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Background: Standard care for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) involves chemoradiotherapy followed by durvalumab. The clinical significance of durvalumab after chemoradiotherapy in patients with LA-NSCLC having a performance status of 2 or aged ≥75 years, however, remains unclear. Therefore, we investigated the clinical benefit of durvalumab after daily carboplatin plus thoracic concurrent radiotherapy., Patients and Methods: In this prospective phase II study, daily low-dose carboplatin (30 mg/m 2 ) was administered before radiotherapy for the first 20 fractions and concurrent radiotherapy (60 Gy) followed by durvalumab. The primary endpoint was 12 months progression-free survival (PFS) rate from durvalumab initiation. The secondary endpoints included rate of therapeutic completion, PFS, overall survival, objective response rate, and safety., Results: Of 86 patients who underwent chemoradiotherapy with daily carboplatin from September 2019 to October 2021, 61 (70.9%) received durvalumab consolidation. The performance status was 0, 1, and 2 in 28 (45.9%), 26 (42.6%), and 7 (11.5%) patients, respectively. The rate of therapeutic completion for durvalumab was 26.2% (16/61). The PFS rate of 12 months after durvalumab initiation was 51.0%, indicating that the primary endpoint was achieved because the expected value of 35% calculated from previous studies was exceeded. The objective response rate after chemoradiotherapy and durvalumab was 47.0% and 57.4%, respectively. The median PFS and overall survival were 12.3 and 28.1 months, respectively. The most common adverse event in grades 3 or 4 was pneumonitis (8.2%). One patient died because of interstitial pneumonitis., Conclusions: Durvalumab consolidation after daily carboplatin with radiotherapy was effective and tolerable for LA-NSCLC vulnerable patients., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Thymic carcinoma (TC) is a rare thymic epithelial tumor, and advanced or recurrent TC has limited prognosis. Treatment for chemotherapy-naïve, advanced, or recurrent TC remains unchanged with the combination of carboplatin and paclitaxel; therefore, a new treatment strategy is warranted. Immune checkpoint blockades inhibiting the programmed cell death-1 (PD-1) pathway (PD-1 and its ligand, PD-L1) have shown potential as a monotherapy for TC, although the efficacy of monotherapy was moderate for previously treated TC. We hypothesized that the combination of an anti-PD-L1 antibody, atezolizumab, with carboplatin and paclitaxel, would be effective in inducing immunogenic cell death in patients with advanced or recurrent TC., Methods: We initiated a multicenter, single-arm, open-label phase II study of atezolizumab combined with carboplatin and paclitaxel for metastatic or recurrent TC. Eligible patients will receive atezolizumab plus carboplatin and paclitaxel every 3 weeks for up to 6 cycles, followed by atezolizumab every 3 weeks for up to 2 years until progression or unacceptable toxicity. A total of 47 patients will be enrolled in this study, with a 24-month enrollment period and 12-month follow-up. The primary endpoint is the objective response rate (ORR), based on an independent central review. The secondary endpoints are the investigator-assessed ORR, disease control rate, progression-free survival, duration of response, overall survival, and safety., Results: This study aims to establish the safety and efficacy of atezolizumab combined with carboplatin and paclitaxel in patients with advanced or recurrent TC., Trial Registration: Japan Registry of Clinical Trials (jRCT), jRCT2031220144. Registered on June 18, 2022, https://jrct.niph.go.jp/en-latest-detail/jRCT2031220144., Competing Interests: Disclosure TA reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Biopharma, MSD, Nippon Kayaku, Ono, Pfizer, Taiho, and Takeda. T Shukuya reports grant support for the current study from Chugai Pharmaceutical; grant support from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, Novartis; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho, and Takeda. YG reports grant support for the clinical trial group from AstraZeneca, Pfizer, institutional grant support from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Kyorin, Novartis, Ono, Pfizer, and Preferred Networks; honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Merck, MSD, Novartis, Ono, Pfizer, Taiho, and Thermo Fischer; participation on an advisory board for AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Guardant Health, Illumina, MSD, Novartis, Ono, Pfizer, and Taiho; and leadership or fiduciary role at Cancer Net Japan and Japanese Association of Medical Technologists. HT reports institutional grant support from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Biopharma, MSD, Ono, Taiho, and Takeda; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, Merck Biopharma, MSD, Novartis, Ono, Sun Pharmaceutical, Taiho, and Takeda. K Takayama reports grant support for Chugai Pharmaceutical; honoraria from Chugai Pharmaceutical. YT reports institutional grant support for Ono and Pfizer Health Research Foundation; honoraria from AstraZeneca, Chugai Pharmaceutical, and Daiichi Sankyo. MT reports honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono, and Takeda. T Suzuki reports honoraria from AstraZeneca and Boehringer Ingelheim. KK reports honoraria from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, Ono, and Taiho. RK reports grant support from AstraZeneca and MSD; honoraria from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, MSD, Ono, Pfizer, Taiho, and Takeda. YZ reports grant support from Amgen, AstraZeneca, Daiichi Sankyo, Merck Biopharma, and MSD; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Kyowa Kirin, MSD, Nihon Kayaku, Novartis, Pfizer, Taiho, and Takeda. HA reports grant support from Amgen, Chugai Pharmaceutica, and MSD; honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho and Takeda; data safety monitoring or advisory board participation with Amgen, Janssen, and Sandoz; and a leadership or fiduciary role with World Conference on Lung Cancer Patient Advocate Committee. JT reports honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Janssen Pharmaceutical, MSD, Nihon Medi-Physics, Ono, Nippon Boehringer-Ingelheim, Nippon Kayaku, Taiho, and Pfizer. SI reports institutional grant support for AstraZeneca and Chugai; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono, Pfizer, and Takeda. SS reports honoraria from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa Kirin, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono, Otsuka, Pfizer, Taiho, Takeda, Thermo Fisher Scientific, Towa Pharmaceutical, and Yakult Honsha. KM reports honoraria from Chugai Pharmaceutical, Eli Lilly, and Ono. K Takahashi reports grant support from Asahi Kasei Pharma, Bayer, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyorin, Nippon Kayaku, Kyowa Kirin, Nippon Pharma, Nippon Shinyaku, Novartis, Ono, Sanofi, Shionogi, Taiho, Takeda, Teijin, Tsumura, and Pfizer; honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Janssen, Kyorin, Meiji Seika Pharma, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Sumitomo Dainippon Pharma, Taiho, Takeda, Thermo Fisher Scientific and Viatris; patent with Oncolys BioPharma; and leadership or fiduciary role with The Japan Lung Cancer Society and The Japan Respiratory Society. All other authors (HM, TM) declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Stathmin-1 regulates microtubule dynamics and is associated with malignant phenotypes in non-small cell lung cancer (NSCLC). This study evaluated its diagnostic value for differentiating between NSCLC and high-grade lung neuroendocrine tumor (HGNET)., Methods: Stathmin-1 protein expression was assessed by immunohistochemistry in 414 NSCLC (305 adenocarcinoma [AD], 102 squamous cell carcinoma [SCC], 7 large-cell carcinoma), 5 typical carcinoid (low-grade lung neuroendocrine tumor), and 34 HGNET (17 small-cell carcinoma [SCLC] and 17 large-cell neuroendocrine carcinoma [LCNEC]) surgical specimens and 57 NSCLC (29 AD and 28 SCC) and 42 HGNET (17 LCNEC and 25 SCLC) biopsy specimens. We also analyzed stathmin-1 mRNA levels in 81 NSCLCs and 26 HGNETs with the use of reverse transcription-polymerase chain reaction., Results: Among NSCLC samples, we saw high stathmin-1 protein expression in only three ADs, one SCC, and one large-cell carcinoma surgical samples, all five of which showed neuroendocrine characteristics in pathologic re-review; and low or intermediate expression in all five typical carcinoid surgical samples and all 57 NSCLC biopsy samples. In contrast, all HGNET surgical (n = 34) and biopsy (n = 42) samples showed high stathmin-1 expression. In reverse transcription-polymerase chain reaction, stathmin-1 expression was significantly higher in HGNET tissues than in NSCLC tissues (p < 0.001)., Conclusions: Stathmin-1 expression can help in differentiating NSCLC from HGNET., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Piebaldism is a pigmentary disorder characterized by a white forelock and depigmented patches. Although the loss-of-function mutations in the KIT gene underlie the disease, the intracellular dynamics of the mutant KIT are largely unknown. We herein report a Japanese family with piebaldism in which the affected members showed a mild phenotype., Objective: The objective of this study is to investigate the functions and intracellular dynamics of the mutant KIT protein., Methods: We performed genetic analyses of the KIT gene using peripheral blood cells. We analyzed the intracellular localization of the mutant KIT protein in HEK293T cells transfected with wild-type (Wt) and/or mutant KIT genes. Immunoprecipitation analyses, immunoblotting and immunofluorescence studies were performed using antibodies against KIT and downstream signaling proteins. Glycosidase digestion analysis was performed to clarify the intracellular localization of KIT protein., Results: A genetic analysis revealed a novel heterozygous mutation c.645&#95;650delTGTGTC which results in the in-frame deletion of Val 216 and Ser 217 in the extracellular domain of KIT. Immunoprecipitation analyses confirmed that the wild and mutant KIT formed a heterodimer after treatment with stem cell factor (SCF); however, the phosphorylation of the downstream signaling factors was decreased. In an immunofluorescence study, the mutant KIT accumulated predominantly in the endoplasmic reticulum (ER) and was sparsely expressed on the cell surface. A glycosidase digestion study revealed that the mutant KIT is predominantly localized in the ER., Conclusion: These data reveal an aberrant function and intracellular localization of mutant KIT protein in piebaldism., (Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Upon initiation and progression of cancer, α 1 -acid glycoprotein (AGP) possessing highly sialylated and fucosylated glycans appears in the serum, and recently has attracted a great deal of attention, as a potential biomarker of tumorigenesis in humans., Methods: To establish a rapid and precise method for the quantitative assay of fucosylated AGP in serum samples, we developed an enzyme immunoassay (EIA) bearing an anti-AGP antibody and a fucose-binding lectin, Aleuria aurantia (AAL) with additional endeavor to improved sample handling, and antibody preparations., Results: The amounts of fucosylated AGP could be determined by the present method with a good performance feature in all tested samples from both cancer patients and healthy controls. From cancer patients under chemotherapy we show that fucosylated AGP could be a clinically relevant biomarker for cancer progression or prognosis as well as for an early assessment of clinical response and treatment outcomes. Furthermore, in a different setting, fucosylated AGP also showed relevance in patients who received immunotherapy with an anti-programmed cell death-1 (PD-1) antibody., Conclusions: α1,3fucosylated AGP is a potential biomarker of cancer initiation, progression and response to treatment in cancer patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Monilethrix is a hair shaft anomaly characterized by beaded hair with periodic changes in hair thickness. Mutations in the desmoglein 4 (DSG4) gene reportedly underlie the autosomal recessive form of the disease. However, the pathogenesis and cellular basis for the DSG4 mutation-induced monilethrix remained largely unknown. We report a Japanese female patient with monilethrix. Observation of her hair shaft by means of transmission electron microscopy showed fewer desmosomes and abnormal keratinization. Genetic analysis revealed a homozygous mutation, c.2119delG (p.Asp707Ilefs*109), in the DSG4 gene, which was predicted to cause a frameshift and premature termination in the intracellular region of the DSG4 protein. The mutation has not been reported previously. In the patient's hair shaft, we detected reduced but partial expression of the mutant DSG4 protein. Cellular analyses demonstrated that the mutant DSG4 lost its affinity to plakoglobin and accumulated in the endoplasmic reticulum (ER). The amounts of mutant DSG4 were increased by proteasome inhibitor treatment, and the expression of an ER chaperone, GRP78/BiP, was elevated in the patient's skin. Collectively, these results suggest that the dysfunctional mutated DSG4, tethered in the ER, undergoes ER-associated degradation, leading to unfolded protein response induction, and thus ER stress may have a role in the pathogenesis of monilethrix.

CD98 has been described to play a crucial role in tumor progression and survival. However, the role of CD98 in biliary tract cancer remains unclear. We found that 36.7% of all patients with biliary tract cancer had a high CD98 expression. Statistical analysis using Spearman's rank correlation showed that CD98 was significantly correlated with L-type amino acid transporter 1 (LAT1, r=0.562, P<0.001), Ki-67 (r=0.230, P=0.006) and CD34 (r=0.290, P=0.005). Multivariate analysis confirmed that a high CD98 expression was an independent prognostic factor for predicting poor outcome. CD98 is closely associated with tumor growth, biological aggressiveness, and survival of patients. With these data we proposed that CD98 expression is necessary for the development and pathogenesis of biliary tract cancer.

Background: Whether fluorine-18-fluorodeoxyglucose ((18)F-FDG) uptake within tumor cells differs between primary and recurrent lung cancers is unknown. The aim of this study was to investigate the prognostic significance of (18)F-FDG uptake by comparing that measured preoperatively at the primary site to that measured postoperatively at sites of non-small cell lung cancer (NSCLC) recurrence. Only patients with postoperative recurrences who received platinum-based chemotherapy as the initial treatment after recurrence were included in the study., Methods: Fifty-two patients underwent (18)F-FDG positron emission tomography (PET) examinations before thoracotomy and at the time of recurrence after curative surgery. All recurrences were treated with platinum-based chemotherapy., Results: (18)F-FDG uptake in the preoperative primary tumors was significantly higher than that in the recurrent tumors (p=0.028), demonstrating a statistically significant correlation (Pearson's correlation coefficient γ=0.482, p<0.001), especially in adenocarcinoma (AC) patients. Low (18)F-FDG avidity within the primary tumor significantly correlated with the presence of epidermal growth receptor factor (EGFR) mutations. (18)F-FDG uptake in the primary tumors was an independent prognostic factor for predicting outcome in NSCLC patients receiving platinum-based chemotherapy for the treatment of postoperative recurrence., Conclusions: In NSCLC patients treated by chemotherapy for recurrence, preoperative measurements of (18)F-FDG uptake may be a more powerful surrogate marker for predicting outcome when measured preoperatively at the primary tumor site rather than postoperatively at sites of recurrence., (© 2013 Published by The Japanese Respiratory Society on behalf of The Japanese Respiratory Society.)

Purpose: To determine the recommended dose (RD) in concurrent conformal radiotherapy with S-1 and cisplatin chemotherapy for inoperable stage III non-small-cell lung cancer., Patients and Methods: Eligible patients with inoperable stage III non-small-cell lung cancer, age ≥ 20 years, performance status 0-1 received 4 cycles of intravenous cisplatin (60 mg/m(2), day 1) and oral S-1 (80, 100, or 120 mg based on body surface area, days 1-14) repeated every 4 weeks. Radiation doses were 66, 70, and 74 Gy for arms 1, 2, and 3, respectively., Results: A total of 24 patients were enrolled in our study, including 6 in arm 1, 6 in arm 2, and 12 in arm 3. The patients consisted of 14 men and 10 women, with a median age of 63 years (range, 44-73 years). The median follow-up was 27.3 months (range, 8.5-42.6 months) for all patients and 33.9 months (range, 15.2-42.6 months) for those still alive. Grade 3 febrile neutropenia, lung toxicities, and heart toxicities occurred in 2, 2, and 2 patients, respectively. Dose-limiting toxicity occurred in 2, none, and 1 patient in arms 1, 2, and 3, respectively. The median survival was not reached, and the 2-year survival rate was 70% (95% CI, 51%-89%). Two-year local relapse-free survival and distant metastasis-free survival were 74% (95% CI, 56%-92%) and 45% (95% CI, 25%-65%), respectively., Conclusions: High-dose radiotherapy with S-1 and cisplatin is feasible, and 74 Gy was determined as the recommended dose., (Copyright © 2013. Published by Elsevier Inc.)

Background: The efficacy of postoperative adjuvant cisplatin (CDDP)-based chemotherapy, such as the combination of CDDP and vinorelbine (VNR), has been established for surgically resected non-small-cell lung cancer (NSCLC). However, the optimal treatment schedule and dosage for CDDP and VNR are unknown. We evaluated patient compliance with and the safety of adjuvant chemotherapy of CDDP at 80 mg/m(2) administered on day 1 plus VNR at 25 mg/m(2) administered on days 1 and 8, every 3 weeks., Methods: Medical records of 100 surgically resected NSCLC patients, treated with a combination of CDDP and VNR at the Shizuoka Cancer Center between February 2006 and October 2011, were retrospectively reviewed., Results: Eighty-three (83%) patients completed the planned 4 cycles of CDDP plus VNR and 59 (59%) received the planned doses. Sixty-eight percent of the patients experienced a decreased neutrophil count (grade 3/4 toxicity); 1%, a decreased platelet count; and 4%, febrile neutropenia. No treatment-related deaths were noted in this study. Univariate analysis of the factors influencing patient compliance with this adjuvant chemotherapy showed that neither patient characteristics nor surgical procedure was significantly associated., Conclusions: Our results indicated that adjuvant chemotherapy with CDDP at 80 mg/m(2) administered on day 1 plus VNR at 25 mg/m(2) administered on days 1 and 8, every 3 weeks, was feasible for surgically resected NSCLC cases., (Copyright © 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Enumeration of circulating tumor cells (CTCs) may be valuable for prognostic assessment in lung cancer patients. In this study, we report the clinical significance of CTCs in small cell lung cancer (SCLC)., Methods: In total, 51 consecutive patients newly diagnosed as having SCLC and starting chemotherapy or chemoradiotherapy were prospectively enrolled. Blood samples were drawn at the baseline, after chemotherapy, and at relapse. CTCs were isolated using the CellSearch System (Veridex LLC). Thresholds of 1 to 100 cells at the baseline were systematically correlated with the overall survival. The optimal cutoff was determined by comparing the Cox proportional hazard ratios (HRs)., Results: Two or more CTCs were detected at baseline in 35 patients (68.6%; 95% confidence interval, 55.0-79.7). The HR signifying the difference between the unfavorable (more than or equal to threshold) and favorable (less than threshold) groups was maximal at the threshold of 8 CTCs (HR, 3.50; 95% confidence interval, 1.45-8.60). Patients with ≥8 CTCs had worse survival than those with <8 CTCs at baseline (p = 0.0014). Patients with ≥8 CTCs posttreatment or at relapse also showed worse survival than those with <8 CTCs (p = 0.0096 and <0.0001). Patients whose baseline and posttreatment CTC levels remained <8 tended to show better survival than those whose CTC level converted from ≥8 to <8 cells (p = 0.0288) or whose posttreatment CTC level was ≥8 cells (p = 0.0047)., Conclusions: CTCs were highly detectable in SCLC, and higher CTC levels were strongly associated with worse survival. Consistently favorable CTC levels were associated with favorable outcomes.

Introduction: It is unknown what type of interstitial lung disease (ILD) has high risk for chemotherapy-related exacerbation of ILD. We investigated the risk of exacerbation of ILD for patients with lung cancer with ILD., Methods: One hundred nine patients with lung cancer with ILD treated with cytotoxic chemotherapy at Shizuoka Cancer Center between August 2002 and April 2010 were retrospectively reviewed., Results: On pretreatment computed tomography (CT) of the chest, 69 patients (63%) were identified with usual interstitial pneumonia (UIP) pattern, and 40 patients (37%) had non-UIP pattern. Patients with UIP pattern developed cytotoxic chemotherapy-related exacerbation of ILD more frequently than those with non-UIP pattern (30 versus 8%, p = 0.005). The incidence of grade 5 pulmonary toxicities was 9% in patients with UIP pattern, compared with 3% in those with non-UIP pattern. Multivariate analyses demonstrated that age (<70 years) and CT pattern (UIP) were significant independent risk factors for cytotoxic chemotherapy-related exacerbation of ILD. In small cell lung cancer, overall survival (OS) from the start of first-line chemotherapy was significantly shorter in UIP pattern than non-UIP pattern (median OS: 9 versus 16 months, p = 0.0475), whereas there was no significant difference in patients with non-small cell lung cancer (median OS: 12 versus 9 months, p = 0.2529)., Conclusions: Our results indicated that the incidence of exacerbation of ILD was significantly higher in patients with lung cancer with UIP pattern on CT findings than in those with non-UIP pattern. Therefore, great care is required when administering cytotoxic chemotherapy agents for patients with lung cancer with UIP pattern.

Background: We investigated the clinical significance of excision repair cross-complementation group 1 (ERCC1), breast cancer susceptibility 1 (BRCA1), and class III β-tubulin (TUBB3) expression in thymic epithelial tumors., Method: Fifty-six patients with thymic epithelial tumors were included in this study. Tumors sections were stained by immunohistochemistry for ERCC1, BRCA1, TUBB3, microvessel density, and p53., Results: ERCC1, BRCA1, and TUBB3 were expressed in 48%, 50%, and 27%, respectively. The expression of ERCC1, BRCA1, and TUBB3 was significantly correlated with the grade of malignancy in thymic epithelial tumors. These biomarkers were closely associated with p53 and microvessel density and were a prognostic marker for predicting poor outcome. We also found that overexpression of ERCC1 and TUBB3 was associated with resistance to platinum- and taxane-based chemotherapy., Conclusion: An expression of ERCC1, BRCA1, and TUBB3 was correlated strongly with each other and was significantly associated with a poor outcome in thymic epithelial tumors. High-ERCC1 and TUBB3 expressions might be associated with resistance to platinum- and taxane-based chemotherapy, respectively.

Objective: L-Type amino acid transporter 1 (LAT1) has associated with tumor growth and poor outcome of patients with non-small cell lung cancer (NSCLC). L-[3-(18)F]-α-methyl tyrosine ((18)F-FAMT) is an amino acid tracer for positron emission tomography (PET) imaging, and (18)F-FAMT uptake is mediated by LAT1. The purpose of this study is to compare the prognostic significance of (18)F-FAMT uptake in the primary tumors with that of LAT1 expression in patients with NSCLC., Methods: Fifty-nine patients with NSCLC were enrolled in this study. All patients underwent (18)F-FAMT PET prior to resection of the tumor, and immunohistochemical staining of the resected tumors were performed to compare the (18)F-FAMT uptake and LAT1 expression. Uptake of (18)F-FAMT was evaluated using semiquantitative standardized uptake value (SUV(max)), and the cutoff value was determined to discriminate patients with high SUV(max) from those with low SUV(max). Expression of LAT1 was evaluated by the score of staining intensity through 1 to 4. SUV(max) and LAT1 expression were compared according to the clinicopathological variables., Results: The best discriminative cutoff value of (18)F-FAMT SUV(max) within the primary tumors was 1.6. The high SUV(max) (>1.6) in (18)F-FAMT PET was significantly associated with male, and positive LAT1 expression was significantly associated with male and nonadenocarcinoma. In the univariate analysis, high SUV(max) (>1.6) in (18)F-FAMT PET and positive LAT1 expression were significant predictor of the poor outcome. Multivariate analysis confirmed that positive LAT1 expression was an independent and significant factor for predicting poor prognosis in NSCLC (P=.035)., Conclusion: LAT1 expression is a stronger prognostic factor than (18)F-FAMT uptake in surgically resected NSCLC., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Pulmonary pleomorphic carcinoma is a rare epithelial tumor and has an aggressive clinical course. As few studies of pulmonary pleomorphic carcinoma have been described, the clinicopathological characteristics of the disease remain unclear. Especially, the information on the epidermal growth factor receptor (EGFR) mutation status of pulmonary pleomorphic carcinoma is sparse., Methods: We retrospectively examined 17 patients with pulmonary pleomorphic carcinoma. EGFR mutation and Ki-67 labeling index were investigated in these patients., Results: The median age of the patients was 72 years (range, 47-84 years). Thirteen patients were men and four were women. EGFR mutation was observed in 3 (18%) of 17 patients. The median value of Ki-67 labeling index was 62% (range, 20-87%). Positron emission tomography with 18-fluorodeoxy-glucose was performed in 16 patients, and the standardized uptake value tended to be high (median 19.3). The survival of patients without surgery demonstrated a significantly poor prognosis compared with those with surgery (P = 0.0096). Palliative chemotherapy was almost poor response in advanced pulmonary pleomorphic carcinoma. The response to gefitinib in a patient with EGFR mutation was small and transient., Conclusion: EGFR mutation was recognized in approximately 20% of patients with pulmonary pleomorphic carcinoma. It is necessary to investigate whether the use of a molecular targeting drug improves outcome for pulmonary pleomorphic carcinoma.

Recent evidence indicates that the presence of epidermal growth factor receptor (EGFR) or KRAS mutations in non-small cell lung cancer (NSCLC) can predict the response of the tumor to gefinitib. However, it is difficult to detect these mutations using formalin-fixed, paraffin-embedded (FFPE) tissues because the fixation process and aging can damage the DNA. In this study, we describe our work in adapting the Smart Amplification Process version 2 (SmartAmp2) to detect EGFR or KRAS mutations in DNA extracted from FFPE tissues. We were able to detect these mutations in 37 (97%) of 38 FFPE lung cancer tissue samples within 60 minutes with the SmartAmp2 assay and to confirm the correlation between EGFR mutations in FFPE tissues and gefitinib responsiveness. All mutations had previously been confirmed in the 38 samples using DNA extracted from frozen tissues. Electrophoresis results indicated that PCR analysis was not reliable for DNA extracted from FFPE tissue when primers with a long amplicon (>300 bp) were used. This study confirms that the SmartAmp2 assay is suitable for use with DNA extracted from FFPE as well as frozen tissues.

Mucosa-associated lymphoid tissue (MALT) lymphoma arising in the thymus is extremely rare and little is known regarding its clinicopathological features. This study examined the clinicopathological features of nine cases of thymic MALT lymphoma. Most patients had autoimmune disease or hyperglobulinemia, and they also had cysts in the tumors. Both increased serum autoantibody levels and polyclonal serum immunoglobulin levels remained essentially unchanged after total thymectomy in all patients. Thymic MALT lymphoma needs to be included in the differential diagnosis in Asian patients with a cystic thymic mass accompanied by autoimmune disease or hyperglobulinemia.

KRAS is an oncogene that can be activated by mutations. Patients with non-small cell lung cancer who have KRAS mutations do not respond to tyrosine kinase inhibitors; therefore, accurate detection of KRAS mutations is important for deciding therapeutic strategies. Although sequencing-related techniques have been frequently used, they are usually too complex, have low sensitivity, and are time-consuming for routine screening in clinical situations. We evaluated peptide nucleic acid (PNA)-clamp smart amplification process version 2 (SmartAmp2) as a detection method for KRAS codon 12 mutations in patient specimens compared with traditional sequencing and polymerase chain reaction-related methods. Among 172 lung adenocarcinoma samples, direct sequencing, enzyme-enriched sequencing, and PNA-enriched sequencing showed that 16 (9.3%), 26 (15.7%), and 28 (16.3%) tumors, respectively, contained KRAS mutations in codon 12. Using PNA-clamp SmartAmp2, we could identify 31 (18.0%) tumors that had KRAS mutations in codon 12 within 60 minutes, three of which were undetected by polymerase chain reaction-related methods. On the other hand, we examined 30 nonmalignant peripheral lung tissue specimens and found no mutations in any of the samples using PNA-clamp SmartAmp2. In this study, we confirmed that PNA-clamp SmartAmp2 has high sensitivity and accuracy and is suitable for the clinical diagnosis of KRAS codon 12 mutations.

A-73-year-old man, a heavy smoker, was admitted to our hospital for pain in the right lower quadrant of the abdomen. The patient had no complaint of respiratory symptoms. But he had noted a skin lesion on his right hip. Physical examination revealed mild tenderness in the right lower quadrant of the abdomen and a soft swelling on the right hip. Laboratory analysis revealed remarkable leukocytosis (38,600 mul: 86% neutrophils) and evaluated C-reactive protein (8.6 mg/dl). Chest radiograph revealed a mass shadow in the right upper field of the lung. A computed tomography of the chest on admission revealed a heterogeneous mass with mediastinal lymphadenopathy. Abdominal computed tomography revealed multiple metastases in the adrenal glands, gallbladder, intestine, and peritoneum. Fluorodeoxyglucose positron emission tomography demonstrated increased uptake in the peritoneal cavity and primary site of lung. There was no evidence of systemic infection. The histologic finding of poorly differentiated carcinoma was confirmed by a needle biopsy of the skin lesion on his right hip. His white blood cell count was elevated, 38,600 to 121,000 mul within 10 days. Suspecting a granulocyte colony-stimulating factor (G-CSF)-producing tumor, we measured serum G-CSF and subsequently found it to be elevated to 372 pg/ml. His condition was rapidly deteriorated, and he died of multiple organ failure 14 days after admission. The poorly differentiated carcinoma found at autopsy revealed positive immunoreactivity for G-CSF. There was evidence of multiple metastases in the adrenal glands, gallbladder, intestine, pancreas, liver, skin, and peritoneum. The final diagnosis obtained at autopsy demonstrated diffuse metastases spreading to peritoneal cavity resulting from G-CSF-producing lung cancer.

Objectives: L-[3-(18)F]-alpha-methyltyrosine ((18)F-FMT) is an amino-acid tracer for positron emission tomography (PET) and is used for tumor detection because malignant tumor cells accumulate (18)F-FMT based on the increased expression of an amino-acid transporter. This study was conducted to investigate the usefulness of (18)F-FMT PET in combination with fluorine-18-fluorodeoxyglucose ((18)F-FDG) PET for the diagnosis of sarcoidosis in patients with suspected malignancy., Setting: Twenty-four sarcoidosis patients with suspected malignancy underwent (18)F-FDG and (18)F-FMT PET. The study included 17 patients with extrapulmonary manifestation mimicking malignant disease (13 patients with systemic lymphadenopathy, 3 of them with concomitant hepatosplenic processes; 3 patients with hepatosplenic processes without concomitant lymphadenopathy; and 1 patient with multiple bone lesions), 3 patients with occurrence of bilateral hilar lymphadenopathy in cancer patients, and 4 patients with multiple nodules mimicking pulmonary metastasis., Results: All patients showed increased uptake of (18)F-FDG and no increase in the accumulation of (18)F-FMT in their lymphadenopathy. Standardized uptake values (SUVs) of (18)F-FDG and (18)F-FMT were 5.01 +/- 2.15 and 0.77 +/- 0.24, respectively (mean +/- SD). All extranodal lesions such as liver, spleen, and bone were visually positive on (18)F-FDG PET and negative on (18)F-FMT PET. No neoplasm was confirmed in all patients. In a control group of patients with lung cancer, SUVs for (18)F-FDG and (18)F-FMT were 6.34 +/- 2.52 and 1.54 +/- 0.82, respectively., Conclusion: The uptake of (18)F-FDG was positive in the sarcoid lesions, and therefore (18)F-FDG PET could not differentiate sarcoidosis from malignant disease. Use of (18)F-FMT PET in combination with (18)F-FDG PET may be the effective method to distinguish sarcoidosis from malignancy.