Keiichiro Uehara

Early Immune-Related Adverse Events and Association with Outcome in Advanced Non–Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study

Introduction Retrospective studies have shown immune‐related adverse events (irAEs) to be associated with better prognosis. However, no prospective clinical trials have been conducted, and little is known regarding the association between irAEs and the outcome of patients with NSCLC after treatment with immunotherapy. Methods We conducted a prospective cohort study of patients with advanced NSCLC who were treated with nivolumab between January and December 2016. The association between clinical outcome and irAEs 2 to 6 weeks after commencement of nivolumab treatment was investigated. IrAEs were assessed by at least three independent medical professionals. Results A total of 43 patients were enrolled, including 19 patients with irAEs 2 weeks after commencement of nivolumab treatment. Common irAEs included rash, pyrexia, and diarrhea. Programmed cell death ligand 1‐positive tumor cell expression was not significantly different between patients with and without irAEs. The objective response and disease control rates were higher in patients with irAEs than in those without irAEs (37% versus 17% and 74% versus 29% [p = 0.17 and p < 0.01], respectively]). Patients with irAEs were associated with a significantly longer median progression‐free survival than those without (6.4 months [95% confidence interval: 2.5‐not reached] versus 1.5 months [95% confidence interval: 1.2–2.3] [p = 0.01]). These findings were comparable to those for patients with and without irAEs 6 weeks after commencement of nivolumab treatment. Conclusions Early irAEs are associated with a better outcome after treatment with immunotherapy. We predicted responses to nivolumab by using early irAEs. Further research is needed to elucidate the mechanisms of these associations.

Aprepitant for refractory nivolumab-induced pruritus

Although substantial progress has been made in the treatment of non-small-cell lung cancer (NSCLC) patients with immune checkpoint inhibitors (ICIs), severe immune-related adverse events (irAEs) sometimes occur. Here, we report a case of severe refractory pruritus after Stevens-Johnson syndrome (SJS) in a patient with NSCLC treated with nivolumab. The patient was a 76-year-old Japanese woman with advanced NSCLC treated with nivolumab. After the second dose, she experienced severe rash with mucous involvement. We diagnosed SJS and started 50mg of oral prednisolone (1mg/kg). The rash completely resolved after prednisolone was started, but we could not manage the severe pruritus with emollients, antihistamines, and steroids. Finally, we administered aprepitant, an oral neurokinin-1 receptor antagonist, for her refractory pruritus. Her symptoms improved within 5days. Severe refractory pruritus can arise from ICIs, and aprepitant may be a useful treatment.

Transformation to large cell neuroendocrine carcinoma as acquired resistance mechanism of EGFR tyrosine kinase inhibitor.

OBJECTIVES Several different acquired resistance mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy have been described. Although rare, the transformation from adenocarcinoma to small cell carcinoma (SCLC) is one of these important mechanisms. We report a rare case that indicates transformation into large-cell neuroendocrine carcinoma (LCNEC) as an acquired resistance mechanism to EGFR-TKI therapy. MATERIALS AND METHODS The patient was a 68-year-old male with a diagnosis of cT2N2M0 pulmonary adenocarcinoma with L858R mutation on exon 21. He received lobectomy and underwent several courses of chemotherapies, including EGFR-TKIs, each time he relapsed. He finally relapsed with a mass that protruded into his left main bronchus. Resection of the metastatic site identified LCNEC that retained the original EGFR mutation. Immunohistochemistry revealed the loss of expression of EGFR and retinoblastoma (Rb) in the LCNEC. CONCLUSIONS This case highlights acquisition of EGFR-TKI resistance by transformation to LCNEC, not SCLC. Loss of EGFR and Rb expression in the LCNEC suggests the same mechanism as transformation to SCLC. Further study is needed to elucidate this mechanism, especially regarding the similarities and differences to SCLC.

Peritoneal keratin granuloma associated with endometrioid adenocarcinoma of the uterine corpus

We present a 69-year-old woman with a chief complaint of postmenopausal bleeding. She was diagnosed as having an endometrioid adenocarcinoma by biopsy, and underwent a total abdominal hysterectomy. At the time of surgery, granulation tissue-like nodules were found on the peritoneal serosa of the uterus. In the intraoperative cytology of peritoneal washing, atypical cells were noted. The intraoperative frozen section of the peritoneal nodule revealed granulation tissue with proliferating mesothelial cells. Microscopic examination of the permanent section showed keratin granulomas without viable adenocarcinoma cells on the serosal surface of the ovaries, fallopian tubes and broad ligaments. Postoperative chemotherapy was administered. She has been alive with no evidence of recurrence for 6 months postoperatively. It should be noted that the prognosis of cases in peritoneal keratin granuloma without viable cancer cells is favorable, and that the histological examination is essential for its diagnosis.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7119869525769574.

Alteration of PD-L1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients

Concurrent chemoradiation therapy (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD-1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CCRT on programmed cell death ligand-1 (PD-L1) expression on tumor cells is unknown. In this study, we analysed paired NSCLC specimens that had been obtained pre- and post-CCRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. A total of 45 patients with LA-NSCLC were included, among which there were sufficient pre- and post-CCRT specimens in 35 patients. Overall, the percentage of tumor cells with PD-L1 expression significantly decreased between pre- and post-CCRT specimens (P = 0.024). Sixteen, 15, and 4 patients had decreased, unchanged, or increased PD-L1 expression after CCRT, respectively. Median OS of patients with decreased, unchanged, or increased PD-L1 expression was 85.1, 92.8, and 14.6 months, respectively (P < 0.001). In conclusion, the percentage of PD-L1-positive tumor cells significantly decreased after CCRT. Alteration of PD-L1 expression after neoadjuvant CCRT was associated with prognosis in patients with LA-NSCLC. These data should be considered when developing the optimal approach of integrating PD-1 axis inhibitors with CCRT.

Predictive Performance of Four Programmed Cell Death Ligand 1 Assay Systems on Nivolumab Response in Previously Treated Patients with Non–Small Cell Lung Cancer

Introduction: Nivolumab has demonstrated efficacy against metastatic NSCLC. Four programmed cell death ligand 1 (PD‐L1) immunohistochemistry (IHC) assay systems are available for identification of responders among patients with NSCLC, and these assays show some differing characteristics. Accordingly, in this study, we evaluated the ability of these assays to identify responders to nivolumab therapy. Methods: We retrospectively analyzed patients with previously treated advanced NSCLC, who received nivolumab between January 2016 and September 2016. Specimens were stained using four PD‐L1 IHC assays (28‐8, 22C3, SP142, and SP263). We classified patients as having test results that were strongly positive (tumor proportion score [TPS] ≥50%), weakly positive (TPS 1%–49%), or negative (TPS <1%). Results: A total of 40 patients with NSCLC and their specimens were analyzed. Analytical comparisons demonstrated good concordance of PD‐L1–stained tumor cells among the 28‐8, 22C3, and SP263 assays (weighted &kgr; coefficient 0.64–0.71), whereas the SP142 assay showed lower concordance with other assays (weighted &kgr; coefficient 0.39–0.55). Progression‐free survival in patients showing strongly positive PD‐L1 staining classified by 28‐8, 22C3, and SP263 assays was significantly longer than that in patients with a negative result for PD‐L1 staining. Predictive performance of response to nivolumab, as assessed by receiver operating characteristic analysis, was also equivalent among the 28‐8, 22C3, and SP263 assays (area under the curve 0.75–0.82), whereas the SP142 assay exhibited lower predictive performance (area under the curve 0.68). Conclusions: The 28‐8, 22C3, and SP263 PD‐L1 IHC assays showed equivalent predictive performance, whereas the SP142 assay showed lower predictive performance.

The prospect of endoscopic submucosal dissection for early anal canal squamous cell carcinoma

Squamous cell carcinoma (SCC) of the anal canal is seldom diagnosed at an early stage. Chemoradiation therapy is a standard in Europe and the United States, though in squamous cell carcinoma there is no evidence-based therapy. In Japan, endoscopic submucosal dissection (ESD) is the standard minimally invasive treatment for early stage cancer of the digestive tract, including the colorectum. Therefore, if the lesion is diagnosed at an early stage, ESD may be selected for anal canal lesions. We experienced two cases of early stage anal canal cancer in which the diagnosis and the extent of the lesions were confirmed using magnifying endoscopy with narrow-band imaging (NBI), as well as performing ESD. Pathological examination showed the resected specimen to be SCC in situ; the horizontal and vertical margins were free of tumor; and in one case there was no lymphovascular invasion. In the other case it showed the tumor was contained within the epithelium; horizontal and vertical margins were free of tumor; The follow-up period is not long enough to assert that ESD for anal canal squamous cell carcinoma may be an option of minimally invasive therapy. However, if there is a possibility of lymphatic invasion as in one of our cases, we need to give serious consideration to ESD for these lesions, and careful follow-up is necessary even if the lesion is in situ.

Natural history and clinical characteristics of multiple pulmonary nodules with ground glass opacity

Ground glass nodules (GGNs) are frequently encountered in the lungs. We report the natural history and characteristics of multiple GGNs, and propose a management plan for patients with multiple GGNs.

Clonally related diffuse large B-cell lymphoma and interdigitating dendritic cell sarcoma sharing MYC translocation

Interdigitating dendritic cell sarcoma (IDCS) is a rare neoplasm considered to derive from a dendritic cell. Recent studies have shown that B- or T-lymphoblastic leukemia/lymphomas can develop clonally related histiocytic/dendritic cell (H/DC) neoplasms, such as histiocytic sarcoma, Langerhans cell

Programmed Cell Death Ligand 1 Expression in Non–Small-cell Lung Cancer Patients With Interstitial Lung Disease: A Matched Case-control Study

Micro‐Abstract: We conducted a case‐control study to evaluate programmed cell death ligand 1 expression in patients with non–small‐cell lung cancer (NSCLC) and interstitial lung disease (ILD). Programmed cell death ligand 1 expression and stromal CD8+ lymphocyte density were comparable between NSCLC patients with and without ILD. Thus, programmed cell death protein 1 axis inhibitors might be effective for NSCLC patients with ILD. Background: Programmed cell death protein 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1) checkpoint inhibitors have demonstrated antitumor activity, and immunohistochemical analysis of PD‐L1 expression has been used to identify the response in patients with non–small‐cell lung cancer (NSCLC). Recently, considerable interest has ensued toward extending the benefit of these inhibitors to high‐risk patients, such as those with NSCLC and interstitial lung disease (ILD). However, no studies have compared PD‐L1 expression in NSCLC patients with and without ILD. Therefore, we conducted a case‐control study to evaluate PD‐L1 expression and stromal CD8+ lymphocyte density in these patients. Materials and Methods: The data from patients with pathologic stage I or II NSCLC who had undergone surgery from January 2007 to January 2016 were analyzed. Results: We identified 62 patients with pathologic stage I or II NSCLC and ILD. We compared these patients with 1:1‐matched cohort. In both groups with and without ILD, approximately 60% were PD‐L1+. Tumor cell PD‐L1 expression was similar between the groups (median, 1%; interquartile range, 0%‐5%; vs. median, 1%; interquartile range, 0%‐5%; P = .49). The proportion of patients with positive (≥ 1%) and strongly positive (≥ 50%) PD‐L1 expression was also similar between the 2 groups (P = .46 and P = 1.00, respectively). Additionally, the CD8+ lymphocyte density did not differ between patients with and without ILD. Conclusion: PD‐L1 expression and stromal CD8+ lymphocyte density were comparable between the NSCLC patients with and without ILD. PD‐1 axis inhibitors might be effective for NSCLC patients with ILD.