Outbreak of 2009 pandemic influenza A(H1N1), Los Lagos, Chile, April-June 2009.

On 17 May 2009, the first two cases of 2009 pandemic influenza A(H1N1) were confirmed in the Metropolitan region (Santiago, Chile). On 6 June 2009, Chile reported 500 confirmed cases, seven severe and two fatal. Because six of the severe cases and the two deaths occurred in the region of Los Lagos in southern Chile, a retrospective study was conducted using data on emergency room visits as well as laboratory viral surveillance, during the period from 1 April to 31 May, in order to establish the date of the beginning of the outbreak. From 1 to 27 June, data were collected in real time, to establish the real magnitude of the outbreak, describe its transmission, clinical severity and secondary attack rates. Confirmed cases, their household contacts and healthcare workers were interviewed. This analysis showed that the outbreak in Los Lagos started on 28 April. By 27 June, a total of 14.559 clinical cases were identified, affecting mostly 5-19 year-olds. The effective reproduction number during the initial phase (20 days) was 1.8 (1.6-2.0). Of the 190 confirmed cases with severe acute respiratory infection, 71 (37.4%) presented a risk condition or underlying illness.

Prolonged fecal shedding of Shiga toxin-producing Escherichia coli among children attending day-care centers in Argentina.

In this report we describe the detection and duration of fecal shedding of Shiga toxin-producing Escherichia coil (STEC) O157 and non-O157 in symptomatic and asymptomatic cases during four events occurred among children in day-care centers in Argentina. In each event, the cases were identified among children, family contacts and staff members of the Institution. The isolates were characterized by pheno-genotyping and subtyping methods. The STEC fecal shedding was prolonged and intermittent. Strains O157:H7 (1st event); O26:H11 (2nd event); O26:H11 (3rd event) and O145:NM (4th event) were shed during 23-30, 37, 31 and 19 days, respectively. Considering the possibility of STEC intermittent long-term shedding, symptomatic and asymptomatic individuals should be excluded from the Institution until two consecutive stool cultures obtained at least 48 h apart, test negative.

On the feasibility of water calorimetry with scanned proton radiation.

Water calorimetry is considered to be the most direct primary method to realize the physical quantity gray for absorbed dose to water. The Swiss Federal Office of Metrology and Accreditation (METAS) has routinely operated a water calorimeter as primary standard for photon radiation since 2001. Nowadays, cancer therapy with proton radiation has become increasingly important and is a well established method. In the framework of the ProScan project conducted by the Paul Scherrer Institute (PSI), the spot-scanning technique is prepared for the subsequent application in hospitals, and adjusted to the recent findings of clinical research. In the absence of primary standards for proton radiation, the metrological traceability is assured by calibrating secondary standards in 60Co radiation and correcting with calculated beam quality correction factors. It is internationally recognized that the development of primary standards for proton radiation is highly desirable. In a common project of PSI and METAS, it is investigated whether a modified version of the water calorimeter in operation at METAS is suitable as primary standard for scanned proton radiation. A feasibility study has been conducted to investigate the linear energy transfer (LET) dependence of the heat defect and the influence of the time and space structure of the scanned beam on the homogeneity and stability of the temperature field in the water calorimeter. Simulations are validated against experimental data of the existing calorimeter used with photon radiation and extended to scanned proton radiation.

Monte Carlo dose calculations for spot scanned proton therapy.

Density heterogeneities can have a profound effect on dose distributions for proton therapy. Although analytical calculations in homogeneous media are relatively straightforward, the modelling of the propagation of the beam through density heterogeneities can be more problematical. At the Paul Scherrer Institute, an in-house dedicated Monte Carlo (MC) code has been used for over a decade to assess the possible deficiencies of the analytical calculations in patient geometries. The MC code has been optimized for speed, and as such traces primary protons only through the treatment nozzle and patient's CT. Contributions from nuclear interactions are modelled analytically with no tracing of secondary particles. The MC code has been verified against measured data in water and experimental proton radiographs through a heterogeneous anthropomorphic phantom. In comparison to the analytical calculation, the MC code has been applied to both spot scanned and intensity modulated proton therapy plans, and to a number of cases containing titanium metal implants. In summary, MC-based dose calculations could provide an invaluable tool for independently verifying the calculated dose distribution within a patient geometry as part of a comprehensive quality assurance protocol for proton treatment plans.

Experimental characterization and physical modelling of the dose distribution of scanned proton pencil beams.

In this paper we present the pencil beam dose model used for treatment planning at the PSI proton gantry, the only system presently applying proton therapy with a beam scanning technique. The scope of the paper is to give a general overview on the various components of the dose model, on the related measurements and on the practical parametrization of the results. The physical model estimates from first physical principles absolute dose normalized to the number of incident protons. The proton beam flux is measured in practice by plane-parallel ionization chambers (ICs) normalized to protons via Faraday-cup measurements. It is therefore possible to predict and deliver absolute dose directly from this model without other means. The dose predicted in this way agrees very well with the results obtained with ICs calibrated in a cobalt beam. Emphasis is given in this paper to the characterization of nuclear interaction effects, which play a significant role in the model and are the major source of uncertainty in the direct estimation of the absolute dose. Nuclear interactions attenuate the primary proton flux, they modify the shape of the depth-dose curve and produce a faint beam halo of secondary dose around the primary proton pencil beam in water. A very simple beam halo model has been developed and used at PSI to eliminate the systematic dependences of the dose observed as a function of the size of the target volume. We show typical results for the relative (using a CCD system) and absolute (using calibrated ICs) dosimetry, routinely applied for the verification of patient plans. With the dose model including the nuclear beam halo we can predict quite precisely the dose directly from treatment planning without renormalization measurements, independently of the dose, shape and size of the dose fields. This applies also to the complex non-homogeneous dose distributions required for the delivery of range-intensity-modulated proton therapy, a novel therapy technique developed at PSI.

[Relationship between aortic arch shape and blood pressure response after coarctation repair]. / Relation entre l'architecture de la crosse aortique et la pression artérielle après cure de coarctation.

The mechanisms of secondary hypertension after repair of coarctation of the aorta are not well understood. Abnormalities of the architecture of the aortic arch and their consequences on blood pressure have not been studied. In order to study the relationship between abnormalities or aortic arch architecture and resting blood pressure ninety-four patients without re-coarctation were followed up prospectively from 1997 to 2004 (mean age 16.9 +/- 8.1 years; mean weight 57.5 +/- 18.3 Kg; interval since surgery 16.3 +/- 5.4 years). All underwent MRI angiography of the thoracic aorta which enabled the abnormalities to be classified in 3 groups: gothic arch, crenellated arch and roman arch. Twenty-four patients (25.5%) were hypertensive and 70 (74.4%) normotensive. There were 40 gothic arches (42.5%). 14 crenellated arches (15%) and 40 roman arches (42.5%). Gothic arches were more commonly observed in the hypertensive patients (18/40, [45%, 95% CI 31-62]) than the crenellated arches (4/14, [28.5%, 95% CI 7-48]) or the roman arches (2/40, [5%, 95% CI 2-12]). Only the gothic arch was independently correlated with hypertension on multivariate analysis. The authors conclude that gothic deformation of the aortic arch is an independent predictive factor of hypertension in patients operated for coarctation with an excellent result on the isthmic region. Patients with a gothic appearance of their aortic arch should be followed up closely.

An intercomparison of two dynamic treatment techniques, ring scan and spot scan, for head and neck tumors with the Piotron.

An evaluation of the ring scan and the spot scan was made for the pion irradiation of head and neck tumors with the Piotron. For the geometry of the Piotron, with its 60 radially converging beams, two scanning techniques have been developed, ring scan and spot scan. They have different characteristics concerning achievable dose distributions and sensitivity to tissue inhomogenities. The optimized 3-dimensional dose distributions for the treatment with ring scan and spot scan techniques were calculated for two examples of the target volume. The comparison of the dose distributions has shown that the ring scan is better in sparing normal tissues than the spot scan for a simple shape target volume but not for an irregular shape target volume with the present status of the technique. The irradiation time needed for the ring scan is longer, for the present examples three times, than for the spot scan. From the practical view point the spot scan is preferable to the ring scan for the treatment of head and neck tumors with the Piotron.

Conformal radiotherapy for unresectable retroperitoneal soft tissue sarcoma.

Local tumor control remains a continuing challenge in the treatment of retroperitoneal soft tissue sarcoma. Though complete resection by means of wide excision or excisional biopsy can be performed in a minority of patients only, aggressive surgical approach remains the treatment of choice. Unresectable sarcoma can rarely be controlled by conventionally applied radiotherapy--only a few percent of patients survive. A superior dose distribution of external radiation is demanded in order to spare healthy tissue. The presumably greatest advantage will occur when radiotherapy is used preoperatively. The possible clinical gain of superior dose distribution is demonstrated by results of the dynamic, 3-D conformal pion radiotherapy at PSI. Between April 1983 and June 1988 a total of 21 patients were treated with high doses (greater than or equal to 30 Gy) for unresectable retroperitoneal soft tissue sarcoma. The follow-up time is 13-74 months, median 24. Fifteen patients were treated with 20 fx, and 19 patients were treated with fraction sizes of 150 or 165 cGy. Except for one patient with thrombocytopenia after chemotherapy, no treatment interruption was necessary. Five patients developed late reactions, caused also by surgery and chemotherapy: two intestinal obstructions, one liver abscess, one leg edema, and one superficial skin necrosis. Nine patients had laparotomy after pion irradiation, five for resection of the previous unresectable tumor; 3/5 sarcoma were completely resected. Morbidity rate after post-pion laparotomy did not increase. Three patients had local tumor progression, 1/3 inside the treatment volume. The actuarial five-year local tumor control rate of these unresectable retroperitoneal sarcoma is 60%, the actuarial five-year survival rate is 33%. Out of the 21 patients, 15 are alive, two have died from local progression, one from peritoneal progression, and three from metastases.

The Piotron: II. Methods and initial results of dynamic pion therapy in phase II studies.

Negative pi-meson (pion) therapy employing dynamic scanning with a focused spot of convergent beams has been in use since 1981 at SIN. Three-dimensional conformation of the treatment volume to the target volume can thus be achieved. Following previously reported Phase I and Ib clinical trials, a Phase II trial was initiated with the goal of treating primary deep-seated tumors in a dose optimization schedule which included stepwise increase of total pion dose and of target volume. Patients with multicentric superficial bladder tumors who were cystectomy candidates were initially selected. Since then, more invasive cases have been treated. A graded scoring of acute tissue reactions was employed. Follow-up periods were from 10 to 20 months. The pion dose escalation ranged from 3000 rad (minimum) to 3600 rad (minimum) in 20 fractions over 5 weeks. The treatment volumes encompassed 190 cc for local to 1,820 cc for extended volume therapy. Treatment reactions ranged from a faint erythema and increase of bladder frequency to dry desquamation, mild nausea, moderate dysuria, and moderate proctitis or diarrhea with mucus. These reactions were closely related to treatment volume and site. One severe late cystitis has occurred in a patient treated with 2 courses of pions (4475 rad). Mild to moderate late proctitis has been seen in 4 patients. Ten of 13 bladder cancer patients had local control of disease while all 3 pancreas or biliary tract cancer patients had microscopic residual disease locally at time of death from metastasis. A total of 11 of 17 patients are thus clinically or pathologically free of local tumor to time of last observation.

The PIOTRON: initial performance, preparation and experience with pion therapy.

The PIOTRON is a large solid angle superconducting channel built for the use of negative pi-mesons in radiotherapy. The pions are produced by protons of 590 MeV striking a target of molybdenum or beryllium. The pions are divided into 60 channels and deflected twice to enter the treatment volume radially. The momentum and the momentum band for all 60 channels can be chosen and the beam spot of Bragg peak pions at the isocenter of the applicator is a few centimeters in each direction. Dynamic scanning can thus achieve 3-dimensionally shaped treatment volumes. Two different methods are available: the ring scan, using changes of pion range; and the spot scan, involving translation of the patient through the fixed beam spot. Dose distributions of individual and multiple beams were plotted in a cylindrical water phantom. Radiobiological experiments with mammalian cells in gel and with mouse feet were performed. A special beam geometry using a sector of 15 beams was selected for the first treatments of patients with metastatic skin nodules. Six patients were treated. Acute skin reactions were scored and compared with those from orthovoltage therapy with comparable beam geometry. The RBE for 10 fractions is between 1.4 and 1.5. The next step involved treatment of patients inside water-bolus rings in preparation for dynamic therapy. Patients were then treated with the spot scan dynamic mode in the water bolus. The initial responses and reactions are favorable and confirm the feasibility and accuracy of dynamic pion therapy.

Dynamic pion irradiation of unresectable soft tissue sarcomas.

Since November 1981, when pion irradiation was introduced for deep seated tumors at the Swiss Institute for Nuclear Research (SIN, now Paul Scherrer Institute, PSI) a dynamic, 3-dimensional spot scan treatment technique has been in use. To exploit this technique a special optimization treatment planning system has been designed. Of a total of 331 patients treated with pions from November 1981-December 1987, 35 were irradiated for unresectable soft tissue sarcomas. In 32/35 patients, tumor sites were retroperitoneal, pelvic or in the groin or thigh. Twenty-nine tumors had a maximum diameter of greater than 10 cm, 18 tumors of greater than 15 cm; 30 tumors had grade 2/3 and 32 Stage III B/IV A/IV B. Eight of 35 patients received a low pion total dose, 7-27 Gy. Twenty-seven patients received a total dose of 30-36 Gy, fraction size 150-170 cGy (90%-isodose), 20 fractions, 4 times per week. Of these 27 patients, severe late reactions appeared in five: 2/8 patients with extremity/groin sarcomas (1/2 caused by biopsy) and 3/19 patients with retroperitoneal/pelvic sarcomas (one a skin reaction after Actinomycin-D, one a small bowel reaction after 36 Gy, a dose no longer used). Seven of 27 patients had metastases at the beginning of irradiation. Three of 27 were treated with excisional biopsy, 9 with incisional biopsy or partial resection and in 15 patients biopsies were performed for histology only. The median follow-up of these 27 patients was 17 months (5-66). There was no progression in eight extremity/groin tumors but in 4 of 19 retroperitoneal/pelvic tumors. Three of these were marginal progressions. The actuarial 5-year rate of local tumor control is 64%; the actuarial 5-year survival rate of patients without metastases at the beginning of treatment is 58%. Dynamic spot scan pion irradiation proves to be a successful treatment technique for unresectable sarcomas with a high rate of tumor control and a very low rate of severe late reactions.

Proton dosimetry intercomparison based on the ICRU report 59 protocol.

BACKGROUND AND PURPOSE: A new protocol for calibration of proton beams was established by the ICRU in report 59 on proton dosimetry. In this paper we report the results of an international proton dosimetry intercomparison, which was held at Loma Linda University Medical Center. The goals of the intercomparison were, first, to estimate the level of consistency in absorbed dose delivered to patients if proton beams at various clinics were calibrated with the new ICRU protocol, and second, to evaluate the differences in absorbed dose determination due to differences in 60Co-based ionization chamber calibration factors. MATERIALS AND METHODS: Eleven institutions participated in the intercomparison. Measurements were performed in a polystyrene phantom at a depth of 10.27 cm water equivalent thickness in a 6-cm modulated proton beam with an accelerator energy of 155 MeV and an incident energy of approximately 135 MeV. Most participants used ionization chambers calibrated in terms of exposure or air kerma. Four ionization chambers had 60Co-based calibration in terms of absorbed dose-to-water. Two chambers were calibrated in a 60Co beam at the NIST both in terms of air kerma and absorbed dose-to-water to provide a comparison of ionization chambers with different calibrations. RESULTS: The intercomparison showed that use of the ICRU report 59 protocol would result in absorbed doses being delivered to patients at their participating institutions to within +/-0.9% (one standard deviation). The maximum difference between doses determined by the participants was found to be 2.9%. Differences between proton doses derived from the measurements with ionization chambers with N(K)-, or N(W) - calibration type depended on chamber type. CONCLUSIONS: Using ionization chambers with 60Co calibration factors traceable to standard laboratories and the ICRU report 59 protocol, a distribution of stated proton absorbed dose is achieved with a difference less than 3%. The ICRU protocol should be adopted for clinical proton beam calibration. A comparison of proton doses derived from measurements with different chambers indicates that the difference in results cannot be explained only by differences in 60Co calibration factors.

Proton radiography as a tool for quality control in proton therapy.

Proton radiography is investigated for its use as a quality control tool in proton therapy. Images were produced both with range and range uncertainty information of protons passing through phantoms (Alderson phantom and a sheep's head). With the range images the correct positioning of the patient with respect to the beam could be verified. The range uncertainty images were used to quantitatively detect range variations of protons passing through inhomogeneities in the patient. These measurements can be used to indicate critical situations during proton therapy or to determine the safety margin around the tumor volume. With the range information the precision of different calibrations of computer tomography Hounsfield values to relative proton stopping power, used for proton treatment planning, was determined. It is found that the precision in range can be improved by a detailed analysis of the calibration data obtained from tissue-substitute measurements, by a factor of 2.5. The resulting range errors are in the order of the positioning precision (approximately 1 mm).

Multiple Coulomb scattering and spatial resolution in proton radiography.

A simple formula for the spatial resolution of transmission proton radiography is derived for two different methods of measuring the proton coordinates. The effect of multiple Coulomb scattering and energy loss are taken into account. Experimental measurements of the spatial resolution have been done and are compared with the calculations. The technique of measuring entrance and exit coordinates in coincidence for each single proton improves the spatial resolution by a factor of 8 compared to a single coordinate measurement.

A technique for calculating range spectra of charged particle beams distal to thick inhomogeneities.

A method was developed for calculating range spectra of charged particles after passing through an inhomogeneous structure whose thickness was comparable to the range of the incident particles. It was shown that the spectra are strongly affected by the influence of multiple Coulomb scattering at interfaces parallel to the beam direction of two media with different relative stopping power. The calculations are in agreement with Monte Carlo simulations. The degraded Bragg peak was calculated on the basis of the computed range spectra behind the inhomogeneity interface. The method can be included into charged particle treatment planning systems where broad pencil beams are used to predict the deteriorated Bragg peak behind inhomogeneity interfaces more precisely.

Performance of a fluorescent screen and CCD camera as a two-dimensional dosimetry system for dynamic treatment techniques.

A two-dimensionally position sensitive dosimetry system has been tested for different dosimetric applications in a radiation therapy facility with a scanning proton beam. The system consists of a scintillating (fluorescent) screen, mounted at the beam-exit side of a phantom and it is observed by a charge coupled device (CCD) camera. The observed light distribution at the screen is equivalent to the two-dimensional (2D)-dose distribution at the screen position. It has been found that the dosimetric properties of the system, measured in a scanning proton beam, are equal to those measured in a proton beam broadened by a scattering system. Measurements of the transversal dose distribution of a single pencil beam are consistent with dose measurements as well as with dose calculations in clinically relevant fields made with multiple pencil beams. Measurements of inhomogeneous dose distributions have shown to be of sufficient accuracy to be suitable for the verification of dose calculation algorithms. The good sensitivity and sub-mm spatial resolution of the system allows for the detection of deviations of a few percent in dose from the expected (intended or calculated) dose distribution. Its dosimetric properties and the immediate availability of the data make this device a useful tool in the quality control of scanning proton beams.

The 200-MeV proton therapy project at the Paul Scherrer Institute: conceptual design and practical realization.

The new proton therapy facility is being assembled at the Paul Scherrer Institute (PSI). The beam delivered by the PSI sector cyclotron can be split and brought into a new hall where it is degraded from 590 MeV down to an energy in the range of 85-270 MeV. A new beam line following the degrader is used to clean the low-energetic beam in phase space and momentum band. The analyzed beam is then injected into a compact isocentric gantry, where it is applied to the patient using a new dynamic treatment modality, the so-called spot-scanning technique. This technique will permit full three-dimensional conformation of the dose to the target volume to be realized in a routine way without the need for individualized patient hardware like collimators and compensators. By combining the scanning of the focused pencil beam within the beam optics of the gantry and by mounting the patient table eccentrically on the gantry, the diameter of the rotating structure has been reduced to only 4 m. In the article the degrees of freedom available on the gantry to apply the beam to the patient (with two rotations for head treatments) are also discussed. The devices for the positioning of the patient on the gantry (x rays and proton radiography) and outside the treatment room (the patient transporter system and the modified mechanics of the computer tomograph unit) are briefly presented. The status of the facility and first experimental results are introduced for later reference.

Intensity modulated proton therapy: a clinical example.

In this paper, we report on the clinical application of fully automated three-dimensional intensity modulated proton therapy, as applied to a 34-year-old patient presenting with a thoracic chordoma. Due to the anatomically challenging position of the lesion, a three-field technique was adopted in which fields incident through the lungs and heart, as well as beams directed directly at the spinal cord, could be avoided. A homogeneous target dose and sparing of the spinal cord was achieved through field patching and computer optimization of the 3D fluence of each field. Sensitivity of the resultant plan to delivery and calculational errors was determined through both the assessment of the potential effects of range and patient setup errors, and by the application of Monte Carlo dose calculation methods. Ionization chamber profile measurements and 2D dosimetry using a scintillator/CCD camera arrangement were performed to verify the calculated fields in water. Modeling of a 10% overshoot of proton range showed that the maximum dose to the spinal cord remained unchanged, but setup error analysis showed that dose homogeneity in the target volume could be sensitive to offsets in the AP direction. No significant difference between the MC and analytic dose calculations was found and the measured dosimetry for all fields was accurate to 3% for all measured points. Over the course of the treatment, a setup accuracy of +/-4 mm (2 s.d.) could be achieved, with a mean offset in the AP direction of 0.1 mm. Inhalation/exhalation CT scans indicated that organ motion in the region of the target volume was negligible. We conclude that 3D IMPT plans can be applied clinically and safely without modification to our existing delivery system. However, analysis of the calculated intensity matrices should be performed to assess the practicality, or otherwise, of the plan.

The precision of proton range calculations in proton radiotherapy treatment planning: experimental verification of the relation between CT-HU and proton stopping power.

The precision in proton radiotherapy treatment planning depends on the accuracy of the information used to calculate the stopping power properties of the tissues in the patient's body. This information is obtained from computed tomography (CT) images using a calibration curve to convert CT Hounsfield units into relative proton stopping power values. The validity of a stoichiometric method to create the calibration curve has been verified by measuring pairs of Hounsfield units and stopping power values for animal tissue samples. It was found that the agreement between measurement and calibration curve is better than 1% if beam hardening effects in the acquisition of the CT images can be neglected. The influence of beam hardening effects on the quantitative reading of the CT measurements is discussed and an estimation for the overall range precision of proton beams is given. It is expected that the range of protons in the human body can be controlled to better than +/-1.1% of the water equivalent range in soft tissue and +/-1.8% in bone, which translates into a range precision of about 1-3 mm in typical treatment situations.

Dose calculation models for proton treatment planning using a dynamic beam delivery system: an attempt to include density heterogeneity effects in the analytical dose calculation.

The gantry for proton radiotherapy at the Paul Scherrer Institute (PSI) is designed specifically for the spot-scanning technique. Use of this technique to its full potential requires dose calculation algorithms which are capable of precisely simulating each scanned beam individually. Different specialized analytical dose calculations have been developed, which attempt to model the effects of density heterogeneities in the patient's body on the dose. Their accuracy has been evaluated by a comparison with Monte Carlo calculated dose distributions in the case of a simple geometrical density interface parallel to the beam and typical anatomical situations. A specialized ray casting model which takes range dilution effects (broadening of the spectrum of proton ranges) into account has been found to produce results of good accuracy. This algorithm can easily be implemented in the iterative optimization procedure used for the calculation of the optimal contribution of each individual scanned pencil beam. In most cases an elemental pencil beam dose calculation has been found to be most accurate. Due to the long computing time, this model is currently used only after the optimization procedure as an alternative method of calculating the dose.