PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment.

Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays. At concentration of the dual PI3Kδ/γ inhibitor duvelisib, which can be achieved in vivo we saw a decrease in AKT phosphorylation at s473 after tumour activation by bone marrow stromal cells (BMSC) and interleukin-6. Moreover, after drug treatment of BMSC/tumour co-culture activation assays only dual PI3kδ/γ inhibition was able to induce MM apoptosis. shRNA lentiviral-mediated targeting of either PI3Kδ or PI3Kγ alone, or both in combination, increased survival of NSG mice xeno-transplanted with MM cells. Moreover, treatment with duvelisib reduced MM tumour burden in vivo. We report that PI3Kδ and PI3Kγ isoforms have distinct functions in MM and that combined PI3kδ/γ isoform inhibition has anti-MM activity. Here we provide a scientific rationale for trials of dual PI3kδ/γ inhibition in patients with MM.

Marrow involvement with T cell lymphoma initially presenting as abnormal myelopoiesis.

Three cases of T cell lymphoma affecting the marrow, in which initial bone marrow appearances were misleading, occurred. In each case the initial clinical presentation was related to cytopenia, but the marrow abnormalities at this time suggested an abnormal myeloid proliferative state, with no evidence of a malignant lymphoid proliferation. Later in the course of the disease, however, the characteristic pattern of marrow infiltration by mature post-thymic T cells became evident. The consequent delay (two to 36 months) in diagnosis was noted.

8;21 translocation with duplication of the der(21) in a patient with myelomonocytic leukemia.

An 8;21 translocation with duplication of the der(21) is described in a 72-year-old man who presented with features of chronic myelomonocytic leukemia. Progression to acute myelomonocytic leukemia occurred within one month of diagnosis. The possible prognostic significance of the t(8;21) with duplicated der(21) in myelodysplasia is discussed.

Monocyte procoagulant activity in breast cancer.

Abnormalities of blood coagulation associated with neoplasia may be important in the pathogenesis of tumour spread. Most patients with advanced malignancy have evidence of activated coagulation, but the mechanisms underlying this are unclear. We have examined in vitro monocyte procoagulant activity and compared this to plasma levels of fibrinopeptide A, in 52 patients with clinically localised breast cancer. Patients with localised breast cancer and activated coagulation displayed a strong positive correlation between monocyte procoagulant activity and level of fibrinopeptide A(r = +0.86, p less than 0.001). No such relationship was demonstrated in a smaller number of patients with metastatic breast cancer. It is concluded that monocyte procoagulant activity plays an important role in coagulation activation in patients with localised breast cancer. The implications of this for adjuvant anticoagulant therapy in breast cancer are discussed.

Unusual presentation of a large infected hemophiliac pseudotumor in an autologous indium-111 WBC scan.

A false-negative In-111 WBC scan was obtained in a case of a large, infected hemophiliac pseudotumor. Following aspiration of the abscess, a positive scan was seen, demonstrating that In-111 WBC imaging occasionally may be misleading as a diagnostic tool.

Effects of tamoxifen on blood coagulation.

Sixteen patients with clinically localized breast carcinoma who had been receiving tamoxifen 20 mg twice daily for between 3 and 38 months (median, 14 months) were studied. Several parameters of coagulation (antithrombin III, protein C, fibrinopeptide A and in vitro monocyte procoagulant activity) were investigated in this group and compared to a group of 15 patients with clinically localised breast carcinoma not given tamoxifen. Tamoxifen did not induce significant changes in these parameters to account for the reported thromboembolic events associated with this therapy. The reduced antithrombin III activity previously described in patients receiving tamoxifen for metastatic breast cancer may reflect disease activity rather than a direct effect of tamoxifen on blood coagulation.

A quantitative study of monocyte procoagulant activity in acute monoblastic and chronic myelomonocytic leukaemias.

Monoblasts from 7 patients with acute monoblastic leukaemia produced significantly less procoagulant activity (PCA) in response to endotoxin (mean 0.7 U/10(6) monocytes, range 0.4-1.4) than monocytes from 6 patients with chronic myelomonocytic leukaemia (mean 6.0 U/10(6) monocytes, range 1.25-10.7) and 15 normal subjects (mean 8.9 U/10(6) monocytes, range 3.1-21.2). However, when expressed as the quantity of monocyte-related PCA generated per millilitre of blood, there was no significant difference between patients with acute monoblastic or chronic myelomonocytic leukaemias, though both types of patients generated significantly higher amounts of PCA than normal subjects or patients in haematological remission. The relationship of these findings to the occurrence of disseminated intravascular coagulation is discussed.

Primary ileocecal lymphoma. A study of 22 patients.

Twenty-two patients with primary ileocecal non-Hodgkin's lymphoma were reviewed. Abdominal pain (67%), altered bowel habits (50%), and weight loss (50%) were the most common presenting symptoms and an abdominal mass was palpable in 50%. Sixteen (73%) had histologic evidence of local lymph node involvement at diagnosis and another two (9%) had nonhistologic evidence of nodal involvement. An abdominal computed tomography (CT) scan was the most helpful staging investigation. Twenty-one (95.5%) patients underwent surgical resection of their disease. Subsequent chemotherapy, with or without radio-therapy, appeared to prolong survival (median, 34 months versus 14 months). There were three treatment-related deaths. Neither the age of the patient nor the stage of disease at presentation (Ann Arbor) appeared to influence survival. Adequate initial surgery combined with chemotherapy may provide optimum therapy in patients with primary ileocecal lymphoma.

Elevated fibrinopeptide A levels in patients with clinically localised breast carcinoma.

58 patients with clinically localised breast carcinoma, treated by either mastectomy alone or lumpectomy plus local radiotherapy, have now been followed for up to 51 months (median 12 months). 21 of the 58 patients (36.2%) had a persistently elevated or rising fibrinopeptide A level after surgery and 11 of these patients (52%) to date have subsequently developed recurrent breast carcinoma up to 27 months after the fibrinopeptide A level became elevated (median 6 months). Conversely, only 2 (5.4%) of the 37 patients with persistently normal post-operative fibrinopeptide A levels have developed recurrent disease. Elevated fibrinopeptide A levels appear to be a marker of persistent tumour activity and precede clinical recurrence in certain patients with breast carcinoma, but normal values do not exclude recurrent or residual disease.

Linkage analysis for major histocompatibility complex-related genetic susceptibility in familial chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) shows evidence of familial aggregation, but the genetic basis is poorly understood. The existence of a linkage between HLA and Hodgkin lymphoma, another B-cell disorder, coupled with the fact that CLL is frequently associated with autoimmune disease, led to the question of whether the major histocompatibility complex (MHC) region is involved in familial cases of CLL. To examine this proposition, 5 microsatellite markers on chromosome 6p21.3 were typed in 28 families with CLL, 4 families with CLL in association with other lymphoproliferative disorders, and 1 family with splenic lymphoma with villous lymphocytes. There was no evidence of linkage in these families to chromosome 6p21.3. The best estimates of the proportions of sibling pairs with CLL that share 0, 1, or 2 MHC haplotypes were not significantly different from the null expectation. This implies that genes within the MHC region are unlikely to be the major determinants of familial CLL. (Blood. 2000;96:3982-3984)