Case report expanding the germline AXIN2- related phenotype to include olfactory neuroblastoma and gastric adenoma.

BACKGROUND: Pathogenic AXIN2 variants cause absence of permanent teeth (hypodontia), sparse hair and eye brows (ectodermal dysplasia), and gastrointestinal polyps and cancer. Inheritance is autosomal dominant with variable penetrance. Only twenty- five patients have been reported from five families. A Mayo Clinic pilot program tested 3009 newly diagnosed cancer patients for pathogenic germline variants in 83 hereditary cancer genes, including AXIN2. We found only one patient with a pathogenic AXIN2 variant. CASE PRESENTATION: The proband was a 49 year-old female who came to Otolaryngology clinic complaining of right-sided nasal obstruction. Biopsy of identified nasal polyp revealed olfactory neuroblastoma (esthesioneuroblastoma). Surgical resection with gross, total tumor resection was followed by radiation therapy. The patient enrolled in a clinical pilot of genetic testing and a pathogenic variant in AXIN2, c.1822del (p.Leu608Phefs*81) (NM_004655.3) was found. She was seen in Medical Genetics clinic and found to have a personal history of hypodontia. Her eyebrows, hair, and nails were all normal. She underwent upper endoscopy and colonoscopy. A four mm gastric adenoma was found and removed. CONCLUSIONS: This is the first case reported on a patient with a pathogenic, germline AXIN2 variant and an olfactory neuroblastoma or a gastric adenoma. We propose that these could be features of the AXIN2 phenotype. The known association between gastric adenomas and familial adenomatous polyposis, the other Wnt/beta-catenin disorder, supports the hypothesis that pathogenic AXIN2 variants increase risk as well. As the odds of a chance co-occurrence of a pathogenic AXIN2 variant and an olfactory neuroblastoma are so rare, it is worth exploring potential causation. We are building a clinical registry to expand understanding of the AXIN2 phenotype and request any clinicians caring for patients with pathogenic AXIN2 variants to contact us.

Assessment of unintended shifts during frame-based stereotactic radiosurgery using cone beam computed tomography image guidance.

PURPOSE: To investigate the frequency, magnitude and possible causes of frame-shifts that may occur between treatment planning and treatment delivery when performing Gamma Knife radiosurgery with rigid frame-based immobilization. METHODS: Differences between computed tomography (CT) framed fiducial stereotactic coordinate reference and cone beam computed tomography stereotactic coordinates after image registration were recorded for 49 frame-based GK radiosurgery cases performed using the Gamma Knife Icon. Parameters recorded include rotational shifts, translational shifts, and the GK-computed Maximum Shot Displacement (MSD) between the two stereotactic coordinate spaces. Other patient-specific parameters were collected and linear regression analysis was performed to evaluate predictors of increased displacement. RESULTS: The median values of rotational shifts were: pitch 0.14°, yaw 0.17°, and roll 0.13°. The median absolute values of translational shifts were: left-right 0.39 mm, anteroposterior 0.14 mm, and superior-inferior 0. 22 mm. The median value of MSD was 0.71 mm. Twelve cases (24.5%) had a MSD of greater than 1.0 mm. Male gender was associated with increased MSD (p = 0.013) and translational shifts (root-mean-squared value, p = 0.017). Cases with large differences between right and left sided pin lengths were also associated with increased MSD (p = 0.011). CONCLUSIONS: The use of CBCT image guidance in frame-based GK radiosurgery allows unintended frame shifts to be identified and corrected. A significant fraction (24.5%) of patients had large enough shifts to result in a MSD of greater than 1.0 mm. Male gender and eccentrically placed frames were associated with increased MSD, and particular care should be taken in these cases.

Hepatitis C prevalence and risk factors in Georgia, 2015: setting a baseline for elimination.

BACKGROUND: The country of Georgia launched the world's first Hepatitis C Virus (HCV) Elimination Program in 2015 and set a 90% prevalence reduction goal for 2020. We conducted a nationally representative HCV seroprevalence survey to establish baseline prevalence to measure progress toward elimination over time. METHODS: A cross-sectional seroprevalence survey was conducted in 2015 among adults aged ≥18 years using a stratified, multi-stage cluster design (n = 7000). Questionnaire variables included demographic, medical, and behavioral risk characteristics and HCV-related knowledge. Blood specimens were tested for antibodies to HCV (anti-HCV) and HCV RNA. Frequencies were computed for HCV prevalence, risk factors, and HCV-related knowledge. Associations between anti-HCV status and potential risk factors were calculated using logistic regression. RESULTS: National anti-HCV seroprevalence in Georgia was 7.7% (95% confidence interval (CI) = 6.7, 8.9); HCV RNA prevalence was 5.4% (95% CI = 4.6, 6.4). Testing anti-HCV+ was significantly associated with male sex, unemployment, urban residence, history of injection drug use (IDU), incarceration, blood transfusion, tattoos, frequent dental cleanings, medical injections, dialysis, and multiple lifetime sexual partners. History of IDU (adjusted odds ratio (AOR) = 21.4, 95% CI = 12.3, 37.4) and blood transfusion (AOR = 4.5, 95% CI = 2.8, 7.2) were independently, significantly associated with testing anti-HCV+ after controlling for sex, age, urban vs. rural residence, and history of incarceration. Among anti-HCV+ participants, 64.0% were unaware of their HCV status, and 46.7% did not report IDU or blood transfusion as a risk factor. CONCLUSIONS: Georgia has a high HCV burden, and a majority of infected persons are unaware of their status. Ensuring a safe blood supply, implementing innovative screening strategies beyond a risk-based approach, and intensifying prevention efforts among persons who inject drugs are necessary steps to reach Georgia's HCV elimination goal.

Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial.

Importance: Oral mucositis causes substantial morbidity during head and neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis-related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used. Objective: To evaluate the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain. Design, Setting, and Participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days. Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo. Main Outcome and Measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or burning. All scales ranged from 0 (best) to 10 (worst). Results: Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group. Conclusions and Relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes. Trial Registration: ClinicalTrials.gov Identifier: NCT02229539.

Late diagnosis of hepatitis C virus infection in the Chronic Hepatitis Cohort Study (CHeCS): Missed opportunities for intervention.

UNLABELLED: To determine the stage of liver disease at initial diagnosis of hepatitis C virus (HCV) infection, we analyzed data from the Chronic Hepatitis Cohort Study (CHeCS), a large U.S. observational study. We examined the temporal relationships of initial HCV infection diagnosis with cirrhosis-defined by liver biopsy or mean FIB-4 score >5.88-and time to onset of cirrhotic decompensation in electronic medical records. We determined time in the health system prior to HCV diagnosis and rates of hospitalization and death following HCV diagnosis. Of 14,717 patients with chronic HCV seen during 2006-2011, 6,166 (42%) had a definable time of initial HCV diagnosis. Of these, 1,056 (17%) patients met our definition for "late diagnosis" with either cirrhosis concurrent with initial HCV diagnosis (n = 550), a first diagnosis of hepatic decompensation before or within 12 months after initial HCV diagnosis (n = 506), or both (n = 314). Patients with late diagnosis had an average of 6 years in the health system before their HCV diagnosis. In a comparison with patients without late diagnosis, hospitalization (59% versus 35%) and death (33% versus 9%) were more frequent among patients with late diagnosis. Among all who died, mean (median) time from initial HCV diagnosis to death was 4.8 (4.2) years. CONCLUSION: Many CHeCS patients had advanced liver disease concurrent with their initial HCV diagnosis despite many years of engagement with the healthcare system, and these patients had high rates of hospitalization and mortality.

Proposed prognostic scoring system evaluating risk factors for biochemical recurrence of prostate cancer after salvage radiation therapy.

OBJECTIVE: To update a previously proposed prognostic scoring system that predicts risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer when using additional patients and a PSA value of 0.2 ng/mL and rising as the definition of BCR. PATIENTS AND METHODS: We included 577 patients who received SRT for a rising PSA after radical prostatectomy in this retrospective cohort study. Clinical, pathological, and SRT characteristics were evaluated for association with BCR using relative risks (RRs) from multivariable Cox regression models. RESULTS: With a median follow-up of 5.5 years after SRT, 354 patients (61%) experienced BCR. At 5 years after SRT, 40% of patients were free of BCR. Independent associations with BCR were identified for the PSA level before SRT (RR [doubling]: 1.25, P < 0.001), pathological tumour stage (RR [T3a vs T2] 1.21, P = 0.19; RR [T3b/T4 vs T2] 2.09, P < 0.001; overall P < 0.001), Gleason score (RR [7 vs <7] 1.63, P < 0.001; RR [8-10 vs <7] 2.28, P < 0.001; overall P < 0.001), and surgical margin status (RR [positive vs negative] 0.71, P = 0.003). We combined these four variables to create a prognostic scoring system that predicted BCR risk with a c-index of 0.66. Scores ranged from 0 to 7, and 5-year freedom from BCR for different levels of the score was as follows: Score = 0-1: 66%, Score = 2: 46%, Score = 3: 28%, Score = 4: 19%, and Score = 5-7: 15%. CONCLUSION: We developed a scoring system that provides an estimation of the risk of BCR after SRT. These findings will be useful for patients and physicians in decision making for radiation therapy in the salvage setting.

Update: Shortened Interval for Postvaccination Serologic Testing of Infants Born to Hepatitis B-Infected Mothers.

Infants born to hepatitis B-infected mothers receive postexposure prophylaxis to reduce their risk for perinatal hepatitis B virus (HBV) infection. Postexposure prophylaxis consists of hepatitis B (HepB) vaccine and hepatitis B immune globulin administered within 12 hours of birth, followed by completion of the 3-dose or 4-dose HepB vaccine series. Postvaccination serologic testing (PVST) assesses an infant's response to HepB vaccination and has typically occurred at age 9-18 months. This report provides a CDC update recommending shortening the interval for PVST from age 9-18 months to age 9-12 months. Providers should order PVST (consisting of hepatitis B surface antigen [HBsAg] and antibody to HBsAg [anti-HBs]) for infants born to HBsAg-positive mothers at age 9-12 months (or 1-2 months after the final dose of the vaccine series, if the series is delayed). This recommendation was prompted by the discontinuation of production of Hib/HepB vaccine (Comvax) and new data from the Enhanced Perinatal Hepatitis B Prevention Program supporting PVST 1・2 months after receipt of the last HepB vaccine dose, and at age ≥9 months.

Launch of a Nationwide Hepatitis C Elimination Program--Georgia, April 2015.

Hepatitis C virus (HCV) infects an estimated 130-150 million persons globally and results in an estimated 700,000 deaths annually from hepatocellular carcinoma or cirrhosis. Georgia, a middle-income Eurasian country, has one of the highest estimated HCV prevalences in the world. In 2011, Georgia began offering treatment to a limited number of HCV-infected persons. Beginning in 2013, when new oral medications that can cure >90% of HCV infections were licensed, Georgia engaged partners to develop a comprehensive HCV prevention and control plan, during which the concept of elimination of HCV transmission and disease emerged. To prepare for the launch of an HCV elimination program, Georgia requested CDC's assistance to describe HCV epidemiology, evaluate laboratory and health care capacity, and conduct program monitoring and evaluation. This report describes the activities undertaken to prepare for the program, launched in April 2015, and early results of its initial phase, focused on improving access to affordable diagnostics and free curative treatment for HCV-infected persons with severe liver disease. A national population-based serosurvey began in May 2015, and four clinical sites and their laboratories were selected as initial pilot sites; since June, three additional sites have been added. Through July 3, 2015, a total of 6,491 persons sought treatment, and 6,177 (95.2%) initiated diagnostic work-up. Among these, 1,519 (24.6%) completed work-up, 1,474 (97.0%) of whom initiated treatment. Georgia is scaling up capacity to meet the demand for HCV treatment and is collaborating with CDC and other partners on development of a comprehensive HCV elimination plan that includes specific goals and activities needed to achieve them.

Negative margin technique - a novel planning strategy to improve dose conformation in SBRT using dynamic conformal arc delivery.

The purpose of this study was to introduce a planning strategy for dynamic conformal arc therapy (DCAT), named negative margin technique (NMT), and evaluate its dosimetric gain in lung stereotactic body radiation therapy (SBRT). In DCAT, the field aperture is continuously conformed to the planning target volume (PTV) with an aperture margin (AM) to compensate for the penumbra effect with gantry rotation. It is a common belief the AM should be positive (or at least 'zero'). However, the radial penumbra width becomes significantly wider because of continuously overlapped beams in arc delivery. Therefore, we hypothesize if the 'negative margin' is applied in the radial direction, it would improve the PTV dose conformation while reducing normal tissue dose. For verification, trial plans were made using the NMT and compared with 'zero margin (ZM)' plans for five lung SBRT cases representing different situations depending on the location of the PTV and organs at risk. All plans met 95% PTV coverage with the prescription dose and spared the spinal cord below the tolerance. Two conventional conformation indices (the ratio of prescription isodose volume to the PTV (CI100) and the ratio of 50% prescription isodose volume to the PTV (CI50)) and a modified conformation index were investigated. The maximum dose at 2 cm from the PTV (Dmax-2cm) and the percent of lung volume receiving 20 Gy (V20) were also evaluated. Another planning simulation was performed with a total of ten randomly selected lung SBRT cases to mimic actual practice. In this simulation, optimization with ZM was first performed and further optimization using the NMT was processed for cases that could not meet a goal of CI100 = 1.2 with the ZM optimization. In all cases, both the CI100 and CI50 values were significantly reduced (overall, 9.4% ± 4.1% and 5.9%± 3.1% for CI100 and CI50, respectively). The modified conformation index values also showed similar improvement (overall, 10.1% ± 5.7% increase). Reduction of Dmax-2cm was also observed in all cases (4.5% ± 2.2%). V20 values decreased in all cases but one (5.7% ± 3.9%, excluding the increased case). In the random group simulation, it was possible to achieve the goal with just one NMT trial for five out of six cases that did not meet the goal in the ZM optimization. Interestingly, however, one case needed as many as six iterations to get the CI100 = 1.2 goal. The NMT turned out to be an effective planning strategy that could bring significant improvement of dose conformation. The NMT can be easily implemented in most clinics with no prerequisite.

Proton Therapy With Concurrent Chemotherapy for Thoracic Esophageal Cancer: Toxicity, Disease Control, and Survival Outcomes.

Purpose: When treating esophageal cancer with radiation therapy, it is critical to limit the dose to surrounding structures, such as the lung and/or heart, as much as possible. Proton radiation therapy allows a reduced radiation dose to both the heart and lungs, potentially reducing the risk of cardiopulmonary toxicity. Here, we report disease control, survival, and toxicity outcomes among patients with esophageal cancer treated with proton radiation therapy and concurrent chemotherapy (chemoradiation therapy; CRT) with or without surgery. Materials and Methods: We enrolled 17 patients with thoracic esophageal carcinoma on a prospective registry between 2010 and 2021. Patients received proton therapy to a median dose of 50.4-GyRBE (range, 50.4-64.8) in 1.8-Gy fractions.Acute and late toxicities were graded per the Common Terminology Criteria for Adverse Events, version 4.0 (US National Cancer Institute, Bethesda, Maryland). In addition, disease control, patterns of failure, and survival outcomes were collected. Results: Nine patients received preoperative CRT, and 8 received definitive CRT. Overall, 88% of patients had adenocarcinoma, and 12% had squamous cell carcinoma. With a median follow-up of 2.1 years (range, 0.5-9.4), the 3-year local progression-free, disease-free, and overall survival rates were 85%, 66%, and 55%, respectively. Two patients (1 with adenocarcinoma and 1 with squamous cell carcinoma) recurred at the primary site after refusing surgery after a complete clinical response to CRT. The most common acute nonhematologic and hematologic toxicities, respectively, were grades 1 to 3 esophagitis and grades 1 to 4 leukopenia, both affecting 82% of patients. No acute cardiopulmonary toxicities were observed in the absence of surgical resection. Reagarding surgical complications, 3 postoperative cardiopulmonary complications occurred as follows: 1 grade 1 pleural effusion, 1 grade 3 pleural effusion, and 1 grade 2 anastomotic leak. Two severe late CRT toxicities occurred: 1 grade 5 tracheoesophageal fistula and 1 grade 3 esophageal stenosis requiring a feeding tube. Conclusion: Proton radiation therapy is a safe, effective treatment for esophageal cancer with increasing evidence supporting its role in reducing cardiopulmonary toxicity.

Evaluation of MDM2, p16, and p53 staining levels as biomarkers of biochemical recurrence following salvage radiation therapy for recurrent prostate cancer.

BACKGROUND AND PURPOSE: The selection of appropriate candidates for salvage radiation therapy (SRT) to address a rising PSA following radical prostatectomy remains challenging. Herein, we provide the first evaluation of the ability of staining levels of the tumor based biomarkers MDM2, p16, and p53 to aid in prediction of biochemical recurrence (BCR) among men undergoing SRT for recurrent prostate cancer. MATERIAL AND METHODS: We identified 152 patients who were treated with SRT between July 1987 and July 2003. Staining levels of MDM2, p16, and p53 in primary tumor samples removed during prostatectomy were detected using monoclonal antibodies and quantified by use of a computer-assisted method. Associations of staining levels with BCR were evaluated using Cox proportional hazards regression models; relative risks (RRs) and 95% confidence intervals (CIs) were estimated. RESULTS: Compared to patients with low staining (≤median) as measured by percentage of cells with nuclear staining, there was no significant difference in risk of BCR for patients with high MDM2 staining (RR: 0.90, 95% CI: 0.57-1.45, P = 0.67), high p16 staining (RR: 0.88, 95% CI: 0.54-1.44, P = 0.62), or high p53 staining (RR: 1.33, 95% CI: 0.84-2.11, P = 0.23) in multivariable analysis. These results were consistent when considering alternate percentile cutpoints and alternate quantifications of biomarker staining. CONCLUSIONS: Our results provide evidence that MDM2, p16, and p53 staining levels are not useful in the prediction of BCR after SRT. As such, these biomarkers are of little clinical use in the selection of appropriate candidates for SRT.

Impact of neoadjuvant chemoradiation on the tumor burden before liver transplantation for unresectable cholangiocarcinoma.

The very early experience with liver transplantation (LT) for cholangiocarcinoma (CC) was dismal because of the poor survival outcomes and the high recurrence rates. However, LT for CC in conjunction with neoadjuvant chemoradiation recently has shown encouraging results, although the data are extremely limited. At our institution between 2001 and 2008, 22 CC patients underwent protocol orthotopic LT at a median age of 45 years (range = 24-63 years). At a median follow-up of 601.5 days (range = 111-1388 days), the median survival time of the cohort was 3.3 years. The 1-, 2-, and 3-year Kaplan-Meier survival probabilities were 90%, 70%, and 63%, respectively, whereas the historical 5-year survival rates were 0% to 18% for intrahepatic CC and 23% to 26% for extrahepatic CC when patients underwent transplantation without neoadjuvant therapy. These encouraging survival rates for patients with this type of tumor, which is difficult to diagnose and treat, are no less significant when they are compared to the national 1- and 3-year survival rates (86% and 68%, respectively) of patients undergoing deceased donor LT for malignant neoplasms of the liver (as reported by the United Network for Organ Sharing). In our series, disease recurrence was significantly associated with a larger residual tumor [6.3 versus 2.0 cm (mean values), P = 0.008] and with a shorter waiting time for LT after the chemoradiation protocol [18 versus 56 days (mean values), P = 0.04]. Our LT protocol for CC was found to be promising for patients with truly extrahepatic CC and for patients within stages I to IIB of the American Joint Committee on Cancer Staging system (100% survival at a median follow-up of 2.2 years), but the results were notably poor for patients with stage III extrahepatic CC (median survival = 1.2 years). These observations highlight the need for accurate preoperative staging of CC for ideal LT recipient selection and the importance of a low tumor burden and a longer wait after neoadjuvant therapy. More effective chemoradiation regimens for reducing the tumor burden and the appropriate timing of LT after neoadjuvant chemoradiation require further research.

Outcomes and Patterns of Recurrence for Anaplastic Thyroid Cancer Treated With Comprehensive Chemoradiotherapy.

PURPOSE: Radiation therapy (RT) plays an important role in locoregional tumor control for anaplastic thyroid cancer (ATC). Due to its rarity, RT guidelines for ATC are lacking. We describe ATC patterns of nodal disease at presentation and progression and propose corresponding RT target volumes. METHODS AND MATERIALS: We identified all patients with ATC treated at our institution with definitive or adjuvant intensity modulated radiation therapy and concomitant chemotherapy from 2006 to 2020. We identified in-field, marginal, and out-of-field sites of locoregional recurrence and progression (LRR). RESULTS: Forty-seven patients met inclusion. Median follow-up was 6.6 months (interquartile range, 1.9-19.6). Nodal levels involved at presentation included: IB (2.1%), II (23.4%), III (21.3%), IV (21.3%), V (12.8%), VI (34%), and mediastinal (6.4%). All patients received elective nodal RT to levels II-IV and VI. RT volumes also included: IA (23.4%), IB (44.7%), V (87.2%), retropharyngeal/retrostyloid (RP/RS) (27.7%), and mediastinal 1 to 6 (53.2%). Cumulative incidence of LRR at 3- and 12-months was 26.1% (95% confidence interval, 15.9-42.8) and 35.7% (23.9-53.4). Isolated LRR risk at 3- and 12-months was 6.5% (2.2-19.8) and 8.9% (3.4-22.9). Fourteen (29.8%) patients experienced in-field LRR in the thyroid gland or postoperative tumor bed, II-IV, VI, and mediastinal 1 and 3A. Four (8.5%) patients had marginal LRRs, 3 of whom progressed in the mediastinum at 2, 3P, 4, and 6. Two (4.3%) patients experienced out-of-field LRRs. Throughout the pretreatment and follow-up period, no patients had disease at IA, and 1 (2.1%) patient each had disease at IB and RP/RS. No baseline or treatment characteristics, including RT dose (stratified by < or ≥66 Gy), were significant predictors of LRR on univariate analysis. CONCLUSIONS: Isolated LRR risk in patients with ATC treated with comprehensive RT and chemotherapy is low. Aggressive multimodality therapy should be reserved for willing, fit patients with no or limited distant disease burden. When treating comprehensively, complete inclusion of mediastinal levels 1 to 6 may be warranted to avoid marginal disease progression. Omission of levels I and RP/RS can be considered.

Dosimetric predictors of pneumonitis in locally advanced non-small cell lung cancer patients treated with chemoradiation followed by durvalumab.

OBJECTIVES: The incidence and predictors of pneumonitis for patients with unresectable, locally advanced non-small cell lung cancer (NSCLC) in the era of consolidation durvalumab have yet to be fully elucidated. In this large single institution analysis, we report the incidence of and factors associated with grade 2 + pneumonitis in NSCLC patients treated with the PACIFIC regimen. MATERIALS AND METHODS: We identified all patients treated at our institution with definitive CRT followed by durvalumab from 2018 to 2021. Clinical documentation and imaging studies were reviewed to determine grade 2 + pneumonitis events, which required the following: 1) pulmonary symptoms warranting prolonged steroid taper, oxygen dependence, and/or hospital admission and 2) radiographic findings consistent with pneumonitis. RESULTS: One-hundred ninety patients were included. The majority received 60 Gray (Gy) in 30 fractions with concurrent carboplatin and paclitaxel. Median number of durvalumab cycles received was 12 (IQR: 4-22). At a median follow-up of 14.8 months, 50 (26.3%) patients experienced grade 2 + pneumonitis with a 1-year cumulative incidence of 27.8% (95% CI: 21.9-35.4). Seventeen (8.9%) patients experienced grade 3 + pneumonitis and 4 grade 5 (2.1%). Dosimetric predictors of pneumonitis included ipsilateral and total lung volume receiving 5 Gy or greater (V5Gy), V10Gy, V20Gy, V40Gy, and mean dose and contralateral V40Gy. Heart V5Gy, V10Gy, and mean dose were also significant variables. Overall survival estimates at 1 and 3 years were 87.4% (95% CI: 82.4-92.8) and 60.3% (95% CI: 47.9-74.4), respectively. CONCLUSION: We report a risk of pneumonitis higher than that seen on RTOG 0617 and comparable to the PACIFIC study. Multiple lung and heart dosimetric factors were predictive of pneumonitis.

Initial response to protease-inhibitor-based antiretroviral therapy among children less than 2 years of age in South Africa: effect of cotreatment for tuberculosis.

BACKGROUND: South African guidelines recommend protease-inhibitor-based antiretroviral therapy (ART) with lopinavir-ritonavir for human immunodeficiency virus (HIV)-infected children <36 months of age. We investigated factors associated with viral suppression and mortality among young children initiating ART. METHODS: Treatment-naive, ART-eligible, HIV-infected children (aged 6-104 weeks) were enrolled in an ART strategies trial in South Africa and initiated protease-inhibitor-based ART. Mortality and the probability of viral suppression (defined as HIV RNA load of <400 copies/mL) by 39 weeks after ART initiation were investigated. RESULTS: Of 254 children who initiated ART, 99 (39%) were cotreated for tuberculosis during follow-up. The mortality rate was 14%. Factors predicting mortality were lower pre-ART weight-for-age z score and higher HIV RNA load. By 39 weeks, 84% of surviving children achieved viral suppression. Children who were not cotreated for tuberculosis were more likely to achieve viral suppression (94.8%) than were children who were receiving cotreatment at ART initiation (74.2%) or who started tuberculosis cotreatment after ART initiation (51.6%; P < .001). Other factors predicting lower probability of viral suppression were lower pre-ART weight- and length-for-age z score, higher HIV RNA load, and World Health Organization disease stage. CONCLUSION: High rates of viral suppression can be achieved among infants and young children who initiate protease-inhibitor-based ART. Cotreatment for tuberculosis reduced viral suppression. How best to treat HIV-infected children who require tuberculosis treatment warrants urgent investigation.

Mask-based immobilization in Gamma Knife stereotactic radiosurgery.

The Gamma Knife Icon (Elekta AB, Stockholm) is a cobalt-based stereotactic radiosurgery (SRS) unit to support the use of a thermoplastic mask in lieu of a rigid frame, using an onboard cone-beam CT (CBCT) and an intrafraction motion management system (IFMM). We retrospectively reviewed 124 patients treated with Gamma Knife SRS from January 2018 to December 2019 at our institution using a mask-based immobilization system. Patient and treatment characteristics were collected and summarized as well as interfraction shifts and treatment-related outcomes. This dataset includes 124 patients with an associated 358 intracranial tumors. Twenty-four patients presented with primary brain tumors, which included 14 meningiomas and 10 other histologies, with 100 patients having brain metastases. Sixty tumors were post-operative, while 298 were intact. The median dose for primary tumors was 25 Gy in 5 fractions. Median doses to metastases were 20 Gy in 1 fraction, 27 Gy in 3 fractions, and 25 Gy in 5 fractions. Median interfraction CBCT shifts were submillimeter. Median patient follow-up was 6.28 months. 91% of patients with metastases maintained local control. Our early clinical experience has demonstrated limited toxicity profiles and high patient tolerance, which suggests that mask-based Gamma Knife SRS provides a safe alternative option for frameless SRS. Patients with large target volumes where fractionation is preferred or with small target volumes in non-eloquent areas can be considered for this approach. Response rates are encouraging, and continued follow-up is necessary to investigate long-term control and survival.

Carbon Ion Radiotherapy in the Management of Hepatocellular Carcinoma.

Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.

Induction versus no induction chemotherapy before neoadjuvant chemoradiotherapy and surgery in oesophageal adenocarcinoma: a multicentre randomised phase II trial (NCCTG N0849 [Alliance]).

AIM: report primary results from the first multicentre randomised trial evaluating induction chemotherapy prior to trimodality therapy in patients with oesophageal or gastro-oesophageal junction adenocarcinoma. Notably, recent data from a single-institution randomised trial reported that induction chemotherapy prolonged overall survival (OS) in patients with well/moderately differentiated tumours. METHODS: In this phase 2 trial (28 centres in the U.S. NCI-sponsored North Central Cancer Treatment Group [Alliance]), trimodality-eligible patients (T3-4N0, TanyN+) were randomised to receive induction (docetaxel, oxaliplatin, capecitabine; Arm A) or no induction chemotherapy (Arm B) followed by oxaliplatin/5-fluorouracil/radiation and subsequent surgery. The primary endpoint was the rate of pathologic complete response (pathCR). Secondary/exploratory endpoints were OS and disease-free survival (DFS). RESULTS: Of 55 patients evaluable for the primary endpoint, the pathCR rate was 28.6% (8/28) in A versus 40.7% (11/27) in B (P = .34). Given interim results indicating futility, accrual was terminated, but patients were followed. After a median follow-up of 60.4 months, a longer median OS in Arm A versus B was unexpectedly observed (3-year rates 57.1% versus 41.7%, respectively) driven by longer DFS after margin-free surgery. In posthoc analysis, induction (versus no induction) chemotherapy was associated with significantly longer OS and DFS among patients with well/moderately differentiated tumours, but not among patients with poorly/undifferentiated tumours (Pinteraction = 0.037). CONCLUSIONS: Adding induction chemotherapy prior to trimodality therapy did not improve the primary endpoint, pathCR. However, induction chemotherapy was associated with longer median OS, particularly among patients with well/moderately differentiated tumours. These findings may inform further development of curative-intent trials in this disease.

Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force.

BACKGROUND: Coronary heart disease and cerebrovascular disease are leading causes of death in the United States. In 2002, the U.S. Preventive Services Task Force (USPSTF) strongly recommended that clinicians discuss aspirin with adults who are at increased risk for coronary heart disease. PURPOSE: To determine the benefits and harms of taking aspirin for the primary prevention of myocardial infarctions, strokes, and death. DATA SOURCES: MEDLINE and Cochrane Library (search dates, 1 January 2001 to 28 August 2008), recent systematic reviews, reference lists of retrieved articles, and suggestions from experts. STUDY SELECTION: English-language randomized, controlled trials (RCTs); case-control studies; meta-analyses; and systematic reviews of aspirin versus control for the primary prevention of cardiovascular disease (CVD) were selected to answer the following questions: Does aspirin decrease coronary heart events, strokes, death from coronary heart events or stroke, or all-cause mortality in adults without known CVD? Does aspirin increase gastrointestinal bleeding or hemorrhagic strokes? DATA EXTRACTION: All studies were reviewed, abstracted, and rated for quality by using predefined USPSTF criteria. DATA SYNTHESIS: New evidence from 1 good-quality RCT, 1 good-quality meta-analysis, and 2 fair-quality subanalyses of RCTs demonstrates that aspirin use reduces the number of CVD events in patients without known CVD. Men in these studies experienced fewer myocardial infarctions and women experienced fewer ischemic strokes. Aspirin does not seem to affect CVD mortality or all-cause mortality in either men or women. The use of aspirin for primary prevention increases the risk for major bleeding events, primarily gastrointestinal bleeding events, in both men and women. Men have an increased risk for hemorrhagic strokes with aspirin use. A new RCT and meta-analysis suggest that the risk for hemorrhagic strokes in women is not statistically significantly increased. LIMITATIONS: New evidence on aspirin for the primary prevention of CVD is limited. The dose of aspirin used in the RCTs varied, which prevented the estimation of the most appropriate dose for primary prevention. Several of the RCTs were conducted within populations of health professionals, which potentially limits generalizability. CONCLUSION: Aspirin reduces the risk for myocardial infarction in men and strokes in women. Aspirin use increases the risk for serious bleeding events.

Public interest in stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) in the United States.

Stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery have become widely used in both palliative and curative treatments for variety of primary and secondary malignancies. Although the indications and use of stereotactic techniques have increased substantially in the past decades, there been no studies to date analyzing public interest in these techniques. Using Google Trends (Google LLC, Mountain View, CA), four search terms ("SBRT," "stereotactic radiosurgery," "Gamma Knife" and "Cyberknife") were analyzed in the U.S. from January 2004 to June 2019. Each term was assigned a relative interest score based on frequency of searches. "SBRT" is becoming an increasingly popular search term, reaching peak interest in October 2018. Conversely, "stereotactic radiosurgery" and "Gamma Knife" radiosurgery initially had high interest, before declining over the past decade. "Cyberknife" was most popular in the mid-2000s but decreased steadily since that time. These trends were subsequently compared against PubMed publication data over the same time.