The diagnosis and management of tracheobronchial papilloma is challenging due to its rarity, and non-specific presenting symptoms. Small percentage undergoes malignant transformation. Herein, we report an unusual case of tracheal papilloma initially misdiagnosed as chronic obstructive pulmonary disease (COPD) in 36-year-old male with triple Y syndrome. It was successfully treated with local debridement and brachytherapy. To the best of our knowledge, this is the first description of brachytherapy for such a condition.

Non‐small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA‐seq), real‐time quantitative PCR (RT‐qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater antiproliferative capacity than specific mitochondrial complex‐I inhibitors. The treatment downregulated genes mediating hypoxia‐inducible factor (HIF)‐1α stability, metabolism and survival, activated adenosine monophosphate‐activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia‐inducible factor‐1α (HIF‐1α) signaling. HIF‐1α knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF‐1α. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin's transcriptional reprogramming. HDAC2 knockdown eliminated HIF‐1α levels and enhanced the antiproliferative effects of canagliflozin. HDAC2‐regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC.

Introduction: Most brachytherapy (BT) procedures require general anesthesia and are therefore considered aerosol generating medical pro-cedures (AGMPs). The COVID-19 pandemic impacted BT as services were prioritized by balancing the harm associated with COVID-19 in-fection versus the effect of delay of potentially curative treatment. This article summarizes the impact of the pandemic on BT programs in two cancer centers in a Canadian province.Methods: As part of a quality assurance project, a retrospective study was conducted for the first five months of the pandemic (March 1 to July 31, 2020). Chart review and COVID-19 related mitigation strategies were identified by BT Clinical Specialist Radiation Thera-pists (bCSRT) in each center using electronic medical records, depart-mental reports, policies and procedures.Results: Impact included start of virtual care (VC), shortened frac-tionation, suspension of services and workflow changes. Both centers implemented VC strategies to reduce clinic visits: "same-day size and treat" strategy for post-operative endometrial cancer patients and vir-tual patient education for all patients. BT services that were suspended were low-dose-rate and high-dose-rate (HDR) prostate treatments (Center 1), lung and esophagus HDR treatments (Center 2). Work-flow changes that affected staff and patients in both centers included COVID-19 screening and the use of personal protective equipment. The centers were marginally different in workflow adjustments for AGMP procedures. Those considered high-risk AGMP and low-risk cancer were suspended temporarily with alternate treatment strategies sought for some patients. Others had temporizing treatment such as androgen deprivation therapy to facilitate oncological safe deferral of procedures.Conclusion: Both BT programs delivered treatment to most patients with minimal delays and cancellations, where feasible. Some of the pandemic workflow changes continued to the current state of the pan-demic. Long-term follow-up is needed to assess the impact of COVID-19 and treatment interruptions on oncologic outcomes.

Purpose: Uncontrolled studies suggest that the addition of high-dose-rate intraluminal brachytherapy (HDRIB) to external beam radiation therapy (EBRT) may improve palliation for patients with advanced non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the potential clinical benefit of adding HDRIB to EBRT in a multicenter randomized trial. Methods and Materials: Patients with symptomatic stage III or IV NSCLC with endobronchial disease were randomized to EBRT (20 Gy in 5 daily fractions over 1 week or 30 Gy in 10 daily fractions over 2 weeks) or the same EBRT plus HDRIB (14 Gy in 2 fractions separated by 1 week). The primary outcome was the proportion of patients who achieved symptomatic improvement in patient-reported overall lung cancer symptoms on the Lung Cancer Symptom Scale (LCSS) at 6 weeks after randomization. Secondary outcomes included improvement in individual symptoms, symptom-progression-free survival, overall survival, and toxicity. The planned sample size was 250 patients based on detection of symptomatic improvement from 40% to 60% with a 2-sided a of .05 and 80% power.Results: A total of 134 patients were randomized over 4.5 years: 67 to each arm. The study closed early owing to slow accrual. The mean age was 69.8 years, and 67% of patients had metastatic disease. At 6 weeks, 19 patients (28.4%) in the EBRT arm and 20 patients (29.9%) in the EBRT plus HDRIB arm experienced an improvement in lung cancer symptoms (P = .84). When limited to patients who completed the LCSS, percentages were 40.4% versus 47.6%, respectively (P = .49). Between group dif-ferences in mean change scores (0.3-0.5 standard deviations) in favor of EBRT plus HDRIB were observed for overall symp-toms, but only hemoptysis was significantly improved (P = .03). No significant differences were observed in progression-free or overall survival. Grade 3/4 toxicities were similar between groups. Conclusions: Small to moderate improvements were seen in symptom relief with the combined therapy, but they did not reach statistical significance. Further research is necessary before recommending HDRIB in addition to EBRT for palliation of lung cancer symptoms. & COPY; 2023 Elsevier Inc. All rights reserved.

PURPOSE:Despite advancements in the early detection of esophageal cancer, optimal radiotherapy methods for treatment of early disease have not yet been determined. Moreover, the benefit of intraluminal brachytherapy on local control or survival remains controversial. We performed a systematic review to establish the role of brachytherapy as boost therapy in stage I esophageal squamous cell carcinoma, and to evaluate associated survival outcomes. METHODS AND MATERIALS:A systematic search of three bibliographic databases from January 1950 to January 2019 was conducted. All studies investigating brachytherapy for curative intent were included and palliative treatment was excluded. Primary outcomes included overall survival and disease-free survival (DFS). Secondary outcomes included loco-regional control (LRC) and toxicity grades and/or complications. Two reviewers independently abstracted data and evaluated study quality using grading of recommendations assessment, development, and evaluation, pooled results were presented through risk ratios. RESULTS:A total of 12 retrospective studies met inclusion criteria. The overall quality of evidence yielded a Grade 1C rating (strong recommendation, low quality evidence). Of 525 included patients, 325 patients received both external beam radiation (EBRT), and brachytherapy, 132 underwent EBRT only, and 68 received brachytherapy with and/or without chemoradiation. For patient group treated with EBRT and brachytherapy, 5-year mortality, DFS and LRC were: 43% (27-59%), 63% (49-76%) and 72% (63-80%) respectively. Rates of complications reported included 82.1% Grade 1 esophagitis for a combined external beam radiation and brachytherapy cohort, 12.3% ulcerations, and 3.3% fistulae. CONCLUSIONS:Brachytherapy as a combined modality is encouraging, given its relative safety and effectiveness. Further prospective analysis using higher quality evidence is warranted to evaluate oncologic outcomes and survival advantage.

While brachytherapy applications are not widely used for cancer diagnoses in the upper GI tract (including the esophagus, liver, stomach, and pancreas), they have a clear role in palliation and symptom management and occasionally definitive locoregional treatment. With the increasing use of image-guided techniques, the incidence of side effects and complications has shown to be lower than many other alternative treatment modalities, making brachytherapy approaches a preferred treatment option. This review examines procedural complications and acute and chronic adverse effects from radiation associated with esophageal, hepatobiliary, and pancreatic brachytherapy and their management.

•Intraluminal brachytherapy (ILBT) decreases the need for biliary drain changes.•Post-ILBT, the median number of drain changes was 0 (range 0–4).•Post ILBT, the 30-day and 60-day patency rates were 88% and 83% respectively.•Most patients had a biochemical response; many had their bilirubin normalized.

A retrospective analysis was completed of six patients. All patients were simulated with three dimensional Computed Tomography (CT) scans without oral or IV contrast or immobilization. The Gross Tumor Volume (GTV) was identified as any abnormality in the primary tumor and surrounding lymph nodes on planning or diagnostic CT imaging, endoscopy, ultrasound or Positron Emission Tomography (PET) scan. A radial margin of 2 cm circumferentially and 4 cm proximally and distally was used for microscopic disease or Clinical Target Volume (CTV). For Planning Target Volume (PTV), a 1 cm expansion was used in all directions as no compensation for motion was completed at simulation. The planning CT scans were then imported into Pinnacle planning software and 3D conformal (3D CRT) 4 beam arrangement plans were created. Retrospectively, VMAT (5 cases) or IMRT (1 case) were created for comparison. Patients were treated with 3D conformal plans. Dose Volume Histograms (DVH) and dose distributions were reviewed in Pinnacle, and mean values for the six patients’ 3D CRT radiotherapy plans were compared with either VMAT (n=5) or IMRT (n=1).

A phase II trial of combined erlotinib and palliative radiation evaluated the patient-reported quality of life (QoL) in 40 patients with advanced non small-cell lung cancer. Although the combination improved QoL overall, the improvement was not more substantial than that observed with radiation alone. Future trials might identify subgroups of patients with metastatic disease who could benefit from combined targeted therapies and radiation.Background: The downstream signaling pathways of the epidermal growth factor receptor might influence radiation resistance. Data from preclinical work support the hypothesis that erlotinib concurrent with radiation therapy (RT) might increase cancer cell killing. The present trial was designed to examine the efficacy and toxicity of combined erlotinib and palliative chest thoracic RT in non small-cell lung cancer (NSCLC). Materials and Methods: Patients with newly diagnosed stage III-IV (American Joint Committee on Cancer, version 6) or recurrent NSCLC received 3 weeks of erlotinib at a dose of 150 mg daily, starting 1 week before palliative thoracic RT to 30 Gy in 10 fractions within 2 weeks. The primary outcome was a change in the quality of life, as measured by the Lung Cancer Symptom Scale (LOSS) question on the "symptoms of lung cancer" from baseline to 4 weeks after treatment. Results: A total of 40 patients were recruited from 2 institutions. Of the 40 patients, 22 (55%) were men, with an average age of 71 years, and 60% had stage IV disease. A total of 26 patients (65%) completed the full course of erlotinib, and 35 (88%) completed the planned RT. Twenty-five patients (62.5%) reported LCSS scores at 4 weeks after treatment, with an average change (improvement) of -12.5 U (95% confidence interval, -23.0 to -1.9; 2P =.023). This was less than the a priori hypothesis of a change of -17.5 U. The median overall and progression-free survival was 5.2 and 3.2 months, respectively. Conclusion: The present single-arm, phase II trial did not demonstrate additional symptomatic benefit from concurrent erlotinib therapy with standard palliative thoracic RT for patients with locally advanced or metastatic NSCLC. Crown Copyright (C) 2016 Published by Elsevier Inc. All rights reserved.

The relevance of radiation-induced bystander effects in humans is unclear. Much of the existing data relate to cell lines but the effect of bystander signals in complex human tissues is unclear. A phase II clinical study was untaken, where blood sera from 60 patients along with 15 cancer-free volunteers were used to detect whether measurable bystander factor(s) could be found in the blood following high dose rate (HDR) brachytherapy. Overall, there was no significant change in bystander signal production (measured in a human keratinocyte reporter system) before and after one treatment fraction of HDR brachytherapy (p>0.05). Further assessment of patient characteristics and environmental modifiable factors including smoking were also analyzed. Similar to previously published data, samples taken from smokers produced weaker signals compared to non-smokers (p<0.05). Although the number of non-smoking subjects was low, there was a clear decrease in cloning efficiency observed in keratinocyte cultures for these patients that requires further study. This study found that samples taken from smokers do not produce bystander signals, whereas samples taken from non-smokers can produce such signals following HDR brachytherapy. These findings highlight the importance of studying the interactions of multiple stressors including environmental modifiers with radiation, since some factors such as smoking may elicit protection in tumor cells which could counteract the effectiveness of radiation therapy.

PURPOSE: To compare three rectal retraction methods on dose to organs at risk, focusing on rectal dose, in cervix cancer patients treated with high-dose-rate intracavitary brachytherapy.METHODS AND MATERIALS: A prospective study was conducted on patients with cervical carcinoma treated with chemoradiotherapy, including external beam radiation and four fractions of high-dose-rate intracavitary brachytherapy prescribed to Point A using a ring and tandem applicator under conscious sedation. Rectal retraction methods included: a rectal retractor blade (RR), vaginal gauze packing (VP), and a tandem Foley balloon (FB). All three methods were used in all patients. The RR was used first, and the following applications were randomly assigned to VP or FB. CT planning was used to calculate D-2cc for rectum, sigmoid, small bowel, and bladder. The Wilcoxon signed rank test was used to determine if the median dose differences between methods were statistically significant.RESULTS: In these 11 patients, median dose (min, max) in cGy to the rectum using RR, FB, and VP was 131 (102, 165), 199 (124, 243), and 218 (149, 299), respectively. The RR demonstrated lower median intrapatient doses to rectum compared with FB and VP (-55 cGy; p = 0.014 and -76 cGy; p = 0.004, respectively). The RR also resulted in lower sigmoid doses. No differences in dose were observed between the VP and FB methods.CONCLUSION: The rectal retractor significantly reduced the dose to rectum and sigmoid compared with FP and VP. In patients treated under conscious sedation, the RR method provides the best rectal sparing. There were no significant differences in dose observed between the 1-13 and VP techniques. (C) 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Purpose: To investigate non-targeted radiation effects in esophageal adenocarcinoma cell lines (OE19 and OE33) using human keratinocyte and colorectal cancer cell reporters following gamma-ray exposure.Materials and methods: Both clonogenic assays and ratiometric calcium endpoints were used to check for the occurrence of bystander signals in reporter cells.Results: We report data suggesting that y-irradiation increases cell killing over the expected linear quadratic (LQ) model levels in the OE19 cell line exposed to doses below 1 Gy, i.e. which may be suggestive to be a low hyper-radiosensitive (HRS) response to direct irradiation. Both EAC cell lines (OE19 and OE33) have the ability to produce bystander signals when irradiated cell conditioned medium (ICCM) is placed onto human keratinocyte reporters, but do not seem to be capable of responding to bystander signals when placed on their autologous reporters. Further work with human keratinocyte reporter models showed statistically significant intracellular calcium fluxes following exposure of the reporters to ICCM harvested from both EAC cell lines exposed to 0.5 Gy.Conclusion: These experiments suggest that the OE19 and OE33 cell lines produce bystander signals in human keratinocyte reporter cells. However, the radiosensitivity of the EAC cell lines used in this study cannot be enhanced by the bystander response since both cell lines could not respond to bystander signals.

BACKGROUND: Tracheal tumors are rare. They are usually unresectable and treated primarily with external beam radiation. The use of palliative endotracheal brachytherapy (ETBT) alone in treating patients with tracheal tumors has not been reported.METHODS: Using a prospective database, demographic, treatment, and outcome data of patients with tracheal tumors treated palliatively with ETBT from 2006 to 2014 were analyzed. Tumor and symptom responses were evaluated based on response evaluation criteria in solid tumors criteria. Survival, in-field disease control, symptom response, and duration of symptom responses were evaluated using descriptive analyses.RESULTS: Sixteen ETBT (median, 2) treatments were delivered to 8 patients. Median age was 63.4 years old. Common symptoms were hemoptysis, cough, and dyspnea. Tracheal lengths of 3.5-11 cm were treated with 5-7 Gy/fraction, using 1-3 fractions. The mean overall survival was 5 months and symptom-free survival was 6.8 months, respectively. After ETBT, 88% of patients experienced symptomatic improvement (hemoptysis [n = 3/3], cough [n = 6/7], and dyspnea [n = = 4/4]). One patient developed Grade 1 stenosis that did not require intervention.CONCLUSIONS: This is among the largest series of tracheal tumors treated palliatively with ETBT alone. ETBT provided effective palliation with symptom improvement and minimal toxicity. (C) 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

PURPOSE:To test whether blood, urine, and tissue based colony-forming assays are a useful clinical detection tool for assessing fractionated treatment responses and non-targeted radiation effects in bystander cells. MATERIALS AND METHODS:To assess patients' responses to radiation treatments, blood serum, urine, and an esophagus explant-based in vivo colony-forming assay were used from oesophageal carcinoma patients. These patients underwent three fractions of high dose rate (HDR) intraluminal brachytherapy (ILBT). RESULTS:Human keratinocyte reporters exposed to blood sera taken after the third fraction of brachytherapy had a significant increase in cloning efficiency compared to baseline samples (p < 0.001). Such results may suggest an induced radioresistance response in bystander cells. The data also revealed a clear inverse dose-rate effect during late treatment fractions for the blood sera data only. Patient characteristics such as gender had no statistically significant effect (p > 0.05). Large variability was observed among the patients' tissue samples, these colony-forming assays showed no significant changes throughout fractionated brachytherapy (p > 0.05). CONCLUSION:Large inter-patient variability was found in the urine and tissue based assays, so these techniques were discontinued. However, the simple blood-based assay had much less variability. This technique may have future applications as a biological dosimeter to predict treatment outcome and assess non-targeted radiation effects.