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Abstract Background Despite the significant upgrading in recent years of the role of 18F-FDG PET/CT in multiple myeloma (MM) diagnostics, there is a still unmet need for myeloma-specific radiotracers. 3′-Deoxy-3′-[18F]fluorothymidine (18F-FLT) is the most studied cellular proliferation PET agent, considered a potentially new myeloma functional imaging tracer. The aim of this pilot study was to evaluate 18F-FLT PET/CT in imaging of MM patients, in the context of its combined use with 18F-FDG PET/CT. Results Eight patients, four suffering from symptomatic MM and four suffering from smoldering MM (SMM), were enrolled in the study. All patients underwent 18F-FDG PET/CT and 18F-FLT PET/CT imaging by means of static (whole body) and dynamic PET/CT of the lower abdomen and pelvis (dPET/CT) in two consecutive days. The evaluation of PET/CT studies was based on qualitative evaluation, semi-quantitative (SUV) calculation, and quantitative analysis based on two-tissue compartment modeling. 18F-FDG PET/CT demonstrated focal, 18F-FDG avid, MM-indicative bone marrow lesions in five patients. In contrary, 18F-FLT PET/CT showed focal, 18F-FLT avid, myeloma-indicative lesions in only two patients. In total, 48 18F-FDG avid, focal, MM-indicative lesions were detected with 18F-FDG PET/CT, while 17 18F-FLT avid, focal, MM-indicative lesions were detected with 18F-FLT PET/CT. The number of myeloma-indicative lesions was significantly higher for 18F-FDG PET/CT than for 18F-FLT PET/CT. A common finding was a mismatch of focally increased 18F-FDG uptake and reduced 18F-FLT uptake (lower than the surrounding bone marrow). Moreover, 18F-FLT PET/CT was characterized by high background activity in the bone marrow compartment, further complicating the evaluation of bone marrow lesions. Semi-quantitative evaluation revealed that both SUVmean and SUVmax were significantly higher for 18F-FLT than for 18F-FDG in both MM lesions and reference tissue. SUV values were higher in MM lesions than in reference bone marrow for both tracers. Conclusions Despite the limited number of patients analyzed in this pilot study, the first results of the trial indicate that 18F-FLT does not seem suitable as a single tracer in MM diagnostics. Further studies with a larger patient population are warranted to generalize the herein presented results.

Abstract Background For patients with metastatic non-small cell lung cancer, timely molecular testing is essential to determine the appropriate course of therapy. Initial treatment with platinum chemotherapy and/or an immune checkpoint inhibitor (ICI) is the standard of care for patients without actionable genomic alterations. Objective We aimed to assess treatment patterns and clinical outcomes among patients with metastatic non-small cell lung cancer, no actionable genomic alterations, and with prior ICI and platinum-based chemotherapy in a community oncology setting. Methods This retrospective observational study examined electronic health records from adult patients with an initial metastatic non-small cell lung cancer diagnosis without actionable genomic alterations from 2017 to 2019. Patients had received a subsequent line of therapy (LOT) [index] after discontinuing platinum-based chemotherapy plus an ICI in the previous one or two LOTs. Patient demographics and clinical characteristics were analyzed descriptively. Clinical outcomes were evaluated using Kaplan–Meier analyses. Results Among the study population (n = 961), the most common index LOT regimens were non-platinum-based chemotherapies (57.3%), platinum-based chemotherapies (12.9%), ICI-based chemotherapies (12.7%), platinum + ICI-based chemotherapies (9.4%), and other (7.7%). The most common post-index LOT regimens were non-platinum based (61.2%), ICI based (15.3%), platinum based (10.7%), platinum + ICI based (3.2%), and other (2.5%). Median time to treatment discontinuation, time to next treatment, and overall survival were numerically longest with index LOT ICI-based regimens (6.5, 9.9, and 18.9 months, respectively) and shortest with platinum-based regimens (2.8, 5.3, and 8.0 months, respectively) and non-platinum-based regimens (2.6, 5.0, and 7.8 months, respectively). Conclusions Among patients with metastatic non-small cell lung cancer without actionable genomic alterations previously treated with platinum + ICIs, non-platinum chemotherapy agents were most commonly prescribed in the index LOT. Clinical outcomes including time to treatment discontinuation, time to next treatment, and overall survival were short, highlighting the unmet need for more effective later-line treatments.

BackgroundThis study investigated real-world time on treatment (rwToT) and overall survival (OS) for patients with metastatic non-small cell lung cancer (mNSCLC) who initiated first-line (1L) pembrolizumab monotherapy. We also explored discontinuation reasons and subsequent treatments, stratified by number of cycles among those who completed ≥17 cycles of 1L pembrolizumab.MethodsPatients with mNSCLC without actionable genetic aberrations, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and unknown, and PD-L1 TPS ≥ 50% starting 1L pembrolizumab monotherapy between 24-Oct-2016 and 31-Dec-2018 within The US Oncology Network were identified retrospectively and evaluated using structured data, with a data cutoff of 30-Sep-2021. Patient characteristics and disposition were summarized using descriptive statistics. OS and rwToT were evaluated using Kaplan-Meier method for all ECOG PS and PS 0-1. A subgroup of patients who completed ≥17 cycles were evaluated using supplemental chart review data to discern reasons for discontinuation.ResultsOf the 505 patients with mNSCLC with PD-L1 TPS ≥50%, 61% had ECOG PS 0-1, 23% had ECOG PS 2, and 65% had nonsquamous histology. Median rwToT and OS of pembrolizumab were 7.0 (95% CI, 6.0–8.4) months and 24.5 (95% CI, 20.1–29.3) months, respectively. In the subgroup with ECOG PS 0-1, they were 7.6 months (95% CI, 6.2-9.2) and 28.8 months (95% CI, 22.4-37.5), respectively. Of the 103 patients who completed ≥17 cycles, 57 (55.3%) patients received 17 – 34 cycles and 46 (44.7%) patients received ≥35 cycles. Approximately 7.7% of the study population received pembrolizumab beyond 35 cycles. Most common reasons for discontinuation were disease progression (38.6%) and toxicity (19.3%) among patients who received 17-34 cycles of pembrolizumab, and disease progression (13.0%) and completion of therapy (10.9%) among patients who received ≥35 cycles.ConclusionConsistent with findings from KEYNOTE-024 and other real-world studies, this study demonstrates the long-term effectiveness of pembrolizumab monotherapy as 1L treatment for mNSCLC with PD-L1 TPS ≥50%. Among patients who completed ≥17 cycles, nearly half completed ≥35 cycles. Disease progression and toxicity were the most common reasons for discontinuation among patients who received 17-34 cycles of pembrolizumab. Reasons for discontinuation beyond 35 cycles need further exploration.

Abstract Background Patient survival in advanced/metastatic melanoma, non‐small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) has improved with immune checkpoint inhibitors (ICI). Biomarkers' role in prognosis and treatment has been limited by conflicting trial results. Methods This retrospective, observational study analyzed baseline demographic, clinical, laboratory, and treatment data versus outcomes of The US Oncology Network adult outpatients. Patients with advanced/metastatic melanoma, NSCLC, or RCC treated between January 1, 2015 and November 30, 2020 were given ICI monotherapy or combination therapy with ipilimumab, pembrolizumab, nivolumab, or atezolizumab. Treatment outcomes (overall survival [OS], time to treatment discontinuation, time to next treatment) were followed longitudinally until May 31, 2021, last patient record, or date of death. Baseline blood cell counts, including absolute monocyte count (AMC), absolute lymphocyte count (ALC), monocyte‐to‐lymphocyte ratio (MLR), absolute neutrophil count (ANC), and eosinophil count, were subdivided into quintiles for univariate and multivariable Cox regression analyses. Results Data from 18,186 patients with advanced/metastatic melanoma (n = 3314), NSCLC (n = 12,416), and RCC (n = 2456) were analyzed. Better OS correlated with increased baseline serum albumin concentration, increased eosinophil and lymphocyte counts, and Western United States physician practice location. Decreased OS correlated with increased AMC, MLR, ANC, age, and worse Eastern Cooperative Oncology Group performance status. Conclusions To our knowledge, this study is the largest to date to associate baseline survival indicators and outcomes in outpatients with advanced/metastatic melanoma, NSCLC, or RCC and receiving ICIs. Results may inform disease‐specific prognostic models and help providers identify patients most likely to benefit from ICI therapy.

Background: Bevacizumab-awwb (MVASI ® ) was the first U.S. Food and Drug Administration-approved biosimilar to Avastin ® (reference product [RP]) for the treatment of several different types of cancers, including metastatic colorectal cancer (mCRC), an indication approved based on extrapolation. Objectives: Evaluate treatment outcomes in mCRC patients who received first-line (1L) bevacizumab-awwb at treatment initiation or as continuing bevacizumab therapy (switched from RP). Design: A retrospective chart review study. Methods: Adult patients who had a confirmed diagnosis of mCRC (initial presentation of CRC on or after 01 January 2018) and initiated 1L bevacizumab-awwb between 19 July 2019 and 30 April 2020 were identified from the ConcertAI Oncology Dataset. A chart review was conducted to evaluate patient baseline clinical characteristics and effectiveness and tolerability outcomes during the follow-up. Study measures were reported stratified by prior use of RP: (1) naïve patients and (2) switchers (patients who switched to bevacizumab-awwb from RP without advancing the line of therapy). Results: At the end of study period, naïve patients ( n = 129) had a median 1L progression-free survival (PFS) of 8.6 months [95% confidence interval (CI), 7.6–9.9] and a 12-month overall survival (OS) probability of 71.4% (95% CI, 61.0–79.5%). Switchers ( n = 105) had a median 1L PFS of 14.1 months (95% CI, 12.1–15.8) and a 12-month OS probability of 87.6% (95% CI, 79.1–92.8%). During treatment with bevacizumab-awwb, 20 events of interest (EOIs) were reported in 18 naïve patients (14.0%) and 4 EOIs reported in 4 switchers (3.8%), of which the most commonly reported events were thromboembolic and hemorrhagic events. Most EOIs resulted in emergency department visit and/or treatment hold/discontinuation/switch. None of the EOIs resulted in death. Conclusion: In this real-world cohort of mCRC patients who were treated 1L with a bevacizumab biosimilar (bevacizumab-awwb), the clinical effectiveness and tolerability data were as expected and consistent with previously published findings from real-world studies of bevacizumab RP in mCRC patients.

Objectives: Cilta-cel is a CAR-T cell therapy that expresses 2 BCMA-targeting single-domain antibodies, designed to confer avidity. In the multicohort, phase 2 CARTITUDE-2 study (NCT04133636), the safety and efficacy of cilta-cel in various clinical settings and suitability of outpatient administration was explored in patients with multiple myeloma. Material and methods: Patients enrolled in Cohort A had progressive MM after 1–3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and were naïve to BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75 × 106 CAR+ viable T cells/kg) was given 5–7 days after start of lymphodepletion (daily cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] for 3 days). The primary outcome was minimal residual disease (MRD) 10-5 negativity. Secondary outcomes were response rates (per IMWG criteria) and safety (per CTCAE; CRS and ICANS by ASTCT). Results: As of the February 2021 data cutoff (median follow-up: 5.8 months [2.5–9.8]), 20 patients (65% male; median age 60 years [38–75]) received cilta-cel; 1 patient was treated in an outpatient setting. Patients (n = 12:

Human Mucosal Melanoma (hMM) is an aggressive neoplasm of neuroectodermal origin with distinctive features from the more common cutaneous form of malignant melanoma (cMM). At the molecular level, hMMs are characterized by large chromosomal aberrations rather than single-nucleotide mutations, typically observed in cMM. Given the scarcity of available cases, there have been many attempts to establish a reliable animal model. In pet dogs, Canine Oral Melanoma (COM) is the most common malignant tumor of the oral cavity, sharing clinical and histological aspects with hMM. To improve the knowledge about COM's genomic DNA alterations, in the present work, formalin-fixed, paraffin-embedded (FFPE) samples of COM from different European archives were collected to set up an array Comparative Genomic Hybridization (aCGH) analysis to estimate recurrent Copy Number Aberrations (CNAs). DNA was extracted in parallel from tumor and healthy fractions and 19 specimens were successfully submitted to labeling and competitive hybridization. Data were statistically analyzed through GISTIC2.0 and a pathway-enrichment analysis was performed with ClueGO. Recurrent gained regions were detected, affecting chromosomes CFA 10, 13 and 30, while lost regions involved chromosomes CFA 10, 11, 22, and 30. In particular, CFA 13 showed a whole-chromosome gain in 37% of the samples, while CFA 22 showed a whole-chromosome loss in 25%. A distinctive sigmoidal trend was observed in CFA 10 and 30 in 25 and 30% of the samples, respectively. Comparative analysis revealed that COM and hMM share common chromosomal changes in 32 regions. MAPK- and PI3K-related genes were the most frequently involved, while pathway analysis revealed statistically significant perturbation of cancer-related biological processes such as immune response, drug metabolism, melanocytes homeostasis, and neo-angiogenesis. The latter is a new evidence of a significant involvement of neovascularization-related pathways in COMs and can provide the rationale for future application in anti-cancer targeted therapies.

The purpose of this study was to investigate the associations and explore the relationships between hormonal factors (serum estrogen, estrogen receptors and ovariohysterectomy) and other clinical/histological prognostic factors and their impact on outcome in dogs with mammary carcinomas. Data from two separate prospective studies on dogs with spontaneous mammary carcinomas were used for this research. All dogs underwent standardized diagnostic testing, staging, surgery and follow-up examinations. Serum estrogen was analyzed by competitive enzyme immunoassay or radioimmunoassay, and tumor estrogen receptor (ER) expression was analyzed by immunohistochemistry. A total of 159 dogs were included; 130 were spayed and 29 remained. High serum estrogen was associated with an overall longer time to metastasis (p = 0.021). When stratifying based on spay group, the effect was only significant in spayed dogs, (p = 0.019). Positive tumor ER expression was also associated with a longer time to metastasis (p = 0.025), but similar to above, only in dogs that were spayed (p = 0.049). Further subgroup analysis revealed that high serum estrogen was significantly associated with improved survival in dogs with ER positive tumors, but only in spayed dogs (p = 0.0052). Interestingly, the effect of spaying was the opposite in dogs with ER negative tumors; here, intact dogs with high serum estrogen but ER negative tumors had a significantly longer time to metastasis (p = 0.036). Low serum estrogen was associated with increased risk for the development of non-mammary tumors in the post-operative period (p = 0.012). These results highlight the dual effect of estrogen in cancer: Estrogen acts as a pro-carcinogen in ER positive mammary tumors, but a may have a protective effect in ER negative tumors, potentially via non-receptor mechanisms. The latter is supported by the decreased risk for non-mammary tumors in dogs with high serum estrogen, and explains the increased incidence of certain non-mammary tumors in in dogs spayed at an early age.

One of the hallmarks of adaptive immunity is the development of a long-term pathogen specific memory response. While persistent memory T cells certainly impact the immune response during a secondary challenge, their role in unrelated infections is less clear. To address this issue, we utilized lymphocytic choriomeningitis virus (LCMV) and Listeria monocytogenes immune mice to investigate whether bystander memory T cells influence Leishmania major infection. Despite similar parasite burdens, LCMV and Listeria immune mice exhibited a significant increase in leishmanial lesion size compared to mice infected with L. major alone. This increased lesion size was due to a severe inflammatory response, consisting not only of monocytes and neutrophils, but also significantly more CD8 T cells. Many of the CD8 T cells were LCMV specific and expressed gzmB and NKG2D, but unexpectedly expressed very little IFN-γ. Moreover, if CD8 T cells were depleted in LCMV immune mice prior to challenge with L. major, the increase in lesion size was lost. Strikingly, treating with NKG2D blocking antibodies abrogated the increased immunopathology observed in LCMV immune mice, showing that NKG2D engagement on LCMV specific memory CD8 T cells was required for the observed phenotype. These results indicate that bystander memory CD8 T cells can participate in an unrelated immune response and induce immunopathology through an NKG2D dependent mechanism without providing increased protection.

Disease progression in response to infection can be strongly influenced by both pathogen burden and infection-induced immunopathology. While current therapeutics focus on augmenting protective immune responses, identifying therapeutics that reduce infection-induced immunopathology are clearly warranted. Despite the apparent protective role for murine CD8⁺ T cells following infection with the intracellular parasite Leishmania, CD8⁺ T cells have been paradoxically linked to immunopathological responses in human cutaneous leishmaniasis. Transcriptome analysis of lesions from Leishmania braziliensis patients revealed that genes associated with the cytolytic pathway are highly expressed and CD8⁺ T cells from lesions exhibited a cytolytic phenotype. To determine if CD8⁺ T cells play a causal role in disease, we turned to a murine model. These studies revealed that disease progression and metastasis in L. braziliensis infected mice was independent of parasite burden and was instead directly associated with the presence of CD8⁺ T cells. In mice with severe pathology, we visualized CD8⁺ T cell degranulation and lysis of L. braziliensis infected cells. Finally, in contrast to wild-type CD8⁺ T cells, perforin-deficient cells failed to induce disease. Thus, we show for the first time that cytolytic CD8⁺ T cells mediate immunopathology and drive the development of metastatic lesions in cutaneous leishmaniasis.