bluuebunny/crossref_metadata_2025_split huggingface dataset:
ALK fusion typing and response to crizotinib in ALK+ lung cancer-naive patients.
Authors: Zhou Xinliang , He Liyuan , Fan Zhisong , Zuo Jing , Feng Li , Wang Long , Han Jing , Liu Jiayin , Zhang Xue , Li Dan , Liu Feiran , Zhao Honghui , Wang Yudong 
Published: June 2022

e21008 Background: Anaplastic lymphoma kinase (ALK) is one of the major oncogenic driver genes in lung cancer, and fusion as the main mutation type, of which EML4 is the most common fusion ligand. With the development of next-generation sequencing (NGS), some other rare fusion ligands and complex fusions have been discovered. The prognosis of patients with EML4-ALK fusion, non EML4-ALK fusion and multiple ALK fusion was different. Methods: We retrospectively analyzed NGS (including tissue, blood, or other body fluid samples) in 61 patients with ALK[+] lung cancer, including 59 patients with NSCLC and 2 patients with SCLC. Grouping was determined according to whether it was EML4-ALK fusion and multiple fusion. Results: In our data, the partner fused to the ALK gene are diverse, including EML4, KIF5B, TSN and others. Among them, EML4 was the most common ligand in ALK[+] NSCLC, accounting for 93.2% (55/59). Among the different fusion sites of EML4-ALK, V1 (E13:A20) and V3 (E6:A20) mutations were the most common, accounting for 45.5% (25/55) and 41.8% (23/55), respectively. Several novel ALK fusion partners were discovered in this study, including MCFD2, LINC01251, MVP17, CREG2, LINCO1498 and so on. In addition, the incidence of intergenic sequence-ALK fusions was 16.4% (10/61), such as ANXA4-ALK(A[intergenic]:A20), CREG2-ALK (C[intergenic]:A20), HCN1-ALK(H[intergenic]:A20), TSN-ALK(T[intergenic]:A20), RSAD2-ALK(R [intergenic]:A20) and so on. 19.0% (12/61) of the patient had multiple fusion, of which only one patient had multiple fusion of EML4-ALK (V2+V5'+V3a/b), and the remaining patients had co-fusion of EML4-ALK and non EML4-ALK (Table). V3 were more likely to coexist with non EML4-ALK fusions than V1 or other variants (P = 0.047). Multiple fusions were more likely to occur with non EML4-ALK fusions (P < 0.000). Compared with EML4-ALK fusion, mPFS treated with crizotinib in non EML4-ALK fusion were significantly shorter (18.2 vs. 8.5 months, P = 0.035). In the context of crizotinib treatment, multiple fusions were associated with worse mPFS compared with single fusions (13.8 vs. 8.4 months, P = 0.008). In addition, For SCLC patients with ALK fusion (n = 2), the PFS of crizotinib treatment were 8.0 and 30.6 months, respectively. Conclusions: Due to the heterogeneity of tumor development resulting in the diversity of ALK fusions, non EML4-ALK fusions and multiple fusions imply a poorer response to crizotinib. ALK gene status prior to ALK-TKI therapy helps predict drug efficacy and patient prognosis.[Table: see text]
Screening of FGFR patients for FGFR directed clinical trials in Network Genomic Medicine (NGM): Real-world data.
Authors: Scharpenseel Heather , Malchers Florian , Terjung Inken , Hillmer Axel , Merkelbach-Bruse Sabine , Scheel Andreas H. , Siemanowski Janna , Scheffler Matthias , Riedel Richard , Eisert Anna , Michels Sebastian Yves Friedrich , Fischer Rieke Nila , Weber Jan-Philip , Westphal Theresa , Kron Anna , Sueptitz Juliane , Thomas Roman K. , Buettner Reinhard , Wolf Juergen , Nogova Lucia 
Published: June 2022

e21013 Background: The fibroblast growth factor receptor (FGFR) 1-4 genes show a heterogenic landscape of alterations in non-small cell lung cancer (NSCLC) whereas only a small amount is yet considered to have oncogenic potential. The frequency of activating FGFR alterations is low, counting for approximately 2% of NSCLC. We have screened NSCLC patients (pts) for FGFR translocations/mutations within NGM and analysed them on FGFR alteration frequency, patient characteristics and outcome. Methods: From 04/2019 to 01/2020 we screened 472 squamous NSCLC for FGFR gene alterations and from 02/2020 to 12/2021 an additional 5286 patients including all NSCLC cases. Of these 5286 pts, 1097 pts were analysed for FGFR fusions. We used DNA-NGS for FGFR-mutations and RNA-NGS for FGFR–translocations. Activating mutations were defined according to the publicly available molecular data bases and published data. Results: Within the cohort of 5758 NSCLC patients, we found 316 (5.5%) patients with FGFR alterations. Sixty-six (20.9% of FGFR, 1.1% of NSCLC) patients had alterations classified as activating, of whom 39 had FGFR point mutations and 27 FGFR translocations. Concerning the patients with activating alterations, they had UICC stage III or IV at time of diagnosis; 22 were females; 58 patients had squamous cell carcinoma, 6 patients had adenocarcinoma and 2 had large cell neuroendocrine carcinoma. Fifty-three patients (80.3%) with activating FGFR alteration had a co-mutation: TP53 (inactivating) co-mutation was seen in 41 cases (62.1%) and 19 cases had either PTEN (7 pts), KRAS (4), EGFR (3), PIK3CA (2), ROS1 (1), ALK (1) or BRAF (1) mutations. Ten patients were included in a FGFR-targeted trial. Sixty patients were available for follow-up. The median overall survival (mOS) was 21.4 month (95%CI: 16.8–25.9) for all patients with activating FGFR alteration, whereas mOS was 18.5 month (95%CI: 13.2-23.9) for FGFR mutation and 25.3 months (95%CI: 17.8-32.9) for FGFR fusions. Conclusions: FGFR 1-4 gene alterations are rare. Large molecular and clinical networks are necessary to identify these pts. Prognostic factors of FGFR patients are currently not defined. Further assessments on molecular and clinical features in FGFR altered NSCLC are needed to identify sensitivity to FGFR inhibition. Clinical trials with specific FGFR inhibitors are ongoing.
MIF improves immune microenvironment of Lewis lung cancer brain metastases after radiotherapy via reducing M2 macrophages.
Authors: Wang Ying , Dong Xiaorong 
Published: June 2022

e21026 Background: Our previous studies showed that inhibition of MIF/CD74 signaling pathway can promote the transformation of intracranial macrophages from M2 to M1 type after radiotherapy in brain metastases(BMs). It is reported that M2 macrophages are the main components of tumor immunosuppression microenvironment, and the surface marker, ARG-1, can decompose the Arginine which is essential in the growth and development of T cells. Therefore, this paper will focus on the mechanism of MIF regulating tumor infiltrating lymphocytes (TILs) by inducing macrophage phenotype transformation. Methods: MIF-Knockdown in Lewis cells were constructed by lentiviral shRNA interference technique. The expression levels of MIF in Lewis and iNOS (M1 type marker), Arg-1 (M2 type marker) in BV2 cells were detected by WB. The RNA expression levels of M1 and M2 tags were detected by qPCR. The expression of iNOS, Arg-1 and Iba-1 in lung cancer BMs model mice was detected by IF. The content of arginine in tumor tissue and clinical patient specimens were detected by Arginine kit. The proportion of TILs in vivo was measured by flow cytometry. BMs tumor growth in mice was observed by Small Animals Imaging Technology. Results: In animal experiments, WB、PCR and IF results showed that MIF knockdown (sh-MIF) combined with whole brain irradiation(IR) can raise the expression of iNOS, while the Arg-1 lessend, suggesting that downregulation of MIF can promote M1 phenotype and reduce M2 phenotype. Flow cytometry results showed that sh-MIF combined with IR increased the proportion of CD8+T/CD4+T cells . After clearance of macrophage, Flow cytometry showed no difference between the sh-MIF group and the control group (NC). Small Animals Imaging results also showed that the inhibition of tumor growth by sh-MIF was less significant than macrophages presence. It is indicated that down-regulation of MIF expression combined with irradiation promote T cell infiltration and inhibit tumor may be mediated by macrophages. Arginine kit results showed that the content of arginine increased after IR or sh-MIF, while it increased overall after macrophage clearance, but the difference between each groups was not significant, suggesting that IR or sh-MIF could increase the content of arginine by reducing M2-type macrophages. Flow cytometry and animals imaging results showed that the CD8+/CD4+TILs ratio was increased and tumor growth was inhibited after the addition of exogenous arginine. In clinical samples, the content of arginine in CSF decreased after radiotherapy, which suggests that arginine supplementation has the potential to improve the effect of radiotherapy. Conclusions: Inhibitory MIF expression can reduce the expression of Arg-1 from M2 type macrophages in BMs, thus raise the content of arginine, promote the infiltration of lymphocytes, improve the immune microenvironment, achieve radiotherapy sensitization finally.
Is recent FDA guidance on HRQoL clinical significance a barrier to clinician/patient treatment risk/benefit discussions: An example using EORTC scale endpoints in a randomized, phase 3 trial.
Authors: Podger Lauren , McManus Shauna , Iaconangelo Charles , Serrano Daniel 
Published: June 2022

e21066 Background: Recent FDA guidance on clinical significance thresholds (CSTs) may adversely affect the evaluation of EORTC endpoints, thereby altering clinician/patient discussions about treatment (Tx) risk/benefit for emerging Tx. Specifically, FDA now rejects historic CSTs for EORTC measures (e.g., Osoba, 1998 10-point change). FDA’s guidance implies that EORTC function/symptom CSTs should be ±33.331; in addition, Tx arms must separate at the CST. Few, if any, EORTC domains are likely to achieve CSTs 3 times those of Osoba (1998). Holding health-related quality of life (HRQoL) endpoints to this standard may limit detection of clinically meaningful patient-centric Tx benefits & clinician/patients dialogue about HRQoL for emerging cancer Tx. The NCI-conducted Sunitinib trial data (NCT00693992), obtained through Project DataSphere, was used to generate revised deterioration thresholds for EORTC scales under an anchor-based meaningful change approach. This this Phase 3 trial met it’s primary PFS endpoint. Evidence from this research highlights the potential implications of the FDAs position on COA-based CSTs. Methods: The Sunitinib trial was a randomized, phase 3 study comparing the efficacy & safety of Sunitinib versus placebo as a maintenance therapy in non-progressing patients following chemotherapy in advanced non-small cell lung cancer. Symptoms & HRQoL were measured by EORTC LC13. The analysis population consisted of 107 patients in the HRQoL substudy completing the QLQ-C30 Global Health/QoL scale (GHS). The GHS was used to categorize patients into: no change (0 pt. change), deterioration (≤-1 pt. change) & improvement (≥1 pt. change). Deterioration thresholds were estimated as the mean LC13 scale change-scores & visualized with empirical cumulative distribution functions (eCDFs). Results: See Table. Within this population, interpretable mean deterioration CSTs were found Dyspnea, Diarrhea, and Nausea/Vomiting. At these CSTs, Tx arms separated in eCDFs except for Dyspnea. However, while Dyspnea & Diarrhea CSTs exceeded Osoba’s CSTs, none met the FDA criterion of + 33.33 points change. Conclusions: The LC13 scores had interpretable CSTs; evidence suggests FDA’s CST criterion may be unachievable for EORTC scales & may thereby affect HRQoL endpoints. This research was limited by the use of the GHS as an anchor variable rather than a PGIS. The main risk is that FDA’s CST criterion may limit the characterization of truly meaningful Tx benefits for patients & clinician communication with patients about HRQoL for emerging Tx. Clinical trial information: NCT00693992. [Table: see text]
Outcomes of cardiac tamponade in patients with lung cancer.
Authors: Aung Pyi Phyo , Park Kyeeun , Nge Htoo Myat 
Published: June 2022

e21083 Background: Cardiac tamponade is a serious complication of pericardial effusion and life-threatening cardio-oncological emergency. The prevalence of malignant pericardial effusion varies between 1% and 20% in autopsy studies. Primary lung cancer is the most common cause of metastatic tumor involving the pericardium. The common triggers for pericardial effusion in patients with lung cancer include cancer itself, chemotherapy and radiation therapy. The outcomes of cardiac tamponade in patients with lung cancer remain to be elucidated. Methods: We conducted a retrospective analysis of the 2016 to 2018 Nationwide Inpatient Sample. Adult patients with lung cancer and cardiac tamponade (age ≥ 18) were selected using the ICD-10 diagnosis code. Discharge-level weight analysis was used to produce a national estimate. A univariate and multivariable hierarchical regression analysis was performed to calculate the odds ratio (OR). Results: During the study period, 1,207,580 patients were admitted due to lung cancer of which 7,105 (0.6%) developed cardiac tamponade. Patients with cardiac tamponade tended to be younger (63.2 SE 0.3 vs 69.1 SE 0.2), male (54.5% vs 51.2%) and large proportion of radiation treatment (0.9% vs 0.7%), and smaller proportion of diabetes (18.5% vs 24.2%), chronic kidney disease (4.5% vs 7.6%) and heart failure (15.9% vs 16.2%). After adjusting for age, sex, comorbidity burden and heart failure, cardiac tamponade increased the risk for in-hospital mortality (OR 2.1; 1.9 – 2.5; p < 0.001), major adverse cardiac events (OR 1.6; 1.3 – 2.1; p < 0.001) and acute respiratory failure (OR 2.3; 2.0 – 2.5; p < 0.001). Furthermore, cardiac tamponade was associated with longer length of stay (8.6 SE 0.2 vs 6.0 SE 0.01, p < 0.001) and higher total hospital cost ($118,708.0 SE $4,027.1 vs $65,369.8 SE $170.6). Conclusions: In conclusion, patients with lung cancer who developed cardiac tamponade were associated with poor outcomes including higher in-hospital mortality, MACE, acute respiratory failure, a longer length of stay by 2.6 days, and higher cost of hospitalization. Cardiac tamponade was more common in males and patients who received radiation therapy. Further studies are warranted to develop an optimal management guideline for this cardio-oncological emergency.
Bone metastasis reduces responsiveness to EGFR-TKIs in patients with EGFR-mutated advanced lung adenocarcinoma.
Authors: Jiang Kan , Lin Gen , Zheng Xinlong , Long Feng 
Published: June 2022

e21085 Background: The response of epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) to bone metastasis site in patients with EGFR mutated lung adenocarcinoma remains to be determined. Methods: This is a retrospective analysis of the efficacy of EGFR-TKIs for lung adenocarcinoma patients with EGFR mutations, comparing patients with bone metastases (BM) and those with no bone metastases (NBM). BM patients need extra imaging to assess the efficacy of bone metastasis sites . Overall response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and progression patterns were evaluated. Results: Of the 502 patients, 175 were enrolled (BM 96, NBM 79) from January 2012 to December 2017. 125 patients had disease progression on January 31, 2018. The clinical characteristics of the two groups were not significantly difference. The median PFS was 11.0 months in NBM group and 7.0 months in BM group ( P= 0.013) . The median PFS in patients with multiple BM (≥ 4) was significantly lower than that in patients with oligometastases (1-3) and NBM (7.0 months vs 10.0 months vs 11.0 months, P = 0.003). Multivariate analysis confirmed that bone metastasis was an independently negative predictor of PFS for EGFR-TKIs ( P = 0.017). The ORR and DCR of NBM group were higher than those of BM group (70.9% vs 56.3%, P = 0.046 and 96.2% vs 85.4%, P= 0.017). Bone was one of the frequently progressive sites of EGFR-TKIs therapy, accounting for 52 of 125 (41.6%). The incidence of bone progression in NBM patients was significantly lower than that in BM patients(11.8% vs 62.2%, P < 0.001). Conclusions: Bone metastasis, especially multiple bone metastasis, reduces the response to EGFR-TKIs for lung adenocarcinoma with EGFR mutations. Bone metastasis monitoring should be a routine clinical practice for BM patients.
Obesity diabetes and dyslipidemia as determinants of immune checkpoint inhibitors response in non-small cell lung cancer.
Authors: Awidi Muhammad , Osataphan Soravis , Jan Yu Jen , Frankenberger Edward , Mariano Melissa , Stafford Katherine Ann , Kolnick Aleksandra , Ghazalah Hind , Patti Mary-Elizabeth , Gunturu Krishna Soujanya , Lam Prudence B. 
Published: June 2022

e21104 Background: Immune checkpoint inhibitors (ICI) are standard of care in the treatment of non-small cell lung cancer (NSCLC). Predictive markers of response to ICI are being studied extensively. Obesity has been correlated with a better response to ICI in NSCLC and other types of cancer. This may in-part be related to high circulating leptin or impaired T-cell fatty acid oxidation within the tumor microenvironment. We aim to further explore the effects of obesity, dyslipidemia and other components of the metabolic syndrome such as diabetes on treatment outcomes on NSCLC patients receiving ICI. Methods: We conducted a retrospective cohort study in patients with NSCLC treated with pembrolizumab, nivolumab, durvalumab, cemiplimab or atezolizumab as monotherapy or combined with chemotherapy at Mount Auburn and Lahey Hospital between January 2016 to June 2021. Obesity was defined as body mass index (BMI) > 30 kg/m2, dyslipidemia and type 2 diabetes were defined by ICD-10 diagnosis codes. Overall survival was evaluated. Kaplan-Meier survival analysis and cox proportional hazards regression were used to assess correlation between overall survival and obesity, dyslipidemia, type 2 diabetes, metformin use and statin use. These were adjusted for age, biological sex, cancer stage, ECOG and smoking status. Patients with BMI < 18.5 were excluded. Results: We identified 408 patients with NSCLC who were treated with ICIs. Of these, 66.7% had adenocarcinoma, 29.1% had squamous and 4.2% had either adenosquamous, large cell or poorly differentiated carcinoma. Among these patients 23.3% were classified as obese, 55.6% had dyslipidemia and 23% had type 2 diabetes. Of these, 66% of patients received ICIs as monotherapy. Median survival was 840 days in obese patients compared to 483 days in non-obese patients (HR 0.66, CI 0.42-0.92, p = 0.014). Conversely, within this cohort, median survival in patients with dyslipidemia was 483 days when compared to 762 days in controls (HR 1.37, CI 1.07-1.81, p = 0.013). Overall survival was not significantly different between type 2 diabetes, metformin use or statin use. Conclusions: Our study shows a trend towards a better survival in obesity and poor survival associated with dyslipidemia. Obesity and dyslipidemia may be important markers of ICI response in patients with NSCLC regardless of treatment strategies. Further studies are needed to explore the molecular mediators within the metabolic syndrome that may provide a synergistic effect with immune checkpoint inhibitors.
Low infiltration of CD8+ FOXP3+ T cells associated with favorable clinical outcomes after first-line targeted therapy in EGFR exon 21 mutated lung adenocarcinoma patients.
Authors: Liu Kejun , Tan Quanquan , Peng Kai-Cheng , Chen Shiyuan , Su Junwei , Zhang Chanyuan , Chen Yuqing , Wu Ligang , Zheng Xue , Zheng Hongbo , Mao Beibei , Zhang Shihao , Jia Jun , Yang Jin-Ji 
Published: June 2022

e21107 Background: As the standard first-line treatment for NSCLC patients with EGFR-sensitive mutation, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) were proved to be highly effective and less toxic compared to traditional chemotherapeutic regimens. But little is known about the correlation between tumor-infiltrating immune cells in the tumor microenvironment and clinical outcomes. This study was designed to investigate the association between tumor-infiltrating immune cells and the clinical outcome after first-line targeted therapy in EGFR exon 21 mutated lung adenocarcinoma (LUAD) patients. Methods: A total of 26 advanced LUAD patients with EGFR exon 21 mutation who received first-generation EGFR-TKIs as initial therapy between January 2017 and October 2019 were included in this study. All the patients were treated at Affiliated Dongguan Hospital, Southern Medical University, China. Patients who progressed within 12 months after first-line EGFR-TKIs therapy were defined as experiencing early progression (EP), and patients who progressed after 12 months or without progression were defined as experiencing late progression (LP). We analyzed immune markers in biopsy from these patients before treatment with EGFR-TKIs and examined the infiltration of immune cells and expression of PD-L1 in immune cells using fluorescent multiplex immunohistochemistry (mIHC) stained with CD8/CD56/CD68/CD163/FOXP3/PD-L1 antibodies. Results: In this cohort, we observed that after first-line EGFR-TKIs therapy in EGFR exon 21 mutated LUAD patients, the density of CD8+ FOXP3+T cells infiltrated in tumor area of LP group was significantly lower than EP group (P = 0.038). However, the difference of the density of the other infiltrated immune cells including CD8+T cells, FOXP3+Treg cells, CD8+PD-L1+T cells, CD68+CD163+M2macrophages, etc., were not significant between LP group and EP group (P > 0.05). The “optimal” cutoff value for CD8+ FOXP3+T cells infiltrated in tumor area was 5.45 (n/mm2) using the survminer package in R software according to PFS. Kaplan-Meier analysis suggested that the density of CD8+ FOXP3+T tell infiltrated in tumor area contributed to risk factor for PFS (HR = 5.56, P = 0.00054). Taking 5.45 (n/mm2) as the cutoff value, the percent of LP patients in low density of CD8+ FOXP3+T cells infiltrated in tumor area group was close to being statistically significant higher than high density of CD8+ FOXP3+T cells group (47% vs. 0%. P = 0.058). Conclusions: This study indicated that the low density of CD8+FOXP3+ T cells infiltrated in tumor area was associated with favorable clinical outcome in EGFR exon 21 mutated LUAD patients treated with first-generation EGFR-TKIs at first-line.