The increased incidence of secondary hematologic malignancies (SHM) is a well-known, potentially fatal, complication after cancer treatment. It is unknown if patients with ductal carcinoma in situ ...(DCIS) of the breast treated with external beam radiotherapy (RT) and who survive long-term have increased risks of secondary hematologic malignancies (SHM), especially for low/intermediate-risk subsets with limited benefits from RT. DCIS patients in Surveillance, Epidemiology, and End Results (SEER) registries (1975-2016) were identified. Relative risks (RR), hazard ratio (HR), and standardized incidence ratios (SIR) were calculated to assess the SHM risk and subsequent survival times. SHM development, defined as a nonsynchronous SHM occurring ≥1 year after DCIS diagnosis, was our primary endpoint. Of 184,363 eligible patients with DCIS, 77,927 (42.3%) in the RT group, and 106,436 (57.7%) in the non-RT group, 1289 developed SHMs a median of 6.4 years (interquartile range, 3.5 to 10.3 years) after their DCIS diagnosis. Compared with DCIS patients in the non-RT group, RT was associated with increased early risk of developing acute lymphoblastic leukemia (ALL; hazard ratio, 3.15; 95% CI, 1.21 to 8.17; P = 0.02), and a delayed risk of non-Hodgkin lymphoma (NHL; hazard ratio, 1.33; 95% CI, 1.09 to 1.62; P < 0.001). This increased risk of ALL and NHL after RT was also observed in subgroup analyses restricted to low/intermediate-risk DCIS. In summary, our data suggest that RT after breast conserving surgery for DCIS patients should be cautiously tailored, especially for low and intermediate-risk patients. Long-term SHM surveillance after DCIS diagnosis is warranted.
Chronic myeloid leukemia (CML) invites biologically based radiation risk modeling because CML is simultaneously well-understood, homogeneous and prevalent. CML is known to be caused by a ...translocation involving the ABL and BCR genes, almost all CML patients have the BCR-ABL translocation, and CML is prevalent enough that its induction is unequivocally detected among Hiroshima A-bomb survivors. In a previous paper, a linear-quadratic-exponential (LQE) dose-response model was used to estimate the lifetime excess risk of CML in the limit of low doses of gamma-rays, R gamma. This estimate assumed that BCR-ABL translocation dose-response curves in stem cells for both neutrons and gamma-rays, differ only by a common proportionality constant from dicentric aberration dose-response curves in lymphocytes. In the present paper we challenge this assumption by predicting the BCR-ABL dose response. The predictions are based on the biophysical theory of dual radiation action (TDRA) as it applies to recent BCR-to-ABL distance data in G0 human lymphocytes; this data shows BCR and ABL geometric distributions that are not uniform and not independent, with close association of the two genes in some cells. The analysis speaks against the previous proportionality assumption. We compute 11 plausible LQE estimates of R gamma, 2 based on the proportionality assumption and 9 based on TDRA predictions. For each estimate of R gamma we also compute an associated estimate of the number of CML target cells, N; the biological basis of the LQE model allows us to form such estimates. Consistency between N and hematological considerations provides a plausibility check of the risk estimates. Within the group of estimates investigated, the most plausible lifetime excess risk estimates tend to lie near R gamma = 0.01 Gy-1, substantially higher than risk estimates based on the proportionality assumption.
Purpose: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P)
in a Phase I study in 25 patients with advanced solid tumors.
...Experimental Design: CA4P was administered in a dose-escalating fashion starting at 18 mg/m 2 i.v. every 21 days, and the maximal dosage was 90 mg/m 2 . Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time
points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett’s formula QTc
= QT/(R-R interval) 1/2 , and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C max versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed.
Results: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points 27.2 ms ( P < 0.0001) and 30.8 ms ( P < 0.0001), respectively and HR at the 3- and 4-h time points 13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm ( P < 0.001), respectively. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%)
of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the
first 4 h was correlated to dose (in milligrams) of CA4P ( P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve ( P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients
had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion.
Conclusions: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent
with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines
limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more
experience is gained regarding potential cardiovascular toxicity with this agent.
Systems Biology Markup Language (SBML) is gaining broad usage as a standard for representing dynamical systems as data structures. The open source statistical programming environment R is widely used ...by biostatisticians involved in microarray analyses. An interface between SBML and R does not exist, though one might be useful to R users interested in SBML, and SBML users interested in R.
A model structure that parallels SBML to a limited degree is defined in R. An interface between this structure and SBML is provided through two function definitions: write.SBML() which maps this R model structure to SBML level 2, and read.SBML() which maps a limited range of SBML level 2 files back to R. A published model of purine metabolism is provided in this SBML-like format and used to test the interface. The model reproduces published time course responses before and after its mapping through SBML.
List infrastructure preexisting in R makes it well-suited for manipulating SBML models. Further developments of this SBML-R interface seem to be warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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