bluuebunny/crossref_metadata_2025 huggingface dataset:
Complex carbohydrates as a predictive marker in metastatic colorectal cancer (mCRC) cancer patients treated with a vascular endothelial growth factor (VEGF) inhibitor and chemotherapy.
Authors: Martin Petra , Fennelly David William , Rudd Pauline , O'Donoghue Diarmuid , Sheahan Kieran , Nolan Blathnaid , O'Sullivan Jacintha , Stockmann Henning
Published: September 2018

e15134

Background: Aberrant expression of complex carbohydrates, known as glycans, is emerging as a key driver in oncopathology. Elevated levels of sialic acid sugars affect tumor growth, escape from apoptosis, metastasis formation, and resistance to therapy. Changes in sialylation can be associated with malignant transformation and with progression and poor prognosis of carcinomas, which can be explained by the recognition of malignant cells by selectins, causing interactions of tumor cells with platelets, leukocytes and endothelium facilitating metastasis. Secreted or proteolytically released carcinoma mucins bearing unusual forms of sialylation can be detected in the bloodstream and are used as diagnostic and prognostic aids. Bevacizumab directly binds VEGF (a glycoprotein) to inhibit angiogenesis. The aim of this study was to analyze the pool of asparagine-linked complex carbohydrates (i.e. the N-glycome), of whole serum to identify sugars that are associated with survival in mCRC patients treated with a VEGF and chemotherapy. Methods: We used our recently developed high-throughput automated platform to precisely measure the levels of complex serum carbohydrates in patients (n = 68) with metastatic colorectal cancer samples of patients who went on to receive bevacizumab and chemotherapy. Survival analysis was performed using the R package ‘survival’. Results: We observed several sialic-acid bearing glycans that correlated with overall survival and progression free survival. A complex tetra-antennary, highly sialylated glycan, known as A4G4S4, correlated with reduced overall survival probability (p = 0.0007, hazard ratio = 1.86). High levels of a sialylated tri-antennary glycan, called A3G3S3 demonstrated significantly reduced progression-free survival (p = 0.002). Conclusions: We believe that sialylated glycans could be excellent predictive markers of response to therapy and warrant further evaluation in clinical trials. Tri and tetra-antennary sialyated glycoproteins were associated with poorer survival in our patient cohort, suggesting that glycans could be key drivers of pathobiology.
Phosphorylated signal transducer and activator of transcription–3 (p-STAT3) expression concordance in paired primary and metastatic colorectal cancers (mCRC): Updated analysis.
Authors: Yokom Daniel , Marginean E. Celia , Jonker Derek J. , Gown Allen M. , Sud Shelly , Asmis Timothy R. , Daneshmand Manijeh , Marginean Horia , Goodwin Rachel Anne
Published: September 2018

e15137

Background: p-STAT3 is a transcription factor which is associated with poor prognosis in multiple cancers. Overexpression of p-STAT3 by immunohistochemistry (IHC) in tumors of patients with mCRC is associated with more aggressive disease and decreased survival. Concordance of p-STAT3 expression in primary and metastatic tumors was assessed to determine the temporal heterogeneity of expression and correlation with clinical outcomes. Methods: Patients with tissue available from both primary and liver metastases were identified retrospectively. Tissue microarrays (TMA) were constructed using 2 x 2mm cores. Nuclear p-STAT3 expression intensity by IHC was graded as absent, low, or high. Primary outcome was concordance of p-STAT3 expression between primary and metastatic sites. Secondary outcome was correlation of p-STAT3 expression with disease outcomes. Results: 91 patients were identified: 55% were male, median age at diagnosis was 63, 60% had left-sided disease and 81% of metastases were synchronous. Expression of p-STAT3 in primary tumors was 23% high, 47% low and absent in 30% compared to 29% high, 50% low, and 21% absent in metastases. Concordant expression was observed in 23% of patients whereas it increased in 46% and decreased in 31% from primary to metastasis. Pearson’s correlation was 0.119 indicating a weak concordance. After a median follow-up of 7 years, 50 of 91 patients died. One-year and 5-year survival rates were 92% and 44% respectively, while the median overall survival (mOS) was 4.7 years [95%CI 3.1-6.4]. No significant prognostic correlation between primary or metastatic p-STAT3 expression and mOS was found. Conclusions: There was low concordance of p-STAT3 expression in primary and metastatic tumors of patients with mCRC. Tumor staining heterogeneity due to sampling of small cores included in TMA and predominance of synchronous metastases may play a role. Further research in the use of p-STAT3 as a biomarker in patients with mCRC is needed.
Molecular characterization of TP53 mutations and copy number change in colorectal cancers.
Authors: Nusrat Maliha , Manyam Ganiraju C. , Loree Jonathan M. , Lam Michael , Overman Michael J. , Maru Dipen M. , Routbort Mark , Morris Jeffrey , Kopetz Scott
Published: September 2018

e15143

Background: TP53 mutations (mut) are prevalent in colorectal cancer (CRC) patients (pts) and can result in oncogenic gain of function effect as well as loss of tumor suppressor function depending on the mut. Methods: The Cancer Genome Atlas (TCGA) data of 220 CRC pts with tumors sequenced and gene copy numbers (CN) annotated was obtained. Pts with CMS subtype data also available were included (n = 167). Chi square test was used to compare frequency of TP53 mut and CN change among CMS subtypes. TP53 mRNA and protein levels were compared by TP53 mut and CN change using independent sample t test. Results: 86 (51.5%) pts were TP53 mutant, with 35.3% missense and 16.2% loss of function (LOF) mut. LOF mut included 14 non-sense and 13 frameshift mut, and occurred mostly in codons 213 and 306. Missense mut mostly affected codons 175, 248 and 273 in 10, 9 and 8 pts respectively. TP53 mut were most frequent in CMS2 and CMS4 subtypes (62.7 and 62.5% respectively). TP53 mut in CMS2 were mostly missense and CMS 4 pts mostly had LOF mut. TP53 CN loss was seen in 74.7% CMS 2, 68.8% CMS 4, 43.5% CMS 3 and 6.9% CMS1 pts. 84.9% pts with TP53 mut had CN loss vs 28.4% of wild type pts (p < 0.001). Frequency of TP53 CN loss did not vary significantly by type of TP53 mut. Pts with TP53 missense mut had higher p53 mRNA and protein levels than those with LOF mut. Pts with TP53 CN loss had lower mRNA levels but no change in protein levels than those with normal CN. Conclusions: The higher TP53 mRNA and protein levels with missense mut suggest possible gain of function. Research on interactions of TP53 change with wnt, myc, and TGF beta pathway genes may reveal synthetic lethal treatment combinations. [Table: see text]
Prognostic impact of tumour laterality in early-stage colon cancer: A population-based study.
Authors: Karim Safiya , Brennan Kelly , Nanji Sulaiman , Berry Scott R. , Booth Christopher M.
Published: September 2018

e15148

Background: Recent data has suggested that disease biology and outcome of colon cancer may differ between right-sided and left-sided tumours. Here we explore differences in laterality based on disease characteristics and outcomes in a population-based cohort of early-stage colon cancer. Methods: Electronic records of treatment were linked to the Ontario Cancer Registry to identify all patients with colon cancer in 2002-2008. The study population included a 25% random sample of all patients with resected stage 0-III disease. Right-sided colon cancer was defined as any tumor arising in the cecum, ascending colon, hepatic flexure or transverse colon. Left-sided colon cancer was defined as any tumor arising from the splenic flexure, descending colon, sigmoid colon or rectosigmoid colon. Log binomial regression was used to identify factors associated with laterality. Cox models were used to explore the association between laterality and overall (OS) and cancer-specific (CSS) survival. Results: Among the study cohort (n = 6391) median age was 72 and 52% (3307/6391) had right-sided disease. Stage distribution was 2% (98/6391) stage 0, 17% (1091/6391) stage I, 38% (2446/6391) stage II, and 43% (2756/6391) stage III. Patients with right-sided colon cancer were more likely to be older (p < 0.001), female (p < 0.001) and have greater co-morbidity (p = 0.001). Right-sided cancer was more likely to be T4 (19% vs 16%, p = 0.001) and poorly differentiated (21% vs 10%, p < 0.001) but less likely to be node positive (42% vs 45%, p = 0.029) compared to left-sided disease. In adjusted analyses there was no difference in long-term survival for right-sided compared to left-sided colon cancer: OS HR 1.00 (95%CI, 0.92-1.08); CSS HR 1.00 (0.91-1.10). These results were consistent when the survival analyses were restricted to stage III disease: OS HR 1.03 (95%CI 0.93-1.14); CSS HR 1.10 (0.97-1.24). Conclusions: In this population-based cohort of early-stage resected colon cancer disease laterality was not associated with long-term survival.
Initial safety results from a randomized, phase II study of high-risk colorectal cancer patients (stage IIIC) treated with either regorafenib or standard of care (no treatment) after adjuvant FOLFOX.
Authors: Cartwright Thomas H. , Nguyen Thu-Cuc , Cohn Allen Lee , Richards Donald A.
Published: September 2018

e15152

Background: Standard adjuvant therapy for colorectal cancer (CRC) is fluoropyrimidine or FOLFOX. The stage IIIC relapse rate is high with a median 5 year survival of only 28%. The multi-kinase inhibitor regorafenib has shown significantly improved overall survival (OS) versus placebo in 3rd-line+ metastatic CRC patients (pts) in 2 phase III trials. We explore whether adding regorafenib to standard adjuvant therapy is able to reduce the high relapse rates in stage IIIC CRC pts. Methods: This study compares efficacy and safety of adjuvant FOLFOX +/- 6 cycles of regorafenib in IIIC CRC pts. Study endpoints include: finding the starting dose of regorafenib that allows ≥75% pts to complete therapy after adjuvant FOLFOX. The first 50 pts are being randomly assigned to either 120 or 160 mg of regorafenib daily for 3 weeks followed by 1 week of rest for a total of 6 cycles. We report the initial safety results on the first 24 pts treated. 6 pts discontinued treatment; 2 received 120 mg and 4 received 160 mg Results: Of the pts completing 6 cycles of regorafenib 120 mg vs 160 mg, the most common grade 3 toxicities were hypertension (0 vs. 30%), rash (10 vs.30%), and lipase elevation (0 vs 10%). No grade 4 or 5 toxicities were observed. Conclusions: The interim analysis reveals no increased toxicities from the addition of regorafenib at either 120 mg or the approved dose (160 mg), to adjuvant FOLFOX. Toxicities observed were mostly grade 1 or 2 and medically manageable. No safety signals have been identified. This study continues to enroll pts. Clinical trial information: NCT02425683.
Early postoperative PET-CT in patients with pathological stage III colon cancer may change their outcome: Results from a large single-institution study.
Authors: Moore Assaf , Ben-Aharon Irit , Purim Ofer , Perl Gali , Ulitsky Olga , Amit Limor , Kundel Yulia , Lewin Ron , Wasserberg Nir , Kashtan Hanoch , Brenner Baruch
Published: September 2018

e15163

Background: Staging of patients (pts) with pathological stage III colon cancer (CC) is currently suboptimal; many pts still recur despite an unremarkable preoperative staging. We previously reported that early postoperative PET-CT can alter the stage and management of up to 15% of pts with high risk stage III CC and later reported also encouraging preliminary results in a larger cohort of consecutive pts with stage III CC, in which staging and management were altered in 14.5%. The aim of the current study was to expand the previous one to a larger cohort and to evaluate the actual impact of early postoperative PET-CT on pts outcome. Methods: A Retrospective study of all consecutive pts with stage III CC who were treated at our institution and underwent early postoperative PET-CT between 2007-2016. Demographic and clinicopathological data were retrieved. Statistical analyses were done using standard methods. Results: 348 pts, 166 (47.7%) males, with a median age of 66 years (range, 29-92), were included. Pathological stage was IIIA, IIIB and IIIC in 21(6%), 254 (73%) and 73 (21%) pts, respectively. The median number of lymph nodes examined and of positive ones were 14 (range, 3-54) and 2 (range, 0-32), respectively. High FDG-uptake was noted in 95 (27.3%) pts, including 23 (6.6%) with clear postoperative changes and 18 (5.2%) with a false positive uptake, of whom 6 underwent invasive diagnostic procedures. PET-CT results modified the management of 52 pts (14.9%) who were found to have true positive findings: 44 (12.6%) with overt metastatic disease and 8 (2.3%) with a second primary tumor. At a median follow-up of 45.6 months, the estimated 5y disease-free survival for true stage III pts was 81.9% and the 6y overall survival of the entire cohort was 76.4%. Interestingly, of the 44 pts found to be metastatic, 12 (27.3%) underwent curative treatments and 8 (66.7%) of those remain free of disease, with a median follow-up of 64.7 months. Conclusions: In this large cohort, early postoperative PET-CT changed the staging and management of 14.9% of pts with resected stage III CC, with encouraging outcome results. We are conducting a prospective trial to further evaluate this strategy.
Utilization of KRAS mutation status testing in stage IV colorectal cancer (CRC) patients in the United States: National Cancer Data Base (NCDB) analysis.
Authors: Orucevic Amila , Bennett Natalie , Gray Keith D , Bell John Lawrence , Robert Heidel
Published: September 2018

e15172

Background: KRAS mutation status is considered a predictive biomarker of personalized treatment in advanced stage CRC. Its testing is recommended by the National Comprehensive Cancer Network guidelines for stage IV CRC, since it determines the benefit of addition of anti-epidermal growth factor receptor therapy in wild-type KRAS CRC. Data on utilization of the test in the clinical practice across the US are lacking. Methods: Utilization of KRAS testing across the US is presented in a retrospective observational study of NCDB patients (pts) from 2010-2014. Demographics of stage IV CRC pts with recorded KRAS results were analyzed using frequency statistics and logistic regression analysis. Results: 479399 pts had CRC, 93514 (19.5%) were stage IV. 57208/93514 pts with known KRAS testing status entered our study. Mean age was 63.3 years; 51.2% were males. Only 33% (18867/57208) of stage IV CRC pts underwent KRAS testing. Testing was significantly ( p<.001) influenced by pts age and socioeconomic status but not by race or facility type in which pts were treated (Table 1 - see adjusted odds ratio [AOR] and 95% CI). Conclusions: KRAS testing of stage IV CRC pts is underutilized in the US. Impact of its underutilization on outcomes of these pts requires further study. [Table: see text]
An observational study of patients with HER2-positive metastatic gastric cancer treated with trastuzumab: Single center experience.
Authors: Basal Fatma Bugdaycı , Demirci Umut , Aslan Ferit , Yazici Ozan , Oksuzoglu Berna
Published: September 2018

e15500

Background: In this study, during a 54-month follow-up period, we presented clinicopathological features and survival results of patients treated with trastuzumab. Methods: We retrospectively analyzed the efficacy of trastuzumab-based chemotherapy in 21 patients with HER2-positive gastric cancer between January 2012 and July 2016. Results: Eighteen (86%) patients were male with a median age of 61 (34-80) years. One of the patients was stage 2, 2 were stage 3 and 18 were stage 4, at the time of diagnosis. From 21 tumours, 11 (52%) were located in the cardia, 5 (23%) in the antrum and 5 (23%) in the corpus. In the histopathological examination, 18 (86%) cases were adenocarcinoma and 3 (14%) were signet-ring cell. Seven of the patients with metastatic disease were operated (total/subtotal gastrectomi). The most common metastatic sites were liver (%86), lung(%33), distant lymph node(%23), and periton(%14). Trastuzumab was administered in combination with chemotherapy as first-line treatment and beyond progression as a secondline, and third-line treatment in 18, 2, and 1 patients, respectively. When tumour response was assessed after three cycles of chemotherapy, one complete response (5%),4 partial response (19%),12 stabil disease (57%) were observed, and 4 (19%) patients had progressive disease. Clinical benefit rate was 81%. The maintenance treatment of trastuzumab was applied to 10 patients (47%). At a median follow-up of 17.8 (5-38) months, median progression-free survival was 12.8 months (3-31) and overall survival 18.6 months (3-91). Conclusions: Proximal gastric carcinomas with intestinal phenotype are found to have a higher expression of HER2-gene (range 8-34%) than distal diffuse gastric carcinomas (range 1-7%). The present results are similar to those of the ToGA study in terms of overall survival and response rate.
Nutritional status and quality of life in patients with gastric cancer in China.
Authors: Li Hongli , Ge Shaohua , Ba Yi
Published: September 2018

e15508

Background: The incidence of gastric cancer is much higher in China than in any other country. Although the overall survival rate of patients with gastric cancer has increased due to the advancements in multimodality management. However, significant morbidity, including loss of appetite, dysphagia, nausea, and vomiting is still associated with gastric cancer patients. These symptoms have a profound impact on nutritional status and quality of life in these patients. The primary objective of the present study was to assess the nutritional status and quality of life in gastric cancer patients. Methods: A preliminary assessment of patients’ nutritional status, quality of life, and medical characteristics was conducted using the Patient Generated Subjective Global Assessment (PG-SGA) and the European Organization for Research and Treatment of Cancer quality of life (QOL-C30, version 3) questionnaires. The PG-SGA is a clinical nutrition assessment tool used to evaluate oncology patients. The nutritional status of the patients fell into three groups by a score of PG-SGA-A, -B, and C. Results: A preliminary assessment of patients’ nutritional status, quality of life, and medical characteristics was conducted using the Patient Generated Subjective Global Assessment (PG-SGA) and the European Organization for Research and Treatment of Cancer quality of life (QOL-C30, version 3) questionnaires. The PG-SGA is a clinical nutrition assessment tool used to evaluate oncology patients. The nutritional status of the patients fell into three groups by a score of PG-SGA-A, -B, and C. Conclusions: These results suggest that the nutritional status of the patients with stomach cancer may impact on their QoL. It is necessary to develop nutritional intervention to improve QoL in gastric cancer patients.
Glutathione system to characterize the biological aggressiveness of the gastric cancer.
Authors: Shalashnaya Elena V. , Goroshinskaya Irina A. , Surikova Ekaterina Igorevna , Medvedeva Dar'ja E. , Kachesova Polina S. , Nemashkalova Ludmila A. , Neskubina Irina Valerevna , Maslov Andrey A. , Kit Oleg I.
Published: September 2018

e15512

Background: The aim was a comparative study of glutathione system of tumor and its peritumoral tissues at gastric signet ring cell carcinoma (SRCC) and gastric adenocarcinoma (AC) to identify pathogenetic features of malignancy. Methods: Content of reduced glutathione (GSH) and the activity of glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione transferase (GST) were determined in the samples of tumor and peritumoral tissues, obtained during the surgery in 21 primary patients: 13 patients with SRCC, 8 patients with AC (G2-G3) without preoperative therapy. Tissue of intact stomach was studied in 12 randomly bereaved. Results: In the AC tumor tissue the GSH level was decreased by 43% and the activity of GPx and the GST was increased by 121.7% and 44.3% (p < 0.05–p < 0.001) compared with intact stomach. In peritumoral tissue both the level of GSH and GPX activity were less than in the tumor tissue at 40-45% (p < 0.05–p < 0.01). In SRCC both the GSH level and the activity of GPx and GST were increased in tumor tissue by 78%, 93.6% and 49.5% (p < 0.05–p < 0.001) compared with the intact stomach. In peritumoral tissue the GSH level was lower than in the tumor tissue by 60.2% (p < 0.01), the enzymes activity was unchanged remaining higher than in the intact stomach. The GSH level both in tumor and in peritumoral tissues was 2-3 folds higher in gastric SRCC than in AC. No significant differences in the activity of glutathione-dependent enzymes in tumors of different histotype were revealed. Conclusions: The results show the differences in the functioning of the glutathione system, depending on the histological type of gastric tumors. It is possible that greater activity of glutathione-dependent system in tissue of SRCC is needed to maintain its increased proliferative activity and determines the features of the biological behavior of this tumor histotype.
Radiation esophageal stent.
Authors: Herskovic Arnold M. , Rivard Mark , Rothstein Richard I , Hussein Zella , Saunders Jennifer , Corcoran Kathleen , Clerc Claude , Favreau John
Published: September 2018

e15514

Baclground:Self-expanding metal stents (SEMS) produce palliative dysphagia relief for esophageal cancers (EC) which is enhanced by brachytherapy. We present a brachytherapy stent designed to deliver radiation to ECs with brachytherapy sources in the porcine esophagus. Methods: A radioactive carrier stent containing I 125 seeds was designed to deliver 60 Gy to 5mm depth over 2 months. One dummy,non-radioactive seeds, and 3 radioactive stents were implanted into the esophagus of Yucatan minipigs. Stents were left in place for up to 43 days after implant, and one pig survived 10 weeks after stent removal. Animals were monitored biweekly via endoscopy and fluoroscopic imaging throughout the study collecting tissue at necropsy. Results: Swine esophageal tissue received doses ranging from 39-48 Gy at the prescription depth of 5mm and 132-160 Gy at the mucosal surface. Tissues were assessed pathologically at 0, 1, and 10 weeks after stent removall. Endoscopic assessment of all irradiated animals found increasingly pronounced and permanent infolding of the proximal stent flare over time, eventually resulting in early stent removal. At stent removal, all animals had numerous benign mucosal polyps ( < 5mm) at both stent flares which mostly resolved. within 6 weeks of removal, At gross necropsy, small amounts of necrotic tissue as well as mucosal polyps were observed along the entire length of the tissue adjacent to the radioactive stent (mostly adjacent to the stent flares). No systemic effects related to radiation were observed. Conclusions: We demonstrated that brachytherapy stent delivery is feasible and reasonably safe for irradiated healthy tissue. Although irradiation > 130 Gy affected the mucosal tissue, stent-related injury appeared to cause more substantial damage to the tissue. Both experimental and control animals showed the most marked tissue reaction at the non radiative stent flares. Tissue reactions along the stent body were consistent with stent related tissue erosion possibly enhanced by radiation exposure, . One animal, assessed up to 10 weeks after stent removal showed nearly complete healing of the esophageal tissue. Future studies will assess safety in a larger cohort of animals with escalated RT doses and different radionuclides.
Study of microflora in stomach cancer and gastritis.
Authors: Zykova Tatiana , Kit Oleg Ivanovich , Gevorkyan Yuri , Legostaev Vladislav , Bogomolova Olga A.
Published: September 2018

e15516

Background: The purpose of the study was to compare the rates of bacterial and fungal colonization of the mucosa in stomach cancer and gastritis. Methods: 59 tumor and healthy tissue samples in stomach cancer and 33 stomach mucosa bioptates in gastritis were studied. DNAs were extracted by the adsorption method. DNAs of Enterobacteriaceae, Staphylococcus spp., Streptococcus spp., Candida spp., Bacteroides spp. were determined by real-time PCR. Results: 40.0% of 30 patients with stomach cancer had adenocarcinoma, 13.3% – signet ring cell carcinoma, 6.7% – undifferentiated cancer, 6.7% – NHL, 3.3% – squamous cell carcinoma, 6.7% – combined signet ring cell carcinoma and neuroendocrine or undifferentiated cancer, 23.3% – combined adenocarcinoma and neuroendocrine, signet ring cell or undifferentiated cancer. The comparison group included 33 patients with morphologically verified superficial gastritis. DNA of Bacteroides spp. was found in tumor and healthy tissues of 80.0% of cancer patients; it was not found in gastritis. DNA of B. fragilis was found in all tumor tissue samples, BFT – in 8.3% of them. The mean amount of Enterobacteriaceae in tumor tissue was 6.7x105 copy/ml, in healthy tissue – 7.0x105 copy/ml, in bioptates in gastritis – 4.0х102 copy/ml; Staphylococcus spp. – 3.4х102 copy/ml, 2.6х102 copy/ml and 8.7х101 copy/ml, Streptococcus spp. – 9.1х105 copy/ml, 1.3х105 copy/ml and 5.1х103 copy/ml, respectively. Thus, the amount of Enterobacteriaceae in tumor tissue in stomach cancer exceeded the value in gastritis by 1675 times, Staphylococcus spp. – by 3.9 times, Streptococcus spp. – by 178 times. Genes of resistance to the penicillin class TEM were found in 50.0% of patients with stomach cancer and in 8.7% of patients with gastritis. DNAs of Candida spp. in stomach cancer were found in 40% of patients in tumor tissue and in 31.0% in healthy tissue, in gastritis – in 8.3% of patients. Conclusions: Enterobacteriaceae and Streptococcus spp., mostly combined, dominate among microflora colonizing gastric mucosa in stomach cancer. The established differences in microbiocenosis in stomach cancer in comparison with gastritis suggest the possible involvement of aerobic and anaerobic microflora in the process of malignant transformation.
A preoperative nomogram for tumor regression grade following induction chemotherapy for esophageal squamous cell carcinoma.
Authors: Kang Xiaozheng , Dai Liang , Yan Wanpu , Yang Yongbo , Zhou Haitao , Fu Hao , Yang Heli , Fan Mengying , Lin Yao , Liang Zhen , Xiong Hongchao , Chen Ke-Neng
Published: September 2018

e15525

Background: To (1) evaluate the continuous distribution of tumor regression grade (TRG) in resection specimens after induction chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC), (2) determine the effects of TRG on survival after esophagectomy, and (3) identify preoperative predictors of TRG. Methods: From June 2001 to October 2012, 212 patients underwent induction chemotherapy followed by esophagectomy for locally advanced ESCC. TRG, assessed as the percentage of residual primary ESCC cells in resection specimens, was classified histologically by pathologists. Random Forest technology was used for data analysis. A nomogram was developed allowing prediction of TRG through use of preoperative clinical factors for patients with clinically locally advanced ESCC who are candidates for treatment with a radical esophagectomy. Results: Twenty-four specimens (11%) had no residual primary cancer (ypT0), 39 (18%) had 1% to 10% residual cancer, 48 (23%) had 11% to 50%, 101 (48%) had more than 50%. Survival was worse with increasing residual primary ESCC, plateauing at 50%. Poorer TRG was associated with worse 3-year overall survival. Better pathologic grade (G), larger number of pack year smoking, fewer cycles of induction chemotherapy, lower level of creatinine, younger age, greater tumor length and clinical T stage were associated with poorer TRG. Conclusions: Better TRG in response to preoperative chemotherapy is associated with a linear increase in survival after esophagectomy for locally advanced ESCC. A nomogram has been developed that can be used to predict TRG. Therefore, for patients with poorer TRG, the role of adjuvant therapy needs to be further assessed in an attempt to improve survival.
Is third-line chemotherapy routine practice in recurrent or metastatic gastric cancer?
Authors: Lee Hyun Woo , Choi Yong Won , Ahn Mi Sun , Kang Seok Yun , Choi Jin-Hyuk
Published: September 2018

e15558

Background: Patients (pts) with recurrent or metastatic gastric cancer eventually experience disease progression during or after completion of first-line chemotherapy. Second-line therapy is generally recommended in the current guidelines. Although third-line therapy is often performed in daily practice in some countries, there are few reports about the benefit of third-line therapy. Methods: A retrospective review was conducted on 683 pts who underwent at least first-line palliative chemotherapy for recurrent (n = 297) or primary metastatic (n = 386) gastric cancer. Clinicopathological characteristics and overall survival (OS) were analyzed according to the lines of chemotherapy as well as for all study pts. Results: One hundred and forty-nine pts (21.8%) underwent third- or further-line therapy. Third- or further-line therapy was more frequently performed in pts with young age ( < 70) (p < 0.0001), ECOG PS 0 or 1 (p < 0.0001) at the initiation of first-line therapy, first-line combination regimen (p = 0.006), and palliative surgical resection before first-line therapy (p = 0.029). The median follow-up duration was 62 months (24-151 months) for the survivors. The median OS for pts after first- and third-line therapy was 10 and 6 months, respectively. The median OS of pts who received third-line therapy was significantly longer than that of pts who received second- or lesser-line therapy (18 vs. 8 months, p < 0.0001). Multivariate analysis revealed that third- or further-line therapy was independently associated with favorable OS (hazard ratio = 0.56, p < 0.0001) along with surgical resection (p < 0.0001) and first-line combination regimen (p = 0.008), whereas signet ring cell histology (p = 0.002) and peritoneal metastasis (p = 0.027) were independent prognostic factors of poor OS. Conclusions: This study suggests that recurrent or metastatic gastric cancer pts may benefit from third-line chemotherapy, although careful selection is essential.
Esophageal cancer in elderly patients: A population-based study.
Authors: Zeng Yuan , Liang Wenhua , He Jianxing
Published: September 2018

e15561

Background: As the aging issue and increased elderly esophageal cancer (EC) patients, we sought to study the clinical characteristics, treatment modality and outcomes of EC patients 70 years or older compared with those younger than 70 years old. Methods: The national Surveillance, Epidemiology, and End Results (SEER) database for the period from 1973 to 2013 was analyzed. The patient and treatment characteristics were compared between the age groups. Multivariate Cox proportional hazard regression analyses were also performed to identify independent prognostic factors. Propensity-score matching analyses (PSA) regarding survival after different treatments were also performed in locoregional EC . Results: Of 61,799 eligible patients, 24,046 patients (38.9%) were 70 years or older and 37,753 patients (61.1%) were younger than 70 years. Compared with the younger group, patients 70 years or older were characterized by having a higher proportion of patients with female gender, white race, localized disease, non-ademocarcinoma and without any treatment, as well as inferior overall survival (HR, 1.324) and EC-specific survival (HR, 1.270). In addition, older patients shared same independent prognostic factors with younger patients, including age, histology and race. Specifically, compared with those receiving no intensive treatments, surgery alone (HR, 0.342), both surgery and RT (HR, 0.323) and RT only (HR, 0.525) were favorable among elderly patients, as confirmed by both multivariate adjustment and PSA. Conclusions: Compared to younger EC patients, those 70 years or older showed distinctive clinical characteristics and inferior survival. Despite showing a higher proportion of localized disease, patients 70 years or older were less likely to be subjected to surgery or/and RT. Thus, the role of intensive treatments, which were identified as favorable factors among elderly patients in this study, warrants further investigation.
The potential prognostic value of expression of stem cell marker of CD44s, EpCAM, and OVA66 in patients with gastric adenocarcinoma.
Authors: Yan Ning , Xu Ying chun , Zhang Fengchun , Chen Siyu
Published: September 2018

e15562

Background: The present study aimed to (i) examine the expression pattern of putative stem cell markers, CD44s, EpCAM, and new tumor specific antigen OVA66, in gastric adenocarcinoma (GA) and normal para-cancer tissues; (ii) determine if the expression of these proteins is associated with overall survival of GA. Methods: 84 GA patients confirmed by histopathology were examined the expressions of CD44s, EpCAM and OVA66 using tissue microarray technique. The immunohistochemistry analysis were carried out to explore the differential expression CD44s , EpCAM and OVA66 in GA compared to normal para-cancer tissues (p = 0.001). Next, Kaplan-Meier analysis was conducted to investigate their effect in overall survival(OS). Results: The immunohistochemistry analysis demonstrated the differential expression CD44s and EpCAM in GA compared to normal para-cancer tissues (p = 0.001), while there was no significant difference of OVA66 expression between cancer and normal specimens (p = 0.366). The upregulated expression of CD44s was well correlated with lymph node metastasis (p = 0.018), however the expression of OVA66 was only associated with gender of the patients (p = 0.025) and age at presentation (p = 0.018). The univariate analysis demonstrated that patients with blood and lymphatic vessel invasion, pT category 3 to 4, pN positive, with faraway metastasis, and stage Ⅲ to Ⅳ had a significantly shorter OS. Both increased expressions of the CD44s and EpCAM was shown in patients with poor OS (p = 0.037) and was confirmed by multivariate analysis. Conclusions: Our study suggested EpCAM is a potential diagnostic marker for gastric cancer and combined with CD44+/EpCAM+ can be regarded as an independent prognostic marker for patients with GA.
PDL-1 and immunohistochemistry markers in esophageal adenocarcinoma.
Authors: Jaroszewski Dawn E. , Xiu Joanne , Gatalica Zoran , Beamer Staci , Stanton Melissa , Pai Rish , Krishna Murli , Thomas Mathew , Ross Helen J. , Ho Thai Huu
Published: September 2018

e15567

Background: Esophageal adenocarcinoma (EAC) prognosis is poor and there is a need to identify patients that benefit most from neoadjuvant therapy. To examine the association of various biomarkers with clinical outcomes in neoadjuvant treatment of EAC, we retrospectively evaluated the biomarker expression (TS, ERCC1, TOPO1, PD-L1, PD-1) in patient matched formalin-fixed paraffin-embedded (FFPE) tumor samples. Methods: Immunohistochemistry of TS (TS106/4H4B1) , ERCC1 (Ab. 8F1), TOPO1 (1D6), PD-L1 (both 22c3 and SP142), PD-1 (NAT105), and chromogenic in-situ hybridization (CISH) of Her2 were performed on FFPE samples from 35 patients across 2 institutions at time of EAC diagnosis and after treatment when available. Retrospective clinical data and survival (5/2006-1/2016) was analyzed with a mean follow up of 110 months (range 22-306). Results: Overexpression (pre/post-treatment) of TS (60%/54%), ERCC1 (69%/16%), TOPO1 (74%/50%), PD-1 (54%/63%), PD-L1 (SP142) (2.9%/4%), PD-L1 (22c3) (0%/4%) and amplification of Her2 (18%/23%) were observed. Pretreatment observed PD-L1 levels were lower in our study (3%) when compared to other studies in EAC specimens (35%). Immunohistochemistry and changes observed after chemoradiation are reviewed in Table. No markers had significant correlation with prognosis however TS negative expression showed a non-significant (p=0.15) trend towards improved survival. Conclusions: Analyzing biomarkers in our neoadjuvant EAC cohort demonstrated a lower than expected PD-L1 positivity. In the largest cohort, to our knowledge, of patient matched FFPE tumor samples, we did not observe a statistically significant association between TS, ERCC1, TOPO1, PD-L1, or PD-1 with improved clinical outcomes. [Table: see text]
How to improve the lymph node detection and staging accuracy in gastric cancer patients: A randomized controlled trial in single center.
Authors: Yao Zengwu , Jiang Lixin
Published: September 2018

e15577

Background: To evaluate the effects of carbon nanoparticles by subserosa injection and different Lymph node retrievals by surgeon or pathologist in improving the positive and total lymph node detection and staging accuracy in patients who undergone the standard D2 gastrectomy. Methods: We collected 200 gastric cancer patients who undergone the standard D2 radical lymph node resection gastrectomy from November 2013 to November 2014 in Gastrointestinal Surgery Ward of Yantai Yuhuangding Hospital. The cases were randomly devidided into 4 groups (N = 50): Pathologist group(PA), surgeon group(SU), surgeon plus carbon nanoparticles group(SU+CN), pathologist plus carbon nanoparticles group (PA+CN) . The number of lymph nodes and the proportion of TNM stages were calculated respectively. Results: In the positive and total number of lymph nodes in all cases, it is significantly higher in Group SU than Group PA (3.64±4.32 VS 2.63±3.45),( 25.46±5.24 VS 20.23±6.32),Group SU+CN than Group PA (4.56±3.86 VS 2.63±3.45 ),(30.76±8.42 VS 20.23±6.32), Group PA+CN than Group PA(3.83±2.09 VS 2.63±3.45),(24.98±6.01 VS 20.23±6.32), Group SU+CN than Group SU(4.56±3.86 VS 2.63±3.45),(30.76±8.42 VS 25.46±5.24), Group SU+CN than Group PA+CN(4.56±3.86 VS 3.83±2.09),( 30.76±8.42 VS 24.98±6.01) (P < 0.05). The proportion of each TNM stage is significantly different in Group SU VS Group PA, Group SU+CN VS Group PA, Group PA+CN VS Group PA, Group SU+CN VS Group SU, Group SU+CN VS Group PA+CN(P < 0.05), while it is similar in Group PA+CN VS Group SU(P < 0.05). The highest proportion of Stage I and II and the lowest proportion of Stage III is in Group PA, and in Group SU+CN by contrary. Multivariate analysis shows carbon nanoparticles by subserosa injection and lymph node retrievals by surgeon are independent factors. Conclusions: Carbon nanoparticles by subserosa injection and lymph node retrievals by surgeon could be used as independent factors to improve the number of positive and total lymph nodes in standard D2 radical lymph node resection gastrectomy. It may also improve the accuracy of pathological staging of gastric cancer patients. Clinical trial information: ChiCTR-TRC-14876411.
Molecular profiling-guided therapy in gastroesophageal carcinoma: A single-institution experience.
Authors: Kankeu Fonkoua Lionel Aurelien , Liao Jason , Yee Nelson S.
Published: September 2018

e15582

Background: Gastroesophageal carcinoma (GEC) including carcinoma of stomach (GC), gastroesophageal junction (GEJ), and esophagus (EC) is the 2nd leading cause of cancer death worldwide. Chemotherapy and HER2-targeted therapy (trastuzumab) have shown limited efficacy. We aim to assess the impact of molecular profile (MP)-guided therapy (MPgt) by correlating expression of select biomarkers in GEC patients (pts) with survival. Methods: 27 GEC (11 GC, 9 GEJ, 7 EC) submitted to Caris Life Sciences for molecular profiling between 2011 and 2016 were analyzed and correlated with pt survival. The impact of MPgt was assessed by calculating the ratio of progression-free survival (PFS) on MPgt to PFS on the preceding empiric therapy. MPgt was deemed beneficial if PFS ratio ≥1.3. Results: In-situ hybridization indicated amplification of HER2 (15.4%) and c-MET (7.4%). Immunohistochemistry revealed increased expression of TOPO1 (57.7%), TOP2A (38.5%), HER2 (15.4%) and c-MET (6.9%), as well as decreased expression of TS (69.2%), ERCC1 (42.3%), and PGP (15.4%). These data suggest sensitivity to topoisomerase inhibitors, anthracyclines, trastuzumab, MET-targeted therapy, fluoropyrimidine, platinums, and taxanes, respectively. Expression of these markers was heterogeneous among pts, and a trend toward improved PFS was noted in pts with low/absent ERCC1 expression on platinum-based therapy ( P= 0.06). Of the 13 pts who had sufficient data to assess the benefit of MPgt, 5 (38%) achieved a PFS ratio ≥1.3. One pt with metastatic HER2-amplified EC who had initially demonstrated clinical benefit from trastuzumab-containing chemotherapy, developed a new HER2 and c-MET co-amplified lung metastasis. Conclusions: While MPgt was beneficial in 38% of pts, tumor-associated plasticity, clonal evolution, and adaptive resistance may have limited efficacy. The emergence of HER2 and c-MET co-amplified clones is a potential resistance mechanism in HER2-amplified GEC, and highlights combined inhibition of receptor tyrosine kinases as a therapeutic strategy. Further studies with expanded data sets will be needed to test the hypothesis that actionable targets can be used independently to predict treatment response in GEC pts.
Association of epithelial-mesenchymal transition with an immunosuppressive tumor microenvironment with elevated levels of PD-L1 in esophageal carcinoma.
Authors: Oki Eiji , Saeki Hiroshi , Tsutsumi Satoshi , Nakashima Yuichiro , Nakanishi Ryota , Sugiyama Masahiko , Kurashige Junji , Ando Koji , Oda Yoshinao , Maehara Yoshihiko
Published: September 2018

e15585

Background: Programmed death-ligand 1 (PD-L1) plays a crucial role in the host immune system in cancer progression and is has become a new target for cancer therapy. PD-L1 gene promoter region contains a binding site of ZEB1, a transcription factor related to epithelial-mesenchymal transition (EMT). The purpose of this study is to clarify relationships between PD-L1, EMT and its clinical importance in esophageal squamous cell carcinoma (ESCC). Methods: We conducted preclinical studies using cell lines and clinical specimens. ZEB1, PD-L1 expression in TE8 cell line, demonstrating EMT phenotype, was determined following ZEB1 knockdown by siZEB1. TE5, 6 and 11 cell lines with non-EMT phenotype were also used for studies of TGF-β1-dependent EMT induction and ZEB1, PD-L1 expression. PD-L1 and ZEB1 expression at the tumor invasive front was examined in resected specimens from 90 patients with ESCC who underwent surgery without preoperative therapy by immunohistochemistry and their expression and clinicopathological factors were compared. Results: A correlation was observed between PD-L1 and ZEB1 expression. In TE8 cells which express EMT character , siZEB1 suppressed PD-L1 and promoted E-cadherin mRNA and protein expression. In TE5, 6 and 11 cell lines which are not EMT phenotype, TGF-β1 induced EMT and surface expression of PD-L1. In cases of high PD-L1 expression at invasive front, greater depth of tumor invasion, EMT, less CD8 expression were significantly observed. High PD-L1 expression was also associated with worse overall and relapse-free survival. Conclusions: PD-L1 expression at the invasive front was related to ZEB1 expression, EMT and poor prognosis in ESCC. We suggest that cooperative mechanism between tumor immune avoidance and EMT contributes to tumor malignancy. Whether or not ZEB1-PD-L1 signal pathway could be a target in treatment for ESCC requires further investigations.
Comparison of demographic variables related to 30-day readmission in cancers with similar risk factors: Analysis of 290,270 hospitalizations.
Authors: Sivsammye Suceil , Kailasam Karthik
Published: September 2018

e15596

Background: There has been increasing focus on reducing hospital readmissions which are an ongoing economic challenge. This study was targeted at cancer of the esophagus (CE), stomach (CS), and pancreas (CP) which share similar risk factors to identify if these patient subsets also share risk for hospital readmission. Methods: Data was extracted from Nationwide Inpatient Sample database, which approximates 20% of U.S. community hospitals. Patients with a diagnosis CE, CS, and CP were identified by Clinical Classification Software code 11, 12, and 17, respectively. Demographic parameters associated with high readmission rates were collected for patients readmitted within 30 days over 2009-2013. Chi-square test was used to asses differences between variables. Results: We identified a total of 290,270 hospitalizations over the 5-year period of which 26.2% were readmitted within 30 days. The total number of readmissions were comparable for CS (28.0%), CP (27.89%), and CE (26.81%). Patients 45 to 64 years (28.58%, p < 0.001), Medicaid insurances (33.4%, p < 0.001), and metropolitan areas (26.8%, p < 0.001) were associated with higher 30-day readmission rates amongst all three cancers. Males had higher readmission rates in CS (25.64%, p < 0.001) and CP (28.6%, p < 0.001) compared to females in CE (28.0%, p < 0.001). Lowest median income for zip code patients were readmitted more often in CS (26.2%, p < 0.001) vs. third median income in CP (27.78, p < 0.001) and fourth (highest) median income in CE (28.38 %, p < 0.001). The most common identified causes of readmission in all three cancers were complications of surgical procedures or medical care (8.51% ± 2.03%), and septicemia (6.5% ± 1.95%). Conclusions: Our analysis shows that some variables for readmission are similar however more studies are needed to further elucidate whether this is primarily due to analogous treatment techniques. If so interventions to limit readmissions related to these treatments should be taken. Differences in readmissions rate amongst income classes could be related to the ease of accessing the most endorsed treatments for each individual cancer, however further studies are needed to clarify this discrepancy.
Antitumor efficacy of CDK 4/6 dual inhibitor, abemaciclib, in an esophageal adenocarcinoma model.
Authors: Omstead Ashten N , Matsui Daisuke , Kosovec Juliann E , Martin Samantha A , Kelly Ronan Joseph , Zaidi Ali Hussainy , Jobe Blair Anderson
Published: September 2018

e15598

Background: Esophageal adenocarcinoma (EAC) is a leading cause of cancer death, and current treatment options are extremely limited. Cell cycle regulators CDK6 and its homolog, CDK4, are known to be up-regulated in EAC and are associated with poor prognosis. At the molecular level, CDK4 and 6 bind to cyclin D1 and activates E2F transcription factor via phosphorylation of pRb. Up-regulation of this pathway leads to deregulation of the G1 checkpoint, resulting in increased cellular proliferation. Previously, studies have shown progressive up-regulation of CDK6 in pre-neoplastic lesions from Barrett’s esophagus to low-grade and high-grade dysplasia, thus establishing a rational for testing of a CDK4/6 dual inhibitor, Abemaciclib, in an established EAC model. Methods: Esophagojejunostomy was performed on Sprague-Dawley rats to induce gastroduodenojejunal reflux resulting in a sequence of histologic and molecular events that lead to the development esophageal adenocarcinoma. At 36 weeks post operatively, rats were randomized to receive Abemaciclib at 26 mg/kg or placebo (acetate buffer), intraperitoneally once daily for 4 weeks. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, histology, and CDK4/6 pathway expression by RT-PCR. Results: Twelve of 15 (80.0%) treated animals and all of 18 (100%) control animals reached study end-point. All of the treatment group mortality consisted of rats afflicted with moderate peritonitis, diarrhea and weight loss. Mean MRI tumor volume decreased by 93.55% in treatment animals and increased by 108.33% in control animals (P = 0.003). Treatment with Abemaciclib demonstrated tumor volume increase in 0% (control = 66.7%) (P = 0.0003), decrease in 75% (control = 0%) (P = 0.00001), and stable volume in 25% (control = 33.3%) (P = 0.63). EAC prevalence in treatment animals decreased by 50%; whereas, prevalence in control animals increased by 5.6% (P = 0.003). mRNA expression, pre- and post-treatment, demonstrated significant downregulation of CDK4, CDK6, RB1, pRB1 and Cyclin-D. Conclusions: Abemaciclib exhibits potent in vivo antitumor efficacy in a de novo EAC model, providing the rationale for clinical testing.