Primary nodal Epstein-Barr virus-positive T-cell/NK-cell lymphoma: Real-world experience.

PTCL-EBV is a disease entity newly recognized in the WHO-HAEMS5 and the ICC of Mature Lymphoid neoplasms classification. Previously, it was classified as a subtype within PTCL-NOS and was known to have a poor prognosis. However, the clinical feature and treatment outcomes are not well known. This retrospective observational study was conducted on patients diagnosed with PTCL-EBV at Samsung Medical Center through a pathology review from 2000 to 2020. We analyzed clinical data from 14 patients. We conducted an investigation of patients with PTCL-EBV into immunohistochemistry and analysis of survival outcomes for each treatment regimen. We analyzed both overall survival and progression-free survival for each treatment regimen. 25% were beta-F1 positive, and 67% were TCRγ positive. TIA-1 and granzyme B exhibited positive results in all cases, whereas the NK cell marker CD56 was negative in only 11% of patients. The CD3 was observed in all of patients. And, the CD4 was 43% positive. The CD8 were investigated in 8 patients, with 37.5% positive. Hepatosplenomegaly was observed in 55% of patients, and 70% of patients displayed B symptoms at the time of diagnosis. Patients who received CHOP or CVP treatment had a median PFS of 2.2 months (95% CI 1.9-2.5 months), and patients who received other treatments had a median PFS of 5.1 months (NA). The objective response rate (ORR) for ICE/dexa as the first or second line treatment was 100% (3 out of 3). But, ORR of CHOP or CVP as the first line treatment was 33.3% (3 out of 9). The median overall survival (OS) for the group that received HSCT after achieving a response was 34.6 months (95% CI 0-74.6 months), and the median OS for the group that did not receive HSCT was 5.0 months (95% CI 2.1-7.9 months) (p=0.04). In conclusion, in the context of PTCL-EBV, despite a limited sample size, the ICE/Dexa regimen shows potential benefits in terms of ORR and PFS. Furthermore, the application of HSCT following the attainment of a complete response may prove advantageous.

Tumor mutation burden in gastro-entero-pancreatic-neuroendocrine neoplasms.

Background: As rare tumors, there are limited treatment options for neuroendocrine neoplasms (NENs). Recently, microsatellite instability (MSI) and tumor mutation burden (TMB) have been emerging as potential biomarkers in various tumors. However, there is a lack of research on the use of these biomarkers in gastro-entero-pancreatic (GEP)-NENs. Methods: We analyzed 31 patients diagnosed with GEP-NEN between 2013 to 2022. The TMB and MSI analyses using next-generation sequencing (NGS) were performed for all patients. The TruSightTM Oncology 500 assay from Illumina was used as the NGS panel. Results: Out of the 31 patients analyzed, the most frequent primary origin was the pancreas (12 patients, 38.7%), followed by the stomach (4 patients, 12.9%), gallbladder (4 patients, 12.9%), rectum (7 patients, 22.6%), small bowel (2 patients, 6.5%), and bile duct (1 patient, 3.2%). Among these patients, 19 (61.3%) were diagnosed with well-differentiated neuroendocrine tumors, with grade 2 being the most common (15 patients, 48.4%), followed by grade 3 (3 patients, 9.7%) and grade 1 (1 patient, 3.2%). Neuroendocrine carcinoma was confirmed in 12 patients (38.7%). The median number of metastases was 2.0 [interquartile range (IQR), 1.0-3.0], and the liver was the most common site of metastasis (23 patients, 74.2%). The median TMB was 4.7 (IQR, 3.1-6.3) mutations/Mb, and all tumors were classified as microsatellite stability (MSS). Only one patient had a high TMB (266.4 mutations/Mb), which was a grade 3 neuroendocrine tumor originating from the pancreas. The TMB value did not vary depending on the primary tumor site or World Health Organization (WHO) grade. Conclusions: This analysis showed that, despite very low incidence, there are GEP-NENs with high TMB. For precision medicine, testing for MSI and TMB is needed for this tumor type.

Trends in Survival Rates of Non-Small Cell Lung Cancer With Use of Molecular Testing and Targeted Therapy in Korea, 2010-2020.

Importance: Over the past 10 years, treatment of non-small cell lung cancer (NSCLC) has been continually revolutionized. However, standard clinical trials may not reflect current multiple lines of treatment and corresponding outcomes in a timely manner. Objective: To investigate outcomes associated with new treatment of NSCLC in a clinical setting. Design, Setting, and Participants: This cohort study included patients with NSCLC between January 1, 2010, and November 30, 2020, who received any anticancer treatment at Samsung Medical Center in Korea. Data were analyzed from November 2021 through February 2022. Exposures: Clinical and pathological stage, histology, and major druggable sequence variation, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, RET, MET exon 14 skipping, BRAF V600E, KRAS G12C, and NTRK between 2 periods (period I: 2010-2015 vs period II: 2016-2020). Main Outcomes and Measures: The primary outcome was the 3-year survival rate of NSCLC. Secondary outcomes included median overall survival, progression-free survival, and recurrence-free survival. Results: Among 21 978 patients with NSCLC (median [range] age at diagnosis, 64.1 [57.0-71.0] years; 13 624 males [62.0%]), there were 10 110 patients in period I and 11 868 patients in period II; adenocarcinoma (AD) was the predominant histology (7112 patients [70.3%] in period I and 8813 patients [74.3%] in period II). There were 4224 never smokers [41.8%] in period I and 5292 never smokers [44.6%] in period II. Compared with patients in period I, patients during period II were more likely to undergo molecular tests in the AD (5678 patients [79.8%] vs 8631 patients [97.9%]) and non-AD (1612 of 2998 patients [53.8%] and 2719 of 3055 patients [89.0%]) groups. In patients with AD in period I, 3-year survival rates were 92.8% (95% CI, 91.8%-93.7%), 72.4% (95% CI, 68.3%-76.8%), 56.7% (95% CI, 53.4%-60.2%), and 28.7% (95% CI, 27.0%-30.4%) for stage I, II, III, and IV, respectively. In period II, 3-year survival rates of patients with AD were 95.1% (95% CI, 94.4%-95.9%), 82.5% (95% CI, 79.1%-86.1%), 65.1% (95% CI, 61.8%-68.6%), and 42.4% (95% CI, 40.3%-44.7%) for each stage, respectively. In patients without AD, 3-year survival rates were 72.0% (95% CI, 68.8%-75.3%), 60.0% (95% CI, 56.2%-64.1%), 38.9% (95% CI, 35.6%-42.5%), and 9.7% (95% CI, 7.9%-12.1%) for each stage in period I. In period II, the 3-year survival rates of patients without AD were 79.3% (95% CI, 76.3%-82.4%), 67.3% (95% CI, 62.8%-72.1%), 48.2% (95% CI, 44.5%-52.3%), and 18.1% (95% CI, 15.1%-21.6%) for each stage. Conclusions and Relevance: In this cohort study of 10 years of clinical data, survival outcomes were improved across all stages, with larger increases in patients with stage III to IV disease. The incidence of never-smokers and the use of molecular testing increased.

The role of ramucirumab plus paclitaxel as second-line therapy after failure of nivolumab plus doublet chemotherapy in patients with advanced gastric cancer.

Background: Adding nivolumab to fluoropyrimidines and platinum agents has been considered a new standard first-line treatment in previously untreated human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC). However, there were few data on the role of ramucirumab plus paclitaxel as second-line treatment after failure of nivolumab plus doublet chemotherapy. Herein, we analyzed the efficacy and safety of second-line ramucirumab plus paclitaxel in AGC patients refractory to nivolumab plus chemotherapy. Methods: This analysis included AGC patients with ramucirumab plus paclitaxel as second-line therapy after failing to respond to nivolumab plus doublet chemotherapy [capecitabine plus oxaliplatin (XELOX) or 5-fluorouracil plus oxaliplatin (FOLFOX)] at Samsung Medical Center, Korea. Twenty patients who progressed on nivolumab plus chemotherapy as first-line therapy were treated with ramucirumab plus paclitaxel between December 2021 and September 2022. Results: The median age was 56 (range, 24-76) years, and 13 (65.0%) were men. Of the 20 patients, 15 (75.0%) patients received nivolumab plus capecitabine, and oxaliplatin, while 5 (25.0%) patients received nivolumab plus 5-fluorouracil, and oxaliplatin. Two showed a partial response (PR) to ramucirumab plus paclitaxel, a response rate of 10%. Patients with stable disease (SD) accounted for a disease control rate (DCR) of 55.0%. The median progression-free survival (PFS) to ramucirumab plus paclitaxel was 2.7 months [95% confidence interval (CI): 1.7-3.7]. Subgroup analysis showed that responders (n=7) to first-line therapy had a PFS of 6.9 months compared to 2.3 months in non-responders (n=13) to first-line therapy. The median overall survival (OS) was 6.3 months (95% CI: 5.5-8.3), representing 6.9 months (95% CI: not calculated) in responders and 6.3 months (95% CI: 3.7-8.9) in non-responders (P=0.401). Conclusions: This analysis suggested that ramucirumab plus paclitaxel as second-line therapy might be further studied in AGC patients after failure of nivolumab plus chemotherapy. A new second-line therapy is needed in AGC patients after nivolumab plus chemotherapy.

Effect of ramucirumab plus paclitaxel in advanced gastric cancer according to the status of programmed cell death-ligand 1 (PD-L1) expression.

Background: Ramucirumab, an anti-vascular endothelial growth factor receptor (VEGFR) monoclonal antibody (mAb), inhibits angiogenesis and reduces tumor activity. Programmed cell death-ligand 1 (PD-L1) might act upon VEGFR2 to induce cancer cell angiogenesis and metastasis. Herein, we investigated the efficacy of combining ramucirumab and paclitaxel according to the status of PD-L1 expression in patients with advanced gastric cancer (AGC). Methods: This analysis included AGC patients who received ramucirumab plus paclitaxel as 2nd line therapy between December 1, 2018, and February 28, 2022, at Samsung Medical Center. All patient data analyses included an evaluation of PD-L1 expression using the combined positive score (CPS). We analyzed the efficacy and the survival of patients according to their PD-L1 expression. Results: We included 117 patients in this analysis, and 80 patients (68.4%) had a PD-L1 CPS of one or more, 37 (31.6%) had five or more, and 19 (16.2%) had ten or more scores. Progression-free survival (PFS) and overall survival (OS) did not differ significantly between patients with a PD-L1 CPS of less than one and one or more {PD-L1 <1% vs. PD-L1 ≥1%; PFS: median 3.6 months [95% confidence interval (CI): 2.4-4.8 months] vs. median 4.1 months (95% CI: 3.5-4.7 months), P=0.93; PD-L1 <1% vs. PD-L1 ≥1%; OS: median 7.0 months (95% CI: 5.4-8.6 months) vs. median 8.1 months (95% CI: 6.4-9.8 months), P=0.32}. PFS and OS did not differ significantly between patients with a PD-L1 CPS of less than 5 and 5 or more [PD-L1 <5% vs. PD-L1 ≥5%; PFS: 3.9 months (95% CI: 3.3-4.5 months) vs. 4.4 months (95% CI: 3.0-5.8 months), P=0.57; OS: 7.4 months (95% CI: 6.5-8.3 months) vs. 10.0 months (95% CI: 1.1-18.9 months), P=0.07]. Interestingly, with a PD-L1 CPS cutoff of 10, PFS and OS did differ significantly [PD-L1 <10% vs. PD-L1 ≥10%; PFS: 3.8 months (95% CI: 3.3-4.3 months) vs. 5.7 months (95% CI: 4.1-7.3 months), P=0.05; OS: 7.2 months (95% CI: 6.5-7.9 months) vs. 18.9 months (95% CI: 6.5-31.3 months), P=0.04]. Conclusions: No biomarkers have been established to predict survival times after ramucirumab plus paclitaxel treatment. This analysis suggests that a PD-L1 CPS cutoff of 10 might be novel a biomarker to predict the survival of AGC patients treated with ramucirumab and paclitaxel.

Effectiveness and safety of amivantamab in EGFR exon 20 insertion (E20I) mutations in non-small cell lung cancer (NSCLC).

Background: In non-small cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) mutation is a representative oncogenic driver mutation. Only about 12% of EGFR mutation patients have the exon 20 insertion mutation, which is the third most frequent mutation among EGFR mutation NSCLC. Amivantamab, an EGFR and MET proto-oncogene, receptor tyrosine kinase (MET) bispecific antibody, was approved for NSCLC patients with the EGFR exon 20 insertion (E20I) mutation. In this study, we described the real-world, single-center efficacy and safety data of amivantamab in E20I mutation patients. Methods: This study included metastatic NSCLC patients with EGFR E20I mutations. From January 2018 to June 2022, patients with EGFR E20I mutations who were treated with amivantamab were analyzed at Samsung Medical Center as part of the clinical trial or the early access program (EAP). We collected the patients' characteristics [age, sex, smoking history, location of mutation, sites of metastasis, programmed death-ligand 1 (PD-L1) expression status, etc.] and analyzed progression-free survival (PFS) and overall survival (OS) stratified by PD-L1 expression status, co-mutation such as tumor protein p53 (TP53), and metastasis sites. Results: A total of 42 patients were analyzed, of which 16 patients were enrolled in the phase 1 study, and 26 patients received amivantamab through EAP. There were 14 (33%) patients with partial remission, 18 (43%) patients with stable disease, and 10 (24%) patients with disease progression. The objective response rate (ORR) was 33%, and the disease control rate (DCR) was 76%. PFS was analyzed by dividing the near and far loop for 31 patients whose mutation location was known. The two groups had no statistically significant difference in PFS [median (range): 11.8 (2.3-21.3) vs. 11.3 (3.4-19.2) months, P=0.69]. For 29 patients with TP53 mutation data, there was no significant difference in PFS between the two groups [median (range): 5.9 (0-18.0) vs. 12.6 (6.9-18.3) months, P=0.11]. When analyzing PFS in 37 patients with PD-L1 expression data, PD-L1 (+) patients showed a poor prognosis [median (range): 11.3 (5.0-17.6) vs. 19.5 (5.3-33.7) months, P=0.04; hazard ratio (HR), 0.44; 95% confidence interval (CI): 0.20-0.98]. Conclusions: The efficacy of amivantamab was confirmed for the real-world population for EGFR E20I-mutated NSCLC. PD-L1 status could be a poor predictive factor, which should be further validated.

Passive droplet generation in aqueous two-phase systems with a variable-width microchannel.

Passive droplet generation for an aqueous two-phase system (ATPS) was performed with a fracture-based variable microchannel. A jet of dextran-rich phase (DEX) in a polyethylene-glycol (PEG)-rich phase was created by focused flow. The width of the inlet channel could be varied over the range 1-10 µm via mechanical strain, which extended the range of operational back pressure. This enabled the spontaneous formation of DEX droplets with an ultralow surface tension of 12 µN m-1. The production of DEX droplets were examined with regard to driving pressure, flow rate, DEX/PEG concentration. The droplet properties are analyzed in terms of production rate (2-20 droplets per s), droplet diameter (10-100 µm), and diameter variance (5-20%). Controlling the inlet-channel width with other operating conditions widened the range of droplet properties. This simple and robust method significantly strengthened droplet-generation in microfluidics, especially for ATPS of low solute concentrations relevant to live cells.

Test-retest reliability of distortion-product otoacoustic emissions in children with normal hearing: a preliminary study.

The test-retest reliability of DPOAEs was investigated in 24 children (43 ears) with normal hearing at five F2 frequencies (2530, 3561, 5014, 7029, and 10,028 Hz). Two DPOAE recordings were performed on the same subjects in the same location using the same equipment. The second recordings were made 13 to 15 days after the first recording. The DPOAE level recorded in the subjects ranged between -13.10 and 20.20 dB for all the five frequencies. The variation in DPOAE level was greater at 10,028 Hz than at other frequencies. The mean difference between the test and retest recordings was 0.52+/-2.87, -1.57+/-4.62, 0.01+/-3.38, -0.55+/-2.85, and -0.56+/-5.57 dB at 2530, 3561, 5014, 7029, and 10,028 Hz, respectively. The intra-correlation coefficients for DPOAE level at each of the five (F2) frequencies were 0.85, 0.68, 0.62, 0.89, and 0.64 respectively. Calculations of mean +2SD showed that retest recordings greater than 6.26, 7.67, 6.81, 5.15, and 10.58 dB SPL at 2530, 3561, 5014, 7029, and 10,028 Hz respectively could possibly be interpreted as a significant change in status of the ear.