leukemia (B-CLL) cells by chlorambucil, fludarabine, or gamma radiation. Spontaneous apoptosis was observed at 24-hour incubation, with additional apoptosis induced by each of the cytotoxic treatments. Although Fas mRNA expression was elevated after exposure to chlorambucil, fludarabine, or gamma radiation, Fas protein levels only increased after irradiation. Therefore, Fas expression may be regulated by multiple mechanisms that allow the translation of Fas mRNA only in response to restricted cytotoxic stimuli. None of the cytotoxic stimuli studied here induced Fas-L expression. An agonistic anti-Fas monoclonal antibody (CH-11) did not significantly augment apoptosis induction by any of the death stimuli. A Fas-blocking antibody (ZB4) did not inhibit spontaneous, chlorambucil-, fludarabine-, or radiation-induced apoptosis. However, procaspase 8 processing was induced by all cytotoxic stimuli. These data suggest that the Fas/Fas-L signaling system does not play a major role in the induction of apoptosis in B-CLL cells treated with cytotoxic drugs or radiation. However, Fas-independent activation of caspase 8 may play a crucial role in the regulation of apoptosis in these cells.