Differentiation between small hepatocellular carcinoma (<3 cm) and benign hepatocellular lesions in patients with Budd-Chiari syndrome: the role of multiparametric MR imaging.

Objective: To investigate the value of multiparametric MR imaging to differentiate between small hepatocellular carcinoma (s-HCC) versus benign liver lesions in patients with Budd-Chiari syndrome. Methods: 12 patients with benign hepatocellular lesions and 32 patients with small (<3 cm) HCCs were assessed. MRI images were reviewed by two radiologists blinded to the patient background information; lesion T1 and T2 signal intensities and ADC values were compared with the background liver. Enhancement of lesion relative to hepatic parenchyma [(T1Enh-T1liver)/T1liver] in the arterial, venous, and delayed phases was also compared between the two groups. A multivariable logistic model was developed using these categorical measures; the predictive value of the model was tested using the Area Under the Receiver operating characteristic (AU-ROC) curve for logistic models. P-values <0.05 were considered statistically significant. Results: There were consistent differences in T1lesion/T1liver, and T2lesion/T2liver, and ADClesion/ADCliver between benign hepatocellular lesions versus the sHCC group (p<0.001, p<0.001, p = 0.045, respectively). Lesion-to-background liver enhancement in the portal venous and delayed phases was different between the benign lesions versus sHCC (p=0.001). ROC analysis for the logistic model that included the T1 ratio, T2 ratio, and portal venous enhancement ratio demonstrated excellent discriminatory power with the area under the curve of 0.94. Conclusion: Multiparametric MR imaging is a useful method to help differentiate benign liver lesions from sHCC in patients with Budd-Chiari syndrome.

ACR Appropriateness Criteria® Suspected Pulmonary Embolism: 2022 Update.

Pulmonary embolism (PE) remains a common and important clinical condition that cannot be accurately diagnosed on the basis of signs, symptoms, and history alone. The diagnosis of PE has been facilitated by technical advancements and multidetector CT pulmonary angiography, which is the major diagnostic modality currently used. Ventilation and perfusion scans remain largely accurate and useful in certain settings. MR angiography can be useful in some clinical scenarios and lower-extremity ultrasound can substitute by demonstrating deep vein thrombosis; however, if negative, further studies to exclude PE are indicated. In all cases, correlation with the clinical status, particularly with risk factors, improves not only the accuracy of diagnostic imaging but also overall utilization. Other diagnostic tests have limited roles. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer-reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer-reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Evaluating T-cell cross-reactivity between tumors and immune-related adverse events with TCR sequencing: pitfalls in interpretations of functional relevance.

T-cell receptor sequencing (TCRseq) enables tracking of T-cell clonotypes recognizing the same antigen over time and across biological compartments. TCRseq has been used to test if cross-reactive antitumor T cells are responsible for development of immune-related adverse events (irAEs) following immune checkpoint blockade. Prior studies have interpreted T-cell clones shared among the tumor and irAE as evidence supporting this, but interpretations of these findings are challenging, given the constraints of TCRseq. Here we capitalize on a rare opportunity to understand the impact of potential confounders, such as sample size, tissue compartment, and collection batch/timepoint, on the relative proportion of shared T-cell clones between an irAE and tumor specimens. TCRseq was performed on tumor-involved and -uninvolved tissues, including an irAE, that were obtained throughout disease progression and at the time of rapid autopsy from a patient with renal cell carcinoma treated with programmed death-1 (PD-1) blockade. Our analyses show significant effects of these confounders on our ability to understand T-cell receptor overlap, and we present mitigation strategies and study design recommendations to reduce these errors. Implementation of these strategies will enable more rigorous TCRseq-based studies of immune responses in human tissues, particularly as they relate to antitumor T-cell cross-reactivity in irAEs following checkpoint blockade.

ACR Appropriateness Criteria® Imaging of Mediastinal Masses.

Mediastinal masses can present with symptoms, signs, and syndromes or incidentally. Selecting the appropriate diagnostic imaging study for mediastinal mass evaluation requires awareness of the strengths and weaknesses of the various imaging modalities with regard to tissue characterization, soft tissue contrast, and surveillance. This publication expounds on the differences between chest radiography, CT, PET/CT, ultrasound, and MRI in terms of their ability to decipher and surveil mediastinal masses. Making the optimal imaging choice can yield diagnostic specificity, avert unnecessary biopsy and surgery, guide the interventionist when necessary, and serve as a means of surveillance for probably benign, but indeterminate mediastinal masses. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Unsuspected COVID-19 pneumonia suggests need for higher level of personal protective equipment usage during routine radiologic examinations: Two case reports.

Two case reports demonstrating the need for enhanced usage of personal protective equipment of face shield, respirator, gloves, and gown during routine radiologic evaluation who may screen negative for COVID-19 and or atypical COVID-19 symptoms. First case is of a 42-year-old woman undergoing preoperative evaluation for endometrial cancer in the outpatient setting. The second case is of a 49-year-old woman presenting with abdominal pain, nausea, and vomiting for abdominal CT imaging from the emergency department. Both cases demonstrate typical lung imaging finding of COVID-19. These cases highlight the need for additional precautions in the outpatient and emergency setting even for patients in whom COVID-19 infection is not suspected.

Multimodal genomic features predict outcome of immune checkpoint blockade in non-small-cell lung cancer.

Despite progress in immunotherapy, identifying patients that respond has remained a challenge. Through analysis of whole-exome and targeted sequence data from 5,449 tumors, we found a significant correlation between tumor mutation burden (TMB) and tumor purity, suggesting that low tumor purity tumors are likely to have inaccurate TMB estimates. We developed a new method to estimate a corrected TMB (cTMB) that was adjusted for tumor purity and more accurately predicted outcome to immune checkpoint blockade (ICB). To identify improved predictive markers together with cTMB, we performed whole-exome sequencing for 104 lung tumors treated with ICB. Through comprehensive analyses of sequence and structural alterations, we discovered a significant enrichment in activating mutations in receptor tyrosine kinase (RTK) genes in nonresponding tumors in three immunotherapy treated cohorts. An integrated multivariable model incorporating cTMB, RTK mutations, smoking-related mutational signature and human leukocyte antigen status provided an improved predictor of response to immunotherapy that was independently validated.

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer.

BACKGROUND: We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab. METHODS: Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint. RESULTS: While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations. CONCLUSIONS: Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Imaging in Therapy Response Assessment and Surveillance of Lung Cancer: Evidenced-based Review With Focus on the Utility of 18F-FDG PET/CT.

This review covers the state-of-the-art imaging in therapy assessment and surveillance of lung cancer with focus on the utility of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). We review different qualitative and quantitative response assessment criteria in lung cancer, common pitfalls and atypical patterns of response to immunotherapy, and imaging features of common immune-related adverse events. In addition, the currently recommended imaging workup in surveillance of asymptomatic patients with non-small-cell and small-cell lung cancer and future developments will be discussed.

Correction to: persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1.

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Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1.

BACKGROUND: Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently. CASE PRESENTATION: We studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations - BRAF-N581I in the NSCLC and AKT1-E17K in the CRC - years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment. CONCLUSIONS: These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade.

Gastric volvulus: unraveling the diagnosis with MPRs.

Gastric volvulus is a rare entity with a spectrum of acute and chronic clinical presentations. Body radiologists must be cognizant of the subtypes of gastric volvulus and identify potential complications. Mortality can be high if unrecognized from gastric necrosis, perforation, and sepsis. CT with multiplanar reformations is critical for complete evaluation beyond radiography and fluoroscopy. This article reviews clinical and imaging features of uncomplicated and complicated gastric volvulus, with the aim of guiding appropriate management.

Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; P = 0.007 and HR 6.91; 95% CI, 1.37-34.97; P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer (N = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.See related commentary by Zou and Meyerson, p. 1038.

Generative Adversarial Networks for the Creation of Realistic Artificial Brain Magnetic Resonance Images.

Even as medical data sets become more publicly accessible, most are restricted to specific medical conditions. Thus, data collection for machine learning approaches remains challenging, and synthetic data augmentation, such as generative adversarial networks (GAN), may overcome this hurdle. In the present quality control study, deep convolutional GAN (DCGAN)-based human brain magnetic resonance (MR) images were validated by blinded radiologists. In total, 96 T1-weighted brain images from 30 healthy individuals and 33 patients with cerebrovascular accident were included. A training data set was generated from the T1-weighted images and DCGAN was applied to generate additional artificial brain images. The likelihood that images were DCGAN-created versus acquired was evaluated by 5 radiologists (2 neuroradiologists [NRs], vs 3 non-neuroradiologists [NNRs]) in a binary fashion to identify real vs created images. Images were selected randomly from the data set (variation of created images, 40%-60%). None of the investigated images was rated as unknown. Of the created images, the NRs rated 45% and 71% as real magnetic resonance imaging images (NNRs, 24%, 40%, and 44%). In contradistinction, 44% and 70% of the real images were rated as generated images by NRs (NNRs, 10%, 17%, and 27%). The accuracy for the NRs was 0.55 and 0.30 (NNRs, 0.83, 0.72, and 0.64). DCGAN-created brain MR images are similar enough to acquired MR images so as to be indistinguishable in some cases. Such an artificial intelligence algorithm may contribute to synthetic data augmentation for "data-hungry" technologies, such as supervised machine learning approaches, in various clinical applications.

Comparative Analysis of Body Radiologist to Neuroradiologist Evaluation of the Spine in Trauma Settings.

INTRODUCTION: CT is routinely performed to evaluate trauma patients. When a radiologist misses an acute finding, there could be serious adverse consequences. In many subspecialty settings, body radiologists and neuroradiologists both interpret the thoracic and lumbar spine. RADPEER has estimated general disagreement rates between radiologists to be 2.9%, but the disagreement rate between neuroradiologists and body radiologists in trauma settings remains unknown. METHODS: This retrospective case review examined reports from the past 10 years of adult CT scans of the chest, abdomen, and pelvis interpreted by body radiologists, with concurrent thoracic and lumbar spine reconstructions interpreted by neuroradiologists. Reports were scrutinized for disagreement on the presence of acute fractures visible to both radiologists. RESULTS: 1,497 report pairs were analyzed. Of them, 33 pairs (2.2%) disagreed on the presence of an unequivocal acute fracture. In scans where only one miss occurred, the body radiologist and neuroradiologist were attributed with 27 (82%) and 6 (18%) of 32 disagreements, respectively. One scan contained a miss by both the body radiologist and neuroradiologist. Transverse processes were most commonly missed, followed by vertebral body fractures. CONCLUSION: Misses by body radiologists comprised the majority of disagreements. Neuroradiologists are more sensitive for detecting spinal fractures likely secondary to experience, education, small field of view reconstructed, and more detailed reporting protocols. Additional studies are needed to determine whether emulating neuroradiology practices may help body radiologists detect subtle fractures.

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer.

BACKGROUND: Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS: In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. RESULTS: Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS: Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute-Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621 .).

Pneumonitis From Anti-PD-1/ PD-L1 Therapy.

Pneumonitis is defined as a focal or diffuse inflammation of the lung parenchyma, and is a known, potentially fatal toxicity of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors. Herein we discuss two patients who developed pneumonitis secondary to anti-PD-1/PD-L1 immune checkpoint inhibitor therapy and illustrate a stepwise approach to the diagnostic evaluation and management of anti-PD-1/PD-L1-related pneumonitis. In the majority of patients who develop this toxicity, pneumonitis appears to clinically resolve with corticosteroid therapy alone; however, a subset of patients require additional immunosuppressive medications. Patients who clinically improve with steroid treatment must be monitored closely in the outpatient setting. If pneumonitis management results in complete clinical and radiologic resolution, patients may be able to restart their immune checkpoint inhibitor therapy. It is currently unclear which population of patients is more susceptible to developing higher-grade or steroid-refractory pneumonitis.

Immuno-oncology Trial Endpoints: Capturing Clinically Meaningful Activity.

Immuno-oncology (I-O) has required a shift in the established paradigm of toxicity and response assessment in clinical research. The design and interpretation of cancer clinical trials has been primarily driven by conventional toxicity and efficacy patterns observed with chemotherapy and targeted agents, which are insufficient to fully inform clinical trial design and guide therapeutic decisions in I-O. Responses to immune-targeted agents follow nonlinear dose-response and dose-toxicity kinetics mandating the development of novel response evaluation criteria. Biomarker-driven surrogate endpoints may better capture the mechanism of action and biological response to I-O agents and could be incorporated prospectively in early-phase I-O clinical trials. While overall survival remains the gold standard for evaluation of clinical efficacy of I-O agents in late-phase clinical trials, exploration of potential novel surrogate endpoints such as objective response rate and milestone survival is to be encouraged. Patient-reported outcomes should also be assessed to help redefine endpoints for I-O clinical trials and drive more efficient drug development. This paper discusses endpoints used in I-O trials to date and potential optimal endpoints for future early- and late-phase clinical development of I-O therapies.

Calcified pancreatic and peripancreatic neoplasms: spectrum of pathologies.

A variety of pancreatic and peripancreatic neoplasms may contain calcifications. We present a review of common to uncommon pancreatic neoplasms that may contain calcifications to include ductal adenocarcinoma, pancreatic neuroendocrine tumors, serous cystadenomas, solid pseudopapillary tumors, intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and lymphoepithelial cysts. In addition, duodenal mucinous adenocarcinoma can present as a peripancreatic mass that may contain calcification. Knowledge of the spectrum of calcification patterns can help the interpreting radiologist provide a meaningful differential.

Small Bowel Gastrointestinal Stromal Tumors: Multidetector Computed Tomography Enhancement Pattern and Risk of Progression.

OBJECTIVE: Small bowel gastrointestinal stromal tumors (SB-GISTs) are rare lesions with a variable appearance on computed tomography (CT). This case series analyzes the CT enhancement pattern with the histologic risk assessment of tumor progression. METHODS: Local institutional pathology database was searched for SB-GISTs from 2000 to 2015. Pathology reports and clinical notes were reviewed. Imaging was qualitatively reviewed for pattern of enhancement categorized into homogeneous or heterogeneous groups. Nonparametric statistical analysis was performed comparing enhancement to segment of bowel involved, presence of necrosis, tumor size, histologic grade (ie, G1 or G2), and histologic risk of progression (ie low, moderate, high). For simplicity, risk of progression was binned into low-risk or non-low-risk groups. RESULTS: Twenty-six pathology-proven, first presentation, nonmetastatic SB-GISTs were included into study. Seventeen were located in duodenum, 7 in jejunum, and 2 within the ileum. Dual phase (arterial and venous) CT imaging was available for 22 cases. Four cases did not have dual phase (three venous phase and one arterial phase only). Seventeen cases demonstrated heterogeneous enhancement and 9 cases homogeneous enhancement. Statistically significant difference was found between size versus enhancement groups (3.1 cm for homogeneous versus 6.8 cm for heterogeneous) (Mann-Whitney U test, n = 26, P = 0.002). Presence of necrosis versus enhancement group was statistically significant (Pearson χ, P = 0.001). Low-risk and non-low-risk groups versus enhancement groups was very significant (P = 0.001). Bowel segment involvement and histologic grading versus enhancement group did not reach statistical significance (P = 0.174 and P = 0.07, respectively). CONCLUSIONS: This case series reveals an important significant association between heterogeneous enhancement and non-low risk (ie, moderate/high) SB-GISTs. Beyond just describing the tumor, using enhancing pattern, the interpreting radiologist can preoperatively suggest additional prognostic information, potentially helpful for surgical planning.

Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264-76. ©2017 AACR.See related commentary by Yang, p. 250This article is highlighted in the In This Issue feature, p. 235.