Introduction
Nivolumab, a programmed death 1 (PD-1) inhibitor, has recently demonstrated efficacy as second-line therapy for esophageal squamous cell carcinoma (ESCC) patients in a phase III trial. ...We report real-world clinical outcomes of nivolumab therapy for ESCC patients.
Methods
ESCC patients refractory/intolerant to at least one line of chemotherapy and who received nivolumab as a subsequent line of therapy were included. The efficacy and safety of nivolumab and the predictive role of PD-L1 and CD8 expression were analyzed.
Results
Fifty-eight patients were analyzed for safety and survival outcomes, while 57 were analyzed for objective response rates (ORR) excluding one with no measurable lesions. Eleven patients achieved a partial response, leading to an ORR of 19.3%. The median response duration was 6.5 months (range 4.1–22.4). The median progression-free survival (PFS) and overall survival were 2.1 (95% confidence interval CI 1.8–2.3) and 7.4 (95% CI 4.8–10.0) months, respectively. Among patients with adequate samples, 56.9% (29/51), 27.5% (14/51), and 17.6% (9/51) expressed a combined positive score (CPS) ≥ 1, ≥ 10, and ≥ 20, respectively, while 24.4% (11/45) and 57.5% (23/40) were positive for intratumoral and peritumoral CD8 + T cell infiltration, respectively. A significantly longer PFS was observed in patients with a CPS ≥ 20 (7.5 95% CI 1.8–13.1 vs. 1.9 1.4–2.3 months,
P
= 0.05), and a trend towards better survival was seen in those with CPS ≥ 10 or intratumoral CD8 + T cell infiltration.
Conclusions
Nivolumab is a valuable option at subsequent treatment lines for patients with advanced ESCC.
The aim of our analysis was to evaluate the prognostic effect of programmed cell death ligand-1 (PD-L1) expression in patients with non–small cell lung cancer (NSCLC).
PD-L1 expression among 1070 ...surgically resected NSCLC specimens was evaluated by immunohistochemical analysis. Data were analyzed using Cox proportional hazard models adjusting for age, sex, smoking status, histologic type, stage, and performance status.
Sixty-eight patients (6%) were strongly PD-L1 positive and 410 (38%) were weakly PD-L1 positive. A significantly higher prevalence of PD-L1 positivity was observed among patients with squamous cell carcinoma and among stage IIIB and IV patients. PD-L1 expression may be associated with poorer overall survival, with an adjusted hazard ratio of 1.56 (95% confidence interval CI: 1.08–2.26, p = 0.02) for strong PD-L1 positivity, 1.18 (95% CI: 0.96–1.46; p = 0.12) for weak PD-L1 positivity, and 1.23 (95% CI: 1.00–1.51; p = 0.05) for the combined strongly and weakly positive groups compared with PD-L1 negativity. Negative prognostic effect of PD-L1 expression was not statistically significant after adjustment for postoperative chemotherapy or radiotherapy. Similar results were observed for progression-free survival. Among stage I patients, the disease recurrence rate was higher in the PD-L1–positive versus in the PD-L1–negative group (48% versus 27%, p < 0.001), with an adjusted hazard ratio for disease-free survival of 2.01 (95% CI, 1.08–3.73; p = 0.03) for strong PD-L1 positivity and 1.57 (95% CI, 1.17–2.11; p = 0.003) for weak PD-L1 positivity compared with PD-L1 negativity.
Tumor PD-L1 expression may be associated with poor prognosis in patients with NSCLC, although its significance weakens when postoperative therapy is considered.
Liposarcoma (LPS) is a tumor derived from adipose tissue, and has the highest incidence among soft tissue sarcomas. Dedifferentiated liposarcoma (DDLPS) is a malignant tumor with poor prognosis. ...Recurrence and metastasis rates in LPS remain high even after chemotherapy and radiotherapy following complete resection. Therefore, the development of advanced treatment strategies for LPS is required. In the present study, we investigated the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor on cell viability and apoptosis in LPS and DDLPS cell lines of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor.
We analyzed cell viability after treatment with TRAIL and a c-Met inhibitor by measuring CCK8 and death receptor 5 (DR5) expression levels via fluorescence activated cell sorting (FACS) in both sarcoma cell lines and DDLPS patient-derived cells (PDCs). Moreover, we validated the effects of TRAIL alone and in combination with c-Met inhibitor on apoptosis in LPS cell lines and DDLPS PDCs via FACS.
Our results revealed that combination treatment with a c-Met inhibitor and human recombinant TRAIL (rhTRAIL) suppressed cell viability and induced cell death in both sarcoma cell lines and DDLPS PDCs, which showed varying sensitivities to rhTRAIL alone. Also, we confirmed that treatment with a c-Met inhibitor upregulated DR5 levels in sarcoma cell lines and DDLPS PDCs. In both TRAIL-susceptible and TRAIL-resistant cells subjected to combination treatment, promotion of apoptosis was dependent on DR5 upregulation.
From these results, our findings validated that DR5 up-regulation caused by combination therapy with a c-Met inhibitor and rhTRAIL enhanced TRAIL sensitization and promoted apoptosis. We propose the use of this approach to overcome TRAIL resistance and serve as a novel treatment strategy for clinical trials.
Background
The purpose of this study is to analyze the clinical impact of radical nephrectomy on retroperitoneal liposarcoma near the kidney.
Methods
Data of patients who underwent surgery for ...unilateral primary retroperitoneal liposarcoma near the kidney were retrospectively collected. Patients were divided into four groups according to whether they underwent nephrectomy and combined resection of other organs. Kaplan–Meier survival analysis was used to estimate disease-free survival and overall survival. Multivariable Cox analysis was used to analyze factors related to disease-free survival and overall survival.
Results
Nephrectomy (HR = 0.260, CI = 0.078–0.873,
p
= 0.029) had a beneficial effect on disease-free survival, while interaction model of nephrectomy*other organ resection (HR = 4.655, CI = 1.767–12.263,
p
= 0.002) showed poor disease-free survival. Other organ resection was not related to disease-free survival (HR = 1.543, CI = 0.146–16.251,
p
= 0.718). Operation method (
p
= 0.007) and FNCLCC grade (
p
< 0.001; G2, HR = 1.833, CI = 0.684–4.915,
p
= 0.228; G3, HR = 9.190, CI = 3.351–25.199,
p
< 0.001) were significant factors for disease-free survival. While combined organ resection without nephrectomy group (HR = 1.604, CI = 0.167–15.370,
p
= 0.682) and radical nephrectomy with combined organ resection group (HR = 1.309, CI = 0.448–3.825,
p
= 0.622) did not show significant difference in disease-free survival from the mass excision only group, radical nephrectomy without combined organ resection group (HR = 0.279, CI = 0.078–0.991,
p
= 0.048) showed superior disease-free survival.
Conclusions
Radical nephrectomy of unilateral primary retroperitoneal liposarcoma near the kidney has a beneficial effect on disease-free survival.
ROS1-rearranged NSCLC is classified as a distinct molecular subset of NSCLC with a therapeutic target. ROS1 rearrangement is most often identified in never-smokers with adenocarcinoma and EGFR and ...ALK receptor tyrosine kinase gene (ALK) wild type. Treatment with tyrosine kinase inhibitors (TKIs), which target the ROS1 kinase domain, is considered the standard of care. TKIs have been shown to have a robust and durable response. However, information regarding the clinical outcomes of TKI treatment, including brain metastasis, remains limited.
We identified 103 consecutive cases of ROS1-positive NSCLC by using break-apart fluorescence in situ hybridization (n = 84), next-generation sequencing (n = 23), or both (n = 3). Information regarding fusion breakpoints was available for eight patients. Clinical data, including patient characteristics, incidence of brain metastasis, response to chemotherapy, or to TKIs, were retrospectively analyzed.
The median patient age was 56 years, and 58.9% of the patients were female. Most of the patients (75.7%) were never-smokers. Adenocarcinoma was predominant (98.1%), and two cases with pleomorphic carcinoma were identified. Sixty percent of patients had an extrathoracic metastatic lesion, and 22% had an intracranial lesion at the initial presentation or at the time of recurrence. The median time to development of brain metastases was 12.0 months (range 2.1–84.1). The most common fusion partner was CD74 molecule gene (CD74), followed by syndecan 4 gene (SDC4), ezrin gene (EZR), tropomyosin 3 gene (TPM3), TRK-fused gene (TFG), zinc finger CCHC-type containing 8 gene (ZCCHC8), sacrolemma associated protein gene (SLMAP), and myosin VC gene (MYO5C). All of these fusion partners preserved the tyrosine kinase domain of ROS1. The median overall survival time was 52.1 months (95% confidence interval CI: 23.6–not reached). In the 90 patients who were treated with pemetrexed-based chemotherapy, the overall response rate and progression-free survival time were 53.3% and 8.0 months (95% CI: 6.4–11.7), respectively. The overall response rate and progression-free survival time were 70.7% and 12.7 months (95% CI: 8.1–21.8), respectively, for the 50 patients treated with TKIs. Brain metastasis was more often observed during TKI treatment (15.5%) than during pemetrexed-based chemotherapy (6.7%).
ROS1-positive NSCLC has distinct clinical characteristics, with an effective and durable response to both TKIs and pemetrexed-based chemotherapies. Regardless, given its novel characteristics and distinct clinical responses to conventional chemotherapies and TKIs, the treatment strategy for ROS1-positive NSCLC remains to be further developed.
•Non-small cell lung cancer treated with afatinib had lower acquired T790 M mutation.•More histologic transformations (6%) occurred in afatinib group.•The highest successful rate (78%) of repeat ...biopsy was observed.•40% of multiple or delayed repeat biopsy revealed T790 M mutation finally.
Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is used for EGFR-mutant non-small cell lung cancer (NSCLC). However, there are few reports about its resistance mechanisms. The aims of this study are to evaluate resistance mechanisms of afatinib compared with other TKIs and analyze the performance of repeat biopsy which is critical for subsequent treatment.
We screened EGFR-mutant NSCLC patients who started first-line afatinib, gefitinib, or erlotinib from 2014 to 2016, and included patients who acquired resistance. Among those patients, T790 M mutation rates and histologic transformation were compared as an acquired resistance mechanism.
A total of 524 patients started EGFR-TKIs, and 347 experienced disease progression until April 2018. After excluding nine patients with de novo T790 M mutations or who were treated with two TKIs before repeat biopsy, 338 patients were included. Among these patients, 263 (78%) were successfully biopsied and evaluated for EGFR mutations and histologic transformation. T790 M mutation was documented in 35 (41%) of 86 evaluable patients in afatinib group, which is significantly lower than in gefitinib (55%, 73/133) and erlotinib groups (57%, 25/44) (p = 0.026). In multivariate analysis considering both baseline EGFR mutation types (deletion 19 or L858R) and sex, the odds ratio for T790M in afatinib group was 0.45 (95% confidence interval: 0.254-0.795, p = 0.006), compared with gefitinib or erlotinib groups. Five histologic transformations (two small cell, three squamous cell) were detected in afatinib group, while one small cell transformation was detected in gefitinib group, and no transformations were detected in erlotinib group.
In our clinical practice, repeat biopsy was possible in nearly four of five patients. Although T790 M mutation appears to be the main resistance mechanism for afatinib, it affects a lower proportion of patients than observed with first-generation TKIs.
We evaluated programmed death ligand 1 (PD-L1) expression and efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary pleomorphic carcinoma (PC).
We created two cohorts of patients diagnosed ...with pulmonary PC from 2016 to 2019, PD-L1 expression and programmed death 1 (PD-1)/PD-L1 inhibitor efficacy cohorts. The PD-L1 expression cohort included all patients evaluated for PD-L1 expression, irrespective of PD-1/PD-L1 inhibitor therapy. High PD-L1 expression was defined as ≥50% positive tumour cells (TC) for 22C3, ≥25% for SP263 or ≥10%/5% TC/immune cell (IC) for SP142. The PD-1/PD-L1 efficacy cohort included patients treated with PD-1/PD-L1 inhibitors, irrespective of PD-L1 tests.
One hundred twenty-five of 175 patients diagnosed with pulmonary PCs were included in the PD-L1 expression cohort. Among them, 112 patients (89.6%) had PD-L1-positive (≥1%) tumours and 100 (80.0%) had tumours with high PD-L1 expression. A total of 49 patients were included in the efficacy cohort: 40 received pembrolizumab, 7 nivolumab and 2 atezolizumab. The objective response rate was 49.0%, with a median progression-free survival (PFS) of 7.2 months and a median overall survival of 22.2 months. In the efficacy cohort, high PD-L1 expression (n = 41) was associated with longer PFS (median: 7.2 versus 1.5 months, hazard ratio HR: 0.53 0.22–1.29, p = 0.16) and overall survival (median: 22.2 versus 3.5, HR: 0.21 0.08–0.57, p = 0.001) than low/negative/unknown PD-L1 expression (n = 8).
PD-1/PD-L1 inhibitors show outstanding efficacy for pulmonary PCs, and this is possibly attributable to high PD-L1 expression in these tumours.
•Pulmonary pleomorphic carcinomas (PCs) are known to express a high level of PD-L1.•Given its poor prognosis, the role of PD-L1 in PCs warrants further investigation.•In this study, 89.6% were PD-L1 positive (≥1%) and 80.0% had high PD-L1 expression.•Immunotherapy showed ORR 49%, mPFS 7.2 months and mOS 22.2 months.•High PD-L1 expression group showed longer PFS (7.2 versus 1.5) and OS (22.2 versus 3.5).
Background
Nuclear protein in testis (NUT) carcinoma is a rare tumor associated with NUT rearrangement that can present as poorly differentiated to undifferentiated carcinoma, with or without abrupt ...squamous differentiation. It is often misdiagnosed as poorly differentiated carcinoma or undifferentiated carcinoma if NUT is not suspected. In this study, we retrospectively analyzed pulmonary NUT carcinoma cases diagnosed with NUT immunohistochemical staining and discuss the differential diagnosis to provide information for this rare and aggressive entity.
Methods
Cases, diagnosed as “NUT carcinoma” in lung pleura and “metastatic NUT carcinoma from the lung” in lymph nodes were diagnosed between 2017 and 2019 at the Samsung Medical Center (SMC). Clinical features such as age, sex, treatment and follow‐up period, and pathological reports were obtained by reviewing patients’ electronic medical records.
Results
A total of 10 NUT carcinoma cases were found in the SMC pathology database. Seven patients were men and six were non‐smokers. Tumor cells showed various cellular features such as round, squamoid, and spindle. Some cases had initially been misdiagnosed as spindle cell neoplasm, round cell sarcoma, squamous cell carcinoma and small cell carcinoma. All cases showed diffuse strong nuclear expression of NUT immunohistochemical staining, and some were positive for p63 staining and negative for CD56 staining.
Conclusions
NUT carcinoma is often misdiagnosed because of its various morphologies. It is important to consider NUT as one of the differential diagnoses when encountering lung biopsy with undifferentiated morphology.
Key points
Due to various morphological features, NUT carcinoma can be misdiagnosed
It is important to consider NUT carcinoma when diagnosing a poorly differentiated or undifferentiated tumor
NUT carcinoma showed poorly differentiated to undifferentiated features with strong nuclear expression of NUT. NUT carcinoma can show various morphologies that can be misdiagnosed. It is important to consider NUT carcinoma in patients of relatively young age.
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