Tumor immunotherapy with T lymphocytes, which can recognize and destroy malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials. We report that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non–cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL). The engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months. Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia. On average, each infused CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells. Furthermore, a CD19-specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission, in two of three patients. Moreover, a portion of these cells persisted as memory CAR+ T cells and retained anti-CD19 effector functionality, indicating the potential of this major histocompatibility complex–independent approach for the effective treatment of B cell malignancies.

The clinical implications of adding plasma-based circulating tumor DNA next-generation sequencing (NGS) to tissue NGS for targetable mutation detection in non-small cell lung cancer (NSCLC) have not been formally assessed. OBJECTIVE To determine whether plasma NGS testing was associated with improved mutation detection and enhanced delivery of personalized therapy in a real-world clinical setting. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study enrolled 323 patients with metastatic NSCLC who had plasma testing ordered as part of routine clinical management. Plasma NGS was performed using a 73-gene commercial platform. Patients were enrolled at the Hospital of the University of Pennsylvania from April 1, 2016, through January 2, 2018. The database was locked for follow-up and analyses on January 2, 2018, with a median follow-up of 7 months (range, 1-21 months). MAIN OUTCOMES AND MEASURES The number of patients with targetable alterations detected with plasma and tissue NGS; the association between the allele fractions (AFs) of mutations detected in tissue and plasma; and the association of response rate with the plasma AF of the targeted mutations. RESULTS Among the 323 patients with NSCLC (60.1% female; median age, 65 years [range, 33-93 years]), therapeutically targetable mutations were detected in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2, or BRAF for 113 (35.0%) overall. Ninety-four patients (29.1%) had plasma testing only at the discretion of the treating physician or patient preference. Among the 94 patients with plasma testing alone, 31 (33.0%) had a therapeutically targetable mutation detected, thus obviating the need for an invasive biopsy. Among the remaining 229 patients who had concurrent plasma and tissue NGS or were unable to have tissue NGS, a therapeutically targetable mutation was detected in tissue alone for 47 patients (20.5%), whereas the addition of plasma testing increased this number to 82 (35.8%). Thirty-six of 42 patients (85.7%) who received a targeted therapy based on the plasma result achieved a complete or a partial response or stable disease. The plasma-based targeted mutation AF had no correlation with depth of Response Evaluation Criteria in Solid Tumors response (r = −0.121; P = .45). CONCLUSIONS AND RELEVANCE Integration of plasma NGS testing into the routine management of stage IV NSCLC demonstrates a marked increase of the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy.

Tuberculosis is a public health problem worldwide, including in the United States-particularly among immunocompromised patients and other high-risk groups. Tuberculosis manifests in active and latent forms. Active disease can occur as primary tuberculosis, developing shortly after infection, or postprimary tuberculosis, developing after a long period of latent infection. Primary tuberculosis occurs most commonly in children and immunocompromised patients, who present with lymphadenopathy, pulmonary consolidation, and pleural effusion. Postprimary tuberculosis may manifest with cavities, consolidations, and centrilobular nodules. Miliary tuberculosis refers to hematogenously disseminated disease that is more commonly seen in immunocompromised patients, who present with miliary lung nodules and multiorgan involvement. The principal means of testing for active tuberculosis is sputum analysis, including smear, culture, and nucleic acid amplification testing. Imaging findings, particularly the presence of cavitation, can affect treatment decisions, such as the duration of therapy. Latent tuberculosis is an asymptomatic infection that can lead to postprimary tuberculosis in the future. Patients who are suspected of having latent tuberculosis may undergo targeted testing with a tuberculin skin test or interferon-γ release assay. Chest radiographs are used to stratify for risk and to assess for asymptomatic active disease. Sequelae of previous tuberculosis that is now inactive manifest characteristically as fibronodular opacities in the apical and upper lung zones. Stability of radiographic findings for 6 months distinguishes inactive from active disease. Nontuberculous mycobacterial disease can sometimes mimic the findings of active tuberculosis, and laboratory confirmation is required to make the distinction. Familiarity with the imaging, clinical, and laboratory features of tuberculosis is important for diagnosis and management. RSNA, 2017.

We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-beta (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) or malignant pleural effusions (MPE) resulted in gene transfer, humoral antitumor immune responses, and anecdotal clinical responses manifested by modified Response Evaluation Criteria in Solid Tumors (RECIST) disease stability in 3 of 10 patients at 2 months and an additional patient with significant metabolic response on positron emission tomography (PET) imaging. This phase I trial was conducted to determine whether using two doses of Ad.IFN-beta vector would be superior. Ten patients with MPM and seven with MPE received two doses of Ad.IFN-beta through an indwelling pleural catheter. Repeated doses were generally well tolerated. High levels of IFN-beta were detected in pleural fluid after the first dose; however, only minimal levels were seen after the second dose of vector. Lack of expression correlated with the rapid induction of neutralizing Ad antibodies (Nabs). Antibody responses against tumor antigens were induced in most patients. At 2 months, modified RECIST responses were as follows: one partial response, two stable disease, nine progressive disease, and two nonmeasurable disease. One patient died after 1 month. By PET scanning, 2 patients had mixed responses and 11 had stable disease. There were seven patients with survival times longer than 18 months. This approach was safe, induced immune responses and disease stability. However, rapid development of Nabs prevented effective gene transfer after the second dose, even with a dose interval as short as 7 days.

PURPOSE To provide evidence-based recommendations to practicing clinicians on radiographic imaging and biomarker surveillance strategies after definitive curative-intent therapy in patients with stage I-III non–small-cell lung cancer (NSCLC) and SCLC. METHODS ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, radiology, primary care, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2019. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 14 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Patients should undergo surveillance imaging for recurrence every 6 months for 2 years and then annually for detection of new primary lung cancers. Chest computed tomography imaging is the optimal imaging modality for surveillance. Fluorodeoxyglucose positron emission tomography/computed tomography imaging should not be used as a surveillance tool. Surveillance imaging may not be offered to patients who are clinically unsuitable for or unwilling to accept further treatment. Age should not preclude surveillance imaging. Circulating biomarkers should not be used as a surveillance strategy for detection of recurrence. Brain magnetic resonance imaging should not be used for routine surveillance in stage I-III NSCLC but may be used every 3 months for the first year and every 6 months for the second year in patients with stage I-III small-cell lung cancer who have undergone curative-intent treatment.

Patients with a history of nephrolithiasis and flank pain are at increased risk for serial CT with potentially high cumulative effective doses.

New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-a (Ad.IFN-a2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-a concentrations resulting in severe "flu-like" symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-a levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-a expression levels. Antitumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-a2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor. Clinical trial registered with www.clinicaltrials.gov (NCT 01212367).

Background Standard imaging modalities are inaccurate in staging malignant pleural mesothelioma (MPM). Single institution studies suggest that volumetric computed tomography (VolCT) is more accurate but labor intensive. We established a multicenter network to test interobserver variability, accuracy (relative to pathologic stage) and prognostic significance of semi-automated VolCT. Methods Six institutions electronically submitted clinical and pathologic data to an established multicenter database on patients with MPM who had surgery. Institutional radiologists reviewed preoperative CT scans for quality then submitted via electronic network (AG mednet) to biostatistical center (BC). Two reference radiologists, blinded to clinical data, performed semi-automated tumor volume calculations using commercially available software (Vitrea Enterprise 6.0), then submitted readings to BC. Study endpoints included: feasibility of network; interobserver variability for VolCT; correlation of tumor volume to pTN stages, and overall survival (OS). Results Of 164 cases, 129 were analyzable and read by reference radiologists. Most tumors were <500cm3. A small bias was observed between readers, as one provided consistently larger measurements than the other (mean difference=47.9, p=.0027), but for 80% of cases, the absolute difference was ≤ 200cm3. Spearman correlation between readers was 0.822. Volume correlated with pTN stages and OS, best defined by 3 groups with average volumes of: 91.2, 245.3, 511.3cm3, associated with median OS of 37, 18, 8 months respectively. Conclusions For the first time, a multicenter network was established and initial correlations of tumor volume to pTN stages and OS shown. A larger multicenter international study is planned to confirm results and refine correlations.