Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells

Patients with solid tumors are increasingly being treated by autologous bone marrow transplantation (BMT). Although response rates appear to be increased, disease recurrence is the commonest cause of treatment failure. Whether relapse is entirely due to residual disease in the patient or arises also from infiltrating malignant cells contained in the autologous marrow transplant has not been resolved. If the latter explanation is correct, then purging would be required as part of the transplantation procedure. We used retrovirally mediated transfer of the neomycin-resistance gene to mark BM harvested from eight patients with neuroblastoma in clinical remission. The marked marrow cells were subsequently reinfused as part of an autologous BMT. At relapse, we sought the marker gene in malignant cell populations. Three patients have relapsed, and in each the marker gene was detected by phenotypic and genetic analyses of resurgent malignant cells at medullary and extramedullary sites. Analysis of neuroblast DNA for discrete marker gene integration sites suggested that at least 200 malignant cells, each capable of tumor formation, were introduced with the autologous marrow transplant and contributed to relapse. Thus, autologous BMTs administered to patients with this solid tumor may contain a multiplicity of malignant cells that subsequently contribute to relapse. The marker-gene technique we describe should permit evaluation of the mechanisms of relapse and the efficacy of purging in patients receiving autologous marrow transplantation for other solid tumors that infiltrate the marrow.     

REVEAL‐1, a phase 2 dose regimen optimization study of vosaroxin in older poor‐risk patients with previously untreated acute myeloid leukaemia

This phase 2 study (N = 116) evaluated single‐agent vosaroxin, a first‐in‐class anticancer quinolone derivative, in patients ≥60 years of age with previously untreated unfavourable prognosis acute myeloid leukaemia. Dose regimen optimization was explored in sequential cohorts (A: 72 mg/m² d 1, 8, 15; B: 72 mg/m² d 1, 8; C: 72 mg/m² or 90 mg/m² d 1, 4). The primary endpoint was combined complete remission rate (complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Common (>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anaemia, neutropenia, sepsis, pneumonia, stomatitis and hypokalaemia. Overall CR and CR/CRp rates were 29% and 32%; median overall survival (OS) was 7·0 months; 1‐year OS was 34%. Schedule C (72 mg/m²) had the most favourable safety and efficacy profile, with faster haematological recovery (median 27 d) and lowest incidence of aggregate sepsis (24%) and 30‐d (7%) and 60‐d (17%) all‐cause mortality; at this dose and schedule, CR and CR/CRp rates were 31% and 35%, median OS was 7·7 months and 1‐year OS was 38%. Overall, vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 mg/m² d 1, 4 is recommended for further study in this population. Registered at www.clinicaltrials.gov : #NCT00607997.     

Angiomyofibroblastoma of the vulva

A 30-year-old female presented with unilateral labial enlargement. The clinical impression was that of a benign cyst. The microscopic features were that of angiomyofibroblastoma showing hyper and hypocellular areas containing spindle and plump stromal cells admixed with blood vessels. This tumour is benign with extremely low rate of recurrence. Surgery is the only treatment as in this case.     

Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis

Lymphoblasts in bone marrow samples, obtained from 43 children with acute lymphoblastic leukemia at diagnosis, were incubated with 1.0 mumols/L [3H] methotrexate for 24 hours in vitro. Nonexchangeable methotrexate and methotrexate polyglutamates were separated and quantitated. Event-free survival at 5 years was 38% +/- 9% for all 43 patients (27 failures), and 44% +/- 10% for the 35 with non-T, non-B- cell acute lymphoblastic leukemia (20 failures). Of these 35 children, those whose lymphoblasts accumulated more than 100 pmol methotrexate and 500 pmol methotrexate polyglutamates per billion cells experienced better 5-year event-free survival than those whose lymphoblasts did not (65% +/- 12% v 22% +/- 9%, P = .010). This difference characterized "good-risk" patients who were female (P = .014), less than age 7 at diagnosis (P = .005), or had low initial white blood cell counts (less than 20 X 10(9)/L, P = .018). Findings were similar for the 43 children with acute lymphoblastic leukemia and for the "good-risk" children in this total group. Thus, the ability of lymphoblasts to accumulate methotrexate and form methotrexate polyglutamates may be important to the curative properties of current therapy of acute lymphoblastic leukemia in children, particularly for "good-risk" patients. In such patients, inherent rather than acquired drug resistance may be the initial event leading to treatment failure.     

Vasodilatory capacity of the skin in venous disease and its relationship to transcutaneous oxygen tension.

Low transcutaneous oxygen tension (Ptc,O2) values in the supramalleolar skin of patients with venous disease are often reported. This measurement involves heating the skin to 43 degrees C to cause maximum vasodilatation and is valid only if liposclerotic and normal skin can vasodilate to the same degree. Forty-four limbs were studied, 15 with lipodermatosclerosis (LDS), 14 with uncomplicated varicose veins, and 15 controls. A Ptc,O2 electrode was modified to incorporate a laser Doppler probe. Laser Doppler flux was measured in the supramalleolar skin before and after local heating to 43 degrees C and the relative increase in flux was measured. The Ptc,O2 was then measured at the same site and on the chest. Vasodilatory capacity was expressed as the ratio of peak:basal laser Doppler flow, and the Ptc,O2 was expressed as a leg:chest ratio. Median laser Doppler flow was higher in limbs with LDS (median 67 mV) than in normal limbs (median 40 mV) (P less than 0.03). Ptc,O2 was higher in control limbs (median ratio 0.94) than in limbs with LDS (median 0.53) (P less than 0.006). The microcirculation in LDS had less capacity to vasodilate after heating (median factor of increase 5.4) than normal skin (median factor of increase 12.3) (P less than 0.001). A simple regression analysis was performed on all pairs of data, and revealed a correlation between Ptc,O2 and vasodilatory capacity (r = 0.524, P less than 0.001). The results indicate that low Ptc,O2 levels in venous disease reflect an inability of the microcirculation to increase its flow in response to local heating; inferences about the oxygen content of liposclerotic skin at normal temperatures cannot be drawn using this technique.