Kenzo Sonoda

Claudin‐18 expression in gastric type adenocarcinoma and HPV ‐associated adenocarcinoma of the uterine cervix

Aims Claudin‐18 (CLDN18) is both a marker for the gastric phenotype and a therapeutic target. However, little is known about its immunoexpression in endocervical adenocarcinomas (ECAs), particularly as detected using the clone 43‐14A antibody, or about the gene expression of its isoforms in ECAs. Methods and results We examined CLDN18, HIK1083, p16 and Rb expression by immunohistochemistry and high‐risk human papillomavirus (HR‐HPV) mRNA by in situ hybridization (ISH) in 121 ECAs, including 35 HPV‐independent adenocarcinomas (gastric type [GAS], n  = 24; non‐GAS, n  = 11) and 86 HPV‐associated ECAs. We also analysed mRNA expression of the CLDN18.1 (lung type) and CLDN18.2 (gastric type) isoforms by quantitative polymerase chain reaction (qPCR) in selected cases. CLDN18 positivity was detected in 8/24 (33%) GASs, 0/11 (0%) non‐GASs and 2/86 (2%) HPV‐associated ECAs, with positivity defined as staining in ≥75% of tumour cells, as in gastric cancer. When a 5% cut‐off was used, CLDN18 positivity was detected in 22/24 (92%) GASs, 0/11 (0%) non‐GASs and 6/86 (7%) HPV‐associated ECAs; CLDN18 expression was thus significantly associated with GAS histology ( P  < 0.0001). Among the 6 cases of HPV‐associated ECAs with CLDN18 expression (ranging from 5% to 80%), the histological patterns included a mix of usual and mucinous features in 4 cases, pure usual type in 1 and villoglandular variant in 1. Otherwise features such as p16 overexpression and the Rb partial loss pattern were consistent with those of HPV‐associated ECAs. Six of 22 (27%) CLDN18‐positive GASs were also positive for p16, but their other features—such as CLDN18 expression and the Rb preserved pattern—were the same as in p16 negative GASs. Expression of CLDN18.2 mRNA but not CLDN18.1 mRNA was confirmed in both GASs and HPV‐associated ECAs. Conclusions CLDN18 (43‐14A) emerged as a potential diagnostic and therapeutic marker for GAS. A minor subset of HPV‐associated ECAs also can be immunoreactive for CLDN18 and express CLDN18.2 mRNA, suggesting divergent gastric phenotypic differentiation. The caution is that GAS and HPV‐associated ECAs can share overlapping histological features and similar expression of CLDN18 and p16.

Immunohistochemical p16 overexpression and Rb loss correlate with high‐risk human papillomavirus infection in endocervical adenocarcinomas

Aimsp16 is a sensitive surrogate marker for transcriptionally active high‐risk human papillomavirus (HR‐HPV) infection in endocervical adenocarcinoma (ECA); however, its specificity is not perfect.Methods and resultsWe examined p16 and Rb expressions by immunohistochemistry (IHC) and the transcriptionally active HR‐HPV infection by mRNA in‐situ hybridisation (ISH) with histological review in 108 ECA cases. Thirteen adenocarcinomas of endometrial or equivocal origin (six endometrioid and seven serous carcinomas) were compared as the control group. HR‐HPV was detected in 83 of 108 ECA cases (77%), including five HPV‐associated adenocarcinomas in situ and 78 invasive HPV‐associated adenocarcinomas. All 83 HPV‐positive cases showed consistent morphology, p16 positivity and partial loss pattern of Rb. Among the 25 cases of HPV‐independent adenocarcinoma, four (16%) were positive for p16, and of these four cases, three of 14 (21%) were gastric type adenocarcinomas and one of 10 (10%) was a clear cell type adenocarcinoma. All 25 HPV‐independent adenocarcinomas showed preserved expression of Rb irrespective of the p16 status. Similarly, all 13 cases of the control group were negative for HR‐HPV with preserved expression of Rb, even though six of 13 (46%) cases were positive for p16. Compared with p16 alone, the combination of p16 overexpression and Rb partial loss pattern showed equally excellent sensitivity (each 100%) and improved specificity (100 versus 73.6%) and positive predictive values (100 versus 89.2%) in the ECA and control groups. Furthermore, HR‐HPV infection correlated with better prognosis among invasive ECAs.ConclusionsThe results suggest that the combined use of p16 and Rb IHC could be a reliable method to predict HR‐HPV infection in primary ECAs and mimics. This finding may contribute to prognostic prediction and therapeutic strategy.

Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA)

PURPOSE This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

Safety evaluation of abdominal trachelectomy in patients with cervical tumors ≥2 cm: a single-institution, retrospective analysis

For oncologic safety, vaginal radical trachelectomy is generally performed only in patients with cervical cancers smaller than 2 cm. However, because inclusion criteria for abdominal trachelectomy are controversial, we evaluated the safety of abdominal trachelectomy for cervical cancers ≥2 cm. We began performing abdominal trachelectomies at our institution in 2005, primarily for squamous cell carcinoma ≤3 cm or adenocarcinoma/adenosquamous carcinoma ≤2 cm. If a positive sentinel lymph node or cervical margin was diagnosed intraoperatively by frozen section, the trachelectomy was converted to a hysterectomy. Medical records of these patients were reviewed retrospectively. Patients who had undergone simple abdominal trachelectomy were excluded from this study. We attempted trachelectomy in 212 patients. Among the 135 patients with tumors <2 cm, trachelectomy was successful in 120, one of whom developed recurrence and none of whom died of their disease. Among 77 patients with tumors ≥2 cm, trachelectomy was successful in 62, 2 of whom developed recurrence and 1 of whom died of her disease. The overall relapse rate after trachelectomy was 1.6% (0.8% in <2 cm group and 3.2% in ≥2 cm group), and the mortality rate was 0.5% (0% in <2 cm group and 1.6% in ≥2 cm group). Recurrence-free survival (p=0.303) and overall survival (p=0.193) did not differ significantly between the <2 cm and ≥2 cm groups. Abdominal trachelectomy with intraoperative frozen sections of sentinel lymph nodes and cervical margins is oncologically safe, even in patients with tumors ≥2 cm.

First-Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open-Label, Phase III Trial

PURPOSE Lenvatinib plus pembrolizumab (len + pembro) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in previously treated advanced or recurrent endometrial cancer (aEC) in the phase III Study 309/KEYNOTE-775. We report results from the phase III, randomized, open-label European Network of Gynaecological Oncological Trial-en9/LEAP-001 study (ClinicalTrials.gov identifier: NCT03884101 ) that evaluated len + pembro versus chemotherapy in first-line aEC. METHODS Patients with stage III to IV or recurrent, radiographically apparent EC and no previous chemotherapy or disease progression ≥6 months after neo/adjuvant platinum-based chemotherapy were randomly assigned 1:1 to lenvatinib 20 mg once daily plus pembrolizumab 200 mg once every 3 weeks or paclitaxel 175 mg/m 2 plus carboplatin AUC 6 mg/mL/min once every 3 weeks. Primary end points were PFS and OS, evaluated in the mismatch repair-proficient (pMMR) and all-comers populations. Noninferiority was assessed for OS at final analysis (FA) for len + pembro versus chemotherapy (multiplicity-adjusted, one-sided nominal alpha, .0159; null hypothesis–tested hazard ratio [HR], 1.1). RESULTS Eight hundred forty-two patients were randomly assigned (len + pembro, n = 420 [pMMR population, n = 320]; chemotherapy, n = 422 [pMMR population, n = 322]). At FA (data cutoff, October 2, 2023), median PFS (95% CI) in the pMMR population was 9.6 (8.2 to 11.9) versus 10.2 (8.4 to 10.5) months with len + pembro versus chemotherapy (hazard ratio [HR], 0.99 [95% CI, 0.82 to 1.21]) and among all-comers was 12.5 (10.3 to 15.1) versus 10.2 (8.4 to 10.4) months (HR, 0.91 [95% CI, 0.76 to 1.09]; descriptive analyses). Median OS (95% CI) in the pMMR population was 30.9 (25.4 to 37.7) versus 29.4 (26.2 to 35.4) months with len + pembro versus chemotherapy (HR, 1.02 [95% CI, 0.83 to 1.26]; noninferiority P = .246, not statistically significant per multiplicity control strategy) and among all-comers was 37.7 (32.2 to 43.6) versus 32.1 (27.2 to 35.7) months (HR, 0.93 [95% CI, 0.77 to 1.12]). Grade ≥3 treatment-related adverse events occurred in 331/420 (79%) versus 274/411 (67%) treated patients. CONCLUSION First-line len + pembro did not meet prespecified statistical criteria for PFS or OS versus chemotherapy in pMMR aEC.