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Purpose: We hypothesized that concurrent ipilimumab with chemoradiationtherapy (chemoRT) followed by maintenance nivolumab would be safe for patients with unresectable stage III non-small cell lung cancer (NSCLC). We aimed to assess the safety (phase 1) and the 12-month progression-free survival (PFS) (phase 2) in a multi-institution prospective trial., Methods and Materials: Eligible patients had unresectable stage III NSCLC. The treatment included platinum doublet chemotherapy with concurrent thoracic radiation therapy to 60 Gy in 30 fractions and ipilimumab (1 mg/kg) delivered during weeks 1 and 4. After chemoRT, maintenance nivolumab (480 mg) was given every 4 weeks for up to 12 cycles. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0. Survival analyses were performed with Kaplan Meier (KM) methods and log-rank tests., Results: The trial was discontinued early after enrolling 19 patients without proceeding to the phase 2 component because of unacceptable toxicity. Sixteen patients (84%) had grade ≥3 (G3+) possible treatment-related toxicity, most commonly pulmonary AEs (n = 8, 42%). Fourteen patients (74%) discontinued study therapy early because of AEs (n = 12, 63%) or patient choice (n = 2, 11%). Eleven patients (58%) experienced G2+ pulmonary toxicity with median time to onset 4.1 months (95% CI 2.6-not reached [NR]), and 12-month freedom from G2+ pulmonary toxicity 37% (95% CI, 16-59). Five patients had G5 AEs, including 3 with G5 pulmonary AEs (1 respiratory failure with pneumonitis and pulmonary embolism, 1 pneumonia/chronic obstructive pulmonary disease exacerbation, 1 pulmonary fibrosis). Despite toxicities, the median PFS was 19.2 months (95% CI 6.1-NR) and the median overall survival was NR (95% CI 6.1-NR) with median follow-up of 30.1 months by the reverse KM method., Conclusions: Concurrent ipilimumab with chemoRT for unresectable stage III NSCLC is associated with pulmonary toxicity that may limit opportunities for improved outcomes. Future studies aiming to incorporate ipilimumab or other anti-CTLA4 therapies into management of unresectable stage III NSCLC should consider careful measures to minimize toxicity risk., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Heart dose and heart disease increase the risk for cardiac toxicity associated with radiation therapy. We hypothesized that computed tomography (CT) coronary calcifications are associated with cardiac toxicity and may help ascertain baseline heart disease., Methods and Materials: We analyzed the cumulative incidence of cardiac events in patients with stage III non-small cell lung cancer receiving median 74 Gy on prospective dose-escalation trials. Events were defined as symptomatic effusion, pericarditis, unstable angina, infarction, significant arrhythmia, and/or heart failure. Coronary calcifications were delineated on simulation CTs using radiation software program (130 HU threshold). Calcifications were defined as "none," "low," and "high," with median volume dividing low and high., Results: Of 109 patients, 26 had cardiac events at median 26 months (range, 1-84 months) after radiation therapy. Median follow-up in surviving patients was 8.8 years (range, 2.3-17.3). On simulation CTs, 64 patients (59%) had coronary calcifications with median volume 0.2 cm 3 (range, 0.01-8.3). Only 16 patients (15%) had baseline coronary artery disease. Cardiac events occurred in 7% (3 of 45), 29% (9 of 31), and 42% (14 of 33) of patients with no, low, and high calcifications, respectively. Calcification burden was associated with cardiac toxicity on univariate (low vs none: hazard ratio [HR] 5.0, P = .015; high vs none: HR 8.1, P < .001) and multivariate analyses (low vs none: HR 7.0, P = .005, high vs none: HR 10.6, P < .001, heart mean dose: HR 1.1/Gy, P < .001). Four-year competing risk-adjusted event rates for no, low, and high calcifications were 4%, 23%, and 34%, respectively., Conclusions: The presence of coronary calcifications is a cardiac risk factor that can identify high-risk patients for medical referral and help guide clinicians before potentially cardiotoxic cancer treatments., (Copyright © 2021 Elsevier Inc. All rights reserved.)

PURPOSE/OBJECTIVES To examine patient characteristics that predispose to higher opioid administration during tandem and ovoid (T&O) high-dose rate (HDR) brachytherapy. METHODS A single-institution retrospective review was performed on patients who underwent brachytherapy for cervical cancer. Patients were included if they received at least one fraction of HDR T&O brachytherapy with analgesia administration recorded in the Medication Administration Record. Fentanyl dose was dichotomized as "low" (mean <125 μg per fraction), or "high" (mean ≥ 125 μg per fraction). Descriptive statistics and multiple logistic regression analysis were performed comparing mean opioid dose per fraction with demographic and clinical information. RESULTS From July 2014 through May 2020, 113 patients underwent 531 T&O HDR brachytherapy fractions with oral benzodiazepine and intravenous opioid fentanyl for conscious sedation. The median opioid dose per fraction was 100 μg fentanyl (range 0-250 μg). Using multiple logistic regression analysis, younger age (OR 1.071, p = 0.002) and higher BMI (OR 1.091, p = 0.019) were associated with increased opioid administration during brachytherapy. Black women received less opioid during brachytherapy when compared to White women (OR 0.296, p = 0.047). FIGO stage, ECOG score, smoking status, prior narcotic use, prior illicit drug use, parity, prior cervical procedure, Smit sleeve placement, and distance to treatment center were not associated with high opioid dose. CONCLUSION Cervical cancer patients who are younger or have higher BMI receive more narcotic analgesia during HDR brachytherapy whereas Black women received less narcotic analgesia, irrespective of age and BMI. This underscores the immediate need to address how pain is assessed and managed during brachytherapy., (Copyright © 2021 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Human papillomavirus (HPV) causes the majority of oropharyngeal, cervical, and anal cancers, among others. These HPV-associated cancers cause substantial morbidity and mortality despite ongoing vaccination efforts. Aside from the earliest stage tumors, chemoradiation is used to treat most HPV-associated cancers across disease sites. Response rates are variable, and opportunities to improve oncologic control and reduce toxicity remain. HPV malignancies share multiple commonalities in oncogenesis and tumor biology that may inform personalized methods of screening, diagnosis, treatment and surveillance. In this review we discuss the current literature and identify promising molecular targets, prognostic and predictive clinical factors and biomarkers in HPV-associated oropharyngeal, cervical and anal cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Whole brain radiation (WBRT) may lead to acute xerostomia and dry eye from incidental parotid and lacrimal exposure, respectively. We performed a prospective observational study to assess the incidence/severity of this toxicity. We herein perform a secondary analysis relating parotid and lacrimal dosimetric parameters to normal tissue complication probability (NTCP) rates and associated models., Methods: Patients received WBRT to 25-40 Gy in 10-20 fractions using 3D-conformal radiation therapy without prospective delineation of the parotids or lacrimals. Patients completed questionnaires at baseline and 1 month post-WBRT. Xerostomia was assessed using the University of Michigan xerostomia score (scored 0-100, toxicity defined as ≥ 20 pt increase) and xerostomia bother score (scored from 0 to 3, toxicity defined as ≥ 2 pt increase). Dry eye was assessed using the Subjective Evaluation of Symptom of Dryness (SESoD, scored from 0 to 4, toxicity defined as ≥ 2 pt increase). The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models., Results: Of 55 evaluable patients, 19 (35%) had ≥ 20 point increase in xerostomia score, 11 (20%) had ≥ 2 point increase in xerostomia bother score, and 13 (24%) had ≥ 2 point increase in SESoD score. For xerostomia, parotid V 10Gy -V 20Gy correlated best with toxicity, with AUC 0.68 for xerostomia score and 0.69-0.71 for bother score. The values for the D 50 , m and n parameters of the LKB model were 22.3 Gy, 0.84 and 1.0 for xerostomia score and 28.4 Gy, 0.55 and 1.0 for bother score, respectively. The corresponding values for the D 50 , γ and s parameters of the RS model were 23.5 Gy, 0.28 and 0.0001 for xerostomia score and 32.0 Gy, 0.45 and 0.0001 for bother score, respectively. For dry eye, lacrimal V 10Gy -V 15Gy were found to correlate best with toxicity, with AUC values from 0.67 to 0.68. The parameter values of the LKB model were 53.5 Gy, 0.74 and 1.0, whereas of the RS model were 54.0 Gy, 0.37 and 0.0001, respectively., Conclusions: Xerostomia was most associated with parotid V 10Gy -V 20Gy , and dry eye with lacrimal V 10Gy -V 15Gy . NTCP models were successfully created for both toxicities and may help clinicians refine dosimetric goals and assess levels of risk in patients receiving palliative WBRT.

Background: The importance of invasive mediastinal nodal staging in early-stage non-small cell lung cancer (NSCLC) in the PET/CT era is dependent on tumor factors that increase risk of nodal metastasis. At our institution, patients undergo biopsy via either CT-guidance (without nodal staging) or navigational bronchoscopy with endobronchial ultrasound transbronchial needle aspiration for nodal staging. This study aims to compare outcomes after stereotactic body radiotherapy (SBRT) stratified by receipt of invasive mediastinal nodal staging., Methods: In this retrospective study, records of all consecutive patients undergoing SBRT for early-stage NSCLC between 2010 and 2017 were analyzed. The association between time-to event outcomes (recurrence and survival) were evaluated with covariates of interest including tumor size, location, histology, smoking history, prior lung cancer history, radiation dose and receipt of nodal staging. Both univariable and multivariable analyses were used to examine these comparisons., Results: Overall, 158 patients were treated with SBRT. One hundred forty-nine out of one hundred fifty-eight patients (94%) underwent PET/CT staging, and all patients underwent tumor-directed biopsy. Seventy-nine patients underwent navigational bronchoscopy with nodal staging and 79 patients underwent CT-guided biopsy without nodal staging. Receipt of nodal staging was not associated with tumor size (P=0.35), yet was associated with central tumor location (P<0.001). There was no statistically significant association between receipt of nodal staging and time-to-event recurrence or survival outcomes; for example 3-year overall survival (OS) was 65% vs. 67% (P=0.65) and 3-year freedom from nodal failure was 84% vs. 69% (P=0.1) for those with and without nodal staging, respectively., Conclusions: Similar recurrence and survival outcomes were observed after SBRT regardless of receipt of invasive mediastinal nodal staging. Further prospective evaluation can help identify which patients might derive greatest benefit from invasive staging of the mediastinum in the PET/CT era., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-2808). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Purpose: The size and growth of U.S. radiation oncology (RO) residency positions have important implications for the RO workforce. There are no data on residency growth by geographic region, major urban centers, and program size. We aim to fill this gap., Methods and Materials: A database of all RO programs and positions from 2003 to 2018 was created using National Resident Matching Program data. Programs were categorized by U.S. Census Bureau geographic region, major metropolitan location (top 10 combined statistical area vs all other), and program size (small [≤6 trainees], medium [7-12], and large [>12 trainees]). Linear regression with interaction terms was used to determine the effect of region, major metropolitan location, and program size on RO program and position growth over time., Results: There has been a 69% (54-91) and 82% (106-193) increase in the number of RO programs and annual positions from 2003 to 2018. Differences in program and position growth, respectively, were seen in each category. Growth in the Northeast (92% and 83%), South (81% and 113%), and West (125% and 130%) has outpaced the Midwest (17% and 33%). Growth in top 10 metropolitan areas (77% and 92%) is higher than in all other areas (63% and 73%). Growth in medium (68% and 80%) and large (175% and 153%) programs is greater than in smaller (36% and 33%) programs., Conclusions: There has been a major increase in the number of RO residency programs and positions over the past 15 years. Growth is occurring in every major category but there are differences in magnitude within each category. This information can inform future decisions about RO training programs in the United States., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Lung cancer is the leading cause of cancer death worldwide. Diagnosis of early-stage disease is becoming more common. In an aging population, more and more patients have substantial comorbidities that might limit feasibility of surgical management of early-stage disease. Stereotactic body radiotherapy (SBRT) enables delivery of high-dose, precisely delivered radiation to early-stage lung cancers without surgical risk. This technique has rates of local control similar to surgery and can be considered in medically operable patients who refuse surgery. This article details the technique of SBRT, the data for its efficacy, as well as the potential toxicities of treatment., Competing Interests: Disclosure The authors have no disclosures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) predicts decreased distant metastasis. However, most patients do not experience pCR, and other risk factors for distant metastasis after NAC are poorly characterized. This study investigated factors predictive of distant metastasis in TNBC without pCR after NAC., Methods: Women with TNBC treated with NAC, surgery, and radiation therapy in 2000 through 2013 were reviewed. Freedom from distant metastasis (FFDM) was compared between patients with and without pCR using the Kaplan-Meier method. In patients without pCR, univariate and multivariable Cox analyses were used to determine factors predictive of distant metastasis., Results: We identified 153 patients with median follow-up of 4.0 years (range, 0.5-14.0 years). After NAC, 108 had residual disease (pCR, 29%). Five-year FFDM was 98% and 55% in patients with and without pCR, respectively (P<.001). Factors independently predicting FFDM in patients without pCR were pathologic nodal positivity (hazard ratio, 3.08; 95% CI, 1.54-6.14; P=.001) and lymphovascular space invasion (hazard ratio, 1.91; 95% CI, 1.07-3.43; P=.030). Patients with a greater number of factors had worse FFDM; 5-year FFDM was 76.5% for patients with no factors (n=38) versus 54.9% and 27.5% for patients with 1 (n=44) and 2 factors (n=26), respectively (P<.001)., Conclusions: Lack of pCR after NAC resulted in worse overall survival and FFDM, despite trimodality therapy. In patients with residual disease after NAC, pathologic lymph node positivity and lymphovascular space invasion predicted worse FFDM.

Purpose: Dry eye is not typically considered a toxicity of whole brain radiation therapy (WBRT). We analyzed dry eye syndrome as part of a prospective study of patient-reported outcomes after WBRT., Methods and Materials: Patients receiving WBRT to 25 to 40 Gy were enrolled on a study with dry mouth as the primary endpoint and dry eye syndrome as a secondary endpoint. Patients received 3-dimensional WBRT using opposed lateral fields. Per standard practice, lacrimal glands were not prospectively delineated. Patients completed the Subjective Evaluation of Symptom of Dryness (SESoD, scored 0-4, with higher scores representing worse dry eye symptoms) at baseline, immediately after WBRT (EndRT), and at 1 month (1M), 3 months, and 6 months. Patients with baseline SESoD ≥3 (moderate dry eye) were excluded. The endpoints analyzed were ≥1-point and ≥2-point increase in SESoD score at 1M. Lacrimal glands were retrospectively delineated with fused magnetic resonance imaging scans., Results: One hundred patients were enrolled, 70 were eligible for analysis, and 54 were evaluable at 1M. Median bilateral lacrimal V20Gy was 79%. At 1M, 17 patients (32%) had a ≥1-point increase in SESoD score, and 13 (24%) a ≥2-point increase. Lacrimal doses appeared to be associated with an increase in SESoD score of both ≥1 point (V10Gy: P = .042, odds ratio [OR] 1.09/%; V20Gy: P = .071, OR 1.03/%) and ≥2 points (V10Gy: P = .038, OR 1.15/%; V20Gy: P = .063, OR 1.04/%). The proportion with increase in dry eye symptoms at 1M for lacrimal V20Gy ≥79% versus <79% was 46% versus 15%, respectively, for ≥1 point SESoD increase (P = .02) and 36% versus 12%, respectively, for ≥2 point SESoD increase (P = .056)., Conclusions: Dry eye appears to be a relatively common, dose/volume-dependent acute toxicity of WBRT. Minimization of lacrimal gland dose may reduce this toxicity, and patients should be counseled regarding the existence of this potential side effect and treatments for dry eye., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Triple negative breast cancer (TNBC) has worse prognosis than other subtypes of breast cancer, and many patients develop brain metastasis (BM). We developed a simple predictive model to stratify the risk of BM in TNBC patients receiving neo-adjuvant chemotherapy (NAC), surgery, and radiation therapy (RT)., Methods: Patients with TNBC who received NAC, surgery, and RT were included. Cox proportional hazards method was used to evaluate factors associated with BM. Significant factors predictive for BM on multivariate analysis (MVA) were used to develop a risk score. Patients were divided into three risk groups: low, intermediate, and high. A receiver operating characteristic (ROC) curve was drawn to evaluate the value of the risk group in predicting BM. This predictive model was externally validated., Results: A total of 160 patients were included. The median follow-up was 47.4 months. The median age at diagnosis was 49.9 years. The 2-year freedom from BM was 90.5%. Persistent lymph node positivity, HR 8.75 (1.76-43.52, P = 0.01), and lack of downstaging, HR 3.46 (1.03-11.62, P = 0.04), were significant predictors for BM. The 2-year rate of BM was 0%, 10.7%, and 30.3% (P < 0.001) in patients belonging to low-, intermediate-, and high-risk groups, respectively. Area under the ROC curve was 0.81 (P < 0.001). This model was externally validated (C-index = 0.79)., Conclusions: Lack of downstaging and persistent lymph node positivity after NAC are associated with development of BM in TNBC. This model can be used by the clinicians to stratify patients into the three risk groups to identify those at increased risk of developing BM and potentially impact surveillance strategies., (© 2019 Wiley Periodicals, Inc.)

Background: This study evaluated factors predictive of locoregional recurrence (LRR) in women with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy who do not experience pathologic complete response (pCR)., Methods: This is a single-institution retrospective review of women with TNBC treated with neoadjuvant chemotherapy, surgery, and radiation therapy in 2000 through 2013. LRR was estimated between patients with and without pCR using the Kaplan-Meier method. Patient-, tumor-, and treatment-specific factors in patients without pCR were analyzed using the Cox proportional hazards method to evaluate factors predictive of LRR. Log-rank statistics were then used to compare LRR among these risk factors., Results: A total of 153 patients with a median follow-up of 48.6 months were included. The 4-year overall survival and LRR were 70% and 15%, respectively, and the 4-year LRR in patients with pCR was 0% versus 22.0% in those without (P<.001). In patients without pCR, lymphovascular space invasion (LVSI; hazard ratio, 3.92; 95% CI, 1.64-9.38; P=.002) and extranodal extension (ENE; hazard ratio, 3.32; 95% CI, 1.35-8.15; P=.009) were significant predictors of LRR in multivariable analysis. In these patients, the 4-year LRR with LVSI was 39.8% versus 15.0% without (P<.001). Similarly, the 4-year LRR was 48.1% with ENE versus 16.1% without (P=.002). In patients without pCR, the presence of both LVSI and ENE were associated with an even further increased risk of LRR compared with patients with either LVSI or ENE alone and those with neither LVSI nor ENE in the residual tumor (P<.001)., Conclusions: In patients without pCR, the presence of LVSI and ENE increases the risk of LRR in TNBC. The risk of LRR is compounded when both LVSI and ENE are present in the same patient. Future clinical trials are warranted to lower the risk of LRR in these high-risk patients.

Background: The prognosis of patients with hepatic metastases from neuroendocrine tumors (NET) is generally good, and radioembolization with Yttrium-90 microspheres is a locoregional therapy that is used in efforts to improve hepatic disease control and survival. This study aims to describe the survival outcomes and toxicities associated with radioembolization for hepatic-predominant metastatic NET in a large single-institution cohort., Methods: A total of 59 patients underwent radioembolization for metastatic NET with hepatic predominant disease at a single academic center. Patient outcomes were analyzed by Kaplan-Meier survival analysis and toxicities were detailed and described. Ten patients within the cohort underwent post-treatment dosimetric analysis using PET-MRI and normal liver dosimetry was correlated with hepatic fibrosis and toxicity., Results: Median overall survival from time of radioembolization in the patient cohort was 31 months, and the 1- and 2-year overall survival was 80.4% and 65.6% respectively. Median hepatic progression-free survival and overall progression-free survival were 18 and 13 months, respectively. Three patients died of hepatic failure that was possibly therapy-related. Ten patients underwent evaluation of post-treatment dosimetry following radioembolization. In patients who did not develop hepatotoxicity or hepatic fibrosis, mean dose to normal liver was 25.4 Gy, while the mean liver dose in patients who experienced toxicity (hepatic fibrosis in n=2 and death from hepatic failure in n=1) was 59.1 Gy., Conclusions: Overall survival following radioembolization for hepatic metastases from NET is excellent; however, deaths that are potentially treatment-related have been observed. Preliminary data regarding dose to normal liver is suggestive of a relation between dosimetry and toxicity, however further work is required to further elucidate the mechanism, correlation with dosimetry, as well as additional patient and tumor factors that may predispose these patients to toxicity., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objective: As the utility of Child-Pugh (C-P) class is limited by the subjectivity of ascites and encephalopathy, we evaluated a previously established objective method, the albumin-bilirubin (ALBI) grade, as a prognosticator for yttrium-90 radioembolization (RE) treatment for patients with hepatocellular carcinoma (HCC)., Materials and Methods: A total of 117 patients who received RE for HCC from 2 academic centers were reviewed and stratified by ALBI grade, C-P class, and Barcelona Clinic Liver Cancer stage. The overall survival (OS) according to these 3 criteria was evaluated by Kaplan-Meier survival analysis. The utilities of C-P class and ALBI grade as prognostic indicators were compared using the log-rank test. Multivariate Cox regression analysis was performed to identify additional predictive factors., Results: Patients with ALBI grade 1 (n=49) had superior OS than those with ALBI grade 2 (n=65) (P=0.01). Meanwhile, no significant difference was observed in OS between C-P class A (n=100) and C-P class B (n=14) (P=0.11). For C-P class A patients, the ALBI grade (1 vs. 2) was able to stratify 2 clear and nonoverlapping subgroups with differing OS curves (P=0.03). Multivariate Cox regression test identified alanine transaminase, Barcelona Clinic Liver Cancer stage, and ALBI grade as the strongest prognostic factors for OS (P<0.10)., Conclusions: ALBI grade as a prognosticator has demonstrated clear survival discrimination that is superior to C-P class among HCC patients treated with RE, particularly within the subgroup of C-P class A patients. ALBI grade is useful for clinicians to make decisions as to whether RE should be recommended to patients with HCC.

Purpose: To identify clinical parameters that are prognostic for improved overall survival (OS) after yttrium-90 radioembolization (RE) in patients with liver metastases from colorectal cancer (CRC)., Materials and Methods: A total of 131 patients who underwent RE for liver metastases from CRC, treated at 2 academic centers, were reviewed. Twenty-one baseline pretreatment clinical factors were analyzed in relation to OS by the Kaplan-Meier method along with log-rank tests and univariate and multivariate Cox regression analyses., Results: The median OS from first RE procedure was 10.7 months (95% confidence interval [CI], 9.4-12.7 months). Several pretreatment factors, including lower carcinoembryonic antigen (CEA; ≤20 ng/mL), lower aspartate transaminase (AST; ≤40 IU/L), neutrophil-lymphocyte ratio (NLR) <5, and absence of extrahepatic disease at baseline were associated with significantly improved OS after RE, compared with high CEA (>20 ng/mL), high AST (>40 IU/L), NLR ≥5, and extrahepatic metastases (P values of <.001, <.001, .0001, and .04, respectively). On multivariate analysis, higher CEA, higher AST, NLR ≥5, extrahepatic disease, and larger volume of liver metastases remained independently associated with risk of death (hazard ratios of 1.63, 2.06, 2.22, 1.48, and 1.02, respectively)., Conclusions: The prognosis of patients with metastases from CRC is impacted by a complex set of clinical parameters. This analysis of pretreatment factors identified lower AST, lower CEA, lower NLR, and lower tumor burden (intra- or extrahepatic) to be independently associated with higher survival after hepatic RE. Optimal selection of patients with CRC liver metastases may improve survival rates after administration of yttrium-90., (Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: 18 F-fluorodeoxyglucose (FDG) positron emission tomography-(PET)/computed tomography (CT) imaging is used for staging and treatment planning of patients with anal cancer. Quantitative pre- and posttreatment metrics that are predictive of recurrence are unknown. We evaluated the association between pre- and posttreatment FDG-PET/CT parameters and outcomes for patients with squamous cell carcinoma of the anus (SCCA)., Methods and Materials: The records of 110 patients treated between 2003 and 2013 with definitive radiation therapy for SCCA were reviewed under an institutional review board-approved protocol. The median radiation therapy dose was 50.4 Gy (range, 35-60 Gy). Concurrent chemotherapy was administered for 109 of 110 patients and generally consisted of 5-fluorouracil and mitomycin C (n = 94). All patients underwent pretreatment FDG-PET/CT and 101 of 110 underwent posttreatment FDG-PET/CT 3 months after completion of radiation therapy. The maximum standard uptake value (SUV max ) was analyzed, in addition to multiple patient and treatment factors, by univariate and multivariate Cox regression for correlation with local recurrence (LR) and overall survival (OS)., Results: The median follow-up was 28.6 months. LR occurred in 1 of 15 (6.7%), 5 of 47 (10.6%), and 6 of 48 (12.5%) patients with stage I, II, and III disease, respectively. On univariate analysis, a significant association was observed between reduced LR and posttreatment SUV max <6.1 ( P = .0095) and between increased OS and posttreatment SUV max <6.1 ( P = .0086). On multivariate analysis, a significant association was observed between reduced LR and posttreatment SUV max <6.1 ( P = .0013) and the use of intensity modulated radiation therapy ( P < .001). A significant multivariate association was observed between increased OS and posttreatment SUV max <6.1 ( P = .0373) and the use of 5-fluorouracil/mitomycin C chemotherapy ( P = .001)., Conclusion: Posttreatment SUV max <6.1 is associated with reduced LR and increased OS after chemoradiation therapy for SCCA independent of T and N stage on multivariate analysis. Greater follow-up is required to confirm this association with late patterns of failure.

Purpose: Preoperative short-course radiation therapy (SCRT) has rarely been used for rectal cancer in the United States, although 2 randomized phase 3 trials demonstrate equivalence to conventional chemoradiation (CRT), and recent updates to national guidelines include this regimen as a treatment option. We sought to evaluate the efficacy and safety of preoperative SCRT followed by immediate surgery within 1 week to treat rectal cancer in the US setting., Methods and Materials: All patients treated with preoperative SCRT (4 Gy × 5 fractions for total 20 Gy) followed by planned surgery within 1 week at our institution were retrospectively evaluated. Censored cases with ≥2 years of follow-up were included along with any disease failure or death. Patients with cM1 disease were excluded. Patients with yp stage II/III disease typically received adjuvant chemotherapy from the 1990s onwards. The primary outcomes were actuarial (Kaplan-Meier) 5-year locoregional control (LC), disease-free survival (DFS), and overall survival (OS) as well as late severe (greater than or equal to grade 3) toxicity., Results: Our analysis included 202 consecutive patients with clinical stage I-III disease treated from 1977 through 2011. Median follow-up was 6.5 years (range, 2-29.2). Five-year disease outcomes were 95.9% ± 1.5% for LC, 76.4% ± 3.1% for DFS, and 84.6% ± 2.6% for OS. For patients with locally advanced rectal cancer (cT3-4 and/or cN+), 5-year LC, DFS, and OS were 95.1% ± 2.1%, 73.3% ± 4.3%, and 80.6% ± 3.7%, respectively. The late severe toxicity rate was 11.4%., Conclusions: SCRT followed by immediate surgery is a safe and effective treatment for patients with rectal cancer in the United States. Though SCRT has not been widely adopted, recent updates to the national guidelines for rectal cancer as well as financial pressures to reduce healthcare costs may lead to increased utilization of this treatment regimen in the future., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: To report outcomes and toxicities of a single-institution phase I/II study of stereotactic body radiotherapy (SBRT) in the treatment of unresectable hepatocellular cancer (HCC) and intrahepatic cholangiocarcinoma (IHC)., Materials and Methods: Patients with Child-Pugh score less than 8 were eligible. A total of 32 lesions in 26 patients were treated with SBRT. Kaplan-Meier survival analysis was performed. Toxicities were graded by CTCAEv4 criteria and response was scored by EASL guidelines., Results: Median prescribed dose was 55Gy (range 40-55Gy) delivered in 5 fractions. Mean tumor diameter was 5.0cm and mean GTV was 107cc. Median follow-up was 8.8months with a median survival of 11.1months, and one-year overall survival was 45%. Overall response rate was 42% and one-year local control was 91%. Nine patients experienced a decline in Child-Pugh class following treatment, and two grade 5 hepatic failure toxicities occurred during study follow-up., Conclusions: Primary hepatic malignancies not amenable to surgical resection portend a poor prognosis, despite available treatment options. Though radiation-induced liver disease (RILD) is rare following SBRT, this study demonstrates a risk of hepatic failure despite adherence to protocol constraints., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

While surgical management is a common approach for gynecologic malignancies; often disease is locally advanced such that surgery is precluded or surgical pathology reveals disease extent that mandates adjuvant treatment. Gynecologic brachytherapy is an important tool for both definitive and adjuvant treatment of cervical and endometrial cancers. Brachytherapy enables high radiation doses to a target with rapid fall-off to protect adjacent normal structures. This paper aims to detail the usage of brachytherapy in gynecologic cancers with a focus on advances in technique.

The goal of this article is to stress the importance of understanding the presence of varying levels of pretreatment anxiety sensitivity to certain anticipated dental events and the role it plays as a predictor of anxious behavior and patient responses when individuals are confronted with fear-causing events, such as dental treatment. The varying intensity of anxiety sensitivity levels (ASL) in individuals serves to lessen or heighten the anxious and fearful response to potentially anxiety-provoking stimuli, such as pain. This level of anxiety sensitivity can often be traced back to the degree of knowledge or lack of information possessed by the patient regarding anticipated treatment and the practitioner's degree of acumen and completeness in history gathering. It has been suggested clinically that the level of anxiety sensitivity is directly related to the ability to predict whether or not treatment compliance will be achieved in an individual. Knowing the factors-either physiological or psychological-that are in play and that produce negative and aversive responses within a patient before and during treatment is key to solving these barriers to dental care.

Injectable delivery systems are attractive as vehicles for localized delivery of therapeutics especially in the context of regenerative medicine. In this study, photocrosslinked polyanhydride (PA) networks were modified by incorporation of microparticles to modulate long-term delivery of macromolecules. The in vitro release of two model proteins (horseradish peroxidase (HRP) and bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA)) were evaluated from networks composed of sebacic acid dimethacrylate (MSA), 1,6-bis-carboxyphenoxyhexane dimethacrylate (MCPH), poly(ethylene glycol) diacrylate (PEGDA), and calcium carbonate (CaCO3), supplemented with gelatin microparticles or sodium chloride crystals. Prior to incorporation into the networks, proteins were formulated into granules by dilution with a cyclodextrin excipient and gelatin-based wet-granulation. Protein release was modulated by incorporation of microparticles into photocrosslinked PA networks, presumably by enabling aqueous channels through the matrix. Furthermore, a dual release system has been demonstrated by incorporation of protein in both the PA matrix and the gelatin microparticles. These results suggest that microparticle incorporation into the photocrosslinked PA system may be a useful strategy to modulate protein release in injectable delivery systems for the long-term delivery of macromolecules. These composites present an interesting class of materials for bone regeneration applications.

Injectable delivery systems are attractive as vehicles for localized delivery of therapeutics especially in the context of regenerative medicine. In this study, the potential of photocrosslinked polyanhydride (PA) networks as an encapsulation matrix for long-term delivery of macromolecules was studied. The in vitro release of two model proteins (horseradish peroxidase (HRP) and bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA)) was evaluated from crosslinked networks composed of sebacic acid dimethacrylate (MSA), 1,6-bis-carboxyphenoxyhexane dimethacrylate (MCPH), and poly(ethylene glycol) diacrylate (PEGDA), supplemented with calcium carbonate. Prior to incorporation into the networks, proteins were formulated by dilution in a cyclodextrin excipient followed by gelatin-based wet granulation. Protein release was quantified by activity assay (HRP) or fluorescence (FITC-BSA). Each protein was readily released from the networks with a unique release behavior. Most importantly, release of protein with retention of activity was achieved for durations ranging from 1 week to 4 months. The released HRP was additionally visualized using SDS-PAGE. In general, a more hydrophobic network resulted in slower rates of protein release. Incorporation of PEGDA into the matrices was critical for maintenance of integrity during degradation. These results suggest that this system may be useful as an injectable delivery system for long-term delivery of macromolecules.

Alloplastic materials, derived from poly(methylmethacrylate), such Bioplant-HTR, are a promising alternative to autologous bone in implant-dentistry and maxillofacial reconstruction. The clinical utility and outcomes using alloplasts such as HTR can be enhanced through the incorporation and release of proteins and growth factors. A simple, water-based process to surface engineer alloplast material to bear proteins has been developed. In this non-covalent process, the protein of choice is formulated into granules using gelatin-wet granulation and immobilized on the HTR alloplast surface, using water-soluble polymeric binders such as poly(vinyl alcohol) and Pluronics. The utility of this process has been verified using bovine serum albumin and horseradish peroxidase as model proteins. The process is capable of rendering these proteins on HTR surface in a reproducible manner, with formulated protein:HTR ratios less than 1:1 favoring more uniform surface coatings. By varying the ratio of the granulated protein to the HTR, surface protein concentration as high as 30 mug/mg of HTR particle can be achieved. By incorporating the protein-modified HTR particles with photocurable polymeric matrices and varying its hydrophobicity, sustained release of active HRP for at least 30 days was observed, with cumulative release ranging from 7-35% of loaded protein, depending on the protein:HTR ratio and the polymeric binder. The integrity of the released protein was also verified using SDS-PAGE gel and enzymatic assay. The simplicity of the surface modification strategy may make this suitable for ceramic and metal substrates as well.

Dental practitioners are sometimes reluctant to treat patients who are on psychopharmacological agents, due perhaps to the belief that these patients will be difficult to deal with. However patients whose medical history indicates emotional and psychiatric disorders and who are being treated with SSRI or SSNRI agents may actually present a more positive and more receptive attitude to treatment than what was sometimes previously encountered in these same individuals.

In the past decade, injectable biomaterials that are capable of in situ formation have garnered increased interest for use in restorative orthopedic procedures. In this study, the in vitro degradation of photocrosslinked polyanhydride matrices, derived from methacrylic anhydrides of 1,6-bis(p-carboxyphenoxy)hexane (MCPH) and sebacic acid (MSA) were evaluated over a 6-week period under physiological conditions. These matrices were augmented with two additives--the reactive diluent poly(ethylene glycol) diacrylate (PEGDA) and the buffering agent calcium carbonate (CaCO3). Disk shaped specimens were produced by crosslinking the components using both chemical and photoinitiators and exposure to visible light. The experimental variables studied included: MCPH:MSA ratio, PEGDA molecular weight and weight fraction, and incorporation of CaCO3. The effects of these variables on local pH, water uptake, mass loss, and mechanical properties were explored. Increasing the MCPH:MSA ratio decreased the mass loss and water uptake at predetermined endpoints, and decreased buffer acidity during degradation. Both PEGDA and CaCO3 were found to decrease acidity and to reduce water uptake during degradation. Incorporation of CaCO3 enabled maintenance of compressive modulus during degradation. These results demonstrate that incorporation of reactive diluents and nonreactive additives into networks of photocrosslinked anhydrides can improve system properties as a material for bone replacement.

During a four-month period in 1998, 250 new patients arriving at the General Dentistry Clinic of Tufts University School of Dental Medicine were asked to complete a questionnaire regarding behavior by dental professionals and its effect on dental care. Surveys were returned by 121 women and 82 men, who evaluated seven behaviors from five previously determined categories of anxiety. Age and gender were the only factors considered in analyzing the results. The data suggest that dentists often may exhibit a variety of negative behaviors and attitudes. These can cause increased levels of concern in patients and may act as fear-provoking stimuli, leading to increased fear and avoidance of dental treatment.

From September through November 1996, 158 of 844 patients at the general dentistry clinic of Tufts University School of Dental Medicine completed surveys concerning their fear of dental treatment. High levels of dental fear affected 65 percent of the respondents, with patients under the age of 45 reporting higher levels of fear than patients ages 45 years and older. Results showed that the four most common causes of fear in patients occur when the dentist seems rushed (65 percent), when the patient feels uninformed (50 percent), when the patient worries if the local anesthetic will be effective (43 percent), and when the patient's feelings are neglected (40 percent).

Dental anxiety has always been and still is a major impediment to regular dental care for a significant proportion of the general public. In years past, dental professionals could afford, by and large, to ignore this problem. Practices could flourish based on their technical virtuosity, and fearful or anxious patients might be considered a burden rather than a concern. Today, however, the laws of supply and demand are causing dentists to pay increased attention to aspects of the profession that extend beyond the science of clinical technique. A successful practice now depends on interpersonal as well as technical skills, particularly the ability to manage dental anxiety. Despite this, most dentists admit to a surprising lack of confidence when it comes to understanding the nature of anxiety and the modern methods advocated for its everyday management, which generally rely on behavioral modes of intervention. This paper is designed to familiarize practitioners with some of the basic elements of dental fear and anxiety, and their day to day management.

It has always been believed that fear and anxiety of dental treatment was a simple continuum of experience that occurs in mild, moderate, or severe form. Past and present studies that attempt to both trace etiology and measure it reflect this view. The numerous studies that are concerned with methods of management are based on this accepted philosophy regarding the etiology of dental fear and anxiety. To a large extent, this may be true. However, there are some notable exceptions, and it is these cases that present the greatest management problem. Omitting the symptoms of fear and anxiety related to physical illness, drug withdrawal, or major mental illness, they present anxiety as a unidimensional learned problem usually conditioned by externally negative forces or experiences. They postulate that the fear and anxiety seen is due to a variety of factors. The interpretation of the definitions of fear, anxiety, and phobias by many in the profession that are presented in this issue also reflect the view that fear, anxiety, and phobias are learned or conditioned responses. This single-minded view has determined much of our understanding and subsequent management of this problem in dentistry.

A more detailed measurement instrument for dental anxiety has been developed. To investigate the dimensionability of the response, two instruments were administered to 452 persons. The first set of items (33) concerned stimuli which might prove fearsome to patients. Some of these were dental specific, others were not. A second instrument (20 items) elicited the anxiety symptoms experienced. By comparing separate Kaiser-Caffrey Alpha Factor Analyses two factors were identified within each instrument. These were labelled "generalized" phobias and "dental specific" phobias; and "endogenous" and "exogenous" (anticipatory) anxiety symptoms. Four scales were constructed using simple summations of highly loaded variables. The scales are quite reliable. Although correlations among the scales proved to be significant they are all quite low, indicating that the four scales give more or less non-redundant information about the patient. The scale had discriminating validity in differentiating between patients who acknowledge experiencing spontaneous panic/anxiety attacks and those who did not. The data confirm that dental fears are relatively independent of other generalized anticipatory fears. The results cast doubt on previously held assumptions regarding the unidimensionality of anxiety. They are consistent with a new classification of anxiety and phobic disorders presented elsewhere. The implications for research and patient management are discussed.