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To determine the incidence and various patterns of radiation-induced liver injury (RILI) and its temporal evolution on fluorodeoxiglucose-positron emission tomography/computed tomography (FDG-PET/CT) after neoadjuvant chemoradiation using precision radiation in patients with esophageal carcinoma.We evaluated 639 patients with locally advanced esophageal carcinoma who had serial FDG-PET/CTs after neoadjuvant chemoradiation. Two readers reviewed the imaging studies in consensus and recorded the cases where new foci of increased FDG uptake were identified within the radiated liver parenchyma. RILI was confirmed by follow-up imaging or percutaneous biopsy.FDG-avid RILI developed in 39/639 (6%) of patients. The caudate and left hepatic lobe were involved in all cases. There were various patterns of increased FDG uptake: 38% of patients had a single focus of increased FDG uptake and 62% had 2 regions of increased FDG uptake, which were focal nodular or diffuse or a combination of focal nodular and diffuse FDG uptake. On CT, 72% of patients had a poorly-marginated region of low attenuation and 28% had a well-defined region of low attenuation with sharp, well-defined linear borders in the location of the radiation, as confirmed by the treatment plan.The caudate and left hepatic lobes were involved in all cases of RILI. The various imaging patterns of RILI on FDG-PET/CT include 1 or 2 regions of increased FDG uptake with a nodular, diffuse, or combined appearance. Awareness of this potential complication of radiation therapy and knowledge of the imaging manifestations of RILI is important to avoid misinterpretation as a metastasis.

Background The assumption that increased [18F] fluoro-2-deoxy-d-glucose (FDG) uptake in hilar nodes on PET/CT imaging is indicative of distant metastasis can result in palliative rather than curative care in patients with esophageal cancer. This study aims to determine the significance of increased FDG uptake in hilar nodes in patients with potentially curable, locally advanced disease at initial staging. Methods We included patients with biopsy-proven esophageal carcinoma who had pretreatment FDG-PET/CT at initial staging, and follow-up imaging >1 year. We excluded patients with distant hematogeneous metastases. Hilar nodes were considered concerning for metastatic disease when SUV max was >2.5 or FDG uptake was visually > mediastinal background were examined. Results We reviewed FDG-PET CT scans from 806 patients treated for esophageal cancer from 2010-2018 and identified 42 patients with FDG avid hilar adenopathy. Thirteen patients underwent histological assessment and 29 were followed with imaging. None of the 42 patients were found to have distant metastatic disease on initial work up and all were treated curatively. In follow up, 2/42 patients eventually manifested hilar nodal metastases after treatment; one who had a biopsy-negative hilar node at initial staging and another who did not have a biopsy of the hilar node. Conclusions Increased FDG uptake in hilar nodes in patients with localized esophageal cancer was not indicative of non-regional nodal metastasis. Patients in these situations should be approached with curative intent. The need for biopsy of FDG avid hilar nodes in this cohort should be carefully considered due to the low diagnostic utility.

The management of patients with esophageal carcinoma (EC) requires accurate clinical staging and post-therapeutic evaluation. Currently, esophagogastroduodenoscopy/endoscopic ultrasound (EGD/EUS), endoscopic ultrasound-fine needle aspiration (EUS-FNA), computed tomography (CT), 18F- fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) and magnetic resonance (MR) imaging are used for the initial clinical staging, evaluation of therapeutic response and follow-up in patients with EC. However, there are limitations and pitfalls that are commonly encountered when imaging these patients that can limit accurate assessment. Knowledge of the limitations and pitfalls associated with the use of these different imaging modalities is essential in avoiding misinterpretation and guaranteeing the appropriate management for patient with EC.

To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.

Background Metastatic head and neck cancers (HNCs) predominantly affect the lungs and have a two-year overall survival (OS) of 15% to 50%, if amenable for pulmonary metastasectomy. Methods Retrospective review of the two-year local control (LC), local-regional control (LRC) within the same lobe, OS, and toxicity rates in consecutive patients with metastatic pulmonary HNC who underwent stereotactic ablative radiotherapy (SABR) January 2007 to May 2018. Results Evaluated 82 patients with 107 lung lesions, most commonly squamous cell carcinoma (SCC; 64%). Median follow-up was 20 months (range: 9.0-97.6). Systemic therapy administered in 34%. LC, LRC, and OS rates were 94%, 90%, and 62%. Patients with oligometastatic disease had a higher OS than polymetastatic disease, 72% vs 44% (HR = 0.30, 95% CI: 0.14-0.64; P = .008). OS in oligometastatic non-SCC and SCC were 100% and 66% (P = .03). There were no grade ≥3 toxicities. Conclusions Metastatic pulmonary HNCs after SABR have a two-year OS rate comparable to pulmonary metastasectomy.

Background Adenocarcinoma of the gastroesophageal junction (AEG) poses a management challenge, as preoperative prediction of occult mediastinal nodal metastasis is difficult. We sought to identify factors predictive of mediastinal involvement among patients undergoing trimodality therapy. Methods Patients undergoing trimodality therapy for Siewert II and III AEG at a single institution between 2000 and 2015 were identified. Mediastinal involvement was defined as pathologic nodal involvement after neoadjuvant chemoradiation (ypN+) in mediastinal stations or mediastinal recurrence 2 years or less after resection. Maximal χ2 analysis and Youden's J index were used to identify the pretreatment proximal tumor extent that best discriminated mediastinal involvement. Results In all, 204 patients (151 [74%] AEG II, 53 [26%] AEG III) were included, of whom 47 (23%) had clinical evidence of thoracic nodal disease. Thirty-one of the 204 patients (15%) met criteria for mediastinal involvement (24 of 31 ypN+, 10 of 31 mediastinal recurrence). Patients with mediastinal involvement had greater proximal tumor extent (median 2 cm [interquartile range, 1.0 to 3.0 cm] vs 1.4 cm [interquartile range, 0.7 to 3.0 cm], P = .030), were more frequently Siewert II lesions (27 of 31 [87.1%] vs 124 of 173 [71.7%], P = .071), and were more often observed to have clinical thoracic nodal metastasis (cN) evidence (13 of 31 [42%] vs 34 of 173 [20%], P = .007) than patients who did not. On multivariable analysis of patients with intrathoracic cN0, esophageal extent of 1.5 cm or greater was independently predictive of mediastinal involvement (odds ratio 5.46, P = .011), whereas Siewert classification was not (Siewert II odds ratio 3.48, P = .116). Conclusions Pretreatment proximal tumor extent, rather than Siewert classification, is an independent predictor of mediastinal involvement among AEG II/III patients without clinical evidence of mediastinal metastasis and should be considered during treatment planning.

The assumption that increased [We included patients with biopsy specimen-proven esophageal carcinoma who had pretreatment FDG-PET/CT at initial staging and follow-up imaging1 year. We excluded patients with distant hematogeneous metastases. Hilar nodes were considered concerning for metastatic disease when the maximum standardized uptake value was2.5 or FDG uptake was visually greater than the mediastinal background.We reviewed FDG-PET CT scans from 806 patients treated for esophageal cancer from 2010 to 2018 and identified 42 patients with FDG-avid hilar adenopathy. Thirteen patients underwent histologic assessment, and 29 were monitored with imaging. None of the 42 patients had distant metastatic disease on the initial workup, and all were treated curatively. In follow-up, 2 of 42 patients eventually manifested hilar nodal metastases after treatment; 1 who had a biopsy specimen-negative hilar node at initial staging and another who did not have a biopsy of the hilar node.Increased FDG uptake in hilar nodes in patients with localized esophageal cancer was not indicative of nonregional nodal metastasis. Patients in these situations should be approached with curative intent. The need for biopsy of FDG-avid hilar nodes in this cohort should be carefully considered due to the low diagnostic utility.

Radiation therapy using conventional fractionated external-beam or high-precision dose techniques including three-dimensional conformal radiotherapy, stereotactic body radiation therapy, intensity-modulated radiation therapy, and proton therapy, is a key component in the treatment of patients with lung cancer. Knowledge of the radiation technique used, radiation treatment plan, expected temporal evolution of radiation-induced lung injury and patient-specific parameters, such as previous radiotherapy, concurrent chemoradiotherapy, and/or immunotherapy, is important in imaging interpretation. This review discusses factors that affect the development and severity of radiation-induced lung injury and its radiological manifestations with emphasis on the differences between conventional radiation and high-precision dose radiotherapy techniques.

PURPOSE: The uptake of shared decision making (SDM) for lung cancer screening (LCS) as required by the Centers for Medicare & Medicaid Services (CMS) is suboptimal. Alternative models for delivering SDM are needed, such as decision coaching in the low-dose computed tomography (LDCT) setting. METHODS AND MATERIALS: The Replicating Effective Programs framework guided our implementation of decision coaching, which included a patient-facilitated component before screening followed by in-person coaching that addressed the required elements for the SDM visit from CMS. We surveyed two LCS patient cohorts (pre-implementation and implementation of decision coaching) about their knowledge of LCS and perception of the SDM process. We conducted time-motion studies to assess the feasibility of implementing decision coaching and audio recorded clinical encounters from the implementation cohort to assess fidelity of the SDM conversation to the CMS requirements. RESULTS: Compared with the pre-implementation cohort (n = 51), the implementation cohort (n = 30) had greater knowledge of LCS ( P < .01) and reported a better SDM process ( P = .01). Coaching took 7.6 ± 4.1 minutes and did not increase visit time ( P = .72). Coaches addressed an average of 6.4 of 7 SDM elements required by CMS. CONCLUSION: Decision coaching in the LDCT setting provides an opportunity for patients to confirm their screening decision by ensuring that patients are truly informed about the potential harms and benefits of LCS. The decision coaching had excellent fidelity in addressing the required SDM elements from CMS and is feasible.

To develop and validate a radiomics signature that can predict the clinical outcomes for patients with stage I non-small cell lung cancer (NSCLC).We retrospectively analyzed contrast-enhanced computed tomography images of patients from a training cohort (n = 147) treated with surgery and an independent validation cohort (n = 295) treated with stereotactic ablative radiation therapy. Twelve radiomics features with established strategies for filtering and preprocessing were extracted. The random survival forests (RSF) method was used to build models from subsets of the 12 candidate features based on their survival relevance and generate a mortality risk index for each observation in the training set. An optimal model was selected, and its ability to predict clinical outcomes was evaluated in the validation set using predicted mortality risk indexes.The optimal RSF model, consisting of 2 predictive features, kurtosis and the gray level co-occurrence matrix feature homogeneity2, allowed for significant risk stratification (log-rank P.0001) and remained an independent predictor of overall survival after adjusting for age, tumor volume and histologic type, and Karnofsky performance status (hazard ratio [HR] 1.27; P2e-16) in the training set. The resultant mortality risk indexes were significantly associated with overall survival in the validation set (log-rank P = .0173; HR 1.02, P = .0438). They were also significant for distant metastasis (log-rank P.05; HR 1.04, P = .0407) and were borderline significant for regional recurrence on univariate analysis (log-rank P.05; HR 1.04, P = .0617).Our radiomics model accurately predicted several clinical outcomes and allowed pretreatment risk stratification in stage I NSCLC, allowing the choice of treatment to be tailored to each patient's individual risk profile.

KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P < 0.001) and overall (P = 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1–positive non–small cell lung cancer. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC. Significance: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. Cancer Discov; 8(7); 822–35. ©2018 AACR. See related commentary by Etxeberria et al., p. 794. This article is highlighted in the In This Issue feature, p. 781

A significant reduction in lung cancer specific mortality rate was demonstrated by the National Lung Screening Trial (NLST) in participants who had annual low-dose computed tomography (LDCT) screening. In addition to early detection of lung cancer, lung cancer screening (LCS) provides an opportunity to detect cardiovascular disease, pulmonary disease (such as chronic obstructive pulmonary disease and interstitial lung disease), and extrapulmonary neoplasms, such as thyroid, breast, kidney, liver, esophageal, pancreatic and mediastinal tumors. Considering the fact that 22.3% of the certified deaths in the computed tomography (CT) arm of the NLST trial were due to extrapulmonary malignancies, compared to 22.9% of deaths from lung cancer, it is possible that early diagnosis and treatment of clinically significant incidental findings may further decrease morbidity and mortality in screening participants. In this article we review prevalence, clinical relevance and management of incidentally detected extrapulmonary malignancies.

The number of screening-detected lung nodules is expected to increase as low-dose computed tomography screening is implemented nationally. Standardized guidelines for image acquisition, interpretation, and screen-detected nodule workup are essential to ensure a high standard of medical care and that lung cancer screening is implemented safely and cost effectively. In this article, we review the current guidelines for pulmonary nodule management in the lung cancer screening setting.

Purpose Precision radiation therapy such as stereotactic body radiation therapy and limited resection are being used more frequently to treat intrathoracic malignancies. Effective local control requires precise radiation target delineation or complete resection. Lung biopsy tracts (LBT) on computed tomography (CT) scans after the use of tract sealants can mimic malignant tract seeding (MTS) and it is unclear whether these LBTs should be included in the calculated tumor volume or resected. This study evaluates the incidence, appearance, evolution, and malignant seeding of LBTs. Methods and materials A total of 406 lung biopsies were performed in oncology patients using a tract sealant over 19 months. Of these patients, 326 had follow-up CT scans and were included in the study group. Four thoracic radiologists retrospectively analyzed the imaging, and a pathologist examined 10 resected LBTs. Results A total of 234 of 326 biopsies (72%, including primary lung cancer [n = 98]; metastases [n = 81]; benign [n = 50]; and nondiagnostic [n = 5]) showed an LBT on CT. LBTs were identified on imaging 0 to 3 months after biopsy. LBTs were typically straight or serpiginous with a thickness of 2 to 5 mm. Most LBTs were unchanged (92%) or decreased (6.3%) over time. An increase in LBT thickness/nodularity that was suspicious for MTS occurred in 4 of 234 biopsies (1.7%). MTS only occurred after biopsy of metastases from extrathoracic malignancies, and none occurred in patients with lung cancer. Conclusions LBTs are common on CT after lung biopsy using a tract sealant. MTS is uncommon and only occurred in patients with extrathoracic malignancies. No MTS was found in patients with primary lung cancer. Accordingly, potential alteration in planned therapy should be considered only in patients with LBTs and extrathoracic malignancies being considered for stereotactic body radiation therapy or wedge resection.

Lung cancer remains the leading cause of cancer-related mortality worldwide. To formulate effective treatment strategies and optimize patient outcomes, accurate staging is essential. Lung cancer staging has traditionally relied on a TNM staging system, for which the International Association for the Study of Lung Cancer (IASLC) has recently proposed changes. The revised classification for this eighth edition of the TNM staging system (TNM-8) is based on detailed analysis of a new large international database of lung cancer cases assembled by the IASLC for the purposes of this project. Fundamental changes incorporated into TNM-8 include (a) modifications to the T classification on the basis of 1-cm increments in tumor size; (b) grouping of lung cancers that result in partial or complete lung atelectasis or pneumonitis; (c) grouping of tumors with involvement of a main bronchus irrespective of distance from the carina; (d) reassignment of diaphragmatic invasion in terms of T classification; (e) elimination of mediastinal pleural invasion from the T classification; and (f) subdivision of the M classification into different descriptors on the basis of the number and site of extrathoracic metastases. In response to these revisions, established stage groups have been modified, and others have been created. In addition, recommendations for classifying patterns of disease that result in multiple sites of pulmonary involvement, including multiple primary lung cancers, lung cancers with separate tumor nodules, multiple ground-glass/lepidic lesions, and consolidation, as well as recommendations for lesion measurement, are addressed. Understanding the key revisions introduced in TNM-8 allows radiologists to accurately stage patients with lung cancer and optimize therapy.

Importance Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. Objective To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. Design, setting, and participants The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. Interventions Chemoradiation and consolidation chemotherapy with or without metformin. Main outcomes and measures The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. Results A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. Conclusions and relevance In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. Trial registration ClinicalTrials.gov Identifier: NCT02186847.

Introduction Approximately 50% of recurrences after standard-dose chemoradiation for locally advanced esophageal cancer occur within the gross tumor volume (GTV). In this prospective phase I/II clinical trial, we explored the use of a simultaneous integrated boost (SIB) dose to the GTV. Methods Forty-four patients with unresectable esophageal cancer received chemoradiation with an SIB of 58.8 to 63 Gy to the GTV and 50.4 Gy to the planning target volume, all in 28 fractions, with 5 weeks of concurrent docetaxel and fluorouracil or capecitabine. The end points were maximum tolerated dose, time to local failure, and clinical response. Results Excluding those with less than 6 months of follow-up, 38 patients were evaluated at the time of analysis. The median age was 65 years (range 37–84). Most patients (71%) were men; 84% had T3 disease, 37% had N1 disease, 26% had N2 disease, 13% had M1 disease, and 50% had adenocarcinoma. The maximum tolerated SIB dose was 63 Gy. None experienced Common Terminology Criteria for Adverse Events grade 4 or 5 toxicity. At a median follow-up time of 13.3 months (range 1.2–36.2), 11 (29%) had local failure (median time to local failure 2.5 months [range 1.5–23.9]). A comparison with 97 similar patients who received 50.4 Gy without an SIB showed that the SIB reduced the local failure rate for patients with node-positive disease (13% versus 56%, p = 0.04), adenocarcinoma (26% versus 59%, p = 0.02), or stage III–IV disease (29% versus 55%, p = 0.04). Conclusions SIB intensity-modulated radiation therapy to gross primary disease may improve local control for patients with unresectable locally advanced esophageal cancer, especially those with adenocarcinoma.

Objective Though interest in expansion of the use of less-invasive therapies among operable non-small-cell lung cancer (NSCLC) patients is growing, it is not clear that post-treatment surveillance has been comparable between treatment modalities. We sought to characterize institutional surveillance patterns after NSCLC therapy with stereotactic body radiation therapy (SBRT) and lobectomy. Methods NSCLC patients treated with lobectomy or SBRT (2005 to 2016) at a single institution were identified. Natural language processing searched data fields within axial surveillance imaging reports for findings suggestive of recurrence. Duration and patterns of institutional surveillance were compared between the 2 groups. Results Three thousand forty-two patients (73.5% lobectomy, 26.5% SBRT) met inclusion criteria. Patients had a longer median duration of surveillance after lobectomy (28.0 months vs SBRT 12.3 months, P < 0.001) and were more likely to undergo histopathological evaluation of clinically suspected relapse (206/274 [75.2%] vs SBRT 54/113 [47.8%], P < 0.001). Patients with clinical suspicion of recurrence had longer durations of institutional surveillance than those who did not among both cohorts (lobectomy 44.4 months vs 25.9, P < 0.001; SBRT 27.9 vs 10.3, P < 0.001). Landmark analyses at 1 and 3 years after therapy identified associations between receipt of lobectomy and ongoing surveillance at each time point (1 year odds ratio [OR] 2.10, P < 0.001; 3 years OR 1.71, P < 0.001) among all patients and those with documented stage I disease. Conclusions We identified potential heterogeneity in institutional surveillance patterns after treatment of NSCLC with 2 therapeutic modalities. As less-invasive treatment options for operable patients expand, it will be critical to implement rigorous surveillance paradigms across all modalities.

Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.

Respiratory motion during the CT and PET parts of a PET/CT scan leads to imperfect alignment of anatomic features seen by the 2 modalities. In this work, we concentrate on the effects of motion during CT. We propose a novel approach for improving the alignment. Methods: Respiratory waveform data were gathered during the CT and PET parts of 28 PET/CT scans of cancer patients with 40 lesions up to 3 cm in size in the lung or upper abdomen. PET list-mode data were reconstructed by 3 reconstruction methods: PET/static (the standard method with no motion correction); PET/ex (a method that calculates a range of expiratory amplitudes from the lowest one to the highest one); and PET/matched (a novel method that uses both waveforms). The 3 methods were compared. The distance between tumor positions in PET and CT were characterized in visual interpretation by physicians as well as quantitatively. Tumor SUVs (SUVmax and SUVpeak) were determined relative to SUV based on the static method. Image noise was evaluated in the liver and compared with PET/static. Results: In visual interpretation, the rate of good alignment was 13 of 21, 13 of 23, and 18 of 21 for the PET/static, PET/ex, and PET/matched methods, respectively, and the mean PET/CT distances were 3.5, 5.1, and 2.8 mm. In visual comparison with PET/ex, the rate of good alignment was increased in 1 of 10 and 7 of 10 cases for PET/static and PET/matched, respectively. SUVmax was on average 21% higher than PET/static when either PET/ex or PET/matched was used. SUVpeak was 12% higher. Image noise in the liver was 15% higher than PET/static for the PET/ex method, and 40% higher for PET/matched; that is, noise was much lower than in gated PET. Conclusion: Acquiring respiratory waveforms both in PET (as in the current state of the art) and in CT (an unusual key step in this approach) has the potential to improve the alignment of PET and CT images. A proposed method for using this information was tested. Improved alignment was demonstrated.

Continuous bed motion (CBM) was recently introduced as an alternative to step‐and‐shoot (SS) mode for PET/CT data acquisition. In CBM, the patient is continuously advanced into the scanner at a preset speed, whereas in SS, the patient is imaged in overlapping bed positions. Previous investigations have shown that patients preferred CBM over SS for PET data acquisition. In this study, we investigated the effect of CBM versus SS on patient breathing and respiratory motion correction. One hundred patients referred for PET/CT were scanned using a Siemens mCT scanner. Patient respiratory waveforms were recorded using an Anzai system and analyzed using four methods: Methods 1 and 2 measured the coefficient of variation (COV) of the respiratory cycle duration (RCD) and amplitude (RCA). Method 3 measured the respiratory frequency signal prominence (RSP) and method 4 measured the width of the HDChest optimal gate (OG) window when using a 35% duty cycle. Waveform analysis was performed over the abdominothoracic region which exhibited the greatest respiratory motion and the results were compared between CBM and SS. Respiratory motion correction was assessed by comparing the ratios of SUVmax, SUVpeak, and CNR of focal FDG uptake, as well as Radiologists’ visual assessment of corresponding image quality of motion corrected and uncorrected images for both acquisition modes. The respiratory waveforms analysis showed that the RCD and RCA COV were 3.7% and 33.3% lower for CBM compared to SS, respectively, while the RSP and OG were 30.5% and 2.0% higher, respectively. Image analysis on the other hand showed that SUVmax, SUVpeak, and CNR were 8.5%, 4.5%, and 3.4% higher for SS compared to CBM, respectively, while the Radiologists’ visual comparison showed similar image quality between acquisition modes. However, none of the results showed statistically significant differences between SS and CBM, suggesting that motion correction is not impacted by acquisition mode.

Stereotactic ablative radiation therapy (SABR) is an emerging treatment option for patients with pulmonary metastases; identifying patients who would benefit from SABR can improve outcomes.We retrospectively analyzed local failure (LF), distant failure (DF), overall survival (OS), and toxicity in 317 patients with 406 pulmonary metastases treated with SABR in January 2006-September 2017 at a tertiary cancer center.Median follow-up time was 23 months. Primary adrenal, colorectal, sarcoma, or pancreatic ("less responsive") tumors led to high rates of LF. LF rates for patients with less responsive vs. responsive tumors were 4.6% vs. 1.6% at 12 months and 12.8% vs. 3.9% at 24 months (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.11-0.73; Log-Rank P = 0.0087). A nomogram for 24-month local control was created using Cox multivariate factors (surgical history, planning target volume, primary disease site, lung lobe location). Treating patients with ≤3 pulmonary metastases vs.3 pulmonary metastases was associated with improved 24-month (74.2% vs. 59.3%) and 48-month (47.7% vs. 35.1%) OS (HR 0.66, 95% CI 0.47-0.95; Log-Rank P = 0.043), and reduced 12-month (22.5% vs. 50.8%) and 24-month (31.8% vs. 61.4%) intrathoracic DF (HR 0.53, 95% CI 0.38-0.74; Log-Rank P 0.0001). The most common toxicity was asymptomatic pneumonitis (14.8%). Six patients had grade 3 events (5 pneumonitis, 1 brachial plexus).SABR for pulmonary metastases was effective and well tolerated. Irradiating limited intrathoracic sites of disease led to improved OS and intrathoracic DM. Higher SABR doses or surgery could be considered for less radio-responsive primary tumors.

Background Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor’s response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting. Methods A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1–20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (

Importance Stereotactic ablative radiotherapy (SABR) is first-line treatment for patients with early-stage non–small cell lung cancer (NSCLC) who cannot undergo surgery. However, up to 1 in 6 such patients will develop isolated local recurrence (iLR) or isolated regional recurrence (iRR). Little is known about outcomes when disease recurs after SABR, or about optimal management strategies for such recurrences. Objective To characterize long-term outcomes for patients with iLR or iRR after SABR for early-stage NSCLC with the aim of informing treatment decision making for these patients with potentially curable disease. Design, Setting, and Participants In this cohort study, a retrospective review was conducted of 912 patients prospectively enrolled in an institutional database at a tertiary cancer center from January 1, 2004, through December 31, 2014. Main Outcomes and Measures Overall survival, progression-free survival, recurrence patterns, demographics, salvage techniques, patterns of salvage failure, and toxic effects. Results Of the 912 patients in the study (456 women and 456 men; median age, 72 years [range, 46-91 years]), 756 (82.9%) had T1 tumors at initial diagnosis; 502 tumors (55.0%) were adenocarcinomas and 309 tumors (33.9%) were squamous cell carcinomas. Of 912 patients with early-stage I to II NSCLC who received definitive SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions), 102 developed isolated recurrence (49 with iLR and 53 with iRR), and 658 had no recurrence. Median times to recurrence after SABR were 14.5 months (range, 1.5-60.8 months) for iLR and 9.0 months (range, 1.9-70.7 months) for iRR; 39 of 49 patients (79.6%) with iLR and 48 of 53 patients (90.6%) with iRR underwent salvage with reirradiation, surgery, thermal ablation, or chemotherapy. Median follow-up times for patients with iLR or iRR were 57.2 months (interquartile range, 37.7-87.6 months) from initial SABR and 38.5 months (interquartile range, 19.9-69.3 months) from recurrence. Rates of overall survival at 5 years from initial SABR were no different between patients with iLR and salvage treatment (57.9%) and patients with no recurrence (54.9%; hazard ratio, 0.89; 95% CI, 0.56-1.43; P = .65) but were lower for patients with iRR and salvage treatment (31.1%; hazard ratio, 1.43; 95% CI, 1.00-2.34; P = .049). Patients receiving salvage treatment had longer overall survival than patients who did not (median, 37 vs 7 months after recurrence; hazard ratio, 0.40; 95% CI, 0.09-0.66; P = .006). Twenty-four of 87 patients (27.6%) who received salvage treatment for iLR or iRR subsequently developed distant metastases. No patient experienced grade 5 toxic effects after salvage treatment. Conclusions and Relevance Life expectancy after salvage treatment for iLR was similar to that for patients without recurrence, but survival after salvage treatment for iRR was similar to that of patients with stage III NSCLC. Patients who received salvage treatment had significantly improved survival. Because salvage treatment for iLR or iRR was based on a consistent multidisciplinary approach, this may help in clinical decision making., This cohort study examines long-term outcomes for patients with isolated local recurrence or isolated regional recurrence after stereotactic ablative radiotherapy for early-stage non–small cell lung cancer with the aim of informing treatment decision making., Key Points Question What are the outcomes for potentially curable local or regional recurrences after stereotactic ablative radiotherapy for early-stage non–small cell lung cancer? Findings In this cohort study of 912 patients who received stereotactic ablative radiotherapy for early-stage I to II non–small cell lung cancer, salvage treatment was significantly associated with improved survival. Survival for patients with local recurrence who received salvage treatment was no different than that for patients with no recurrence, and survival for patients with regionally recurrent disease was similar to that for patients with stage III disease. Meaning This study provides data on outcomes for patients with recurrence after stereotactic ablative radiotherapy, which may help in clinical decision making.

Lung cancer is the leading cause of cancer-related death in the United States and accounts for more deaths than colorectal, breast, prostate, and pancreatic cancers combined. The eighth edition of the tumor-node-metastasis staging system (TNM-8), which has been accepted by the Union for International Cancer Control and the American Joint Committee on Cancer based on proposals from the International Association for the Study of Lung Cancer, includes key changes to T and M descriptors and overall stage groups and introduces new recommendations for classifying patterns of disease with multiple sites of pulmonary involvement. As accurate staging is necessary for the formulation of appropriate treatment strategies, radiologists must be able to identify these features on imaging studies.

Background: Patients may be found to have stage IIIA-N2 at the final pathology after the initial surgery. We want to determine the survival rate in this unique group of patients. Methods: We reviewed all patients who underwent surgical resection for lung cancer from 2000 to 2011 who had pathologic stage N2 without induction therapy. We determined the clinicopathologic characteristics and survival rate in this unique group of patients. Results: A total of 101 patients met the inclusion criteria. The average age of the group was 65 years old with 53 (53%) females. The chest computed tomography (CT) scans showed 30 patients (30%) with mediastinal lymphadenopathy (>1 cm) and 13 (13%) with multistation disease. The positron emission tomography-computed tomography (PET-CT) showed 24 patients (24%) with N2 positive uptake. Invasive mediastinal staging prior to surgery occurred in 43 patients (43%). Eighty-four patients underwent a lobectomy (83%), 7 with bilobectomy (7%), and 10 with pneumonectomy (10%). The most common pathology was adenocarcinoma with 73 patients (72%) and the second most common was squamous cell carcinoma with 22 patients (22%). Most of the patients completed the adjuvant chemoradiation therapy (86%). The 5-year survival rate was 48% and the 10-year survival rate was 24%. Conclusions: Pathologic stage IIIA-N2 non-small cell lung cancer (NSCLC) is a heterogeneous disease process with a very small group of patients undergoing initial surgery. Patients with occult stage IIIA-N2 who undergo initial surgery have an excellent overall survival rate.

Lung cancer is the leading cause of cancer death in both men and women in the United States. The National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography (CT) screening reduces lung cancer mortality by 20% compared to screening with chest radiography. Currently, many institutions in the US are implementing lung cancer screening programs. The use of lung-RADS as a quality assurance tool allows standardization of lung cancer screening CT lexicon, reporting and management recommendations, and reduces confusion in lung cancer screening CT interpretations. Lung-RADS will also facilitate outcome monitoring and future auditing of lung cancer screening programs, assist research, and consequently refine and improve lung cancer screening practices. Familiarity with lung-RADS version 1.0 is essential not only for radiologists interpreting low-dose computed tomography screening studies, but all medical personnel involved in multidisciplinary lung cancer screening programs. This article reviews the Lung-RADS categories and management recommendations using a case-based approach.

Our aim is to evaluate in phantom and patient studies a recently developed elastic motion debluring (EMDB) technique which makes use of all the acquired PET data and compare its performance to other conventional techniques such as phase based gating (PBG) and HDChest (HDC) both of which use fractions of the acquired data. Comparisons were made with respect to static whole-body (SWB) images with no motion correction. Methods: A phantom simulating respiratory motion of the thorax with lung lesions (5 spheres with ID=10- 28 mm) was scanned with 0, 1, 2, and 3 cm motion. Four reconstructions were performed: SWB, PBG, HDC, and EMDB. For PBG, the average (PBGave) and maximum bin (PBGmax) were used. To compare the reconstructions, the ratios of SUVmax (RSmax), SUVpeak (RSpeak), and CNR (RCNR) were calculated with respect to SWB. Additionally, 46 patients with lung or liver tumors 0.54 HDC > 0.41 PBGmax > 0.31 PBGave). Similar results were seen in patient studies. The SUVmax/SUVpeak were higher by 19.3/11.1% EMDB, 21.6/13.9% HDC, 22.8/12.8% PBGave, and 45.6/26.8% PBGmax compared to SWB. Lung/liver noise increased EMDB (3/15%), HDC (35/56%), PBGave (100/170%), and PBGmax (146/219%). CNR increased in lung/liver tumors only for EMDB (18/13%), and decreased for HDC (-14/-23%), PBGave (-39/-63%), and PBGmax (-18/-46%). Average radiologist scores of image quality were SWB (4.0 ± 0.8) > EMDB (3.7 ± 1.0) > HDC (3.1 ± 1.0) > PBG (1.5 ± 0.7). Conclusion: The EMDB algorithm had the least increase in image noise, improved lesion CNR, and had the highest overall image quality score.

The number of screening-detected lung nodules is expected to increase as low-dose computed tomography screening is implemented nationally. Standardized guidelines for image acquisition, interpretation, and screen-detected nodule workup are essential to ensure a high standard of medical care and that lung cancer screening is implemented safely and cost effectively. In this article, we review the current guidelines for pulmonary nodule management in the lung cancer screening setting.

This article reviews the role of 18F-2-deoxy- d -glucose (FDG) positron emission tomography (PET) imaging in staging, radiation therapy planning, and determination of prognosis and therapeutic response in patients with nonsmall cell lung cancer. In addition, radiotracers that interrogate different metabolic pathways, receptors, and targets to overcome the potential limitations of FDG-PET in staging, as well as early response evaluation and monitoring of response to targeted therapies, are reviewed. 18F-2-deoxy-D-glucose (FDG) positron emission tomography (18FDG-PET) imaging has a key role in staging, radiation therapy planning, and determination of prognosis and therapeutic response in patients with non-small cell lung cancer. FDG-PET-CT is not optimal in determination of T descriptors (additional small lung nodules, locoregional invasion, etc.) as respiratory motion and or low-radiation-dose imaging degrade image quality. Radiotracers interrogate different metabolic pathways, receptors, and targets to overcome the potential limitations of FDG-PET in staging, as well as perform early response evaluation and monitoring of response to targeted therapies. A PET-CT-defined tumor target is usually smaller than that defined by CT, and incorporation of PET-CT into radiotherapy planning can allow radiation-dose escalation without increasing side effects. FDG is the only Medicare-approved PET-CT tracer for evaluation of cancer. Novel PET radiotracers that interrogate different metabolic pathways beyond glycolysis, receptors, and targets are being evaluated in staging, response evaluation, and targeted therapy assessment.

Primary lung cancer is the leading cause of cancer mortality in the world. Thorough clinical staging of patients with lung cancer is important, because therapeutic options and management are to a considerable degree dependent on stage at presentation. Radiologic imaging is an essential component of clinical staging, including chest radiography in some cases, computed tomography, MRI, and PET. Multiplanar imaging modalities allow assessment of features that are important for surgical, oncologic, and radiation therapy planning, including size of the primary tumor, location and relationship to normal anatomic structures in the thorax, and existence of nodal and/or metastatic disease.

Resectable esophageal adenocarcinoma (EAC) patients often receive chemoradiation followed by surgery. However, most patients experience recurrences. Overexpression of MTDH, an oncoprotein with multiple functions, has been found to be associated with poor prognosis in breast cancer, glioblastoma, melanoma and various gastrointestinal malignancies, but not in EAC. We sought to establish its role in resistant EAC (post-treatment residual EAC). MTDH was assessed by immunohistochemistry in resected EAC, and results were correlated with clinical outcomes. MTDH expression was detectable in 72.5% (50/69) of patients, while expression levels were high (positive) in 50.7% (35/69). Of 69 patients analyzed, 25 had no relapse and 44 patients had a relapse (8 with local-regional and 36 with distant). The median follow-up duration was 3 years (0.4-11.6). The median overall survival was not associated with MTDH status (2.79 years for MTDH-negative and 3.60 years for MTDH-positive patients, p = 0.121). In addition, MTDH was not associated with either the type of relapse (local or distant), baseline clinical stage, tumor grade, presence of signet ring cells, surgical (yp) stage, percentage of residual EAC or presence of lymphovascular invasion. Our data reveal that MTDH is not a prognostic biomarker in resistant EAC after trimodality therapy.

// Yusuke Shimodaira 1 , Rebecca S. Slack 2 , Kazuto Harada 1 , Manoop S. Bhutani 3 , Elena Elimova 1 , Gregg A. Staerkel 4 , Nour Sneige 5 , Jeremy Erasmus 6 , Hironori Shiozaki 1 , Nikolaos Charalampakis 1 , Venkatram Planjery 1 , Dilsa Mizrak Kaya 1 , Fatemeh G. Amlashi 1 , Mariela A. Blum 1 , Heath D. Skinner 7 , Bruce D. Minsky 7 , Dipen M. Maru 5 , Wayne L. Hofstetter 8 , Stephen G. Swisher 8 , Jeannette E. Mares 1 , Jane E. Rogers 9 , Quan D. Lin 1 , William A. Ross 3 , Brian Weston 3 , Jeffrey H. Lee 3 and Jaffer A. Ajani 1 1 Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 2 Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 3 Department of Gastroenterology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 4 Department of Anatomic Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 5 Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 6 Department of Diagnostic Radiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 7 Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 8 Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 9 Department of Pharmacy, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Correspondence to: Jaffer A. Ajani, email: // Keywords : esophageal carcinoma, fine-needle aspiration, endoscopic ultrasound, upper mediastinal lymph nodes, positron emission tomography Received : March 15, 2017 Accepted : April 17, 2017 Published : May 23, 2017 Abstract Implications of assessing the proximal and far para-tracheal or sub-carinal nodes (para-tracheal [PTN] or sub-carinal [SCN]) associated with lower primary esophageal carcinomas (ECs) are unclear. To evaluate the value of endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) for PTN and SCN, we analyzed results by positron emission tomography (PET) avidity, 4 EUS node malignancy features, and EUS-FNA results in all patients with Siewert’s I or II EC. Of 133 patients (PTN, n =102; SCN, n =31) with EUS-FNA, 47 (35%) patients had malignant node, leading to treatment modifications. EUS-FNA diagnosed significantly more patients with malignant nodes ( p =0.02) even when PET and EUS features were combined. Among 94 PET-negative and EUS-negative patients, 9 (10%) had malignant EUS-FNA. At a minimum follow-up of 1 year, only 3 (5%) of 62 patients with benign EUS-FNA had evidence of malignancy in the nodal area of prior EUS-FNA. Patients with malignant EUS-FNA independently had a much shorter overall survival (OS) than those with benign EUS-FNA ( p