Identification and Characterization of Leptomeningeal Metastases Using SPINE, A Web-Based Collaborative Platform.

BACKGROUND AND PURPOSE: Leptomeningeal metastases (LMs) carry a poor prognosis. Existing LM scoring systems show limited reproducibility. We assessed the contribution of education level on the reproducibility of LM scoring using structured planning and implementation of new experiments (SPINE), a novel web-based platform. METHODS: Stringent radiological definitions of LM and a customized interactive scoring system were implemented in SPINE. Five patients with brain LM and 3 patients with spine, but no brain LM, were selected. Each patient's baseline post-contrast T1-weighted brain MRI was analyzed by three attending neuroradiologists, two neuroradiology fellows, and two radiology residents. Raters identified and characterized all LMs based on: (1) location (cerebrum, cerebellum, brainstem, ventricle, and/or cranial nerves); (2) shape (nodular and/or linear/curvilinear); (3) size (≥ or <5mm in two orthogonal diameters); (4) spatial extension (focal or diffuse). Inter-rater agreement and association of LM with patient survival were investigated. RESULTS: On average, 6.5 LMs per case were detected. Forty-nine percent of LMs were cerebral, 77.7% were nodular, 86.6% were focal, and 66% were <5 × 5 mm. Agreement on the total number of LMs and the above-mentioned common LM characteristics was higher between attendings (intra-class correlation [ICC] = 0.8-0.94) than fellows (ICC = 0.6-0.82) or residents (ICC = 0.43-0.73). Agreement on ventricular, cranial nerve, and nodular + linear LM was low even between attendings. The number of brainstem LMs showed significant correlation with survival. CONCLUSION: Structured education using SPINE may improve consistency in LM reporting. Future work should address the impact of the presented approach on the reproducibility of longitudinal analyses directly relevant to the assessment of treatment-response.

Radiation-induced and neurofibromatosis-associated malignant peripheral nerve sheath tumors (MPNST) have worse outcomes than sporadic MPNST.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) may be sporadic or associated with neurofibromatosis or prior radiation. MPNST may behave aggressively with a high rate of local recurrence and distant metastasis. METHODS: In an IRB approved protocol, we reviewed the clinical characteristics, treatment, and outcomes of 280 patients treated for MPNST at Massachusetts General Hospital (MGH) between 1960 and 2016. RESULTS: There were 138 men and 142 women with a median age of 41 (range: 3-95) years. Tumors were classified as neurofibromatosis-associated (nfMPNST, n = 77), radiation-induced (rMPNST, n = 21), or sporadic (sMPNST, n = 182) MPNST. The median time to development of rMPNST from prior radiation was 15 years. With a median follow-up of 43.1 months, the median overall survival (OS) was 65.3 months. Older age, nfMPNST, rMPNST, increased tumor size, lymph node involvement, metastatic disease, intermediate to high grade, radiotherapy alone, and R2 resection were related to worse OS, whereas surgery with radiotherapy was associated with improved OS. Among the 251 patients without metastasis, nfMPNST, rMPNST, and increased tumor size were correlated with worse metastasis-free survival; nfMPNST, radiotherapy alone, and R1/R2 resection were associated with local recurrence, whereas surgery with adjuvant radiotherapy was related to improved local control in patients with R1/R2 resection. CONCLUSIONS: Both radiation-induced and neurofibromatosis-associated MPNSTs have poorer prognosis than sporadic MPNSTs. Complete resection of the tumor is a significant prognostic factor for MPNST. The addition of radiotherapy after surgery should be considered especially when the surgical margins are positive.

Characteristics and Predictors for Secondary Leukemia and Myelodysplastic Syndrome in Ewing and Osteosarcoma Survivors.

PURPOSE: Long-term survivors of Ewing sarcoma (ES) and osteosarcoma may be at risk for therapy-related acute leukemia or myelodysplastic syndrome (t-AL/MDS). METHODS AND MATERIALS: We retrospectively reviewed the clinicopathologic characteristics of 1071 patients with osteosarcoma (n = 757) and ES (n = 314) who were treated between 1985 and 2014. Multivariable competing risk analysis was used to analyze predictors of t-AL/MDS, including a radiation dose (≥55.8 Gy vs <55.8 Gy) × disease site (pelvis/spine vs other) interaction term. A supplemental nested case-control study was conducted to assess the association between cumulative chemotherapy dose and t-AL/MDS. RESULTS: The median follow-up for surviving patients was 97 months (range, 0.03-380). Twenty patients developed t-AL/MDS, all of whom received chemotherapy and 15 of whom were treated with radiation therapy. Radiation therapy to ≥55.8 Gy was associated with development of t-AL/MDS (adjusted hazard ratio, 2.89; 95% confidence interval [CI], 1.23-6.80; P = .015), and there was a significant radiation dose × disease site interaction term (adjusted hazard ratio, 6.70; 95% CI, 2.71-16.53; Pinteraction < .001). The 5-year cumulative incidence of t-AL/MDS in patients receiving ≥55.8 Gy radiation therapy to the pelvis or spine was 5.0% (95% CI, 0.9-14.9) for osteosarcoma and 10.7% for ES (95% CI, 3.3-23.2). In our nested case-control study, cumulative doses of ifosfamide and etoposide were associated with development of t-AL/MDS. CONCLUSIONS: Patients with osteosarcoma and ES receiving ≥55.8 Gy of radiation therapy to the pelvis or spine appear to be at increased risk for t-AL/MDS. Treatment with high cumulative doses of chemotherapy may further augment this risk.

Extraskeletal osteosarcoma: A large series treated at a single institution.

Purpose: This study is to present a large cohort of extraskeletal osteosarcoma (ESOS) and evaluate prognostic factors and treatment options. Methods: Medical records were reviewed retrospectively for 41 patients with extraskeletal osteosarcoma that was diagnosed by pathology, and treated at our institution between 1960 and 2016. Kaplan-Meier analysis and Cox proportional hazards regression were used to identify variables that affect survival outcomes. Results: 41 patients were identified from 952 osteosarcomas. 32 patients had non-metastatic disease. Prognostic factors were identified by univariate analysis and multi-variate analysis. Surgery (p<0.001), and surgery type (p<0.001) both were shown to significantly affect overall survival (OS). Chemotherapy and radiation therapy (RT) did not show any significant effect on OS, local recurrence, or progression free survival as a whole. However for patients who had incomplete resection with residual tumor RT improved OS (p=0.03). The survival curve for ESOS follows more closely that of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Conclusions: ESOS is a very rare tumor. Attempt to achieve wide resection is the treatment of choice. However for patients who are not able to achieve complete resection, RT may improve OS. The behavior of ESOS more closely follows that of NRSTS than osteosarcoma of the bone.

Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma.

Purpose: Angiotensin system inhibitors (ASI) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.Experimental Design: We performed an analysis of the records of ASI users and nonuser patients with PDAC seen at Massachusetts General Hospital (Boston, MA) between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA sequencing (RNA-Seq) of resected primary lesions.Results: A total of 794 consecutive patients were included. In 299 resected patients, ASI users experienced longer overall survival (OS) in both univariate (median OS, 36.3 vs. 19.3 months, P = 0.011) and adjusted multivariate [HR, 0.505; 95% confidence interval (CI), 0.339-0.750; P = 0.001] analyses. Propensity score-adjusted analysis also showed a longer median OS for chronic ASI users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g., WNT and Notch signaling), and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature that is predictive of survival in independent validation cohorts.Conclusions: In patients with nonmetastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASIs reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC. Clin Cancer Res; 23(19); 5959-69. ©2017 AACR.

Improved local control with an aggressive strategy of preoperative (with or without intraoperative) radiation therapy combined with radical surgical resection for retroperitoneal sarcoma.

BACKGROUND AND OBJECTIVES: We sought to examine our outcomes with advanced preoperative and intraoperative radiation therapy (XRT) combined with aggressive en bloc surgical resection of retroperitoneal sarcoma (RPS) as a strategy to minimize the risk of local recurrence (LR). METHODS: From 2003 to 2013, 46 patients with RPS received preoperative XRT followed by radical en bloc surgical resection, with or without intraoperative electron radiation therapy (IOERT). Clinical and pathologic variables predictive of LR and distant recurrence (DR) were evaluated. RESULTS: Thirty-seven patients had primary tumors and 80% were intermediate grade or higher. All patients received preoperative XRT to a median dose of 50.4 Gy and underwent complete (R0/R1) tumor resection, and 16 patients received IOERT. After a median follow-up of 53 months, 33 (72%) patients were disease-free, and there were 8 (17%) DRs, 2 (4%) abdominal recurrences outside of the XRT field, and 5 (10.9%) LRs. High tumor grade and recurrent disease at presentation were the only factors associated with higher rates of recurrence. CONCLUSIONS: Excellent local control can be achieved with a coordinated strategy of preoperative (±intraoperative) XRT combined with aggressive en bloc surgical resection of RPS, but systemic failure remains a problem for higher-grade tumors.

High-Dose Proton Beam-Based Radiation Therapy in the Management of Extracranial Chondrosarcomas.

PURPOSE: Radiation therapy (RT) improves local tumor control in axial chondrosarcomas (CS). It is, however, often difficult to safely deliver the high doses (range, 70.2-77.4 Gy) required for achieving a high likelihood of local control, especially in the spine, using photons. This, however, can be achieved with proton beam therapy (PBT) due to its unique physical characteristics. The main goal of our study is to evaluate the outcomes of CS patients treated with passive scattered PBT. MATERIALS AND METHODS: Forty-four patients (N = 44) were identified who received PBT as part of their treatment from 1990 to 2012. A retrospective review of their medical and RT treatment records was conducted. Multivariate analyses were performed to identify patient- and tumor-related factors predicting for improved local control and overall survival. RESULTS: Median age was 45.5 years and 55% were female. Median tumor size was 13 cm. Most common anatomical location was the spine (80%). Median follow-up was 29.1 months. Median external beam RT dose was 70.2 Gy relative biological effectiveness (RBE) at 1.8 Gy (RBE) per fraction typically administered using a combination of photon RT + PBT (77%) or PBT alone (23%). Local control was 76% and 57%, and overall survival was 90% and 68% at 2 and 5 years, respectively. Toxicity was acceptable, with the most frequent being wound complications (16%). On multivariate analyses, grade III tumors were significantly associated with decreased local control (P = 0.019), while female sex (P = 0.037) and grade III tumors (P = 0.005) were associated with a poorer overall survival. CONCLUSIONS: High-dose proton-based RT in combination with surgery resulted in local tumor control in most of these high-risk CS patients. Female sex was predictive for decreased survival, while higher tumor grade (grade III) was predictive of decreased local control and survival. Proton beam therapy is an attractive treatment modality for these challenging tumors.

The Width of the Surgical Margin Does Not Influence Outcomes in Extremity and Truncal Soft Tissue Sarcoma Treated With Radiotherapy.

BACKGROUND AND OBJECTIVES: It is unclear whether the quantitative width of the surgical margin influences outcomes in patients with extremity and truncal soft tissue sarcoma (STS) treated with radiotherapy (RT). METHODS: We performed a retrospective review of 382 patients with localized extremity or truncal STS who underwent limb-sparing surgery and RT from 1983 to 2010, and we analyzed the significance of resection margin status and quantitative margin width on outcomes. RESULTS: Surgical margins were positive in 68 (18%) patients and negative in 314 (82%) patients. For those patients with a reported quantitative margin width (n = 235), the width of the negative margin was ≤1 mm (n = 128), >1 mm and ≤5 mm (n = 79), and >5 mm (n = 28). At a median follow-up of 82 months, the local recurrence rates were 5.4% and 11.8% for margin-negative and margin-positive patients, respectively. There were no differences in the rates of local or distant recurrence nor of any survival outcome based on the quantitative width of the surgical margin, provided that it was negative. CONCLUSIONS: In patients undergoing RT and limb-sparing surgery for STS, achieving a negative margin is essential for optimizing both local control and survival. However, the absolute quantitative width of the negative margin does not significantly influence outcome, and so attempts at wide margins of resection appear to be unnecessary. Importantly, the conclusions drawn from this study must not be applied to those patients undergoing surgery alone as the local treatment of their STS, in which case wider margins of resection may be necessary. IMPLICATIONS FOR PRACTICE: In patients undergoing radiation therapy and limb-sparing surgery for soft tissue sarcoma, the quantitative width of the negative margin does not influence outcome, and so attempts at wide margins of resection appear to be unnecessary, especially when such attempts compromise the functional outcome. Importantly, the conclusions drawn from this study must not be applied to those patients undergoing surgery alone as the local treatment of their soft tissue sarcoma, in which case wider margins of resection may be necessary.

Prognostic factors in alveolar soft part sarcoma: A SEER analysis.

OBJECTIVES: We reviewed the clinical characteristics and outcomes of patients treated for alveolar soft part sarcoma (ASPS) and analyzed the effect of surgery for patients presenting with and without metastatic disease (DM). METHODS: The SEER Registry was queried for patients with ASPS from 1973-2012. The Kaplan-Meier estimate and Cox proportional hazards were used to analyze survival outcomes and risk variables. RESULTS: Among 251 patients, 43% had DM and 67% locoregional disease (LR) on presentation. The 5-year overall survival (OS) for all patients was 56% (82% and 27% for LR and DM, respectively). Multivariate analysis identified older age (hazard ratio [HR] = 1.03 per year, P < 0.001), tumor size >10 cm (HR = 2.76, P = 0.013), DM at diagnosis (HR = 3.79, P < 0.001), and truncal primary site (HR = 1.63, P = 0.035) as independent factors predicting worse OS. For LR patients, surgery plus radiotherapy (RT) resulted in better OS compared to surgery alone P = 0.014. For DM patients, primary site surgery significantly improved survival (P < 0.001). CONCLUSION: ASPS presents with high metastasis rate but has a relatively indolent clinical course and a favorable prognosis with prolonged survival. Aggressive treatment using adjuvant RT with surgery is indicated in patients with LR disease and surgery is indicated in patients presenting with DM. J. Surg. Oncol. 2016;113:581-586. © 2016 Wiley Periodicals, Inc.

Post-operative renal function following nephrectomy as part of en bloc resection of retroperitoneal sarcoma (RPS).

BACKGROUND AND OBJECTIVES: Although resection of RPS with en bloc nephrectomy confers the potential benefit of improved locoregional tumor control, little has been published about the long-term post-operative renal function of these patients. METHODS: Retrospective review of 54 patients undergoing nephrectomy for RPS was performed. Clinicopathologic and treatment characteristics, pre- and post-operative creatinine (Cr) values, and estimated glomerular filtration rates (eGFR) were recorded. The primary outcome measure was progression of chronic kidney disease (CKD) stage. RESULTS: Median preoperative eGFR was 85 ml/min. Post-nephrectomy, median nadir eGFR was 44 ml/min, rebounding to 62 ml/min at median follow-up of 50 months. Of 49 patients with preoperative eGFR ≥60 ml/min (CKD stage 1,2), 51% preserved eGFR ≥60 postoperatively, whereas 49% progressed to CKD stage 3 (eGFR 30-59). Independent risk factors for progression of CKD stage were age and preoperative eGFR. Eleven patients died of recurrent disease, whereas no patient died of end stage renal disease (ESRD) or required dialysis. CONCLUSIONS: Although progression of CKD stage occurs in nearly one-half of patients followed for more than 4 years after nephrectomy for RPS, no patient progressed to ESRD or had a limitation in systemic therapy options, even with progression to CKD stage 3.

New azaborine-thiophene heteroacenes.

A new class of heteroacenes containing B, N and S elements in the 22-electron aromatic nucleus has been synthesized by reaction of diaminoterthiophenes with dichlorophenylborane. Their structure was studied by X-ray crystallography and DFT calculations. UV-Vis absorption /emission spectroscopy shows high rigidity and deep-blue fluorescence of these compounds.

An evaluation of the use of digital study models in orthodontic diagnosis and treatment planning.

The purpose of the present study was to determine the diagnostic and treatment planning value of digital models when compared with plaster study casts. In addition, the level of orthodontic experience of the examiner was assessed to determine whether this would have an influence on the decision-making process. Thirty randomly selected orthodontic patients from the Department of Orthodontics at the University of Alabama were selected for the study. From the 30 record sets, seven were selected attempting to mirror cases required for presentation to the American Board of Orthodontics. The seven evaluators were divided into two groups on the basis of their level of orthodontic experience. Initially, each evaluator assessed each patient record. Each evaluator was given a standardized questionnaire which recorded the evaluator's diagnosis based on use of the digital study models (T1). Regardless of whether the evaluator requested a review of the plaster study casts, the evaluator was given the plaster study casts. The evaluator then, using the plaster casts, filled out another identical questionnaire (T2). A chi-square test was used to determine any group differences in the frequency of changed diagnostic characteristics, treatment mechanical procedures, or proposed treatment plans after evaluating plaster study models. The statistical significance selected was P = .05 level of significance. The results showed that 12.8% of diagnostic characteristics, 12% of treatment mechanic procedures, and 6% of proposed treatment plans changed after T2. The results of the present study indicate that in the vast majority of situations digital models can be successfully used for orthodontic records.

Evaluation of the debonding characteristics of 2 ceramic brackets: an in vitro study.

The objectives of this study were to evaluate and compare the shear bond strengths and bond failure locations of 2 currently available orthodontic ceramic brackets. Forty polycrystalline ceramic brackets (Clarity, 3M Unitek, Monrovia, Calif) and 40 monocrystalline ceramic brackets (Inspire, Ormco, Orange, Calif) were bonded to 80 extracted premolars with the same bonding system. All bonded specimens were placed in distilled water for 42 hours at 37 degrees C followed by thermal cycling for 700 complete cycles. Forty ceramic brackets, 20 of each type, were tested on a universal testing machine to determine the shear force levels required to debond them. Forty ceramic brackets were removed with the debonding pliers recommended by the manufacturers. All teeth were examined under an optical microscope, and the adhesive remnant index was used to assess the bond failure locations. The mean shear bond strength of the Clarity brackets was 21.67 +/- 5.19 MPa, and the mean shear bond strength of the Inspire brackets was 20.32 +/- 8 MPa. The mean shear bond strengths of both brackets were higher than those considered clinically optimal. Most of the brackets (85% of Clarity and 75% of Inspire) tested on the machine failed at the bracket-adhesive interface. One premolar bonded with an Inspire bracket had enamel fracture upon debonding. Most of the brackets (90% of Clarity and 95% of Inspire) debonded with pliers failed at the bracket-adhesive interface. No enamel damage was evident in any specimen when the brackets were removed with the appropriate pliers. The results indicate that the safest way to remove ceramic brackets with respect to reducing the chance of enamel damage is to use the debonding technique specifically designed for each.