Multi-objective ensemble deep learning using electronic health records to predict outcomes after lung cancer radiotherapy.

Accurately predicting treatment outcome is crucial for creating personalized treatment plans and follow-up schedules. Electronic health records (EHRs) contain valuable patient-specific information that can be leveraged to improve outcome prediction. We propose a reliable multi-objective ensemble deep learning (MoEDL) method that uses features extracted from EHRs to predict high risk of treatment failure after radiotherapy in patients with lung cancer. The dataset used in this study contains EHRs of 814 patients who had not achieved disease-free status and 193 patients who were disease-free with at least one year follow-up time after lung cancer radiation therapy. The proposed MoEDL consists of three phases: (1) training with dynamic ensemble deep learning; (2) model selection with adaptive multi-objective optimization; and (3) testing with evidential reasoning (ER) fusion. Specifically, in the training phase, we employ deep perceptron networks as base learners to handle various issues with EHR data. The architecture and key hyper-parameters of each base learner are dynamically adjusted to increase the diversity of learners while reducing the time spent tuning hyper-parameters. Furthermore, we integrate the snapshot ensembles (SE) restarting strategy, multi-objective optimization, and ER fusion to improve the prediction robustness and accuracy of individual networks. The SE restarting strategy can yield multiple candidate models at no additional training cost in the training stage. The multi-objective model simultaneously considers sensitivity, specificity, and AUC as objective functions, overcoming the limitations of single-objective-based model selection. For the testing stage, we utilized an analytic ER rule to fuse the output scores from each optimal model to obtain reliable and robust predictive results. Our experimental results demonstrate that MoEDL can perform better than other conventional methods.

Complete remission after hypofractionated radiotherapy for a patient with inoperable adenoid cystic carcinoma of bronchus: A case report.

RATIONALE: Tracheobronchial adenoid cystic carcinoma (TACC) is a rare malignancy. Surgical resection remains the standard treatment of choice. But it is frequently unresectable due to its local extension. The practicability and safety of hypofractionated radiotherapy (HRT) for TACC remains unknown since most of the TACCs are centrally located. PATIENT CONCERNS: A 57-year-old female presented with paroxysmal cough, expectoration, and hemoptysis. DIAGNOSES: Computed tomography (CT) scan of the chest revealed a nodule originating from the wall of right primary bronchus, with 1.9*1.2 cm in size. Bronchoscope confirmed the node on the medial wall of the right primary bronchus extending towards the carina, with a close distance of 0.5 cm. Biopsy from the node was considered as adenoid cystic carcinoma (ACC). The clinical stage of the patient was T3N0M0. INTERVENTIONS: The patient underwent HRT with a total dose of 60Gy in twelve fractions. OUTCOMES: The patient experienced complete remission after HRT. No symptomatic radiation-induced toxicity (≥grade 2) was observed during the follow-up. LESSONS: HRT may be a safe and effective modality for inoperable TACC.

A rare seizure: Tumor lysis syndrome after radiation therapy of a solid tumor.

Tumor lysis syndrome (TLS) is an uncommon but life threatening condition seen in oncology patients. Due to its underlying pathophysiology, it is classically associated with hematologic malignancies following chemotherapeutic treatment. In this article, we present a case of TLS in the setting of two rare features: a solid tumor malignancy and the absence of recent chemotherapy. We briefly review risk factors and the diagnosis of this potentially fatal but treatable condition.

Whole-body hybrid imaging concept for the integration of PET/MR into radiation therapy treatment planning.

Modern radiation therapy (RT) treatment planning is based on multimodality imaging. With the recent availability of whole-body PET/MR hybrid imaging new opportunities arise to improve target volume delineation in RT treatment planning. This, however, requires dedicated RT equipment for reproducible patient positioning on the PET/MR system, which has to be compatible with MR and PET imaging. A prototype flat RT table overlay, radiofrequency (RF) coil holders for head imaging, and RF body bridges for body imaging were developed and tested towards PET/MR system integration. Attenuation correction (AC) of all individual RT components was performed by generating 3D CT-based template models. A custom-built program for µ-map generation assembles all AC templates depending on the presence and position of each RT component. All RT devices were evaluated in phantom experiments with regards to MR and PET imaging compatibility, attenuation correction, PET quantification, and position accuracy. The entire RT setup was then evaluated in a first PET/MR patient study on five patients at different body regions. All tested devices are PET/MR compatible and do not produce visible artifacts or disturb image quality. The RT components showed a repositioning accuracy of better than 2 mm. Photon attenuation of -11.8% in the top part of the phantom was observable, which was reduced to -1.7% with AC using the µ-map generator. Active lesions of 3 subjects were evaluated in terms of SUVmean and an underestimation of -10.0% and -2.4% was calculated without and with AC of the RF body bridges, respectively. The new dedicated RT equipment for hybrid PET/MR imaging enables acquisitions in all body regions. It is compatible with PET/MR imaging and all hardware components can be corrected in hardware AC by using the suggested µ-map generator. These developments provide the technical and methodological basis for integration of PET/MR hybrid imaging into RT planning.

[Apropos of 5 cases of optic nerve tumors diagnosed during a 6-year-period]. / À propos de 5 cas de tumeurs du nerf optique sur une période de 6ans.

INTRODUCTION: Optic nerve tumors are uncommon and rarely described. By way of five patients treated at the University Hospital of Clermont-Ferrand, France, over a six-year-period, we discuss their clinical and radiological characteristics, their treatment and their course. OBSERVATIONS: We report two cases of optic nerve glioma in small children, two cases of optic nerve sheath meningioma and a 57-year-old patient treated for lung cancer with an optic nerve metastasis and choroidal and brain metastases. The diagnosis was confirmed by imaging in all patients and histologically for the cases of optic nerve glioma. RESULTS: The children with glioma were exclusively treated with chemotherapy, the two women with meningioma exclusively with radiation therapy, and the man with the optic nerve metastasis by chemotherapy and radiotherapy. The tumors were stabilized in all cases except for a progression in one case of glioma, one year after treatment. DISCUSSION: Gliomas and meningiomas are the most frequent tumors; other tumors are rare. Through a literature review and many illustrations, we discuss epidemiologic, clinical and radiologic characteristics, treatment and course of these uncommon tumors. CONCLUSION: The diagnosis of optic nerve tumors must be considered in cases of anterior or posterior progressive optic neuropathy. Treatment must be a compromise between effective treatment of the tumor and preservation of visual function. Decisions are made through multidisciplinary consultations, in which the role of the ophthalmologist is crucial for the diagnosis and success of the treatment.

Long-term results of curative intraluminal high dose rate brachytherapy for endobronchial carcinoma.

BACKGROUND: The treatment strategy of central lung tumors is not established. Intraluminal brachytherapy (ILBT) is widely used for palliative treatment of endobronchial tumors, however, it is also a promising option for curative treatment with limited data. This study evaluates the results after ILBT for endobronchial carcinoma. METHOD: Sixteen-endobronchial carcinoma of 13 patients treated with ILBT in curative intent for 2000 to 2008 were retrospectively reviewed. ILBT using high dose rate 192 iridium thin wire system was performed with 5 Gy/fraction at mucosal surface. The patient age ranged from 57 to 82 years old with median 75 years old. The 16 lesions consisted of 13 central endobronchial cancers including 7 roentgenographically occult lung cancers and 3 of tracheal cancers. Of them, 10 lesions were treated with ILBT of median 20 Gy combined with external beam radiation therapy of median 45 Gy and 6 lesions were treated with ILBT alone of median 25 Gy. RESULTS: Median follow-up time was 32.5 months. Two-year survival rate and local control rate were 92.3% and 86.2%, respectively. Local recurrences were observed in 2 lesions. Three patients died due to lung cancer (1 patient) and intercurrent disease (2 patients). Complications greater than grade 2 were not observed except for one grade 3 dyspnea. CONCLUSIONS: ILBT combined with or without EBRT might be a curative treatment option in inoperable endobronchial carcinoma patients with tolerable complication.

[Percutaneous CT-guided high-dose brachytherapy (CT-HDRBT) ablation of primary and metastatic lung tumors in nonsurgical candidates]. / Perkutane CT-gesteuerte Hochdosis-Brachytherapie (CT-HDRBT) von primären und metastatischen Lungentumoren in nicht chirurgischen Kandidaten.

PURPOSE: To evaluate the safety and efficacy of CT-guided high-dose brachytherapy (CT-HDRBT) ablation of primary and metastatic lung tumors. MATERIALS AND METHODS: Between November 2007 and May 2010, all consecutive patients with primary or metastatic lung tumors, unsuitable for surgery, were treated with CT-HDRBT. Imaging follow-up after treatment was performed with contrast-enhanced CT at 6 weeks, 3 months and every 6 months after the procedure. The endpoints of the study were local tumor control and time to progression. The Kaplan-Meier method was used to estimate survival functions and local tumor progression rates. RESULTS: 34 procedures were carried out on 33 lesions in 22 patients. The mean diameter of the tumors was 33.3 mm (SD = 20.4). The first contrast-enhanced CT showed that complete ablation was achieved in all lesions. The mean minimal tumor enclosing dose was 18.9 Gy (SD = 2). Three patients developed a pneumothorax after the procedure. The mean follow-up time was 13.7 (3 - 29) months. 2 of 32 lesions (6.25 %) developed a local tumor progression. 8 patients (36.3 %) developed a distant tumor progression. After 17.7 months, 13 patients were alive and 9 patients had died. CONCLUSION: CT-HDRBT ablation is a safe and attractive treatment option for patients with lung malignancies and allows targeted destruction of tumor tissue with simultaneous preservation of important lung structures. Furthermore, CT-HDRBT is independent of the size of the lesion and its location within the lung parenchyma.

Sleeve resections with unprotected bronchial anastomoses are safe even after neoadjuvant therapy.

OBJECTIVES: Sleeve resection is the operation of choice in patients with centrally located tumours, in order to avoid a pneumonectomy. Most surgeons protect the bronchial anastomoses with tissue to prevent insufficiencies. The purpose of this study is to report on outcome of unwrapped bronchial anastomoses, especially after neoadjuvant chemo- or chemoradiotherapy. METHODS: Between 2000 and 2010, 103 patients [59 years (range 16-80), 40 females] underwent bronchial sleeve resections without coverage of the anastomosis with a tissue flap. We retrospectively reviewed the data for morbidity, mortality and survival, especially with regard to the type of resection, neoadjuvant therapy and stage. RESULTS: Sleeve lobectomy was performed in 88, sleeve bilobectomy in 8, sleeve pneumonectomy in 4 and sleeve resection of the main bronchus in 3 patients. Twenty-seven patients had a combined vascular sleeve resection. Neoadjuvant chemotherapy was performed in 20 and radiochemotherapy in 5 patients. Non-small cell lung cancer (NSCLC) was present in 76 patients (squamous cell carcinoma in 44, adenocarcinoma in 24, large cell carcinoma in 6 and mixed cell in 2) and neuroendocrine tumour in 20 and other histological types in 7 patients. The pathologic tumour stage in NSCLC was stage I in 26, stage II in 26, stage IIIA in 16, stage IIIB in 7 and stage IV in 1 patient. There were no anastomotic complications, especially no fistulas. One patient developed narrowing of the intermediate bronchus without need for intervention. Twenty-four patients had early postoperative complications, including 11 surgery-related complications (air leakage, nerve injury, haemothorax or mediastinal emphysema). The 30-day mortality was 3% (one patient died due to heart failure and two with multiorgan failure). The 5-year survival rate was 63% in NSCLC patients and 86% in neuroendocrine tumour patients. CONCLUSIONS: Sleeve resection without wrapping the bronchial anastomoses with a tissue flap is safe even in patients who underwent neoadjuvant chemo- or chemoradiotherapy. Therefore, wrapping of the bronchial anastomoses is not routinely mandatory.

In tumor cells regulation of DNA double strand break repair through EGF receptor involves both NHEJ and HR and is independent of p53 and K-Ras status.

PURPOSE: The purpose of this study was to examine whether the epidermal growth factor receptor (EGFR) may be used as a general target to modulate DNA double strand break (DSB) repair in tumor cells. MATERIAL AND METHODS: Experiments were performed with human tumor cell lines A549, H1299 and HeLa and primate cell line CV1. EGF, ARG and TGFα were used for EGFR activation, cetuximab or erlotinib for inhibition. Overall DSB repair was assessed by γH2AX/53BP1 co-immunostaining and non-homologous end-joining (NHEJ) and homologous recombination (HR) by using NHEJ and HR reporter cells; cell cycle distribution was determined by flow cytometry and protein expression by Western blot. RESULTS: EGFR activation was found to stimulate overall DSB repair as well as NHEJ regardless of the ligand used. This stimulation was abolished when EGFR signaling was blocked. This regulation was found for all cell lines tested, irrespective of their p53 or K-Ras status. Stimulation and inhibition of EGFR were also found to affect HR. CONCLUSIONS: Regulation of DSB repair by EGFR involves both the NHEJ and HR pathway, and appears to occur in most tumor cell lines regardless of p53 and K-Ras mutation status.

[Endobronchic palliative brachytherapy]. / Brachythérapie endobronchique palliative.

Brachytherapy, the placement of an encapsuled radioactive source (Iridium) in or near a tumor, is a palliative therapeutic modality available for patients suffering of a bronchogenic cancer, especially if they present invalidating symptoms such an incoercible cough, haemoptysis, dyspnea. The treatment modality is indicated if chemotherapy or external irradiation are not possible. It is typically a team work.

Palliative high-dose-rate endobronchial brachytherapy for recurrent carcinoma: the University of Louisville experience.

PURPOSE: To determine the efficacy and toxicity of iridium-192 high-dose-rate (HDR) endobronchial brachytherapy (EBBT) for symptomatic palliation of respiratory symptoms caused by endobronchial carcinoma. METHODS: We reviewed the treatment outcomes of 52 patients with carcinoma who underwent HDR EBBT between July 1995 and July 2005 for recurrent tumors at the University of Louisville School of Medicine. The subjective clinical response was assessed by patient reports. The objective response was assessed by bronchoscopy and chest computed tomography. RESULTS: The median actuarial survival measured from the first EBBT treatment session was 7 months. Forty-eight patients (92%) showed improvement in one or more symptoms. The median time to symptomatic relapse was 6 months. Bronchoscopic regression of tumor occurred in 45 patients (87%). Tumor regression as determined by bronchoscopy correlated with symptomatic response. Complications occurred in two patients (one pneumothorax and one fatal hemoptysis). CONCLUSIONS: The results confirm the efficacy of endobronchial brachytherapy in relieving obstructive airway symptoms from endoluminal bronchogenic carcinomas. We demonstrated a low morbidity associated with EBBT treatment and a high objective response (87%) and subjective response (92%).

High dose-rate endobronchial radiotherapy for proximal airway obstruction due to lung cancer: 8-year experience of a referral center.

The efficacy of high dose-rate endobronchial radiotherapy (HDERT) against proximal airway obstruction that results from lung cancer has not been thoroughly evaluated. This study retrospectively reviewed tumor/obstruction characteristics prior to therapy, interventions applied, symptoms before and after intervention, complications, and survival of all patients with proximal airway obstruction resulting from lung cancer who received HDERT between 1995 and 2003 in a tertiary teaching center. Thirty-four (34) patients received HDERT, while 28 had additional treatment (external radiotherapy = 23, neodymium yttrium aluminum garnet laser ablation = 9, stenting = 7, electrosurgery = 5, cryosurgery = 3, and photodynamic therapy = 1). Sixteen (16) patients developed complications, the most frequent being respiratory failure and bronchial-wall necrosis, while 19 experienced symptomatic relief. The median (95% confidence interval) survival of these 34 patients was 7.8 (5.9-9.8) months, significantly longer (p = 0.004) than a historic control of 3.9 (3.7-7.1) months from the Cleveland Clinic Foundation, in Cleveland, OH, and comparable to other previous reports. No single factor predicted complications or symptomatic relief. However, female gender, presence of only one symptom, absence of fatigue/weight loss, >1 HDERT sessions, and postprocedure symptom relief were associated with improved survival. Contemporary HDERT with or without additional treatment modalities is effective against central airway compromise resulting from lung cancer.

[Clinical treatment outcome of grade III, non-small cell bronchogenic carcinoma using "whole-body" gamma-knife system].

The results of treatment of 80 patients with non-small cell lung cancer using the Chinese-made "Whole-Body" gamma-knife system were analyzed. Primary focus and involved lymph nodes were exposed. Neither gap between primary focus and involved lymph node or nodes, nor organs of the mediastinum were exposed. Exposure regimens were: STD = 4 Gy (2.5 - 10 Gy) 5 times a week; TTD=48 Gy (27-52 Gy) per primary focus and 4 Gy (3-6 Gy) 5 times a week; TTD = 43.5 Gy (30-52 Gy) per lymph nodes (105.6 - 150 Gy = equ.). Complete response was observed in 27.5% (22/80), partial - 42.5% (34/80). Overall survival was 61.3% among those sick for one year; 41.5%--2 years and 20.75%--3 years (mean survival time--20 months).

X-irradiation of human bronchial cancer cells causes the bystander effects in normal bronchial cells in vitro.

Using X radiation commonly used in radiotherapy of cancers we investigated bystander interactions between human cells: irradiated A549 bronchial carcinoma human cells and non irradiated BEAS-2B normal bronchial epithelial cells. Non irradiated cells were incubated in medium transferred from irradiated A549 cells (ICM-irradiation conditioned medium) for 48h and next the chromosomal damage and apoptosis were estimated. Conditioned medium collected from irradiated cancer cells induced in non irradiated cells of the same line as well as in BEAS-2B normal cells genetic changes such as micronuclei, chromatid and chromosomal breaks and condensation of chromatin characteristic for processes of apoptosis. Addition of only 1% of conditioned medium to fresh medium was sufficient to induction of bystander response to normal bronchial cells. The presented results in this study could have implications for human radiation risk and in evaluating the secondary effects of radiotherapy.

Treatment of recurrent bronchial carcinoma: the role of high-dose-rate endoluminal brachytherapy.

PURPOSE: This study's aim was to assess outcome and toxicity of high-dose-rate endoluminal brachytherapy (HDREB) for recurrent bronchial carcinoma. METHODS AND MATERIALS: From 1987 to 2005, 41 patients were treated with HDREB for symptomatic recurrent bronchial carcinoma. All patients had previously undergone external beam radiotherapy (EBRT) with a median dose of 56 Gy (range, 30-70 Gy). The median HDREB dose applied was 15 Gy (range, 5-29 Gy). The median time interval between primary EBRT and reirradiation was 9 months (range, 2-54 months). RESULTS: After a median follow-up of 6.7 months, the 6-, 12-, and 24-month overall survival rates were 58%, 18%, and 7%, respectively. The median overall survival time was 6.7 months. Local remission was achieved in 73% of patients (n = 30). A total of 24% of patients (n = 10) showed no response or progressive disease within 8 weeks after treatment. In 1 patient, treatment response was not documented. The 6-, 12-, and 24-month local control rates were 38%, 17%, and 3%, respectively. The median local progression-free survival time was 4 months (range, 1-23 months). Prognostic factors were a total dose of >or=15 Gy of HDREB (p = 0.029) and a Karnofsky performance score of >or=80% (p = 0.0012). The cause of death was locoregional progression in 27% of patients (n = 11), distant metastases in 24% of patients (n = 10), fatal hemorrhage in 15% of patients (n = 6), and other causes in 29% of patients (n = 12). None of the patients with locally controlled disease showed grade 3 or 4 late effects. CONCLUSIONS: Palliative treatment of symptomatic, locally recurrent bronchial carcinoma with HDREB can effectively relieve symptoms in the majority of patients while causing only few complications. Still, time to progression is short.

Radiation-induced lipid peroxidation activates src kinase and triggers nuclear EGFR transport.

PURPOSE: Elucidation of the molecular mechanism of radiation-induced activation of src kinase, which initiates EGFR internalization and nuclear transport. MATERIAL AND METHODS: Radiation-induced src activation was investigated in the bronchial carcinoma cell line A549. Proteins were Western blotted and quantified by the help of specific antibodies. Residual DNA-damage was quantified with gammaH(2)AX-foci analysis. Radiation-induced lipid peroxidation was prevented by acetyl-cysteine. RESULTS: The radiation-induced src activation and EGFR stabilization could be mimicked by addition of hydroxy-nonenal (HNE), one of the major lipid peroxidation products. Radiation-generated HNE is bound to EGFR and src and correlated with complex formation between both following radiation. Treatment with HNE activated src and stimulated radiation-associated EGFR and caveolin 1 phosphorylations resulting in increased nuclear transport of EGFR. Consequently, radiation-induced phosphorylation and activation of DNA-PK were increased. This phosphorylation was associated with improved removal of residual damage 24h after irradiation. Inhibition of radiation-induced HNE generation by acetyl-cysteine blocked radiation-induced src activation and EGFR phosphorylation. CONCLUSIONS: HNE generated in response to radiation exposure activates src kinase and is involved in regulation of radiation-stimulated DNA-repair processes.

[Palliative radiation of bone metastasis in the spine for symptom control and stabilisation: indication and limits]. / Palliative Strahlentherapie bei Knochenmetastasen in der Wirbelsäule zur Schmerztherapie und Stabilisierung: Indikationen und Grenzen.

On the basis of a case study the success of palliative radiation of metastasis of a non-small-cell lung cancer in the spine is demonstrated and the limits of this palliative therapy are discussed. Pain control seems to be the first aim, stabilisation of the spine and myelodecompression to prevent paraplegia could be another.