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B7 homolog 3 protein (B7-H3), an immune checkpoint molecule belonging to the B7 family, has been studied as a target for the development of anti-cancer treatment; however, changes in B7-H3 expression during the clinical course remain unknown. This retrospective study aimed to investigate changes in B7-H3 expression of lung cancer specimens in patients with advanced lung cancer following various anti-cancer treatments. The immunohistochemistry (IHC) score was evaluated on a 0-3 scale, and B7-H3 expression was considered positive for grade ≥ 2. The difference in IHC scores before and after anti-cancer treatment was defined as the change in B7-H3 expression. Among 160 patients with lung cancer who received anti-cancer treatment, 88 (55%) and 101 (63%) had B7-H3 expression before and after anti-cancer treatment, respectively. Before treatment, B7-H3 expression was significantly more common in squamous cell carcinoma specimens than in adenocarcinoma specimens (95% vs. 49%, P < 0.001). Of the 19 patients with squamous cell carcinoma, 18 (95%) continued to have high (IHC score: 3) B7-H3 expression following treatment. In contrast, of the 130 patients with adenocarcinoma, 46 (35%) and 17 (13%) showed an increased and a decreased expression, respectively. Patients who received targeted therapy had a significant increase in B7-H3 expression compared with those who received chemotherapy alone (P = 0.015). Overall, squamous cell carcinoma specimens maintained high B7-H3 expression during the clinical course, whereas adenocarcinoma specimens showed changes in expression following anti-cancer treatments. Our results provide the basis for further studies on the development of anti-cancer treatments targeting B7-H3., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Trophoblast cell-surface antigen 2 (TROP2) is expressed on the surface of trophoblast cells and many malignant tumor cells. However, data on TROP2 expression in advanced lung cancer are insufficient, and its changes have not been fully evaluated., Methods: We assessed the prevalence and changes in TROP2 expression in patients with lung cancer who received anti-cancer treatments using immunohistochemical (IHC) analysis with an anti-TROP2 antibody (clone: SP295). IHC scores were graded from 0 to 3; grade ≥ 2 was considered positive for TROP2 expression. We defined a difference in IHC score, before and after anti-cancer treatments, as the change in TROP2 expression., Results: Before anti-cancer treatment, TROP2 expression was observed in 89% (143/160) of the patients and was significantly more common in adenocarcinoma and squamous cell carcinoma than in neuroendocrine carcinoma (P < 0.001). After anti-cancer treatment, TROP2 expression was observed in 87% (139/160) of the patients. The distribution of TROP2 expression in post-treatment samples was analogous to that in pre-treatment samples when compared using the Wilcoxon signed-rank test (P = 0.509). However, an increase in TROP2 expression was seen in 19 (12%), and a decrease in 20 (13%) patients. Patients treated with targeted therapy showed significantly higher changes in TROP2 expression (P = 0.019) and thoracic radiotherapy was more likely to increase TROP2 expression than chemotherapy alone., Conclusion: Although some anti-cancer treatments might alter the TROP2 expression, TROP2 was expressed in most lung cancer specimens before and after anti-cancer treatments. These results support the development of TROP2-directed therapy against advanced lung cancer in various treatment lines., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Management of leptomeningeal metastasis-related hydrocephalus (LM-H) is particularly challenging regarding the control of severe headache, nausea, and vomiting due to intracranial hypertension. To investigate the improvements of performance status and outcome with cerebrospinal fluid (CSF) shunt surgery for LM-H in patients with lung adenocarcinoma., Methods: Data on patients with leptomeningeal metastasis-related hydrocephalus from lung adenocarcinoma diagnosed by MR imaging and/or cytological examination were retrospectively analyzed. Between August 2008 and July 2017, the authors reviewed 31 patients requiring CSF shunt, who underwent ventriculo-peritoneal or lumbo-peritoneal shunt., Results: The patients consisted of 11 men and 20 women with a median age of 59 years. Twenty-six patients received EGFR-tyrosine kinase inhibitors (TKIs). CSF shunt surgery yielded rapid improvement in the performance status of 90.3% of patients. Median overall survival from the diagnosis of LM in patients with ECOG performance status less than 2 was 7.7 months, and this was significantly longer than those in patients with PS 3 or 4 (4.4 or 1.5 months; p<0.001). Multivariate analysis by Cox regression revealed survival differences according to PS at diagnosis of LM [PS 1-3 vs. PS4, hazard ratio (HR) 0.201, p = 0.034], controlled extracranial disease (HR 0.248, p = 0.005), and post-shunt EGFR-TKI for LM treatment (HR 0.193, p = 0.008). Postoperative symptomatic peritoneal carcinomatosis was observed in one patient (3.2%)., Conclusion: CSF shunting may be a safe and effective strategy in patients with LM-H from lung adenocarcinoma. A prospective study is needed to establish the effectiveness and safety of palliative CSF shunt for LM-H., Competing Interests: Dr. K. Mitsuya report personal fees from Accuray, Chugai Pharmaceutical, and Daiichi Sankyo outside the submitted work. Dr. T. Takahashi reports grants and personal fees from Ono Pharmaceutical, MSD, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, grants from Pfizer, personal fees from Boehringer Ingelheim, Roche Diagnostics outside the submitted work. Dr. H. Murakami reports grants and personal fees from AstraZeneca, personal fees from Lilly Japan, Chugai Pharmaceutical, Boehringer Ingelheim, Phizer, Taiho Pharmaceutical, Novartis, Bristol-Myers Squibb, Ono Pharmaceutical, Merck Sharp & Dohme outside the submitted work. Dr. H. Kenmotsu reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, grants and personal fees from Boehringer Ingelheim during the conduct of the study, personal fees from Ono Pharmaceutical, Bristol-Myers, Eli Lilly, Kyowa Hakko Kirin, Novartis Pharma outside the submitted work. Dr. A. Ono reports grants and personal fees from Ono Pharmaceutical, Chugai Pharma, Taiho Pharmaceutical and research funding to our institution from Chugai Pharma and Taiho Pharmaceutical outside the submitted work. Dr. K. Wakuda reports Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical outside the submitted work. Dr. H. Harada reports personal fees from BrainLAB, Chugai Pharmaceutical, AstraZeneca and Daiichi Sankyo outside the submitted work. Dr. Y. Nakasu, Dr. S. Deguchi, Dr. N. Hayashi, and Dr. T. Naito have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The expression of programmed death ligand 1 (PD-L1) is considered a predictive biomarker of anti-programmed death 1 (PD-1)/PD-L1 cancer therapies. However, changes in PD-L1 expression of tumor cells during clinical courses have not been fully evaluated. We evaluated changes in PD-L1 expression for non-small cell lung cancer (NSCLC) patients who received anticancer treatments during clinical courses., Methods: In 76 NSCLC patients, PD-L1 expression was evaluated before and after anticancer treatment by immunohistochemical (IHC) analysis using an anti-PD-L1 antibody. We defined two cut-off points of PD-L1 expression (1 and 50%) and three corresponding IHC groups (A: 0%, B: 1-49%, and C: ≥50%). IHC group B and C were considered to be positive expression, and we defined the difference of IHC group between pre- and post-treatment as 'major change' in PD-L1 expression., Results: Before anticancer treatment, PD-L1 expression was observed in 38/76 (50%) patients, and was significantly less common in patients harboring mutations in the epidermal growth factor receptor gene (EGFR) than in those without (P = 0.039). After anticancer treatment, PD-L1 expression was observed in 36/76 (47%) patients. Major increases in PD-L1 expression were seen in 11 (14%), and major decreases in 18 (24%) patients. Among 13 patients harboring EGFR mutations treated with EGFR tyrosine-kinase inhibitor (EGFR-TKI), five (38%) showed major increases., Conclusion: Major changes of PD-L1 expression in tumor cells were observed in 38% of NSCLC patients who received anticancer treatments. And, treatments with EGFR-TKI may increase PD-L1 expression in NSCLC patients harboring EGFR mutations.

A patient with a history of lung adenocarcinoma was admitted because of palpitation. Transthoracic echocardiogram revealed a mass (74×42 mm) in the right ventricle. Computed tomography showed a tumor lesion in the right ventricular cavity but no other distant metastasis. Coronary angiography revealed well-developed small branches to the tumor. After right heart catheterization, a pathological analysis of a tumor biopsy demonstrated adenocarcinoma. We diagnosed the patient with right ventricular metastasis of lung cancer. With large cardiac metastasis, a tumor biopsy with a right heart catheter may help obtain a pathological diagnosis and also serve as a re-biopsy to confirm the gene mutation status.

CYFRA 21-1 is a prognostic marker for non-small cell lung cancer. The serum CYFRA 21-1 level is also known as an adjunct for the diagnosis of lung squamous cell carcinoma. This study aimed to examine whether CYFRA 21-1 has predictive implications for nivolumab therapy in patients with advanced lung adenocarcinoma. Of the 79 patients who were treated with nivolumab therapy at the Shizuoka Cancer Center between December 2015 and September 2016, we retrospectively reviewed the data of 50 patients. The patient characteristics were as follows: age <70/≥70 years: 43 (86%)/7; male/female: 31 (62.0%)/19; Eastern Cooperative Oncology Group performance status 0-1/2: 43 (86%)/7; smoking status: no/yes: 18 (36%)/32; epidermal growth factor receptor mutation status negative/positive: 36 (72%)/14; CYFRA 21-1 ≥2.2/<2.2 ng/mL: 28 (56%)/22; carcinoembryonic antigen ≥5/<5 ng/mL: 29 (58%)/21; and number of prior regimens 2-3/≥4: 16 (32%)/34. With a median follow-up of 263.5 (range, 64-352) days, the median progression-free survival was 70 days. The clinical variables investigated using univariate analysis were as follows: age (p = 0.423), carcinoembryonic antigen (p = 0.888), epidermal growth factor receptor mutation status (p = 0.105), performance status (p = 0.968), sex (p = 0.210), number of prior regimens (p = 0.146), CYFRA 21-1 (p = 0.026), and smoking status (p = 0.041). A multivariate analysis identified a serum CYFRA 21-1 level ≥2.2 ng/mL as an independent predictor of a favorable outcome (hazard ratio, 0.44; 95% confidence interval, 0.23-0.85; p = 0.015; median progression-free survival, 155 vs 51.5 days). In conclusion, CYFRA 21-1 might be an independent predictor of outcome for patients with advanced lung adenocarcinoma treated with nivolumab.

Background: Skeletal muscle wasting during curative treatment is an important issue faced by esophageal cancer patients. However, it has not been clarified whether skeletal muscle change during neoadjuvant chemotherapy followed by surgery adversely affects prognosis. This study aimed to determine the relation between skeletal muscle change and survival for patients with advanced esophageal cancer who underwent neoadjuvant chemotherapy followed by surgery., Methods: This study retrospectively analyzed 66 patients with thoracic esophageal cancer who had undergone neoadjuvant chemotherapy followed by esophagectomy. The study investigated the correlation between the change in the total muscle cross-sectional area at the third lumbar vertebra before and 4 months after surgery as well as the postoperative recurrence and overall survival (OS)., Results: Of the 66 patients, 39 (59%) showed a skeletal muscle decrease from baseline to 4 months after esophagectomy. The change in the skeletal muscle index from baseline to 4 months after surgery was -1.2 cm 2 /m 2 . Multivariable analysis showed that nonsquamous cell carcinoma subtype (hazard ratio [HR] 2.57; p = 0.029), pathologic stage (HR 5.73; p < 0.01), and skeletal muscle wasting (HR per 1 unit decrease in skeletal muscle index, 1.16; p = 0.015) were the independent prognostic factors associated with worse OS. Additionally, pathologic stage (HR 6.03; p < 0.01) and skeletal muscle wasting (HR per 1 unit decrease in skeletal muscle index, 1.11; p = 0.048) also were found to be independent prognostic factors associated with worse recurrence-free survival., Conclusions: The study findings suggest that skeletal muscle wasting from baseline has a negative impact on cancer recurrence and survival.

Introduction: A recent retrospective analysis found that 23% of non-small cell lung cancer patients who acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) demonstrated "disease flare" after discontinuation of EGFR-TKIs. However, limitations of this study present the need for further investigation to elucidate this phenomenon in more detail., Methods: We reviewed the clinical records of EGFR mutated patients with advanced lung adenocarcinoma who were treated with gefitinib monotherapy in our hospital between January 2007 and December 2010. Disease flare was defined as unexpected interventions (e.g. radiation therapy or pleural drainage), hospitalization, or death attributable to disease progression after gefitinib discontinuation., Results: Among 52 eligible patients, only two experienced disease flare (4%; 95% confidence interval: 1-13%). In both cases, interval time from gefitinib discontinuation to disease flare was 11 days, and the brain was the site of flare. Survival time after gefitinib was significantly shorter in the flare patients (78 and 97 days, respectively) compared with the no-flare patients (median 388 days)., Conclusions: Our analysis demonstrated a lower incidence rate of disease flare after gefitinib discontinuation compared with the previous report, but the prognosis was similarly poor., (Copyright © 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

A woman in her 30s visited our hospital with stool abnormality. Esophagogastroduodenoscopy revealed a depressed lesion on the greater curvature of the gastric antrum. The tumor was diagnosed as a well-differentiated tubular adenocarcinoma based on the analysis of the biopsy specimen. The rapid urease test, histological examination, and serum anti-Helicobacter pylori antibody indicated that the patient was Helicobacter pylori negative. Gastric mucosal atrophy was not evident on esophagogastroduodenoscopy. Complete cure en bloc resection was successfully performed. The tumor was confined to the mucosa (pT1a-M). Immunohistochemistry showed positive CD10, MUC2, and CDX2 expression and negative MUC5AC and MUC6 expression. Thus, the phenotype was diagnosed as the intestinal phenotype. Helicobacter pylori-negative, well-differentiated early gastric cancer with intestinal phenotype has not been previously reported. Here, we report a rare and valuable case of Helicobacter pylori-negative early gastric cancer with intestinal phenotype treated by endoscopic submucosal dissection.

Here we report a rare case of late recurrence of pancreatic cancer 8 years after surgery. A woman in her mid-fifties was hospitalized for examination of epigastralgia. Computed tomography (CT) revealed a 4 cm nodule at the pancreatic head with suspected invasion of the superior mesenteric vein. She underwent pancreaticoduodenectomy with wedge resection of superior mesenteric vein and intraoperative radiation therapy. Pathological findings showed moderately differentiated tubular adenocarcinoma and T3N1M0, Stage IIB according to The Union for International Cancer Control (UICC) TNM classification. As adjuvant chemotherapy, 56 courses of gemcitabine (GEM) were administered in 3.5 years. Because of long-term use of GEM, common terminology criteria for adverse events (CTCAE) Grade 3 anemia occurred, and chemotherapy was discontinued. Tumor markers were evaluated every month and CT scans were taken every 6 months for 5 years. Subsequently, CT was performed annually. The patient was hospitalized for high-grade fever, 8.5 years after surgery. CT, magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) detected local recurrence with liver metastases. GEM was administered again, but was ineffective. The patient died 9 years after surgery. In conclusion, even if long-term survival is achieved in pancreatic cancer, follow-ups should not be stopped.

A-39-year-old man presented to a nearby clinic owing to long-term diarrhea and painful defecation. He was diagnosed with a well-differentiated tubular adenocarcinoma of the rectosigmoid and underwent a laparotomy at another hospital. At surgery, the tumor was seen to deeply invade into the urinary bladder with the presence of intra-abdominal abscess. Loop sigmoid colostomy was performed due to possible invasion into the pelvic wall and peritoneal dissemination. The patient was referred to the our hospital for systemic chemotherapy. After 32 courses of FOLFIRI, 10 courses of CapeOX + Bmab, and 34 courses of LV5FU2 + Bmab, radiographic examination revealed complete response (CR) of the rectal tumor, and low anterior resection of the rectum was carried out. Since pathological examination showed no viable cancer cells in any specimen, the patient was considered to have achieved a CR from a pathological standpoint.

Background: Whether the mutant allele frequency (MAF) may also have predictive implications for tyrosine kinase inhibitor (TKI) therapy in patients with advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (AELAd) remains unknown., Patients and Methods: Based on a biobanking system in conjunction with our institution, we assessed EGFR mutation status using pyrosequencing (Py) and by outsourcing laboratory tests, such as the Cycleave (Cy) and the Scorpion ARMS (A)., Results: Out of 705 patients enrolled in the Shizuoka Lung Cancer Mutation Study between July 2011 and March 2013, 102 AELAd patients were identified as carrying the L858R mutation (L858Rm) using Py to analyze histological specimens. Of these 102 patients, the EGFR mutation status was assessed using both Py and Cy in 48 patients: the median MAF of L858R (MAFLR) was 18.5% (range: 8%-82%), and 45 patients (94%) were identified as having an L858Rm using both Py and Cy. Three patients (6%) with discrepant L858Rm findings were only identified using Py. The plotting of a receiver operating characteristic curve to identify the discordance in L858Rm findings showed that the area under the curve for MAFLR was 0.967 (95% confidence interval: 0.91-1) and that an MAFLR of 9% resulted in high sensitivity (100%) and specificity (99%). Also, 29 patients with AELAd, excluding those with postoperative recurrences, had their L858R status assessed using Cy or A. The median age, 69 years (range: 47-84 years); male/female, 14 (48%)/15 (52%); smokers/never-smokers 13 (45%)/16 (55%); ECOG PS 0-1/2-3, 26 (90%)/3 (10%); stage IIIB/IV, 4 (14%)/25 (86%); median MAFLR, 18% (range: 8%-63%). Patients with an MAFLR of ≤9% had a significantly shorter progression-free survival (PFS) period after TKI therapy than those with an MAFLR of >9% (mPFS: 92 versus 284 days, P = 0.0027)., Conclusion: The MAF may be a potential predictive factor of TKI treatment efficacy in patients with AELAd carrying the L858Rm., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

MicroRNAs have been increasingly recognized as useful biomarkers for colorectal cancers (CRC). We have recently observed that microRNA-31 (miR-31) expression is associated with BRAF mutation and prognosis in CRC. Moreover, high miR-31 expression is frequently detected in sessile serrated adenomas compared with hyperplastic polyps (HPs). These results suggest that miR-31 may contribute to the progression of serrated lesions. At a follow-up colonoscopy, we observed the case of a 75-year-old man with a 7-mm flat-elevated lesion in the cecum and diagnosed the lesion as an early invasive carcinoma with serrated features. Tissue specimens were obtained from the representative areas to compare the molecular alterations in the carcinoma component with those in the HP component. Higher miR-31 expression was observed in the carcinoma component (57-fold increase) and the HP component (8-fold increase) compared with the paired normal mucosa, suggesting that miR-31 may be one of the key molecules in serrated pathway progression.

A 61-year-old woman presented with fever and was diagnosed with choledocholithiasis, which was removed endoscopically. Incidentally, a markedly elevated serum α-fetoprotein(AFP)level was detected(1,951 ng/mL), but computed tomography( CT)showed only diffuse gallbladder wall thickening. Subsequently, markedly elevated serum AFP-L3 and human chorionic gonadotropin(HCG)levels were detected(99.6%and 2,867mIU/mL, respectively). Fluorodeoxyglucose(FDG)- positron emission tomography/CT demonstrated high FDG uptake only in the gallbladder. Gallbladder cancer was suspected and the patient was scheduled for a cholecystectomy. However, CT just prior to surgery revealed multiple liver metastases. Percutaneous gallbladder biopsy revealed a moderately differentiated adenocarcinoma positive for AFP but not HCG. The patient underwent chemotherapy consisting of gemcitabine and cisplatin. A CT scan obtained 12 weeks later showed disease progression and AFP and HCG levels were found to have increased to 4,021 ng/mL and 66,000mIU/mL, respectively. Although immunohistochemistry of biopsy specimen did not demonstrate HCG production, increased serum HCG level on disease progression definitely suggested HCG production of gallbladder cancer. We believe the biopsy specimen was very small and therefore did not prove HCG production. Gallbladder cancer with simultaneous production of AFP and HCG is rare, and we therefore report this case together with a review of the literature.

Objectives: Among patients with locally advanced lung adenocarcinoma, the frequency of epidermal growth factor receptor (EGFR) and KRAS mutations was unknown. In addition, it has not been fully evaluated about the role of these mutations treated with concurrent chemoradiotherapy (CCR)., Methods: The clinical records of locally advanced lung adenocarcinoma patients treated with CCR at Shizuoka Cancer Center between September 2002 and December 2009 were reviewed., Results: Forty-four patients were eligible for this study. EGFR mutation was detected in 13 (29.5%) of 44 patients, and KRAS mutation was detected in 2 (6.5%) of 31 patients. Among EGFR mutation status known patients, overall response rate, median progression-free survival (PFS), and median survival time were 52.3%, 11.5 months, and 35.8 months, respectively. Overall response rate was significantly higher in EGFR mutant group than in EGFR wild-type group (76.9% vs. 41.9%, P=0.02), but this difference did not translate into a significant PFS benefit (9.6 vs. 13.2 mo, P=0.78). Locoregional relapse occured less frequently in patients with EGFR mutation than those with EGFR wild-type, but not significant (15.4% vs. 32.3%, P=0.46). Brain was the most frequent metastatic site of relapse in EGFR mutant group., Conclusions: Among locally advanced lung adenocarcinoma, EGFR mutation was detected in 29.5% and KRAS mutation was detected in 6.5%. We were not able to detect a difference in PFS or overall survival between EGFR mutant and wild-type patients treated with conventional CCR. Locoregional relapse was approximately half in the EGFR mutant group compared with the EGFR wild-type group; however, this finding did not reach statistical significance.

Background: Serum CYFRA 21-1 is one of the most important serum markers in the diagnosis of non-small cell lung cancer (NSCLC), especially squamous-cell carcinoma. However, it remains unknown whether pretreatment serum CYFRA 21-1 values (PCV) may also have prognostic implications in patients with advanced lung adenocarcinoma., Methods: We retrospectively reviewed the data of 284 patients (pts) who were diagnosed as having advanced lung adenocarcinoma and had received initial therapy., Results: Of the study subjects, 121 pts (43%) had activating epidermal growth factor receptor (EGFR) mutations (Mt+), while the remaining 163 pts (57%) had wild-type EGFR (Mt-). Univariate analysis identified gender (male/ female), ECOG performance status (PS) (0-1/ ≥2), PCV (<2.2 ng/ml/ ≥2.2 ng/ml), EGFR mutation status (Mt+/ Mt-), pretreatment serum CEA values (<5.0 ng/ml/ ≥5.0 ng/ml), smoking history (yes/ no) and EGFR-TKI treatment (yes/ no) as prognostic factors (p = .008, p < .0001, p < .0001, p < .0001, p = .036, p = .0012, p < .0001 respectively). Cox's multivariate regression analysis identified PCV < 2.2ng/ml as the only factor significantly associated with prolonged survival (p < .0001, hazard ratio: 0.43, 95% CI 0.31-0.59), after adjustments for PS (p < .0001), EGFR mutation status (p = .0069), date of start of initial therapy (p = .07), gender (p = .75), serum CEA level (p = .63), smoking history (p = .39) and EGFR-TKI treatment (p = .20). Furthermore, pts with Mt+ and PCV of <2.2 ng/ml had a more favorable prognosis than those with Mt+ and PCV of ≥2.2 ng/ml (MST: 67.0 vs. 21.0 months, p < .0001), and patients with Mt- and PCV of <2.2 ng/ml had a more favorable prognosis than those with Mt- and PCV of ≥2.2 ng/ml (MST: 24.1 vs. 10.2 months, p < .0001)., Conclusion: PCV may be a potential independent prognostic factor in both Mt+ and Mt- patients with advanced lung adenocarcinoma.

Background: A phase I dose-escalation study was performed to investigate the safety and pharmacokinetics of the combination of S-1 and gefitinib in patients with pulmonary adenocarcinoma who had failed previous chemotherapy., Methods: Patients received gefitinib at a fixed daily oral dose of 250 mg, and S-1 was administered on days 1-14 every 21 days at doses starting at 60 mg/m(2) (level 1) and escalating to 80 mg/m(2) (level 2). The primary end point of the study was determination of the recommended dose for S-1 given in combination with a fixed dose of gefitinib., Results: Twenty patients were enrolled in the study. Two of the first six patients at dose level 2 experienced a dose-limiting toxicity (elevation of alkaline phosphatase of grade 3 in one patient; elevations of aspartate and alanine aminotransferases of grade 3 in the other). The recommended dose was thus determined as level 2, and an additional 11 patients were assigned to this level. All observed adverse events were well managed. The response rate was 50 % (10 of 20 patients), and the median progression-free survival (PFS) and overall survival times were 10.5 and 21.2 months, respectively. In EGFR mutation-positive patients (n = 9), seven patients achieved an objective response and the median PFS was 12.4 months, whereas none with wild-type EGFR (n = 6) responded. No pharmacokinetic interaction between S-1 and gefitinib was detected., Conclusions: The combination of S-1 and gefitinib is well tolerated and appears to possess activity against EGFR mutation-positive NSCLC.

Background: In recent years, the incidence of carcinomatous meningitis (CM) in lung adenocarcinoma has been rising. However, it remains unclear which treatment strategies improve the outcome of these patients., Patients and Methods: We retrospectively reviewed data for 67 lung adenocarcinoma patients diagnosed with CM between September 2002 and March 2011 in order to identify factors which would improve prognosis., Results: In multivariate analysis, the female gender, a good performance status (PS) 0-2 and the mutant epidermal growth factor receptor (EGFR) gene were identified as factors associated with a favorable prognosis. The survival time was significantly prolonged for patients treated with EGFR-tyrosine kinase inhibitors (TKIs) (240 vs. 57 days, p<0.0001) and for patients who underwent radiotherapy of the central nervous system (CNS) (201 vs. 76 days, p=0.0038) after diagnosis of CM. The median survival time (MST) of patients treated with gefitinib before diagnosis of CM and with erlotinib after diagnosis was significantly longer than the MST of patients treated with gefitinib both before and after the diagnosis of CM (407 vs. 205 days, p=0.0015). Patients treated with both radiotherapy for CNS and EGFR-TKI had longer survival compared to patients without radiotherapy for the CNS (379 vs. 122 days, p=0.032)., Conclusion: EGFR-TKI combined with radiotherapy may be a therapeutic approach capable of improving the prognosis of patients with lung adenocarcinoma with CM harboring the EGFR gene mutation.

MUC1 expression has been described as a predictor for tumor progression and worsening of prognosis in various human neoplasms. However, little is known about the role of MUC1 expression in pulmonary metastatic tumors. The aim of this study is to examine the clinicopathological significance of MUC1 expression in pulmonary metastatic tumors (PMT). One hundred forty-seven patients with PMT who underwent (18)F-FDG PET before metastasectomy were included in this study. Tumor sections were stained by immunohistochemistry for MUC1, glucose transporter 1 (Glut1), hypoxia-inducible-1α (HIF-1α) and vascular endothelial growth factor (VEGF). (18)F-FDG uptake and the expression of these biomarkers were correlated in primary lung cancer. MUC1 expression pattern was classified into high-grade polarized expression (HP), low-grade polarized expression (LP), or depolarized expression (DP) group. Of 147 patients, HP, LP and DP group were 9 (6%), 114 (78%) and 24 (16%), respectively. The expression of Glut1, HIF-1αand VEGF, and (18)F-FDG uptake were significantly higher in DP group than HP or LP groups. MUC1 expression with HP and DP pattern was significantly higher in primary lung cancer than in PMT, whereas, MUC1 expression with LP pattern yielded a significantly high positive rate in PMT. LP group was recognized in the majority of patients with pulmonary metastatic adenocarcinoma, especially colon cancer, whereas, HP group was significantly low in pulmonary metastatic adenocarcinoma as compared with primary adenocarcinoma. Polarized MUC1 has a different expression pattern between primary and metastatic tumors with adenocarcinoma, and depolarized MUC1 is closely associated with glucose metabolism and hypoxia.

Background: The aim of this study was to investigate whether L-type amino acid transporter 1 (LAT1) expression can predict poor outcome after chemotherapy in patients with non-small cell lung cancer (NSCLC)., Materials and Methods: Immunohistochemistry was carried out to examine the expression of LAT1, CD98, vascular endothelial growth factor (VEGF), Ki-67, phosphorylation of Akt (p-Akt), phosphorylation of mammalian target of rapamycin (p-mTOR) and p53 in resected lung tumor specimens obtained from 56 patients treated with platinum-based chemotherapy., Results: Positive LAT1 and CD98 expression was recognized in 45% (25/56) and 34% (19/56), respectively. In NSCLC (N=56), LAT1, CD98, VEGF, Ki-67 and p53 were significant factors for predicting poor outcome, and adenocarcinoma was an independent factor for predicting favorable prognosis. LAT1 expression was closely associated with chemoresistance. In adenocarcinoma (N=37), a statistically significant inverse relationship was observed between the expression of LAT1, VEGF and Ki-67 and epidermal growth factor receptor (EGFR) mutation, and positive expression of LAT1 and VEGF was an independent factor for predicting poor prognosis after chemotherapy., Conclusion: LAT1 expression may be useful for predicting response and outcome after systemic chemotherapy.

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: 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.

A 51-year-old woman was referred to our hospital with a complaint of disturbance in vision. Ophthalmologic examination revealed multiple choroidal tumors. High-resolution CT showed a nodular shadow in the left lower lobe. Transbronchial biopsy and right supraclavicular lymph node biopsy specimens showed a poorly-differentiated adenocarcinoma. We concluded that the choroidal tumors had metastasized from the lung. Combined chemotherapy (CDDP + CPT-11) followed by irradiation of both eyes and brain were performed. Nevertheless, she died 6 months after the initial presentation. It is important to notice ophthalmologic symptoms because lung cancer may metastasize to the choroids.

Purpose: We analyzed the possible risk factors for metachronous colon tumors after endoscopic resection of initial tumors., Methods: Three hundred and twenty-one patients entered the surveillance study after colonoscopic resection of initial tumors between 1985 and 1999. Histology of initial tumors was adenoma in 214 patients and carcinoma in 107 patients. Solitary tumor was observed in 196 patients and multiple tumors in 125 at initial endoscopy. The median surveillance period was 39 (range, 12-112) months, and the median frequency of surveillance colonoscopy was three (range, 2-10) times., Results: Metachronous neoplasms were identified in 114 of 321 surveillance cases (36%). In the 114 cases, the number of patients with metachronous adenoma was 103 (90%) and that of carcinoma was 11 (10%). Clinical characteristics at entry - including age, gender, multiplicity of polyp, histology of polyp, and site of polyp - were not different between patients with metachronous tumors and those without metachronous tumors. Kaplan-Meier analysis revealed that patients with a histology of carcinoma and those with multiple polyps at entry developed metachronous tumors significantly earlier than did patients with initial adenomas and initial solitary polyp, respectively ( P<0.001, P<0.001). However, other characteristics at entry did not produce significant differences in the rate of the development of metachronous tumors using Kaplan-Meier analysis. Proportional hazards model analysis revealed that histology of the initial tumor as carcinoma (relative risk, 1.690, 95% confidence interval, 1.118-2.555) and multiplicity (1.472, 1011-2.143) were significant risk factors for metachronous colon tumors. The 75%, 50%, and 25% metachronous tumor-free periods after initial polypectomy were 14, 21, and 39 months, respectively., Conclusions: These results may help optimizing surveillance strategies for metachronous colon tumors and raising the economic benefit of colonoscopy.

We report 2 patients with advanced gastric cancer treated with a new combination chemotherapy of low-dose FP and daily oral administration of low-dose etoposide. Patient 1 was an 84-year-old man. He was diagnosed with cancer of the remnant stomach with multiple liver metastases. For eight months, he was treated as an outpatient and his performance status (PS) stayed at stage 1. Patient 2 was a 67-year-old man with lymph node metastasis of the lung. For the first 6 weeks, he was treated under hospitalization and for the following 10 months he was treated as an outpatient. His PS remained in stage 1 and blood CEA value fell from 2,420 ng/ml to 46.9 ng/ml. Upper gastrointestinal series showed a recovery of the extension of his lower gastric body. Both cases were so-called prolonged NC. From the viewpoint of patient QOL, this new combination is a possible candidate for a more effective chemotherapy.

The levels of sialyl Lewis X-i antigen (SLX), which is one of the cancer-associated carbohydrate antigens, were evaluated in 83 malignant and 46 benign pleural effusions. SLX levels in pleural effusion due to lung adenocarcinoma were significantly higher than those due to benign diseases (p < 0.0001), lung cancer other than adenocarcinoma (p = 0.0052), and adenocarcinoma originating from other organs (p = 0.0492). According to receiver operating characteristic (ROC) curve analysis, the optimal cut-off level in the discrimination between malignant and benign pleural effusions was 92 U/ml, which gave a sensitivity of 57.1% and a specificity of 77.8%. The cut-off level of pleural effusion in patients with carcinomatous pleuritis might be higher than that of serum (38 U/ml).

A 39-year-old man with a known diagnosis of lung adenocarcinoma developed intermittent double vision with right pupil dilatation. His symptoms eventually progressed to complete oculomotor nerve palsy on the right. Postmortem examinations revealed a metastasis of the adenocarcinoma involving the root of right oculomotor nerve.