The Tumor Immune Microenvironment Is Associated With Recurrence in Early-Stage Lung Adenocarcinoma.

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study.

Introduction: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types. Methods: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system). Results: The study subjects comprised patients with head and neck cancer (n = 50), urothelial cancer (n = 42), renal cell cancer (n = 37), gastric cancer (n = 20), esophageal cancer (n = 10), malignant pleural mesothelioma (n = 6), or microsatellite instability-high tumors (n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients. Conclusion: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy.

Efficacy of Crizotinib After Entrectinib Resistance Due to MET Polysomy in ROS1-Rearranged NSCLC: A Case Report.

Resistance to ROS1 tyrosine kinase inhibitors is inevitable, but it has been unclear whether crizotinib might be effective after the development of entrectinib resistance. We here present a case of ROS1-rearranged NSCLC that responded to crizotinib after tumor progression due to MET polysomy during entrectinib treatment. This case suggests that crizotinib is an effective option for patients with MET polysomy, even after disease progression on entrectinib.

Successful treatment with atezolizumab combination chemotherapy in a patient with high-grade fetal adenocarcinoma of the lung: A case report.

High-grade fetal lung adenocarcinoma (H-FLAC) is a rare tumor, with little known of its response to chemotherapy with or without an immune checkpoint inhibitor or of its molecular profile. We report the first case of a 56-year-old man with stage IV H-FLAC who was successfully treated with carboplatin plus nab-paclitaxel in combination with atezolizumab. In addition, the tumor was found to be positive for amplification of the human epidermal growth factor receptor 2 gene.

Implication of changes in PD-L1 expression during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen in esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant docetaxel plus cisplatin and 5-FU (NAC-DCF) and adjuvant nivolumab monotherapy are the standard care for locally advanced resectable esophageal squamous cell carcinoma (ESCC). However, no effective biomarkers have been found in perioperative setting. We investigated how programmed death-ligand 1 (PD-L1) changes before and after NAC-DCF and how it relates to the therapeutic effect of NAC-DCF in resectable ESCC. METHODS: PD-L1 expression in paired diagnostic biopsy and surgically resected tissues from ESCC patients who underwent surgical resection after receiving two or three NAC-DCF cycles was evaluated. PD-L1 positivity was defined as a combined positive score (CPS) of 10% ≤ . Gene expression analysis was conducted using samples before NAC-DCF. RESULTS: Sixty-six paired samples from 33 patients were included in PD-L1 expression analysis, and 33 Pre-NAC samples acquired by diagnostic biopsy were included in gene expression analysis. Pretreatment, 3 (9%), 13 (39%), and 17 (52%) patients harbored tumors with CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. After NAC-DCF, 5 (15%), 15 (45%), and 13 (39%) tumors presented CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. The concordance rate between Pre-and Post-NAC-DCF samples was 45%. Patients with PD-L1-negative tumors both before and after NAC-DCF (n = 9) had shorter survival and different gene expression profile characterized by upregulation in WNT signaling or neutrophils. CONCLUSIONS: A substantial PD-L1 expression alteration was observed, resulting in low concordance rate before and after NAC-DCF. Tumors persistently lacking PD-L1 had distinct gene expression profile with worse clinical outcomes, raising the need for further investigation.

The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC.

Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.

Yolk Sac Tumor in a Recurrence of Colonic Adenocarcinoma With Shared Mutations in APC and TP53 Genes: A Case Report.

Only four cases of colorectal adenocarcinoma with a yolk sac tumor (YST) component have been reported in the English literature. No genetic investigation has been performed in these cases. We report a case of colorectal adenocarcinoma in which the recurrent tumor had a YST component. A 49-year-old woman presented with a pelvic tumor three years after endoscopic mucosal resection of sigmoid colon adenocarcinoma. The pelvic tumor consisted of an undifferentiated carcinoma component and a YST component. The serum alpha-fetoprotein level was elevated to 42 ng/mL. Treatment as conventional colorectal carcinoma produced some anticancer effects, but the patient died 14 months after the recurrence and 49 months after the EMR. With the help of the next-generation sequencing results of the recurrent tumor, APC c.835 - 8A > G and TP53 c.524G > A (p.R175H) mutations were identified by direct sequencing in both the primary and the recurrent tumors, confirming the relationship between the two metachronous tumors.

Interstitial lung disease associated with capmatinib therapy in a patient with non-small cell lung cancer harboring a skipping mutation of MET exon 14.

Capmatinib is a MET tyrosine kinase inhibitor (TKI) that has recently been approved for the treatment of advanced non-small cell lung cancer (NSCLC) positive for skipping mutations of MET exon 14 (METex14). Drug-induced interstitial lung disease (ILD) is a relatively rare, but potentially serious, side effect of TKIs administered for lung cancer treatment. Here we report a case of capmatinib-induced ILD in a patient with NSCLC harboring a METex14 skipping mutation. Capmatinib should be immediately discontinued if ILD is suspected, and treatment with corticosteroid should be considered.

Safety and efficacy of cetuximab-containing chemotherapy after immune checkpoint inhibitors for patients with squamous cell carcinoma of the head and neck: a single-center retrospective study.

Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy.

Thymic epithelial tumor treatment in Japan: analysis of hospital cancer registry and insurance claims data, 2012-2014.

INTRODUCTION: Thymic epithelial tumors are a rare type of neoplasm. Accordingly, it is difficult to perform phase III trials in patients with thymic epithelial tumors, and thus, no standard treatment has been established for these tumors. In this study, we aimed to investigate the current status of thymic epithelial tumor treatment in Japan. METHODS: This retrospective observational study enrolled patients with thymic epithelial tumor whose data were recorded in a nationwide Hospital-based Cancer Registry that was linked with health insurance claims data for the registered patients between 2012 and 2014. The patients' treatment details were obtained from a health insurance claims database. RESULTS: A total of 813 patients with thymoma and 547 with thymic carcinoma were included in the analysis. Overall, 549 (67.5%) thymoma patients underwent surgical resection alone. Among patients with thymic carcinoma, 230 (42.0%) underwent initial surgery, and 124 (53.9%) received subsequent radiotherapy and chemotherapy. Chemotherapy regimens varied across the hospitals; overall, 21 and 22 regimens were used to treat thymoma and thymic carcinoma, respectively. Platinum-based combination regimens were predominantly selected for both diseases. CONCLUSIONS: This study revealed the real-world patterns of thymic epithelial tumor treatment in Japan. Although the nature of this study did not enable the determination of optimal treatment strategies, the simultaneous analysis of nationwide registry, insurance, efficacy and prognostic data may contribute to the establishment of a standard treatment strategy for rarely occurring cancers such as thymic epithelial tumor.

Eribulin-induced Interstitial Pneumonia: A Case Series and Retrospective Cohort Study.

Eribulin is a chemotherapeutic agent used for advanced breast cancer, but there are some reports of eribulin-induced lung injuries. Three of our patients experienced eribulin-related lung injuries. Radiology revealed organizing pneumonia in two cases and diffuse ground-glass shadows indicative of hypersensitivity pneumonitis in the third. A retrospective survey of patients treated with eribulin at our hospital identified no other cases of eribulin-induced lung injuries. Overall, drug-related lung injuries occurred in 2.8% of our eribulin-treated patients, which is similar to the rates reported for other anticancer drugs. The findings from these three cases provide guidance for the safe use of eribulin.

Septic pulmonary embolism caused by Pseudomonas aeruginosa after a CO2 laser surgery for rhinitis.

A 26-year-old healthy patient had a fever and chest pain three days after nasal carbon dioxide (CO2) laser surgery for chronic and allergic rhinitis. In the emergency room, he was diagnosed as a right pneumothorax and managed as outpatients with oral antibiotic therapy and close follow-up. Six days later, in follow-up clinic, his presenting signs and symptoms included right chest pain, tachypnoea and elevated levels of white blood cell count and C reactive protein. He was diagnosed as septic pulmonary embolism (SPE) by the detection of multiple nodules with cavitation on chest CT. Culture of pleural fluids showed Pseudomonas aeruginosa Intravenous antibiotic treatment and drainage of the pleural effusion improved his condition. Since SPE occurred after nasal CO2 laser surgery in this case, careful attention should be paid to infectious complications of nasal CO2 laser surgery.

Primary Synovial Sarcoma of the Mediastinum with Long-term Follow-up.

Chest radiography showed a right posterior mass on the mediastinum of an 84-year-old woman. The mass had been growing gradually for four years. Surgical excision was performed, and a pathological examination found the mass to be consistent with primary synovial sarcoma (SS) of the mediastinum. To our knowledge, this is a rare case in which follow-up imaging was able to be performed over a period of four years. This disease is aggressive, and its early diagnosis is key to achieving a cure. It is important to consider primary SS in the differential diagnosis of a primary intra-thoracic tumor, even if the tumor grows slowly.