Search

Aim To analyze the outcomes using the hypofractionated palliative radiotherapy regimen "QUAD-Shot" with concurrent radiosensitizing chemotherapy for advanced head and neck cancer. Materials and methods We analyzed twenty-one patients with newly-diagnosed or recurrent head and neck cancer treated with palliative hypofractionated concurrent chemoradiation using the QUAD-Shot regimen. Results All patients received at least one cycle of RT, with sixteen patients (76%) completing all three cycles. 85.7 % of patients had objective response to therapy with five patients (23.8%) demonstrating complete response (CR) and thirteen patients (61.9%) demonstrating partial response (PR). Palliation of symptoms was achieved in all (100%) of the sixteen patients that completed the three cycles. Median overall survival and median progression-free survival were 7 and 4 months, respectively. Conclusion QUAD-Shot palliative radiation therapy coupled with radiosensitizing chemotherapy is efficacious and well-tolerated in patients with newly-diagnosed or recurrent head and neck cancer not amenable to curative therapy.

Patients diagnosed with head and neck cancer are traditionally treated with photon radiotherapy. Proton therapy is currently being used clinically and may potentially reduce treatment-related toxicities by minimizing the dose to normal organs in the treatment of postoperative oropharyngeal cancer. The finite range of protons has the potential to significantly reduce normal tissue toxicity compared to photon radiotherapy. Seven patients were planned with both proton and photon modalities. The planning goal for both modalities was achieving the prescribed dose to 95% of the planning target volume (PTV). Dose-volume histograms were compared in which all cases met the target coverage goals. Mean doses were significantly lower in the proton plans for the oral cavity (1771cGy photon vs 293cGy proton, p < 0.001), contralateral parotid (1796cGy photon vs 1358 proton, p < 0.001), and the contralateral submandibular gland (3608cGy photon vs 3251cGy proton, p = 0.03). Average total integral dose was 9.1% lower in proton plans. The significant dosimetric sparing seen with proton therapy may lead to reduced side effects such as pain, weight loss, taste changes, and dry mouth. Prospective comparisons of protons vs photons for disease control, toxicity, and patient-reported outcomes are therefore warranted and currently being pursued.

The impact of the coronavirus disease 2019 (COVID-19) pandemic on the management of head and neck cancer must be addressed. Immediate measures to reduce transmission rates and protect patients and providers take priority and necessitate some delays in care, particularly for patients with mild symptoms or less aggressive cancers. However, strict guidelines have yet to be developed, and many unintentional delays in care are to be expected based on the magnitude of the looming public health crisis. The medical complexity of head and neck cancer management may lead to prolonged delays that worsen treatment outcomes. Therefore, those caring for patients with head and neck cancer must take action to reduce these negative impacts as the country rallies to overcome the challenges posed by this pandemic.

Objective: One approach to reduce treatment-related morbidity for human papilloma virus (HPV)-associated tonsil cancer is omitting radiotherapy to the contralateral neck. Pathologic risk factors for early contralateral neck disease, however, are poorly understood. We report on the risk contralateral neck failures from the time of pre-operative diagnostic imaging to time of planning for adjuvant radiation in a single institution series of HPV-associated tonsillar cancer patients undergoing surgery followed by radiotherapy (RT). Methods: Retrospective analysis of 123 patients with T1–T3 HPV-positive tonsillar squamous cell carcinoma treated between 2010 and 2016 with transoral robotic surgery and selective ipsilateral neck dissection followed by adjuvant RT. Contralateral neck recurrence was classified as the detection of a pathologic node in the contralateral neck prior to initiation of adjuvant RT. Results: Seven patients (5.7%) developed contralateral neck disease/failure between the time of pre-operative diagnostic neck imaging and time of planning of adjuvant radiation. Increased ratio of positive/resected nodes [odds ratio (OR) 1.073, p = 0.005] was significantly associated with increased risk of contralateral neck recurrence, with a trend found for close/positive margins (OR 5.355, p = 0.06), tumor size (OR 2.046, p = 0.09), and total number of nodes positive (OR 1.179, p = 0.062). Conclusions: Patients who develop very early contralateral neck disease, between completion of ipsilateral neck dissection and the initiation of radiotherapy, have a higher ratio of positive nodes to total nodes resected in the ipsilateral neck. These findings suggest that proper selection of patients for omission of treatment of the contralateral, node-negative neck should be made with this in mind, with future studies needed to document the impact on toxicity and disease outcomes from such an approach. Advances in knowledge: Pathologic risk factors in the dissected, ipsilateral neck in patients with tonsil cancer may inform the risk of contralateral neck failure. Patient selection for future, prospective efforts to examine sparing of the contralateral neck need to be based with these risk factors in mind.

Despite the fact that a large portion of medical students pursue training in a cancer-related discipline, oncology is emphasized to a disproportionately lesser extent than are other disciplines in medical school. Medical students have wide gaps in their oncology-specific knowledge, and undergraduate medical education fails to address the multidisciplinary nature of oncology. To address these shortcomings and improve medical students’ understanding of the multidisciplinary nature of oncology, we have instituted a clinical oncology elective for medical students: an optional, 2-day session held after classes and promoted by student interest groups. Day 1 comprised a series of short faculty lectures beginning with the concepts of and rationale for staging, an approach to breaking bad news, guideline-based management, and multidisciplinary tumor board discussion. Three multidisciplinary tumor boards were simulated on the second day, run by attending surgeons, medical oncologists, and radiation oncologists with expertise in the cancer of interest, using real patient examples. Ultimately, the clinical oncology elective shows medical students how the oncology care team works together to care for cancer patients.

Management of melanoma has been revolutionized by the use of immune checkpoint inhibitors. Immune system changes associated with aging may affect the efficacy of immune-based therapies. Using the National Cancer Database, we evaluated the impact of age on the receipt and efficacy of modern immunotherapies in patients with metastatic melanoma. We identified 11,944 patients from 2011–2015, of whom 25% received immunotherapy. Older (≥60 years), compared with younger, patients were less likely to receive immunotherapy (odds ratio, 0.69; 95% confidence interval [CI], 0.61–0.78; p < .001). Immunotherapy was associated with a survival benefit in both younger and older patients (

Background For patients with head and neck squamous cell carcinoma (SCC) undergoing surgery followed by postoperative radiotherapy (PORT), time from surgery to completion of adjuvant therapy, "package time" impacts locoregional control (LRC). However, the significance of package time in HPV+ oropharyngeal SCC (OPSCC) is unknown. Methods We examined patients undergoing TORS resection with PORT for HPV+ OPSCC from January 2010 to December 2015 with ≥18 months follow-up (n = 267). A cutoff of 15 weeks was used to delineate patients into short and long package time groups. LRC loss was defined as any recurrence after surgery. Results Prolonged package time >15 weeks was associated with inferior LRC in this HPV+ OPSCC cohort, driven primarily by interval from surgery to PORT initiation. Multivariate analysis showed that package time and T classification are both independently associated with LRC. Conclusions Among HPV+ OPSCC, prolongation of package time appears to compromise LRC, but not survival.

OBJECTIVE In patients with head and neck carcinoma of unknown primary (HNCUP;pT0) following TORS-assisted workup, we have adopted a pharyngeal-sparing radiation therapy (PSRT) approach targeting only the at-risk neck and omitting treatment of the pharynx. We report outcomes following PSRT, and compare to institutional historical control subjects who received pharyngeal-targeted RT (PRT). METHODS Between 2009 and 2018, 172 patients underwent TORS-assisted endoscopy as part of their workup for HNCUP. Following TORS, 54 patients had pT0 disease, of which 45 received RT. Forty-nine percent received PSRT and 51% received PRT. RESULTS No statistically significant differences existed between the PSRT and PRT groups with respect to overall nodal distribution, p16 positivity (55% vs. 43%, P = .12), neck dissection rates (77% vs. 65%, P = .51), and administration of chemotherapy (55% vs. 65%, P = .55). Median follow-up for PSRT and PRT groups were 24 and 28 months, respectively (P = .04). Two-year RFS was 86% and 74% for PSRT and PRT patients, respectively (log-rank P = .30). Three and six patients recurred after PSRT and PRT, respectively. Two-year OS for PSRT and PRT patients was 91% and 74%, respectively (log-rank P = .31). Compared to PRT, PSRT was associated with statistically significantly less: grade 2+ mucositis (18% vs. 91%, P

Contouring (segmentation) of Organs at Risk (OARs) in medical images is required for accurate radiation therapy (RT) planning. In current clinical practice, OAR contouring is performed with low levels of automation. Although several approaches have been proposed in the literature for improving automation, it is difficult to gain an understanding of how well these methods would perform in a realistic clinical setting. This is chiefly due to three key factors - small number of patient studies used for evaluation, lack of performance evaluation as a function of input image quality, and lack of precise anatomic definitions of OARs. In this paper, extending our previous body-wide Automatic Anatomy Recognition (AAR) framework to RT planning of OARs in the head and neck (H&N) and thoracic body regions, we present a methodology called AAR-RT to overcome some of these hurdles. AAR-RT follows AAR's 3-stage paradigm of model-building, object-recognition, and object-delineation. Model-building: Three key advances were made over AAR. (i) AAR-RT (like AAR) starts off with a computationally precise definition of the two body regions and all of their OARs. Ground truth delineations of OARs are then generated following these definitions strictly. We retrospectively gathered patient data sets and the associated contour data sets that have been created previously in routine clinical RT planning from our Radiation Oncology department and mended the contours to conform to these definitions. We then derived an Object Quality Score (OQS) for each OAR sample and an Image Quality Score (IQS) for each study, both on a 1-to-10 scale, based on quality grades assigned to each OAR sample following 9 key quality criteria. Only studies with high IQS and high OQS for all of their OARs were selected for model building. IQS and OQS were employed for evaluating AAR-RT's performance as a function of image/object quality. (ii) In place of the previous hand-crafted hierarchy for organizing OARs in AAR, we devised a method to find an optimal hierarchy for each body region. Optimality was based on minimizing object recognition error. (iii) In addition to the parent-to-child relationship encoded in the hierarchy in previous AAR, we developed a directed probability graph technique to further improve recognition accuracy by learning and encoding in the model "steady" relationships that may exist among OAR boundaries in the three orthogonal planes. Object-recognition: The two key improvements over the previous approach are (i) use of the optimal hierarchy for actual recognition of OARs in a given image, and (ii) refined recognition by making use of the trained probability graph. Object-delineation: We use a kNN classifier confined to the fuzzy object mask localized by the recognition step and then fit optimally the fuzzy mask to the kNN-derived voxel cluster to bring back shape constraint on the object. We evaluated AAR-RT on 205 thoracic and 298 H&N (total 503) studies, involving both planning and re-planning scans and a total of 21 organs (9 - thorax, 12 - H&N). The studies were gathered from two patient age groups for each gender - 40-59 years and 60-79 years. The number of 3D OAR samples analyzed from the two body regions was 4301. IQS and OQS tended to cluster at the two ends of the score scale. Accordingly, we considered two quality groups for each gender - good and poor. Good quality data sets typically had OQS ≥ 6 and had distortions, artifacts, pathology etc. in not more than 3 slices through the object. The number of model-worthy data sets used for training were 38 for thorax and 36 for H&N, and the remaining 479 studies were used for testing AAR-RT. Accordingly, we created 4 anatomy models, one each for: Thorax male (20 model-worthy data sets), Thorax female (18 model-worthy data sets), H&N male (20 model-worthy data sets), and H&N female (16 model-worthy data sets). On "good" cases, AAR-RT's recognition accuracy was within 2 voxels and delineation boundary distance was within ∼1 voxel. This was similar to the variability observed between two dosimetrists in manually contouring 5-6 OARs in each of 169 studies. On "poor" cases, AAR-RT's errors hovered around 5 voxels for recognition and 2 voxels for boundary distance. The performance was similar on planning and replanning cases, and there was no gender difference in performance. AAR-RT's recognition operation is much more robust than delineation. Understanding object and image quality and how they influence performance is crucial for devising effective object recognition and delineation algorithms. OQS seems to be more important than IQS in determining accuracy. Streak artifacts arising from dental implants and fillings and beam hardening from bone pose the greatest challenge to auto-contouring methods.

6047 Background: Increasing use of transoral robotic surgery (TORS) for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is likely to impact recurrence patterns and outcomes. Profiling HPV+ HNSCC recurrences after TORS and identifying features predictive of lethal outcome would facilitate tailoring adjuvant therapy and guide surveillance post-therapy. This study uses long term follow-up of patients at the first institution to bring TORS into clinical use to describe the recurrence patterns, distinguish outcomes associated with distinct patterns, and create a risk model for lethal recurrence. Methods: This retrospective cohort study at a single academic tertiary center analyzed 634 consecutive, treatment-naïve HPV+ HNSCC patients receiving TORS and neck dissection for clinical features at presentation and pathologic traits identified by surgical resection. The main outcomes were distant metastatic recurrence (DMR) and locoregional recurrence (LRR). Multivariate logistic regression with backward stepwise elimination was used to identify features associated with recurrence. Results: 6.5% of patients developed DMR at a median of 12.4 months after surgery and had a 5-year overall survival (OS) of 52.5% (95% CI, 33.9%-68.2%), whereas the 6.2% patients developing LRR alone had 5-year OS of 83.3% (95% CI, 66.2%-92.2%; P =.01). After recurrence, 5-year progression-free survival was 24.7% (95% CI, 11.4%-40.7%) for DMR cases and 85.7% (95% CI, 65.1-94.6%) for cases with LRR alone (P

Objectives Comparisons of induction chemotherapy (IC) against upfront chemoradiation (CRT) for locally advanced head and neck cancer (LA-HNSCC) have demonstrated no differences except greater toxicity with IC. Effective induction regimens that are less toxic are therefore warranted. To inform future efforts with IC, we present our institutional experience comparing a less toxic IC regimen to CRT. Methods We included patients with LA-HNSCC treated with organ-preservation CRT (+/-induction) between 2008 and 2011. Patients were of age above 18 years, ECOG performance status 0-1, and had minimum 6 months follow-up. IC consisted of 8 weekly cycles of cetuximab, carboplatin, and paclitaxel followed by CRT. The CRT regimen was platinum based, with cetuximab reserved for patients contraindicated to receive platinum. Results Of 118 patients, 24 (20%) received IC and 94 (80%) received CRT. Median follow-up was 17 (IC) and 19 (CRT) months (P=0.05). There were no differences in toxicity between the groups. IC patients were more likely male, with more advanced tumor and nodal stage. Even when controlling for these factors, IC was still associated with worse locoregional control (HR=3.6, P=0.02), distant metastasis-free survival (HR=5.3, P=0.02), and overall survival (HR=5.1, P Conclusions IC patients had greater disease burden than those receiving CRT. IC was well tolerated, but with significant rates of locoregional and systemic failures. Given the retrospective nature of the study, our findings are not meant to be definitive or conclusive, but rather suggestive in directing future efforts with IC. For now, we favor CRT as the standard option for treatment of inoperable LA-HNSCC.

10054 Background: Checkpoint blockade improves survival in patients with melanoma, with durable complete responses (CR) after stopping therapy. Based on data from KEYNOTE-001, immunotherapy is often continued for 24 months in patients with confirmed CR. Outcomes with treatment of less than 24 months hav not been adequately evaluated and reported. If equally efficacious, shorter courses would potentially reduce health care costs and toxicity. Methods: 45 patients with locally advanced stage III and IV melanoma who received immunotherapy (pembrolizumab, nivolumab or ipilimumab/nivolumab) as 1st line or subsequent therapy, achieved a CR, and stopped therapy were identified under an IRB approved protocol at Penn. Disease Free Survival (DFS) was defined as time from declaration of CR until recurrence or date of analysis (1/15/20). Landmark DFS from time of CR was analyzed based on duration of therapy (less than or greater than 7 months, based on early trial requirements to treat patients with confirmed CR for at least 6 months). Rationale for stopping (toxicity or CR) was also analyzed. Results: Of 45 patients with CR, 27 (60%) were treated less then 7 months (median 4.8, range 1 day to 6.7 months) and 18 (40%) were treated for greater than 7 months (median 12.4, range 7.5 to 24.2 months). Patients who were treated for less than 7 months had a median DFS from time of CR of 30.4 months (95% CI 23.7 to 37.2, range 2.9 to 65.7 months). Patients treated for greater than 7 months had a median DFS of 28.0 months (95% CI 18.9 to 37, range 8.5 to 73.7 months). Patients who stopped due to toxicity (N = 17, 40%) had a median treatment duration of 3.7 months. Their median DFS from time of CR was 30.4 months (95% CI 20.7 to 40.1, range of 2.9 to 65.7 months). Patients who stopped due to CR (N = 28, 60%) had a median treatment duration of 8.5 months. Their median DFS was 27.6 months (95% CI 21.2 to 34 range 7.2 to 73.7 months). Two of 27 (7.4%) patients treated for less then 7 months and 3 out of 18 (16%) patients treated greater than 7 months recurred after stopping. One out of 17 (5.8%) recurred after stopping for toxicity vs. 4/28 (14.3%) who stopped after CR. Conclusions: Patients who stop therapy at less than 7 months have CRs that are equally durable as those treated longer than 7 months, without reduction in landmark DFS. Patients who stopped therapy due to toxicity and then achieved a CR had no difference in DFS compared to patients treated until CR. There was no significant difference in recurrence after achieving a complete response in patients treated for a longer vs shorter treatment course.

Objective: To evaluate dosimetric consequences of inter-fraction setup variation and anatomical changes in patients receiving multifield optimised (MFO) intensity modulated proton therapy for post-operative oropharyngeal (OPC) and oral cavity (OCC) cancers. Methods: Six patients receiving MFO for post-operative OPC and OCC were evaluated. Plans were robustly optimised to clinical target volumes (CTVs) using 3 mm setup and 3.5% range uncertainty. Weekly online cone beam CT (CBCT) were performed. Planning CT was deformed to the CBCT to create virtual CTs (vCTs) on which the planned dose was recalculated. vCT plan robustness was evaluated using a setup uncertainty of 1.5 mm and range uncertainty of 3.5%. Target coverage, D95%, and hotspots, D0.03cc, were evaluated for each uncertainty along with the vCT-calculated nominal plan. Mean dose to organs at risk (OARs) for the vCT-calculated nominal plan and relative % change in weight from baseline were evaluated. Results: Robustly optimised plans in post-operative OPC and OCC patients are robust against inter-fraction setup variations and range uncertainty. D0.03cc in the vCT-calculated nominal plans were clinically acceptable across all plans. Across all patients D95% in the vCT-calculated nominal treatment plan was at least 100% of the prescribed dose. No patients lost ≥10% weight from baseline. Mean dose to the OARs and max dose to the spinal cord remained within tolerance. Conclusion: MFO plans in post-operative OPC and OCC patients are robust to inter-fraction uncertainties in setup and range when evaluated over multiple CT scans without compromising OAR mean dose. Advances in knowledge: This is the first paper to evaluate inter-fraction MFO plan robustness in post-operative head and neck treatment.

56 Background: Recent studies suggest that changes in the gut microbiome modulate response to cancer treatment, including immune checkpoint inhibitors (ICI). Broad-spectrum antibiotics (Abx) are known to cause significant dysbiosis. We hypothesize that recent Abx exposure worsens outcomes in patients (pts) with stage III/IV melanoma (MM) receiving ICI. Methods: We identified MM pts treated with ICI from our institutional database. All received their first ICI between 2004-2019. Antibiotic exposure was defined as receipt of Abx within 3 months prior to the first infusion of ICI. The primary outcome was overall survival (OS) and the secondary outcome was immune-mediated colitis requiring intravenous (IV) steroids. Stage III and IV pts were analyzed separately for the primary analysis. Results: Of 568 pts in our database, 20% received Abx within the 3 months prior to ICI. 36% of pts had stage III disease and 26% of pts were treated with either adjuvant or neoadjuvant ICI. 1.6% of pts died of causes other than MM. The Abx+ and Abx- groups were balanced in terms of stage, race, age, sex, BRAF status, LDH, prior systemic therapies, and class of ICI received. Only 4 pts were hospitalized due to the infection prompting the Abx, and no pts died due to the infection. In the Stage IV group, Abx+ pts had worse OS on MV analysis (HR 1.6, 95% CI 1.1-2.2). Stage III Abx+ also had worse OS (HR 2.8, 95% CI 1.3-5.9). In a sensitivity analysis excluding pts who received IV Abx or were admitted due to infection, survival was still worse for Abx+ pts (HR 1.7, 95% CI 1.2-2.4). In a Fine-Grey competing risk MV model, Abx+ had a higher rate of immune-mediated colitis requiring IV steroids (HR 2.1, 95% CI 1.02-4.5). Conclusions: In MM pts treated with ICI, receipt of Abx within 3 months prior to ICI initiation was associated with decreased OS and increased colitis. Future research should include prospective studies to better define the risk/benefit profile of antibiotics in close proximity to ICI. [Table: see text]

Purpose A new dual-layer multi-leaf collimator (MLC) system with several improved characteristics was introduced with the Varian Halcyon™ treatment platform. This study evaluated this new MLC’s impact on head and neck plan quality and delivery efficiency. Methods Nine patients were retrospectively studied with Institutional Review Board (IRB) approval. To compare plan quality between the Halcyon dual-layer MLC and Truebeam® MLC, all patients were replanned with the same prescription and target coverage following the institutional clinical protocol for both platforms and using both intensity modulated radiation therapy (IMRT) or volumetrically modulated arc therapy (VMAT) techniques. Organs-at-risk (OAR) dose-volume histogram (DVH) statistics were compared along with total plan monitor units (MU). To evaluate delivery efficiency, actual beam-on time for five patients’ plans were recorded and compared. To evaluate the impact of MLC performance parameters on plan quality, virtual MLC models were generated by matching Truebeam MLC’s parameters to those of the Halcyon dual-layer MLC both individually and combined. OAR doses were then compared between these virtual MLCs, the Truebeam MLC, and the actual Halcyon MLC. Results Overall the Halcyon dual-layer MLC provided similar plan quality compared to Truebeam MLC for VMAT plans, and improved sparing for majority of the OARs when using IMRT. Paired comparison showed median dose differences in mean doses to the parotids, cochlea, esophagus, and larynx ranged from -0.83 Gy to 0.37 Gy for VMAT, and from -4.79 Gy to -0.04 Gy for IMRT, with negative values indicating improved performance by Halcyon. Despite a slight increase in plan MU, the Halcyon reduced the total beam-on time by 42.8 ± 8.5%. Virtual MLC simulations demonstrated that matching MLC transmission accounted for nearly half of the total dose difference between Halcyon and Truebeam IMRT plans. Conclusion When compared to the Truebeam, the Halcyon’s dual-layer MLC achieved similar plan quality using VMAT, and improved OAR sparing using IMRT, while providing nearly twice as fast treatment delivery. Reduction in MLC transmission is the dominating factor contributing to dosimetric differences in OAR sparing.

Objectives Stereotactic body radiotherapy (SBRT) is potentially curative treatment for small hepatocellular carcinomas (HCC), but data are limited on its efficacy and toxicity. We hypothesized that SBRT can achieve excellent local control (LC) with acceptable toxicity treating HCC lesions, even in advanced cirrhosis. Materials and methods Thirty-seven nonmetastatic HCC patients received SBRT to 43 lesions between October 2012 and April 2016. Median dose was 50 Gy/5 fractions. All Child-Pugh (CP) ≥B patients underwent a planned 1-month break after the first 3 fractions to assess hepatic toxicity. Patients were treated without separately placed fiducial markers using Linac-based SBRT with breath-hold (67%) or 4D-computed tomography with compression belt (33%) to reduce motion. Patients underwent magnetic resonance imaging q3 months post-SBRT. Results Median age was 65 (range, 44 to 88). Pre-SBRT mean CP was 6.4 (range, A5 to C11). Nine (24%) had CP≥B8. Thirty-one of 33 patients (93%) had prior liver-directed therapy (median 2). Seventeen (40%) had solitary lesions. Median lesion diameter was 2.7 cm (range, 1.1 to 5.6). Median follow-up was 14 months (range, 2 to 45). There was 1 local failure (multifocal HCC with 3 prior transarterial chemoembolization). LC, freedom from liver progression, and overall survival at 12 months was 95%, 66%, 87% in the full cohort, and 100%, 76%, 93% for patients with solitary lesions. Four had grade 3 toxicity (ascites [n=2]/gastrointestinal bleed [n=1]/capsular pain [n=1]). Eight of 9 CP≥B8 patients had no grade ≥3 hepatic toxicity. Conclusions SBRT for HCC is well-tolerated even in patients with advanced cirrhosis and prior liver-directed treatment and provides excellent LC even for larger lesions that cannot be controlled with radiofrequency ablation. LC with SBRT compares favorably to other liver-directed therapies. Prospective studies comparing SBRT with other liver-directed therapies are warranted.

Contouring of the organs at risk is a vital part of routine radiation therapy planning. For the head and neck (H and N) region, this is more challenging due to the complexity of anatomy, the presence of streak artifacts, and the variations of object appearance. In this paper, we describe the latest advances in our Automatic Anatomy Recognition (AAR) approach, which aims to automatically contour multiple objects in the head and neck region on planning CT images. Our method has three major steps: model building, object recognition, and object delineation. First, the better-quality images from our cohort of H and N CT studies are used to build fuzzy models and find the optimal hierarchy for arranging objects based on the relationship between objects. Then, the object recognition step exploits the rich prior anatomic information encoded in the hierarchy to derive the location and pose for each object, which leads to generalizable and robust methods and mitigation of object localization challenges. Finally, the delineation algorithms employ local features to contour the boundary based on object recognition results. We make several improvements within the AAR framework, including finding recognition-error-driven optimal hierarchy, modeling boundary relationships, combining texture and intensity, and evaluating object quality. Experiments were conducted on the largest ensemble of clinical data sets reported to date, including 216 planning CT studies and over 2,600 object samples. The preliminary results show that on data sets with minimal (

Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced pancreatic carcinoma. We performed a phase 1 study using a 3 + 3 dose escalation strategy to determine the safety and tolerability of dose-escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with two cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy. Nine patients received nab-paclitaxel at a dose level of either 100 mg/m2 (n = 3) or 125 mg/m2 (n = 6). There were no observed grade 3 gastrointestinal toxicities. One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m2 of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%) and neutropenia (11%). No grade 4 toxicities were observed. Following chemoradiotherapy, four patients (borderline resectable, n = 2 and unresectable, n = 2) underwent surgical resection, all with negative margins and with significant treatment effect with limited tumor viability. The combination of fractionated radiation and weekly full dose nab-paclitaxel was safe and well-tolerated.

Purpose: To investigate the potential impact of anatomic change in the treatment of locally advanced oropharyngeal cancer with proton pencil beam scanning. Materials and Methods: Ten patients with locally advanced oropharyngeal cancer who previously received intensity-modulated radiation therapy (IMRT) and synchronous chemotherapy underwent replanning by using RapidArc IMRT and proton pencil beam scanning. Deformable image registration deformed the planning computed tomography (CT), target volumes, and organs at risk (OARs) contours onto each weekly cone-beam CT scan. Target and OARs volumes were reviewed and modified. Treatment plans were forward calculated onto each corrected cone-beam CT scan and dose-volume histograms produced for targets and OARs volumes. Results: Proton pencil beam scanning compared with RapidArc IMRT achieved lower mean doses to the contralateral parotid gland (14.8 Gy versus 20.6 Gy, P

BACKGROUND The purpose of this study was to determine national disparities in head and neck cancer treatment package time (the time interval from surgery through the completion of radiation) and the associated impact on survival. METHODS We conducted an observational cohort study using the National Cancer Database of 15 234 patients with resected head and neck cancer who underwent adjuvant radiotherapy from 2004-2012. Predictors of prolonged package time were identified by multivariable linear regression. Survival outcomes were assessed using a multivariable Cox model. RESULTS Mean package time was 100 days (SD 23). Package time was 7.52 days (95% confidence interval [CI] 6.23-8.81; P

We evaluated whether staging with positron emission tomography (PET) or treatment with rituximab after involved-field radiation therapy (IFRT) results in an improved progression-free survival (PFS) for early-stage indolent non-Hodgkin lymphoma (NHL).We identified 42 patients with stage I/II low-grade NHL treated with initial IFRT at our institution between 1992 and 2009, who had been staged with computed tomography (CT) or PET. A retrospective analysis was performed to evaluate PFS according to staging by CT or PET, and by receipt of rituximab after IFRT.Overall PFS was 68% and 61% at 5 and 10 years, respectively. There was no significant difference in PFS whether patients were staged by CT (n=17) or by PET (n=25), with 5-year PFS rates of 76% and 60%, respectively. Eleven patients received 4 weekly doses of rituximab after IFRT, with no improvement in 5-year PFS: 46% for rituximab-treated patients versus 72% for patients who were not given rituximab. However, more patients who were given rituximab were stage II.Patients with limited stage indolent NHL staged with either CT or PET and treated with IFRT have favorable PFS compared with historical controls. The administration of 4 weekly doses of rituximab after IFRT did not improve PFS in these patients. The use of rituximab in this setting should be evaluated in a randomized prospective study.

OBJECTIVES/SPECIFIC AIMS: Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of ~16 months. Novel methods to improve local control are needed. Nab-paclitaxel (abraxane) has shown efficacy in pancreatic cancer and is FDA approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced disease. METHODS/STUDY POPULATION: We performed a phase 1 study using a 3+3 dose-escalation strategy to determine the safety and tolerability of dose escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with 2 cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy. RESULTS/ANTICIPATED RESULTS: Nine patients received nab-paclitaxel at a dose level of either 100 mg/m2 (n=3) or 125 mg/m2 (n=6). One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m2 of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%), and neutropenia (11%). No grade 4 toxicities were observed. With a median follow-up of 8 months (range 5–28 months), median survival was 19 months and median progression-free survival was 10 months. Following chemoradiation, 3 patients underwent surgical resection, all with negative margins and limited tumor viability. Of the 3 patients, 2 initially had borderline resectable tumors and 1 had an unresectable tumor. Tumor (SMAD-4, Caveolin-1) and peripheral (circulating tumor cells and microvesicles) biomarkers were collected and are being analyzed. DISCUSSION/SIGNIFICANCE OF IMPACT: The combination of fractionated radiation and weekly nab-paclitaxel was safe and well tolerated. This regimen represents a potentially promising therapy for patients with unresectable and borderline resectable pancreatic cancer and warrants further investigation.

Natural killer T (NKT) cells have recently been implicated in atherogenesis, primarily for their ability to recognize and respond to lipid antigens. Because the atherosclerotic lesion is characterized by the retention and modification of lipids in the vascular wall, NKT cells may be involved in promoting the local vascular inflammatory response. Here, we investigate the proatherogenic role of NKT cells in an adoptive transfer model of atherosclerosis, using as recipients immune-deficient, atherosclerosis-susceptible RAG1(-/-)LDLR(-/-) mice. The adoptive transfer of an NKT cell-enriched splenocyte population from Valpha14Jalpha18 T-cell receptor transgenic mice resulted in a 73% increase in aortic root lesion area compared with recipients of NKT cell-deficient splenocytes derived from CD1d(-/-) mice after 12 weeks of Western-type diet feeding. The total serum from hypercholesterolemic mice leads to a small but significant activation of Valpha14Jalpha18 T-cell receptor-expressing hybridoma line by dendritic cells that is CD1d-dependent. Therefore, these studies demonstrate that NKT cells are proatherogenic in the absence of exogenous stimulation, and this activity is likely associated with endogenous lipid antigens carried by lipoproteins in the circulation and perhaps also in the atherosclerotic plaque.

Purpose Reirradiation to the esophagus carries a significant risk of complications. Proton therapy may offer an advantage in the reirradiation setting due to the lack of exit dose and potential sparing of previously radiated normal tissues. Methods and Materials Between June 2010 and February 2014, 14 patients with a history of thoracic radiation and newly diagnosed or locally recurrent esophageal cancer began proton beam reirradiation on a prospective trial. Primary endpoints were feasibility and acute toxicity. Toxicity was graded according Common Toxicity Criteria version 4.0. Results The median follow-up was 10 months (2-25 months) from the start of reirradiation. Eleven patients received concurrent chemotherapy. The median interval between radiation courses was 32 months (10-307 months). The median reirradiation prescription dose was 54.0 Gy (relative biological effectiveness [RBE]) (50.4-61.2 Gy[RBE]), and the median cumulative prescription dose was 109.8 Gy (76-129.4 Gy). Of the 10 patients who presented with symptomatic disease, 4 patients had complete resolution of symptoms, and 4 had diminished or stable symptoms. Two patients had progressive symptoms. The median time to symptom recurrence was 10 months. Maximum acute nonhematologic toxicity attributable to radiation was grade 2 (64%, N=9), 3 (29%, N=4), 4 (0%), and 5 (7%, N=1). The acute grade 5 toxicity was an esophagopleural fistula more likely related to tumor progression than radiation. Grade 3 nonhematologic acute toxicities included dysphagia, dehydration, and pneumonia. There was 1 late grade 5 esophageal ulcer more likely related to tumor progression than radiation. There were 4 late grade 3 toxicities: heart failure, esophageal stenosis requiring dilation, esophageal ulceration from tumor, and percutaneous endoscopic gastrostomy tube dependence. The median time to local failure was 10 months, and the median overall survival was 14 months. Conclusions Our data demonstrate that proton reirradiation is feasible, with an encouraging symptom control rate, modest radiation-related toxicity, and favorable survival in this high-risk population.

Background Atherosclerosis is a chronic inflammatory disorder, and several studies have demonstrated a positive association between plasma serum amyloid A ( SAA ) levels and cardiovascular disease risk. The aim of the study was to examine whether SAA has a role in atherogenesis, the underlying basis of most cardiovascular disease. Methods and Results Mice globally deficient in acute‐phase isoforms Saa1 and Saa2 ( Saa −/− ) were crossed to Ldlr −/− mice ( Saa −/− Ldlr −/− ). Saa −/− Ldlr −/− mice demonstrated a 31% reduction in lesional area in the ascending aorta but not in the aortic root or innominate artery after consuming a high‐fat, high‐cholesterol Western‐type diet for 6 weeks. The lesions were predominantly macrophage foam cells. The phenotype was lost in more mature lesions in mice fed a Western‐type diet for 12 weeks, suggesting that SAA is involved in early lesion development. The decreased atherosclerosis in the Saa −/− Ldlr −/− mice occurred despite increased levels of blood monocytes and was independent of plasma lipid levels. SAA is produced predominantly by hepatocytes and macrophages. To determine which source of SAA may have a dominant role in lesion development, bone marrow transplantation was performed. Ldlr −/− mice that received bone marrow from Saa −/− Ldlr −/− mice had slightly reduced ascending aorta atherosclerosis compared with Saa −/− Ldlr −/− mice receiving bone marrow from Ldlr −/− mice, indicating that the expression of SAA by macrophages may have an important influence on atherogenesis. Conclusions The results indicate that SAA produced by macrophages promotes early lesion formation in the ascending aorta.

Age has been used as a prognostic factor for patients with peripheral neuroblastic tumours (pNTs). The latest analysis disclosed a cut-off around 18 months for the optimal prognostic distinction. The International Neuroblastoma Pathology Classification (INPC) distinguishes favourable and unfavourable histology based on the age-appropriate evaluation of histologic indicators (grade of neuroblastic differentiation, mitosis-karyorrhexis index) in the categories of neuroblastoma and ganglioneuroblastoma, nodular. This study showed that age tested by using 3 different cut-offs (12, 18, 24 months) was prognostically significant. INPC remained prognostically significant regardless of the age group to which it was applied. Prognostic effects of age and histologic indicators were independently significant, i.e., age had prognostic ability beyond that of histologic indicators, and histologic indicators had prognostic ability beyond that of age. Due to the fact that INPC incorporated age factor (18, 60 months) in the system, it served better than age by itself for prognostic distinction of pNT patients.

BACKGROUND This study was conducted to investigate the prognostic significance and biologic relevance of trkA expression levels in peripheral neuroblastic tumors (pNTs) (i.e., neuroblastoma, ganglioneuroblastoma, and ganglioneuroma). METHODS Levels of trkA expression from a total of 265 pNTs were determined by quantitative polymerase chain reaction analysis with Genescan software. The results were analyzed according to histopathology (favorable histology [FH] vs. unfavorable histology [UH] according to the International Neuroblastoma Pathology Classification) and MYCN tumor status (amplified vs. nonamplified) along with clinical stage and outcomes of the patients. RESULTS The levels of trkA expression differed significantly between the group of patients who were alive and well (n = 170 patients) and the group that had progressed or died (n = 95 patients) and between the group that was alive (n = 188 patients) and the group that died (n = 77 patients). However, the trkA expression levels were not independent predictors of clinical outcome when the proportional hazards model contained the known prognostic variables of clinical stage, histopathology, and MYCN status (all tests were done in 196 patients). In the neuroblastoma category (n = 173 tumors), tumors in the FH/nonamplified MYCN subset (n = 112 tumors) expressed higher levels of trkA and showed an age-dependent neuroblastic differentiation: They were classified into either a poorly differentiated subtype (n = 91 tumors; all patients age < 1.5 years at diagnosis) or a differentiating subtype (n = 21 tumors; 57% of patients ages 1.5–5.0 years). Tumors in the UH/amplified MYCN subset (n = 30 tumors) expressed significantly lower levels of trkA and showed very limited neuroblastic differentiation. Tumors in the FH/amplified MYCN subset were very rare (n = 3 tumors) and expressed higher levels of trkA. Tumors in the UH/nonamplified MYCN subset (n = 28 tumors) had trkA levels in a wide range and showed limited neuroblastic differentiation. CONCLUSIONS For patients with pNTs, levels of trkA expression did not add significant information to prognostic grouping, as defined by the combination of clinical stage, histopathology, and MYCN status. There was a biologically relevant correlation between molecular properties (trkA expression and MYCN status) and histopathologic features of the tumors in the neuroblastoma category. Cancer 2004. © 2004 American Cancer Society.

This study tests the hypothesis that autoantibodies to oxidation epitopes on oxidized LDL (OxLDL) promote the clearance of OxLDL from the plasma. Human LDL (hLDL) was injected into immune-competent apolipoprotein E-deficient (apoE(-/-)) mice and immune-deficient apoE(-/-)/recombination-activating gene-deficient mice that lack mature T and B cells and thus antibodies. There was a progressive decrease in human apoB-100 in the plasma in all mice, but the rate of clearance was not greater in the immune-competent mice than in the immune-deficient mice. Interestingly, oxidized phospholipid (OxPL) epitopes as detected by the EO6 antibody on the hLDL increased over time, suggesting de novo oxidation of the LDL or transfer of OxPL to the particles. Because the native LDL was not extensively modified, we also examined the clearance of copper OxLDL. Although the extensively OxLDL was cleared faster than the native LDL, there was no difference in the rate of clearance as a function of immune status. There appeared to be some transfer of OxPL to the endogenous murine LDL. Together, these results suggest that oxidation-specific antibodies do not participate to any great extent in the clearance of OxLDL from plasma. However, it is possible that such antibodies may bind to oxidation epitopes and modulate lesion formation within the vessel wall.

BACKGROUND According to the International Neuroblastoma Pathology Classification, neuroblastomas exhibiting MYCN amplification (A-MYCN) have unique histologic features—namely, undifferentiated/poorly differentiated subtype with a high mitosis-karyorrhexis index (U/PD-H). Nonetheless, certain tumors possessing these histologic characteristics contain a nonamplified MYCN gene (NA-MYCN). METHODS The clinical characteristics of patients from the Children's Cancer Group (CCG) 3881 and 3891 studies who had neuroblastoma, U/PD-H, exhibiting A-MYCN (n = 68) or NA-MYCN (n = 33) were investigated. The histologic and cytologic features of tumors (A-MYCN, n = 62; NA-MYCN, n = 28) filed at the Pathology Reference Laboratory, Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles, were reviewed, and nucleolar areas in undifferentiated neuroblastic cells were evaluated using image analysis methods. RESULTS All 68 patients whose tumors exhibited A-MYCN had disease that was in an advanced clinical stage (Stage III or IV); 89.7% of these patients were diagnosed between ages 0.5 and 3.5 years, and 67 of the 68 had been treated with the high-risk protocol in the CCG-3891 study. Children whose tumors exhibited NA-MYCN were evenly distributed across all age groups; 30 of these 33 children had advanced-stage disease, and 26 had been treated with a high-risk protocol. The prognosis associated with A-MYCN (event free survival [EFS], 15.7%; overall survival [OS], 22.2%) was significantly poorer than the prognosis associated with NA-MYCN (EFS, 56.1%; OS, 69.3%). The lone histologic/cytologic difference between tumors exhibiting A-MYCN and tumors exhibiting NA-MYCN involved nucleolar appearance. Neuroblastic cells in tumors exhibiting A-MYCN were characterized by the presence of 1 or more large, prominent nucleoli, and the mean nucleolar area was significantly greater in the 18 tumors exhibiting A-MYCN that were assessed (7.63 μm2) than in the 16 tumors exhibiting NA-MYCN that were assessed (5.53 μm2; P = 0.004). CONCLUSIONS Neuroblastomas, U/PD-H, were found to vary in terms of molecular background and clinical behavior. The results of the current study indicate that nucleolar enlargement in neuroblastic cells may be a sign of MYCN amplification. Cancer 2005. © 2004 American Cancer Society.

Objective— We sought to examine whether there is a site-specific effect on atherosclerosis of the absence of mature T and B cells caused by a recombination activating-gene deficiency in LDL receptor-deficient mice and whether this effect is influence by the extent of backcrossing to C57BL/6 mice. Methods and Results— Male mice were fed atherogenic diets for 3 months. In strain 1 mice, in which ≈93% of the genes were from C57BL/6 mice, the absence of mature T and B cells led to a significant reduction in atherosclerosis in both the aortic sinus and the innominate artery. In strain 2 mice, in which ≈99+% of the genes were from C57BL/6 mice, immune system deficiency led to a site-specific effect on atherosclerosis, with a reduction in atherosclerosis in the aortic sinus but not in the innominate artery, similar to previous results obtained with apolipoprotein E−/− mice. All of the immune system-incompetent mice had lower plasma total and VLDL cholesterol levels regardless of strain or diet, indicating that differences in lipid levels were unlikely to be responsible for these site-specific effects of immune system deficiency. Conclusions— These results suggest that immune system deficiency has a site-specific effect on atherosclerosis that is sensitive to the genetic background of the mice.

WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection1. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis2. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions, suggesting that the product of the affected gene may be important in the natural control of this infection. We describe here the localization of the gene associated with WHIM syndrome to a region of roughly 12 cM on chromosome 2q21 and the identification of truncating mutations in the cytoplasmic tail domain of the gene encoding chemokine receptor 4 (CXCR4). Haplotype and mutation analyses in a pedigree transmitting myelokathexis as an apparently autosomal recessive trait support genetic heterogeneity for this aspect of the WHIM syndrome phenotype. Lymphoblastoid cell lines carrying a 19-residue truncation mutation show significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor. The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection.