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Shivani C Patel,1 Jonathan E Dowell1,2 1Division of Hematology and Oncology, University of Texas Southwestern, 2Section of Hematology and Oncology, Veterans Affairs North Texas Healthcare System, Dallas, TX, USA Abstract: Malignant pleural mesothelioma (MPM) is a deadly disease that produces a significant worldwide health care burden. The majority of cases are associated with prior asbestos exposure, but recent studies have identified a possible genetic predisposition in a minority of patients. Historically, obtaining a pathologic diagnosis of MPM was challenging, but with current pathological techniques, a secure diagnosis is possible in the majority of patients. Curative therapy for MPM remains elusive, and the primary treatment option for fit patients is platinum-based chemotherapy. Encouraging recent reports suggest that there may be a benefit to the addition of bevacizumab to standard chemotherapy as well as with the use of immune checkpoint inhibitors in MPM. Selected patients may be considered for aggressive surgical approaches, but there is considerable controversy regarding the true benefit of surgery and multimodality therapy in this disease. Keywords: mesothelioma, asbestos, chemotherapy, surgery

Purpose: The purpose of this study was to evaluate the incidence of acute renal failure (ARF) in patients with mild to moderate renal dysfunction, receiving renally adjusted zoledronic acid (ZA) and compare it to patients with normal baseline renal function, receiving standard-dose ZA.Methods: This was a retrospective study of patients receiving ZA for the treatment of bone metastasis due to cancer. Patients were divided into two groups: (1) normal group with baseline creatinine clearance (CrCl) of greater than 60 mL/min and standard ZA dose; (2) impaired group with baseline CrCl of 30-60 mL/min and renally adjusted ZA dose. Primary endpoint of ARF was defined as an increase in serum creatinine (SCr) of 0.5 mg/dL or 1.0 mg/dL from a baseline SCr of <1.4 mg/dL or ≥ 1.4 mg/dL, respectively.Results: In total, 1,472 evaluable doses of ZA were given to 220 patients. Of these, 184 patients were in the normal group and 36 patients in the impaired group. There were 38 patients (20.7%) who developed ARF in the normal group versus 7 patients (19.4%) in the impaired group. There was no difference in the mean time to the incidence of ARF at 6.1 months in both groups. Incidence of ARF based on CrCl (≥ 25% decline in CrCl) was similar between groups (39.1% vs. 41.7%; p = 0.78).Conclusion: The incidence of ARF is similar between patients in the normal group and impaired group when the ZA dose is renally adjusted. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer is the most common cancer in men in the United States with low survival rates once metastasized. Abiraterone is approved for use in castrate-sensitive and castrate-resistant prostate cancer and is used extensively in the Veterans Affairs (VA) healthcare system. Spironolactone, a diuretic used to treat heart failure, edema, ascites, and hypertension, may increase androgen levels and reduce effectiveness of abiraterone when used concurrently to treat prostate cancer patients. While previous case studies support this, no large epidemiology studies have been conducted. The current study utilizes the large, VA prostate cancer data core and evaluates the effect of concomitant spironolactone on efficacy of abiraterone treatment in metastatic prostate cancer patients., Patients and Methods: The study selected 18,943 veterans with metastatic prostate cancer on abiraterone treatment. Of these, 581 patients (3.1%) were also on concomitant spironolactone. The concomitant treatment group, abiraterone + spironolactone, significantly differed from the abiraterone-only group in body mass index, prevalence rates of heart failure and liver disease, and being previously treated with docetaxel. A 1:1 propensity score matching method was used to balance sample sizes and baseline traits between the two treatment groups, abiraterone versus abiraterone + spironolactone. Kaplan-Meier curves and Cox proportional hazard model were used to compare 5-year overall survival and all-cause mortality outcomes, respectively, between the two groups., Results: After propensity score matched, the abiraterone + spironolactone group was treated with abiraterone significantly longer than the abiraterone-only group (mean ± standard deviation days 549.0 ± 552.3 vs. 435.5 ± 474.1; p = 0.0002) and had a higher 5-year overall survival rate (44% vs. 37%; p = 0.0116). Veterans with metastatic prostate cancer treated with abiraterone + spironolactone also had a lower 5-year all-cause mortality compared to those only on abiraterone (hazard ratio 0.80, 95% confidence intervals 0.61-0.96; p = 0.012)., Conclusion: This large VA observational study suggests that concomitant use of spironolactone does not compromise cancer control or survival of metastatic prostate cancer patients treated with abiraterone., (© 2024 The Author(s). The Prostate published by Wiley Periodicals LLC.)

Purpose: Consolidative durvalumab, an anti-programmed death ligand 1 (PDL1) immune checkpoint inhibitor, administered after concurrent chemoradiation improves outcomes of patients with locally advanced non-small cell lung cancer (NSCLC) without substantially increasing toxicities. We studied a chemotherapy-free regimen of thoracic radiation therapy (RT) with concurrent and consolidative durvalumab., Methods and Materials: This single-arm phase 2 trial enrolled patients with stage III NSCLC (regardless of tumor PDL1 expression), Eastern Cooperative Oncology Group (ECOG) performance status 0-1, adequate pulmonary function, and RT fields meeting standard organ constraints. Participants received 2 cycles of durvalumab (1500 mg every 4 weeks) concurrently with thoracic RT (60 Gy in 30 fractions), followed by up to 13 cycles of consolidative durvalumab., Results: After 10 patients were enrolled, the trial was closed because of poor clinical outcomes. With a median follow-up of 12 months, 5 patients had disease progression and 8 patients died. Six patients experienced 15 treatment-related, grade ≥3 events, including 1 grade 4 acute kidney injury during consolidation and 2 fatal pulmonary events. One fatal pulmonary event occurred during the concurrent phase in an active smoker; the other occurred after the first cycle of consolidative durvalumab. The primary endpoint of progression-free survival at 12 months was 20% (50% for PDL1≥1% vs 0% for PDL1 unavailable or <1%). Median overall survival was not reached, 10.5 months, and 7 months, for PDL1 ≥1%, <1%, and unavailable, respectively., Conclusions: In PDL1 unselected stage III NSCLC, thoracic RT plus concurrent and consolidative durvalumab is associated with high-grade toxicity and early disease progression., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.

Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI., Methods: Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women)., Results: Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P =1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 ( P =0.05) and multi-organ ( P =0.02) irAE., Conclusions: In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other., Competing Interests: The 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 © 2024 von Itzstein, Yang, Wang, Hsiehchen, Sheffield, Fattah, Popat, Ahmed, Homsi, Dowell, Rashdan, Lohrey, Hammers, Hughes, Wang, Xie and Gerber.)

Introduction: The KRAS G12C inhibitor sotorasib was approved for treating advanced NSCLC in the second line or later on the basis of the CodeBreaK100 trial. Nevertheless, data on the real-world efficacy and safety of sotorasib, and to its optimal dose, remain limited., Methods: Patients treated with sotorasib for NSCLC through the Veterans Health Administration were retrospectively identified from the Corporate Data Warehouse. Survival, response, and toxicity data were obtained from chart review., Results: Among the 128 patients treated with sotorasib through the Veterans Health Administration, objective response rate was 34%, progression-free survival (PFS) six months, and overall survival 12 months. Similar PFS was observed among the 16 patients who received frontline sotorasib without any prior systemic therapy for NSCLC. Toxicity leading to sotorasib interruption or dose reduction occurred in 37% of patients, whereas sotorasib discontinuation for toxicity occurred in 25%. Notably, sotorasib dose reduction was associated with substantially improved PFS and OS., Conclusions: In this real-world study, the observed efficacy of sotorasib was similar to the results of CodeBreaK100. Patients who received frontline sotorasib had similar PFS to our overall cohort, suggesting that first-line sotorasib monotherapy may benefit patients who are not eligible for chemotherapy. Toxicities leading to sotorasib interruption, dose reduction, or discontinuation were common. Sotorasib dose reduction was associated with improved survival, suggesting that sotorasib dose reduction may not compromise efficacy., Competing Interests: Dr. Lin reported serving as a consultant for Rigel and on the advisory board of Autolus. Dr. Dowell participated in advisory boards for Mirati, Astra Zeneca, Catalyst, and Takeda. Dr. Kelley reported research funding (paid to his institution) from 10.13039/100004336Novartis, 10.13039/100002491Bristol-Myers Squibb, 10.13039/100009857Regeneron, and Mirati Therapeutics. The remaining authors declare no conflict of interest.

Introduction: Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors., Methods: Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively., Results: Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p  = 0.029 and odds ratio = 1.90, p  = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively)., Conclusions: Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy., Competing Interests: Dr. McCoach reports working as an employee at Genentech. Dr. G. Liu reports receiving institutional grants from NCI, CIHR, CCSRI, AstraZeneca, 10.13039/100016040Takeda, Boehringer Ingelheim, AMGEN, EMD Serono, 10.13039/100004319Pfizer, and 10.13039/100004326Bayer; receiving personal honoraria from AstraZeneca, Pfizer, EMD Serono, and Takeda; and participating on the Data Safety Monitoring Board/Advisory Board for AstraZeneca, Pfizer, EMD Serono, Merck, AbbVie, Jazz, Takeda, Anheart, Roche, Bristol-Myers Squibb, Novartis, and Lilly. Dr. Nieva reports receiving institutional grants from 10.13039/100004328Genentech and Merck; receiving consulting fees from ANP Technologies, Aadi Biosciences, AstraZeneca, BioAtla, G1 Therapeutics, Genentech, Mindmed, Naveris, and Sanofi; receiving travel support from 10.13039/100004325AstraZeneca; having a patent planned with Cansera; participating on the Data Safety Monitoring Board/Advisory Board for Kalivir; and having stock in Amgen, Novartis, Johnson & Johnson, and Cansera. Dr. Marrone reports receiving grants from 10.13039/100016957Mirati Therapeutics and Bristol-Myers Squibb; receiving consulting fees from Daiichi Sankyo, Regeneron, Janssen, Mirati, Amgen, and AstraZeneca; receiving honoraria from Merck, Regeneron, Bristol-Myers Squibb, and AstraZeneca; and participating on the Data Safety Monitoring Board/Advisory Board for Puma. Dr. Lam reports receiving grants from 10.13039/100002491Bristol-Myers Squibb, Merck, SeaGen, and AstraZeneca; receiving consulting fees from SeaGen, Bristol-Myers Squibb, AstraZeneca, Guardant Health, Takeda, and Anheart Therapeutics; and participating on the Data Safety Monitoring Board/Advisory Board for Iovance Therapeutics. Dr. Velcheti reports receiving consulting fees from Bristol-Myers Squibb, Merck, OnCOC4, AstraZeneca, Roche, Novocure, Takeda, Taiho, and Regeneron. Dr. S. Liu reports receiving institutional grants from 10.13039/100006483AbbVie, 10.13039/100018529Alkermes, AstraZeneca, Elevation Oncology, Ellipses, Genentech, Gilead, Merck, Merus, Nuvalent, OSE Immunotherapeutics, Puma, RAPT, and Turning Point Therapeutics; receiving consulting fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, Daiichi Sankyo, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Pfizer, RAPT, Regeneron, Revolution Medicines, Sanofi, and Takeda; and participating on a Data Safety Monitoring Board/Advisory Board for Candel Therapeutics. Dr. Patil reports receiving research funding from 10.13039/100004755EMD Serono, 10.13039/100005565Janssen, and 10.13039/100005564Gilead; receiving consulting fees from AstraZeneca, Biocept, Boehringer Ingelheim, Bristol-Myers Squibb, Bicara, Caris, Daiichi, Guardant Health, Guidepoint, EMD Serono, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Natera, Pfizer, Sanofi, Regeneron, Roche/Genentech, and Takeda; and participating on the Data Safety Monitoring Board/Advisory Board for Elevation Oncology. Dr. Weiss reports receiving institutional grants from AstraZeneca, 10.13039/100019799G1, Loxo/10.13039/100019518Lilly, Mirati, SDP, BI, and PDS; receiving consulting fees from AZD, EMD Serono, Genentech, G1, Jounce, AbbVie, Nanobiotix, Merck, Sanofi, Gilead, PDS, and AMGEN; participating on a Data Safety Monitoring Board or Advisory Board for Jounce and Beigene; having a leadership or fiduciary role for Cancergrace; and having stock/stock options for Nektar, Vesselon, Achilles, Nuvalent, Lyell, En Fuego, and Vertex. Dr. Dowell reports receiving consulting fees from Takeda, Catalyst, Beigene, and Janssen. Dr. Villaruz reports receiving consulting fees from Sanofi, Gilead, Johnson & Johnson, EMD Serono, Daiichi Sankyo, AstraZeneca, and Janssen. Dr. Cass reports receiving honoraria from OncLive, Medscape, and PharmacyTimes; and participating on the Data Safety Monitoring Board/Advisory Board for G1 Therapeutics, Takeda, and Regeneron. Dr. Iams reports receiving consulting fees from OncLive, Clinical Care Options, Chardan, Cello Health, and Curio Science; and participating on the Data Safety Monitoring Board/Advisory Board for Genentech, Mirati, Outcomes Insights, Jazz Pharmaceuticals, G1 Therapeutics, Takeda, AstraZeneca, Sanofi, Janssen, Amgen, Bristol Myers Squibb, and NovoCure. Dr. Aisner reports receiving consulting fees from Merus, Genentech, Bayer, AbbVie, and AstraZeneca; receiving support for attending meetings from AstraZeneca; and serving as Chair of Board for Genomics Organization for Academic Laboratories. Dr. Aggarwal reportsreceiving consulting fees from Genentech, Lilly, Merck, AstraZeneca, Daiichi Sankyo, Sanofi/Regeneron, Pfizer, Janssen, Boehringer-Ingelheim, Takeda, Arcus Biosciences, Mirati Therapeutics, Gilead Sciences, Novocure, AbbVie, and Jazz Pharmaceuticals; receiving speaking fees from AstraZeneca and Roche/Genentech; and receiving research funding from 10.13039/100004334Merck Sharp & Dohme, AstraZeneca/10.13039/501100004628MedImmune, 10.13039/501100022274Daiichi Sankyo, Loxo@Lilly, and Candel Therapeutics. Dr. Camidge reports receiving honoraria for consulting from AbbVie, Anheart, Beigene, Eli Lilly, Immunocore, Janssen, Prelude, Seattle Genetics, Valence, Appolomics, AstraZeneca/Daiichi, Dizal, EMD Serono, Elevation, Hengrui, Hummingbird, Medtronic, Mersana, Mirati, Nalo Therapeutics, Onkure, Regeneron, Roche, Sanofi, Takeda, Theseus, and Xcovery. Dr. Marmarelis reports receiving research funding from Eli Lilly, AstraZeneca, and Merck; receiving consulting fees from AstraZeneca, Novocure, Boehringer Ingelheim, Janssen, Takeda, Blueprint Pharmaceuticals, Bayer, Bristol Myers Squibb, Ikena, and Regeneron; receiving honoraria from Thermo Fisher; and having stock in Merck and Johnson & Johnson. Dr. Sun reports receiving honoraria from Bayer and participating on the Data Safety Monitoring Board/Advisory Board for Seagen, Sanofi Genzyme, and Regeneron. The remaining authors declare no conflict of interest., (Crown Copyright © 2024 Published by Elsevier Inc. on behalf of the AGA Institute.)

Background: Approximately 30-40% of patients with advanced and metastatic non-small cell lung cancer (NSCLC) present with an impaired performance status (PS). There are limited prospective data on the safety and efficacy of durvalumab in these patients., Methods: In this single-arm phase II clinical trial (NCT02879617), patients with previously untreated Stage IIIB/IV NSCLC and ECOG PS of 2 received durvalumab 1500 mg every 28 days until progression or unacceptable toxicity. The primary endpoints were overall survival (OS) and safety determined by grade ≥3 treatment-related adverse events (TRAEs)., Findings: Between April 2017 and March 2021, 50 patients were enrolled, of whom 47 received durvalumab. With a median follow-up of 28 months, median OS was 6 months (95% CI 4-10). TRAEs grade 3 occurred in nine of 47 patients (19%, 95% CI 9%-33%). OS in patients with a PD-L1 TPS of 0, 1-49%, and ≥50% was six months (95% CI 3-15), 11 months (95% CI 4-16), and 11 months (95% CI 0-not reached (NR)), respectively. Health related quality of life (HQRL) assessed at baseline and during therapy demonstrated no statistically significant change over the course of treatment., Interpretation: This study demonstrates that single agent durvalumab is safe and well tolerated in the 1st line treatment of patients with advanced NSCLC and ECOG PS of 2, with an encouraging OS benefit in patients with PD-L1 positive tumors. This trial is amongst the largest prospective studies evaluating durvalumab in the 1st line treatment of advanced stage NSCLC and a PS of 2., Funding: AstraZeneca, NCI P30CA047904., Competing Interests: L.C.V. declares research funding from Janssen, BMS, Merck, Regeneron, GSK, AstraZeneca, BioAtla, Black Diamond Therapeutics, Jazz, Genentech, and Beigene and consulting with compensation with Takeda, Janssen, Intervenn Biosciences, Sanofi, Daiichi Sankyo, Jazz, BMS, and Gilead. D.M. declares consulting with fees from AstraZeneca, Beigene, Cardinal Health, Daiichi Sankyo, Janssen, and Karyopharm. M.A.S. declares research funding from Genentech, Spectrum, Novartis, AstraZeneca, Daiichi-Sankyo, Beigene, Cullinan, Mirati, and Pfizer, speaker bureau fees from Genentech, AstraZeneca, Lilly, Janssen, G1 Therapeutics, BMS, Guardant, Regeneron and participation in steering committee/advisory board membership with Lilly, Beigene, Genentech, Mirati, and Spectrum. J.E.D. declares steering committee/advisory board membership with Janssen, Beigene, Astra Zeneca, Catalyst, Takeda, Oncohost. D.E.G. declares research funding from Astra-Zeneca, BerGenBio, Karyopharm, Novocure, consulting fees from Astra-Zeneca, Catalyst Pharmaceuticals, Daiichi-Sankyo, Elevation Oncology, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, U.S. patent applications 16/487,335, 17/045,482, 63/386,387, 63/382,972, 63/382,257, stock options with Gilead, Medtronic, Walgreens, and Co-founder and Chief Scientific Officer, OncoSeer Diagnostics, LLC. The other authors declare that they have no competing financial interests., (© 2023 The Author(s).)

Introduction: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab., Methods: This is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response., Conclusion: This phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Preclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI., Methods and Materials: Pre- and post-ICI blood samples were collected from patients enrolled in a prospective immunotherapy biospecimen protocol. Mutiplex panels of 40 cytokines and 120 autoantibodies (Ab) were analyzed. We identified differences in these parameters according to receipt, timing, and type of prior RT. We calculated P values using the Pearson product-moment correlation coefficient and false discovery rate (FDR) using the Benjamini-Hochberg Procedure., Results: Among 277 total patients, 69 (25%) received RT in the 6 months prior to ICI initiation. Among RT-treated patients, 23 (33%) received stereotactic RT, and 33 (48%) received curative intent RT. There was no significant difference in demographics or type of immunotherapy between patients according to prior RT exposure. Baseline complement C8 Ab and MIP-1d/CCL15 were significantly higher among patients with prior RT. For MIP-1d/CCL15, only prior stereotactic RT was associated with significant differences., Conclusions: Prior RT is associated with few changes in systemic immune parameters in patients receiving ICI. The underlying mechanisms and optimal approach to harnessing the potential synergy of RT and ICI require further prospective clinical investigation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: US Patent Applications 16/487335 and 17/045482 PREDICTION AND TREATMENT OF IMMUNOTHERAPEUTIC TOXICITY (to Farjana Fattah., Yang Xie., Jason Park., Quan-Zhen Li., Edward K. Wakeland., and David E. Gerber)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: AXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC., Materials and Methods: Escalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m 2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured., Results: 21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7-10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m 2 with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes., Conclusion: Bemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers., (© 2022. The Author(s).)

Antibiotic administration is associated with worse clinical outcomes and changes to the gut microbiome in cancer patients receiving immune checkpoint inhibitors (ICI). However, the effects of antibiotics on systemic immune function are unknown. We, therefore, evaluated antibiotic exposure, therapeutic responses, and multiplex panels of 40 serum cytokines and 124 antibodies at baseline and six weeks after ICI initiation, with p < 0.05 and false discovery rate (FDR) < 0.2 considered significant. A total of 251 patients were included, of whom the 135 (54%) who received antibiotics had lower response rates and shorter survival. Patients who received antibiotics prior to ICI initiation had modestly but significantly lower baseline levels of nucleolin, MDA5, c-reactive protein, and liver cytosol antigen type 1 (LC1) antibodies, as well as higher levels of heparin sulfate and Matrigel antibodies. After ICI initiation, antibiotic-treated patients had significantly lower levels of MDA5, CENP.B, and nucleolin antibodies. Although there were no clear differences in cytokines in the overall cohort, in the lung cancer subset (53% of the study population), we observed differences in IFN-γ, IL-8, and macrophage inflammatory proteins. In ICI-treated patients, antibiotic exposure is associated with changes in certain antibodies and cytokines. Understanding the relationship between these factors may improve the clinical management of patients receiving ICI.

Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G 1 -phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling., (©2021 The Authors; Published by the American Association for Cancer Research.)

Patients with small cell lung cancer (SCLC) are more likely to have synchronous brain metastasis (SBM) at the time of diagnosis than patients with any other extracranial primary malignancy. We sought to identify which factors predicted an increased risk of SBM in SCLC as well as which factors affected the prognosis of these patients. 38,956 Patients in the Surveillance, Epidemiology, and End Results (SEER) database with microscopically confirmed SCLC from 2010 to 2016 were identified. 6264 (16.1%) Patients with SCLC had SBM at the time of diagnosis. In the multivariable logistic regression, disease specific factors that were predictive of SBM were primary tumor size > 7 cm (adjusted OR = 1.14, 95% CI [1.02, 1.28], p = 0.02), synchronous lung metastases, and synchronous bone metastases. Demographic specific factors predictive of increased SBM risk in this model were younger age, male sex, and race (American Indian/Alaska Native and black patients). Patients insured through Medicaid were less likely to present with SBM. In the multivariate Cox proportional hazards model, lack of insurance was the strongest predictor of mortality (adjusted HR = 1.47, 95% CI [1.26, 1.73], p < 0.001). Other factors associated with an increased risk of mortality include male sex, older age, health insurance coverage through Medicaid, synchronous liver metastasis, synchronous lung metastasis, and primary tumor size > 7 cm. In contrast, Asian patients had a lower risk of mortality. This study identifies risk factors for SBM among patients with SCLC, as well as indicators of prognosis among this patient population.

Background: Bavituximab, an immunomodulator, targets phosphatidylserine (PS), a membrane lipid externalized on tumor and endothelial cells in response to sorafenib., Objective: The objective of this phase II study was to assess the efficacy of combination bavituximab and sorafenib in advanced hepatocellular carcinoma (HCC)., Methods: In this single-arm phase II study, patients with HCC determined to be unresectable with Eastern Cooperative Oncology Group (ECOG) score ≤ 2, Child-Pugh score A/B7 received intravenous bavituximab 3 mg/kg weekly and oral sorafenib 400 mg twice daily until disease progression or intolerable toxicity. We investigated time to progression (TTP) for patients receiving combination bavituximab and sorafenib compared with that for sorafenib-only historical controls., Results: In total, 38 patients were accrued. The median follow-up was 6.1 months. Patient characteristics were as follows: median age 61 years; male 82%; hepatitis C virus 79%; Black 39%, Hispanic 26%, White 29%; previous treatment 39%; macrovascular invasion 84%; and extrahepatic metastases 24%. The median TTP was 6.7 months (95% confidence interval [CI] 4-17). The median overall survival was 6.1 months (95% CI 5-8), and the median disease-specific survival was 8.6 months (95% CI 6-14). Two patients experienced partial responses; none had a complete response. The disease control rate was 58%. Treatment-related adverse events were observed in 63% of patients, with the most commonly reported therapy-related symptoms being diarrhea (32%), fatigue (26%), and anorexia (24%)., Conclusions: The efficacy of adding bavituximab to sorafenib for the treatment of advanced HCC was inconclusive; however, the combination regimen did not exacerbate toxicities associated with single-agent sorafenib. CLINICALTRIALS., Gov Identifier: NCT01264705.

Primary pericardial mesothelioma (PPM) is a rare cancer for which there is no consensus on treatment. We evaluated and summarized a large contemporary population of published PPM cases to characterize risk factors, treatment patterns, and clinical outcomes. Using Ovid and PubMed, literature published from 2000 through 2016 was searched using the terms "primary pericardial mesothelioma," "pericardial mesothelioma," and "malignant pericardial mesothelioma." We identified 6 case series and 84 case reports for a total of 103 PPM cases published from 2000 through 2016. The median age at diagnosis was 55 years, and the median overall survival was 6 months. In univariate analyses of clinical characteristics including gender, asbestos exposure, tobacco use, prior radiation exposure, histologic subtype, and metastasis and/or mediastinal spread, only the presence of metastasis and/or mediastinal spread was a significant predictor of decreased survival (P = .015). Surgery did not provide a statistically significant survival benefit (P = .12). A survival benefit was noted in those who received chemotherapy (median survival, 13 months vs. 0.5 months, P = .002), specifically chemotherapy with a platinum agent with or without pemetrexed. In multivariate analysis, only the receipt of chemotherapy was associated with improved survival. PPM remains a rare and poorly understood malignancy with unclear etiology and a poor prognosis. In this retrospective systematic review, a survival benefit was seen in patients who received chemotherapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a β-lapachone (β-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death., Methods: We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200)., Results: A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m 2 as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06)., Conclusions: ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.

Importance: Patterns-of-failure studies suggest that in metastatic non-small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited., Objective: To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non-progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS)., Design, Setting, and Participants: This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy., Interventions: Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy., Main Outcomes and Measures: The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival., Results: A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy-alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy-alone arm (P = .01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly., Conclusions and Relevance: Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings., Trial Registration: clinicaltrials.gov Identifier: NCT02045446.

Malignant pleural mesothelioma (MPM) is a rare, but aggressive cancer. Surgery and radiation offer limited benefit, and systemic chemotherapy remains the primary treatment modality for the majority of patients. Vascular endothelial growth factor (VEGF) and its receptor have been recognized as important players in the biology of this disease. Bevacizumab is a monoclonal antibody that binds VEGF and blocks its interaction with the VEGF receptor. Recent studies have shown benefit with the addition of bevacizumab to the combination of cisplatin and pemetrexed in MPM. This combination is now included in the National Comprehensive Cancer Network guidelines (with a category 2A recommendation) as a possible first-line treatment for unresectable MPM in appropriately selected patients. This review discusses the rationale behind the use of bevacizumab in MPM, as well as summarizes the pharmacology, efficacy, safety, and toxicity of bevacizumab across multiple trials. The use of small-molecule inhibitors of angiogenesis in the treatment of MPM is also discussed., Competing Interests: Disclosure Dr JE Dowell receives research funding from Astex, Medimmune, and Taiho. PA Levin reports no conflicts of interest in this work.

Purpose: Preclinical studies demonstrated anti-tumor efficacy of the combination of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in non-small cell lung cancer (NSCLC) models that were insensitive to erlotinib monotherapy. We therefore studied this combination in a phase 1 clinical trial in previously treated advanced NSCLC., Methods: Romidepsin (8 or 10mg/m(2)) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150 mg orally daily), with romidepsin monotherapy lead-in during Cycle 1. Correlative studies included peripheral blood mononuclear cell HDAC activity and histone acetylation status, and EGFR pathway activation status in skin biopsies., Results: A total of 17 patients were enrolled. Median number of prior lines of therapy was 3 (range 1-5). No cases had a sensitizing EGFR mutation. The most common related adverse events were nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%). Dose-limiting nausea and vomiting occurred at the romidepsin 10 mg/m(2) level despite aggressive antiemetic prophylaxis and treatment. Among 10 evaluable patients, the best response was stable disease (n=7) and progressive disease (n=3). Median progression-free survival (PFS) was 3.3 months (range 1.4-16.5 months). Prolonged PFS (>6 months) was noted in a KRAS mutant adenocarcinoma and a squamous cell cancer previously progressed on erlotinib monotherapy. Romidepsin monotherapy inhibited HDAC activity, increased histone acetylation status, and inhibited EGFR phosphorylation., Conclusions: Romidepsin 8 mg/m(2) plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Cyclooxygenase 2 (COX-2)-dependent signaling represents a potential mechanism of resistance to therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This is mediated in part through an EGFR-independent activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) by prostaglandin E2 (PGE2). PGE2 promotes downregulation of E cadherin and epithelial to mesenchymal transition. The current study investigated EGFR and COX-2 inhibition in patients with non-small cell lung cancer (NSCLC) and elevated baseline urinary metabolite of PGE2 (PGEM)., Methods: Patients with stage IIIB/IV (AJCC 6th edition) NSCLC who progressed after at least 1 line of therapy or refused standard chemotherapy were randomized to receive erlotinib and celecoxib versus erlotinib and placebo. The primary endpoint was progression-free survival (PFS) with 80% power to detect a 50% improvement with a 1-sided significance level of .2 in the intent-to-treat and elevated baseline PGEM populations. Secondary endpoints included response rate, overall survival, and evaluation of molecular markers to assess targeting COX-2-related pathways and evaluate EGFR tyrosine kinase inhibitor resistance., Results: A total of 107 patients were enrolled with comparable baseline characteristics. Among the patients treated with celecoxib, those with wild-type EGFR were found to have an increased PFS (3.2 months vs 1.8 months; P = .03). PFS was numerically improved among patients in the intent-to-treat group who received erlotinib and celecoxib compared with those treated with erlotinib and placebo (5.4 months vs 3.5 months; P = .33) and was increased in patients in the erlotinib and celecoxib arm with elevated baseline PGEM (5.4 months vs 2.2 months; P = .15). Adverse events were similar in both treatment arms., Conclusions: The combination of erlotinib and celecoxib did not appear to improve outcomes in an unselected population, but selection by elevated baseline PGEM led to an increase in PFS with this combination. Patients with EGFR wild-type status may benefit from the combination of erlotinib and celecoxib., (© 2015 American Cancer Society.)

Background: Nitric oxide donors decreased cell survival in vitro and tumor load in vivo in models of rectal cancer subjected to ionizing radiation. Nitroglycerin (NTG) transdermal patches, added to chemotherapy, have been shown to improve outcomes in lung cancer patients., Methods: This open-label, nonrandomized, multicohort, dose escalation, phase I trial had a primary endpoint to evaluate the safety, tolerability, feasibility, dose-limiting toxicity and maximum tolerated dose of topical NTG in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of locoregionally advanced operable rectal cancer. The secondary endpoint was rate of pathologic complete response (pCR). Patients were assigned to 3 sequential cohorts of escalating dose levels of commercially available NTG patches (0.2, 0.4, and 0.6 mg/h), each cohort was intended to consist of 3 patients., Results: Thirteen patients were enrolled in the trial as specified in the dose escalation protocol. They were all male with a median age of 59.4 ± 2.5 (SEM) years. The observed toxicities were mild to moderate and manageable. Four patients developed asymptomatic grade 3 lymphopenia during the chemoradiation that resolved promptly upon completion. One patient had a non-ST segment elevation MI and 1 patient developed diarrhea. None of these toxicities were attributed to NTG except for 1 patient who developed a grade 3 headache. This required an additional group of patients at the same dose and no other patient experienced headaches. pCR was 17%., Conclusion: NTG patches are well-tolerated and it is feasible to proceed with a phase II trial at the maximum dose examined (0.6 mg/h)., (Published by Elsevier Inc.)

Background: A previous study has shown that shorter bevacizumab infusions (0.5 mg/kg/min) can be safely administered without increasing the risk of infusion-related hypersensitivity reactions (HSRs). However, the risk of proteinuria and hypertension in patients receiving shorter infusions of bevacizumab is undetermined., Patients and Methods: This was a multicenter, prospective, observational study in patients receiving <10 mg/kg of bevacizumab infused over 0.5 mg/kg/min. Patients were observed until discontinuation of bevacizumab for progression of cancer or toxicity. The incidence of hypertension and proteinuria was compared with a prior cohort of patients who had received standard duration infusions of bevacizumab., Results: Sixty-three patients received a total of 392 doses of shorter bevacizumab infusions. Nineteen (30.2%) patients experienced proteinuria while receiving bevacizumab. Out of 19 patients, 13 had grade 1 and 6 had grade 2 proteinuria. None of the patients experienced grade 3 or 4 proteinuria. Hypertension was reported in 32 (50.8%) patients receiving bevacizumab. Twelve (19%) patients developed grade 3 or greater hypertension on bevacizumab. The incidence of proteinuria and hypertension was 38.3% and 56.6%, respectively, in patients (N = 120, 1347 infusions) receiving standard duration infusions of bevacizumab., Conclusions: Shorter bevacizumab infusions (0.5 mg/kg/min) do not increase the risk of proteinuria and hypertension.

Purpose: Peripherally inserted central catheters (PICCs) are often used in place of mediport catheters because of cost and lack of operating room time and to prevent delays in therapy. One common complication associated with their use is upper extremity venous thrombosis (UEVT). The purpose of this study was to ascertain risk factors associated with an increased risk of PICC-associated UEVT in patients with cancer., Methods: Retrospective analysis identified 237 patients with cancer who received PICCs at the Dallas Veterans Affairs Medical Center from 2006 to 2009. We analyzed many risk factors, including PICC infection (PI), use of erythropoiesis-stimulating agents (ESAs), antiplatelet agents (APAs), treatment dose anticoagulation (TDA), and bevacizumab., Results: Of 237 patients, 36 (15%) were found to have UEVT. Stepwise logistic regression analysis showed risk factors positively associated with UEVT were use of ESAs (odds ratio [OR], 10.66; 95% CI, 2.25 to 50.49), hospitalization (OR, 2.38; 95% CI, 1.05 to 5.39), PI (OR, 2.46; 95% CI, 1.03 to 5.86), and TDA (OR, 8.34; 95% CI, 2.98 to 23.33), whereas patients receiving APAs had a lower risk of UEVT (OR, 0.25; 95% CI, 0.07 to 0.92)., Conclusion: Specific factors significantly increase the risk of UEVT in patients with cancer with PICCs, whereas use of APAs seems to have a protective effect against UEVT. These results may aid in the development of a predictive model for identifying patients at high risk of UEVT who may benefit from APAs, as well as in determining preventive strategies for reducing the risk of PICC-associated UEVT.

Introduction: Malignant mesothelioma (MM) cells express the vascular endothelial growth factor (VEGF) receptor, and VEGF protein expression is detected in a majority of human mesothelioma biopsy specimens. Bevacizumab is a recombinant humanized monoclonal antibody that blocks the binding of VEGF to its receptor. We evaluated the addition of bevacizumab to cisplatin and pemetrexed as first-line treatment in patients with advanced, unresectable MM., Methods: Previously untreated MM patients with advanced, unresectable disease received cisplatin (75 mg/m(2)), pemetrexed (500 mg/m(2)), and bevacizumab (15 mg/kg) intravenously every 21 days for a maximum of 6 cycles. Patients with responsive or stable disease received bevacizumab (15 mg/kg) intravenously every 21 days until progression or intolerance. The primary endpoint was progression-free survival rate at 6 months., Results: 53 patients were enrolled at 4 centers; 52 were evaluable for this analysis. The progression-free survival rate at 6 months was 56% and the median progression-free survival was 6.9 months (95% confidence interval [CI], 5.3-7.8 months). The partial response rate was 40% and 35% of patients had stable disease. Median overall survival was 14.8 months (95% CI; 10.0-17.0 months). Grade 3/4 toxicities included neutropenia in 11%, hypertension in 6%, and venous thromboembolism in 13% of patients., Conclusion: This trial evaluating the addition of bevacizumab to cisplatin and pemetrexed in patients with previously untreated, advanced MM failed to meet the primary endpoint of a 33% improvement in the progression-free survival rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone., (Published by Elsevier Ireland Ltd.)

Germ cell tumor (GCT)-associated hematologic malignancies present a unique challenge to hematologists and hematopathologists. As most GCTs are of gonadal origin, only a small percentage occur at extragonadal sites in the midline. Extragonadal GCTs are believed to originate from the ectopic primordial germ cells that fail to migrate to the urogenital ridge during development. An overactive KIT pathway and overexpression of genes on chromosome 12p are strongly implicated in GCT development. Approximately 54% of extragonadal GCTs are located in the anterior mediastinum. This is disproportionally high among the midline structures, presumably due to a favorable microenvironment for GCT development in the developing thymus. The mediastinal nonseminomatous GCTs have two unique features. First, they are often refractory to current treatment modality with the worst prognosis among GCTs of all sites. Second, they have a tendency to give rise to secondary hematologic neoplasia. The outcome is grave for patients with GCT-associated hematologic malignancies. As standard chemotherapy used to treat their bone marrow-derived counterparts has been ineffective, the best treatment modality to achieve long-term survival is allogeneic hematopoietic stem cell or cord blood transplant for a very limited number of cases.

Unlabelled: Heparin-induced thrombocytopenia (HIT) antibodies are screened by an enzyme-linked immunosorbent assay (ELISA). Polyspecific ELISA detects anti-PF4/heparin IgG, IgA, and IgM. Recently, anti-PF4/heparin IgG ELISA has been shown to be more specific. However, the impact of using the IgG-ELISA on the incidence of isolated HIT (thrombocytopenia alone without clinically evident thrombosis) and the risk of developing subsequent thrombosis are still unknown., Methods: A total of 492 consecutive patients with clinically suspected HIT at The University of Texas Southwestern Medical Center and affiliated hospitals were retrospectively reviewed from December 2008 to May 2010., Results: 29 patients (6%) were diagnosed with HIT based on clinical findings and positive ELISA. 19 of the 29 patients (65%) had thrombosis at the time of diagnosis; whereas 10 of the 29 (35%) had only isolated HIT. The ten patients with isolated HIT had serial follow up for at least 3 months. 3 of 10 were treated with direct thrombin inhibitors and 5 of 10 were treated with Warfarin for at least 1 month upon discharge. None of them developed symptoms or signs of thrombosis during 3 months of follow up., Conclusion: The incidence of isolated HIT in this study was 35%, which is significantly lower than previously reported in the literature. It is possible that some patients previously thought to have HIT by the poly-specific ELISA assay had false positive results. The improved specificity of the IgG- ELISA appears to reduce the incidence of isolated HIT which may have lower risk of subsequent thrombosis.

Purpose: Low rates of participation in cancer clinical trials have been attributed to patient, institutional, and study characteristics. However, few studies have examined factors related to the consent process. We therefore evaluated the impact of consent timing and experience on markers of patient interest in research., Methods: We performed a retrospective analysis of patients enrolled in a cancer center tissue repository. During enrollment, patients were asked if they were willing to be contacted in the future to provide medical follow-up information and/or to participate in other clinical research. We analyzed the association between patient responses to these questions and consent process factors using univariate analysis and multivariate logistic regression., Results: Of 922 patients evaluated, 85% agreed to be contacted to provide follow-up information, and 83% agreed to be contacted to participate in future research studies. In univariate analysis, willingness to be contacted for future research was associated with consenter experience (P = .01) and had a trend toward association with the timing of enrollment in relation to diagnosis (P = .08), but it was not associated with patient sex, race, or diagnosis. In multivariate analysis, responses remained associated with consenter experience (P = .02)., Conclusion: Factors related to the consent process, including consenter experience and timing of study enrollment, are significantly associated with or have a trend toward association with markers of patient interest in clinical research. These understudied and potentially modifiable variables warrant further evaluation.

Background: Overexpression of excision repair cross complementing group 1 (ERCC1), a DNA repair enzyme, is associated with resistance to cisplatin., Materials and Methods: Tissues from 73 patients with squamous cell carcinoma of the head and neck (HNSCC) who received concurrent cisplatin and radiation was analyzed immunohistochemically to determine if ERCC1 expression predicted for survival and response. Expression was scored as follows: 0=0% tumor nuclei positive, 1+=<50%, 2+=50-75% and 3+=>75%., Results: ERCC1 expression was 0 in 0%, 1+ (14%), 2+ (42%) and 3+ (44%). In uni- and multivariate analyses, 3+ ERCC1 expression was not a significant predictor of survival or response. Median survival for the ERCC1 3+ patients was 2.9 years versus 2.1 years for the ERCC1 <3+ group (p=0.44)., Conclusion: In this retrospective review of HNSCC patients receiving concurrent cisplatin and radiation, ERCC1 expression was not a significant predictor of survival or response.

Study Objective: To compare the differences between the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions in patients receiving therapeutic doses of warfarin., Design: Retrospective medical record review., Setting: Large academic Veterans Affairs health care system., Patients: Twenty-four patients who received concomitant therapeutic doses of warfarin and at least one dose of a fluoropyrimidine--5-fluorouracil or capecitabine--between January 2004 and May 2008., Measurements and Main Results: The primary outcome was mean change in international normalized ratio (INR) from baseline to end of 90-day study period. Only patients who were taking warfarin before starting either fluoropyrimidine-based chemotherapy were included in the primary analysis. Of the 24 eligible patients, 15 (9 receiving 5-fluorouracil, 6 receiving capecitabine) were taking warfarin before receiving either fluoropyrimidine. No significant differences were noted in the average weekly warfarin dose or baseline INR between the 5-fluorouracil and capecitabine groups. The mean change in INR for patients taking warfarin before fluoropyrimidine use was 4.62 in the 5-fluorouracil group compared with 5.11 in the capecitabine group (p=0.87). The capecitabine group had a similar proportion of patients achieving an INR above 9 while taking warfarin compared with the 5-fluorouracil group (17% vs 22%). In those patients who required a warfarin dosage reduction, the dose was reduced by 38% and 41% in the 5-fluorouracil and capecitabine groups, respectively. No significant differences in bleeding events were reported within 90 days of concurrent use of either fluoropyrimidine with warfarin., Conclusion: Our study suggests that in patients receiving concomitant warfarin and a fluoropyrimidine, no significant differences in INR elevation or bleeding events were noted with 5-fluorouracil compared with capecitabine.

Introduction: Chemotherapy prolongs survival without substantially impairing quality of life for medically fit patients with advanced non-small cell lung cancer (NSCLC), but population-based studies have shown that only 20 to 30% of these patients receive chemotherapy. These earlier studies have relied on Medicare-linked Surveillance, Epidemiology, and End Results (SEER) data, thus excluding the 30 to 35% of lung cancer patients younger than 65 years. Therefore, we determined the use of chemotherapy in a contemporary, diverse NSCLC population encompassing all patient ages., Methods: We performed a retrospective analysis of patients diagnosed with stage IV NSCLC from 2000 to 2007 at the University of Texas Southwestern Medical Center. Demographic, treatment, and outcome data were obtained from hospital tumor registries. The association between these variables was assessed using univariate analysis and multivariate logistic regression., Results: In all, 718 patients met criteria for analysis. Mean age was 60 years, 58% were men, and 45% were white. Three hundred fifty-three patients (49%) received chemotherapy. In univariate analysis, receipt of chemotherapy was associated with age (53% of patients younger than 65 years versus 41% of patients aged 65 years and older; p = 0.003) and insurance type (p < 0.001). In a multivariate model, age and insurance type remained associated with receipt of chemotherapy. For individuals receiving chemotherapy, median survival was 9.2 months, compared with 2.3 months for untreated patients (p < 0.001)., Conclusions: In a contemporary population representing the full age range of patients with advanced NSCLC, chemotherapy was administered to approximately half of all patients-more than twice the rate reported in some earlier studies. Patient age and insurance type are associated with receipt of chemotherapy.

Non-Hodgkin lymphoma can produce a number of metabolic derangements including, in rare instances, lactic acidosis. This case illustrates an example of significant lactic acidosis and hypoglycemia secondary to diffuse large B-cell lymphoma with hepatic involvement in a patient with hepatitis C infection. A review of the literature on the occurrence of lactic acidosis and lymphoma, including the risk factors for its development and the resultant prognosis, are discussed. In addition, the evidence linking hepatitis C infection and lymphoma are reviewed.

Although the incidence of small cell lung cancer (SCLC) has declined during the past 30 years, it remains a significant cause of cancer mortality in the United States and across the world. With appropriate treatment, about 20% of patients who present with limited stage SCLC can be cured of their disease. Unfortunately, the outcome for the remainder of patients is extremely poor. The only significant advance in extensive stage SCLC in the past 2 decades is the recent discovery that prophylactic cranial irradiation improves survival in those patients whose disease has responded to initial chemotherapy. Numerous attempts to enhance the antitumor effects of traditional chemotherapy for SCLC have not been successful. As the understanding of the biology of SCLC increased, a number of rational molecular targets for therapy have been identified. Although initial attempts at "targeted therapy" in SCLC have been unsuccessful, several newly identified targets hold promise and give hope that significant improvements in therapy for this challenging disease are not far away.

Background: To explain the historically low rates of participation in cancer clinical trials, several factors have been studied. These include subject characteristics and attitudes, clinical trial availability and eligibility criteria, and physician attitudes and communication skills. However, the impact of nonphysician research personnel, who often consent patients for studies, is unclear. We therefore evaluated the association between consenter characteristics and subject interest in clinical research., Methods: We performed a retrospective review of subjects enrolled in a university-based cancer center tissue repository. During enrollment, subjects were asked if they were willing to be contacted in the future to (a) provide medical follow-up information and (b) participate in other clinical research. We analyzed the association between responses to these questions and consenter characteristics using univariate analysis and multivariate logistic regression., Results: In total, 181 consenters enrolled 922 subjects. The majority of subjects agreed to be contacted for follow-up (84.9%) and future research (83.1%). Subject willingness to be contacted for future research was associated with greater consenter experience in univariate and multivariate analyses. In multivariate analysis, subject willingness to be contacted for future research was associated with discordance between subject and consenter gender, but not with subject gender, race, or income, or consenter gender or race., Conclusions: Consenter experience and subject-consenter gender discordance were associated with greater subject interest in participating in future research. The role of consenters in clinical research merits future study and should be considered in efforts to increase cancer clinical trial accrual.

Introduction: Pemetrexed is synergistic with gemcitabine in preclinical models of non-small cell lung cancer (NSCLC). The optimal dose and utility of gemcitabine and pemetrexed was evaluated in a dose-escalating study., Methods: The phase 1 study included patients with advanced tumors, whereas the phase 2 study included patients with locally advanced or metastatic NSCLC. Gemcitabine was infused over 30 minutes, followed by pemetrexed administered over 10 minutes on day 1 of a 14-day cycle. Treatment continued for 12 cycles or until disease progression. All patients received folic acid, Vitamin B12, and steroid prophylaxis., Results: Maximum tolerated dose was gemcitabine 1500 mg/m, followed by pemetrexed 500 mg/m. Fifty-three patients (29 male, 24 female) were enrolled in the phase 2 study. Response rate was 20.8% (95% CI: 0.108-0.341), and the clinical benefit rate (CR + PR + SD) was 64.2%. Median time to disease progression was 4.6 months (95% CI: 2.79-6.18), median survival was 10.1 month (95% CI: 5.95-14.09, censorship = 20.75%), and 1-year survival was 41.0%. Common grade 3 or 4 adverse events (% of patients) were neutropenia (28.3%), fatigue (22.6%), and febrile neutropenia (9.4%)., Conclusions: Twice-monthly gemcitabine and pemetrexed was well tolerated, with overall survival and clinical benefit indicating disease activity in NSCLC patients.

Purpose: Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients., Experimental Design: We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m(2) as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done., Results: We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied., Conclusions: Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.