Ten fraction hypofractionated stereotactic body radiotherapy for the management of ultracentral lung tumors: a retrospective analysis of dosimetry, outcomes, and toxicity.

BACKGROUND: The management of ultracentral thoracic tumors with ablative dose of radiotherapy remains challenging given proximity to critical central structures. We report patient outcomes, toxicity, and dosimetry for ultracentrally located tumors with hypofractionated stereotactic body radiotherapy (hfSBRT). METHODS: Seventy-eight individuals (50 initial radiotherapy, 28 re-irradiation) undergoing 10 fraction hfSBRT for ultracentrally located thoracic tumors treated between 2009 and 2020 at a single institution were retrospectively reviewed. Overall survival (OS), progression free survival (PFS), and local control (LC) were calculated. Incidence and grade of treatment related toxicity were evaluated. Dosimetric analysis of treatment plans and critical adjacent OARs was performed. RESULTS: At a median follow up time of 13 months, 1- and 3-year OS, PFS, and LC were 89%/63%, 37%/18%, and 84%/65%, respectively. Median dose was 65 Gy (BED10 = 107.25 Gy). Median primary bronchial tree maximum dose (Dmax) was 60 Gy (V50 = 0.96 cc). Median esophageal Dmax was 38 Gy (V40 = 0 cc). Median great vessel Dmax was 68 Gy (V50 = 3.53 cc). The most common ≥ grade 2 adverse event was pneumonitis, in 15 individuals (20%). Grade 3 or higher toxicity was observed in 9 individuals (12%): three cases of grade 3 pneumonitis (two re-irradiation, one initial radiotherapy), one grade 3 esophageal stricture following re-irradiation, two grade 3 endobronchial obstructions both following initial radiotherapy, and three grade 5 hemoptysis events (two re-irradiation, one initial radiotherapy). One hemoptysis event was categorized as "possibly" related to treatment, while the remaining two events were categorized as "unlikely" related to treatment in patients with clear evidence of disease progression. CONCLUSIONS: hfSBRT to ultracentral lung tumors delivered over 10 fractions is a safe and effective treatment option, with acceptable rates of toxicity and good rates of tumor control. TRIAL REGISTRATION: IRB registration number 12573.

Strongyloides colitis, a rare but important mimic of Crohn's disease, resulting in coma and multi-organ failure: a case report.

BACKGROUND: Strongyloides colitis is a severe form of strongyloidiasis that carries a high mortality rate if untreated. There is an overlapping clinical presentation between Strongyloides colitis and Crohn's disease. Here, we present a case of a patient who was diagnosed with Crohn's disease and was treated with immunosuppressant therapy which resulted in a poor outcome. CASE PRESENTATION: A middle-aged, native African male presented with diarrhea, abdominal pain, and weight loss. Colonoscopy showed some patchy inflammation in the caecum, which on biopsy was suggestive of Crohn's disease. He had a short course of steroids before being admitted to an emergency with abdominal pain, diarrhea, malnutrition, and severe weight loss. Initial conservative treatment failed, and he became acutely unwell and septic with peritonitis. Laparotomy was carried out, which showed mild inflammation in the terminal ileum, which was not resected. Postoperatively, the patient became comatose and went into multi-organ dysfunction. He failed to progress, and a further laparotomy and subtotal colectomy were performed on the 12th postoperative day. His multi-organ failure progressed, and he succumbed to death 4 days later. DISCUSSION: Strongyloides stercoralis is a parasite causing an enteric infection in animals and humans. Strongyloidiasis in immunocompetent individuals is usually an indolent disease. However, in immunocompromised individuals, it can cause hyperinfective syndrome. Patients with strongyloid colitis should undergo colonoscopy and biopsy where acute inflammation with eosinophilic infiltrates indicates parasitic infiltration of the colonic wall. Surgery is generally not indicated, and any surgical intervention with misdiagnosis of a flare-up of IBD can be very detrimental to the patient. CONCLUSION: Strongyloid colitis can very harmfully mimic Crohn's colitis, and the use of steroids and immunosuppressants can disseminate parasitic infection. Hyperinfection syndrome can lead to sepsis, organ dysfunction, and comma. Disseminated infection carries a high mortality.

Stereotactic Body Radiation Therapy for Apical Lung Tumors: Dosimetric Analysis of the Brachial Plexus and Preliminary Clinical Outcomes.

PURPOSE: Dosimetric constraints of the brachial plexus have not yet been well-established for patients undergoing stereotactic body radiation therapy (SBRT). This study evaluated long-term experience with the treatment of early-stage apical lung tumors with SBRT and reports on dosimetric correlates of outcome. METHODS AND MATERIALS: Between 2009 and 2018, a total of 78 consecutive patients with 81 apical lung tumors underwent SBRT for T1-3N0 non-small cell lung cancer. Apical tumors were those with tumor epicenter superior to the aortic arch. The brachial plexus (BP) was anatomically contoured according to the Radiation Therapy Oncology Group atlas. Patient medical records were reviewed retrospectively to determine incidence of brachial plexus injury (BPI) and a normal tissue complication probability model was applied to the dosimetric data. RESULTS: Five patients (6.4%) reported neuropathic symptoms consistent with BPI and occurred a median 11.9 months after treatment (range, 5.2-28.1 months). Most common dose and fractionation in those developing BPI were 50 Gy in 5 fractions (4 patients). Symptoms consisted of pain in 2 patients (40.0%), numbness in the hand or axilla in 4 patients (80.0%), and ipsilateral hand weakness in 1 patient (20.0%). In the overall cohort the median BP Dmax (EQD23 Gy) was 5.13 Gy (range, 0.18-217.2 Gy) and in patients with BPI the median BP Dmax (EQD23 Gy) was 32.14 Gy (range, 13.4-99.9 Gy). The normal tissue complication probability model gave good fit with an area under the curve of 0.75 (odds ratio, 7.3; 95% confidence interval, 0.8-68.3) for BP Dmax (EQD23 Gy) threshold of 20 Gy. CONCLUSIONS: Significant variation exists in the dose delivered to the brachial plexus for patients treated by SBRT for apical lung tumors. The incidence of neuropathic symptoms in the post-SBRT setting was appreciable and prospective clinical correlation with dosimetric information should be used to develop evidence-based dose constraints.

The use of whole-body fluorine-18-fluorodeoxyglucose positron emission tomography integrated with computed tomography for accurate staging and surveillance in the case of mucosa-associated lymphoid tissue.

We present the case of a 79-year-old male, who was initially treated for mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) of the right eyelid, and later for disease relapse in the stomach. During follow up, he was noted to have developed left arm nodules just medial to the proximal biceps muscle, which were found to be multiply enlarged lymph nodes on subsequent ultrasound imaging. Excisional biopsy of these nodes revealed MALT lymphoma. He was initially referred for consideration of radiation, but a restaging F-18 fluorodeoxyglucose positron emission tomography integrated with computed tomography (F-18 FDG PET/CT) further identified a focus of suspicious uptake in left calf, which was later also biopsy proven to be MALT lymphoma. His disease was upstaged as the result of this later finding, and the overall recommendation for treatment changed to favor systemic treatment with Rituximab.

Ultra-central Thoracic Re-irradiation Using 10-fraction Stereotactic Body Radiotherapy for Recurrent Non-small-cell Lung Cancer Tumors: Preliminary Toxicity and Efficacy Outcomes.

BACKGROUND: We report our clinical outcomes of patients with recurrent non-small-cell lung cancer (NSCLC) tumors with ultra-central (UC) location treated with hypofractionated 10-fraction stereotactic body radiotherapy (hSBRT) in the context of thoracic re-irradiation. PATIENTS AND METHODS: This study was conducted from 2009 to 2017 on 20 patients with recurrent NSCLC from previous thoracic radiation treatment who underwent hSBRT to 21 total UC located recurrent tumors. The planning target volumes (PTVs) that overlapped with previous treatment fields (within the 50% isodose line) were included in this analysis with endpoints of overall survival, tumor control, and toxicity. RESULTS: The median follow-up time was 17.8 months. The median total dose of hSBRT and total biologically effective dose (BED10) were 65 Gy and 107.25 Gy, respectively. The median time from previous treatment was 14.6 months. The 1-year overall survival, progression-free survival, and local control rates were 68%, 35%, and 83%, respectively. The median time to local progression was 13.3 months. The most common toxicity was grade 2 or above pneumonitis (35%). One patient, whose tumor was abutting the esophagus, experienced grade 3 esophagitis. Two (10%) patients died from "unlikely" treatment-related hemorrhage from local tumor progression at 10 and 24 months after hSBRT. Bronchoscopic evaluation of 1 patient suggested endobronchial tumor progression, and clear radiographic evidence of treated hilar tumor progression was documented in the second patient's case. CONCLUSION: Despite having a high-risk population with recurrent ultra-central NSCLC tumors in the setting of re-irradiation, our results demonstrate that ablative doses of hSBRT may serve as a feasible option for these challenging cases and concur with current reported literature.

Correlation of clinical outcome, radiobiological modeling of tumor control, normal tissue complication probability in lung cancer patients treated with SBRT using Monte Carlo calculation algorithm.

PURPOSE/BACKGROUND: We analyzed the predictive value of non-x-ray voxel Monte Carlo (XVMC)-based modeling of tumor control probability (TCP) and normal tissue complication probability (NTCP) in patients treated with stereotactic body radiotherapy (SBRT) using the XVMC dose calculation algorithm. MATERIALS/METHODS: We conducted an IRB-approved retrospective analysis in patients with lung tumors treated with XVMC-based lung SBRT. For TCP, we utilized tumor size-adjusted biological effective dose (s-BED) TCP modeling validated in non-MC dose calculated SBRT to: (1) verify modeling as a function of s-BED in patients treated with XVMC-based SBRT; and (2) evaluate the predictive potential of different PTV dosimetric parameters (mean dose, minimum dose, max dose, prescription dose, D95, D98, and D99) for incorporation into the TCP model. Correlation between observed local control and TCPs was assessed by Pearson's correlation coefficient. For NTCP, Lyman NTCP Model was utilized to predict grade 2 pneumonitis and rib fracture. RESULTS: Eighty-four patients with 109 lung tumors were treated with XVMC-based SBRT to total doses of 40 to 60 Gy in 3 to 5 fractions. Median follow-up was 17 months. The 2-year local and local-regional control rates were 91% and and 78%, respectievly. All estimated TCPs correlated significantly with 2-year actuarial local control rates (P < 0.05). Significant corelations between TCPs and tumor control rate according to PTV dosimetric parameters were observed. D99 parameterization demonstrated the most robust correlation between observed and predicted tumor control. The incidences of grade 2 pneumonitis and rib fracture vs. predicted were 1% vs. 3% and 10% vs. 13%, respectively. CONCLUSION: Our TCP results using a XVMC-based dose calculation algorithm are encouraging and yield validation to previously described TCP models using non-XVMC dose methods. Furthermore, D99 as potential predictive parameter in the TCP model demonstrated better correlation with clinical outcome.

Epigastric port retrieval of the gallbladder following laparoscopic cholecystectomy is associated with the reduced risk of port site infection and port site incisional hernia: An updated meta-analysis of randomized controlled trials.

AIMS: The objective of this article is to compare the surgical outcomes for epigastric port or umbilical port retrieval of the gallbladder (GB) following laparoscopic cholecystectomy (LC). METHODS: The data retrieved from the published randomized, controlled trials (RCT) comparing the surgical outcomes for epigastric port or umbilical port retrieval of the GB following LC was analysed using the principles of meta-analysis. The summated outcome of continuous variables was expressed as standardized mean difference (SMD) and dichotomous data was presented in odds ratio (OR). RESULTS: Eight RCTs on 2676 patients comparing the surgical outcomes for epigastric port or umbilical port retrieval of the GB following LC were analysed. In the random effects model analysis using the statistical software Review Manager 5.3, the GB retrieval through epigastric port was associated with the reduced duration of operation (SMD, 0.41; 95% CI, 0.18, 0.64; z = 3.52; P = 0.0004). Epigastric retrieval was also associated with reduced risk of surgical site infection (OR, 1.95; 95% CI, 0.75, 5.11; z = 1.36; P = 0.17), and port site incisional hernia (OR, 4.22; 95% CI, 0.43, 41.40; z = 1.24; P = 0.22) compared to umbilical port retrieval though it did not reach statistical significance. The need for port enlargement to retrieve the GB was similar in both groups. In contrast, the umbilical port retrieval of the GB was associated with significantly less post-operative pain (SMD, -0.51; 95% CI, -0.95, -0.06; z = 2.24; P = 0.03), reduced GB perforation rate, reduced port site bleeding rate and reduced difficulty in GB retrieval. CONCLUSION: GB retrieval through epigastric port following LC has clinically proven advantage of reduced retrieval site infection rate, lower operation time and incisional hernia rate but at the cost of increased pain at 24 h, higher risk of GB perforation, port site bleeding and technical difficulties.

Brachial plexopathy after stereotactic body radiation therapy for apical lung cancer: Dosimetric analysis and preliminary clinical outcomes.

PURPOSE: The treatment of apical lung tumors with stereotactic body radiation therapy (SBRT) is challenging due to the proximity of the brachial plexus and the concern for nerve damage. METHODS AND MATERIALS: Between June 2009 and February 2017, a total of 75 consecutive patients underwent SBRT for T1-T3N0 non-small cell lung cancer involving the upper lobe of the lung. All patients were treated with 4-dimensional computed tomography (CT)-based image guided SBRT to a dose of 40 to 60 Gy in 3 to 5 fractions. For dosimetric analysis, only apical tumors as defined by the location of the tumor epicenter superior to the aortic arch were included. The anatomical brachial plexus was delineated using the Radiation Therapy Oncology Group atlas. RESULTS: Thirty-one patients with 31 apical lung tumors satisfied the anatomical criteria for inclusion. The median age was 73 years (range, 58-89). The median planning target volume was 26.5 cc (range, 8.2-81.4 cc). The median brachial plexus, brachial plexus maximum dose (Dmax), Dmax per fraction, V22 (cc, 3-4 fractions), V30 (cc, 5 fractions), and biologically effective dose 3 Gy were 15.8 Gy (range, 1.7-66.5 Gy), 3.4 Gy (range, 0.6-14.7 Gy), 0.0 cc (range, 0-0.9 cc), 0.06 cc (range, 0-2.5 cc), and 31.5 Gy (range, 3.3-133.1 Gy), respectively. At a median follow-up of 17 months, the observed incidence of brachial plexopathy was 0%. CONCLUSIONS: There is significant variation in dose to the brachial plexus for patients treated with SBRT for apical lung tumors. Although the incidence of neuropathic symptoms in this series was zero, further attention should be focused on the clinical implications of these findings.

Volumetric-modulated arc therapy (VMAT) for whole brain radiotherapy: not only for hippocampal sparing, but also for reduction of dose to organs at risk.

A prospective clinical trial, Radiation Therapy Oncology Group (RTOG) 0933, has demonstrated that whole brain radiotherapy (WBRT) using conformal radiation delivery technique with hippocampal avoidance is associated with less memory complications. Further sparing of other organs at risk (OARs) including the scalp, ear canals, cochleae, and parotid glands could be associated with reductions in additional toxicities for patients treated with WBRT. We investigated the feasibility of WBRT using volumetric-modulated arc therapy (VMAT) to spare the hippocampi and the aforementioned OARs. Ten patients previously treated with nonconformal WBRT (NC-WBRT) using opposed lateral beams were retrospectively re-planned using VMAT with hippocampal sparing according to the RTOG 0933 protocol. The OARs (scalp, auditory canals, cochleae, and parotid glands) were considered as dose-constrained structures. VMAT plans were generated for a prescription dose of 30 Gy in 10 fractions. Comparison of the dosimetric parameters achieved by VMAT and NC-WBRT plans was performed using paired t-tests using upper bound p-value of < 0.001. Average beam on time and monitor units (MUs) delivered to the patients on VMAT were compared with those obtained with NC-WBRT. All VMAT plans met RTOG 0933 dosimetric criteria including the dose to hippocampi of 100% of the volume (D100%) of 8.4 ± 0.3 Gy and maximum dose of 15.6 ± 0.4 Gy, respectively. A statistically significant dose reduction (p < 0.001) to all OARs was achieved. The mean and maximum scalp doses were reduced by an average of 9 Gy (32%) and 2 Gy (6%), respectively. The mean and maximum doses to the auditory canals were reduced from 29.5 ± 0.5 Gy and 31.0 ± 0.4 Gy with NC-WBRT, to 21.8 ± 1.6 Gy (26%) and 27.4 ± 1.4 Gy (12%) with VMAT. VMAT also reduced mean and maximum doses to the cochlea by an average of 4 Gy (13%) and 2 Gy (6%), respectively. The parotid glands mean and maximum doses with VMAT were 4.4 ± 1.9 Gy and 15.7 ± 5.0 Gy, compared to 12.8 ± 4.9 Gy and 30.6 ± 0.5 Gy with NC-WBRT, respectively. The average dose reduction of mean and maximum of parotid glands from VMAT were 65% and 50%, respectively. The average beam on time and MUs were 2.3minutes and 719 on VMAT, and 0.7 minutes and 350 on NC-WBRT. This study demonstrated the feasibility of WBRT using VMAT to not only spare the hippocampi, but also significantly reduce dose to OARs. These advantages of VMAT could potentially decrease the toxicities associated with NC-WBRT and improve patients' quality of life, especially for patients with favorable prognosis receiving WBRT or patients receiving prophylactic cranial irradiation (PCI).

Patterns of lymph node positivity on 11C-acetate PET imaging in correlation to the RTOG pelvic radiation field for prostate cancer.

PURPOSE: 11C-acetate positron emission tomography (PET) imaging allows for the detection of occult metastatic disease that may otherwise go undetected with standard imaging for prostate cancer (PCa). The aim of this study was to evaluate lymph node coverage of the standard Radiation Therapy Oncology Group (RTOG) whole pelvic radiation therapy (WPRT) field in patients found to have node-positive PCa determined by 11C-acetate PET imaging. METHODS AND MATERIALS: A retrospective analysis was conducted on 125 PCa patients who underwent 11C-acetate PET scans at our institution between 2007 and 2014. Patients were included if they had evidence of nodal disease without distant metastatic cancer. Individual lymph nodes were characterized by location, size, and relationship to the RTOG WPRT field. RESULTS: A total of 55 11C-acetate PET scans (from 54 men) met criteria for inclusion in the study. Median age at diagnosis was 61 years. Median prostate-specific antigen values at diagnosis and at the time of the scan were 9.2 and 8.1 ng/mL, respectively. A total of 159 positive lymph nodes were identified, 78% of which were smaller than 1 cm. The most frequently involved lymphatic regions were the external iliacs (38.4%), para-aortics (19.5%), and common iliacs (16.3%). Additionally, 10.1% of positive nodes were identified as nodes of Cloquet. Of the positive nodes, 51.6% were determined to reside outside of the radiation field and, of those, the most common sites were para-aortic (36.9%), proximal common iliac (17.8%), distal external iliac (17.8%), and nodes of Cloquet (17.8%). CONCLUSIONS: Based on 11C-acetate PET imaging in patients with PCa, the standard RTOG WPRT field may miss more than one-half of all positive lymph nodes. Clinicians should be aware of the potential for insufficient nodal coverage when using the standard RTOG WPRT field in patients with node-positive PCa. 11C-acetate PET imaging may be useful in defining target volumes for these patients.

Linac-based stereotactic radiosurgery (SRS) in the treatment of refractory trigeminal neuralgia: Detailed description of SRS procedure and reported clinical outcomes.

PURPOSE/OBJECTIVES: To present our linac-based SRS procedural technique for medically and/or surgically refractory trigeminal neuralgia (TN) treatment and simultaneously report our clinical outcomes. MATERIALS AND METHODS: Twenty-seven refractory TN patients who were treated with a single fraction of 80 Gy to TN. Treatment delivery was performed with a 4 mm cone size using 7-arc arrangement with differential-weighting for Novalis-TX with six MV-SRS (1000 MU/min) beam and minimized dose to the brainstem. Before each treatment, Winston-Lutz quality assurance (QA) with submillimeter accuracy was performed. Clinical treatment response was evaluated using Barrow Neurological Institute (BNI) pain intensity score, rated from I to V. RESULTS: Out of 27 patients, 22 (81%) and 5 (19%) suffered from typical and atypical TN, respectively, and had median follow-up interval of 12.5 months (ranged: 1-53 months). For 80 Gy prescriptions, delivered total average MU was 19440 ± 611. Average beam-on-time was 19.4 ± 0.6 min. Maximum dose and dose to 0.5 cc of brainstem were 13.4 ± 2.1 Gy (ranged: 8.4-15.9 Gy) and 3.6 ± 0.4 Gy (ranged: 3.0-4.9 Gy), respectively. With a median follow-up of 12.5 months (ranged: 1-45 months) in typical TN patients, the proportion of patients achieving overall pain relief was 82%, of which half achieved a complete pain relief with BNI score of I-II and half demonstrated partial pain reduction with BNI score of IIIA-IIIB. Four typical TN patients (18%) had no response to radiosurgery treatment. Of the patients who responded to treatment, actuarial pain recurrence free survival rates were approximately 100%, 75%, and 50% at 12 months, 15 months, and 24 months, respectively. Five atypical TN patients were included, who did not respond to treatment (BNI score: IV-V). However, no radiation-induced cranial-toxicity was observed in all patients treated. CONCLUSION: Linac-based SRS for medically and/or surgically refractory TN is a fast, effective, and safe treatment option for patients with typical TN who had excellent response rates. Patients, who achieve response to treatment, often have durable response rates with moderate actuarial pain recurrence free survival. Longer follow-up interval is anticipated to confirm our clinical observations.

On the use of volumetric-modulated arc therapy for single-fraction thoracic vertebral metastases stereotactic body radiosurgery.

To retrospectively evaluate quality, efficiency, and delivery accuracy of volumetric-modulated arc therapy (VMAT) plans for single-fraction treatment of thoracic vertebral metastases using image-guided stereotactic body radiosurgery (SBRS) after RTOG 0631 dosimetric compliance criteria. After obtaining credentialing for MD Anderson spine phantom irradiation validation, 10 previously treated patients with thoracic vertebral metastases with noncoplanar hybrid arcs using 1 to 2 3D-conformal partial arcs plus 7 to 9 intensity-modulated radiation therapy beams were retrospectively re-optimized with VMAT using 3 full coplanar arcs. Tumors were located between T2 and T12. Contrast-enhanced T1/T2-weighted magnetic resonance images were coregistered with planning computed tomography and planning target volumes (PTV) were between 14.4 and 230.1cc (median = 38.0cc). Prescription dose was 16Gy in 1 fraction with 6MV beams at Novalis-TX linear accelerator consisting of micro multileaf collimators. Each plan was assessed for target coverage using conformality index, the conformation number, the ratio of the volume receiving 50% of the prescription dose over PTV, R50%, homogeneity index (HI), and PTV_1600 coverage per RTOG 0631 requirements. Organs-at-risk doses were evaluated for maximum doses to spinal cord (D0.03cc, D0.35cc), partial spinal cord (D10%), esophagus (D0.03cc and D5cc), heart (D0.03cc and D15cc), and lung (V5, V10, and maximum dose to 1000cc of lung). Dose delivery efficiency and accuracy of each VMAT-SBRS plan were assessed using quality assurance (QA) plan on MapCHECK device. Total beam-on time was recorded during QA procedure, and a clinical gamma index (2%/2mm and 3%/3mm) was used to compare agreement between planned and measured doses. All 10 VMAT-SBRS plans met RTOG 0631 dosimetric requirements for PTV coverage. The plans demonstrated highly conformal and homogenous coverage of the vertebral PTV with mean HI, conformality index, conformation number, and R50% values of 0.13 ± 0.03 (range: 0.09 to 0.18), 1.03 ± 0.04 (range: 0.98 to 1.09), 0.81 ± 0.06 (range: 0.72 to 0.89), and 4.2 ± 0.94 (range: 2.7 to 5.4), respectively. All 10 patients met protocol guidelines with maximum dose to spinal cord (average: 8.83 ± 1.9Gy, range: 5.9 to 10.9Gy); dose to 0.35cc of spinal cord (average: 7.62 ± 1.7Gy, range: 5.4 to 9.6Gy); and dose to 10% of partial spinal cord (average 6.31 ± 1.5Gy, range: 3.5 to 8.5Gy) less than 14, 10, and 10Gy, respectively. For all 10 patients, the maximum dose to esophagus (average: 9.41 ± 4.3Gy, range: 1.5 to 14.9Gy) and dose to 5cc of esophagus (average: 7.43 ± 3.8Gy, range: 1.1 to 11.8Gy) were kept less than protocol requirements 16Gy and 11.9Gy, respectively. In a similar manner, all 10 patients met protocol compliance criteria with maximum dose to heart (average: 4.62 ± 3.5Gy, range: 1.3 to 10.2Gy) and dose to 15cc of heart (average: 2.23 ± 1.8Gy, range: 0.3 to 5.6Gy) less than 22 and 16Gy, respectively. The dose to the lung was retained much lower than protocol guidelines for all 10 patients. The total number of monitor units was, on average, 6919 ± 1187. The average beam-on time was 11.5 ± 2.0 minutes. The VMAT plans demonstrated dose delivery accuracy of 95.8 ± 0.7%, on average, for clinical gamma passing rate with 2%/2mm criteria and 98.3 ± 0.8%, on average, with 3%/3mm criteria. All VMAT-SBRS plans were considered clinically acceptable per RTOG 0631 dosimetric compliance criteria. VMAT planning provided highly conformal and homogenous dose distributions for the lower-dose vertebral PTV and the spinal cord as well as organs-at-risk such as esophagus, heart, and lung. Higher QA pass rates and shorter beam-on time suggest that VMAT-SBRS is a clinically feasible, fast, and effective treatment option for patients with thoracic vertebral metastases.

Treatment planning strategy for whole-brain radiotherapy with hippocampal sparing and simultaneous integrated boost for multiple brain metastases using intensity-modulated arc therapy.

PURPOSE: To retrospectively evaluate the accuracy, plan quality and efficiency of intensity-modulated arc therapy (IMAT) for hippocampal sparing whole-brain radiotherapy (HS-WBRT) with simultaneous integrated boost (SIB) in patients with multiple brain metastases (m-BM). MATERIALS AND METHODS: A total of 5 patients with m-BM were retrospectively replanned for HS-WBRT with SIB using IMAT treatment planning. The hippocampus was contoured on diagnostic T1-weighted magnetic resonance imaging (MRI) which had been fused with the planning CT image set. The hippocampal avoidance zone (HAZ) was generated using a 5-mm uniform margin around the paired hippocampi. The m-BM planning target volumes (PTVs) were contoured on T1/T2-weighted MRI registered with the 3D planning computed tomography (CT). The whole-brain planning target volume (WB-PTV) was defined as the whole-brain tissue volume minus HAZ and m-BM PTVs. Highly conformal IMAT plans were generated in the Eclipse treatment planning system for Novalis-TX linear accelerator consisting of high-definition multileaf collimators (HD-MLCs: 2.5-mm leaf width at isocenter) and 6-MV beam. Prescription dose was 30Gy for WB-PTV and 45Gy for each m-BM in 10 fractions. Three full coplanar arcs with orbit avoidance sectors were used. Treatment plans were evaluated using homogeneity (HI) and conformity indices (CI) for target coverage and dose to organs at risk (OAR). Dose delivery efficiency and accuracy of each IMAT plan was assessed via quality assurance (QA) with a MapCHECK device. Actual beam-on time was recorded and a gamma index was used to compare dose agreement between the planned and measured doses. RESULTS: All 5 HS-WBRT with SIB plans met WB-PTV D2%, D98%, and V30Gy NRG-CC001 requirements. The plans demonstrated highly conformal and homogenous coverage of the WB-PTV with mean HI and CI values of 0.33 ± 0.04 (range: 0.27 to 0.36), and 0.96 ± 0.01 (range: 0.95 to 0.97), respectively. All 5 hippocampal sparing patients met protocol guidelines with maximum dose and dose to 100% of hippocampus (D100%) less than 16 and 9Gy, respectively. The dose to the optic apparatus was kept below protocol guidelines for all 5 patients. Highly conformal and homogenous radiosurgical dose distributions were achieved for all 5 patients with a total of 33 brain metastases. The m-BM PTVs had a mean HI = 0.09 ± 0.02 (range: 0.07 to 0.19) and a mean CI = 1.02 ± 0.06 (range: 0.93 to 1.2). The total number of monitor units (MU) was, on average, 1677 ± 166. The average beam-on time was 4.1 ± 0.4 minute . The IMAT plans demonstrated accurate dose delivery of 95.2 ± 0.6%, on average, for clinical gamma passing rate with 2%/2-mm criteria and 98.5 ± 0.9%, on average, with 3%/3-mm criteria. CONCLUSIONS: All hippocampal sparing plans were considered clinically acceptable per NRG-CC001 dosimetric compliance criteria. IMAT planning provided highly conformal and homogenous dose distributions for the WB-PTV and m-BM PTVs with lower doses to OAR such as the hippocampus. These results suggest that HS-WBRT with SIB is a clinically feasible, fast, and effective treatment option for patients with a relatively large numbers of m-BM lesions.

Assessment of Monte Carlo algorithm for compliance with RTOG 0915 dosimetric criteria in peripheral lung cancer patients treated with stereotactic body radiotherapy.

The purpose of the study was to evaluate Monte Carlo-generated dose distributions with the X-ray Voxel Monte Carlo (XVMC) algorithm in the treatment of peripheral lung cancer patients using stereotactic body radiotherapy (SBRT) with non-protocol dose-volume normalization and to assess plan outcomes utilizing RTOG 0915 dosimetric compliance criteria. The Radiation Therapy Oncology Group (RTOG) protocols for non-small cell lung cancer (NSCLC) currently require radiation dose to be calculated using tissue density heterogeneity corrections. Dosimetric criteria of RTOG 0915 were established based on superposition/convolution or heterogeneities corrected pencil beam (PB-hete) algorithms for dose calculations. Clinically, more accurate Monte Carlo (MC)-based algorithms are now routinely used for lung stereotactic body radiotherapy (SBRT) dose calculations. Hence, it is important to determine whether MC calculations in the delivery of lung SBRT can achieve RTOG standards. In this report, we evaluate iPlan generated MC plans for peripheral lung cancer patients treated with SBRT using dose-volume histogram (DVH) normalization to determine if the RTOG 0915 compliance criteria can be met. This study evaluated 20 Stage I-II NSCLC patients with peripherally located lung tumors, who underwent MC-based SBRT with heterogeneity correction using X-ray Voxel Monte Carlo (XVMC) algorithm (Brainlab iPlan version 4.1.2). Total dose of 50 to 54 Gy in 3 to 5 fractions was delivered to the planning target vol-ume (PTV) with at least 95% of the PTV receiving 100% of the prescription dose (V100% ≥ 95%). The internal target volume (ITV) was delineated on maximum intensity projection (MIP) images of 4D CT scans. The PTV included the ITV plus 5 mm uniform margin applied to the ITV. The PTV ranged from 11.1 to 163.0 cc (mean = 46.1 ± 38.7 cc). Organs at risk (OARs) including ribs were delineated on mean intensity projection (MeanIP) images of 4D CT scans. Optimal clinical MC SBRT plans were generated using a combination of 3D noncoplanar conformal arcs and nonopposing static beams for the Novalis-TX linear accelerator consisting of high-definition multileaf collimators (HD-MLCs: 2.5 mm leaf width at isocenter) and 6 MV-SRS (1000 MU/min) beam. All treatment plans were evaluated using the RTOG 0915 high- and intermediate-dose spillage criteria: conformity index (R100%), ratio of 50% isodose volume to the PTV (R50%), maximum dose 2 cm away from PTV in any direction (D2cm), and percent of normal lung receiving 20Gy (V20) or more. Other OAR doses were documented, including the volume of normal lung receiving 5 Gy (V5) or more, dose to < 0.35 cc of spinal cord, and dose to 1000 cc of total normal lung tissue. The dose to < 1 cc, < 5 cc, < 10 cc of ribs, as well as maximum point dose as a function of PTV, prescription dose, and a 3D distance from the tumor isocenter to the proximity of the rib contour were also examined. The biological effective dose (BED) with α/ß ratio of 3 Gy for ribs was analyzed. All 20 patients either fully met or were within the minor deviation dosimetric compliance criteria of RTOG 0915 while using DVH normalization. However, only 5 of the 20 patients fully met all the criteria. Ten of 20 patients had minor deviations in R100% (mean = 1.25 ± 0.09), 13 in R50% (mean = 4.5 ± 0.6), and 11 in D2cm (mean = 61.9 ± 8.5). Lung V20, dose to 1000 cc of normal lung, and dose to < 0.35 cc of spinal cord were met in accordance with RTOG criteria in 95%, 100%, and 100%, respectively, with exception of one patient who exhibited the largest PTV (163 cc) and experienced a minor deviation in lung V20 (mean = 4.7±3.4%). The 3D distance from the tumor isocenter to the proximal rib contour strongly correlated with maximum rib dose. The average values of BED3Gy for maximum point dose and dose to < 1 cc of ribs were higher by a factor of 1.5 using XVMC compared to RTOG 0915 guidelines. The preliminary results for our iPlan XVMC dose analyses indicate that the majority (i.e., 75% of patient population) of our patients had minor deviations when compared to the dosimetric guidelines set by RTOG 0915 protocol. When using an exclusively sophisticated XVMC algorithm and DVH normalization, the RTOG 0915 dosimetric compliance criteria such as R100%, R50%, and D2cm may need to be revised. On average, about 7% for R100%, 13% for R50%, and 14% for D2cm corrections from the mean values were necessary to pass the RTOG 0915 compliance criteria. Another option includes rescaling of the prescription dose. No further adjustment is necessary for OAR dose tolerances including normal lung V20 and total normal lung 1000 cc. Since all the clinical MC plans were generated without compromising the target coverage, rib dose was on the higher side of the protocol guidelines. As expected, larger tumor size and proximity to ribs correlated to higher absolute dose to ribs. These patients will be clinically followed to determine whether delivered MC-computed dose to PTV and the ribs dose correlate with tumor control and severe chest wall pain and/or rib fractures. In order to establish new specific MC-based dose parameters, further dosimetric studies with a large cohort of MC lung SBRT patients will need to be conducted.

Monte Carlo evaluation of tissue heterogeneities corrections in the treatment of head and neck cancer patients using stereotactic radiotherapy.

The purpose of this study was to generate Monte Carlo computed dose distributions with the X-ray voxel Monte Carlo (XVMC) algorithm in the treatment of head and neck cancer patients using stereotactic radiotherapy (SRT) and compare to heterogeneity corrected pencil-beam (PB-hete) algorithm. This study includes 10 head and neck cancer patients who underwent SRT re-irradiation using heterogeneity corrected pencil-beam (PB-hete) algorithm for dose calculation. Prescription dose was 24-40 Gy in 3-5 fractions (treated 3-5 fractions per week) with at least 95% of the PTV volume receiving 100% of the prescription dose. A stereotactic head and neck localization box was attached to the base of the thermoplastic mask fixation for target localization. The gross tumor volume (GTV) and organs-at-risk (OARs) were contoured on the 3D CT images. The planning target volume (PTV) was generated from the GTV with 0 to 5 mm uniform expansion; PTV ranged from 10.2 to 64.3 cc (average = 35.0±17.5 cc). OARs were contoured on the 3D planning CT and consisted of spinal cord, brainstem, optic structures, parotids, and skin. In the BrainLab treatment planning system (TPS), clinically optimal SRT plans were generated using hybrid planning technique (combination of 3D conformal nonco-planar arcs and nonopposing static beams) for the Novalis-Tx linear accelerator consisting of high-definition multileaf collimators (HD-MLCs: 2.5 mm leaf width at isocenter) and 6 MV-SRS (1000 MU/min) beam. For the purposes of this study, treatment plans were recomputed using XVMC algorithm utilizing identical beam geometry, multileaf positions, and monitor units and compared to the corresponding clinical PB-hete plans. The Monte Carlo calculated dose distributions show small decreases (< 1.5%) in calculated dose for D99, Dmean, and Dmax of the PTV coverage between the two algorithms. However, the average target volume encompassed by the prescribed percent dose (Vp) was about 2.5% less with XVMC vs. PB-hete and ranged between -0.1 and 7.8%. The averages for D100 and D10 of the GTV were lower by about 2% and ranged between -0.8 and 3.1%. For the spinal cord, both the maximal dose difference and the dose to 0.35 cc of the structure were higher by an average of 4.2% (ranged 1.2 to -13.6%) and 1.4% (ranged 7.5 to -11.3%), respectively, with XVMC calculation. For the brainstem, the maximal dose dif-ferences and the dose to 0.5 cc of the structure were, on average, higher by 2.4% (ranged 6.4 to -8.0%) and 3.6% (ranged 6.4 to -9.0%), respectively. For the parotids, both the mean dose and the dose to 20 cc of parotids were higher by an average of 3% (ranged -0.2 to -5.9%) and 4% (ranged -0.2 to -8%), respectively, with XVMC calculation. For the optic apparatus, results from both algorithms were similar. However, the mean dose to skin was 3% higher (ranged 0 to -6%), on average, with XVMC compared to PB-hete, although the maximum dose to skin was 2% lower (ranged -5% to 15.5%). The results from our XVMC dose calculations for head and neck SRT patients indicate small to moderate underdosing of the tumor volume when compared to PB-hete calculation. However, Vp was up to 7.8% less for the lower-neck patient with XVMC. Critical structures, such as spinal cord, brainstem, or parotids, could potentially receive higher doses when using XVMC algorithm. Given the proximity to critical structures and the smaller volumes treated with SRT in the region of the head and neck, the differences between XVMC and PB-hete calculation methods may be of clinical interest.

Potential for reduced radiation-induced toxicity using intensity-modulated arc therapy for whole-brain radiotherapy with hippocampal sparing.

The purpose of this study was to retrospectively investigate the accuracy, plan quality, and efficiency of using intensity-modulated arc therapy (IMAT) for whole brain radiotherapy (WBRT) patients with sparing not only the hippocampus (following RTOG 0933 compliance criteria) but also other organs at risk (OARs). A total of 10 patients previously treated with nonconformal opposed laterals whole-brain radiotherapy (NC-WBRT) were retrospectively replanned for hippocampal sparing using IMAT treatment planning. The hippocampus was volumetrically contoured on fused diagnostic T1-weighted MRI with planning CT images and hippocampus avoidance zone (HAZ) was generated using a 5 mm uniform margin around the hippocampus. Both hippocampi were defined as one paired organ. Whole brain tissue minus HAZ was defined as the whole-brain planning target volume (WB-PTV). Highly conformal IMAT plans were generated in the Eclipse treatment planning system for Novalis TX linear accelerator consisting of high-definition multileaf collimators (HD-MLCs: 2.5 mm leaf width at isocenter) and 6 MV beam for a prescription dose of 30 Gy in 10 fractions following RTOG 0933 dosimetric criteria. Two full coplanar arcs with orbits avoidance sectors were used. In addition to RTOG criteria, doses to other organs at risk (OARs), such as parotid glands, cochlea, external/middle ear canals, skin, scalp, optic pathways, brainstem, and eyes/lens, were also evaluated. Subsequently, dose delivery efficiency and accuracy of each IMAT plan was assessed by delivering quality assurance (QA) plans with a MapCHECK device, recording actual beam-on time and measuring planed vs. measured dose agreement using a gamma index. On IMAT plans, following RTOG 0933 dosimetric criteria, the maximum dose to WB-PTV, mean WB-PTV D2%, and mean WB-PTV D98% were 34.9 ± 0.3 Gy, 33.2 ± 0.4 Gy, and 26.0± 0.4Gy, respectively. Accordingly, WB-PTV received the prescription dose of 30Gy and mean V30 was 90.5% ± 0.5%. The D100%, and mean and maximum doses to hippocampus were 8.4 ± 0.3 Gy, 11.2 ± 0.3 Gy, and 15.6 ± 0.4 Gy, on average, respectively. The mean values of homogeneity index (HI) and conformity index (CI) were 0.23 ± 0.02 and 0.96 ± 0.02, respectively. The maximum point dose to WB-PTV was 35.3 Gy, well below the optic pathway tolerance of 37.5 Gy. In addition, compared to NC-WBRT, dose reduction of mean and maximum of parotid glands from IMAT were 65% and 50%, respectively. Ear canals mean and maximum doses were reduced by 26% and 12%, and mean and maximum scalp doses were reduced by 9 Gy (32%) and 2 Gy (6%), on average, respectively. The mean dose to skin was 9.7 Gy with IMAT plans compared to 16 Gy with conventional NC-WBRT, demonstrating that absolute reduction of skin dose by a factor of 2. The mean values of the total number of monitor units (MUs) and actual beam on time were 719 ± 44 and 2.34 ± 0.14 min, respectively. The accuracy of IMAT QA plan delivery was (98.1 ± 0.8) %, on average, with a 3%/3 mm gamma index passing rate criteria. All of these plans were considered clinically acceptable per RTOG 0933 criteria. IMAT planning provided highly conformal and homogenous plan with a fast and effective treatment option for WBRT patients, sparing not only hippocampi but also other OARs, which could potentially result in an additional improvement of the quality life (QoL). In the future, we plan to evaluate the clinical potential of IMAT planning and treatment option with hippocampal and other OARs avoidance in our patient's cohort and asses the QoL of the WBRT patients, as well as simultaneous integrated boost (SIB) for the brain metastases diseases.

Proctitis following stereotactic body radiation therapy for prostate cancer.

BACKGROUND: Proctitis after radiation therapy for prostate cancer remains an ongoing clinical challenge and critical quality of life issue. SBRT could minimize rectal toxicity by reducing the volume of rectum receiving high radiation doses and offers the potential radiobiologic benefits of hypofractionation. This study sought to evaluate the incidence and severity of proctitis following SBRT for prostate cancer. METHODS: Between February 2008 and July 2011, 269 men with clinically localized prostate cancer were treated definitively with SBRT monotherapy at Georgetown University Hospital. All patients were treated to 35-36.25Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). Rectal bleeding was recorded and scored using the CTCAE v.4. Telangiectasias were graded using the Vienna Rectoscopy Score (VRS). Proctitis was assessed via the Bowel domain of the Expanded Prostate Index Composite (EPIC)-26 at baseline and at 1, 3, 6, 9, 12, 18 and 24 months post-SBRT. RESULTS: The median age was 69 years with a median prostate volume of 39 cc. The median follow-up was 3.9 years with a minimum follow-up of two years. The 2-year actuarial incidence of late rectal bleeding ≥ grade 2 was 1.5%. Endoscopy revealed VRS Grade 2 rectal telangiectasias in 11% of patients. All proctitis symptoms increased at one month post-SBRT but returned to near-baseline with longer follow-up. The most bothersome symptoms were bowel urgency and frequency. At one month post-SBRT, 11.2% and 8.5% of patients reported a moderate to big problem with bowel urgency and frequency, respectively. The EPIC bowel summary scores declined transiently at 1 month and experienced a second, more protracted decline between 6 months and 18 months before returning to near-baseline at two years post-SBRT. Prior to treatment, 4.1% of men felt their bowel function was a moderate to big problem which increased to 11.5% one month post-SBRT but returned to near-baseline at two years post-SBRT. CONCLUSIONS: In this single institution cohort, the rate and severity of proctitis observed following SBRT is low. QOL decreased on follow-up; however, our results compare favorably to those reported for patients treated with alternative radiation modalities. Future prospective randomized studies are needed to confirm these observations.

Rectal endoscopy findings following stereotactic body radiation therapy for clinically localized prostate cancer.

BACKGROUND: Treating prostate cancer with SBRT could potentially minimize radiation proctitis by reducing high-dose rectal irradiation. In addition, it offers the potential radiobiologic benefits of hypofractionation. This study reports the endoscopic changes and the associated clinical rectal toxicity in these patients. METHODS: We reviewed the records of patients treated from 2008-2011 for localized prostate cancer who had rectal endoscopy following SBRT. SBRT was delivered either as primary treatment in 5 fractions of 7-7.25 Gy, or as an initial boost in 3 fractions of 6.5 Gy followed by conventionally fractionated radiotherapy to 45-50.4 Gy. Endoscopic changes were graded using the Vienna Rectoscopy Score (VRS). Rectal toxicity was graded via CTCAEv.4. Rectal quality of life (QOL) was assessed via the bowel domain of the EPIC-26 questionnaire. RESULTS: Fifty-one patients with a median 23 months follow-up were analyzed. Thirty-five patients completed SBRT monotherapy and 16 patients received SBRT as a boost to conventionally fractionated IMRT. The median interval from SBRT to rectal endoscopy was 13 months. Endoscopy revealed VRS Grade 1-2 telangiectasias for 10 patients and VRS Grade 1-2 mucosal edema for 12 patients. No rectal ulcerations, strictures or necrosis were observed. Grade 1-2 late rectal bleeding occurred in 10 patients. There were no CTCAEv.4 Grade ≥3 toxicities. Mean EPIC bowel scores decreased from a baseline value of 96.9 to 82.3 at 1-month, but subsequently increased to 91.0 at 24 months. CONCLUSIONS: In this cohort that is skewed towards patients with rectal complaints, the rate and severity of endoscopic changes following SBRT is low. Rectal toxicity and QOL were comparable to patients treated with other radiation modalities. Prospective trials examining the endoscopic outcomes following SBRT for prostate cancer are needed for confirmation of the findings of this study. TRIAL REGISTRATION: The Georgetown Institutional Review Board has approved this retrospective study (IRB 2009-510).

Osteoprotegerin (OPG) and related proteins (RANK, RANKL and TRAIL) in thyroid disease.

BACKGROUND: Osteoprotegerin (OPG), receptor activator of nuclear factor kappaB (RANK), RANK ligand (RANKL), and TNF related apoptosis inducing ligand (TRAIL) are the key proteins in the development of bone metastases. Osteoprotegerin improves tumor cell survival and inhibits TRAIL induced apoptosis of cancer cell lines. It also binds to RANKL and inhibits its interaction with RANK (cell surface receptor), which influences osteoclast formation and function. The aim of the present study was to characterize the expression of OPG, RANK, RANKL, and TRAIL in benign and malignant thyroid tissue and thyroid cell lines. METHODS: Archived thyroid tissue from 79 patients (60 differentiated thyroid cancers and 19 benign thyroids) was stained for OPG, RANK, RANKL, and TRAIL by immunohistochemistry. Staining was assessed semiquantitatively and correlated with pathology. Western blots were performed on three human thyroid cell lines: Nthy-ori 3-1 (thyroid follicular epithelium), FTC-133 (follicular thyroid carcinoma), and K1E7 (subclone of papillary thyroid carcinoma). RESULTS: Osteoprotegerin and RANKL staining was cytoplasmic; RANK staining was nuclear; and TRAIL staining was predominantly cytoplasmic. All four proteins were expressed in benign and malignant tissue. There was significant difference in RANK expression between malignant and benign tissue (8 vs. 84%, respectively; Fisher's exact test; P < 0.001). RANKL expression was significantly increased in malignant tissue (Fisher's exact test; P = 0.04). Western blotting showed OPG expression in all cell lines and TRAIL in none. RANK and RANKL were not detected in papillary and follicular cell lines, respectively. CONCLUSIONS: Nuclear expression of RANK protein in thyroid tissue is paradoxical; it could be due to nuclear migration after ligand binding. Suppression of RANK and increased expression of RANKL in malignant tissue warrant further investigation.

Spontaneous resolution of solitary rectal ulcer syndrome during pregnancy: report of a case.

Solitary rectal ulcer syndrome is a rare condition that is associated with disordered defecation and is thought to be an ischemic injury from repeated mucosal trauma. Treatment is designed to alleviate the underlying defecatory problems and is only moderately successful. We report an interesting case of solitary rectal ulcer syndrome in a young woman, which was resistant to standard nonoperative management but completely resolved during two pregnancies only to recur when she was not pregnant, and we suggest a possible hormonal explanation for this unique occurrence.