Publications by authors named "Yasushi Yatabe"

461 Publications

MYB mediates downregulation of the colorectal cancer metastasis suppressor heterogeneous nuclear ribonucleoprotein L-like during epithelial-mesenchymal transition.

Cancer Sci 2021 Jul 19. Epub 2021 Jul 19.

Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan.

Heterogeneous nuclear ribonucleoprotein L-like (HNRNPLL), a suppressor of colorectal cancer (CRC) metastasis, is transcriptionally downregulated when CRC cells undergo epithelial-mesenchymal transition (EMT). Here we show that decrease of MYB mediates the downregulation of HNRNPLL during EMT. The promoter activity was attributed to a region from -273 to -10 base pairs upstream of the transcription start site identified by 5'-RACE analysis, and the region contained potential binding sites for MYB and SP1. Luciferase reporter gene assays and knockdown or knockout experiments for genes encoding the MYB family proteins, MYB, MYBL1, and MYBL2, revealed that MYB was responsible for approximately half of the promoter activity. On the other hand, treatment with mithramycin A, an inhibitor for SP1 and SP3, suppressed the promoter activity and their additive contribution was confirmed by knockout experiments. The expression level of MYB was reduced on EMT while that of SP1 and SP3 was unchanged, suggesting that the downregulation of HNRNPLL during EMT was mediated by the decrease of MYB expression while SP1 and SP3 determine the basal transcription level of HNRNPLL. Histopathological analysis confirmed the accumulation of MYB-downregulated cancer cells at the invasion front of clinical CRC tissues. These results provide an insight into the molecular mechanism underlying CRC progression.
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http://dx.doi.org/10.1111/cas.15069DOI Listing
July 2021

Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for -mutated resectable non-small-cell lung cancer: NeoADAURA.

Future Oncol 2021 Jul 19. Epub 2021 Jul 19.

Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center & Weill Cornell Medical College, New York, NY 10021, USA.

Osimertinib is a third-generation, irreversible oral EGFR-tyrosine kinase inhibitor), that potently inhibits EGFR-tyrosine kinase inhibitor-sensitizing mutations and T790M resistance mutations together with efficacy in CNS metastases in patients with non-small-cell lung cancer (NSCLC). Here we describe the rationale and design for the Phase III NeoADAURA study (NCT04351555), which will evaluate neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone prior to surgery, in patients with resectable stage II-IIIB N2 mutation-positive NSCLC. The primary end point is centrally assessed major pathological response at the time of resection. Secondary end points include event-free survival, pathological complete response, nodal downstaging at the time of surgery, disease-free survival, overall survival and health-related quality of life. Safety and tolerability will also be assessed. Trial Registration number: NCT04351555 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2021-0549DOI Listing
July 2021

Maximum standardized uptake value of the primary tumor does not improve candidate selection for sublobar resection.

J Thorac Cardiovasc Surg 2021 Jul 2. Epub 2021 Jul 2.

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

Objective: This retrospective study examined whether adding the maximum standardized uptake value of a primary tumor to the consolidation-to-tumor ratio from a high-resolution computed tomography scan can improve the predictive accuracy for pathological noninvasive lung cancer and lead to better patient selection for sublobar resection.

Methods: We included 926 patients with clinical stage IA non-small cell lung cancer. Pathological noninvasive cancer (n = 515) was defined as any case without lymphatic invasion, vascular invasion, or lymph node metastasis. The prediction accuracies of maximum standardized uptake value and consolidation-to-tumor ratio were evaluated using receiver operating characteristic curves and area under the curve.

Results: For consolidation-to-tumor ratio or maximum standardized uptake value alone, the area under the curves were 0.733 (95% confidence interval, 0.708-0.758) and 0.842 (95% confidence interval, 0.816-0.866), respectively. When the consolidation-to-tumor ratio and maximum standardized uptake value were combined, the area under the curve was 0.854 (95% confidence interval, 0.829-0.876). However, to obtain a predictive specificity of 97%, sensitivity needed to be 42.5% for the consolidation-to-tumor ratio, 38.3% for the maximum standardized uptake value, and 45.0% for these 2 in combination.

Conclusions: Our results suggest that despite the high area under the curve for maximum standardized uptake value, caution is needed when using maximum standardized uptake value to select candidates for sublobar resection. We found that a low maximum standardized uptake value did not mean the tumor was a pathological noninvasive lung cancer. Therefore, using consolidation-to-tumor ratios from high-resolution computed tomography to decide whether sublobar resection is appropriate for patients with clinical stage IA non-small cell lung cancer is better than using maximum standardized uptake value when setting specificity to a conservative 97% for predicting pathological noninvasive lung cancer.
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http://dx.doi.org/10.1016/j.jtcvs.2021.06.053DOI Listing
July 2021

Tumor size in patients with severe pulmonary emphysema might be underestimated on preoperative CT.

Eur Radiol 2021 Jun 16. Epub 2021 Jun 16.

Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Objectives: To evaluate the effect of emphysema on tumor diameter measured on preoperative computed tomography (CT) images versus pathological specimens.

Materials And Methods: We investigated patients who underwent primary lung cancer surgery: 55 patients (57 tumors) with severe emphysema and 57 patients (57 tumors) without emphysema. The tumor diameters measured in the postoperative pathological specimens were compared with those measured on the axial CT images and on multiplanar reconstruction (MPR) CT images by two independent radiologists; a subgroup analysis according to tumor size was also performed. A paired or unpaired t test was performed, depending on the tested subjects.

Results: In the emphysema group, the mean axial CT diameter was significantly smaller than the mean pathological diameter (p = 0.025/0.001 for reader 1/2), whereas in the non-emphysema group, the mean axial CT diameter was not significantly different from the pathological one for both readers. The difference between CT axial diameter and pathological diameter (= CT diameter - pathological diameter) was significantly smaller (i.e., had a stronger tendency toward underestimation on radiological measurements) in the emphysema group compared with the non-emphysema group (p = 0.014/0.008 for reader 1/2), and the difference was significantly smaller in tumors sized > 30 mm than tumors sized ≤ 20 mm in both groups.

Conclusions: Tumor size is significantly smaller on preoperative CT in patients with severe emphysema compared to patients without emphysema, especially in the case of large tumors. MPR measurement using the widest of three dimensions should be used to select T-stage for patients with severe emphysema.

Key Points: • The presence of emphysema affects the accuracy of tumor size measurements on CT. • Compared to patients without emphysema, the tumor size in severe emphysema patients tends to be measured smaller in preoperative CT than the pathological specimen. • This trend is more evident when large tumors are measured on axial CT images alone.
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http://dx.doi.org/10.1007/s00330-021-08105-3DOI Listing
June 2021

Appropriate use of cancer comprehensive genome profiling assay using circulating tumor DNA.

Cancer Sci 2021 Jun 15. Epub 2021 Jun 15.

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

Comprehensive genomic profiling (CGP) is being increasingly used for the routine clinical management of solid cancers. In July 2018, the use of tumor tissue-based CGP assays became available for all solid cancers under the universal health insurance system in Japan. Several restrictions presently exist, such as patient eligibility and limitations on the opportunities to perform such assays. The clinical implementation of CGP based on plasma circulating tumor DNA (ctDNA) is also expected to raise issues regarding the selection and use of tissue DNA and ctDNA CGP. A Joint Task Force for the Promotion of Cancer Genome Medicine comprised of three Japanese cancer-related societies has formulated a policy proposal for the appropriate use of plasma CGP (in Japanese), available at https://www.jca.gr.jp/researcher/topics/2021/files/20210120.pdf, http://www.jsco.or.jp/jpn/user_data/upload/File/20210120.pdf, and https://www.jsmo.or.jp/file/dl/newsj/2765.pdf. Based on these recommendations, the working group has summarized the respective advantages and cautions regarding the use of tissue DNA CGP and ctDNA CGP with reference to the advice of a multidisciplinary expert panel, the preferred use of plasma specimens over tissue, and multiple ctDNA testing. These recommendations have been prepared to maximize the benefits of performing CGP assays and might be applicable in other countries and regions.
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http://dx.doi.org/10.1111/cas.15022DOI Listing
June 2021

Cytokeratin-positive Malignant Tumor in the Abdomen With EWSR1/FUS-CREB Fusion: A Clinicopathologic Study of 8 Cases.

Am J Surg Pathol 2021 May 27. Epub 2021 May 27.

Departments of Diagnostic Pathology Medical Oncology Hepatic and Pancreatobiliary Oncology Pediatric Oncology Head and Neck Medical Oncology Division Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.

ATF1, CREB1, and CREM, which encode the CREB family of transcription factors, are fused with EWSR1 or FUS in human neoplasms, such as angiomatoid fibrous histiocytoma. EWSR1/FUS-CREB fusions have recently been reported in a group of malignant epithelioid tumors with a predilection to the peritoneal cavity and frequent cytokeratin expression. Here, we studied 8 cytokeratin-positive abdominal malignancies with these fusions for further characterization. The tumors affected males (15 to 76 y old) and presented as intra-abdominal masses with concurrent or subsequent peritoneal dissemination, ascites, and/or metastases to the liver or lymph nodes. Four patients died of the disease within 18 to 140 months. Cases 1 to 5 showed multinodular growth of monomorphic epithelioid cells with focal serous cysts. Lymphoplasmacytic infiltration was prominent and was associated with systemic inflammatory symptoms. Two patients suffered from membranous nephropathy with nephrosis. The tumors displayed partly overlapping phenotypes with malignant mesothelioma, including diffuse strong expression of AE1/AE3 and WT1 and membranous positivity of sialylated HEG1, although calretinin was negative. Case 6 showed similar histology to cases 1 to 5, but expressed smooth muscle actin diffusely, lacked WT1 and HEG1, and harbored prominent pseudoangiomatous spaces. Cases 7 and 8 displayed dense growth of small oval to short spindle cells, with occasional molding and minor swirling, superficially resembling small cell carcinoma. Lymphoplasmacytic infiltration was not observed. The tumors were positive for AE1/AE3 and CD34 (focal), whereas calretinin, WT1, and HEG1 were negative. The detected fusions were FUS-CREM (n=4), EWSR1-ATF1 (n=2), EWSR1-CREB1 (n=1), and EWSR1-CREM (n=1). We confirmed the prior observation that these tumors do not fit perfectly with known entities and provided additional novel clinicopathologic information. The tumors require wider recognition because of more aggressive behavior than angiomatoid fibrous histiocytoma despite similar genetics, and potential misdiagnosis as unrelated diseases, such as neuroendocrine neoplasms.
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http://dx.doi.org/10.1097/PAS.0000000000001742DOI Listing
May 2021

Analysis of factors affecting the diagnostic yield of image-guided percutaneous core needle biopsy for peritoneal/omental lesions.

Abdom Radiol (NY) 2021 May 28. Epub 2021 May 28.

Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Purpose: To evaluate the diagnostic yield, safety, and factors associated with the diagnostic yield of percutaneous core needle biopsy (PNB) for peritoneal/omental lesions.

Methods: Consecutive 297 patients (67 men, 230 women; median age, 64 years [range 15-87]) who underwent a PNB for 311 peritoneal/omental lesions at a single center from April 2010 to March 2020 were evaluated retrospectively. The preprocedural CT findings, diagnostic yield, sensitivity, specificity, PPV, NPV, technical success rate, and adverse events were analyzed. Surgical or clinical diagnosis with follow-up was the diagnostic reference standard. Adverse events were evaluated using the Society of Interventional Radiology guidelines.

Results: The median anteroposterior (AP) diameter and CT value of the target lesion were 24 mm (range 5-78) and 46 HU (range - 75 to 140), respectively. Ascites was interposed on the puncture route in 106 patients (34.1%). The technical success rate was 100%. The diagnostic yield, sensitivity, specificity, PPV, and NPV were 93.9%, 93.8%, 100%, 100%, and 20.8%, respectively. Minor complications were observed following five procedures (1.6%). The diagnostic yield was lower for fat-dominant lesions than for other lesions (82.6% vs. 95.8%, p = 0.002). The diagnostic PNB group had a greater AP diameter than did the non-diagnostic PNB group (27.3 ± 13.0 vs. 20.7 ± 8.4 mm, p = 0.037).

Conclusion: PNB for peritoneal/omental lesions provided a sufficiently high diagnostic yield and minimal adverse events. Lesions with a greater AP diameter and a higher density on CT would provide more diagnostic specimens from this technique.
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http://dx.doi.org/10.1007/s00261-021-03088-7DOI Listing
May 2021

Phase II Study of Neoadjuvant Concurrent Chemo-immuno-radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage IIIA-B (Discrete N2) Non-small-cell Lung Cancer: SQUAT trial (WJOG 12119L).

Clin Lung Cancer 2021 Apr 27. Epub 2021 Apr 27.

Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. Electronic address:

Introduction: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069).

Patients And Methods: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%.

Conclusion: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2021.04.006DOI Listing
April 2021

Visualization of Intratumor Pharmacokinetics of [fam-] Trastuzumab Deruxtecan (DS-8201a) in HER2 Heterogeneous Model Using Phosphor-integrated Dots Imaging Analysis.

Clin Cancer Res 2021 Jul 12;27(14):3970-3979. Epub 2021 May 12.

Division of Molecular Pharmacology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

Purpose: We assessed the intratumor pharmacokinetics of [fam-] trastuzumab deruxtecan, T-DXd (known as DS-8201a), a novel HER2-targeted antibody-drug conjugate, using phosphor-integrated dots (PID)-imaging analysis to elucidate its pharmacologic mechanism.

Experimental Design: We used two mouse xenograft models administered T-DXd at the concentration of 4 mg/kg: (i) a heterogeneous model in which HER2-positive and HER2-negative cell lines were mixed, and (ii) a homogeneous model in which both cell types were transplanted separately into the same mouse. PID imaging involved immunostaining using novel high-intensity fluorescent nanoparticles. The distribution of T-DXd was assessed by PID imaging targeting the parent antibody, trastuzumab, and the payload, DXd, in serial frozen sections, respectively.

Results: After T-DXd administration in the heterogeneous model, HER2 expression tended to decrease in a time-dependent manner. The distribution of trastuzumab and DXd was observed by PID imaging along the HER2-positive area throughout the observation period. A detailed comparison of the PID distribution between trastuzumab and DXd showed that trastuzumab matched almost perfectly with the HER2-positive area. In contrast, DXd exhibited widespread distribution in the surrounding HER2-negative area as well. In the HER2-negative tumor of the homogeneous model, the PID distribution of trastuzumab and DXd remained extremely low throughout the observation period.

Conclusions: Our results suggest that T-DXd is distributed to tumor tissues via trastuzumab in a HER2-dependent manner and then to adjacent HER2-negative areas. We successfully visualized the intratumor distribution of T-DXd and its mechanism of action, the so-called "bystander effect."
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0397DOI Listing
July 2021

[Pathological and Molecular Biological Classification of Small Cell Lung Cancer].

Authors:
Yasushi Yatabe

Gan To Kagaku Ryoho 2021 Apr;48(4):472-475

Dept. of Diagnostic Pathology, National Cancer Center Hospital.

The name of small cell carcinoma is becoming unified with neuroendocrine carcinoma in many other cancers except lung cancer, and following this trend, small cell carcinoma of the lung categorized into a subtype under neuroendocrine carcinoma in the 2015 WHO classification. However, small cell carcinoma has been retained and remain as a distinct entity. In this article, I introduced the history and current concept of small cell lung cancer classification, as well as the molecular biological classification of small cell lung cancer based on 4 definitive molecules, ASCL1, NEUROD1, YAP1, and POU2F3, proposed in 2019.
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April 2021

Alectinib for Miliary Lung Metastasis in -Positive Lung Adenocarcinoma.

Onco Targets Ther 2021 30;14:2911-2915. Epub 2021 Apr 30.

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Background: Miliary pulmonary metastasis characterized by tiny nodules is a rare metastatic pattern in advanced non-small cell lung cancer (NSCLC) and is usually seen in patients harboring an mutation, and amylase-producing lung cancer is highly uncommon and rarely reported in NSCLC patients who have an mutation.

Case: A 32-year-old Japanese female was found to have miliary pulmonary nodules throughout both lung fields on a chest x-ray examination during an annual health check-up. Further examination by computed tomography (CT) revealed diffuse, bilateral, miliary nodules. Blood tests showed no increased tumor marker levels, but there was a significantly increased serum amylase level. A diagnosis of -rearranged adenocarcinoma was made based on the results of a mediastinal lymph node biopsy obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Treatment with alectinib resulted in rapid regression of the CT shadows and a reduction in the patient's serum amylase level.

Conclusion: We have reported a case of -rearranged NSCLC with a miliary pulmonary metastasis pattern that was sensitive to alectinib and in which the serum amylase level decreased in response to treatment with alectinib. Young patients with miliary pulmonary metastasis should be checked for all driver mutations.
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http://dx.doi.org/10.2147/OTT.S300229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096437PMC
April 2021

Long-Term Prognosis of Patients With Resected Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma of the Lung.

J Thorac Oncol 2021 Aug 27;16(8):1312-1320. Epub 2021 Apr 27.

Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.

Introduction: The WHO classification of lung tumors defines adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) as cancers with no or limited histologic invasive components. The probability of patients with AIS or MIA being recurrence free for 5 years postoperatively has been found to be 100%. This study aimed to analyze the prognosis of patients with AIS or MIA after more than 5 postoperative years.

Methods: We reviewed the pathologic findings of 4768 patients who underwent resection for lung cancer between 1998 and 2010. Of these, 524 patients with curative resection for AIS (207 cases, 39.5%) and MIA (317 cases, 60.5%) were included. Postoperative recurrence, survival, and development of secondary primary lung cancer (SPLC) were analyzed.

Results: Of the included patients, 342 (65.3%) were of female sex, 333 (63.5%) were nonsmokers, and 229 (43.7%) underwent sublobar resection. Average pathologic total tumor diameter was 15.2 plus or minus 5.5 mm. Median postoperative follow-up period was 100 months (range: 1-237). No recurrence of lung cancer was observed for either AIS or MIA cases. Estimated 10-year postoperative disease-specific survival rates were 100% and 100% (p = 0.72), and overall survival rates were 95.3% and 97.8% (p = 0.94) for AIS and MIA cases, respectively. Estimated incidence rates of metachronous SPLC at 10 years after surgery were 5.6% and 7.7% for AIS and MIA, respectively (p = 0.45), and these were not correlated with the EGFR mutation status.

Conclusions: Although the development of metachronous SPLC should be noted, the risk of recurrence is quite low at more than 5 years after resection of AIS and MIA. This finding strengthens the clinical value of distinguishing AIS and MIA from other adenocarcinomas of the lung.
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http://dx.doi.org/10.1016/j.jtho.2021.04.007DOI Listing
August 2021

Feasibility of next-generation sequencing (Oncomine™ DX Target Test) for the screening of oncogenic mutations in advanced non-small-cell lung cancer patients.

Jpn J Clin Oncol 2021 Jul;51(7):1114-1122

Department of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan.

Background: The Oncomine™ Dx Target Test based on next-generation sequencing has been approved for the screening of oncogenic mutations in advanced non-small-cell lung cancer patients.

Methods: We assessed the tissue sample factors that affect the success rate of Oncomine™ Dx Target Test companion diagnostics and the feasibility of using biopsy specimens for Oncomine™ Dx Target Test companion diagnostics in advanced non-small-cell lung cancer patients.

Results: Ninety-nine biopsy samples were subjected to genetic testing using the Oncomine™ Dx Target Test companion diagnostics to detect v-raf murine sarcoma viral oncogene homologue B1 mutations (Cohort 1), and 136 biopsy samples were examined using Oncomine™ Dx Target Test companion diagnostics for the detection of multiple oncogenic mutations (Cohort 2) between July 2018 and April 2020. We retrospectively collected clinical and pathological data, including tissue size and tumour cell content. The success rate was 77% (76/99) in Cohort 1 and 93% (127/136) in Cohort 2. In Cohort 1, the success rate was significantly associated with the tumour cell content: the success rate was 63% for samples with a tumour cell content of <20%, whereas it was 83% for samples with a tumour cell content of 20% or higher (P = 0.0446). The tissue size also affected the success rate: a success rate of 57% was obtained for tissue sizes <4 mm2, whereas a success rate of 95% was obtained for tissue sizes of 4 mm2 or larger (P < 0.0001). In Cohort 2, the success rate was 100% when tumour specimens with a tissue size of 4 mm2 or larger were used.

Conclusions: Tissue size and tumour cell content were significantly associated with the success rate of Oncomine™ Dx Target Test companion diagnostics.
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http://dx.doi.org/10.1093/jjco/hyab059DOI Listing
July 2021

Neck Dissections Based on Sentinel Lymph Node Navigation Versus Elective Neck Dissections in Early Oral Cancers: A Randomized, Multicenter, and Noninferiority Trial.

J Clin Oncol 2021 Jun 20;39(18):2025-2036. Epub 2021 Apr 20.

National Cancer Center Hospital, Tokyo, Japan.

Purpose: This study aimed to compare patients with early oral cavity squamous cell carcinoma (OCSCC) (tumor category [T] 1-2, node-negative, and no distant metastasis) treated with traditional elective neck dissection (ND) with those managed by sentinel lymph node biopsy (SLNB) using survival and neck function and complications as end points.

Methods: Sixteen institutions in Japan participated in the study (trial registration number: UMIN000006510). Patients of age ≥ 18 years with histologically confirmed, previously untreated OCSCC (Union for International Cancer Control TNM Classification of Malignant Tumors 7th edition T1-2, node-negative no distant metastasis), with ≥ 4 mm (T1) depth of invasion, were randomly assigned to undergo standard selective ND (ND group; n = 137) or SLNB-navigated ND (SLNB group; n = 134). The primary end point was the 3-year overall survival rate, with a 12% noninferiority margin; secondary end points included postoperative neck functionality and complications and 3-year disease-free survival. Sentinel lymph nodes underwent intraoperative multislice frozen section analyses for the diagnosis. Patients with positive sentinel lymph nodes underwent either one-stage or second-look ND.

Results: Pathologic metastasis-positive nodes were observed in 24.8% (34 of 137) and 33.6% (46 of 134) of patients in the ND and SLNB groups, respectively ( = .190). The 3-year overall survival in the SLNB group (87.9%; lower limit of one-sided 95% CI, 82.4) was noninferior to that in the ND group (86.6%; lower limit 95% CI, 80.9; for noninferiority < .001). The 3-year disease-free survival rate was 78.7% (lower limit 95% CI, 72.1) and 81.3% (75.0) in the SLNB and ND groups, respectively ( for noninferiority < .001). The scores of neck functionality in the SLNB group were significantly better than those in the ND group.

Conclusion: SLNB-navigated ND may replace elective ND without a survival disadvantage and reduce postoperative neck disability in patients with early-stage OCSCC.
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http://dx.doi.org/10.1200/JCO.20.03637DOI Listing
June 2021

Characterization of the large-scale Japanese patient-derived xenograft (J-PDX) library.

Cancer Sci 2021 Jun;112(6):2454-2466

National Cancer Center Research Institute, Chuo-ku, Japan.

The use of patient-derived xenografts (PDXs) has recently attracted attention as a drug discovery platform with a high predictive clinical efficacy and a preserved tumor heterogeneity. Given the racial differences in genetic variations, it would be desirable to establish a PDX library from Japanese cancer patients on a large scale. We thus tried to construct the Japanese PDX (J-PDX) library with a detailed clinical information for further clinical utilization. Between August 2018 and May 2020, a total of 1126 cancer specimens from 1079 patients were obtained at the National Cancer Center Hospital and National Cancer Center Hospital East, Japan, and were immediately transplanted to immunodeficient mice at the National Cancer Center Research Institute. A total of 298 cross-cancer PDXs were successfully established. The time to engraftment varied greatly by cancer subtypes, especially in the first passage. The engraftment rate was strongly affected by the clinical stage and survival time of the original patients. Approximately 1 year was needed from tumor collection to the time when coclinical trials were conducted to test the clinical utility. The 1-year survival rates of the patients who were involved in establishing the PDX differed significantly, from 95.6% for colorectal cancer to 56.3% for lung cancer. The J-PDX library consisting of a wide range of cancer subtypes has been successfully established as a platform for drug discovery and development in Japan. When conducting coclinical trials, it is necessary to consider the target cancer type, stage, and engraftment rate in light of this report.
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http://dx.doi.org/10.1111/cas.14899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177812PMC
June 2021

RB1 gene mutations are a distinct predictive factor in Merkel cell carcinoma.

Pathol Int 2021 May 22;71(5):337-347. Epub 2021 Mar 22.

Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that tends to show local recurrence and metastasis. Typically, MCC is polyomavirus (MCPyV)-associated and cytokeratin 20 (CK20) positive. However, little is known about this tumor and its origins. Here, we aimed to determine the developmental origins of MCC and to identify prognostic clinicopathologic factors. Initial examinations revealed that CK20 and MCPyV expression (CK20+, MCPyV+ (60%); CK20+, MCPyV- (10%); CK20-, and MCPyV- (30%)) did not affect overall survival. With RB1 gene sequencing of FFPE specimens, which covered an entire exon, all RB1 mutation-positive cases showed positive regional lymph node and/or distant metastases (8/8 cases, 100%), whereas the frequency of the metastasis was statistically significantly lower in RB1 mutation-negative cases, (10/16 cases, 62%, P = 0.033). The results were also confirmed with immunohistochemistry, and either RB1 alterations, entire exon sequencing, or immunohistochemistry was associated with the metastasis (P = 0.007). RB1 alterations may be used to access the aggressive clinical course of MCC.
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http://dx.doi.org/10.1111/pin.13090DOI Listing
May 2021

Clinicopathologic Characterization of Epithelioid Hemangioendothelioma in a Series of 62 Cases: A Proposal of Risk Stratification and Identification of a Synaptophysin-positive Aggressive Subset.

Am J Surg Pathol 2021 05;45(5):616-626

Departments of Diagnostic Pathology.

Epithelioid hemangioendothelioma (EHE) is a rare vascular endothelial neoplasm with characteristic histology and distinctive fusion genes. Its clinical presentation and outcome are heterogeneous, and the determinants of survival are controversial. In this study, we aimed to identify clinicopathologic prognostic factors of EHE in a retrospective cohort of 62 cases with CAMTA1/TFE3/WWTR1 alterations. The tumors were of the CAMTA1 subtype for 59 cases, TFE3 subtype for 2 cases, and variant WWTR1 subtype (WWTR1-ACTL6A) for 1 case. Twenty-two tumors (35.5%) demonstrated atypical histology, defined by having at least 2 of the following 3 findings: high mitotic activity (>1/2 mm2), high nuclear grade, and coagulative necrosis. During a median follow-up of 34 months, 11 patients (18%) died, and the 5-year overall survival rate was 78.8%. Survival did not correlate with such clinical parameters as age, sex, tumor sites, multifocality, and multiorgan involvement. Conversely, based on both univariate and multivariate analyses, large tumor size (>30 mm) and histologic atypia were significantly associated with a shorter survival. A proposed 3-tiered risk assessment system using these 2 parameters significantly stratified the patients into low-risk, intermediate-risk, and high-risk groups with 5-year overall survival rates of 100%, 81.8%, and 16.9%, respectively (P<0.001). Four tumors (6.4%) expressed synaptophysin, which all belonged to the high-risk group and pursued an aggressive course. The present study demonstrated the independent prognostic significance of large tumor size and atypical histology in EHE, as well as the value of risk stratification using these 2 factors. Moreover, we revealed a small EHE subset with aberrant synaptophysin expression, which may have potential prognostic and diagnostic implications.
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http://dx.doi.org/10.1097/PAS.0000000000001660DOI Listing
May 2021

The International Association for the Study of Lung Cancer Global Survey on Programmed Death-Ligand 1 Testing for NSCLC.

J Thorac Oncol 2021 04 2;16(4):686-696. Epub 2021 Mar 2.

Carolinas Pathology Group, Charlotte, North Carolina.

Introduction: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is required to determine the eligibility for pembrolizumab monotherapy in advanced NSCLC worldwide and for several other indications depending on the country. Four assays have been approved/ Communauté Européene-In vitro Diagnostic (CV-IVD)-marked, but PD-L1 IHC seems diversely implemented across regions and laboratories with the application of laboratory-developed tests (LDTs).

Method: To assess the practice of PD-L1 IHC and identify issues and disparities, the International Association for the Study of Lung Cancer Pathology Committee conducted a global survey for pathologists from January to May 2019, comprising multiple questions on preanalytical, analytical, and postanalytical conditions.

Result: A total of 344 pathologists from 64 countries participated with 41% from Europe, 24% from North America, and 18% from Asia. Besides biopsies and resections, cellblocks were used by 75% of the participants and smears by 11%. The clone 22C3 was most often used (69%) followed by SP263 (51%). They were applied as an LDT by 40% and 30% of the users, respectively, and 76% of the participants developed at least one LDT. Half of the participants reported a turnaround time of less than or equal to 2 days, whereas 13% reported that of greater than or equal to 5 days. In addition, quality assurance (QA), formal training for scoring, and standardized reporting were not implemented by 18%, 16%, and 14% of the participants, respectively.

Conclusions: Heterogeneity in PD-L1 testing is marked across regions and laboratories in terms of antibody clones, IHC assays, samples, turnaround times, and QA measures. The lack of QA, formal training, and standardized reporting stated by a considerable minority identifies a need for additional QA measures and training opportunities.
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http://dx.doi.org/10.1016/j.jtho.2020.12.026DOI Listing
April 2021

NTRK fusion-positive colorectal cancer in Japanese population.

Pathol Int 2021 May 25;71(5):355-359. Epub 2021 Feb 25.

Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

ALK, ROS1 and NTRK fusions are involved in the tumorigenesis of various organs, including colorectal cancer. This study aims to clarify the prevalence of these fusions in colorectal cancer in the Japanese population. Immunohistochemical analysis of 1012 specimens of colorectal cancer revealed two NTRK-positive cases (0.2%) whereas no ALK- or ROS1-positive cases were identified. Reverse transcription polymerase chain reaction (RT-PCR) detected an LMNA-NTRK1 fusion in a case of adenosquamous carcinoma and a TPM3-NTRK1 fusion in a case of tubular adenocarcinoma. Both NTRK1 fusion-positive cases lacked activating mutations in KRAS and BRAF and were mismatch repair-deficient with loss of MLH1 and PMS2 expression and MLH1 promoter methylation. Our results show that receptor tyrosine kinase fusions are rare but present in colorectal cancers in Japanese patients, with a prevalence similar to that reported in other countries.
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http://dx.doi.org/10.1111/pin.13082DOI Listing
May 2021

Radiological imaging and pathological findings of small lung adenocarcinoma: a narrative review.

J Thorac Dis 2021 Jan;13(1):366-371

Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.

The eighth edition of the Lung Cancer Handling Regulations defines the pathological findings of "invasion" in the pathological diagnosis of lung adenocarcinoma and terms it as adenocarcinoma in situ/minimally invasive carcinoma. In addition, the invasion diameter (tumor diameter excluding the lepidic growth region) was adopted as the pT factor, and the classification further reflected prognosis (degree of invasion/progression). Meanwhile, computed tomography imaging-based classification, where the consolidation (nodule) diameter excluding the ground glass shadow area was defined as cT, and the classification reflected the pathological invasion diameter. It is clear that the revision of the eighth edition has reduced discrepancies in the pathological findings of lung adenocarcinoma in CT imaging and assessment of the degree of invasion and progression. At the same time, the 8th edition is not yet accurate enough. Therefore, we will discuss imaging techniques to better predict the extent of adenocarcinoma invasion and progression, based on our own findings and the literature.
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http://dx.doi.org/10.21037/jtd-20-844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867796PMC
January 2021

O-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms.

BMC Cancer 2020 Dec 7;20(1):1195. Epub 2020 Dec 7.

Department of Pathology, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan.

Background: Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ.

Methods: In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs).

Results: In GI-NETs, MGMT scores of ≥2 and ≥ 3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥ 6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = - 0.4570; MGMT score: P = 0.0064, ρ = - 0.4399; H-score: P = 0.0110, ρ = - 0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy.

Conclusion: The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.
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http://dx.doi.org/10.1186/s12885-020-07579-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720403PMC
December 2020

Attempting to define sentinel node micrometastasis in oral squamous cell carcinoma.

Fukushima J Med Sci 2020 Dec 2;66(3):143-147. Epub 2020 Dec 2.

Department of Head and Neck Surgery and Otolaryngology, Asahi University Hospital.

Objective: The aim of this supplemental study of a sentinel node (SN) biopsy (SNB) trial for oral squamous cell carcinoma (OSCC) was to assess the effectiveness in identifying micrometastasis and determining whether elective neck dissection (END) is necessary.

Materials And Methods: Twenty-three patients with pathologically positive SNs were included. The sizes of the metastatic lesions in positive SNs (SMSNs) were classified and the rates of occult metastasis of non-SNs were compared.

Results: The patients were divided according to the SMSN:<0.2 mm (group A, n=3);0.2 mm to <2.0 mm (group B, n=7);and ≥2.0 mm (group C, n=13). The rates of occult metastasis in groups A, B, and C were 0% (0/3), 14% (1/7) and 23% (3/13), respectively.

Conclusion: Rare cancer cell distribution to nodes other than SNs was observed in the patients with SN metastatic lesions of at least smaller than 0.2 mm in size, suggesting the possibility of defining SN micrometastasis in N0 OSCC.
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http://dx.doi.org/10.5387/fms.2020-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790463PMC
December 2020

Full-coverage TP53 deep sequencing of recurrent head and neck squamous cell carcinoma facilitates prognostic assessment after recurrence.

Oral Oncol 2021 02 26;113:105091. Epub 2020 Nov 26.

Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan. Electronic address:

Objectives: This study aims to evaluate whether the accumulation of TP53 mutations is associated with clinical outcome by comparing full-coverage TP53 deep sequencing of the initial and recurrent head and neck squamous cell carcinoma (HNSCC).

Materials And Methods: Medical records and surgical specimens of 400 patients with HNSCC surgically treated with curative intent, of which 95 patients developed local or locoregional recurrence, were reviewed. Of these patients, 63 were eligible for genomic analysis. Full-coverage TP53 deep sequencing of 126 paired initial and recurrent tumor samples was examined using next-generation sequencing (NGS). Temporal changes in the mutation status, molecular characterization, and clinical outcome were compared. Fisher's exact test, Kaplan-Meier method, log-rank test, and Cox regression models were used for statistical analysis.

Results: Of the recurrent tumors, 22% harbored accumulation of TP53 mutations, and 16% lost the original mutation. The accumulation of TP53 mutations was significantly more frequent in oral cancer than in pharyngeal or laryngeal cancer (33% vs. 7%, p = 0.016). Two-year post-recurrence survival (PRS) was associated with TP53 status for recurrent tumors, but not for initial tumors. The TP53 status for recurrent tumors was an independent risk factor in multivariate analysis (hazard ratio, 5.76; 95% confidence interval, 1.86-17.8; p = 0.0023).

Conclusion: Approximately one-third of the recurrent HNSCC cases showed a different TP53 status from the initial tumor. Temporal changes in the mutation status differed by primary site. Full-coverage TP53 deep sequencing of recurrent tumors was useful in predicting post-recurrence prognosis.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105091DOI Listing
February 2021

Reassessing the SCLC Subtypes.

Authors:
Yasushi Yatabe

J Thorac Oncol 2020 12;15(12):1819-1822

Department of Diagnostic Pathology, National Cancer Center, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2020.10.011DOI Listing
December 2020

Comparison of Surgical Outcomes Between Invasive Mucinous and Non-Mucinous Lung Adenocarcinoma.

Ann Thorac Surg 2020 Nov 24. Epub 2020 Nov 24.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.

Background: Invasive mucinous adenocarcinoma (IMA) is a rare subtype of invasive lung adenocarcinoma. However, the clinical course and prognostic outcomes following IMA resection, particularly postoperative recurrence, remain unclear.

Methods: We pathologically reevaluated 1362 lung adenocarcinoma resections performed at our institution, categorizing cases into the IMA group (72 cases) and non-IMA group (1290 cases). The IMA group was further classified into pneumonia and nodular types based on preoperative computed tomography.

Results: Overall, the IMA group had lower carcinoembryonic antigen levels (3 vs 8 ng/mL; P < .01), fewer lymph node metastasis (4% vs 24%; P < .01), and more KRAS mutations (56% vs 7%; P < .01) than the non-IMA group. Although postoperative recurrence rates did not differ between both groups (32% vs 27%; P = 0.35), lung recurrence occurred more frequently in the IMA group (83% vs 17%; P < .01). Propensity score-matched pair analysis showed that the IMA group had fewer lymph node metastasis (3% vs 35%; P < .01), more KRAS mutations (56% vs 9%; P < .01), and higher intrapulmonary recurrence rate (84% vs 31%; P < .01) than the non-IMA group. The 5-year overall survival rates did not differ between both groups (74% vs 81%; P = 0.26). However, among patients with intrapulmonary recurrence, those in the IMA group had significantly worse prognosis than those in the non-IMA group (35% vs 77%; P < .01).

Conclusions: Intrapulmonary recurrence, which induced significantly worse prognosis, was more likely to occur in the IMA than non-IMA group.
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http://dx.doi.org/10.1016/j.athoracsur.2020.09.042DOI Listing
November 2020

The Isoform Matters in NUT Carcinoma: A Diagnostic Pitfall of p40 Immunohistochemistry.

J Thorac Oncol 2020 10;15(10):e176-e178

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2020.07.017DOI Listing
October 2020

Multiplex gene-panel testing for lung cancer patients.

Pathol Int 2020 Dec 21;70(12):921-931. Epub 2020 Sep 21.

Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.

The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.
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http://dx.doi.org/10.1111/pin.13023DOI Listing
December 2020

Lung cancer biomarker tests: the history and perspective in Japan.

Transl Lung Cancer Res 2020 Jun;9(3):879-886

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

Biomarker testing is recognized as being indispensable for selecting patients with advanced lung cancer. EGFR mutation is the first biomarker for therapeutic selection of lung cancer patients since the identification of the correlation between EGFR TKI response and EGFR mutation status. The biomarker testing in Japan mostly follows those corresponding to the US. However, there are some differences due to the national health care program and the medical environment. In this review, we introduce the history and current status of the biomarker testing for lung cancer in Japan and discuss perspectives, focusing on cell-free DNA (cfDNA)-based panel testing.
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http://dx.doi.org/10.21037/tlcr.2020.03.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354153PMC
June 2020
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