bluuebunny/crossref_metadata_2025 huggingface dataset:
Tisagenlecleucel for secondary CNS lymphoma, a case series.
Authors: Mann Shivtaj , Dhaliwal Armaan , Husnain Muhammad , Kumar Abhijeet , Persky Daniel O.
Published: June 2022

e19507

Background: Secondary CNS lymphoma (SCNSL) in setting of relapsed, refractory (R/R) B cell lymphoma has unmet needs as this disease state has a poor prognosis with a reported median survival of 2 to 5 months. Historically, the mainstay of treatment for SCNSL in setting of R/R B cell lymphoma included high dose methotrexate, whole brain radiation (WBRT), and/or chemotherapy followed by autologous stem cell transplant. More recently, chimeric antigen receptor (CAR)-T cell therapy has gained attention as a new modality of therapy for patients with R/R SCNSL. The first two CAR-T cell products to gain FDA approval for R/R B cell lymphoma were Axicabtagene ciloleucel and Tisagenlecleucel. In the initial studies for these products, patients with SCNSL were excluded due to concerns for immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS). Retrospective data has shown that patients with R/R SCNSL treated with Axicabtagene ciloleucel or Tisagenlecleucel could achieve high response rates; however, the data on the durability of response remains unclear. Recently, Lisocabtagene maraleucel, another CAR-T cell product, was approved for the treatment of R/R B cell lymphoma. The TRANSCEND trial which led to Lisocabtagene maraleucels approval did not exclude patients with SCNSL; however, only 3% of the patients had SCNSL. As such, literature on the durability of response of CAR-T cell therapy in R/R SCNSL still remains sparse. Here, we share our single institution experience of patients with R/R SCNSL treated with Tisagenlecleucel, an anti- CD19CAR-T cell therapy. Methods: For this observational study, patients with R/R SCNSL were identified and placed on a follow up list. Data was collected from May 2021 till December 2021. Data was analyzed for incidence of ICANS, CRS, and for duration of response. Results: A total of 3 patients with SCNSL were identified and treated at our center with Tisagelecleucel. One patient achieved complete response 30 days post CAR-T therapy but the day +100 imaging revealed progression of disease and was placed on subsequent line of therapy. One patient had partial response with progression of disease noted on day +60 imaging and died from complications of disease progression. One patient died from complications of CNS toxicity after receiving CAR-T therapy. Two patients had ICANS grade 4 and CRS grade 1 toxicities. One patient had no CNS or CRS toxicity. Conclusions: Our series is limited by the number of patients; however, suggests that though CAR-T therapy may result in disease response in R/R SCNSL the duration of response may be limited and that such patients may require other therapies such as autologous stem cell transplant to improve long term prognosis.
CAR T-cells effective for post-CART relapse: A new treatment paradigm.
Authors: Holland Elizabeth M. , Yates Bonnie , Silbert Sara K. , Foley Toni , Little Lauren , Fry Terry J. , Highfill Steven , Stroncek David , Shalabi Haneen , Shah Nirali N.
Published: June 2022

e19508

Background: Chimeric antigen receptor T-cells (CART) induce remarkable responses in B-cell acute lymphoblastic leukemia (B-ALL), but relapse remains a challenge. Effective therapies for post-CART relapse are limited but may include infusion of a unique CART construct, a strategy distinct from reinfusion of the same CART product. Given limited data evaluating outcomes of a unique CART as salvage therapy for post-CART relapse, we report on the impact of prior CART constructs on subsequent CART responses. Methods: This was a retrospective review (NCT03827343) of children and young adults receiving CD19 and/or CD22 CART therapy for B-ALL between 7/1/12-12/30/21 at our center. Patients included received at least 2 unique CART constructs at some point in therapy, excluding interim CART reinfusions. CART-A was the first CART construct ever received and CART-B the second unique CART. The primary objective was to evaluate complete remission (CR) rates following CART-A versus CART-B. Results: Of 135 heavily pretreated patients, 54 (40%) received at least one prior CART. The majority (n=37, 68.5%) were male. Median age at CART-A and CART-B was 12.5 (range, 3.3-30.4) and 13.7 years (range, 4.5-30.7), respectively. In 42 (77.8%) patients, CART-B targeted a different antigen than CART-A, primarily due to loss of antigen target after CART-A. CR rate was substantially lower with CART-B (n=35, 64.8%) than with CART-A (n=48, 88.9%, p=0.006) (Table). Still, two (3.7%) patients with CART-A nonresponse attained CR with CART-B. Most CART-B responders (n=31, 88.6%) had CART-B targeting a different antigen than CART-A, suggesting limitations of same antigen targeting even with a unique CART construct. CART-B responses amongst 10 patients with interim hematopoietic stem cell transplantation (HSCT) after CART-A were similar to CART-B responses in those without interim HSCT (5 of 10, 50% vs. 30 of 44, 68.2%, p=0.3). In those where CRS grade was known for both CART infusions (n=40), CRS severity was milder with CART-B (≥grade 3, n=1, 2.5%) than with CART-A (≥grade 3, n=15, 37.5%, p=0.0001). Conclusions: Using an alternative CART for post-CART relapse is effective in a substantial proportion of patients, particularly when targeting a unique antigen. As post-CART relapse occurs more frequently and patients receive multiple CARTs, identifying optimization strategies for CART-B will be critical. Further investigation of indication for CART-B, role of interim HSCT, and optimal timing for sequential CART infusions is underway.[Table: see text]
A phase 2 expanded access study of zanubrutinib (ZANU) in patients (pts) with Waldenström Macroglobulinemia (WM).
Authors: Castillo Jorge J. , Kingsley Ed , Narang Mohit , Yimer Habte Aragaw , Dasanu Constantin A , Melear Jason M. , Coleman Morton , Farber Charles Michael , Gupta Mukul , Shulman Jonah , Mantovani Emily H. , Zhang Xiaowei , Cohen Aileen , Huang Jane
Published: June 2022

e19522

Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. The next-generation BTK inhibitor ZANU (BGB-3111), designed to maximize BTK occupancy and minimize off-target inhibition of other kinases, is approved by the United States (US) Food and Drug Administration, Health Canada, and the European Union at a dose of 320 mg once daily (QD) or 160 mg twice daily (BID) for adult pts with WM. BGB-3111-216 is a single-arm expanded access study of ZANU in treatment-naïve (TN) pts who were unsuitable for standard chemoimmunotherapy or pts with relapsed refractory (R/R) WM. This study provides real-world experience with ZANU in pts with WM. Methods: Eligible pts with TN or R/R WM received ZANU 320 mg QD or 160 mg BID orally. Primary endpoint was the number of pts enrolled/treated and enrolling sites. Secondary endpoints included treatment-emergent adverse events (TEAEs) of special interest, disease response rate, progression-free survival (PFS), and overall survival (OS). Response was evaluated by investigator assessment according to the 6th International Workshop on WM ( Br J Haematol. 2013;160(2):171-6) every 6 mo at minimum. The study was closed by the sponsor in July 2021 and active pts were transitioned to commercial ZANU via a patient assistance program. Results: Fifty pts with WM (17, TN; 33, R/R) were enrolled between December 2019 and June 2021 across 10 academic and community medical centers in the US. Median age was 72 years, 54% had intermediate-, 40% had high-risk disease, and the median number of prior therapies for R/R pts was 2. Median treatment exposure was 9.2 mo (range, 1.4-20.0). Thirty-eight (76%) pts had ≥1 TEAE, and 36 (72%) had ≥1 TEAE of special interest. Grade ≥3 TEAEs of special interest were hypertension (8%), infection (8%), atrial fibrillation/flutter (2%), neutropenia (2%), and second primary malignancy (2%). No new safety signals were observed. In pts with ≥1 response evaluation, 39% achieved a best overall response (BOR) of very good partial response. Overall response rate was 85.4% and major response rate was 73.2% (Table). Of the 4 pts with BOR of progressive disease, 3 had IgM values that met partial response criteria before the 6-mo response assessment. PFS and OS were immature due to short follow-up, and the median was not met. Conclusions: These real-world expanded access study results were consistent with the established ZANU profile in WM or other B-cell malignancies when administered as oral monotherapy at 160 mg BID or 320 mg QD in pts with intermediate or high-risk R/R or TN WM. Clinical trial information: NCT04052854. [Table: see text]
Newly identified molecular and genetic characteristics of primary mediastinal large B-cell lymphoma.
Authors: Kamaeva Inna A. , Novikova Inna A. , Lysenko Irina B. , Timoshkina Natalya N. , Nikolaeva Nadezhda V. , Kapuza Elena A. , Gaysultanova Yakha S. , Pushkareva Tatiana F. , Tishina Anna V. , Samaneva Natalia Yu. , Vladimirova Liubov Yu
Published: June 2022

e19580

Background: Many studies have been devoted to the molecular profile of diffuse large B-cell lymphoma; however, a clear molecular and genetic picture of primary mediastinal large B-cell lymphoma (PMBLC) has not yet been described. Studies have reported various signaling pathways involved in PMBCL pathogenesis, with the best known JAK-STAT and NF-kB. This study was aimed at the detection of previously undescribed mutations, as well as the identification of signaling pathways that may be of interest in the search for new therapeutic targets for PMBCL. Methods: Tumor biopsy specimens from 23 PMBCL patients were examined by next-generation sequencing (NGS) on the Illumina NextSeq 550 system with an average coverage of at least 100x using the AVENIO Tumor Expanded Panel (Roche, USA) containing 77 genes. Analytical sensitivity of mutation detection was 5%. The pathogenicity of the identified nucleotide substitutions was assessed according to ACMG (American College of Medical Genetics and Genomics) and AMP (Association of Molecular Pathology) recommendations. Genomic DNAs were extracted from FFPE blocks using the Gene Read DNA FFPE Kit panel (Qiagen, USA) according to the standard protocol. DNA concentrations were measured fluorimetrically on the Qubit 2.0 fluorometer (Life Technologies, USA). The AVENIO Oncology Analysis Software was used to process the data and to search for clinically significant mutations. The genetic material was analyzed for clinically significant mutations among well-known databases: COSMIC: V83, TCGA 9.0, Exac: 1.0, DBSNP: 150, 1000 Genomes: phase_3_v5b, Snpeff: 4.2. Results: The targeted high-performance sequencing of PMBLC samples showed a newly revealed range of polymorphisms in 9 genes in patients with PMBLC (Alk, TP53, CCND3, RNF43, PIK3CA, FGFR3, SMO, MET, EZH2), previously not described for this cancer. We also interpreted signal pathways related to the mutated genes. Conclusions: The identified polymorphisms and the relationship of mutated genes with PMBLC signaling paths can serve as new therapeutic targets for patients with PMBLC.
Retrospective analysis of responses to second-line treatments of multiple myeloma after disease progression in patients who underwent ASCT.
Authors: Awada Hussein , Hajj Ali Adel , Ali Muhammad Faizan , Adroja Shubham , Mahalwar Gauranga , Kumar Ashish , Babar Arslan , Anwer Faiz
Published: June 2022

e20004

Background: Most Multiple Myeloma (MM) patients who respond to initial treatment ultimately progress. Data regarding 2nd line treatment remains scarce, but in general treatment relies on whether the disease is refractory to Lenalidomide (R) or not. Here, we report responses to 2nd line treatments of MM patients in with disease progression (PD) following Autologous Stem Cell Transplant (ASCT). Methods: We retrospectively reviewed MM patients with PD after ASCT at Cleveland Clinic during the period of April 1, 2016 till December 31, 2021. Baseline demographic, clinical and cytogenetic features were obtained from electronic records. Patients who had PD after ASCT, as defined by IMWG criteria, were divided into two smaller subcohorts: R-refractory and R-sensitive. Outcomes were compared among treatment groups within each subcohort. Continuous variables are reported as means with standard deviations, while categorical variables are presented as percentages. Categorical variables were compared using the chi-squared test while the t test and ANOVA were used for continuous variables. Results: 127 patients who had PD following ASCT were identified (Table). Most common cytogenetic aberrancies were del(13) (RB) 34.6%, t(11;14) 18.9% and gain(1q) 15%. Pre-PD maintenance included R 58.3%, Bortezomib (V) 7.1%, RV combination 8.7% and other R-based regimens 9.4%, with no difference in time to disease progression (TTPD) between them (p = 0.82), and an average of 15.5 months TTPD among all patients. ISS III patients were likely to progress earlier than ISS II or I (10.91 vs 14.56 vs 20.33 months; p = 0.008), while high and standard-risk cytogenetics did not predict TTPD (12.62 vs 16.85 months; p = 0.092). Patient who achieved CR either pre or post-ASCT were less likely to progress compared to others with weaker responses (p = 0.032; p = 0.002). Patients who did not achieve CR post-ASCT progressed earlier than those with CR (12.37 vs 16.53 months; p = 0.041). In R-sensitive patients (n = 25), PD was not significantly different in patients on 2nd line Daratumumab (D), R and dexamethasone (d) vs RVd (45.5% vs 60%; p = 0.505). In R-refractory patients (n = 57), PD was also not significantly different in DVd, Dd with Pomalidomide, or Carfilzomib (C)-based regimens (81.3% vs 68.2% vs 60%; p = 0.426). Time to 2nd PD was significantly longer in DRd vs RVd (12.4 vs 3 months; p = 0.026) but similar in DVd vs DPd vs C-based regimens (6.75 vs 8 vs 5.89 months; p = 0.711). Conclusions: TTPD in MM post-ASCT is determined by the ISS stage and achieving CR but not by cytogenetic risk or maintenance choice. Current regimens used as 2nd line in R-refractory patients are statistically indifferent, but DRd delays further PD compared to RVd in R-sensitive patients.[Table: see text]
miR-6124: A potential new prognosis biomarker for lung squamous cell carcinoma through m5C regulating mechanism.
Authors: Wang Qian , Zou Yuqing , Xiao Shanshan , Wang Tao ,   Hangzhou Repugene Technology Co,.Ltd
Published: June 2022

e20568

Background: RNA methylation is an important epigenetic modification that can act as tumor prognosis biomarkers, and which is regulated by methyltransferase, RNA binding protein, and demethylase. 5-Methylcytosine (m5C) is a well-known post-transcriptional modification that plays an important role in cell differentiation and apoptosis. Although gene mutations in those regulator genes are associated with various cancers, the m5C regulating mechanism and its roles in cancer prognosis largely remains unknown. This study aimed to find new microRNA biomarkers associated with prognosis of clinical outcomes through m5C regulating mechanism in lung squamous cell carcinoma (LUSC). Methods: The RNA-seq expression data of LUSC were collected from the The Cancer Genome Atlas (TCGA). In total, we obtained 501 LUSC tumor samples and 49 normal samples from 502 LUSC patients. We firstly identified differential expressed genes of the 13 previously reported m5C regulators between the tumor tissues and adjacent normal tissues. Then miRNAs were identified using Pearson correlation analysis between the microRNA expression and the differential expressed m5C regulator genes. Pathway enrichment analysis of the miRNAs was performed using clusterProfiler to examine their cancer development roles. Furthermore, cox regression analysis was used to evaluate the risk factor for overall survival. Targeted relationship between miRNA and genes were confirmed by miRTarBase. Results: Differential analysis revealed 4 significantly up-regulated (NOP2, NSUN2, DNMT3B and ALYREF) genes in tumor among 13 interested m5C regulators. Pearson correlation analysis identified 39 correlated miRNAs. After cox regression, we found out one micro-RNA miR-6124, which is highly correlated with DNMT3B gene and is significantly associated with worse overall survival (OS, p < 0.01). We then identified the regulatory targets of miR-6124 using miRTarBase database. In total we identified 181 target genes. Among them, H3F3A which encode histone H3 synergistically work with DNMT3B gene as showed in the previous studies and promote DNA methylation of the oncogenes. Such preliminary results showed miR-6124 may be involved in cancer pathway regulating and was a potential prognosis biomarker candidate in LUSC. Conclusions: We identified a potential new prognosis biomarker in lung squamous cell carcinoma. The identified miR-6124 is involved in DNMT3B and m5C regulating mechanism. Further evidences are needed to study its’ role in clinical applications.
Pathological response to neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer (NSCLC): A systematic review and meta-analysis.
Authors: Syaj Sebawe , Akhdar Marah , Ababneh Obada Ehab , Hamouri Shadi
Published: June 2022

e20582

Background: The advantage of combining chemotherapy and immune checkpoint inhibitors (ICIs) in resectable non-small cell lung cancer (NSCLC) patients has recently been studied in clinical trial settings. We aim to systematically revise the evidence of efficacy and safety of neoadjuvant chemoimmunotherapy treatment. Methods: We carried out a systematic search on MEDLINE, Scopus, Cochrane, and ASCO meetings library. Screening was done to include clinical trials of stage I-IIIA NSCLC patients who underwent any combination of ICIs and chemotherapy. The primary outcomes were major pathological response (MPR) and pathological complete response (pCR), and the secondary outcomes were 24-month overall survival (OS) and safety measured by adverse events (AEs). A meta-analysis was conducted for intention-to-treat MPR and pCR outcomes, in addition to a mixed-effects meta-regression model to investigate the effect of PD-L1 expression, tumor mutational burden (TMB), N stage (AJCC 8th), tumor size and tumor histology on MPR and pCR. PD-L1+ patients were defined to have a tumor proportion score of more or equal to 1%. Results: We included 9 phase II clinical trials and 1 phase III trial, all consisting of 471 patients. Trials administered neoadjuvant chemotherapy agents like carboplatin (N = 6 studies), cisplatin (N = 5), nab-paclitaxel (N = 4), pemetrexed (N = 2), and others, either as a doublet- or a triplet-agent regimen. ICIs used were anti-PD-1 (N = 5), anti-PD-L1 (N = 3), or anti-CTLA-4 agents (N = 2). Meta-analysis of 447 patients from 9 trials showed a pooled MPR of 49.2% (95% CI: 34.8 to 63.7%) with high heterogeneity (I2 = 87%, p < 0.01). Pooling the pCR from 10 trials including 471 patients results in an estimate of 27.5% (95% CI: 17.2 to 38.2%) with significant heterogeneity (I2 = 80%, p < 0.01). Meta-regression has found a significant association between being PD-L1+ and achieving MPR (odds ratio = 3.82, 95% CI: 1.55 to 9.58). However, this effect diminished in the multiple meta-regression that included age, tumor histology, in addition to PD-L1 status. None of these factors was correlated to achieving a pCR. Investigating the effect of tumor size, T stage, N stage, or TMB on MPR or pCR was not possible due to underreported data. Three trials of 137 patients reported a 24-month OS of 84.4% (95% CI: 77.6 to 90.2%) with low heterogeneity (I2 = 11%, p = 0.33). The most prevalent grade 3/4 AEs from the neoadjuvant treatment were neutropenia in 7.2% of patients, diarrhea in 3.2%, fatigue in 3.0%, and anemia in 2.1% of patients. The commonest any-grade AEs were fatigue (43.9%), alopecia (38.4%), diarrhea (31.6%), anemia (23.8%) and neutropenia (17.0%). Conclusions: The addition of ICIs to chemotherapy in neoadjuvant settings is an effective and feasible option. Effect of tumor size, PD-L1 status and TMB on MPR and pCR should be further investigated for better selection of treatment candidates.
Real-world data of durvalumab plus chemotherapy for extended stage small cell lung cancer patients: A Chilean experience.
Authors: Samtani Suraj Rajesh , Rojas Carlos , Gonzalez Jaime , Godoy Luis , Burotto Mauricio
Published: June 2022

e20600

Background: Immunotherapy has changed the landscape for small cell lung cancer treatment. The aim of this study was to evaluate the efficacy of durvalumab plus chemotherapy in small cell lung cancer (SCLC) patients in real world experience. Methods: Eligibility criteria included, histologically confirmed extended stage SCLC (ES-SCLC), evaluable disease and no prior therapy. Patients received durvalumab plus chemotherapy until progressive disease (PD) or unacceptable toxicity. The main aim of the study was to report the efficacy and safety profile of durvalumab plus chemotherapy in patients with SCLC of our everyday clinical practice. The secondary aim was to perform subgroup analysis by clinical features. Results: From May 2020 to January of 2022, 15 patients were enrolled. The patients demographics were: median age 62 years, 67% male; 93,3% former/current smoker; 100% of patients presented with extended stage SCLC at diagnosis and 26,6% had brain metastasis at diagnosis. The most frequent sites of metastasis were distant lymph nodes 67%, liver metastasis 40% and bone metastasis 33%. Number of average cycles was 16,5. The median overall survival was 11,43 months and overall response rate (ORR) was 46%. In terms of safety profile, 73% developed treatment related adverse effects, 40% were grade 2 and 20% were grade 3. No treatment adverse effects leading to deaths were observed in our cohort of patients. Conclusions: This study represents one of the first real word experience with durvalumab plus chemotherapy in ES SCLC and the results are consistent with previously reported in clinical trials.
Cytokine profiles of peripheral blood in patients with non-small cell lung cancer receiving anti-PD1 therapy.
Authors: Teplyakova Maria A. , Vladimirova Liubov Yu , Popova Irina L. , Lyanova Aza A. , Abramova Natalia A. , Storozhakova Anna E. , Ryadinskaya Ludmila A. , Tikhanovskaya Natalia M. , Udalenkova Irina A. , Kalabanova Elena A. , Kabanov Sergey N. , Sagakyants Aleksandr B. , Zlatnik Elena Yu , Shulgina Oksana G. , Zolotareva Ekaterina I. , Ulianova Elena P. , Kecheryukova Takhmina M. , Sergeeva Marina M. , Lazutin Yuriy N. , Kharagezov Dmitry A.
Published: June 2022

e21068

Background: Lung cancer (LC) is one of the most commonly diagnosed cancers and leading causes of cancer death worldwide. A limited clinical benefit of checkpoint inhibitor therapy (CIT) remains an important issue. Various units of the immune system are involved in both antitumor immunity and the development of CIT-induced side effects. Cytokines play a special role in these phenomena. The purpose of this study was to evaluate the cytokine profiles of peripheral blood in patients with non-small cell lung cancer (NSCLC) receiving CIT. Methods: The study included 32 NSCLC patients aged 41-83 years. CIT (pembrolizumab 2 mg/kg once every 21 days or 200 mg once every 21 days) continued until the appearance of reliable signs of the disease progression (in combination with symptomatic deterioration of the patient's condition). The effect was assessed by RECIST 1.1. The levels of cytokines (TNF-α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ) in the blood serum of patients were determined by ELISA before treatment, after 4 and after 8 injections. The results were expressed as specific content (units/mg). Results: The disease progression was registered in 14 patients, complete response in 7, partial response in 3 and stabilization in 8 patients. Only TNF-α was increased after CIT by 39% (11.3 [10.5; 15.4] vs. 8.1 [7.37;10.2] pg/mL, p≤0.037), while levels of IL-2, IL-4, IL-6 and IL-10 were lower than the initial values by 96%, 100%, 36% and 56%, respectively (0.06 [0.03; 0.45] vs. 1.65 [1.2;2.3], p≤0.034; 0 [0; 0.02] vs. 0.09 [0.05; 1.1], p≤0.031; 14.5 [8.5; 15.9] vs. 22.9 [18.1; 24.3], p≤0.042; 3.3 [2.7; 4.1] vs. 7.5 [6.4; 8.3] pg/mL, p≤0.038). No changes were found in the levels of IL-1β and IL-8 in the peripheral blood. Conclusions: Immunotherapy with pembrolizumab in the studied cohort of NSCLC patients after the 8th CIT cycle was characterized by a decline in the levels of cytokines (IL-2, IL-4, IL-6 and IL-10) determining the development of the cellular and humoral immune response, which may contribute to the treatment results.
Phase 2 study of first-line pembrolizumab in elderly patients with non-small cell lung cancer expressing high PD-L1.
Authors: Hamai Kosuke , Masuda Takeshi , Fujitaka Kazunori , Suzuki Tomoko , Matsumoto Naoko , Matsumura Mirai , Isoyama Shoko , Ueno Sayaka , Mito Mineyo , Yamaguchi Kakuhiro , Sakamoto Shinjiro , Kawano Reo , Masuda Ken , Nishino Ryohei , Ishikawa Nobuhisa , Yamasaki Masahiro , Hattori Noboru
Published: June 2022

e21156

Background: Pembrolizumab is the recommended first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, its efficacy and safety for patients ≥75 years has not been prospectively investigated; this was the aim of this study. Methods: This multi-center and open-label single-arm phase II study was conducted at 12 institutions. Chemotherapy-naïve patients with advanced NSCLC and a PD-L1 TPS of ≥50% without EGFR mutations or translocation of the ALK received pembrolizumab (200 mg) every 3 weeks. The primary endpoint was progression-free survival (PFS) with a threshold of 4.3 months. The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety. Quality of life (QOL) was assessed using EORTC QLQ-C30 and EORTC QLQ-LC13. The patients completed the questionnaires immediately after providing informed consent, and also before the third, sixth, twelfth, eighteenth, and twenty-fourth treatment cycles. Results: Twenty-six patients were enrolled between October 2017 and March 2020. The median PFS was 9.6 (95% confidence interval [CI], 2.1–20.6) months. The lower limit of the 95% CI did not exceed the target. The median OS was 21.6 (95% CI, 15.1–not reached) months.The ORR and DCR were 41.7% (24.5–61.2) and 70.8% (50.8–85.1), respectively. The proportion of patients with Grade ≥3 treatment-related adverse events was 15.4%. The Score of Global Health Status/QOL, symptom scales and/or items, and functioning scales of EORTC QLQ-C30 and EORTC QLQ-LC13 did not change significantly during the treatment. Conclusions: This study showed pembrolizumab was tolerable treatment for the elderly patients. Although the primary endpoint, the median PFS (9.6 months) was slightly shorter than that (10.3 months) of the previous phase III study (KEYNOTE-024 study), the median PFS, did not achieve the expected value. Clinical trial information: UMIN000040474.
AKT inhibition as a therapeutic strategy to constrain histological transdifferentiation in EGFR-mutant lung adenocarcinoma.
Authors: Quintanal-Villalonga Alvaro , Taniguchi Hirokazu , Zhan Yingqian A. , Egger Jacklynn V. , Bhanot Umesh , Qiu Juan , de Stanchina Elisa , Rekhtman Natasha , Houck-Loomis Brian , Koche Richard P. , Sen Triparna , Rudin Charles M.
Published: June 2022

e21166

Background: In lung adenocarcinomas (LUADs), lineage plasticity drives neuroendocrine (NE) and squamous cell (LUSC) transdifferentiation in the context of acquired resistance to targeted inhibition of driver mutations, with up to 14% and 9% incidences in EGFR-mutant tumors relapsed on EGFR inhibitors, respectively. Notably, survival of patients with NE- or LUSC-transdifferentiated tumors is remarkably lower than those of LUAD or de novo LUSC patients. The paucity of transforming clinical specimens amenable for molecular analyses has hindered the identification of histological transformation drivers, and to date no specific therapies aimed to prevent or delay transdifferentiation-led therapy relapse are available for patients at high risk of transformation. Methods: We performed multi-omic profiling of LUAD-to-LUSC and LUAD-to-NE transdifferentiating clinical samples, including comprehensive and integrative genomic (whole exome sequencing), epigenomic (bisulfite sequencing), transcriptomic (RNAseq) and protein (antibody arrays) characterization. Clinical findings were validated in preclinical models including cell lines as well as LUSC- and NE-transdifferentiation patient-derived xenograft models. Results: Our data supports that histological transdifferentiation from LUAD to LUSC or NE tumors is driven by epigenetic remodeling rather than by mutational events, and indicate that transdifferentiated tumors retain epigenomic features of their previous LUAD state. Integrative epigenomic, transcriptomic and protein analysis revealed divergent biological pathways dysregulated for each histological outcome, such as downregulation of RTK signaling and Notch-related genes in NE-transformed tumors, and upregulation of genes involved in Hedgehog and Notch signaling and MYC targets in LUSC-transdifferentiated tumors. Most interestingly, these analyses identified commonly dysregulated pathways in both NE- and LUSC-transdifferentiating tumors, including remarkable downregulation of a variety of immune-related pathways and upregulation of genes involved in AKT signaling and in the PRC2 epigenetic remodeling complex. Concurrent activation of AKT and MYC overexpression induced a squamous phenotype in EGFR-mutant LUAD preclinical models, further accentuated by EGFR inhibition. Pharmacological targeting of AKT in combination with osimertinib delayed both squamous and NE transformation in different EGFR-mutant patient-derived xenograft transdifferentiation models. Conclusions: These results identify common and divergent dysregulated pathways in NE and LUSC transdifferentiation, and nominate AKT as a therapeutic target to prevent the acquisition of resistance to EGFR-targeted therapies through histological transdifferentiation.
Temporal evolution in quality of life following melphalan percutaneous hepatic perfusion for patients with metastatic uveal melanoma.
Authors: Vigneswaran Ganesh , Woodcock Pippa , Gibson Tom , Patel Shian , Adil Maryam , Wheater Matthew , Karydis Ioannis , Gupta Sanjay , Stedman Brian , Modi Sachin
Published: June 2022

e21520

Background: Recent studies have demonstrated a clear survival benefit of melphalan percutaneous hepatic perfusion (M-PHP) for liver metastases from ocular melanoma (mUM). Importantly, the survival benefit relating to each treatment cycle must be carefully balanced with changes in patient Quality of Life. We contribute our single centre findings on the temporal change in the quality of life after M-PHP therapy. Methods: We performed a retrospective analysis of the change in quality of life (QoL) using the Functional Assessment of Cancer Therapy - General (FACT-G) with mUM patients receiving M‐PHP at our institutions (n = 13). The FACT-G score which comprises physical (PWB), social (SWB), emotional (EWB) and functional (FWB) wellbeing were measured pre-procedure and at day 1, day of discharge, 7, 14 and 28 days after M-PHP therapy. Paired t-test was used to assess for any significant change in each QoL domain. Results: The baseline FACT-G score was 93.4 out of 108 +/- 14.7 (mean +/- std). Quality of life scoring significantly decreased immediately after the procedure (day 1; 84.8 +/- 13.1, p = 0.01) and gradually improved over time, with no significant difference in total score by the day of discharge; 88.7 +/- 13.7, c.f baseline p = 0.22). By day 28, there was a trend for overall improved QoL (96.6 +/-9.3, p = 0.25). Sub-score analysis revealed that by day 28 there was a statistically significant improvement in EWB (p = 0.02), a trend towards improved scores in PWB and SWB domains. FWB was slightly below baseline by day 28 (23.8 vs 23.2). Conclusions: Quality of life following M-PHP decreases immediately after therapy and is not significantly different from baseline by the day of discharge. By day 28 there is a trend towards improved overall quality of life. This study could provide the basis for determining the optimal time between treatment cycles.
Association of baseline corticosteroid treatment with outcomes for patients (pts) with BRAF-mutant melanoma brain metastases (MBMs) in COMBI-MB treated with dabrafenib and trametinib (DT).
Authors: Wilmott James S. , Banerjee Hiya , Saiag Philippe , Robert Caroline , Grob Jean-Jacques , Long Georgina V. , Davies Michael A.
Published: June 2022

e21546

Background: The COMBI-MB trial showed that DT was safe for BRAF-mutant melanoma pts with MBMs. However, slightly lower intracranial response rates (ICRR) and markedly shorter intracranial progression-free survival (PFS) were observed than in previous trials in pts with extracranial metastases (EM) only. In order to understand the basis of this difference in outcomes, and to inform patient management, we performed post hoc analyses of baseline clinical features to identify associations with ICRR, PFS, and overall survival (OS). Methods: Analyses were performed on all patients (n = 125) enrolled in the COMBI-MB trial. Baseline features included age, gender, ECOG performance status (PS), BRAF genotype (V600E vs V600 other), number of MBM, sum of longest diameters (SLD) of MBMs, maximum MBM size, presence of EM, serum lactate dehydrogenase (LDH), baseline corticosteroid treatment, prior treatments (systemic, radiotherapy to brain, surgery to brain), and presence of uncontrolled MBM symptoms. Univariate (UV) and multivariate (MV, all variables entered) analysis utilized Cox proportional hazards modeling. Associations with ICRR were identified using logistic regression modelling. P values of > 0.05 were considered significant. Results: Corticosteroids treatment at baseline was the only factor associated with ICRR on either UV (p = 0.021) or MV (p = 0.048) analysis. Pts on corticosteroids (n = 13) had an ICRR of 39% versus 63% for patients not on steroids (n = 63) (OR 0.323, 95% CI 0.105-0.996 on MV). Pts receiving corticosteroids also had shorter PFS [median 4.3 versus 6.2 months (mos), HR 1.931, CI 1.061-3.513, P = 0.031 on MV]. BRAF V600E genotype (n = 104, median 5.9 months) was associated with improved PFS versus BRAF V600 other (n = 21, median 4.2 months, HR 0.565, CI 0.321-0.996, P =0.0483 in MV). On UV analysis, OS was associated with elevated LDH (median 10.6 versus 12.7 months, HR 1.595, CI 1.045- 2.434, P = 0.0305), baseline treatment with corticosteroids (median 9.3 versus 13.5 months, HR 1.642, CI 1.037- 2.598, P = 0.0343), and ECOG PS status of 0 (median 18.9 versus 8.2 months, HR 0.435, CI 0.285-0.664). Only ECOG status remained significant on MV of OS (HR 0.441, CI 0.249-0.779, P = 0.0048). Conclusions: Baseline corticosteroid treatment was independently associated with inferior clinical outcomes in MBM pts treated with D+T in COMBI-MB, similar to previous associations reported in immunotherapy trials for pts with MBMs. Likewise, superior outcomes in COMBI-MB patients with BRAFV600E genotype and ECOG status of zero builds on similar observations in COMB-D/V trials of extracranial disease only. The use of corticosteroids to treat symptoms is a major obstacle for the efficacy of systemic treatments for MBMs. Clinical trial information: NCT02039947.
MAP3K8 and ALK alterations in pediatric patients with atypical Spitz tumors and Spitz melanoma.
Authors: Nagel Maggie , Yuan Xiaomeng , McPherson Valerie , Bahrami Armita , Pappo Alberto S.
Published: June 2022

e21569

Background: Pediatric atypical Spitz tumors and Spitz melanoma (AST/SM) are characterized by structural variants (rearrangements/truncations) of various kinase genes more commonly involving MAP3K8 and ALK. The clinical features associated with these genomic abnormalities have not been well characterized. Methods: We reviewed the clinical characteristics and outcomes of children and adolescents with AST/SM who were enrolled on our institutional comprehensive registry for melanocytic lesions MACMEL (Cancer 127:3825, 2021) and abstracted clinical and outcome data for patients with MAP3K8, ALK, and other less common genomic aberrations. Results: Table shows the characteristics and outcomes of patients with AST/SM who had MAP3K8, ALK, and other genomic aberrations. There were 49 patients of whom 21 had MAP3K8 rearrangements/ truncations (n = 11;22%) or ALK rearrangements (n = 10;20%). The remaining 28 patients had fusions involving ARAF (1), ROS1 (2), NTRK1 (3), ERBB2 (1) or rare mutations (ATM = 1) or copy number changes (n = 14) or no identifiable genomic abnormality (n = 6). Female sex was more common in all three groups (32 female and 17 male). The median age for the entire cohort was 7.5 years. Most lesions arose in the extremities (n = 32; 65%). About half had stage III disease. 40 patients underwent sentinel node biopsy (SLNB), 25 had at least one positive node (7/9 MAP3K8, 5/8 ALK, 13/23 other), Forty-four patients had FISH analysis for CDKN2A and homozygous loss was seen in 9/11 MAP3K8-rearranged, 2/6 ALK-rearranged, and 11/27 other tumors. No TERT promoter mutation was detected in any of the 45 tumors that were analyzed. Two patients experienced local recurrence, one with a MAP3K8-STX fusion and one with a FLOT2-ARAF fusion and activating RAC1 mutation. All patients are alive and currently disease free (median follow up of 2.33 years). There were no statistically significant associations between gene mutations and tumor site, gender, or stage. Conclusions: Approximately 40% of patients with AST/SM harbored ALK or MAP3K8 alterations in our pediatric melanoma registry. We found no significant association between the individual genes and any specific clinical features in this limited cohort.[Table: see text]
Clinical outcomes and life expectancy of patients with unplanned excisions of soft tissue sarcoma.
Authors: Morinaga Sei , Yamamoto Norio , Hayashi Katsuhiro , Takeuchi Akihiko , Miwa Shinji , Igarashi Kentaro , Yonezawa Hirotaka , Asano Yohei , Saito Shiro , Tsuchiya Hiroyuki
Published: June 2022

e23554

Background: As soft tissue sarcomas are rare, it is not uncommon that soft tissue sarcoma excision is performed without the required preoperative imaging, staging, or wide resection margins for sarcomas. This study investigated the characteristics of unplanned excision and analyzed the recurrence, life expectancy, and proper treatment for unplanned excision. Methods: Patients who underwent unplanned excision at another institution followed by additional wide excision at our hospital from January 2002 to December 2018 were identified. Forty-two patients met our criteria. The relationships between variables and oncological outcomes were statistically analyzed. Results: The mean age was 57.3 years (15–85 years). Sixty-nine percent (29 in 42) of tumors was in the subcutaneous tissue. Six tumors were located in the upper extremity, 24 in the lower extremity, and 12 in the trunk. Surgical margin after additional wide excision was positive in 10 cases and negative in 32 cases. Pathological examination of specimen showed 34 of 42 cases (80.9%) had residual tumor after primary tumor excision. Fourteen patients (33.3%) required reconstructions. Of the 42 patients, one had both preoperative MRI and biopsy, while nine patients underwent MRI only. Among them, only one patient had enhanced MRI. Ten patients had chemotherapy while no patient had radiotherapy over the follow-up period. The mean tumor size was 5.3 cm (0.8-20 cm). The unplanned excisions were performed by orthopaedic surgeons in 18 cases, by general surgeons in eight, by plastic surgeons in seven, by other surgeons in four. Four primary surgeries (9.5%) were performed in a sarcoma center. On multivariate analysis, positive surgical margin (HR 4.04, 95% CI 1.57-10.4, p < 0.01) was significantly associated with lower 5-year recurrence-free survival. Conclusions: First, to reduce the number of cases of unplanned excision, it should be recognized that small, subcutaneous tumors may be malignant. Second, it is considered that the high recurrence rate with positive margins after additional wide excision might be due to failure to recognize the nature and extent of the tumor without enhanced MRI and biopsy before primary surgery. Finally, surgeons should be aware that positive margin at additional wide excision is an independent risk factor for local recurrence.[Table: see text]
Prolonged disease control with pazopanib following radiation of primary tumor for locally advanced and metastatic soft tissue sarcoma.
Authors: Pan Minggui , Yu Jeanette C , Sidhu Manpreet Kaur
Published: June 2022

e23563

Background: Pazopanib is approved for second or later line therapy for advanced soft tissue sarcoma (STS). Whether or not Pazopanib and radiation have cooperative effect remains unclear. Methods: We retrospectively reviewed 10 patients with locally advanced or metastatic soft tissue sarcoma treated with pazopanib either at the start of radiation or within 4 weeks after the start of radiation. Results: Seven patients were females and age ranged 39-80. Four patients had undifferentiated pleomorphic sarcoma (UPS), two leiomyosarcoma (LMS), two synovial sarcoma (SS), and two dedifferentiated liposarcoma (DDLS). All patients had a large primary tumor that was unresectable with or without distant metastasis. The disease burden with the distant metastasis was low for patients with metastatic disease. Radiation was delivered to the large primary tumor with dose ranging from 15 to 50 Gy (median dose 30 Gy). Pazopanib dose ranged from 400 to 800 mg (majority received 600-800 mg). Eight patients had received one to two lines of chemotherapy previously. Three patients whose pazopanib treatment is still ongoing with stable disease (SD) at 4 (UPS), 25 (LMS), and 26 (DDLS) months respectively. One patient (UPS) with SD discontinued Pazopanib after 3.5 months due to liver toxicities. One patient with SS obtained PR that lasted for 11 months and one patient with SS had SD for 12 months. One patient with relapsed abdominal DDLS obtained a PR followed by resection of residual tumor 8 months after the start of Pazopanib, however, disease relapsed again 3 months after the resection. Three other patients had SD for 8, 8 and 13 months respectively. Conclusions: Our results suggest that Pazopanib at the start or within 4 weeks of radiation in palliative dose can achieve prolonged disease control for patients with locally advanced or metastatic STS. This approach can be considered for selective STS patients with large primary tumor and low distant disease burden.
Relationship between diabetes and its severity, frailty and adverse surgical outcomes among older adults with cancer.
Authors: Martes Josue , Tin Amy L. , Shahrokni Armin
Published: June 2022

e24023

Background: Presence and severity of comorbid conditions impact surgical outcomes of older adults with cancer. The aim of our study is to evaluate the relationship between diabetes mellitus (DM), and preoperative HgbA1c (pHgbA1c) with frailty and adverse surgical outcomes among older adults with cancer. Methods: Retrospective study of patients aged 65 and older who underwent elective cancer surgery with at least one-day hospital stay in 2015-18 at our institution. For our primary aim, we assessed the association between DM and frailty, sociodemographic and clinical characteristics by reporting the characteristics stratified by presence of DM. Frailty was assessed using the Memorial Sloan Kettering Frailty Index (MSK-FI), which composes of 10 comorbidities and one functional component. This score ranges from 0-11, with higher score corresponding to greater frailty. Our secondary aim to assess the association between pHgbA1c and frailty was evaluated by a linear regression with pHgbA1c as the outcome and MSK-FI as the predictor. For our tertiary aim to assess the association between pHgbA1c and adverse surgical outcomes, we used a univariable logistic regression model with the outcome as the composite definition of 30-day readmission, 30-day emergency room visit, 30-day major complication, or 90-day mortality, and pHgbA1c as the predictor. We also used a multivariable logistics regression model, adjusting for age, gender, American Society of Anesthesiologist Performance Status (ASA-PS), and operation time.Analyses related to pHgbA1c excluded patients without pHgbA1c records. Results: Among 4417 patients, 1024 (23%) had DM and among those 403 (39%) had pHgbA1c values recorded. The results showed patients with DM were older, had higher ASA-PS, more comorbidities and higher MSK-FI scores than those without DM. Moreover, pHgbA1c was not found to be statistically associated with degree of frailty (β for one unit change in MSK-FI 0.11, 95% CI 0.00, 0.21; p = 0.057). Lastly, in both unadjusted and adjusted models pHgbA1c was not associated with adverse surgical outcomes (OR for both models, 0.99, 95% CI 0.83, 1.16, p = 0.9). Conclusions: In this cohort of patients whose pHgbA1c values were recorded, pHgbA1c was not associated with adverse surgical outcomes. Further studies are needed to confirm this study with more focus on perioperative care process of patients with DM and find cohorts whose pHgbA1c measurements can better predict frailty and adverse surgical outcomes.