Efficient all-electron hybrid density functionals for atomistic simulations beyond 10 000 atoms.

Hybrid density functional approximations (DFAs) offer compelling accuracy for ab initio electronic-structure simulations of molecules, nanosystems, and bulk materials, addressing some deficiencies of computationally cheaper, frequently used semilocal DFAs. However, the computational bottleneck of hybrid DFAs is the evaluation of the non-local exact exchange contribution, which is the limiting factor for the application of the method for large-scale simulations. In this work, we present a drastically optimized resolution-of-identity-based real-space implementation of the exact exchange evaluation for both non-periodic and periodic boundary conditions in the all-electron code FHI-aims, targeting high-performance central processing unit (CPU) compute clusters. The introduction of several new refined message passing interface (MPI) parallelization layers and shared memory arrays according to the MPI-3 standard were the key components of the optimization. We demonstrate significant improvements of memory and performance efficiency, scalability, and workload distribution, extending the reach of hybrid DFAs to simulation sizes beyond ten thousand atoms. In addition, we also compare the runtime performance of the PBE, HSE06, and PBE0 functionals. As a necessary byproduct of this work, other code parts in FHI-aims have been optimized as well, e.g., the computation of the Hartree potential and the evaluation of the force and stress components. We benchmark the performance and scaling of the hybrid DFA-based simulations for a broad range of chemical systems, including hybrid organic-inorganic perovskites, organic crystals, and ice crystals with up to 30 576 atoms (101 920 electrons described by 244 608 basis functions).

NECI: N-Electron Configuration Interaction with an emphasis on state-of-the-art stochastic methods.

We present NECI, a state-of-the-art implementation of the Full Configuration Interaction Quantum Monte Carlo (FCIQMC) algorithm, a method based on a stochastic application of the Hamiltonian matrix on a sparse sampling of the wave function. The program utilizes a very powerful parallelization and scales efficiently to more than 24 000 central processing unit cores. In this paper, we describe the core functionalities of NECI and its recent developments. This includes the capabilities to calculate ground and excited state energies, properties via the one- and two-body reduced density matrices, as well as spectral and Green's functions for ab initio and model systems. A number of enhancements of the bare FCIQMC algorithm are available within NECI, allowing us to use a partially deterministic formulation of the algorithm, working in a spin-adapted basis or supporting transcorrelated Hamiltonians. NECI supports the FCIDUMP file format for integrals, supplying a convenient interface to numerous quantum chemistry programs, and it is licensed under GPL-3.0.

Hypofractionated stereotactic radiotherapy of acoustic neuroma: volume changes and hearing results after 89-month median follow-up.

PURPOSE: The goal of this work was to evaluate toxicity and local control following hypofractionated stereotactic radiation treatment with special focus on changes in tumor volume and hearing capacity. PATIENTS AND METHODS: In all, 29 patients with unilateral acoustic neuroma were treated between 2001 and 2007 within a prospective radiation protocol (7 × 4 Gy ICRU dose). Median tumor volume was 0.9 ml. Follow-up started at 6 months and was repeated annually with MRI volumetry and audiometry. Hearing preservation was defined as preservation of Class A/B hearing according to the guidelines of the American Academy of Otolaryngology (1995). RESULTS: No patient had any intervention after a median imaging follow-up of 89.5 months, one patient showed radiological progression. Transient increase of tumor volume developed in 17/29 patients, whereas 22/29 patients (75.9%) presented with a volume reduction at last follow-up. A total of 21 patients were eligible for hearing evaluation. Mean pure tone average (PTA) deteriorated from 39.3 to 65.9 dB and mean speech discrimination score (SDS) dropped from 74.3 to 38.1%. The 5-year actuarial Class A/B hearing preservation rate was 50.0 ± 14.4%. CONCLUSION: Radiation increases only minimally, if at all, the hearing deterioration which emerges by observation alone. Presbyacusis is not responsible for this deterioration. Transient tumor enlargement is common. Today radiation of small- and medium-sized acoustic neuroma can be performed with different highly conformal techniques as fractionated treatment or single low-dose radiosurgery with equal results regarding tumor control, hearing preservation, and side effects. Hypofractionation is more comfortable for the patient than conventional regimens and represents a serious alternative to frameless radiosurgery.

IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: long term results of an ISIORT pooled analysis.

PURPOSE: Linac-based intraoperative radiotherapy with electrons (IOERT) was implemented to prevent local recurrences after breast conserving therapy (BCT) and was delivered as an intraoperative boost to the tumor bed prior to whole breast radiotherapy (WBI). A collaborative analysis has been performed by European ISIORT member institutions for long term evaluation of this strategy. MATERIAL AND METHODS: Until 10/2005, 1109 unselected patients of any risk group have been identified among seven centers using identical methods, sequencing and dosage for intra- and postoperative radiotherapy. A median IOERT dose of 10 Gy was applied (90% reference isodose), preceding WBI with 50-54 Gy (single doses 1.7-2 Gy). RESULTS: At a median follow up of 72.4 months (0.8-239), only 16 in-breast recurrences were observed, yielding a local tumor control rate of 99.2%. Relapses occurred 12.5-151 months after primary treatment. In multivariate analysis only grade 3 reached significance (p=0.031) to be predictive for local recurrence development. Taking into account patient age, annual in-breast recurrence rates amounted 0.64%, 0.34%, 0.21% and 0.16% in patients <40 years; 40-49 years; 50-59 years and ≥ 60 years, respectively. CONCLUSION: In all risk subgroups, a 10 Gy IOERT boost prior to WBI provided outstanding local control rates, comparing favourably to all trials with similar length of follow up.

Non-small cell lung cancer in stages I-IIIB: Long-term results of definitive radiotherapy with doses ≥ 80 Gy in standard fractionation.

PURPOSE: To investigate therapeutic outcome of dose escalation ≥ 80 Gy in nonresected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: 124 consecutive patients with histologically/cytologically proven NSCLC were enrolled. Tumor stage I, II, IIIA, and IIIB was diagnosed in 30, eight, 39, and 47 patients, respectively. 38 patients (31%) had weight loss > 5% during the 3 months before diagnosis. A median dose of 88.2 Gy (range 80.0-96.0 Gy), 69.3 Gy (63.0-88.0 Gy) and 56.7 Gy was applied to primary lesions, involved lymph nodes, and elective nodes (within a region of about 6 cm cranial to macroscopically involved nodes), respectively. Daily fractional ICRU doses of 2.0-2.2 Gy were delivered by the conformal target-splitting technique. 58 patients (47%) received induction chemotherapy, in median two cycles prior to radiotherapy. RESULTS: Median follow-up time of all patients was 19 months, of patients alive 72.4 months (69-121 months). The cumulative actual overall survival rate at 2 and 5 years amounts to 39% and 11.3%, respectively, resulting in a median overall survival time of 19.6 months. According to stages I, II, IIIA, and IIIB, the median overall survival times are 31.8, 31.4, 19.0, and 14.5 months, respectively. The locoregional tumor control rate at 2 years is 49%. Apart from one treatment-related death (pneumonitis), acute toxicity according to EORTC/RTOG scores was moderate: lung grade 2 (n = 7), grade 3 (n = 3); esophagus grade 1 (n = 11); heart grade 3 (n = 1, pericarditis). No late toxicity grade > 1 has been observed. CONCLUSION: Sequential, conventionally fractionated high-dose radiotherapy by conformal target splitting is well tolerated. The results for survival and locoregional tumor control seem to at least equalize the outcome of simultaneous chemoradiation approaches, which, at present, are considered "state of the art" for patients with nonresected NSCLC. A higher potential of radiation therapy might be reached by accelerated fractionation regimens.

Nonresected non-small-cell lung cancer in Stages I through IIIB: accelerated, twice-daily, high-dose radiotherapy--a prospective Phase I/II trial with long-term follow-up.

PURPOSE: Our purpose was to investigate the tolerability of accelerated, twice-daily, high-dose radiotherapy. The secondary endpoints were survival and locoregional tumor control. METHODS AND MATERIALS: Thirty consecutive patients with histologically/cytologically proven non-small-cell lung cancer were enrolled. Tumor Stage I, II, IIIA, and IIIB was found in 7, 3, 12, and 8 patients, respectively. We applied a median of 84.6 Gy (range, 75.6-90.0 Gy) to the primary tumors, 63.0 Gy (range, 59.4-72.0 Gy) to lymph nodes, and 45 Gy to nodes electively (within a region of about 6 cm cranial to macroscopically involved sites). Fractional doses of 1.8 Gy twice daily, with an interval of 11 hours, were given, resulting in a median treatment time of 35 days. In the majority of patients the conformal target-splitting technique was used. In 19 patients (63%) two cycles of induction chemotherapy were given. The median follow-up time of survivors is 72 months (range, 62-74 months). RESULTS: We found Grade 1, 2 and 3 acute esophageal toxicity in 11 patients (37%), 2 patients (7%), and 2 patients (7%), respectively. Grade 2 acute pneumonitis was seen in 2 patients (7%). No late toxicity greater than Grade 1 was observed. The actual overall survival rates at 2 and 5 years are 63% and 23%, respectively; the median overall survival, 27.7 months. In 9 patients a local failure occurred, 7 of them presenting initially with an atelectasis without availability of 18-fluorodeoxyglucose-positron emission tomography staging at that time. In 4 patients recurrence occurred regionally. CONCLUSIONS: This Phase I/II trial with long-term follow-up shows low toxicity with promising results for survival and locoregional tumor control.

Target splitting in radiation therapy for lung cancer: further developments and exemplary treatment plans.

BACKGROUND: Reporting further developments evolved since the first report about this conformal technique. METHODS: Technical progress focused on optimization of the quality assurance (QA) program, especially regarding the required work input; and on optimization of beam arrangements. RESULTS: Besides performing the regular QA program, additional time consuming dosimetric measurements and verifications no longer have to be accomplished.'Class solutions' of treatment plans for six patients with non-resected non-small cell lung cancer in locally advanced stages are presented. Target configurations comprise one central and five peripheral tumor sites with different topographic positions to hilus and mediastinum. The mean dose to the primary tumor is 81,9 Gy (range 79,2-90,0 Gy), to macroscopically involved nodes 61,2 Gy (range 55,8-63,0 Gy), to electively treated nodes 45,0 Gy. Treatments are performed twice daily, with fractional doses of 1,8 Gy at an interval of 11 hours. Median overall treatment time is 33 days. The set-up time at the linac does not exceed the average time for any other patient. CONCLUSION: Target splitting is a highly conformal and nonetheless non-expensive method with regard to linac and staff time. It enables secure accelerated high-dose treatments of patients with NSCLC.

Amphotericin B lozengers: prophylaxis for esophagitis in thoracic radiotherapy: a prospective study.

BACKGROUND AND PURPOSE: Esophagitis is an important side effect in thoracic radiotherapy, no preventive drug therapy has been established yet. The aim of the present study was to prospectively evaluate the effectiveness of prophylactic antimycotic treatment with amphotericin B lozengers. PATIENTS AND METHODS: 40 consecutive patients with high-dose thoracic radiotherapy for lung cancer were investigated in a nonrandomized study. 20 patients receiving a median maximal esophageal dose of 67 Gy (range 61-80 Gy) were treated with amphotericin B lozengers four times daily from day 8 to the end of radiotherapy. Another 20 patients with a lower median maximal esophageal dose of 60 Gy (range 51-67.5 Gy) constituted the control group. Length of the irradiated esophagus and dose-length indices were evaluated. Side effects were prospectively scored according to the RTOG/EORTC criteria. There was a trend toward higher esophageal volumes in the prophylaxis group; furthermore, patients in this group were older, had a worse median Karnofsky Index and had more often received induction chemotherapy. RESULTS: In the prophylaxis group, 15 patients remained free from esophagitis and five patients developed esophagitis grade 1. In the control group, four patients remained free from symptoms, 14 patients showed esophagitis grade 1 and two patients grade 2. The difference between the two groups was statistically significant (p < 0.05). The start of symptoms was delayed in the prophylaxis group in comparison to the control group: day 21 (median, range 14-44) and day 18 (median, range 10-32) respectively. Amphotericin B lozengers were tolerated without side effects by all patients. CONCLUSION: Prophylactic administration of amphotericin B lozengers seems to effectively prevent radiation-induced esophagitis.

A strategy for the use of image-guided radiotherapy (IGRT) on linear accelerators and its impact on treatment margins for prostate cancer patients.

BACKGROUND AND PURPOSE: In external beam radiotherapy of prostate cancer, the consideration of various systematic error types leads to wide treatment margins compromising normal tissue tolerance. We investigated if systematic set-up errors can be reduced by a set of initial image-guided radiotherapy (IGRT) sessions. PATIENTS AND METHODS: 27 patients received daily IGRT resulting in a set of 882 cone-beam computed tomographies (CBCTs). After matching to bony structures, we analyzed the dimensions of remaining systematic errors from zero up to six initial IGRT sessions and aimed at a restriction of daily IGRT for 10% of all patients. For threshold definition, we determined the standard deviations (SD) of the shift corrections and selected patients out of this range for daily image guidance. To calculate total treatment margins, we demanded for a cumulative clinical target volume (CTV) coverage of at least 95% of the specified dose in 90% of all patients. RESULTS: The gain of accuracy was largest during the first three IGRTs. In order to match precision and workload criteria, thresholds for the SD of the corrections of 3.5 mm, 2.0 mm and 4.5 mm in the left-right (L-R), cranial-caudal (C-C), and anterior-posterior (A-P) direction, respectively, were identified. Including all other error types, the total margins added to the CTV amounted to 8.6 mm in L-R, 10.4 mm in C-C, and 14.4 mm in A-P direction. CONCLUSION: Only initially performed IGRT might be helpful for eliminating gross systematic errors especially after virtual simulation. However, even with daily IGRT performance, a substantial PTV margin reduction is only achievable by matching internal markers instead of bony anatomical structures.

"Augmented reality" in conventional simulation by projection of 3-D structures into 2-D images: a comparison with virtual methods.

BACKGROUND AND PURPOSE: In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time. PATIENTS AND METHODS: Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters. RESULTS: Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66). CONCLUSION: The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.

Concepts and techniques of intraoperative radiotherapy (IORT) for breast cancer.

The standard treatment for early breast cancer comprises wide local excision, sentinel lymph node biopsy or axillary lymph node dissection, adjuvant medical treatment and radiotherapy to the whole breast. Many studies suggest that local control plays a crucial role in overall survival. The local recurrence rate is estimated to be 1% per year and varies between 4 and 7% after 5 years and up to 10 to 20% in the long-term follow up. On the basis of low local recurrence rates the concept of whole breast irradiation comes up for discussion, and partial breast irradiation (PBI) is increasingly under consideration. Intraoperative radiotherapy (IORT) is referred to as the delivery of a single high dose of irradiation directly to the tumor bed (confined target) during surgery. PBI (limited field radiation therapy, accelerated partial breast irradiation APBI) is the irradiation exclusively confined to a breast volume, the tumor surrounding tissue (tumor bed) either during surgery or after surgery without whole breast irradiation. Various methods and techniques for IORT or PBI are under investigation. The advantage of a very short radiation time or the integration of the complete radiation treatment into the surgical procedure convinces at a first glance. The promising short-term results of those studies must not fail to mention that local recurrence rates could probably increase and furthermore give rise to distant metastases and a reduction in overall survival. The combination of IORT in boost modality and whole breast irradiation has the ability to reduce local recurrence rates. The EBCTCG overview approves that differences in local treatment that substantially affect local recurrence rates would avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.

A dosimetric comparison of IORT techniques in limited-stage breast cancer.

BACKGROUND AND PURPOSE: For intraoperative radiotherapy (IORT) during breast-conserving treatment four different techniques have been addressed: interstitial brachytherapy, an inflatable balloon with a central high-dose-rate source (MammoSite), a miniature orthovolt system (Intrabeam), and linac-based electron radiotherapy (IOERT). The dosimetric properties of these methods are compared. MATERIAL AND METHODS: Planning target volumes (PTVs) of the same size but of different shapes are assumed, corresponding to the technique's specific situs. Dose distributions for the PTVs and for surrounding tissues are demonstrated by dose-volume histograms and a list of physical parameters. A dose inhomogeneity index (DII) is introduced to describe the deviation of a delivered from the prescribed dose, reaching its minimal value 0 in case of perfect homogeneity. RESULTS: In terms of DII, IOERT reaches the lowest value followed by the MammoSite, the Intrabeam and interstitial implants. The surrounding tissues receive the smallest average dose with IOERT, closely followed by the orthovolt system. CONCLUSION: When comparing simplified geometric figures, IOERT delivers the most homogeneous dose distributions. However, in clinical reality PTVs often present asymmetric shapes instead of ideal geometries. Due to a strictly centric dose fall-off, any system with a round central applicator will have technical limits. During IOERT margin-directed applicator guidance is possible and interstitial brachytherapy allows for polygonal dose shaping. These techniques seem to be superior for asymmetric PTV irradiation.