Yukihiro Imai

Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations.

The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR‐tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation.

Frequency of EGFR and KRAS Mutations in Japanese Patients with Lung Adenocarcinoma with Features of the Mucinous Subtype of Bronchioloalveolar Carcinoma

Introduction: Adenocarcinoma of the lung, especially bronchioloalveolar carcinoma (BAC) and adenocarcinoma with BAC features (AWBF), is potentially sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs); however, the efficacy seems to differ between the histologic subtypes. Mucinous BAC and AWBF (MBAC/AWBF) are not particularly responsive to EGFR-TKIs compared with nonmucinous BAC/AWBF (N-MBAC/AWBF). This may be due to the rarity of EGFR mutations and high frequency of KRAS mutations in MBAC/AWBF in contrast to N-MBAC/AWBF. Methods: One hundred ninety-one patients with adenocarcinoma of the lung underwent surgery at our institution. There were 59 patients (30%) diagnosed with BAC/AWBF; 20 had MBAC/AWBF (10%) and 39 had N-MBAC/AWBF (20%). We isolated 44 tissue specimens from these patients (20 consecutive cases of MBAC/AWBFs and 24 randomly chosen cases of N-MBAC/AWBFs as the control group), and we analyzed them for EGFR and KRAS mutations. We used the peptide nucleic acid-locked nucleic acid polymerase chain reaction clump method to detect EGFR mutations and conventional DNA sequencing to identify KRAS mutations. Results: EGFR mutations were found in three of the 20 MBAC/AWBFs (15%) and in 14 of the 24 N-MBAC/AWBFs (58%) (p = 0.005). In addition, there were 14 KRAS mutations identified in the 20 MBAC/AWBFs (70%) and seven in the 24 N-MBAC/AWBFs (29%) (p = 0.0144). Conclusions: The incidence of EGFR mutation is low and that of KRAS mutation is frequent in MBAC/AWBFs. Conversely, the incidence of EGFR mutation is high and KRAS mutation is low in N-MBAC/AWBFs. Based on these findings, EGFR-TKIs may not be effective in patients with MBAC/AWBF.

Clinical Features and Outcome of Acute Exacerbation of Interstitial Pneumonia: Collagen Vascular Diseases-Related versus Idiopathic

Background: Relatively little is known about acute exacerbation (AE) of interstitial pneumonia associated with collagen vascular diseases (CVD-IPs). Objectives: This study was aimed at clarifying clinical characteristics and outcome in AE of CVD-IPs, compared with those of idiopathic interstitial pneumonias (IIPs). Methods: We retrospectively reviewed 112 admission cases with suspected AE of CVD-IPs or IIPs during 2003–2009. IIPs were diagnosed with idiopathic pulmonary fibrosis (IPF) or non-IPF, mostly based on radiologic findings. Of these, 15 AEs of CVD-IPs (6 rheumatoid arthritis, 6 dermatomyositis and 3 systemic sclerosis) and 47 AEs of IIPs (13 IPF and 34 non-IPF) were included. Results: The clinical characteristics in AE of CVD-IPs were similar to those of IIPs, except for younger age (63.3 ± 6.8 vs. 73.8 ± 9.1 years; p = 0.0001) and higher PaO2/FiO2 at the onset of AE (205 ± 81.2 vs. 145 ± 53.8 mm Hg; p = 0.002) in the former. Dermatomyositis-related interstitial pneumonia (IP) showed a relatively indolent onset and was often associated with worsening control of the underlying disease, whereas AE of other CVD-IPs resembled that of IIPs. 90-day mortality of 33% in AE of CVD-IPs was similar to that of IIPs (44%; p = 0.44) or non-IPF (34%; p = 0.94), but was significantly better than that of IPF (69%; p = 0.04). Conclusion: Clinical features and outcome in AE of CVD-IPs were similar, if not identical, to those of IIPs, having a significant impact on the clinical course. AE of advanced IPF with typical radiologic features seems to have higher mortality compared with other forms of IP.

Complex Mutations in the Epidermal Growth Factor Receptor Gene in Non-small Cell Lung Cancer

Introduction: Mutation of the epidermal growth factor receptor (EGFR) gene can predict the efficacy of EGFR-tyrosine kinase inhibitors. Different mutations have been shown to co-occur in a single tumor. However, the frequency of these so-called “complex mutations” and the efficacy of gefitinib in treating patients with these mutations are unclear. Methods: We investigated the frequency of complex mutations in 783 patients with non-small cell lung cancer seen at our institutes between April 2006 and May 2009. Mutational analysis was performed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Gefitinib efficacy was evaluated in patients found to have complex mutations. Results: EGFR mutations were detected in 318 (41%) patients, with 21 (6.6%) of these individuals having complex mutations. Sixteen of these 21 patients received gefitinib. The response rate (RR) was 67% (95% confidence interval [CI], 35–90%) and median progression-free survival was 12.2 months (95% CI, 1.3 months to undeterminable). Analysis of RR according to mutation type revealed that patients with deletional mutation in exon 19 (Del-19) and a point mutation in exon 21 (L858R) had a better RR (86%, 6 of 7) than those with other complex mutation patterns such as a point mutation in exon 18 (G719S) + L858R (40%, 2 of 5) (p = 0.2222). The median progression-free survival was also longer in these patients (16.5 months; 95% CI, 1.1 months to undeterminable versus 3.8 months; 95% CI, 0.7–10.0 months) (p = 0.0459). Conclusions: Complex EGFR mutations are not rare. Gefitinib has different efficacy according to the type of complex EGFR mutations. Patients with Del-19 and L858R mutations may benefit more from gefitinib than other types of complex mutations.

18F-FLT PET performs better than 18F-FDG PET in differentiating malignant uterine corpus tumors from benign leiomyoma

PurposeThe aim of this study is to test the hypothesis that positron emission tomography (PET) with 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) can differentiate malignancy from benign leiomyoma better than PET with 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG), and to evaluate whether 18F-FLT and 18F-FDG uptake correlate with immunohistochemical index of cell proliferation.MethodsThe protocol of this prospective study was approved by the institutional ethics committee, and all patients gave written informed consent. Fifteen patients (aged 26–65xa0years, median 44xa0years) with uterine corpus tumor which has the possibility of being leiomyosarcoma underwent 18F-FLT and 18F-FDG PET scans. Maximum standard uptake value (SUVmax) of PET scans and Ki-67 labeling index of surgical specimens were evaluated. Mann–Whitney’s U test was used for comparing uptakes between benign and malignant, and linear regression analysis was used for evaluating the correlation between Ki-67 labeling index and SUVmax.ResultsFive cases were diagnosed as malignant (leiomyosarcoma for 3 cases, and carcinoma for 2 cases), and the others were benign leiomyoma. Sensitivity and negative predictive value of both tracers for detecting malignancy was 100xa0%. Specificity, positive predictive value and accuracy of 18F-FLT PET were higher than those of 18F-FDG PET. Difference in SUVmax between malignant and benign was significant for 18F-FLT PET (Pxa0<xa00.01), but not for 18F-FDG PET. While all the malignant cases showed positive uptake in both tracers, a case of leiomyosarcoma with huge necrosis showed relatively low uptake. Uptake of 18F-FLT showed better correlation with Ki-67 labeling index compared with 18F-FDG (R2xa0=xa00.91 vs. R2xa0=xa00.26).ConclusionNegative findings on additional 18F-FDG or 18F-FLT PET may rule out the possibility of malignancy for the patients with suspected leiomyosarcoma diagnosed by conventional methods. 18F-FLT PET is superior to 18F-FDG PET in differentiating malignant from benign leiomyoma. Moreover, 18F-FLT uptake correlated well with the immunohistochemical index of cell proliferation.

Angiosarcoma Arising from Right Atrium: Remarkable Response to Concurrent Chemoradiotherapy with Carboplatin and Paclitaxel

To the Editor: We read with interest the case report by Fehr et al.1 and the concise review by Orlandi et al.2 regarding cardiac sarcomas. Concurrent chemoradiotherapy (CRT) to cardiac angiosarcomas has been scarcely documented, and only one case was reported with the benefit from concurrent CRT with docetaxel.3 Although efficacy of weekly paclitaxel (PTX) for unresectable angiosarcoma has been demonstrated,4 CRT with weekly PTX was not reported before the report by Fehr et al. We present herein a case of metastatic angiosarcoma arising from the right atrium, which remarkably responded to concurrent CRT with weekly carboplatin and PTX. A 40-year-old man was referred to our institute, presenting a tumor in the right atrium and multiple bilateral lung nodules with the computed tomography (Figures 1A, B). Histology obtained by wedge resection of a lung nodule revealed a high-grade epithelial angiosarcoma, thus the patient was diagnosed with angiosarcoma from right atrium with multiple lung metastases. We judged it to be unresectable and decided to perform concurrent CRT (30 fractions of 2Gy) with weekly carboplatin (area under the curve 2) and PTX (60 mg/m) for 6 consecutive weeks. The radiation field was limited to the primary cardiac tumor. After the therapy, almost all bilateral pulmonary nodules disappeared, and a large tumor in the right atrium was markedly reduced (Figure 2A, B). Although grade 2 esophagitis and neutropenia were observed, the treatment was generally well tolerated. No evidence of progression has been confirmed after more than 5 months of follow-up. Multimodality treatment combined with surgery and adjuvant chemotherapy and/or radiotherapy is indicated as the standard care for patients with cardiac angiosarcomas. Nevertheless, the majority of patients with cardiac sarcoma are already unresectable and metastatic disease at their initial diagnosis and have a poor prognosis. CRT is desirable in some cases with cardiac sarcoma to control both the primary cardiac tumor and metastatic lesions. In our case, a combined regimen including PTX was chosen to obtain better response of metastatic lesions, and good response was clearly observed. Moreover, the efficacy and tolerability of concurrent CRT with carboplatin PTX have been recently demonstrated in locally advanced non-small cell lung cancer.5 To our knowledge, this is the first report demonstrating the efficacy of concurrent CRT with carboplatin PTX for cardiac angiosarcoma. Nevertheless, there is no other evidence of CRT with doublet regimens. Future studies to explore usefulness of concurrent CRT for cardiac angiosarcomas are warranted.

Programmed death-ligand 1 expression and T790M status in EGFR-mutant non-small cell lung cancer

BACKGROUNDnDifferential biology and prognosis between T790M+ and T790M- populations imply immunological differences also.nnnMETHODSnWe retrospectively analyzed programmed death-ligand 1 (PD-L1) expression and T790M status in rebiopsied samples of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). PD-L1 immunohistochemistry was performed using the SP142 antibody for tumour cell (TC) and tumour-infiltrating immune cell (IC) and the 28-8 antibody for TC. PD-L1+ was defined as TC or IC ≥1%.nnnRESULTSnWe investigated 67 available rebiopsied histologic samples in 47 patients. Using the SP142, prevalence of PD-L1 any+, moderate+, and strong+ in T790M+ vs. T790M- samples were 31% vs. 61%, 8% vs. 15%, and 0% vs. 2%, respectively, representing PD-L1+ prevalence of T790M+ samples was significantly lower than that of T790M- (p=0.0149). Prevalence of any TC+/IC+ in T790M+ vs. T790M- samples were TC: 31% vs. 51% (p=0.0997) and IC: 8% vs. 27% (p=0.0536), respectively. Using the 28-8, median percentage of PD-L1+ in T790M+ samples was 1.9 (range, 0-27.2), whereas T790M- was 4.1 (range, 0-89.8) (p=0.0801). Prevalence of PD-L1+ ≥1%, ≥5%, and ≥10% in T790M+ vs. T790M- samples were 77% vs. 83% (p=0.5476), 31% vs. 49% (p=0.1419), and 12% vs. 27% (p=0.1213), respectively. In 9 of 11 patients receiving multiple rebiopsies, T790M and/or PD-L1 expression revealed temporal dynamism. Survival curves according to PD-L1 expression/T790M status suggested better prognosis in PD-L1-/T790M+ population.nnnCONCLUSIONSnT790M+ status was correlated to lower PD-L1 expression. PD-L1 expression might have a prognostic value and interaction with T790M mutation in EGFR-mutant NSCLC.

Macroscopic appearance of a uterus with a cesarean scar pregnancy

Cesarean scar pregnancy (CSP) is an ectopic pregnancy implanted in a previous cesarean scar. Such implantation occurs in approximately 1 in 2000 pregnancies and accounts for 6% of ectopic pregnancies among women with a prior cesarean delivery in high-income countries [1]. Diagnosis is usually made via vaginal or abdominal ultrasound. Many ultrasonographic and magnetic resonance imaging photographs of CSPs have been published [1–3]; however, there are only a few published images showing themacroscopic appearanceof a uteruswith a CSP [2,3]. In their obstetrics textbook, Cunningham et al. [2] included a color photograph of a hysterectomy specimen with a CSP, which was transversely sectioned at the level of the uterine isthmus and the gestational sac. In a recent case series, Maekawa et al. [3] included a black-and-white photograph of a hysterectomy specimen with a CSP (in which the gestational sac can be observed directly), which was opened in the anterior muscle layer just beneath the endometrium. In 2004, awomanpresented to theKobe CityMedical Center General Hospital, Kobe, Japan,with a CSP. Shehad alreadygivenbirth to3 infants via cesarean delivery and did not desire uterine preservation; she underwent hysterectomy at 7 weeks of pregnancy (Fig. 1). Resection of the uterus was achieved by abdominal hysterectomy via laparotomy. The uterine corpus muscle layer was opened in the posterior wall just beneath the endometrium. The endometrium was opened in the posterior wall. The uterine cavity was observed in the center of the uterus. Thick endometrium was also observed. A gestational sac was observed in the thick endometrium at the depressed part of the lower anterior uterine wall. The endometrium just beyond the gestational sac was opened, and the gestational sac was easily extracted from the depressed part of the previous cesarean scar. The embryo was embedded within the amniotic membrane, which was surrounded by a small amount of chorion. The functional endometrium was flapped over and the uterine muscle layer with thin basic endometrium (endometrium contagiosum) was observed. The previous cesarean scar silk suture was observed in the right side of the depressed part of the cesarean scar. The amniotic membranewas opened and the embryo observed directly. Adhesion among themuscle layer, the endometrium, and the gestational sac was loose. As indicated in the present case, pregnancy contents are loosely adhered to each other, and the gestational sac is comparatively small until 7 weeks of gestation. Extraction of the contents of a CSP can be undertaken safely via a vaginal approach with abdominal ultrasound guidance and ample anesthesia.

Programmed death-ligand 1 expression according to epidermal growth factor receptor mutation status in pretreated non-small cell lung cancer

Background Current clinical trials have suggested poorer efficacies of anti-programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) immunotherapies for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, implying lower PD-L1 expression in EGFR-mutant NSCLC than in EGFR-wild type. Methods We retrospectively analyzed correlation between PD-L1 expression and EGFR status in clinical samples of pretreated NSCLC. PD-L1 immunohistochemistry was performed using the 28-8 anti-PD-L1 antibody for tumor cell membrane staining. H-score was adopted to evaluate both percentage and intensity. We investigated H-scores ≥1, ≥5, and ≥10 as PD-L1+ cut-offs. H-score ≥10 was defined as strong PD-L1+. Results We investigated 96 available histologic samples in 77 pretreated patients with NSCLC. Median H-score in EGFR-mutant samples (n=65) was 3 (range, 0-150), whereas EGFR-wild-type (n=31) was 8 (range, 0-134) (p=0.0075). Using H-scores ≥1, ≥5, and ≥10 cut-offs, incidence of PD-L1+ in EGFR-mutant vs. EGFR-wild-type samples were: 85% (55/65) vs. 94% (29/31) (p=0.2159); 42% (27/65) vs. 74% (23/31) (p=0.0027); and 22% (14/65) vs. 48% (15/31) (p=0.0074), respectively. Patient-oriented (n=77) univariate analysis for strong PD-L1+ found age of sample (p=0.0226) and EGFR mutation status (p=0.0490) as significant factors. Multivariate analysis identified EGFR mutation status as the only significant factor (p=0.0121, odds ratio 2.99) for strong PD-L1+. H-scores of PD-L1 expression varied in all 11 cases receiving multiple rebiopsies, and categories of positivity migrated in 10 (91%) of 11 patients. Conclusions PD-L1 expression was significantly lower in EGFR-mutant NSCLC samples than in EGFR wild-type samples. Its expression could be dynamic and affected by age of sample.

Correlation of Expression Levels of Copper Transporter 1 and Thymidylate Synthase with Treatment Outcomes in Patients with Advanced Non-small Cell Lung Cancer Treated with S-1/Carboplatin Doublet Chemotherapy

Background: Copper transporter 1 (CTR1) is a critical determinant of the uptake and cytotoxic effect of the platinum drugs carboplatin and cisplatin. Thymidylate synthase (TS) is an enzyme involved in DNA synthesis and is associated with resistance of tumor cells to 5-fluorouracil. We investigated the correlation between CTR1 and TS expression levels and treatment outcomes in patients with advanced non-small-cell lung cancer (NSCLC) treated with S-1/carboplatin doublet chemotherapy. Methods: Twenty-nine patients were enrolled in this study. Tumor expression of CTR1 and TS was measured immunohistochemically and analyzed for correlation with tumor response, progression-free survival (PFS), and overall survival (OS). Results: Tumor response was significantly better in patients with CTR1High tumors than in patients with CTR1Low tumors (64% vs. 18%, P = 0.02). Patients with TSLow tumors had a significantly longer OS (median 21.2 vs. 8.5 months, P = 0.02), but not PFS, than patients with TSHigh tumors. When CTR1 and TS co-expression was analyzed, patients with either CTR1High or TSLow tumors showed a significantly better tumor response (50% vs. 0%, P = 0.01), longer PFS (median 4.2 vs. 2.1 months, P = 0.03), and longer OS (median 21.2 vs. 8.5 months, P = 0.01) than patients with both CTR1Low and TSHigh tumors. Conclusions: Our study suggests that combined CTR1/TS expression status has the potential to be an important predictor of good treatment outcomes in patients with advanced NSCLC treated with S-1/carboplatin doublet chemotherapy.