Prognosis versus Actual Outcomes in Stereotactic Radiosurgery of Brain Metastases: Reliability of Common Prognostic Parameters and Indices.

This study aims to evaluate the clinical outcome of stereotactic radiosurgery as the sole treatment for brain metastases and to assess prognostic factors influencing survival. A total of 108 consecutive patients with 213 metastases were retrospectively analyzed. Treatment was determined with close-meshed MRI follow-up. Various prognostic factors were assessed, and several prognostic indices were compared regarding their reliability to estimate overall survival. Median overall survival was 15 months; one-year overall survival was 50.5%. Both one- and two-year local controls were 90.9%. The rate of new metastases after SRS was 49.1%. Multivariate analysis of prognostic factors revealed that the presence of extracranial metastases, male sex, lower KPI, and progressive extracranial disease were significant risk factors for decreased survival. Of all evaluated prognostic indices, the Basic Score for Brain Metastases (BSBMs) showed the best correlation with overall survival. A substantial survival advantage was found for female patients after SRS when compared to male patients (18 versus 9 months, p = 0.003). SRS of brain metastasis is a safe and effective treatment option when frequent monitoring for new metastases with MRI is performed. Common prognostic scores lack reliable estimation of survival times. Female sex should be considered as an additional independent positive prognostic factor influencing survival.

Survival, Treatment Outcome, and Safety of Multiple and Repeated Courses of Stereotactic Body Radiotherapy for Pulmonary Oligometastases of Head and Neck Squamous Cell Carcinoma.

Current literature regarding survival and treatment outcome of SBRT in patients with pulmonary oligometastatic head and neck squamous cell carcinoma (HNSCC) is limited. Additionally, most of the published studies include metastatic lesions deriving also from primaries with histologies other than SCC when investigating the outcome of SBRT. The aim of the present retrospective study is to explore local control (LC) of treated metastases, progression-free survival (PFS), and overall survival (OS) of exclusively pulmonary oligometastatic HNSCC-patients treated with SBRT. Between 2006 and 2021, a total of 46 patients were treated with SBRT for a maximum of four pulmonary oligometastases (PM) concurrently (mean PM per patient = 2.0; range 1 to 6 PM, total of 92). Of these, 17 patients (37.0%) developed new pulmonary metastases after their first SBRT. Repeated courses of SBRT were required once in 15 patients (88.2%) and twice in 2 patients (11.8%). Median follow-up was 17 months (range, 0-109 months). One year after completion of SBRT, LC rate, PFS, and OS were 98.7%, 37.9%, and 79.5%, respectively. After two years, LC rate, PFS, and OS were 98.7%, 28.7%, and 54.9%; as well as 98.7%, 16.7%, and 31.0% after five years. Radiochemotherapy (HR 2.72, p < 0.001) or radiotherapy as primary treatment (HR 8.60; p = 0.003), as well as reduced patient performance status (HR 48.30, p = 0.002), were associated with lower PFS. Inferior OS correlated with poor performance status (HR 198.51, p < 0.001) and surgery followed by radiochemotherapy (HR 4.18, p = 0.032) as primary treatment, as well as radiotherapy alone (HR 7.11, p = 0.020). Treatment of more than one PM is an independent predictor of impaired OS (HR 3.30, p = 0.016). SBRT of HNSCC-derived PMs results in excellent LC rates and encouraging OS rates of 54.9% at two years along with good tolerability (no more than grade 2 toxicities). Favourable outcome and low toxicity also apply to repeated courses of SBRT of newly emerging PMs.

Chemoradiotherapy Combined with Brachytherapy for the Definitive Treatment of Esophageal Carcinoma.

This study aims to investigate the effect of dose escalation with brachytherapy (BT) as an addition to definitive chemoradiotherapy (CRT) on local control and survival in esophageal cancer. From 2001 to 2020, 183 patients with locally limited or locally advanced esophageal cancer received definitive CRT with or without brachytherapy in a two-center study. External-beam radiotherapy was delivered at 50.4 Gy in 1.8 Gy daily fractions, followed by a sequential boost to the primary tumor of 9 Gy in 1.8 Gy daily fractions if indicated. Intraluminal high dose rate (HDR) Ir-192 brachytherapy was performed on 71 patients at 10 Gy in two fractions, with one fraction per week. The combined systemic therapy schedules used included 5-fluorouracil/cisplatin or 5-fluorouracil alone. Cisplatin was not administered in patients receiving brachytherapy. The median local progression-free survival was significantly extended in the BT group (18.7 vs. 6.0 months; p < 0.0001), and the median local control was also significantly prolonged (30.5 vs. 11.3 months, p = 0.008). Overall survival (OS) significantly increased in the BT group (median OS 22.7 vs. 9.1 months, p < 0.0001). No significant difference in the overall rate of acute toxicities was observed; however, the rate of acute esophagitis was significantly higher in the BT group (94.4% vs. 81.2%). Likewise, the overall rate of late toxicities (43.7% vs. 18.8%) was significantly higher in the BT group, including the rate of esophageal stenosis (22.5% vs. 9.8%). There was no difference in the occurrence of life-threatening or lethal late toxicities (grades 4 and 5). Brachytherapy, after chemoradiation with single-agent 5-FU, represents a safe and effective alternative for dose escalation in the definitive treatment of esophageal cancer.

Dynamic intrafractional position monitoring with implanted fiducial markers for enhanced accuracy in radiotherapy of prostate cancer.

INTRODUCTION: Recent advances in the radiation therapy of prostate cancer have brought a shift toward moderate- and ultra-hypofractionated treatment schedules. Reducing safety margins can broaden the therapeutic window in stereotactic treatments and alleviate concerns for toxicity in high dose-per-fraction treatment schedules. Management of intrafractional motion is a necessity for stereotactic body radiation therapy (SBRT). It can be achieved by performing intrafractional image guidance and position corrections. We evaluate the suitability of such a novel prostate motion management system and its potential benefit for treatment accuracy. METHODS: Intrafractional IGRT was performed for 22 patients during 149 treatment sessions using repeated orthogonal kV-XR imaging of implanted fiducial markers with the ExacTrac Dynamic (EXTD) system. Position measurements were taken four times during each arc of the applied volumetric modulated arc therapy (VMAT). Position correction was performed if translational deviation exceeded 2 mm in any direction. RESULTS: Of 677 single EXTD measurements, 20.6% exceeded the predefined threshold of 2 mm 3D deviation. Without intrafractional corrections, 39.4% of all individual measurements would exceed the threshold. The 3D accuracy could thus significantly be improved, reducing mean 3D shifts from 1.97 (± 1.44) mm to 1.39 (± 1.01) mm by performing intrafractional IGRT. In total, 34% of all treatment sessions required correction of intrafractional position shifts. CONCLUSION: Monitoring of prostate motion using repeated intrafractional orthogonal kV-X-ray-based position measurements of implanted fiducial markers proved to be a reliable method to improve precision of stereotactic irradiations of the prostate. It can prevent unacceptable translation deviations in one third of all sessions.

Systematic risk analysis of radiation pneumonitis in breast cancer: role of cotreatment with chemo-, endocrine, and targeted therapy.

PURPOSE: A major complication of sequential and concomitant chemoradiation in breast cancer treatment is interstitial pneumonitis induced by radiation therapy (RT), systemic therapy, or a combination of both. Dose and volume of co-irradiated lung tissue directly correlate with the risk of radiation pneumonitis. Especially in case of combined treatment, it is often unclear which of the used therapeutic agents promote pneumonitis. METHODS: This was a prospective monocentric study including 396 breast cancer patients. A systematic analysis of single and combined therapeutic measures was performed in order to identify treatment-related factors enhancing the risk of pneumonitis post RT. RESULTS: Overall incidence of pneumonitis of any grade was 38%; 28% were asymptomatic (grade 1) and 10% were symptomatic (> grade 1). Pneumonitis > grade 2 did not occur. Beside age, smoking status, and mean lung dose, the combined treatment with goserelin and tamoxifen significantly enhanced the risk of pneumonitis in a supra-additive pattern (odds ratio [OR] 4.38), whereas each agent alone or combined with other drugs only nonsignificantly contributed to a higher pneumonitis incidence post RT (OR 1.52 and OR 1.16, respectively). None of the other systemic treatments, including taxanes, increased radiation pneumonitis risk in sequential chemoradiation. CONCLUSION: Common treatment schedules in sequential chemoradiation following breast-conserving surgery only moderately increase lung toxicity, mainly as an asymptomatic complication, or to a minor extent, as transient pneumonitis ≤ grade 2. However, combined treatment with tamoxifen and the LHRH analog goserelin significantly increased the risk of pneumonitis in breast cancer patients after chemoradiation. Thus, closer surveillance of involved patients is advisable.

Impact of COVID-19 on Radiation Oncology, an Austrian Experience.

The COVID-19 pandemic has an unprecedented impact on cancer treatment worldwide. We aimed to evaluate the effects of the pandemic on the radiation treatment of patients in order to provide data for future management of such crises. We compared the number of performed radiotherapy sessions of the pandemic period from February 2020 until May 2021 with those of 2018 and 2019 for reference. At our department, no referred patients had to be rejected or postponed, nor any significant changes in fractionation schedules implemented. Nevertheless, there was a substantial drop in overall radiotherapy sessions in 2020 following the first incidence wave of up to -25% (in June) in comparison to previous years. For breast cancer, a maximum decline of sessions of -45% (July) was recorded. Only a short drop of prostate cancer sessions (max -35%, May) followed by a rebound (+42%, July) was observed. Over the investigated period, a loss of 4.4% of expected patients never recovered. The severe impact of COVID-19 on cancer treatment, likely caused by retarded diagnosis and delayed interdisciplinary co-treatment, is reflected in a lower count of radiotherapy sessions. Radiation oncology is a crucial cornerstone in upholding both curative treatment options and treatment capacity during a pandemic.

Hypofractionated and single-fraction radiosurgery for brain metastases with sex as a key predictor of overall survival.

Overall survival (OS) of patients with brain metastases treated with hypofractionated (HFSRT) or single-fraction (SRS) radiosurgery depends on several prognostic factors. The aim of this study was to investigate the potential of sex as an independent predictor of OS and evaluate the predictive accuracy of common prognostic scores. Retrospective analysis of 281 consecutive patients receiving radiosurgery of brain metastases was performed. Kaplan-Meier survival curves and Cox proportional hazards models were used to compare OS between SRS and HFSRT and by sex, before and after propensity-score matching (PSM) on key baseline prognostic covariates. Prognostic scores were evaluated using Harrell's concordance index. Median OS was 11 months after both SRS and HFSRT. After PSM, median OS was 12 months after SRS (95% CI: 7.5-16.5) and 9 months after HFSRT (95% CI: 5.0-13.0; p = 0.77). Independent prognostic factors were sex, primary tumor, KPI, and systemic disease status. Median OS was 16 months for women and 7 months for male patients (p < 0.001). After excluding sex specific tumors, PSM revealed a median OS of 16 months for women and 8 months for male patients (p < 0.01). Evaluation of prognostic indices showed BSBM to be the most accurate (Harrell's C = 0.68), followed by SIR (0.61), GPA (0.60), RPA (0.58), and Rades et al. (0.57). OS after HFSRT and SRS did not differ, although PSM revealed a non-significant advantage for SRS. Female sex was found to be a major independent positive prognostic factor for survival, and thus should be considered in the personalized decision-making of brain metastases treatment.

Interdigitated aluminium and titanium sensors for assessing epithelial barrier functionality by electric cell-substrate impedance spectroscopy (ECIS).

Electric cell-substrate impedance spectroscopy (ECIS) enables non-invasive and continuous read-out of electrical parameters of living tissue. The aim of the current study was to investigate the performance of interdigitated sensors with 50 µm electrode width and 50 µm inter-electrode distance made of gold, aluminium, and titanium for monitoring the barrier properties of epithelial cells in tissue culture. At first, the measurement performance of the photolithographic fabricated sensors was characterized by defined reference electrolytes. The sensors were used to monitor the electrical properties of two adherent epithelial barrier tissue models: renal proximal tubular LLC-PK1 cells, representing a normal functional transporting epithelium, and human cervical cancer-derived HeLa cells, forming non-transporting cancerous epithelial tissue. Then, the impedance spectra obtained were analysed by numerically fitting the parameters of the two different models to the measured impedance spectrum. Aluminium sensors proved to be as sensitive and consistent in repeated online-recordings for continuous cell growth and differentiation monitoring as sensors made of gold, the standard electrode material. Titanium electrodes exhibited an elevated intrinsic ohmic resistance in comparison to gold reflecting its lower electric conductivity. Analysis of impedance spectra through applying models and numerical data fitting enabled the detailed investigation of the development and properties of a functional transporting epithelial tissue using either gold or aluminium sensors. The result of the data obtained, supports the consideration of aluminium and titanium sensor materials as potential alternatives to gold sensors for advanced application of ECIS spectroscopy.

Intrafractional 6D head movement increases with time of mask fixation during stereotactic intracranial RT-sessions.

BACKGROUND: The present study investigates the intrafractional accuracy of a frameless thermoplastic mask used for head immobilization during stereotactic radiotherapy. Non-invasive masks cannot completely prohibit head movements. Previous studies attempted to estimate the magnitude of intrafractional inaccuracy by means of pre- and postfractional measurements only. However, this might not be sufficient to accurately map also intrafractional head movements. MATERIALS AND METHODS: Intrafractional deviation of mask-fixed head positions was measured in five patients during a total of 94 fractions by means of close-meshed repeated ExacTrac measurements (every 1.4 min) conducted during the entire treatment session. A median of six (range: 4 to 11) measurements were recorded per fraction, delivering a dataset of 453 measurements. RESULTS: Random errors (SD) for the x, y and z axes were 0.27 mm, 0.29 mm and 0.29 mm, respectively. Median 3D deviation was 0.29 mm. Of all 3D intrafractional motions, 5.5 and 0.4% exceeded 1 mm and 2 mm, respectively. A moderate correlation between treatment duration and mean 3D displacement was determined (rs = 0.45). Mean 3D deviation increased from 0.21 mm (SD = 0.26 mm) in the first 2 min to a maximum of 0.53 mm (SD = 0.31 mm) after 10 min of treatment time. CONCLUSION: Pre- and post-treatment measurement is not sufficient to adequately determine the range of intrafractional head motion. Thermoplastic masks provide both reliable interfractional and intrafractional immobilization for image-guided stereotactic hypofractionated radiotherapy. Greater positioning accuracy may be obtained by reducing treatment duration (< 6 min) and applying intrafractional correction. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03896555, Registered 01 April 2019 - retrospectively registered.

Occurrence of pneumonitis following radiotherapy of breast cancer - A prospective study.

AIM: of this study is to determine the temporal resolution of therapy-induced pneumonitis, and to assess promoting factors in adjuvant treated patients with unilateral mammacarcinoma. PATIENTS AND METHODS: A total of 100 post-surgery patients were recruited. The cohort was treated by 2 field radiotherapy (2FRT; breast and chest wall, N = 75), 3 field radiotherapy (3FRT; + supraclavicular lymphatic region, N = 8), or with 4 field radiotherapy (4FRT; + parasternal lymphatic region, N = 17). Ninety-one patients received various systemic treatments prior to irradiation. Following an initial screening visit post-RT, two additional visits after 12 and 25 weeks were conducted including radiographic examination. In addition, general anamnesis and the co-medication were recorded. The endpoint was reached as soon as a pneumonitis was developed or at maximum of six months post-treatment. RESULTS: A pneumonitis incidence of 13% was determined. Of 91 patients with prior systemic therapy, 11 patients developed pneumonitis. Smoking history and chronic obstructive pulmonary disease (COPD) appeared to be positive predictors, whereas past pneumonia clearly promoted pneumonitis. Further pneumonitis-promoting predictors are represented by the applied field extensions (2 field radiotherapy [2FRT] < 3 field radiotherapy [3FRT] < 4 field radiotherapy [4FRT]) and the type of combined initial systemic therapies. As a consequence, all of the three patients in the study cohort treated with 4FRT and initial chemotherapy combined with anti-hormone and antibody protocols developed pneumonitis. A combination of the hormone antagonists tamoxifen and goserelin might enhance the risk for pneumonitis. Remarkably, none of the 11 patients co-medicated with statins suffered from pneumonitis. CONCLUSIONS: The rapidly increasing use of novel systemic therapy schedules combined with radiotherapy (RT) needs more prospective studies with larger cohorts. Our results indicate that contribution to pneumonitis occurrence of various (neo)adjuvant therapy approaches followed by RT is of minor relevance, whereas mean total lung doses of >10 Gy escalate the risk of lung tissue complications. The validity of potential inhibitors of therapy-induced pneumonitis as observed for statin co-medication should further be investigated in future trials.

Sex Differences in Renal Proximal Tubular Cell Homeostasis.

Studies in human patients and animals have revealed sex-specific differences in susceptibility to renal diseases. Because actions of female sex hormones on normal renal tissue might protect against damage, we searched for potential influences of the female hormone cycle on basic renal functions by studying excretion of urinary marker proteins in healthy human probands. We collected second morning spot urine samples of unmedicated naturally ovulating women, postmenopausal women, and men daily and determined urinary excretion of the renal tubular enzymes fructose-1,6-bisphosphatase and glutathione-S-transferase-α Additionally, we quantified urinary excretion of blood plasma proteins α1-microglobulin, albumin, and IgG. Naturally cycling women showed prominent peaks in the temporal pattern of urinary fructose-1,6-bisphosphatase and glutathione-S-transferase-α release exclusively within 7 days after ovulation or onset of menses. In contrast, postmenopausal women and men showed consistently low levels of urinary fructose-1,6-bisphosphatase excretion over comparable periods. We did not detect changes in urinary α1-microglobulin, albumin, or IgG excretion. Results of this study indicate that proximal tubular tissue architecture, representing a nonreproductive organ-derived epithelium, undergoes periodical adaptations phased by the female reproductive hormone cycle. The temporally delimited higher rate of enzymuria in ovulating women might be a sign of recurring increases of tubular cell turnover that potentially provide enhanced repair capacity and thus, higher resistance to renal damage.

Cryo-immunoelectron microscopy of adherent cells improved by the use of electrospun cell culture substrates.

Electrospun nanofibres are an excellent cell culture substrate, enabling the fast and non-disruptive harvest and transfer of adherent cells for microscopical and biochemical analyses. Metabolic activity and cellular structures are maintained during the only half a minute-long harvest and transfer process. We show here that such samples can be optimally processed by means of cryofixation combined either with freeze-substitution, sample rehydration and cryosection-immunolabelling or with freeze-fracture replica-immunolabelling. Moreover, electrospun fibre substrates are equally suitable for complementary approaches, such as biochemistry, fluorescence microscopy and cytochemistry.

Monitoring of the dynamics of epithelial dome formation using a novel culture chamber for long-term continuous live-cell imaging.

Epithelial tissue guarantees proper performance of many organs, e.g., the kidneys, the gastrointestinal organs, and endocrine glands. Epithelial layers are responsible for the formation and maintenance of separate compartments with distinct solute composition. This is achieved by epithelial layers forming a barrier between the two compartments and concomitantly allowing site-directed transepithelial transport, uptake or secretion of electrolytes, energy substrates, proteins, and other solutes.Research on epithelial tissue functions has highly profited from the establishment of tissue culture technologies allowing to cultivate primary epithelial cells or established epithelial cell lines. A property of transporting epithelia cultured in vitro that has long been noted is the formation of the so-called domes on solid growth supports, which represent fluid filled blisters between the solid growth surface and the cell layer. Formation of domes is regarded as a sign of active transport processes and an intact epithelial barrier function due to functional tight junctional cell-cell contacts. A novel methodology for long-term live-cell light microscopy is described in the present article, which allows the monitoring of the dynamic nature of structures, such as epithelial domes over days to weeks of tissue culture ("under the microscope").

3D versus 2D cell culture implications for electron microscopy.

Cell culture systems are indispensable tools for basic research and a wide range of clinical in vitro studies. However, conventional 2D cell cultures poorly mimic the conditions in the living organism. This limitation may seriously compromise the reliability and significance of data obtained from such approaches. Therefore, we present here a comparative study on selected 3D and 2D cell cultures of U87-MG human glioblastoma cells that were processed by means of high-pressure freezing and freeze-substitution as well as by conventional chemical fixation and Tokuyasu cryo-section immuno-labeling. Three-dimensional cultures comprised pseudo-vascularized cultures, fiber and bead scaffold cultures, and spheroid cultures. Cell cultures in dishes and on coverslips were the static 2D culture systems used as reference models. We will discuss morphological and immuno-cytochemical observations with respect to the feasibility of the cell culture systems investigated for the state-of-the-art electron microscopy.

Potential of Macrostomum lignano to recover from gamma-ray irradiation.

Stem cells are the only proliferating cells in flatworms and can be eliminated by irradiation with no damage to differentiated cells. We investigated the effect of fractionated irradiation schemes on Macrostomum lignano, namely, on survival, gene expression, morphology and regeneration. Proliferating cells were almost undetectable during the first week post-treatment. Cell proliferation and gene expression were restored within 1 month in a dose-dependent manner following exposure to up to 150 Gy irradiation. During recovery, stem cells did not cross the midline but were restricted within lateral compartments. An accumulated dose of 210 Gy resulted in a lethal phenotype. Our findings demonstrate that M. lignano represents a suitable model system for elucidating the effect of irradiation on the stem cell system in flatworms and for improving our understanding of the recovery potential of severely damaged stem-cell systems.

The surface properties of nanocrystalline diamond and nanoparticulate diamond powder and their suitability as cell growth support surfaces.

Nanocrystalline diamond (NCD) films and nanoparticulate diamond powder (DP) are the two main representatives of diamond at the nanoscale. This study was designed to investigate the suitability of these biomaterials as cell growth supports and to determine surface characteristic properties best suited to cell attachment and proliferation. Surface topography, chemical termination and wetting properties of NCD- and DP-coated borosilicate glass substrates were correlated to attachment, proliferation and differentially regulated gene expression of human renal epithelial cells (HK-2 cell line) cultured on these surfaces. Hydrogen-terminated NCD (NCD-H) surfaces were shown to inhibit cell attachment, which indicates that the lack of functional polar groups prevents adherent cells from settling on a surface, whether nanostructured or not. In contrast to NCD-H, oxygen-terminated NCD (NCD-O) as well as DP surfaces demonstrated improved cell attachment, as compared to borosilicate glass, which is a commonly used material for cell growth supports. NCD-O not only revealed an increased cell attachment, but also a markedly increased proliferation rate. Finally, none of the investigated surface modifications appeared to cause adverse cellular reactions or markedly alter cellular phenotype.

IFN-alpha induces barrier destabilization and apoptosis in renal proximal tubular epithelium.

Type I IFNs, like IFN-alpha, are major immune response regulators produced and released by activated macrophages, dendritic cells, and virus-infected cells. Due to their immunomodulatory functions and their ability to induce cell death in tumors and virus-infected cells, they are used therapeutically against cancers, viral infections, and autoimmune diseases. However, little is known about the adverse effects of type I IFNs on nondiseased tissue. This study examined the effects of IFN-alpha on cell death pathways in renal proximal tubular cells. IFN-alpha induced apoptosis in LLC-PK1 cells, characterized by the activation of caspase-3, -8, and -9, DNA fragmentation, and nuclear condensation. IFN-alpha also caused mitochondrial depolarization. Effector caspase activation was dependent on caspase-8 and -9. In addition to apoptosis, IFN-alpha exposure also decreased renal epithelial barrier function, which preceded apoptotic cell death. Caspase inhibition did not influence permeability regulation while significantly attenuating and delaying cell death. These results indicate that IFN-alpha causes programmed cell death in nondiseased renal epithelial cells. IFN-alpha-induced apoptosis is directed by an extrinsic death receptor signaling pathway, amplified by an intrinsic mitochondrial pathway. Caspase-dependent and -independent apoptotic mechanisms are involved. These findings reveal a novel aspect of IFN-alpha actions with implications for normal renal function in immune reactions and during IFN-alpha therapy.

Opposing roles of EGF in IFN-alpha-induced epithelial barrier destabilization and tissue repair.

Balance between damaging influences and repair mechanisms determines the degree of tissue deterioration by inflammatory and other injury processes. Destabilization of the proximal tubular barrier has been previously shown to be induced by IFN-alpha, a cytokine crucial for linking innate and adaptive immune responses. EGF was implicated in rescue mechanisms from renal injury. To study the interplay between the two processes, we determined if EGF can prevent IFN-alpha-induced barrier permeabilization. EGF did not counteract but even exacerbated the IFN-alpha-induced decrease of transepithelial electrical resistance in LLC-PK1 monolayers. For this effect Erk1/2 activation was necessary, linking barrier regulation to EGF-induced cell cycle progression. In contrast to its damage-intensifying effect, EGF also facilitated the regeneration of epithelial barrier function after the termination of IFN-alpha treatment. This effect was not mediated by Erk1/2 activation or cell proliferation since U0126, an Erk1/2 inhibitor, did not prevent but ameliorated recovery. However, EGF accelerated the downregulation of caspase-3 in recovering cells. Similarly, a pan-caspase inhibitor was able to block caspase activity and, concomitantly, promote restoration of barrier function. Thus, barrier repair might be linked to an EGF-mediated antiapoptotic mechanism. EGF appears to sensitize epithelial cells to the detrimental effects of IFN-alpha but also helps to restore barrier function in the healing phase. The observed dual effect of EGF might be explained by the different impact of proproliferative and antiapoptotic signaling pathways during and after cytokine treatment. The timing of epithelial exposure to damaging agents and repair factors was identified as a crucial parameter determining tissue fate.

Optimized conformal paraaortic lymph node irradiation is not associated with enhanced renal toxicity.

BACKGROUND AND PURPOSE: For patients with gynecologic carcinomas, irradiation of paraaortic lymph nodes (PLNs) is a routine treatment concept. Planning target volumes (PTVs) individually optimized by radiation field delineations along the big vessels permit the inclusion of at least 97% of potentially involved PLNs. However, this novel treatment technique might increase radiation-induced nephrotoxicity. Therefore, the actual incidence of kidney damage after PLN irradiation has to be assessed in order to validate the safety of this treatment concept. PATIENTS AND METHODS: 19 patients were treated with irradiation alone (50.4 Gy; 5 x 1.8 Gy/week) and monitored for up to 90 months. Functional renal parameters, namely renal plasma flow (RPF) and glomerular filtration rate (GFR), were assessed by dynamic renal scintigraphy. Additionally, patients were clinically observed (i.e., hypertension, proteinuria) and calculations of normal-tissue complication probability (NTCP) values for nonuniform kidney irradiation were performed using the Lyman-Wolbarst algorithm. RESULTS: Two patients with anticipated moderate NTCP values (12.6% and 8.7%) showed slightly impaired RPF rates at 12, 24, and after 48 months of follow-up. Only one patient in the subgroup showing NTCP values > 50% (n = 9) developed a notable impairment of renal RPF. However, all patients including those with elevated complication probabilities exhibited neither impaired GFR nor clinically apparent symptoms related to a loss of functioning renal tissue from 12 to > 48 months post irradiation. CONCLUSION: Conformal irradiation of retroperitoneal lymph nodes with individual PTV delineation appears not to be associated with clinically relevant functional impairment of the kidneys.

Competing irradiation techniques for para-aortic lymph nodes: dose distribution and NTCP for the kidney.

PURPOSE: Partial coirradiation of both kidneys is an unavoidable consequence of adequate dose delivery in radiation therapy of para-aortic lymph nodes (PLN). Depending on total dose anteroposterior/posteroanterior (AP/PA), opposed-fields or multifield techniques are used. To optimize the treatment of potentially tumor-affected PLN with minimal kidney involvement, we calculated normal tissue complication probabilities (NTCPs) of coirradiated kidneys for four common irradiation techniques used in the PLN area. METHODS AND MATERIALS: Planning target volume (PTV) delineation was performed in computed tomography scans of 21 patients with a lateral safety margin of 3 cm from the aorta and 2 cm aside the vena cava. Ventral and dorsal margins of the PTV were delineated 2 cm from the vessels. As previously shown (Nevinny-Stickel M, et al. Int J Radiat Oncol Biol Phys 2000;48:147-151), PTVs optimized by these altered delineations permit inclusion of at least 97% of potentially involved PLN in contrast to standard delineations based on bony structures that are more likely to miss affected lymph nodes. The present study compared NTCPs for individual PTV-based treatment planning with NTCPs for standard planning based on bony structures. For each patient, four hypothetical treatment plans were created: (A) standard AP/PA opposed fields technique with lateral field margins along the tips of the transverse processes of the vertebral bodies; (B) individually planned AP/PA opposed fields with lateral field margins according to the optimized PTV; (C) standard four-field box technique with lateral width as described for (A), with dorsal borders at the center of the vertebral bodies and ventral margins 3 cm in front of the vertebrae; and (D) individually planned four-field box with lateral field margins according to the optimized PTV. Calculation of irradiation-induced complication probability values for nonuniform kidney irradiation was performed for model doses 19.8 Gy, 30.6 Gy, and 50.4 Gy according to the Lyman-Wolbarst model. RESULTS: No dose showed a statistically significant difference (p < 0.00833, corrected for six multiple interrelated comparisons) in the median of total organ kidney NTCPs between techniques A, C, and D, with technique D intermediately ranging between technique A and C (e.g., for 50.4 Gy: A: median, 0.39; range, 0.01-0.83; C: median, 0.27 range; 0.05-0.68; D: 0.36; range, 0.03-0.72). In comparison to techniques A, C, and D, the individually planned AP/PA opposed-fields technique (B) was accompanied by significantly higher and intolerable overall kidney NTCP rates (e.g., for 50.4 Gy: median, 0.68; range, 0.01-0.99). CONCLUSION: Conformal four-field planning with individually optimized PTVs (D) resulted in only moderate tissue complication probabilities in both kidneys with the advantage of providing significantly greater inclusion of potentially involved PLNs in comparison to accepted standard procedures (A and C).