Self-Shielding Gyroscopic Radiosurgery: A Prospective Experience and Analysis of the First 100 Patients.

Background Stereotactic radiosurgery is a well-established treatment option for the management of various benign and malignant brain tumors. It can be delivered with several treatment platforms, usually requiring shielded radiation vaults to meet regulatory safety requirements. Recent technical advances have led to the first self-shielding platform enabling the delivery of gyroscopic radiosurgery (GRS). Given the limited number of GRS treatment platforms, the novelty of its characteristics, and the lack of available data, we report our prospective experience with the first 100 patients treated with GRS. Materials and methods Patients undergoing GRS for the treatment of intracranial tumors were enrolled in this prospective study. Patient and treatment characteristics, including patient satisfaction, were collected and analyzed. Results A total of 100 patients with 155 tumors were treated. The most commonly treated tumors comprised brain metastases (BM) (49%), vestibular schwannomas (31%), and meningiomas (14%). The median prescription dose for malignant and benign tumors was 20 and 13 Gy, respectively. The median prescription isodose line was 56%. Gross tumor volumes were small, with a median of 0.37 cc for BM and 0.92 cc for the other entities. The median total treatment time was 40 minutes. Dosimetric performance indices showed median values of 1.20 (conformity index), 1.24 (new conformity index), 1.74 (homogeneity index), and 3.13 (gradient index). Volumetric assessment of the treated tumors showed an overall decrease in size at the first available follow-up. Most patients were satisfied with the treatment experience. Conclusion Our first prospective experience of the use of GRS is favorable. Analyses of the dosimetric performance, treatment times, volumetric assessment, and patient satisfaction demonstrate its suitability for stereotactic treatments of intracranial tumors. Further prospective clinical and dosimetric analyses for GRS are pending.

Robotic stereotactic body radiotherapy for localized prostate cancer: final analysis of the German HYPOSTAT trial.

PURPOSE: We report results of the first German prospective multicenter single-arm phase II trial (ARO 2013-06; NCT02635256) of hypofractionated robotic stereotactic body radiotherapy (SBRT) for patients with localized prostate cancer (HYPOSTAT). METHODS: Patients eligible for the HYPOSTAT study had localized prostate cancer (cT1­3 cN0 cM0), Gleason score ≤ 7, prostate-specific antigen (PSA) ≤ 15 ng/ml, prostate volume ≤ 80 cm3, and an International Prostate Symptom Score (IPSS) ≤ 12. Initially, inclusion was limited to patients ≥ 75 years or patients 70-74 years with additional risk factors. The trial protocol was later amended to allow for enrolment of patients aged ≥ 60 years. The treatment consisted of 35 Gy delivered in 5 fractions to the prostate and for intermediate- or high-risk patients, also to the proximal seminal vesicles using the CyberKnife system (Accuray Inc., Sunnyvale, CA, USA). Primary endpoint was the rate of treatment-related gastrointestinal or genitourinary grade ≥ 2 toxicity based on the RTOG scale 12-15 months after treatment. Secondary endpoints were acute toxicity, late toxicity, urinary function, quality of life, and PSA response. RESULTS: From July 2016 through December 2018, 85 eligible patients were enrolled and received treatment, of whom 83 could be evaluated regarding the primary endpoint. Patients mostly had intermediate-risk disease with a median PSA value of 7.97 ng/ml and Gleason score of 7a and 7b in 43.5% and 25.9% of patients, respectively. At the final follow-up 12-15 months after treatment, no patient suffered from treatment-related gastrointestinal or genitourinary grade ≥ 2 toxicity. Acute toxicity was mostly mild, with three grade 3 events, and the cumulative rate of grade ≥ 2 genitourinary toxicity was 8.4% (95% CI 4.1-16.4%). There were no major changes in urinary function or quality of life. The median PSA value dropped to 1.18 ng/ml 12-15 months after treatment. There was one patient who developed distant metastases. CONCLUSION: Robotic SBRT with 35 Gy in 5 fractions was associated with a favorable short-term toxicity profile. Recruitment for the HYPOSTAT­2 trial (ARO-2018­4; NCT03795337), which further analyses the late toxicity of this regimen with a planned sample size of 500 patients, is ongoing.

Robotic stereotactic body radiotherapy for the management of adrenal gland metastases: a bi-institutional analysis.

PURPOSE: Adrenal gland metastases (AGMs) are a common manifestation of metastatic tumor spread, especially in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In patients with a limited systemic tumor burden, effective treatments for AGMs are needed. Due to varying fractionation schemes and limited reports, short-course treatment results for stereotactic body radiotherapy (SBRT) for AGMs are lacking. This work analyzes the outcomes of short-course SBRT for AGMs. METHODS: Patients who underwent robotic SBRT for AGMs with one to five fractions were eligible for analysis. RESULTS: In total, data from 55 patients with 72 AGMs from two institutions were analyzed. Most AGMs originated from renal cell carcinoma (38%) and NSCLC (35%). The median follow-up was 16.4 months. The median prescription dose and isodose line were 24 Gy and 70%, respectively. Most patients (85%) received SBRT with just one fraction. The median biologically effective dose assuming an α/ß ratio of 10 (BED10) was 80.4 Gy. The local control and progression-free survival after 1 and 2 years were 92.9%, 67.8%, and 46.2%, as well as 24.3%, respectively. Thirteen patients (24%) suffered from grade 1 or 2 toxicities. The BED10 showed a significant impact on LC (p < 0.01). Treatments with a BED10 equal to or above the median were associated with a better LC (p < 0.01). CONCLUSION: Robotic SBRT is an efficient and safe treatment modality for AGM. Treatment-associated side effects are sporadic and manageable. Results suggest short-course SBRT to be a preferable and time-saving treatment option for the management of AGMs if an adequate BED10 can be safely applied.

Single-fraction prostate-specific membrane antigen positron emission tomography- and multiparametric magnetic resonance imaging-guided stereotactic body radiotherapy for prostate cancer local recurrences.

OBJECTIVE: To analyse the efficacy and safety of focal prostate-specific membrane antigen positron emission tomography (PSMA-PET)- and multiparametric magnetic resonance imaging (mpMRI)-guided single-fraction stereotactic body radiotherapy (SBRT) for the treatment of prostate cancer (PCa) local recurrences. PATIENTS AND METHODS: Patients with PSMA-PET-positive PCa local recurrences treated with single-fraction SBRT between 2016 and 2020 were included. Identification for subsequent recurrences or metastatic spread based on increasing prostate-specific antigen (PSA) levels were evaluated using PSMA-PET imaging. RESULTS: A total of 64 patients were identified. Patients received various treatments before SBRT (31 patients with radical prostatectomy [RP], 18 external beam radiotherapy [EBRT] with RP, five EBRT, and the remaining 10 other combinations). The median follow-up was 21.6 months. The median PSA level before SBRT was 1.47 ng/mL. All patients received a single-fraction treatment with a median prescription dose and isodose line of 21 Gy and 65%, respectively. At the time of SBRT, six patients (9%) received an androgen deprivation therapy (ADT). PSA levels decreased after SBRT (P = 0.03) and three local recurrences were detected during the follow-up. The progression-free survival after 1-, 2-, and 3-years was 85.3%, 65.9%, and 51.2%, respectively. Six patients (9%) started ADT after SBRT due to disease progression. The rates of newly started ADT after 1-, 2-, and 3-years were 1.8%, 7.3%, and 22.7%, respectively. Grade 1 or 2 toxicities occurred in six patients (9%); no high-grade toxicity was observed. CONCLUSION: While the available data for SBRT in the PCa local recurrence setting describe outcomes for fractionated irradiations, the findings of this first analysis of single-fraction, PSMA-PET- and mpMRI-guided focal SBRT are encouraging. Such treatment appears to be a safe, efficient, and time-saving therapy even in intensively pretreated patients. Recurrence-directed treatments can delay the use of ADT and could avoid prostate bed irradiation in selected patients.

Intracranial Hemorrhage in Patients with Anticoagulant Therapy Undergoing Stereotactic Radiosurgery for Brain Metastases: A Bi-Institutional Analysis.

BACKGROUND: Stereotactic radiosurgery (SRS) is a well-established treatment modality for brain metastases (BM). Given the manifold implications of metastatic cancer on the body, affected patients have an increased risk of comorbidities, such as atrial fibrillation (AF) and venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep-vein thrombosis (DVT). These may require therapeutic anticoagulant therapy (ACT). Limited data are available on the risk of intracranial hemorrhage (ICH) after SRS for patients with BM who are receiving ACT. This bi-institutional analysis aimed to describe the bleeding risk for this patient subgroup. METHODS: Patients with ACT at the time of single-fraction SRS for BM from two institutions were eligible for analysis. The cumulative incidence of ICH with death as a competing event was assessed during follow-up with magnetic resonance imaging or computed tomography. RESULTS: Forty-one patients with 97 BM were included in the analyses. The median follow-up was 8.2 months (range: 1.7-77.5 months). The median and mean BM volumes were 0.47 and 1.19 cubic centimeters, respectively. The most common reasons for ACT were PE (41%), AF (34%), and DVT (7%). The ACT was mostly performed utilizing phenprocoumon (37%), novel oral anticoagulants (32%), or low-molecular-weight heparin (20%). Nine BM from a group of five patients with ICH after SRS were identified: none of them caused neurological or any other deficits. The 6-, 12-, and 18-month cumulative bleeding incidences per metastasis were 2.1%, 12.4%, and 12.4%, respectively. The metastases with previous bleeding events and those originating from malignant melanomas were found to more frequently demonstrate ICH after SRS (p = 0.02, p = 0.01). No surgical or medical intervention was necessary for ICH management, and no observed death was associated with an ICH. CONCLUSION: Patients receiving an ACT and single-fraction SRS for small- to medium-sized BM did not seem to have a clinically relevant risk of ICH. Previous bleeding and metastases originating from a malignant melanoma may favor bleeding events after SRS. Further studies are needed to validate our reported findings.

The Role of Stereotactic Radiosurgery in the Management of Foramen Magnum Meningiomas-A Multicenter Analysis and Review of the Literature.

BACKGROUND: Foramen magnum meningiomas (FMMs) represent a considerable neurosurgical challenge given their location and potential morbidity. Stereotactic radiosurgery (SRS) is an established non-invasive treatment modality for various benign and malignant brain tumors. However, reports on single-session or multisession SRS for the management and treatment of FMMs are exceedingly rare. We report the largest FMM SRS series to date and describe our multicenter treatment experience utilizing robotic radiosurgery. METHODS: Patients who underwent SRS between 2005 and 2020 as a treatment for a FMM at six different centers were eligible for analysis. RESULTS: Sixty-two patients met the inclusion criteria. The median follow-up was 28.9 months. The median prescription dose and isodose line were 14 Gy and 70%, respectively. Single-session SRS accounted for 81% of treatments. The remaining patients received three to five fractions, with doses ranging from 19.5 to 25 Gy. Ten (16%) patients were treated for a tumor recurrence after surgery, and thirteen (21%) underwent adjuvant treatment. The remaining 39 FMMs (63%) received SRS as their primary treatment. For patients with an upfront surgical resection, histopathological examination revealed 22 World Health Organization grade I tumors and one grade II FMM. The median tumor volume was 2.6 cubic centimeters. No local failures were observed throughout the available follow-up, including patients with a follow-up ≥ five years (16 patients), leading to an overall local control of 100%. Tumor volume significantly decreased after treatment, with a median volume reduction of 21% at the last available follow-up (p < 0.01). The one-, three-, and five-year progression-free survival were 100%, 96.6%, and 93.0%, respectively. Most patients showed stable (47%) or improved (21%) neurological deficits at the last follow-up. No high-grade adverse events were observed. CONCLUSIONS: SRS is an effective and safe treatment modality for FMMs. Despite the paucity of available data and previous reports, SRS should be considered for selected patients, especially those with subtotal tumor resections, recurrences, and patients not suitable for surgery.

Image-Guided Robotic Radiosurgery for the Treatment of Same Site Spinal Metastasis Recurrences.

BACKGROUND: Due to recent medical advancements, patients suffering from metastatic spinal disease have a prolonged life expectancy than several decades ago, and some will eventually experience relapses. Data for the retreatment of spinal metastasis recurrences occurring at the very same macroscopic spot as the initially treated lesion are limited. Previous studies mainly included recurrences in the boundary areas as well as other macroscopic parts of the initially affected vertebrae. This study exclusively analyzes the efficacy and safety of spinal reirradiation for recurrences on the same site utilizing single-session robotic radiosurgery. MATERIALS AND METHODS: Patients between 2005 and 2020 who received radiotherapy for a spinal metastasis suffering from a local recurrence were eligible for analysis. Only patients undergoing a single-session reirradiation were included. All recurrences must have been occurred in the same location as the initial lesion. This was defined as a macroscopic recurrence on computed tomography occurring at the same site as the initial spinal metastasis. All other lesions, including those in the boundary areas or other parts of the initially affected vertebrae, were excluded. RESULTS: Fifty-three patients with fifty-three lesions were retreated for spinal metastases. The median dose and number of fractions for the initial radiotherapy were 36 Gy and 15, respectively. Eleven patients were initially treated with stereotactic body radiotherapy. Retreatment was performed with a median dose of 18 Gy prescribed to a median isodose of 70%. The local control was 77% after a median follow-up of 22.2 months. Patients experiencing a second recurrence received a lower dose (p = 0.04), mostly below 18 Gy, and had a worse coverage (p = 0.01) than those showing local tumor control. 51% of patients experienced an improvement in pain control after treatment delivery. Besides, four vertebral compression fractures (7% of patients) but no other adverse events higher than grade 2 were observed. CONCLUSION: Single-session robotic radiosurgery appears to be a safe, time-saving, and effective treatment modality for spinal metastasis recurrences occurring in the same initial location if a considerable dose and coverage can be applied. Treatment results are comparable to reirradiated metastases in the boundary areas.

Image-Guided Robotic Radiosurgery for the Management of Spinal Ependymomas.

BACKGROUND: Ependymomas are rare neoplasms of the central nervous system (CNS), usually localized intracranially and most commonly diagnosed in children. Spinal ependymomas are more frequent in young adults. They are either primary lesions or manifest as disseminated seeding of cranial tumors. Data on the management of spinal ependymoma lesions remain scarce, especially concerning stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). The purpose of this study is to report the treatment outcomes of two institutions using robotic radiosurgery (RRS) for the treatment of spinal ependymomas. MATERIALS AND METHODS: All patients with a histopathologically confirmed diagnosis of an ependymoma WHO grade II or III who were treated with RRS for one or more spinal lesions were included in this analysis. RESULTS: Twelve patients underwent RRS for the treatment of 32 spinal ependymoma lesions between 2005 and 2020. Two patients were below the age of 18 when treated, whereas nine patients (75%) suffered from a primary spinal ependymoma. The median dose was 15 Gy prescribed to a median isodose of 70%, with 27 lesions (84%) receiving a single-session treatment. The local control (LC) after a median follow-up of 56.7 months was 84%. LC rates at 1, 3, and 5 years were 92, 85, and 77%, respectively. The Kaplan-Meier estimated overall survival after 1, 3, and 5 years were 75, 75, and 64%, respectively. Five patients died, all of them suffering from an anaplastic ependymoma, with widespread CNS tumor progression being the reason for death in four patients. The majority of patients (58%) showed a stable neurological status at the last available follow-up. Overall, the treatment was well tolerated. CONCLUSION: RRS appears to be a safe and efficient treatment modality for managing primary and secondary spinal ependymal tumors in patients with multiple lesions and local recurrences.

Robotic Radiosurgery for Persistent Postoperative Acromegaly in Patients with Cavernous Sinus-Invading Pituitary Adenomas-A Multicenter Experience.

BACKGROUND: The rates of incomplete surgical resection for pituitary macroadenomas with cavernous sinus invasion are high. In growth hormone-producing adenomas, there is a considerable risk for persistent acromegaly. Thus, effective treatment options are needed to limit patient morbidity and mortality. This multicenter study assesses the efficacy and safety of robotic radiosurgery (RRS) for patients with cavernous sinus-invading adenomas with persistent acromegaly. METHODS: Patients who underwent RRS with CyberKnife for postoperative acromegaly were eligible. RESULTS: Fifty patients were included. At a median follow-up of 57 months, the local control was 100%. The pretreatment insulin-like growth factor 1 (IGF-1) levels and indexes were 381 ng/mL and 1.49, respectively. The median dose and prescription isodose were 18 Gy and 70%, respectively. Six months after RRS, and at the last follow-up, the IGF-1 levels and indexes were 277 ng/mL and 1.14, as well as 196 ng/mL and 0.83, respectively (p = 0.0001 and p = 0.0002). The IGF-1 index was a predictor for biochemical remission (p = 0.04). Nine patients achieved biochemical remission and 24 patients showed biochemical disease control. Three patients developed a new hypopituitarism. CONCLUSIONS: RRS is an effective treatment for this challenging patient population. IGF-1 levels are decreasing after treatment and most patients experience biochemical disease control or remission.

Image-Guided Robotic Radiosurgery for the Management of Intramedullary Spinal Cord Metastases-A Multicenter Experience.

BACKGROUND: Intramedullary metastases are rare and bear a dismal prognosis. Limited data are available on the treatment of such lesions. As surgery may be the mainstay of treatment for patients with resectable and localized metastatic spread, previous case reports and case series suggest radiosurgery to be another viable treatment modality. This multicenter study analyzes the efficacy and safety of robotic radiosurgery (RRS) for intramedullary metastases. METHODS: Patients who received RRS for the treatment of at least one intramedullary metastasis were included. RESULTS: Thirty-three patients with 46 intramedullary metastases were treated with a median dose of 16 Gy prescribed to a median isodose of 70%. The local control was 79% after a median follow-up of 8.5 months. The median overall survival (OS) was 11.7 months, with a 12- and 24-month OS of 47 and 31%. The 12-month progression-free survival was 42% and at 24 months 25%. In addition, 57% of patients showed either an improved or stable neurological function after treatment delivery. Systemic disease progression was the main cause of death. No significant treatment-related toxicities were observed. CONCLUSIONS: RRS appears to be a safe, time-saving and effective treatment modality for intramedullary metastases, especially for patients with unresectable lesions and high burden of disease.

Image-guided robotic radiosurgery for glomus jugulare tumors-Multicenter experience and review of the literature.

BACKGROUND: Glomus jugulare tumors (GJTs) are challenging to treat due to their vascularization and location. This analysis evaluates the effectiveness and safety of image-guided robotic radiosurgery (RRS) for GJTs in a multicenter study and reviews the existing radiosurgical literature. METHODS: We analyzed outcome data from 101 patients to evaluate local control (LC), changes in pretreatment deficits, and toxicity. Moreover, radiosurgical studies for GJTs have been reviewed. RESULTS: After a median follow-up of 35 months, the overall LC was 99%. Eighty-eight patients were treated with a single dose, 13 received up to 5 fractions. The median tumor volume was 5.6 cc; the median treatment dose for single-session treatments is 16 Gy, and for multisession treatments is 21 Gy. Fifty-six percentage of patients experienced symptom improvement or recovered entirely. CONCLUSIONS: RRS is an effective primary and secondary treatment option for GJTs. The available literature suggests that radiosurgery is a treatment option for most GJTs.

Single-session image-guided robotic radiosurgery and quality of life for glomus jugulare tumors.

BACKGROUND: Limited data are available on the efficacy and impact on the quality of life (Qol) of single-session image-guided robotic radiosurgery (RRS) for glomus jugulare tumors (GJTs). This study investigates the role of RRS in the management of GJTs and reviews the RRS literature. METHODS: We analyzed 53 GJT patients treated with RRS to evaluate the safety, local control, clinical outcome, and Qol assessed by the SF12v2. RESULTS: The local control was 98% at a median follow-up of 38 months. The median tumor volume was 4.3 cc and tumors were treated with a median dose of 16.5 Gy. At the last follow-up, 35 patients had recovered from their symptoms or experienced symptom improvement. Qol analyses showed no significant decline while bodily pain significantly decreased. CONCLUSIONS: RRS is a safe and efficient tool for the treatment of GJTs. Qol of patients after treatment is stable and tends to improve over time.

Long-term Survival in Patients Treated with a Robotic Radiosurgical Device for Liver Metastases.

PURPOSE: The treatment of liver metastases with local procedures is a fast progressing field. For the most, long-term survival data is missing raising questions with regard to the efficacy of such modalities when compared to surgical resection. Radiosurgery using the CyberKnife device enables the treatment of liver lesions with a single-session approach. Here we present long-term survival data to explore the curative potential of this strategy. MATERIALS AND METHODS: Patients with oligo-metastatic disease limited to the liver have been treated with single-session or hypo-fractioned radiosurgery in curative intent and prospectively followed until death. Follow-up (FU) was performed using magnetic resonance imaging (MRI) 2 months after radiation and at 3-month intervals for the first 2 years. After that annual computed tomography or MRI scans were performed until 5 years post-treatment. Local recurrence in the radiated volume and recurrence outside the treated volume were used to define local and distant progression. Survival times were censored at the time of the last FU. RESULTS: One hundred twenty-six patients treated between 2005 and 2015 with 194 lesions were included into this study. Median FU was 30.0 months. According to Response Evaluation Criteria in Solid Tumors, 55.2% had a complete remission and 11.3% a partial remission. Seventy-two point two percent recurred outside the radiated lesion and median overall survival was 35.2 months with a 3-year survival rate of 47.7%. CONCLUSION: This is currently the largest cohort of stereotactic body radiation therapy treated liver lesions with a median long-term follow of 30 months. Robotic radiosurgery using a single session approach has a high efficacy to control the radiated lesion with the potential to cure patients.

Robotic Radiosurgery for Adrenal Gland Metastases.

INTRODUCTION: The purpose of this study was to investigate the safety and efficacy of CyberKnife (CK) robotic radiosurgery for treatment of adrenal metastases. METHODS: We performed a retrospective analysis of 23 patients with adrenal metastases who had been treated with CK between October 2006 and December 2015. Fifteen patients received chemotherapy prior to radiosurgery, all patients underwent computer tomography (CT) fluoroscopically guided percutaneous placement of one to three gold fiducials into the adrenal gland. Nineteen patients were selected for single-fraction radiosurgery with a median dose of 22 Gy, four patients were treated in three fractions with a median dose of 13.5 Gy. RESULTS: Median follow-up time was 23.6 months. Four patients (17%) experienced local relapse during the evaluation period with a mean time of 19 months to tumor progression. The actuarial local tumor control rate was 95% after one year and 81% after two years. Three of the four patients with local recurrence were retreated with CK radiosurgery. Dynamic tumor tracking enabled accurate treatment with correlation errors less than 2 mm, despite extensive respiration-induced target motion up to 22 mm. Apart from nausea directly after treatment in five patients, we observed no early or late treatment-related side effects. CONCLUSIONS: Single fraction robotic radiosurgery for adrenal gland metastases is a safe and effective treatment option for patients who are not eligible for surgical resection.

Feasibility and toxicity of concomitant radio/immunotherapy with MabThera (Rituximab®) for patients with non-Hodkin's Lymphoma: results of a prospective phase I/II study.

PURPOSE: Non-Hodgkin's lymphomas (NHL) have a high radio- and chemosensitivity. Although initially responsive, approximately 50% of low grade B-cell lymphomas relapse after 10-15 years. Besides chemo- and radiotherapy, rituximab, a mouse/human chimeric antibody targeting CD20 antigen on the surface of B-cell lymphoma cells, is another treatment approach. In vitro data showed potentiation of radiation-induced apoptosis by addition of rituximab. The purpose of this study was to evaluate the feasibility and toxicity of radiotherapy with concomitant application of rituximab in NHL patients. PATIENTS AND METHODS: A total of 21 patients with B-cell lymphoma (stage I: n = 11; II: n = 5; III: n = 1; IV: n = 4) were included in this study, treated with radiotherapy of 30-40 Gy and weekly application of rituximab (375 mg/m²). Nine patients had R-CHOP chemotherapy previously, 1 patient leuceran chemotherapy, and 2 patients an initial treatment with 6 cycles of rituximab. Mean time of follow-up was 41.7 months. RESULTS: No grade 4 toxicity or treatment-related death was observed. In 1 patient, rituximab application had to be stopped after 3 cycles due to radiation-induced side effects. No late toxicities were reported. All patients were in complete remission after treatment. Progression or relapse was observed in 6 patients (28%); the mean time to progression was 27 months. The mean overall survival (OS) was 53 months. CONCLUSION: Combined radio/immunotherapy is feasible and safe. Treatment was well tolerated, no late toxicities were observed, and treatment outcome is promising. Randomized trials are necessary to clarify the benefit of this treatment approach and its applicability.

Noninvasive detection of lung cancer by analysis of exhaled breath.

BACKGROUND: Lung cancer is one of the leading causes of death in Europe and the western world. At present, diagnosis of lung cancer very often happens late in the course of the disease since inexpensive, non-invasive and sufficiently sensitive and specific screening methods are not available. Even though the CT diagnostic methods are good, it must be assured that "screening benefit outweighs risk, across all individuals screened, not only those with lung cancer". An early non-invasive diagnosis of lung cancer would improve prognosis and enlarge treatment options. Analysis of exhaled breath would be an ideal diagnostic method, since it is non-invasive and totally painless. METHODS: Exhaled breath and inhaled room air samples were analyzed using proton transfer reaction mass spectrometry (PTR-MS) and solid phase microextraction with subsequent gas chromatography mass spectrometry (SPME-GCMS). For the PTR-MS measurements, 220 lung cancer patients and 441 healthy volunteers were recruited. For the GCMS measurements, we collected samples from 65 lung cancer patients and 31 healthy volunteers. Lung cancer patients were in different disease stages and under treatment with different regimes. Mixed expiratory and indoor air samples were collected in Tedlar bags, and either analyzed directly by PTR-MS or transferred to glass vials and analyzed by gas chromatography mass spectrometry (GCMS). Only those measurements of compounds were considered, which showed at least a 15% higher concentration in exhaled breath than in indoor air. Compounds related to smoking behavior such as acetonitrile and benzene were not used to differentiate between lung cancer patients and healthy volunteers. RESULTS: Isoprene, acetone and methanol are compounds appearing in everybody's exhaled breath. These three main compounds of exhaled breath show slightly lower concentrations in lung cancer patients as compared to healthy volunteers (p < 0.01 for isoprene and acetone, p = 0.011 for methanol; PTR-MS measurements). A comparison of the GCMS-results of 65 lung cancer patients with those of 31 healthy volunteers revealed differences in concentration for more than 50 compounds. Sensitivity for detection of lung cancer patients based on presence of (one of) 4 different compounds not arising in exhaled breath of healthy volunteers was 52% with a specificity of 100%. Using 15 (or 21) different compounds for distinction, sensitivity was 71% (80%) with a specificity of 100%. Potential marker compounds are alcohols, aldehydes, ketones and hydrocarbons. CONCLUSION: GCMS-SPME is a relatively insensitive method. Hence compounds not appearing in exhaled breath of healthy volunteers may be below the limit of detection (LOD). PTR-MS, on the other hand, does not need preconcentration and gives much more reliable quantitative results then GCMS-SPME. The shortcoming of PTR-MS is that it cannot identify compounds with certainty. Hence SPME-GCMS and PTR-MS complement each other, each method having its particular advantages and disadvantages. Exhaled breath analysis is promising to become a future non-invasive lung cancer screening method. In order to proceed towards this goal, precise identification of compounds observed in exhaled breath of lung cancer patients is necessary. Comparison with compounds released from lung cancer cell cultures, and additional information on exhaled breath composition in other cancer forms will be important.

Modified radical neck dissection and minimal invasive tumor surgery in the middle of split course of concomitant chemoradiotherapy of advanced HNSCC.

OBJECTIVE: The effectiveness of modified radical neck dissection with concomitant chemoradiotherapy in patients with N2/3 advanced head and neck cancer was evaluated. STUDY DESIGN AND SETTING: Retrospective study of 35 patients treated at the University Hospital, Medical University, Innsbruck. The treatment consisted of a split course radiation up to 70 Gy with concomitant chemotherapy with Mytomicin C and 5-fluorouracil. Neck dissection and/or tumor resection was performed between the two cycles of radiation and chemotherapy. RESULTS: The 2-year progression-free survival was 64%, locoregional control 92% and overall survival 55. Observed toxicities included mucositis (grade 3, 35%; grade 4, 16%), neutropenia (grade 4, 28%), and thrombocytopenia (grade 4, 26%). No complications related to modified radical neck dissection were observed. CONCLUSION: Intermittent neck dissection was highly effective in controlling the neck disease. Mitomycin C-based chemoradiotherapy for treatment of locally advanced cancer seems to be an option to cisplatin-based regimens.

Rituximab enhances radiation-triggered apoptosis in non-Hodgkin's lymphoma cells via caspase-dependent and - independent mechanisms.

Rituximab (RTX), a chimeric human anti-CD20 monoclonal antibody, is currently employed in the treatment of malignant non-Hodgkin's lymphoma (NHL) either alone or in combination with other cytotoxic approaches. The present study examines the effects of ionizing radiation in combination with RTX on proliferation and apoptosis development in B-lymphoma RL and Raji cells. RTX was used at a concentration of 10 microg/mL 24 hours prior to irradiation at a single dose of 9 Gy. CD20 expression, cell viability, apoptosis, mitochondrial membrane potential and apoptosis-related proteins were evaluated in the treated B cells. The constitutive level of CD20 expression in RL and Raji lymphoma cells did not play an essential role in RTX-induced cell growth delay. Both lymphoma cells showed similar inhibition of cell proliferation without apoptosis development in response to RTX treatment. Exposure to ionizing radiation induced cell growth delay and apoptosis in RL cells, whereas Raji cells showed moderate radio-resistance and activation of cell growth at 24 hours after irradiation, which was accompanied by increased radiation-triggered CD20 expression. The simultaneous exposure of lymphoma cells to ionizing radiation and RTX abrogated radioresistance of Raji cells and significantly enhanced cell growth delay and apoptosis in RL cells. X-linked inhibitor of apoptosis protein (XIAP) and the inducible form of heat shock protein 70 (Hsp70) were positively modulated by RTX in combination with ionizing radiation in order to induce apoptosis. Furthermore, it was demonstrated that mitochondrial membrane potential dissipation is not an essential component to induce apoptosis-inducing factor (AIF) maturation and apoptosis. Our results show that RTX-triggered enhancement of radiation-induced apoptosis and cell growth delay is achieved by modulation of proteins involved in programmed cell death.

Irradiation causes biphasic neutrophilic granulocyte phagocytic function.

BACKGROUND AND PURPOSE: The anti-inflammatory effect of low-dose radiotherapy is clinically well described. Nevertheless, until now neither the optimal dose nor the background of tissue reactions have been defined. The current study examines the influence of low radiation doses on neutrophilic granulocyte function, which could be helpful in finding the optimal dose for either stimulation or suppression of anti-inflammatory activity. MATERIAL AND METHODS: Lymphoprep density gradient-purified neutrophilic granulocytes of three voluntary, healthy donors were used for all experiments. Granulocytes were incubated 48 h in RPMI 1640 and irradiated with single doses of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, and 12 Gy using a (137)Cs IBL 437L irradiator. Their function was assessed by measuring granulocytic release of reactive oxygen species (ROS) with luminol-enhanced chemiluminescence after stimulation with phorbol myristate acetate (PMA). RESULTS: Relative changes of ROS release (ROS release before stimulation was set to 100%) increased after stimulation with PMA (mean +/- standard deviation [SD]): 0 Gy: 147.6% +/- 60%; 0.5 Gy: 153.6% +/- 70%; 1.0 Gy: 164.9% +/- 63%; 1.5 Gy: 177.8% +/- 66%; 2.0 Gy: 162.5% +/- 57%; 2.5 Gy: 156.2% +/- 60%; 3.0 Gy: 159.2% +/- 60%; 3.5 Gy: 126.9% +/- 55%; 4.0 Gy: 137.9% +/- 71%; 6.0 Gy: 148.3% +/- 65%; 12.0 Gy: 156.1% +/- 52%. The relative ROS release showed a significant increase at 1.5 Gy (p < 0.001) after PMA stimulation and a significant decrease of ROS release at 3.5 Gy (p < 0.005) and less markedly at 4.0 Gy (p < 0.05). 6.0 and 12.0 Gy showed a significant (p < 0.05) increase again. CONCLUSION: This ex vivo in vitro study on native human neutrophilic granulocytes shows an increase at 1.5 Gy and a significant decrease of granulocyte function at 3.5 and 4.0 Gy, as it was described for different other phenomena in low-dose radiotherapy. These results may provide a further explanation for the local anti-inflammatory effect of low-dose ionizing irradiation.