bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.