Ion recombination correction factors and detector comparison in a very-high dose rate proton scanning beam.

PURPOSE: Accurate dosimetry is paramount to study the FLASH biological effect since dose and dose rate are critical dosimetric parameters governing its underlying mechanisms. With the goal of assessing the suitability of standard clinical dosimeters in a very-high dose rate (VHDR) experimental setup, we evaluated the ion collection efficiency of several commercially available air-vented ionization chambers (IC) in conventional and VHDR proton irradiation conditions. METHODS: A cyclotron at the Orsay Proton Therapy Center was used to deliver VHDR pencil beam scanning irradiation. Ion recombination correction factors (ks) were determined for several detectors (Advanced Markus, PPC05, Nano Razor, CC01) at the entrance of the plateau and at the Bragg peak, using the Niatel model, the Two-voltage method and Boag's analytical formula for continuous beams. RESULTS: Mean dose rates ranged from 4 Gy/s to 385 Gy/s, and instantaneous dose rates up to 1000 Gy/s were obtained with the experimental set-up. Recombination correction factors below 2 % were obtained for all chambers, except for the Nano Razor, at VHDRs with variations among detectors, while ks values were significantly smaller (0.8 %) for conventional dose rates. CONCLUSIONS: While the collection efficiency of the probed ICs in scanned VHDR proton therapy is comparable to those in the conventional regime with recombination coefficiens smaller than 1 % for mean dose rates up to 177 Gy/s, the reduction in collection efficiency for higher dose rates cannot be ignored when measuring the absorbed dose in pre-clinical proton scanned FLASH experiments and clinical trials.

Shaping of a laser-accelerated proton beam for radiobiology applications via genetic algorithm.

Laser-accelerated protons have a great potential for innovative experiments in radiation biology due to the sub-picosecond pulse duration and high dose rate achievable. However, the broad angular divergence makes them not optimal for applications with stringent requirements on dose homogeneity and total flux at the irradiated target. The strategy otherwise adopted to increase the homogeneity is to increase the distance between the source and the irradiation plane or to spread the beam with flat scattering systems or through the transport system itself. Such methods considerably reduce the proton flux and are not optimal for laser-accelerated protons. In this paper we demonstrate the use of a Genetic Algorithm (GA) to design an optimal non-flat scattering system to shape the beam and efficiently flatten the transversal dose distribution at the irradiated target. The system is placed in the magnetic transport system to take advantage of the presence of chromatic focusing elements to further mix the proton trajectories. The effect of a flat scattering system placed after the transport system is also presented for comparison. The general structure of the GA and its application to the shaping of a laser-accelerated proton beam are presented, as well as its application to the optimisation of dose distribution in a water target in air.

Fast dose fractionation using ultra-short laser accelerated proton pulses can increase cancer cell mortality, which relies on functional PARP1 protein.

Radiotherapy is a cornerstone of cancer management. The improvement of spatial dose distribution in the tumor volume by minimizing the dose deposited in the healthy tissues have been a major concern during the last decades. Temporal aspects of dose deposition are yet to be investigated. Laser-plasma-based particle accelerators are able to emit pulsed-proton beams at extremely high peak dose rates (~109 Gy/s) during several nanoseconds. The impact of such dose rates on resistant glioblastoma cell lines, SF763 and U87-MG, was compared to conventionally accelerated protons and X-rays. No difference was observed in DNA double-strand breaks generation and cells killing. The variation of the repetition rate of the proton bunches produced an oscillation of the radio-induced cell susceptibility in human colon carcinoma HCT116 cells, which appeared to be related to the presence of the PARP1 protein and an efficient parylation process. Interestingly, when laser-driven proton bunches were applied at 0.5 Hz, survival of the radioresistant HCT116 p53-/- cells equaled that of its radiosensitive counterpart, HCT116 WT, which was also similar to cells treated with the PARP1 inhibitor Olaparib. Altogether, these results suggest that the application modality of ultrashort bunches of particles could provide a great therapeutic potential in radiotherapy.

Clinical outcome of mild fetal ventriculomegaly.

OBJECTIVE: Our purpose was to evaluate the outcome of fetuses with mild cerebral ventriculomegaly. STUDY DESIGN: We prospectively collected all cases of mild cerebral ventriculomegaly (transverse diameter of the atrium of the cerebral lateral ventricles between 10 and 15 mm) diagnosed antenatally between January 1990 and December 1996. Associated ultrasonographic abnormalities including markers of aneuploidy, presence of chromosomal anomalies, structural malformations detected at birth, and neurologic outcome were recorded. Outcome information was available on all cases. In addition, published series of cases of fetal mild cerebral ventriculomegaly were reviewed to identify prognostic indicators. RESULTS: Eighty-two cases fulfilled the inclusion criteria: 48 were isolated and 34 were associated with other ultrasonographic markers or anomalies. Among the 45 surviving euploid isolated cases, neurologic follow-up was normal at a mean age of 28 months (range 3 to 72 months). Male fetuses and those with a transverse atrial size <12 mm had a good prognosis. Ventricular atria > or =12 mm were more often associated with other anomalies (56% vs 6%) and, when isolated, with abnormal postnatal neurodevelopment (23% vs 3%). Aneuploidy was present in two cases of isolated mild cerebral ventriculomegaly, both of which were associated with advanced maternal age, and in seven cases associated with other anomalies. CONCLUSIONS: Mild cerebral ventriculomegaly should prompt targeted ultrasonographic examination, inclusive of markers of aneuploidies, visualization of the corpus callosum, and echocardiogram as well as serologic evaluation for congenital infections. In isolated mild cerebral ventriculomegaly genetic counseling should take into account clinical, laboratory, and ultrasonographic findings. A review of the published series suggests that cognitive or motor delay is predominantly mild and that it occurs in about 9% of cases of isolated mild cerebral ventriculomegaly.

Amnioinfusion for prevention of pulmonary hypoplasia in second-trimester rupture of membranes.

We conducted a study to evaluate the feasibility and benefits of transabdominal amnioinfusion in preterm premature rupture of membranes with persistent oligohydramnios for the prevention of pulmonary hypoplasia. To this purpose, we designed a cohort study in which the pregnancy outcome of women with rupture of membranes at < or = 25 weeks and persistent (> or = 4 days) oligohydramnios managed with serial amnioinfusions (n = 18) was compared with that of a historic cohort group (controls) with similar characteristics but managed expectantly (n = 16). Pulmonary hypoplasia was diagnosed at birth in the presence of strict radiological and pathological criteria. No amnioinfusion-related complications occurred. The prevalence of pulmonary hypoplasia was significantly lower among the amnioinfused cases compared with the controls (46% [6 of 13] vs 86% [12 of 14], odds ratio [OR] = 0.4, 95% confidence interval [CI] 0.2-0.9), despite a lower gestational age at rupture of membranes in the treated group. Within the group undergoing amnioinfusions, those in which the infused solution was rapidly lost had a higher rate of pulmonary hypoplasia compared with those in which amnioinfusion alleviated oligohydramnios for > 48 hours (considered successful) (0 of 4 vs. 6 of 9, OR = 2.3, 95% CI 1-5.5). Cases of successful amnioinfusion had a longer interval between membrane rupture and appearance of oligohydramnios than those in which the procedure failed to correct oligohydramnios, even though both groups had similar gestational age at appearance of oligohydramnios. This suggests that the rate of loss of amniotic fluid after membrane rupture may predict the rate of loss of the infused solution, and therefore identify a subset of patients who may benefit from the procedure.

Natural history of uterine leiomyomas in pregnancy.

A prospective study was conducted over a 6 year period to determine the natural history of uterine leiomyomas in pregnancy. All pregnant women with myomas detected during obstetric ultrasonographic examination and with three or more sonographic examinations were included; 134 patients fulfilled the inclusion criteria. Sonograms were obtained at 2 week intervals until 20 weeks of gestation, and monthly thereafter. The following observations were made: (1) the majority of myomas 5 cm or less in average diameter could no longer be seen during pregnancy; (2) the majority of myomas greater than 5 cm in diameter tended to remain stable or decrease in size during pregnancy; and (3) multiple myomas were less likely to disappear than solitary myomas.

Risk factors for pulmonary hypoplasia in second-trimester premature rupture of membranes.

OBJECTIVE: Our purpose was to determine the independent contribution of gestational age at rupture of membranes, latency period, and severity of oligohydramnios to the prediction of pulmonary hypoplasia in patients with second-trimester premature rupture of membranes. STUDY DESIGN: All women with premature rupture of membranes at < 28 weeks diagnosed between January 1982 and December 1990 were managed conservatively with a consistent protocol until intrauterine death or spontaneous or induced delivery. The diagnosis of pulmonary hypoplasia was made by strict pathologic and radiographic criteria. RESULTS: A total of 63 patients fulfilled the inclusion criteria. Pulmonary hypoplasia was present in 15 cases: two of nine stillborns, 12 of 25 neonatal deaths, and one of 24 survivors. All fetuses with pulmonary hypoplasia had oligohydramnios. Univariate analysis showed that the occurrence of pulmonary hypoplasia was significantly associated with gestational age at premature rupture of membranes (p = 0.002), oligohydramnios during the latency period (p = 0.005), and duration of the latency period (p = 0.02). However, logistic regression analysis showed that only the first two variables were independent predictors of pulmonary hypoplasia. CONCLUSION: Gestational age at premature rupture of membranes and oligohydramnios are independent predictors of the occurrence of pulmonary hypoplasia.

Prognostic indicators in the prenatal diagnosis of agenesis of corpus callosum.

OBJECTIVE: Our aim was to determine the accuracy of ultrasonography in the prenatal diagnosis of agenesis of the corpus callosum and to establish whether ultrasonography can provide prognostic indicators in cases of agenesis of the corpus callosum. STUDY DESIGN: Prospective ultrasonographic study of the corpus callosum in all cases during an 8-year period in which fetal cerebral ventriculomegaly was detected. RESULTS: A total of 14 cases of agenesis of the corpus callosum are reported. In seven cases agencies of the corpus callosum was an isolated finding, and in seven cases it was associated with other abnormalities. Six cases involved mendelian syndromes (3 Lissencephaly syndrome, 2 Aicardi syndrome, and 1 Andermann syndrome), and one case was associated with trisomy 13. In 5 of 14 fetuses, all male, agenesis of the corpus callosum was an isolated benign finding. The corpus callosum could never be visualized before midgestation, but diagnosis of agenesis of the corpus callosum was very accurate after 20 weeks. CONCLUSION: Prenatal ultrasonographic findings suggestive of agenesis of the corpus callosum should be followed by a careful search for associated anomalies that may indicate genetic syndromes. Isolated agenesis of the corpus callosum is often an isolated, benign finding, particularly in male fetuses. In families at risk for mendelian syndromes associated with agenesis of the corpus callosum, lack of visualization of this structure is suggestive of the diagnosis.

Screening for congenital heart disease with the four-chamber view of the fetal heart.

OBJECTIVE: Our objective was to determine the efficacy of the four-chamber view of the fetal heart in routine ultrasonographic examination as a screening tool for congenital heart defects. STUDY DESIGN: A prospective cohort study compared the detection rate of congenital heart defects among 5336 pregnant women screened with the ultrasonographic four-chamber view of the fetal heart from 1987 through 1989 with that among 3680 patients examined ultrasonographically without the four-chamber view during the 2 preceding years (1985 through 1986). All patients were followed until delivery or termination of pregnancy, and clinical or autopsy confirmation of prenatal findings were obtained on all cases. RESULTS: The overall incidence of congenital heart diseases was 5.2 per 1000 (47/9016). During the years 1985 through 1986 15 neonates with congenital heart diseases were identified, seven of which were prenatally diagnosed (sensitivity 43%). During the period 1987 through 1989 a four-chamber view of the fetal heart was obtained in 95% of cases; 32 cases of congenital heart disease occurred, 26 of which were diagnosed antenatally (sensitivity 81%; p = 0.01). Two false-positive diagnoses were made during the second time period, giving a specificity of 99.9%. CONCLUSION: The four-chamber view of the fetal heart is easily obtained, does not significantly increase the duration of a routine ultrasonographic examination, and has an excellent sensitivity for the identification of congenital heart diseases.