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Introduction: The Thoracic Centers International coronavirus disease 2019 (COVID-19) Collaboration (TERAVOLT) registry found approximately 30% mortality in patients with thoracic malignancies during the initial COVID-19 surges. Data from South Africa suggested a decrease in severity and mortality with the Omicron wave. Our objective was to assess mortality of patients with thoracic malignancies with the Omicron-predominant wave and evaluate efficacy of vaccination., Methods: A prospective, multicenter observational study was conducted. A total of 28 institutions contributed data from January 14, 2022, to February 4, 2022. Inclusion criteria were any thoracic cancer and a COVID-19 diagnosis on or after November 1, 2021. End points included mortality, hospitalization, symptomatic COVID-19 infection, asymptomatic COVID-19 infection, and delay in cancer therapy. Analysis was done through contingency tables and a multivariable logistic model., Results: We enrolled a total of 346 patients. Median age was 65 years, 52.3% were female, 74.2% were current or former smokers, 86% had NSCLC, 72% had stage IV at time of COVID-19 diagnosis, and 66% were receiving cancer therapy. Variant was unknown for 70%; for those known, Omicron represented 82%. Overall mortality was 3.2%. Using multivariate analysis, COVID-19 vaccination with booster compared with no vaccination had a protective effect on hospitalization or death (OR = 0.30, confidence interval: 0.15-0.57, p  = 0.0003), whereas vaccination without booster did not (OR = 0.64, confidence interval: 0.33-1.24, p  = 0.1864). Cancer care was delayed in 56.4% of the patients., Conclusions: TERAVOLT found reduced patient mortality with the most recent COVID-19 surge. COVID-19 vaccination with booster improved outcomes of hospitalization or death. Delays in cancer therapy remain an issue, which has the potential to worsen cancer-related mortality., (© 2022 The Authors.)

The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitors in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C mutant cancer cells. Mechanistically, the combination of selinexor with KRAS G12C inhibitors suppressed cell growth signaling and downregulated the expression of cell cycle markers, KRAS and NF-kB as well as increased nuclear accumulation of tumor suppressor protein Rb. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models., Significance: In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment., Competing Interests: Conflict of interest statement: ASA received funding from Karyopharm, EISAI, Jannsen and Rhizen. ASA received speaker fees from Karyopharm Therapeutics Inc. ASA is a council member at GLG and Guidepoint. HM received honorarium from AztraZeneca and has advisory role in Zentalis. DU is on the advisory board of Daiichi Sankyo and AstraZeneca.

Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of lung cancer biology has led to the development of many effective targeted therapies as well as of immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in the treatment of non-small cell lung cancer (NSCLC) and are now being used as first-line therapies in metastatic disease, consolidation therapy following chemoradiation in unresectable locally advanced disease, and adjuvant therapy following surgical resection and chemotherapy in resectable disease. Despite these benefits, predicting who will respond to ICIs has proven to be difficult and there remains a need to discover new predictive immunotherapy biomarkers. Furthermore, resistance to ICIs in lung cancer is frequent either because of a lack of response or disease progression after an initial response. The utility of ICIs in the treatment of small cell lung cancer (SCLC) remains limited to first-line treatment of extensive stage disease in combination with chemotherapy with modest impact on overall survival. It is thus important to explore and exploit additional targets to reap the full benefits of immunotherapy in the treatment of lung cancer. Here, we will summarize the current state of immunotherapy in lung cancer, discuss novel targets, and explore the intersection between DNA repair defects and immunotherapy., Competing Interests: The authors have following conflicts of interest within the past 2 years, none of which influenced the work being submitted. HM: Advisory role – Zentalis. GD: Research grant - BMS, AstraZeneca, Merck; Honoraria - AstraZeneca, Curio Science. SJ: Research grant - AstraZeneca, Astex, Tesaro; Consultant – Adaptimmune. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mamdani, Matosevic, Khalid, Durm and Jalal.)

Background: HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors., Methods: We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data., Results: Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004)., Conclusion: A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis., (Copyright © 2021. Published by Elsevier Inc.)

Cancer/testis antigens (CTAs) are strongly expressed in some solid tumors but minimally expressed in normal tissue, making them appealing therapeutic targets. KK-LC-1 (CXorf61) has cytoplasmic expression in gastric, breast, and lung cancer. We characterized the molecular subtypes of non-small cell lung cancer (NSCLC) expressing KK-LC-1 to inform rational clinical trials of T-cell receptor therapy (TCR-T) targeting KK-LC-1. 9790 NSCLC tumors that underwent whole transcriptome sequencing (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ) were analyzed. Tumors were split into quartiles based on KK-LC-1 expression and pathological and molecular differences were investigated. Adenocarcinoma had significantly higher KK-LC-1 expression than squamous cell carcinoma (median, 3.25 vs. 1.17 transcripts per million (TPM), p < 0.0001). Tumors with the highest quartile of KK-LC-1 expression had a greater proportion of tumors with high tumor mutation burden (TMB) (≥10 mutations per megabase; 44% vs. 28% in Q1, p < 0.001). Increased KK-LC-1 expression was associated with increased M1 macrophage abundance. Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with high TMB. TCR-T therapy directed against KK-LC-1 should be considered in patients whose clinical features reflect these characteristics., Competing Interests: CONFLICTS OF INTEREST Dr. Nieva receives personal fees from Astra Zeneca, Fujirebio and Naveris. He receives research support from Merck and Genentech. Dr. Hsu was a consultant for Targeted Healthcare Communications. Ms. Baca and Dr. Xiu are employees of Caris Life Sciences. Dr. Kim is a consultant or advisory board member for Novartis, Janssen, AstraZeneca, and PierianDx and has received research funding to his institution from AstraZeneca, Bristol-Myers Squibb, Novartis, Genentech, Regeneron, Spectrum, Mirati, Debiopharm, Karyopharm, and Janssen. Dr. Mamdani is a consultant for Zentalis and has been a consultant for AstraZeneca, Caris Life Sciences, and Takeda. Dr. Nagasaka is a consultant for Caris and a speaker for Blueprint. She has also participated in advisory boards for AstraZeneca, Daiichi, Takeda, Novartis, EMD Serono, JNJ, Pfizer, Lilly, Genentech, and has received travel support from AnHeart Therapuetics. Dr. Puri is a consultant/advisor for AstraZeneca and G1 Therapeutics. Dr. Liu is a consultant/serves on advisory board for Amgen, AstraZeneca, Bayer, Beigene, Blueprint, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/MSD, Novartis, Regeneron, Takeda, Turning Point Therapeutics. He also has received research funding to his institution from Alkermes, Bayer, Blueprint, Bristol-Myers Squibb, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics. Dr. Korn is an employee of Caris Life Sciences and has stock ownership and stock options from Caris Life Sciences. He also receives consultant fees from Merck. All other authors have no conflicts of interests to disclose., (Copyright: © 2021 Hsu et al.)

KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS -mutated non-small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type.Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS -mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%). KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Increased patient survivorship following initial primary lung cancer (IPLC) diagnosis and treatment has uncovered new clinical challenges as individuals post-IPLC are at growing subsequent risk of developing second primary lung cancer (SPLC). Proper SPLC surveillance guidelines aimed at monitoring IPLC survivors are crucial to enhancing health outcomes. This study aims to categorize risk factors associated with SPLC emergence in IPLC survivors for clinical use following IPLC treatment., Materials and Methods: Using the Karmanos Cancer Institute Tumor Registry, patients diagnosed with IPLC from 2000 to 2017 were identified. Patients diagnosed with SPLC were matched to individuals who did not develop SPLC. Logistic and Cox regression analyses were performed to identify risk factors for SPLC emergence and overall survival (OS)., Results: One hundred twenty-one patients diagnosed with IPLC who later developed SPLC were identified and compared with 120 patients with IPLC who did not develop SPLC. Several factors such as stage at first diagnosis, histology, age, and smoking history were not associated with SPLC risk. The median time to SPLC was 1.79 years. Patients who were treated with surgical resection had a significantly higher probability of developing SPLC. After correcting for potential immortal time bias, the median OS was 3.63 years (95% confidence interval [CI], 3.05-5.00) and 7.31 years (95% CI, 4.62-10.90) for SPLC and no SPLC groups, respectively., Conclusion: This study uncovered notable associations and lack thereof between several competing SPLC risk factors, as well as mortality. Further characterization of SPLC risk factors is essential for enhancing surveillance recommendations., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To identify the key themes for evaluating the quality of initiatives to engage patients and family caregivers in decision-making across the organisation and system domains of healthcare systems., Methods: We conducted a scoping review. Seven databases of journal articles were searched from their inception to June 2019. Eligible articles were literature reviews published in English and provided useful information for determining aspects of engaging patients and family caregivers in decision-making to evaluate. We extracted text under three predetermined categories: structure, process and outcomes that were adapted from the Donabedian conceptual framework. These excerpts were then independently open-coded among four researchers. The subsequent themes and their corresponding excerpts were summarised to provide a rich description of each theme., Results: Of 7747 unique articles identified, 366 were potentially relevant, from which we selected the 42 literature reviews. 18 unique themes were identified across the three predetermined categories. There were six structure themes: engagement plan, level of engagement, time and timing of engagement, format and composition, commitment to support and environment. There were four process themes: objectives, engagement approach, communication and engagement activities. There were eight outcome themes: decision-making process, stakeholder relationship, capacity development, stakeholder experience, shape policy/service/programme, health status, healthcare quality, and cost-effectiveness., Conclusions: The 18 themes and their descriptions provide a foundation for identifying constructs and selecting measures to evaluate the quality of initiatives for engaging patients and family caregivers in healthcare system decision-making within the organisation and system domains. The themes can be used to investigate the mechanisms through which relevant initiatives are effective and investigate their effectiveness., Competing Interests: Competing interests: JM is employed by Family Caregivers of British Columbia, a paid partner of the Patients as Partners Initiative and a non-profit organisation that provides support and advocates for family caregivers within British Columbia, Canada. The Patient as Partners Team members are employed by the British Columbia Ministry of Health that provide partial support for this project., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes., Methods: Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate., Results: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144-3.264 p = 0.012). XPO1 amplification was not associated with survival., Conclusions: XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Concurrent chemoradiation (CRT) followed by surgery is a standard of care for locally advanced esophageal adenocarcinoma. It remains unclear if surgery following CRT offers any meaningful survival benefit compared to CRT alone in patients with clinical N3 disease who are at the highest risk of developing distant disease relapse., Methods: We conducted analysis of the National Cancer Database (NCDB) to compare overall survival (OS) of patients with locally advanced esophageal adenocarcinoma (cTanyN1-3M0 based on AJCC 7th staging system) who underwent CRT with or without surgery and analyzed outcomes based on the cN stage., Results: 7,520 patients were included in the analysis-74.7% had cN1 disease, 21.1% had cN2 disease, and 4.3% had cN3 disease. The median OS advantage offered by CRT followed by surgery was 22, 15.8, and 9.6 months compared to CRT alone in cN1, cN2, and cN3 patients, respectively. The 5-year OS estimates in the surgical group were 36.9%, 31.6% and 15.9% in cN1, cN2 and cN3 groups, respectively., Conclusions: Surgery following CRT in patients with locally advanced esophageal adenocarcinoma leads to improvement in OS, with the largest benefit noted in patients with cN1 and cN2 disease. Surgery following CRT also confers meaningful long-term survival advantage for a subset of cN3 patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jgo-21-314). HM reports that she has received payment for participation in advisory board for Zentalis and AstraZeneca, as well as travel reimbursement from AstraZeneca for presentation of investigator-initiated trial in national research meeting. SIJ reports that she has received payment for participation in advisory board for Adaptimmune. She is the principal investigator of investigator-initiated trials with AstraZeneca, Astex, and Tesaro where the funding was provided to the institution. TB has no conflicts of interest to declare., (2021 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Most patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients., Methods: We conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population., Results: Thirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56-84%) with median RFS of 21 months (95% CI, 14-40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs . 66.7%, p = 0.1551) and ≥1 (84.2% vs . 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05-0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15-0.93, p = 0.0351, respectively)., Conclusions: Adjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS., Competing Interests: The authors report following relationships with the companies, none of which has resulted in an actual or potential conflict of interest with regard to this manuscript. HM: Consulting/Advisory board – AstraZeneca, Zentalis; Travel Accommodations: AstraZeneca (IITpresentation at Immuno-oncology conference). BS: Clinical trials funding to the institution – Merck. P. Kasi: Consultancy/advisory board: Taiho (to institution), Ipsen (to institution), Foundation Medicine, Bayer, Axiom, Natera, Roche, IPBA, Merck, QED, Tempus Labs, Daiiche Sankyo, Boston Health Care, Delcath, Eli Lily; Research/Grant Funding: BMS (institution), Advanced Accelerator Applications (institution), Array Biopharma (institution), Tesaro (institution), Boston Scientific (institution), Celgene (institution); Travel Accommodations: AstraZeneca (IITpresentation at Immuno-oncology conference). SJ: Consulting/Advisory board – Adaptimmune; Clinical trials funding to the institution- AstraZeneca, Tesaro, Astex. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mamdani, Schneider, Perkins, Burney, Kasi, Abushahin, Birdas, Kesler, Watkins, Badve, Radovich and Jalal.)

The development of targeted therapies that inhibit cancer-driving oncogenes has improved outcomes of patients diagnosed with lung adenocarcinoma (LUAD). In contrast, patients diagnosed with lung squamous cell carcinoma (LUSC) suffer worse survival outcomes and lack effective targeted treatment options. Identification of molecular drivers of LUSC to support development of targeted treatments is urgently needed. Addressing this need, the current report introduces the novel cancer gene SLIT- and NTRK-like family member 3 (SLITRK3) and its role in activating the neurotrophic receptor tyrosine kinase 3 (NTRK3) in LUSC cells. Multiple genome-wide data sets from patient samples were produced by us or downloaded from public databases to analyze tumor gene copy number aberrations, mRNA expression and associated survival outcomes. An accompanying mechanistic study employed LUSC cell lines and multiple methods, including in situ immunofluorescence, sphere-formation assay, and fluorescence-activated cell sorting analysis of the CD133-positive cell fraction. Altogether, the results indicate that gene amplification and consequent high expression of SLITRK3 in LUSC is associated with worse outcomes and induces SLITRK3-dependent activation of NTRK3 to promote a cancer stem cell phenotype that is inhibited by existing NTRK-targeted inhibitors. Based on a recent literature search, this is the first report of a mechanistic role for SLITRK3 in cancer., (© 2021. The Author(s).)

Purpose: PROCLAIM-CX-2029 is a phase I first-in-human study of CX-2029, a Probody-drug conjugate targeting CD71 (transferrin receptor 1) in adults with advanced solid tumors. Although the transferrin receptor is highly expressed across multiple tumor types, it has not been considered a target for antibody-drug conjugates (ADCs) due to its broad expression on normal cells. CX-2029 is a masked form of a proprietary anti-CD71 antibody conjugated to monomethyl auristatin E, designed to be unmasked in the tumor microenvironment by tumor-associated proteases, therefore limiting off-tumor toxicity and creating a therapeutic window for this previously undruggable target., Patients and Methods: This was a dose-escalation, multicenter trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029. The primary endpoint was to determine the maximum tolerated dose (MTD) and cycle 1 dose-limiting toxicity (DLT). CX-2029 was administered i.v. every 3 weeks., Results: Forty-five patients were enrolled in eight dose levels. No DLTs were reported in the dose escalation through 4 mg/kg. At 5 mg/kg, there were two DLTs (febrile neutropenia and pancytopenia). Following expansion of the 4 mg/kg dose to six patients, two additional DLTs were observed (infusion-related reaction and neutropenia/anemia). Both the 4 and 5 mg/kg doses were declared above the maximum tolerated dose. The recommended phase II dose is 3 mg/kg. The most common dose-dependent hematologic toxicities were anemia and neutropenia. Confirmed partial responses were observed in three patients, all with squamous histologies., Conclusions: The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity. See related commentary by Oberoi and Garralda, p. 4459 ., (©2021 American Association for Cancer Research.)

Esophagogastric cancer is associated with rising incidence and high mortality. Nearly 40% of patients have metastatic disease at the time of diagnosis with poor 5-year overall survival. The treatment of squamous cell carcinoma of the esophagus and gastroesophageal adenocarcinoma has started to bifurcate in recent years, owing to the evolving understanding of the biologic and genomic characteristics of these tumors. Incorporation of HER2-directed therapy in the form of monoclonal antibody and antibody-drug conjugate is now standard of care for patients with HER2-positive disease. The addition of immune checkpoint inhibitors to the therapeutic landscape of metastatic esophagogastric cancer is associated with modest improvement in overall survival, and definition of predictive biomarkers of response to checkpoint inhibition remains imprecise. A number of therapeutic targets including FGFR2b, Claudin 18.2, DKK-1, and DNA repair defects are being explored in clinical trials. Similarly, combination immunotherapy and novel HER2-targeting agents, such as bispecific antibody and small-molecule inhibitors, are at various stages of clinical development. Despite the progress made in the field of targeted therapies and checkpoint inhibition, chemotherapy remains an integral part of treatment of metastatic esophagogastric cancer but is associated with considerable toxicity. Clinical trials focusing on minimizing toxicity of currently available therapeutic agents, development of novel biomarker-driven treatment strategies, and overcoming resistance to immune checkpoint inhibition will define the future of this traditionally indelible disease.

Epigenetic modulation, including acetylation, methylation, phosphorylation, and ubiquitination, plays a pivotal role in regulation of gene expression. Histone acetylation-a balance between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs)-is one of the key epigenetic events. Our understanding of the role of HDACs in cancer is evolving. A number of HDAC isoenzymes are overexpressed in a variety of malignancies. Aberrant histone acetylation is associated with dysregulation of tumor suppressor genes leading to development of several solid tumors and hematologic malignancies. Pre-clinical studies have demonstrated that HDAC-1 gene expression is associated with lung cancer progression. Histone hypoacetylation is associated with more aggressive phenotype in adenocarcinoma of the lung. HDAC inhibitors (HDACi) have pleiotropic cellular effects and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest, inhibit angiogenesis, and inhibit transition to a mesenchymal phenotype. Consequently, treatment with HDACi has shown anti-proliferative activity in non-small cell lung cancer (NSCLC) cell lines. Despite promising results in pre-clinical studies, HDACi have shown only modest single agent activity in lung cancer clinical trials. HDAC activation has been implicated as one of the mechanisms causing resistance to chemotherapy, molecularly targeted therapy, and immune checkpoint inhibition. Therefore, there is a growing interest in combining HDACi with these agents to enhance their efficacy or reverse resistance. In this paper, we review the available preclinical and clinical evidence for the use of HDACi in NSCLC. We also review the challenges precluding widespread clinical utility of HDACi as a cancer therapy and future directions., (Copyright © 2020 Mamdani and Jalal.)

The therapeutic landscape of lung cancer has expanded significantly over the past decade. Advancements in molecularly targeted therapies, strategies to discover and treat resistance mutations, and development of personalized cancer treatments in the context of tumor heterogeneity and dynamic tumor biology have made it imperative to obtain tumor samples on several different occasions through the course of patient treatment. While this approach is critical to the delivery of optimal cancer treatment, it is fraught with a number of barriers including the need for invasive procedures with associated complications, access to limited amount of tissue, logistical delays in obtaining the biopsy, high healthcare cost, and in many cases inability to obtain tissue because of technically difficult location of the tumor. Given multiple limitations of obtaining tissue samples, the use of blood-based biomarkers ("liquid biopsies") may enable earlier diagnosis of cancer, lower costs by avoiding complex invasive procedures, tailoring molecular targeted treatments, improving patient convenience, and ultimately supplement clinical oncologic decision-making. In this paper, we review various blood-based biomarkers including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), tumor derived exosomes, tumor educated platelets (TEPs), and microRNA; and highlight current evidence for their use in detection and treatment of lung cancer., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Hepatocellular carcinoma (HCC) is an aggressive cancer associated with high mortality worldwide. HCC develops in the setting of underlying cirrhosis due to chronic liver disease. Surgery is usually considered the treatment of choice for early disease; however, most patients have locally advanced or metastatic HCC at diagnosis in which case treatments are limited. Immune checkpoint blockade of programmed death receptor-1 (PD-1) pathway offers a potential treatment strategy based on the encouraging results of the phase I/II trial of nivolumab (Checkmate 040 trial). This has led to the off-label use of nivolumab after failure of treatment with sorafenib either due to intolerance or progression of disease. Although rare (<5%), clinical response to anti-PD-1 antibody may be preceded by "pseudoprogression" -- increase in the size and number of tumor lesions before actual tumor shrinkage. We report a case of pseudoprogression followed by an excellent response in an HCC patient treated with nivolumab and review the literature for ongoing trials of immune checkpoint blockade in HCC. The pseudoprogression in our case is supported by increase in both tumor size and alpha-fetoprotein after four treatments with nivolumab; however, regression of tumor size and normalization of alpha-fetoprotein occurred after subsequent treatments. To our knowledge, there are no reports of pseudoprogression in HCC although pseudoprogression has been well described in melanoma.

Background: Radium-223 is a bone-targeting radiopharmaceutical that extends survival in mCRPC. Postapproval data are limited, and the value of biochemical and radiologic monitoring during radium therapy is unknown., Patients and Methods: We conducted a retrospective study of 29 patients with mCRPC who received radium-223 at 1 of 3 participating institutions between August 2013 and December 2014. Trend of PSA, radiographic changes, and association of biochemical and clinical variables with PSA trend were measured., Results: The median age of patients was 70 years, 79% of patients (N = 23) were European Americans, and 17% of patients (N = 5) were African Americans. Twenty patients (69%) had received at least 3 lines of prior therapies. Some 38% of patients (N = 11) received all 6 cycles of radium-223. Twenty patients (69%) had an increase in PSA during radium therapy, and 4 patients (14%) had a decline in PSA levels. Five patients had visceral metastases on computed tomography imaging performed during the course of radium-223., Conclusions: Radium therapy in mCRPC was associated with an increase in PSA in the majority of these heavily pretreated patients. The development of visceral disease was not uncommon, suggesting a need for follow-up computed tomography monitoring during radium-223 therapy. The significance of early increases in PSA and pain with radium-223 is still uncertain. Although pain and PSA flare have been reported in patients who subsequently have a dramatic response to therapy, we observed that a PSA increase or pain flare correlates to an improvement in bone scans only in a minority of patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Older adults represent the majority of approximately 20,000 new patients diagnosed with acute myeloid leukemia (AML) in the United States each year. While the treatment goal for younger patients is to achieve a cure with intensive therapeutic protocols, including standard chemotherapy and hematopoietic stem cell transplantation, these goals are less well defined in the elderly population. This is in part due to the continuous decline in treatment outcomes with increasing age secondary to a number of patient-related and disease-specific factors, ranging from the presence of comorbid conditions to the higher frequency of adverse cytogenetic and unfavorable molecular markers. Although best supportive care, low-dose cytarabine, and epigenetic drugs represent well recognized treatment concepts, no universally accepted strategy for the management of elderly patients with AML exists. Therapeutic decisions are widely based on the patient's age, general health, the disease features, as well as the patient's personal wishes. The predicament of treating AML in the elderly population is the central theme of this review., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor of the lung with a tendency to metastasize widely early in the course of the disease. The VA staging system classifies the disease into limited stage (LS) which is confined to one hemithorax and can be included into one radiation field or extensive stage (ES) which extends beyond one hemithorax. Current standard of care is concurrent chemoradiation for LS disease and chemotherapy alone for ES disease. Only a quarter of patients with LS disease will be cured with current standard treatments and majority of the patients ultimately succumb to their disease. A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate, however, at the same time this complexity can form the basis for effective targeted therapy for the disease. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors have been unsuccessful in showing a survival advantage in this disease. Several others including DNA repair inhibitors, cellular developmental pathway inhibitors, antibody drug conjugates (ADCs), as well as immune therapy with vaccines, immunomodulators, and immune checkpoint inhibitors are being tested. So far, none of these agents are approved for use in SCLC and the majority are in phase I/II clinical trials, with immune checkpoint inhibitors being the most promising therapeutic strategy. In this article, we will discuss these novel therapeutic agents and currently available data in SCLC.

Opinion Statement: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the USA. The treatment of locally advanced NSCLC (LA-NSCLC) is challenging and must be individualized. For patients with completely resected stage III NSCLC, adjuvant cisplatin-based chemotherapy for 4 cycles is recommended. For patients with inoperable or unresectable stage III NSCLC, chemoradiation is the preferred treatment. Patients with a good performance status, minimal or no weight loss, and adequate pulmonary function should be offered concurrent chemoradiation. The optimal chemotherapeutic agents to be used concurrently with radiation remain undefined. In the USA, cisplatin plus etoposide or carboplatin plus paclitaxel are the most commonly used regimens. In addition, the optimal duration of therapy remains undefined, including the role of consolidation chemotherapy. Thus far, randomized phase III trials have failed to identify a survival advantage for administering chemotherapy beyond that delivered during radiation therapy. Molecularly targeted agents, angiogenesis inhibitors, and immunotherapy have a defined role for patients with metastatic disease. The role, if any, of these new classes of agents is undergoing investigation for patients with earlier stage disease, including stage III disease.

Patients with nephrotic syndrome, particularly those with membranous nephropathy tend to be in a hypercoagulable state and often present with thromboembolic phenomena. The association of nephrotic syndrome with a bleeding diathesis however is much less common and the etiologies less well recognized. We report a patient who presented with coagulopathy and recurrent spontaneous hemorrhage in association with nephrotic syndrome. The case highlights key diagnostic and therapeutic challenges and strategies: 1) work up to establish a unifying etiology for both nephrotic syndrome and the bleeding disorder; 2) decision making to obtain a tissue biopsy, select the site of biopsy and understand the relative yields for each site; 3) recognizing the risk and managing peri-procedural bleeding; and 5) developing a treatment strategy with the lowest risk of possible complications. Our patient underwent a kidney biopsy without any complications and a definitive diagnosis of AL amyloidosis was reached. He was treated with anti-plasma cell chemotherapy followed by autologous stem cell transplant with resultant complete hematologic response, improved coagulation parameters, and no further bleeding.

Background: Early diagnosis of autism spectrum disorders (ASD) is of crucial importance, but lengthy delays are common. We examined whether this issue could be reliably addressed by local teams trained by a specialist ASD assessment team., Method: Four local teams were trained in diagnostic assessment. Their assessments of 38 children and young people using the Autism Diagnostic Observation Schedule-Generic (ADOS-G) were video recorded and independently assessed by the specialist team., Results: There was a high level of correspondence between the diagnoses of the local teams and of the specialist team. The number of assessments carried out increased and there was a considerable reduction in waiting times., Conclusion: This study has demonstrated the potential feasibility of creating local, multi-agency ASD assessment teams, which will serve to reduce waiting times, improve clinical skills at a lower level of specialism and thereby improve the overall quality of ASD services.

A system is reported for the recombinant expression of individual ketoreductase (KR) domains from modular polyketide synthases (PKSs) and scrutiny of their intrinsic specificity and stereospecificity toward surrogate diketide substrates. The eryKR(1) and the tylKR(1) domains, derived from the first extension module of the erythromycin PKS and the tylosin PKS, respectively, both catalyzed reduction of (2R, S)-2-methyl-3-oxopentanoic acid N-acetylcysteamine thioester, with complete stereoselectivity and stereospecificity, even though the substrate is not tethered to an acyl carrier protein or an intact PKS multienzyme. In contrast, and to varying degrees, the isolated enzymes eryKR(2), eryKR(5), and eryKR(6) exercised poorer control over substrate selection and the stereochemical course of ketoreduction. These data, together with modeling of diketide binding to KR(1) and KR(2), demonstrate the fine energetic balance between alternative modes of presentation of ketoacylthioester substrates to KR active sites.