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The goal of this project was to demonstrate that subpopulations of cells in tumors can uniquely fluctuate in size in response to environmental conditions created during drug treatment, thereby acting as a dynamic "rheostat" to create a favorable tumor environment for growth. The cancer modeling used for these studies was subpopulations of melanoma cells existing in cultured and tumor systems that differed in aldehyde dehydrogenase (ALDH) activity. However, similar observations were found in other cancer types in addition to melanoma, making them applicable broadly across cancer. The approach was designed to show that either ALDH high and ALDH low subpopulations rapidly epigenetically transition between stem-cell-like high into nonstem-like low production states to create an environment during drug treatment that would enable optimal cellular proliferation and tumor expansion to facilitate drug resistance. The controlled experiments showed proportional changes in each cell population to reach an evolutionarily stable equilibrium mediated by the needed levels of ALDH enzyme activity. Mechanistically, cell population size changes served to functionally move the aldehyde and the resulting reactive oxygen species (ROS) levels to those compatible with optimal cellular proliferation with population fluctuations dependent on the levels of drug induced tumor stress. This is the first report documenting fluctuations in the sizes of cell populations in tumors to cooperatively assist in drug resistance development., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Introduction: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the White population. Unfortunately, the prognosis of advanced cSCC is poor, and management can be challenging. Until recently, the choice of systemic medications was limited, and those that were available had modest efficacy. Cemiplimab is an anti-programmed cell-death protein 1 inhibitor and the first immunotherapeutic agent approved for the treatment of metastatic or locally advanced cSCC. The purpose of this study was to evaluate the efficacy of cemiplimab when used as adjuvant or neoadjuvant therapy in patients treated at our institution., Methods: A retrospective review of patients with locally advanced or metastatic cSCC who were treated with cemiplimab as adjuvant or neoadjuvant therapy at a single institution between February 2019 and November 2022 was performed. Response to treatment was objectively assessed based on Response Evaluation Criteria in Solid Tumors, version 1.1, criteria. The primary end point was objective response rate. Secondary endpoints included time to observed response, disease-control rate, progression-free survival, overall survival, and adverse effects of therapy., Results: A total of 6 patients were identified with a median age of 79 years (range, 51-90 years). Four patients had locally advanced cSCC, and 2 had distant metastasis. Cemiplimab was used as adjuvant therapy in 3 patients and neoadjuvant therapy in 2 patients. There was 1 patient in which it was used for limb salvage, who would have otherwise required an amputation. Objective response rate, complete response, and partial response were 66% (4 of 6), 33% (2 of 6), and 33% (2 pf 6), respectively. Average time to observed response was 2.9 months. Disease-control rate was 83% (5 of 6), and average progression-free survival was 10 months. Toxicity was reported in 2 patients, both of which were grade 1 severity., Conclusions: Cemiplimab has established its utility in the treatment of advanced cSCC, demonstrating clinical efficacy while generally having a tolerable adverse effect profile. Our preliminary results suggest that cemiplimab has potential as an adjuvant or neoadjuvant therapy in combination with surgery for treatment of cSCC., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with bladder cancer (BC) who are cisplatin ineligible or have unresectable disease have limited treatment options. Previously, we showed targeting programmed death-ligand 1 (PD-L1) with durvalumab (durva) and radiation therapy (RT) combination was safe in BC. We now report results from a phase II study evaluating the toxicity and efficacy of durva and RT in localized BC., Methods: This is a single-arm, multi-institutional phase II study; N=26. Enrolled patients had pure or mixed urothelial BC (T2-4 N0-2 M0) with unresectable tumors and were unfit for surgery or cisplatin ineligible. Patients received durva concurrently with RT ×7 weeks, followed by adjuvant durva × 1 year., Primary Endpoints: (A) progression-free survival (PFS) at 1 year and (B) disease control rate (DCR) post adjuvant durva. Key secondary endpoints: (A) complete response (CR) post durvaRT (8 weeks), (B) overall survival (OS), (C) PFS and (D) toxicity. Correlative studies included evaluation of baseline tumor and blood (baseline, post durvaRT) for biomarkers., Results: Median follow-up was 27 months. Evaluable patients: 24/26 post durvaRT, 22/26 for DCR post adjuvant durva, all patients for PFS and OS. Post adjuvant durva, DCR was seen in 72.7%, CR of 54.5%. 1-year PFS was 71.5%, median PFS was 21.8 months. 1-year OS was 83.8%, median OS was 30.8 months. CR at 8 weeks post durvaRT was 62.5%. Node positive (N+) patients had similar median PFS and OS. DurvaRT was well tolerated. Grade ≥3 treatment-related adverse events: anemia, high lipase/amylase, immune-nephritis, transaminitis, dyspnea (grade 4-COPD/immune), fatigue, rash, diarrhea and scleritis. No difference in outcome was observed with PD-L1 status of baseline tumor. Patients with CR/PR or SD had an increase in naïve CD4 T cells, a decrease in PD-1+CD4 T cells at baseline and an increase in cytokine-producing CD8 T cells, including interferon gamma (IFNγ) producing cells, in the peripheral blood., Conclusion: Durva with RT followed by adjuvant durva was safe with promising efficacy in localized BC patients with comorbidities, including N+ patients. Larger randomized studies, like S1806 and EA8185, are needed to evaluate the efficacy of combining immunotherapy and RT in BC., Trial Registration Number: NCT02891161., Competing Interests: Competing interests: MJ: Advisory board for Seagen (personal fees). Research funds—AstraZeneca, Pfizer, Eisai (drug only), BMS LT: None. JZ: None. VW: None. TS: None. MK: None. DK: None. JL: None. SH: Research grant—Eli Lilly, BMSHE: None. AS: None. SM: None. HZ: Pfizer, personal fees from BeiGene, personal fees from BMS, outside the submitted work. JW: None. RH: None. BG: None. MS: None. JD: Personal fees from Sanofi outside the submitted work. DJD: Research funds-BMSYZ: Advisory Board: Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Array, Bayer, Pfizer, Clovis, EMD serono. Grant/research support from: Institution clinical trial support from NewLink Genetics, Pfizer, Exelixis, Eisai. DSMC: Janssen Research and Development. Consultant honorarium: Pfizer, Novartis., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma., Methods: Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label., Results: Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator's choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P)., Conclusion: In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma., Competing Interests: Competing interests: YZ reports personal fees for Advisory Board: Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Array, Bayer, Pfizer, Clovis, and EMD serono. Grant/research support from Institutional clinical trial support from NewLink Genetics, Pfizer, Exelixis, and Eisai. DSMC honorarium: Janssen Research and Development. Consultant honorarium: Pfizer, Novartis. RRM reports personal fees from Newlink Genetics, outside the submitted work. MFS and RK report personal fees from Illumina Inc, BMS, and Qiagen. DM reports grants from NewLink Genetics, during the conduct of the study; grants and personal fees from NewLink Genetics, outside the submitted work. In addition, DM has a patent US patent 8,232,313 licensed to NewLink Genetics, and a patent US patent 6,451,840 licensed to NewLink Genetics. MM reports personal fees from Blueprints Medicine, Immunocore, Amgen, Treiza, Array Biopharma, Biontech, and Novartis. LLT, CMS, EPK, CJL, NNV, JY, ELB, and GRR were employed by NewLink Genetics at the time of conducting the study. All remaining authors have declared no conflicts of interest., (© 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.)

Cancer of Unknown Primary (CUP) occurs in 3-5% of patients when standard histological diagnostic tests are unable to determine the origin of metastatic cancer. Typically, a CUP diagnosis is treated empirically and has very poor outcomes, with median overall survival less than one year. Gene expression profiling alone has been used to identify the tissue of origin but struggles with low neoplastic percentage in metastatic sites which is where identification is often most needed. MI GPSai, a Genomic Prevalence Score, uses DNA sequencing and whole transcriptome data coupled with machine learning to aid in the diagnosis of cancer. The algorithm trained on genomic data from 34,352 cases and genomic and transcriptomic data from 23,137 cases and was validated on 19,555 cases. MI GPSai predicted the tumor type in the labeled data set with an accuracy of over 94% on 93% of cases while deliberating amongst 21 possible categories of cancer. When also considering the second highest prediction, the accuracy increases to 97%. Additionally, MI GPSai rendered a prediction for 71.7% of CUP cases. Pathologist evaluation of discrepancies between submitted diagnosis and MI GPSai predictions resulted in change of diagnosis in 41.3% of the time. MI GPSai provides clinically meaningful information in a large proportion of CUP cases and inclusion of MI GPSai in clinical routine could improve diagnostic fidelity. Moreover, all genomic markers essential for therapy selection are assessed in this assay, maximizing the clinical utility for patients within a single test., 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 © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels., Methods: CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS)., Results: In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment., Conclusions: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab., (© 2020 American Cancer Society.)

Background: Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined., Methods: We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology., Results: 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%)., Conclusions: Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate., Competing Interests: Competing interests: YGN: Research funding: Merck, Pfizer, BMS. Advisory Board: Array. KKS: Institutional funding: Oncosec, Regeneron. ZE: Research support: Novartis. Advisory board: Array, Regeneron. SC: Advisory Board and (non branded) Speaker’s Bureau for BMS. RC: Consulting: Array, BMS, Castle Biosciences, Compugen, Immunocore, I-Mab, InxMed, Merck, Roche/Genentech, Pierre Fabre, PureTech Health, Sanofi Genzyme, Sorrento Therapeutics. Clinical/Scientific Advisory Boards: Aura Biosciences, Chimeron, Rgenix. Research Funding to Columbia University: Amgen, Array, Astellis, AstraZeneca, Bayer, Bellicum, BMS, Corvus, Eli Lilly, Immunocore, Incyte, Macrogenics, Merck, Mirati, Novartis, Pfizer, Plexxikon, Roche/Genentech. JMK: Grants and personal fees from Bristol‐Myers Squibb and Immunocore; personal fees from Novartis, Iovance, and Elsevier; grants from Checkmate and Merck; Consulting or advisory role for Bristol‐Myers Squibb, Novartis, Array BioPharma, Merck, Roche, Amgen, and Immunocore. RS: Consulting/Advisory Boards: Amgen, Array, BMS, Merck, Novartis, Genentech, Compugen, Replimmune. Research support: Merck, Amgen. DJ: Advisory boards for Array Biopharma, Bristol-Myers Squibb, Incyte, Merck, Novartis, and Genoptix. Research support from Bristol-Myers Squibb and Incyte. AS: Advisory Board: Bristol-Myers Squibb, Immunocore, Castle Biosciences Institutional Research Support: Bristol-Myers Squibb, Immunocore, XcoveryTravel: Parker Institute for Cancer Immunotherapy., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Measures of mitotic activity predict behavior of noninvasive papillary urothelial carcinoma of the urinary bladder, but it is unclear what role these should have in tumor grading. In this article, we compare measures of mitotic activity to contemporary tumor grading, specifically in their association with recurrence of noninvasive papillary urothelial carcinoma. The study uses a retrospective cohort of 199 tumors from 124 patients. Mitotic activity was treated as a categorical variable (mitotic-inert, mitotic-low, or mitotic-high). Evaluating only first-occurrence tumors, recurrence was more frequent in mitotic-high (hazard ratio [HR], 8.8; P < .0001, Cox model) and mitotic-low tumors (HR, 3.7; P = .017) compared with mitotic-inert tumors, when controlling for treatment with intravesical bacillus Calmette-Guerin, age, and sex. Recurrence was likewise more frequent in high-grade tumors (HR, 3.1; P = .00019, Cox model) compared with low-grade tumors, controlling for these factors. However, mitotic group, but not tumor grade, was significantly associated with recurrence in a multivariate Cox model including mitotic group, tumor grade, and treatment status (HR, 6.5 [P = .0025] for mitotic-high versus reference; HR, 3.7 [P = .018] for mitotic-low versus reference). Frailty models including both first-occurrence and recurrent tumors showed similar results. Isolating the analysis to first occurrence, low-grade tumors, recurrence was more frequent in mitotic-high (HR, 6.8; P = .0044, Cox model) and mitotic-low (HR, 3.4; P = .027) tumors compared with mitotic-inert tumors. The findings indicate that mitotic activity is associated with behavior of noninvasive papillary urothelial carcinoma and may be valuable as an adjunct to the contemporary grading system., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A 54-year-old man presented with a painful lesion on the right posterior calf with MRI identifying a 5 cm lesion in the medial head of the gastrocnemius. He underwent wide local excision of the tumour, and the final pathology was consistent with atypical granular cell tumour. Three years later, he developed a recurrent right popliteal mass. Complete staging workup also identified multiple lung nodules and a caecal polyp that were consistent with metastatic granular cell tumour. He was started on pazopanib and deemed a poor candidate for palliative resection due to encasement of the popliteal vessels. The patient refused above-the-knee amputation (AKA) at that point and was evaluated for isolated limb infusion as an alternative. He received three cycles of isolated limb infusion within a 2-year period and achieved good response from the first two cycles. He underwent AKA 4 years after his diagnosis of malignant granular cell tumours and is currently doing well., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)