Squamous Cell Adenocarcinoma Research Articles

Abstract 4010: Adjuvant chemotherapy based on the intratumoral expressions of class III β tubulin and thymidylate synthase improved disease-free survival in patients with resected locally advanced non-small cell lung cancer

Objectives: Although the molecular targeted therapy and immune-check point inhibitors improved survival of some populations of patients with non-small cell lung cancer (NSCLC), most of patients still remain to need conventional chemotherapy. Adjuvant chemotherapy is recommended for patients with resected locally advanced NSCLC. However, selection of the optimal adjuvant chemotherapy regimen is difficult. Regarding the predictive biomarkers for chemotherapy, the intratumoral expressions of class III β tubulin (TUBB3) has been reported to be a biomarker for taxanes, and thymidylate synthase (TS) for 5-fluorouracil (5-FU) derivatives and pemetrexed. Therefore, we conducted a prospective clinical study to evaluate the effectiveness of tailor-made adjuvant chemotherapy based on TUBB3 and TS. Methods: Between November 2011 and December 2016, 54 patients with pathological stage IIB to IIIB NSCLC who underwent complete resection were studied. The expressions of TUBB3 and TS were estimated by immunohistochemistry. When less than 50% of the tumor cells in a given specimen were positively stained for TUBB3, the tumor was classified as TUBB3-low. When less than 50% of the tumor cells in a given specimen were positively stained for TS, the tumor was classified as TS-low. Concerning to adjuvant chemotherapy, patients with TUBB3-low tumors were preferably treated with Taxane-based chemotherapy, and patients with TS-low tumors were preferably treated with chemotherapy including 5-FU derivatives or pemetrexed. Patients who could receive tailor-made adjuvant chemotherapy based on evaluations of TUBB3 and TS were assigned to tailor-made group. Patients who could not receive tailor-made adjuvant chemotherapy were assigned to non-tailor-made group, due to several reasons, such as both TUBB3-high and TS-high tumors and renal dysfunction. Results: Among 54 tumors, 39 tumors were adenocarcinomas, 14 were squamous cell carcinomas, and 1 was adenosquamous cell carcinoma. Regarding pathological stage, 19 tumors were stage IIB, 32 were stage IIIA, and 3 were stage IIIB. Concerning to survival, the disease-free survival (DFS) rate was significantly higher in tailor-made group than in non-tailor-made group (5-year DFS rate: 58.6% vs 12.0%; P Conclusion: Adjuvant chemotherapy based on the intratumoral expressions of TUBB3 and TS is considered to be clinically useful for patients with resected locally advanced NSCLC. Citation Format: Ryota Sumitomo, Tatsuya Hirai, Hiyoaki Murakami, Yosuke Otake, Cheng-long Huang. Adjuvant chemotherapy based on the intratumoral expressions of class III β tubulin and thymidylate synthase improved disease-free survival in patients with resected locally advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4010.

Abstract 1166: TDO2 overexpression is associated with cancer stem cells and poor prognosis in esophageal squamous cell carcinoma

Abstract Objective: Esophageal cancer is one of the deadliest cancers in the world, and the main subtype is esophageal squamous cell carcinoma (ESCC), which comprises 90% of cases. We previously analyzed the gene expression profile of spheroid colonies and parental cells derived from gastric cancer (GC) cell lines by microarray analysis. Among the genes upregulated in spheroid colonies, tryptophan 2,3-dioxygenase (TDO2) is dramatically upregulated in MKN-1 cells (derived from adenosquamous cell carcinoma) compared with other GC cell lines. Expression of TDO2, an enzyme involved in tryptophan catabolism, has been linked with tumor survival and poor prognosis of brain and breast cancer. However, no studies have investigated the potential role of TDO2 in esophageal cancer. Here we explored the expression and biological significance of TDO2 in ESCC. Methods: To explore the expression of TDO2 in cancer and normal samples, we used an online analytical tool, the Broad Institute TCGA Genome Data Analysis Center, http://firebrowse.org/. For quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we used 10 ESCC samples (tumor tissues and the corresponding non-neoplastic tissue). TDO2 protein expression was evaluated in 90 ESCC tissue samples by immunohistochemistry. TDO2 function in ESCC cell lines and spheroid colony formation was evaluated by RNA interference (RNAi). Cell growth was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Modified Boyden chamber assays were performed to examine cell invasiveness. Results: TDO2 expression was upregulated in most cancers except for liver cancer and pancreas cancer. The fold change expression of TDO2 between normal and cancer tissue was the highest in esophageal cancer. TDO2 overexpression was associated with tumor stage, recurrence status and the CD44 cancer stem cell marker in ESCC. TDO2 overexpression was correlated with poor outcome of ESCC patients. Inhibition of TDO2 expression by RNAi in TE-10 and TE-11 cell lines reduced both the number and the size of spheroid colonies as well as cell proliferation and invasive activity. Knockdown of TDO2 expression also induced inactivation of the EGFR signaling pathway. Conclusion: Our results imply that TDO2 could play an important role in the progression of ESCC. Furthermore, TDO2 may be a potential therapeutic target in ESCC. Citation Format: Thang Quoc Pham, Naohide Oue, Yohei Sekino, Yuji Yamamoto, Naoya Sakamoto, Ririno Honma, Kazuhiro Sentani, Wataru Yasui. TDO2 overexpression is associated with cancer stem cells and poor prognosis in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1166.

Abstract 4010: Adjuvant chemotherapy based on the intratumoral expressions of class III β tubulin and thymidylate synthase improved disease-free survival in patients with resected locally advanced non-small cell lung cancer

Abstract Objectives: Although the molecular targeted therapy and immune-check point inhibitors improved survival of some populations of patients with non-small cell lung cancer (NSCLC), most of patients still remain to need conventional chemotherapy. Adjuvant chemotherapy is recommended for patients with resected locally advanced NSCLC. However, selection of the optimal adjuvant chemotherapy regimen is difficult. Regarding the predictive biomarkers for chemotherapy, the intratumoral expressions of class III β tubulin (TUBB3) has been reported to be a biomarker for taxanes, and thymidylate synthase (TS) for 5-fluorouracil (5-FU) derivatives and pemetrexed. Therefore, we conducted a prospective clinical study to evaluate the effectiveness of tailor-made adjuvant chemotherapy based on TUBB3 and TS. Methods: Between November 2011 and December 2016, 54 patients with pathological stage IIB to IIIB NSCLC who underwent complete resection were studied. The expressions of TUBB3 and TS were estimated by immunohistochemistry. When less than 50% of the tumor cells in a given specimen were positively stained for TUBB3, the tumor was classified as TUBB3-low. When less than 50% of the tumor cells in a given specimen were positively stained for TS, the tumor was classified as TS-low. Concerning to adjuvant chemotherapy, patients with TUBB3-low tumors were preferably treated with Taxane-based chemotherapy, and patients with TS-low tumors were preferably treated with chemotherapy including 5-FU derivatives or pemetrexed. Patients who could receive tailor-made adjuvant chemotherapy based on evaluations of TUBB3 and TS were assigned to tailor-made group. Patients who could not receive tailor-made adjuvant chemotherapy were assigned to non-tailor-made group, due to several reasons, such as both TUBB3-high and TS-high tumors and renal dysfunction. Results: Among 54 tumors, 39 tumors were adenocarcinomas, 14 were squamous cell carcinomas, and 1 was adenosquamous cell carcinoma. Regarding pathological stage, 19 tumors were stage IIB, 32 were stage IIIA, and 3 were stage IIIB. Concerning to survival, the disease-free survival (DFS) rate was significantly higher in tailor-made group than in non-tailor-made group (5-year DFS rate: 58.6% vs 12.0%; P < 0.001). In particular, the DFS rate was significantly higher in tailor-made group than in non-tailor-made group, both in stage IIB (5-year DFS rate: 83.3% vs 28.6%; P = 0.013) and stage IIIA (5-year DFS rate: 43.8% vs 8.3%; P =0.034). The overall survival of the tailor-made group tended to be longer than that of non-tailor-made group (5-year overall survival rate: 76.6% vs 65.8%; P = 0.160). Conclusion: Adjuvant chemotherapy based on the intratumoral expressions of TUBB3 and TS is considered to be clinically useful for patients with resected locally advanced NSCLC. Citation Format: Ryota Sumitomo, Tatsuya Hirai, Hiyoaki Murakami, Yosuke Otake, Cheng-long Huang. Adjuvant chemotherapy based on the intratumoral expressions of class III β tubulin and thymidylate synthase improved disease-free survival in patients with resected locally advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4010.

Computer-aided Quantification of Pulmonary Fibrosis in Patients with Lung Cancer: Relationship to Disease-free Survival.

Background Interstitial lung abnormalities (ILAs) are present at CT in about 10% of individuals undergoing lung cancer screening. The relationship between histologic findings of ILAs and their influence on patient prognosis remains unknown. Purpose To evaluate the percentage of ILAs at preoperative CT, as measured by radiologists and a computer-aided detection (CAD) software, as a predictor of disease-free survival in patients with lung cancer. Materials and Methods This retrospective study evaluated 217 consecutive patients who underwent complete resection of lung cancer from April 2010 to December 2015. Two radiologists, blinded to the patients' clinical information, scored percentage fibrosis extent and determined whether ILAs and the usual interstitial pneumonia (UIP) pattern were present. They assessed ILA progression at follow-up CT. Two pathologists determined the presence of an UIP pattern. Percentage fibrosis extent was also measured by using CAD. Binary logistic regression analysis was performed to determine whether the CAD percentage fibrosis extent was associated with ILA at CT. Multivariable Cox regression analysis was used to evaluate the significance of CAD percentage fibrosis extent as a predictor of prognosis. Results The radiologists classified 47 patients with ILAs and 24 patients with a UIP pattern at chest CT. The pathologists detected a UIP pattern in 25 patients. CT abnormalities showed progression over a 2-year period in all patients with histologic evidence of UIP. After adjustment for age, sex, and smoking index, the CAD percentage fibrosis extent was independently associated with ILA (odds ratio: 3.1; 95% confidence interval [CI]: 2.1, 4.7; P < .001). After adjustment for age, forced expiratory volume in 1 second (percentage predicted) radiologist-assessed percentage fibrosis extent, and pathologic stage, CAD percentage fibrosis extent was independently associated with worse disease-free survival (hazard ratio: 1.3; 95% CI: 1.1, 1.6; P < .001). Conclusion Greater computer-aided detection percentage fibrosis extent at preoperative CT independently predicted worse disease-free survival in patients with lung cancer. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Goo in this issue.

The association between BRAF mutation class and clinical features in BRAF-mutant Chinese non-small cell lung cancer patients.

e14681 Background: BRAF mutations, occurring in 2-4% NSCLC patients, can be classified into 3 classes based on signaling mechanism and kinase activity: V600-mutant RAS-independent kinase activating monomers (class I), RAS-independent kinase activating dimers (class II) and RAS-dependent kinase inactivating heterodimers (class III). The association between functional classes and clinical features of Chinese NSCLC patients remain elusive. Methods: Sequencing data of either plasma or tissue samples obtained from 8,405 Chinese (Stage I-IV NSCLC) patients were retrospectively analyzed to screen for BRAF mutations. Of the patients with BRAF mutations, 79% (188/238) were diagnosed with adenocarcinoma,7.6% with squamous cell carcinomas (SCC) and the remaining patients were either adenosquamous carcinoma or large cell carcinoma. Results: BRAF mutations were detected in 238 patients, revealing a prevalence of 2.8%. Among them, 32% (75/238), 21% (51/238) and 13% (31/238) had class I, II and III mutations, respectively. The remaining 35% (81/238) had other BRAF mutations. V600 (32%, 75/238) and G469 (13%, 32/238) were the 2 most predominant mutations. BRAF mutations, when considered collectively, including non-class I-III mutations, were more likely to occur in males ( p&lt; 0.01). However, class I mutations have a female predominance (p = 0.003); whereas, class II mutations showed a trend of male predominance (p = 0.09) and class III had no gender preference (p = 0.22). We also revealed no association between histology types and the class of BRAF mutations. Next, we investigated co-occurring classic lung cancer driver mutations in this cohort and revealed that patients with class II and III mutations were more likely to have concurrent KRAS mutations (p = 0.001). We also compared the overall survival (OS) of chemotherapy-treated patients and revealed comparable OS among the 3 groups. Conclusions: Our study revealed a 2.8% BRAF mutation rate in Chinese NSCLC patients. Our data also showed a male predominance when all BRAF mutations were considered collectively, and a female predominance for class I mutations. Furthermore, patients with BRAF V600E is less likely to have concurrent KRAS mutations.

The continued osimertinib plus chemotherapy overcoming resistance after histologic transformation in EGFR-mutant lung adenocarcinoma treated with osimertinib.

e20615 Background: Although the third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is more potent, histologic transformation from lung adenocarcinoma to other histological types is still a mechanism of resistance in EGFR-mutant adenocarcinoma. Those with histologic transformation usually have poor prognosis. Hence, we focused on the unique molecular mechanism of histologic transformation after osimertinib and explore the strategy of treatment. Methods: Pathology was confirmed in 55 EGFR-mutant patients treated with osimertinib at baseline and disease progression. They were all lung adenocarcinoma at baseline. We established the patient-derived xenograft (PDX) mouse model from an EGFR-mutant adenocarcinoma transforming to neuroendocrine carcinoma. Preclinical efficacy of erlotinib versus osimertinib was evaluated in vivo. All the clinical data of these patients were analyzed. Results: The frequency of histologic transformation after resistance to osimertinib was 14.5% (8/55). Three of them were transformed to small-cell lung cancer totally, two transformed to complex small-cell lung cancer, two transformed to adenosquamous cell carcinoma and one transformed to neuroendocrine carcinoma without T790M mutation in which an PDX mouse model was successfully established. The genetic profiles of those transformed to small-cell lung cancer were characterized by Rb1, TP53 mutations, and PI3K/AKT/MTOR aberrances. Those transformed to adenosquamous carcinoma were characterized by KRAS amplification and EGFR amplification. The median progression-free survival (PFS) was not significantly different between the patients with histologic transformation and those without during the treatment of osimertinib (7.7 VS. 5.7 months, P = 0.763). One went on first-line osimertinib, added etoposide/ cisplatin (EP) chemotherapy meanwhile after progressive disease, and achieved minor response after 2 cycles. The other one received the treatment of EP + osimertinib + erlotinib, and acheived partial response with a PFS of 7 months without obvious toxicities. The PDX model showed more sensitivity to erlotinib than osimertinib. Conclusions: Continued osimertinib plus chemotherapy might be effective in overcoming the resistance. Particularly, the first-generation EGFR-TKI seems to be efficacious in histologically-transformed EGFR-mutant patients without T790M mutation. Further investigations of these patients and PDXs are warranted.

Cervical screening and risk of adenosquamous and rare histological types of invasive cervical carcinoma: population based nested case-control study

ObjectivesTo examine the association of cervical cytology screening with the risk of adenosquamous cell carcinoma (ASC) and rare histological types of invasive cervical carcinoma (RICC), using comprehensive registry data, and...

Parallel-group controlled trial of esophagectomy versus chemoradiotherapy in patients with clinical stage I esophageal carcinoma (JCOG0502).

7 Background: Esophagectomy (E) is the standard of care for stage I esophageal squamous cell carcinoma (ESCC), while chemoradiotherapy (CRT) is a treatment option. A parallel-group controlled trial including randomized arms to confirm the non-inferiority of CRT to E for stage IA ESCC was conducted. Methods: Patients (pts) with thoracic ESCC, adenosquamous cell, or basaloid cell carcinoma with stage IA (T1bN0M0), age 20 to 75, performance status 0 to 1, and adequate organ function were eligible. If pts accepted randomization, they were randomly allocated to E with 2-3 field lymph node dissection (arm A) or CRT (arm B). However, if pts had a preference and refused randomization, they were allocated to pts preference arm, E (arm C) or CRT (arm D). CRT consisted of cisplatin and 5-FU, with radiation at the dose of 60 Gy concurrently. The primary endpoint was overall survival (OS) of arm A and B, secondary endpoint included OS of arm C and D using inverse probability weighting with propensity score. The planned sample size in arm A and B was 114 pts in total with one-sided alpha of 10%, power of 75% and non-inferiority margin of HR as 1.78. The sample size in arm C and D was at least 156 pts in each arm with one-sided alpha of 2.5%, power of 85% and non-inferiority margin of HR as 1.78. Results: Between December 2006 and February 2013, 379 (Arm A: 4, B: 7, C: 209 C, D: 159) pts were enrolled. Primary endpoint was not calculated due to small number of randomized arms. Patients characteristics of arm C and D were as follows; median age: 62 and 65, male (%): 82.8 and 88.1, PS 0 (%): 99.5 and D 98.1. All histologic type was SCC except one basaloid cell carcinoma in arm C. The 3- and 5-year OS were 94.7% and 86.5% in arm C, and 93.1% and 85.5% in arm D (adjusted HR 1.05; 95% CI 0.67-1.64 [&lt; 1.78]).Treatment related death were observed in two pts in arm C and none in arm D. Conclusions: Though the accrual of randomized arms was shortened, CRT showed trend toward non-inferiority compared to E in pts preference arms. CRT is considered as a treatment option for stage IA ESCC with organ preservation. Clinical trial information: UMIN000000551.

Rare subtypes of pancreatic cancer: Clinical outcomes and implications for clinical trial enrollment.

445 Background: Pancreatic cancer subtypes such as adenosquamous (AS) and squamous cell carcinoma (SCC) are rare and poorly understood. Treatment recommendations are extrapolated from pancreatic adenocarcinoma (AC) and these patients are often included in AC clinical trials. Herein, we describe clinical outcomes and inclusion of these subtypes in AC clinical trials. Methods: The National Cancer Database (NCDB) was queried to identify patients with AC, AS, and SCC between 2004 and 2014. Overall survival was evaluated using Kaplan-Meier methodology and multivariable (MVA) cox regression models were fit to identify differences in survival outcomes between subtypes adjusted by baseline demographic and clinical variables. ClinicalTrials.gov was interrogated to identify inclusion of AS and/or SCC in contemporary PA clinical trials. Results: We identified 115,061 patients with pancreatic cancer. Median age was 69 (range 18 – 90) and median follow up was 54 months (95% CI 53 – 55). Age, sex, median income, education, comorbidities, race, and stage were significantly associated with overall survival (OS). OS by subtype compared to AC: AS HR of 0.98 (p = 0.59) and SCC HR 1.29 (p &lt; 0.001). OS by subtype and stage compared to AC: stage I/II, AS HR of 0.98 (p = 0.59), SCC HR 1.44 (p = 0.001); stage III, AS HR of 1.32 (p = 0.02) and SCC HR 1.48 (p = 0.01); stage IV, AS HR of 1.1 (p = 0.06), SCC HR 1.2 (p = 0.06). Data from 283 phase II or III interventional trials completed between 2008-2018 were exported from clinicaltrials.gov. The majority of trials listed did not specify inclusion or exclusion of AS or SCC subtypes. Conclusions: This is the largest report of clinical outcomes in rare subtypes of pancreatic cancer. SCC and to a lesser extent, AS, have worse OS compared to AC. It is unclear how rare pancreatic cancer subtypes are handled in the inclusion and analysis of clinical trial data and how this may impact enrollment and survival outcomes.[Table: see text]

Gallbladder Adenosquamous Carcinoma Associated with Biliopancreatic Maljunction: aggressive resection and survival

Background: Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join outside the duodenal wall. It has been reported to be associated with an increased risk of gallbladder carcinoma. Gallbladder adenosquamous carcinoma is rare, with a worse prognosis compared to patients with adenocarcinoma. We report a case of adenosquamous carcinoma of gallbladder associated with PBM. Methods: A 56-year-old woman was admitted to the hospital complaining of pain in right hypochondrium. Ultrasonography and computed tomography revealed an elevated lesion inside the gallbladder and dilated extrahepatic bile duct. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed PBM with biliary dilatation of 15mm in the largest diameter. Results: Cholecystectomy, bile duct resection with a Roux-en-Y hepaticojejunostomy and hepatic resection (S4b-S5) with regional lymphadenectomy was performed. Histology demonstrated an adenosquamous cell carcinoma of the gallbladder with invasion to the muscle layer and two metastases of the resected lymph nodes (T2N1M0). Fourteen months after the operation, the patient is doing well with no signs of recurrence. Conclusion: PBM is a high risk factor for the development of gallbladder carcinoma because of a continuous reflux of pancreatic juice into the biliary tract. Aggressive surgical resection without residual tumor (R0) provides a chance for long-term survival in patients with gallbladder adenosquamous carcinoma.

Intestinal obstruction caused by primary adenosquamous cell carcinoma of the small intestine: A case report and review of the literature.

Primary adenosquamous cell carcinoma (ASCC) arising from the ileum is an exceptionally rare malignant neoplasm exhibiting mixed glandular and squamous differentiation. The clinicopathological characteristics of ASCC have not been clearly determined due to its rarity. We herein report a case of a 74-year-old man with a successfully treated ASCC of the ileum. The patient visited a medical clinic due to abdominal pain. Abdominal computed tomography imaging revealed an intestinal tumor in the ileum. Prior to undergoing capsule endoscopy, the patient complained of severe abdominal pain due to intestinal obstruction from the patency capsule and the tumor. Thus, the patient was referred to our hospital for emergency surgery. Upon relieving the obstruction by partial resection of the ileum, an impacted patency capsule with a tumor with ulceration was identified. On histological examination, the tumor consisted of malignant glandular and squamous cell elements. The postoperative course was uneventful, without complications. The patient subsequently received adjuvant chemotherapy with oxaliplatin and capecitabine for 6 months. The patient has no evidence of recurrence 20 months after surgery. To the best of our knowledge, only 8 cases of ASCC have been reported in the English literature to date. This case serves as an important reminder to consider small intestinal carcinoma, including ASCC, in the differential diagnosis of intestinal obstruction.

P2.09-14 The Detection of EGFR Gene Mutation from Washing Solution of Devices used for the Bronchoscopic Examination

The detection of epidermal growth factor receptor (EGFR) gene mutation is necessary for selection of lung cancer treatment. Recently, biopsy specimens are used in many genomic and immunohistochemical examination methods to select the treatment policy, so it is important not to waste valuable cancer cell samples. For detection of EGFR gene mutation we examine the washing solution of devices used for the bronchoscopic examination in order to solve the issue. In this report, we investigate the detection ratio of EGFR mutation using this cytological sample. A total of 336 washing solution samples from lung cancer patients were examined for EGFR gene mutation testing in the period between November 2010 and October 2017. 328 cases of 336 excepting 8, which were carried out as re-biopsy, were surveyed in this examination. After the regular biopsy or scraping method, all devices were washed with 10ml saline liquid. Half volume of washing solution was used for regular cell examination to detect cancer cells. Only if a sufficient amount of non-small cancer cells were observed from it, the other volume was submitted for EGFR mutation examination. Final diagnosis was decided by histological specimen. Presence or absence of EGFR mutation and their types were observed from 328 samples retrospectively. Histological diagnosis of all 328 biopsy specimens are as follows; 200 Adenocarcinoma (AD), 100 Squamous cell carcinoma (SQ), 13 non-small cell lung carcinoma(NSCLC), 3 adenosquamous cell carcinoma(ADSQ), 7 high grade neuroendocrine carcinoma (HGNEC), and 5 others. The detection number of EGFR mutation from AD, SQ, ADSQ and NSCLC are 65, 4, 2, and 3 respectively. There is no EGFR mutation from remaining histology cases. In all of 74 EGFR mutation positive cases, Exon 19 deletion was detected in 33 cases (45%) and Exon 21 L858R was detected in 33 cases (45%). The detection rate of EGFR gene mutation from washing solution of devices is 33% (65/200) in AD and 4% (4/100) in SQ. These results are approximate to previous reports. Consequently, it is acceptable to use this method to investigate EGFR gene mutation of non-small lung cancer patients. Furthermore, it is an advantage that we can carry out an EGFR mutation test using this method with a cytology sample earlier than a method with a histology sample.

P3.08-09 Surgical Resection of Pulmonary Oligo-Recurrence of Non-Small Cell Lung Cancer

The concept of oligo-recurrence, which is theoretically curable by definitive local therapy, has been proposed in several cancers. But the efficacy of surgical resection for pulmonary oligo-recurrence of lung cancer is unclear. The aim of this study was to investigate the efficacy of surgical resection of pulmonary oligo-recurrence of non-small cell lung cancer (NSCLC). We retrospectively analyzed the data on 21 patients who underwent lung resection for pulmonary oligo-recurrence in our institution, between 2000 and 2016. We evaluated independent risk factors for progression-free survival after pulmonary resection. There were 14 men and 7 women with median age of 71 years [interquartile range (IQR), 65-72]. The median follow-up time was 48.8 months [IQR, 17.2-69.2]. Previous therapies for NSCLC were pulmonary resections in 16 (76.2%) patients, stereotactic radiosurgery for brain metastasis in 2 (9.5%), chemoradiotherapy in 2 (9.5%) and chemotherapy (ALK-TKI) in 1 (4.8%). Median progression-free interval between previous therapy and pulmonary resection of oligo-recurrence was 28.0 months [IQR, 16.0-40.0]. Histopathology was adenocarcinoma in 18 (85.9%) patients, squamous cell carcinoma, adenosquamous carcinoma and large cell neuroendocrine carcinoma in 1 (4.7 %). Surgical procedures were wedge resection in 11 patients, segmentectomy in 3, lobectomy in 5 and pneumonectomy in 2. There were no perioperative deaths. Three-year overall survival and progression-free survival were 68.6% and 59.3%. Postoperative recurrence occurred in 8 (38.1%) patients (local; 4, distant; 2, local and distant; 4). Univariate analyses identified progression-free interval between previous therapy and pulmonary resection of oligo-recurrence as independent risk factor for progression-free survival after pulmonary resection. Surgical resections of pulmonary oligo-recurrence of NSCLC are feasible and the postoperative survival is acceptable. But there are highly selective patients in our study, further study is needed for curative intent treatment.

Definitive chemoradiotherapy for anal canal cancer: single-center experience.

Chemoradiotherapy (CRT) is a standard treatment for anal canal cancer although many patients with anal canal cancer undergo surgery in Japan. The efficacy of CRT for anal canal cancer was evaluated retrospectively. Medical charts of 13 patients with anal canal cancer treated by definitive CRT from October 2004 to May 2016 were reviewed. Twelve patients had squamous cell carcinoma and one had adeno-squamous carcinoma. PET/CT simulation was performed in nine patients. The median total dose was 59.4Gy (range 57.6-63.4Gy) with fractions of 1.8-2.0Gy. Ten patients received chemotherapy with mitomycin C (10mg/m2) and fluorouracil (5-FU) (800mg/m2 over 4 days) in weeks 1 and 5, while two patients were treated with cisplatin (40mg) and 5-FU (750mg over 5 days) in weeks 1 and 5. One elderly patient received radiotherapy (RT) alone. All 13 patients were alive after a median follow-up period of 102months (range 16-121months). Local failure only occurred in the patient with adeno-squamous cell carcinoma, while there was no loco-regional recurrence or distant metastasis in the other 12 patients. The 5-year loco-regional control rate (LRC) and 5-year overall survival rate (OS) were 92% and 100%, respectively. Acute toxicities of ≥ grade 3 were observed in six patients (46%), mainly being dermatitis around the anal verge, and late toxicity of ≥ grade 3 occurred in one patient. CRT for squamous cell carcinoma of the anal canal achieved good LRC and OS with acceptable toxicities.

Human Papillomavirus T-Cell Cross-reactivity in Cervical Cancer

Clinical trials are testing vaccines that target human papillomavirus 16 (HPV-16) oncoproteins for the treatment of cervical cancer regardless of the HPV type of the tumor. For patients with HPV-18-positive cancers, this strategy relies on cross-reactivity of HPV-16-reactive T cells against the HPV-18 oncoproteins. To determine the prevalence of HPV-16 and HPV-18 metastatic cervical cancers in women enrolling in clinical trials at a US medical center and to assess whether HPV oncoprotein-targeting tumor-infiltrating lymphocytes (TILs) and T-cell receptors (TCRs) possess HPV-16/HPV-18 oncoprotein cross-reactivity. This study was conducted at the National Institutes of Health Clinical Center, a tertiary care research hospital in the United States. The HPV type of the tumors from 65 consecutive patients with cervical cancer who were evaluated for participation in clinical trials was determined by retrospective medical record review. Immunological assays testing HPV cross-reactivity were conducted on all available archived samples of oncoprotein-reactive TILs from HPV-positive tumors (n = 16) and on a library of previously identified TCRs (n = 10). The HPV genotype of each patient's tumor was determined. The cross-reactivity of archived TILs and a library of TCRs was assessed. The main outcomes were the prevalence of each HPV genotype and the frequency of TILs or TCRs with HPV oncoprotein-T-cell cross-reactivity. Cross-reactivity was assessed by enzyme-linked immunospot assays and interferon-γ production assays. The median (range) age of 65 referred patients was 44 (24-64) years. Ethnicity was recorded for 39 of 65 patients; 35 (89.7%) were white, 3 (7.7%) were Asian, and 1 (2.6%) was American Indian/Alaskan Native. Histologic tumor subtype was recorded for 41 of 65 patients; 25 (61.0%) were squamous cell carcinomas, 12 (29.3%) were adenocarcinomas, 2 (4.9%) were adenosquamous cell carcinomas, and 2 (4.9%) were neuroendocrine tumors. Thirty-nine of 65 patients (60.0%) had HPV-16-positive tumors and 21 patients (32.3%) had HPV-18-positive tumors. In the analysis of cross-reactivity, 1 of 16 oncoprotein-reactive archived TILs (9 from cervical cancers and 7 from other cancers) displayed HPV-16/HPV-18 cross-reactivity. None of the 10 oncoprotein-reactive TCRs displayed HPV-16/HPV-18 cross-reactivity. Cervical cancers that tested positive for HPV-18 were common in this study and may be common in other US clinical trial populations. Results showed that HPV-16/HPV-18 intergenotype T-cell cross-reactivity of T cells from HPV-16-positive and HPV-18-positive cancers was uncommon. These findings support clinical trial designs in which the HPV type targeted by a therapeutic vaccine is matched with the HPV type of a cancer and suggest a change is necessary in the design of active clinical trials.

Abstract 2562: Affinity-enhanced T-cell receptor (TCR) for adoptive T-cell therapy targeting MAGE-A4

Abstract Melanoma-associated antigens-A (MAGE-A) are members of an extensive family of cancer/testis (CT) antigens. Although emerging studies highlight the potential role of MAGE-A family members in promoting cancer growth, the biological function of MAGE-A4 remains poorly understood. MAGE-A4 is an attractive target because it has a high frequency of expression in multiple solid tumors according to The Cancer Genome Atlas (https://cancergenome.nih.gov/). In an attempt to further characterize its expression in solid tumors, immunohistochemistry analysis was performed in 534 resected non-small cell lung carcinoma (NSCLC) cases, stage I to IV with clinicopathological information including overall survival and recurrence. MAGE-A4 expression was observed in 24% of all NSCLC cases, with higher frequency observed in squamous cell carcinoma (SCC) (51%) versus adenocarcinoma (8%). MAGE-A4 expression was observed in 23% of the primary tumors and 48% of the recurrent tumor samples. Log-rank (Mantel-Cox) analysis showed that histology diagnosis, pathological stage, and MAGE-A4 expression are independent prognostic factors in NSCLC. However, no MAGE-A4 prognostic value was observed when analyzing the SCC subtype. An HLA-A*02-restricted MAGE-A4 TCR specific for MAGE-A4230-239 peptide GVYDGREHTV was identified from a pool of parental TCRs and engineered to optimize specificity and activity (MAGE-A4c1032). TCR fine specificity was assessed initially by mapping the response of the MAGE-A4c1032T-cells to panels of synthetic peptides with combinatorial substitutions at each amino acid with every other possible amino acid (X-Scan), to identify potentially cross-reactive peptides in the human and common pathogen proteomes. Secondly, MAGE-A4c1032T-cells were screened against a wide panel of normal primary cells from multiple organ systems, induced pluripotent stem cell-derived cells (iCells), and autologous whole blood to test for off-target reactivity, and against a panel of EBV-derived B-lymphoblastic cell lines expressing a wide range of HLA molecules to assess the risk of alloreactivity. Alloreactivity was observed in antigen negative cells expressing HLA-A*02:05, and therefore this allele is exclusionary. MAGE-A4c1032T-cell potency was assessed by a variety of in vitro assays, including proliferation, IFN-γ release and cytotoxicity in response to antigen-positive tumor lines in 2D and 3D culture, and cytokine release in response to freshly prepared antigen-positive primary tumor material. In conclusion, MAGE-A4 is a promising target for SPEAR T-cell therapy, and clinical trial opened this year to treat patients with inoperable or metastatic (advanced) NSCLC (SCC, adenosquamous, or large cell carcinoma), ovarian, head and neck SCC, gastric, esophageal (SCC or adenocarcinoma), urothelial tumors and melanoma (NCT03132922). Citation Format: Joana Senra, Pamela Villalobos, Barbara Mino, Luisa Solis, Carmen Behrens, Joseph P. Sanderson, Manoj Saini, Andrew B. Gerry, Nicholas J. Pumphrey, Miguel Maroto, Boris Sepesi, Patrick Hwu, David S. Hong, Elizabeht A. Mittendorf, George S. Blumenschein, Ignacio I. Wistuba, Gwendolyn Binder-Scholl, Rafael Amado. Affinity-enhanced T-cell receptor (TCR) for adoptive T-cell therapy targeting MAGE-A4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2562.

The pathological types of pancreatic carcinoma: an analysis based on US SEER database

Objective To study the component ratios of pancreatic carcinoma, and prognosis of patients with the different pathological types. Methods The data of 92 011 pancreatic carcinoma patients who were diagnosed by the definite pathological method from 2004 to 2014 were extracted from the US SEER database. The life table was used to calculate the 1-, 3- and 5-year survival rates. The Kaplan-Meier was used to construct the survival curves of the patients. The Cox univariate analysis was applied to evaluate the HR of the different pathological types, and the χ2 test and independent sample t-test were used to evaluate the baseline data. Results The overall 5-year survival of 92 011 pancreatic carcinoma patients was 7.6%. The median survival time was 8.8 months and the component ratios of the pancreatic ductal adenocarcinoma (PDAC), pancreatic epithelium cancer bedside the PDAC, neuroendocrine tumors, undifferentiated carcinoma, mesenchymal carcinoma and rare cancer unclassified were 85.78%, 6.40%, 6.67%, 0.97%, 0.10% and 0.08%, respectively. The differences were statistically significant between the baseline data such as age, gender, race and position (P<0.05). The overall 5-year survivals of the PDAC, pancreatic epithelium cancer beside the PDAC, neuroendocrine tumors, undifferentiated carcinoma, mesenchymal carcinoma and rare cancer unclassified were 4.2%, 13.4%, 49.2%, 5.0%, 29.2% and 24.5%, respectively, and the median survival times were 5 months, 7 months, 58 months, 2 months, 26 months and 7 months respectively. The distant metastasis rate of neuroendocrine carcinoma was the lowest (35.0%). The undifferentiated carcinoma was the most prone to distant metastases (65.2%). Basically, half of the other types of pancreatic cancer had metastasis at the time of diagnosis. In pancreatic epithelium cancer beside the PDAC, the high to low 5-year survival rates were solid pseudopapillary carcinoma (87.3%), cystadenocarcinoma (36.8%), intraductal papillary mucinous neoplasm (36.5%), acinar cell carcinoma (20.0%), and pancreatic adenocarcinoma mixed with other subtypes (19.7%). The incidence of the other types of pancreatic carcinoma was less than 8%, such as mucinous carcinoma, squamous cell carcinoma, adenosquamous carcinoma and signet ring cell carcinoma. In neuroendocrine tumor, the 5-year survival rate of insulinoma (77.1%) was higher than those of neuroendocrine tumor (malignant) (NET, 62.0%) and neuroendocrine carcinoma (NEC, 46.5%). Conclusion The prognosis of pancreatic carcinoma was poor, and the pathological types had a significant impact on the prognosis of the patients. Key words: Pancreatic carcinoma; Prognosis; Pathological types; Surveillance, epidemiology, and end results (SEER)

KF-finder: identification of key factors from host-microbial networks in cervical cancer

BackgroundThe human body is colonized by a vast number of microbes. Microbiota can benefit many normal life processes, but can also cause many diseases by interfering the regular metabolism and immune system. Recent studies have demonstrated that the microbial community is closely associated with various types of cell carcinoma. The search for key factors, which also refer to cancer causing agents, can provide an important clue in understanding the regulatory mechanism of microbiota in uterine cervix cancer.ResultsIn this paper, we investigated microbiota composition and gene expression data for 58 squamous and adenosquamous cell carcinoma. A host-microbial covariance network was constructed based on the 16s rRNA and gene expression data of the samples, which consists of 259 abundant microbes and 738 differentially expressed genes (DEGs). To search for risk factors from host-microbial networks, the method of bi-partite betweenness centrality (BpBC) was used to measure the risk of a given node to a certain biological process in hosts. A web-based tool KF-finder was developed, which can efficiently query and visualize the knowledge of microbiota and differentially expressed genes (DEGs) in the network.ConclusionsOur results suggest that prevotellaceade, tissierellaceae and fusobacteriaceae are the most abundant microbes in cervical carcinoma, and the microbial community in cervical cancer is less diverse than that of any other boy sites in health. A set of key risk factors anaerococcus, hydrogenophilaceae, eubacterium, PSMB10, KCNIP1 and KRT13 have been identified, which are thought to be involved in the regulation of viral response, cell cycle and epithelial cell differentiation in cervical cancer. It can be concluded that permanent changes of microbiota composition could be a major force for chromosomal instability, which subsequently enables the effect of key risk factors in cancer. All our results described in this paper can be freely accessed from our website at http://www.nwpu-bioinformatics.com/KF-finder/.

Prothymosin-α and parathymosin expression predicts poor prognosis in squamous and adenosquamous carcinomas of the gallbladder.

The present study aimed to investigate the expression patterns of prothymosin-α (PTMA) and parathymosin (PTMS) in patients with squamous cell carcinoma (SCC), adenosquamous cell carcinoma (ASC) and adenocarcinoma (AC) of the gallbladder, and to assess their association with the clinicopathological characteristics and prognosis of the patients. A retrospective analysis of data pertaining to patients with SCC/ASC (n=46) and AC (n=80) of the gallbladder, who were treated with surgical resection, was conducted. Kaplan-Meier survival analysis was also performed to assess the correlation of the expression pattern with survival. The results revealed a higher percentage of patients with a large tumor diameter (>3 cm) in the SCC/ASC group as compared with those in the AC group (P<0.05). No significant differences were observed between patients with SCC/ASC and those with AC with respect to the patient sex, presence of gallstones, TNM stage, lymph node metastasis, invasive growth into anatomically contiguous structures, surgical methods used, survival rate, and the expression levels of PTMA and PTMA (P>0.05). However, positive expression of PTMA and PTMA was associated with tumor size, TNM stage, lymph node metastasis, locally invasive growth, and treatment with radical resection in patients with SCC/ASC and AC (P<0.05). In addition, positive expression of PTMA and PTMA was observed in a significantly lower number of patients with advanced AC as compared with those in early AC (P<0.05), while these expression levels were also associated with shorter survival in the SCC/ASC group and AC group (P<0.05). Cox multivariate analysis also demonstrated a negative correlation between PTMA and PTMA levels, and the postoperative survival rate in the two groups. In conclusion, the present study indicated that the expression levels of PTMA and PTMA were closely associated with the tumorigenesis and progression of SCC, ASC and AC of the gallbladder. Positive expression of PTMA and PTMA may serve as a valuable prognostic factor in these patients.

Video-assisted thoracic surgery double sleeve lobectomy for non-small cell lung cancer: a report of seven cases

Background: Video-assisted thoracic surgery (VATS) double sleeve lobectomy has been rarely reported. We aimed to summarize the techniques and outcomes of this challenging procedure for non-small cell lung cancer (NSCLC) involving both the bronchus and pulmonary artery. Methods: From May 2012 to December 2016, seven patients were selected for VATS double sleeve lobectomy at our center, including four cases of left upper lobectomy and three cases of right upper lobectomy. Surgical procedures were performed with four ports for the first patient and three ports for the other patients. The “hollow out” process was designed for hilum dissection. The main pulmonary artery and interlobar artery were then blocked using two releasable atraumatic endoscopic Bulldog Clamps. Bronchovascular reconstruction was accomplished by the “two-needle-holder suturing technique” through directly watching a video monitor. Low-molecular heparin was subcutaneously administered during the first week after surgery. Results: The operations were uneventful. Surgical duration ranged from 250 to 480 min (median, 318 min) with blood loss between 30 to 200 mL (median, 200 mL). The average number of the dissected lymph nodes was 13 (range, 11–19). Two patients developed postoperative pneumonia with no mortalities. Prolonged air leak (>5 days) was observed in three patients. The median postoperative hospital stay was 15.5 days (range, 5–33 days). There were two cases of adenosquamous cell carcinoma and five cases of squamous cell carcinoma. One patient died of hemoptysis 50 days after surgery, and one died of metastatic lung cancer 2 years after surgery. The other five patients were alive without local recurrence at 4–58 months of follow-up. Conclusions: VATS bronchovascular double sleeve lobectomy is technically difficult but feasible for skilled thoracoscopic surgeons in experienced centers. More data are encouraged to assess the long-term outcomes of this new procedure.