High risk lung nodule: A multidisciplinary approach to diagnosis and management.

Pulmonary nodules are often discovered incidentally during CT scans performed for other reasons. While the vast majority of nodules are benign, a small percentage may represent early-stage lung cancer with the potential for curative treatments. With the growing use of CT for both clinical purposes and lung cancer screening, the number of pulmonary nodules detected is expected to increase substantially. Despite well-established guidelines, many nodules do not receive proper evaluation due to a variety of factors, including inadequate coordination of care and financial and social barriers. To address this quality gap, novel approaches such as multidisciplinary nodule clinics and multidisciplinary boards may be necessary. As pulmonary nodules may indicate early-stage lung cancer, it is crucial to adopt a risk-stratified approach to identify potential lung cancers at an early stage, while minimizing the risk of harm and expense associated with over investigation of low-risk nodules. This article, authored by multiple specialists involved in nodule management, delves into the diagnostic approach to lung nodules. It covers the process of determining whether a patient requires tissue sampling or continued surveillance. Additionally, the article provides an in-depth examination of the various biopsy and therapeutic options available for malignant lung nodules. The article also emphasizes the significance of early detection in reducing lung cancer mortality, especially among high-risk populations. Furthermore, it addresses the creation of a comprehensive lung nodule program, which involves smoking cessation, lung cancer screening, and systematic evaluation and follow-up of both incidental and screen-detected nodules.

Neoantigen Identification and Response to Adoptive Cell Transfer in Anti-PD-1 Naïve and Experienced Patients with Metastatic Melanoma.

PURPOSE: Immune checkpoint blockade (ICB) agents and adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) are prominent immunotherapies used for the treatment of advanced melanoma. Both therapies rely on activation of lymphocytes that target shared tumor antigens or neoantigens. Recent analysis of patients with metastatic melanoma who underwent treatment with TIL ACT at the NCI demonstrated decreased responses in patients previously treated with anti-PD-1 agents. We aimed to find a basis for the difference in response rates between anti-PD-1 naïve and experienced patients. PATIENTS AND METHODS: We examined the tumor mutational burden (TMB) of resected tumors and the repertoire of neoantigens targeted by autologous TIL in a cohort of 112 anti-PD-1 naïve and 69 anti-PD-1 experienced patients. RESULTS: Anti-PD-1 naïve patients were found to possess tumors with higher TMBs (352.0 vs. 213.5, P = 0.005) and received TIL reactive with more neoantigens (2 vs. 1, P = 0.003) compared with anti-PD-1 experienced patients. Among patients treated with TIL ACT, TMB and number of neoantigens identified were higher in ACT responders than ACT nonresponders in both anti-PD-1 naïve and experienced patients. Among patients with comparable TMBs and predicted neoantigen loads, treatment products administered to anti-PD-1 naïve patients were more likely to contain T cells reactive against neoantigens than treatment products for anti-PD-1 experienced patients (2.5 vs. 1, P = 0.02). CONCLUSIONS: These results indicate that decreases in TMB and targeted neoantigens partially account for the difference in response to ACT and that additional factors likely influence responses in these patients. See related commentary by Blass and Ott, p. 2980.

A machine learning model for ranking candidate HLA class I neoantigens based on known neoepitopes from multiple human tumor types.

Tumor neoepitopes presented by major histocompatibility complex (MHC) class I are recognized by tumor-infiltrating lymphocytes (TIL) and are targeted by adoptive T-cell therapies. Identifying which mutant neoepitopes from tumor cells are capable of recognition by T cells can assist in the development of tumor-specific, cell-based therapies and can shed light on antitumor responses. Here, we generate a ranking algorithm for class I candidate neoepitopes by using next-generation sequencing data and a dataset of 185 neoepitopes that are recognized by HLA class I-restricted TIL from individuals with metastatic cancer. Random forest model analysis showed that the inclusion of multiple factors impacting epitope presentation and recognition increased output sensitivity and specificity compared to the use of predicted HLA binding alone. The ranking score output provides a set of class I candidate neoantigens that may serve as therapeutic targets and provides a tool to facilitate in vitro and in vivo studies aimed at the development of more effective immunotherapies.

Characteristics of Matriculants to Thoracic Surgery Residency Training Programs.

BACKGROUND: Thoracic surgery (TS) residency positions are in high demand. There is no study describing the nationwide attributes of successful matriculants in this specialty. We examined the characteristics of TS resident applicants and identified factors associated with acceptance. METHODS: Applicant data from 2014 to 2017 application cycles was extracted from the Electronic Residency Application System and stratified by matriculation status. Medical education, type of general surgery residency, and research achievements were analyzed. The number of peer-reviewed publications and the corresponding impact factor for the journals where they were published were quantified. RESULTS: There were 492 applicants and 358 matriculants. The overall population was primarily male (79.5%), white (55.1%), educated at United States allopathic medical schools (66.5%), and trained at university-based general surgery residencies (59.6%). Education at United States allopathic schools (odds ratio [OR], 2.54; P < .0001), being a member of the American Osteopathic Association (OR, 3.27; P = .021), general surgery residency affiliation with a TS residency (OR, 2.41; P = .0003) or National Cancer Institute designated Comprehensive Cancer Center (OR, 1.76; P = .0172), and being a first-time applicant (OR, 4.71, P < .0001) were independently associated with matriculation. Matriculants published a higher number of manuscripts than nonmatriculants (median of 3 vs 2, P < .0001) and more frequently published in higher impact journals (P < .0001). CONCLUSIONS: Our study includes objective and quantifiable data from recent application cycles and represents an in-depth examination of applicants to TS residency. The type of medical school and residency, as well as academic productivity, correlate with successful matriculation.

mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer.

BACKGROUNDTherapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODSWe recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTSThe vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSIONThis vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATIONPhase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDINGCenter for Clinical Research, NCI, NIH.

Incidence of Asymptomatic Brain Metastases in Metastatic Colorectal Cancer.

BACKGROUND: Current literature suggests that brain metastasis is an infrequent occurrence in metastatic colorectal cancer. Outside of rare autopsy studies, these retrospective reports describe the incidence of symptomatic brain metastasis and therefore lack a description of the incidence in asymptomatic patients. With improved survival and a lack of routine brain imaging, the true incidence of brain metastasis among patients with metastatic colorectal cancer is likely under-recognized. At our research institution, protocol criteria require brain imaging regardless of neurologic symptoms. Therefore, we aim to describe the incidence of asymptomatic brain metastases in patients with metastatic colorectal cancer. PATIENTS AND METHODS: This study included patients with metastatic colorectal cancer enrolled onto a clinical trial screening protocol at the National Cancer Institute that underwent brain imaging (n = 171) between 2010 and 2019. RESULTS: The median age of patients at initial colorectal cancer diagnosis was 48.1 years. Most had stage IV disease with synchronous metastases. Twenty-five (14.6%) patients were identified with brain metastases, of which 19 (76%) were asymptomatic. Those with asymptomatic lesions were more likely to have presented with synchronous metastases, have a shorter time from primary diagnosis to development of metastatic disease, and have smaller brain metastases. CONCLUSION: We identified a high number of asymptomatic brain metastasis and subsequently a higher cumulative incidence of brain metastases in patients with metastatic colorectal cancer than historical reports would suggest. This may represent a heretofore unknown aspect of the natural course of disease now being exposed owing to an increasing life expectancy of these patients and could play a pivotal role in therapeutic decisions.

Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens.

PURPOSE: The purpose of this study was to evaluate antigen experienced T cells in peripheral blood lymphocytes (PBL) for responses to p53 neoantigens. EXPERIMENTAL DESIGN: PBLs from patients with a mutated TP53 tumor were sorted for antigen-experienced T cells and in vitro stimulation (IVS) was performed with p53 neoantigens. The IVS cultures were stimulated with antigen-presenting cells expressing p53 neoantigens, enriched for 41BB/OX40 and grown with rapid expansion protocol. RESULTS: T-cell responses were not observed in the PBLs of 4 patients who did not have tumor-infiltrating lymphocyte (TIL) responses to mutated TP53. In contrast, 5 patients with TIL responses to mutated TP53 also had similar T-cell responses in their PBLs, indicating that the PBLs and TILs were congruent in p53 neoantigen reactivity. CD4+ and CD8+ T cells were specific for p53R175H, p53Y220C, or p53R248W neoantigens, including a 78% reactive T-cell culture against p53R175H and HLA-A*02:01. Tracking TCRB clonotypes (clonality, top ranked, and TP53 mutation-specific) supported the enrichment of p53 neoantigen-reactive T cells from PBLs. The same T-cell receptor (TCR) from the TIL was found in the IVS cultures in three cases and multiple unique TCRs were found in another patient. TP53 mutation-specific T cells also recognized tumor cell lines bearing the appropriate human leukocyte antigen restriction element and TP53 mutation, indicating these T cells could recognize processed and presented p53 neoantigens. CONCLUSIONS: PBL was a noninvasive source of T cells targeting TP53 mutations for cell therapy and can provide a window into intratumoral p53 neoantigen immune responses.See related commentary by Olivera et al., p. 1203.

Adoptive T-Cell Therapy for Solid Malignancies.

The use of immunotherapies for solid and hematologic malignancies has demonstrated durable antitumor effects. Use of checkpoint inhibitors allows for immunologic reactivation of the adaptive immune system against tumor-specific neoantigens and effective rejection. Recent developments in adoptive transfer of T cells has shown effective immune rejection of solid malignancies and durable regression. Adoptive cell transfer involves extraction of in vivo T lymphocytes, selection for or introduction of tumor reactive cells, in vitro expansion, and delivery of the T-cell product back to the patient. This article discusses the different approaches, challenges, and further directions of adoptive T-cell transfer in solid malignancies.

Memory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patients.

T cells targeting shared oncogenic mutations can induce durable tumor regression in epithelial cancer patients. Such T cells can be detected in tumor infiltrating lymphocytes, but whether such cells can be detected in the peripheral blood of patients with the common metastatic epithelial cancer patients is unknown. Using a highly sensitive in vitro stimulation and cell enrichment of peripheral memory T cells from six metastatic cancer patients, we identified and isolated CD4+, and CD8+ memory T cells targeting the mutated KRASG12D and KRASG12V variants, respectively, in three patients. In an additional two metastatic colon cancer patients, we detected CD8+ neoantigen-specific cells targeting the mutated SMAD5 and MUC4 proteins. Therefore, memory T cells targeting unique as well as shared somatic mutations can be detected in the peripheral blood of epithelial cancer patients and can potentially be used for the development of effective personalized T cell-based cancer immunotherapy across multiple patients.

Surgeon, not disease severity, often determines the operation for acute complicated diverticulitis.

BACKGROUND: The "best" operation in the setting of acute complicated diverticulitis has been debated for decades. Multiple studies, including a recent prospective randomized trial, have reported improved outcomes with primary anastomosis. The aim of this study was to determine whether surgeon or patient-specific factors drives the choice of operative procedure. STUDY DESIGN: Consecutive adult patients with sigmoid diverticulitis, requiring emergent operative treatment for acute complicated diverticulitis, from 1997 to 2012 at an academic medical center, were identified from a prospectively maintained complications database. Patient characteristics, surgeon, choice of operation, and outcomes including postoperative complications and stoma reversal were noted. The use of primary anastomosis and associated outcomes between colorectal and noncolorectal surgeons were compared. RESULTS: There were 151 patients who underwent urgent resection during the study period, and 136 met inclusion criteria. Eighty-two resections (65.1%) were performed by noncolorectal surgeons and 44 by colorectal surgeons (34.9%). Noncolorectal surgeons performed more Hartmann procedures (68.3% vs 40.9%, p = 0.01) despite similar demographics, American Society of Anesthesiologists (ASA) classification, and Hinchey stage. Length of stay, time to stoma reversal, ICU days, and postoperative complications were lower in the colorectal group (43.2% vs 16.7, p = 0.02). CONCLUSIONS: Although patient-specific factors are important, surgeon is a potent predictor of operation performed in the setting of severe acute diverticulitis. A more aggressive approach to primary anastomosis may lower the complication rate after surgical treatment for severe acute diverticulitis.

miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells.

MicroRNAs (miRNAs) negatively and post-transcriptionally regulate expression of multiple target genes to support anabolic pathways for bone formation. Here, we show that miR-218 is induced during osteoblast differentiation and has potent osteogenic properties. miR-218 promotes commitment and differentiation of bone marrow stromal cells by activating a positive Wnt signaling loop. In a feed forward mechanism, miR-218 stimulates the Wnt pathway by down-regulating three Wnt signaling inhibitors during the process of osteogenesis: Sclerostin (SOST), Dickkopf2 (DKK2), and secreted frizzled-related protein2 (SFRP2). In turn, miR-218 expression is up-regulated in response to stimulated Wnt signaling and functionally drives Wnt-related transcription and osteoblast differentiation, thereby creating a positive feedback loop. Furthermore, in metastatic breast cancer cells but not in normal mammary epithelial cells, miR-218 enhances Wnt activity and abnormal expression of osteoblastic genes (osteomimicry) that contribute to homing and growth of cells metastatic to bone. Thus, miR-218/Wnt signaling circuit amplifies both the osteoblast phenotype and osteomimicry-related tumor activity.