bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequency of relapse over time based on baseline stage in esophageal cancer patients treated with definitive chemoradiation (DCRT).
Authors: Wadhwa Roopma , Xiao Lianchun , Sudo Kazuki , Taketa Takashi , Blum Mariela A. , Skinner Heath D. , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Komaki Ritsuko , Rice David C. , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: March 2020

e15013

Background: Evidence for definitive chemoradiotherapy (bimodality therapy [BMT]) has been established for patients with Esophageal and Gastroesophageal Junction cancers (EGEJC) who do not qualify for surgery. Frequency of relapse over time based on baseline clinical stage is not well described. Methods: We analyzed 276 patients with EGEJC who underwent BMT. All the patients had pre- and post- chemoradiation, endoscopic biopsy and imaging study. The type and timing of first relapse or persistent disease after BMT was analyzed using 12-month intervals and was grouped by the baseline stage. Multiple statistical methods were used. Results: For 276 patients, the median follow-up time was 53.0 months (95% confidence interval [CI], 47.3-58.7) and the median overall survival was 27.0months (95% CI, 20.7-33.3). A total of 184 (66.7%) patients had a persistent disease or relapse after BMT: 120 distant metastases (43.5% of 276) and 64 local-regional disease (23.2% of 276). The table below demonstrates that baseline clinical stage has a great deal of influence on the frequency and timing of relapse (see Table).

Conclusions: These data demonstrate that relapse timing and patterns are associated with the baseline clinical stage. Our data can contribute to an evidence-based surveillance strategy.[Table: see text]
Why African Americans are more predisposed to pancreatic cancer: Nature versus nurture.
Authors: Thompson Wesley , Latif Naeem , Rahberg Robert
Published: March 2020

e15018

Background: There are known risk factors for pancreatic cancer like diabetes mellitus; cigarette smoking; poverty, and alcoholism; all of which are more common in African American patients than the general population. The purpose was to determine if these established risk factors were more associated within African American pancreatic cancer patients to explain their 50 – 90% increased incidence in the U.S. population. Methods: This retrospective study reviewed 172 biopsy-proven pancreatic cancer patients diagnosed over ten years at University of Florida Jacksonville. We employed linear regression models to determine statistical significance of established risk factors with prevalence of pancreatic cancer among cohorts. Results: Our data showed no increased association of diabetes, tobacco use, alcohol use between African Americans and Caucasians. However, Africans Americans as a group were twice as likely to be found at stage III or IV upon diagnosis, conferring an increased mortality risk (OR = 2.2, (95% CI 1.1 – 4.39)). Among these African Americans at advanced stage of diagnosis, females were at triple risk by odds ratio to be underinsured compared to Caucasian males (OR = 3.1, (95% CI 1.29 – 7.49, p = 0.015)). African American females were almost twice as likely to be underinsured compared to Caucasian females (OR = 1.72, (95% CI 0.646, 4.558)). The lack of healthcare access maybe related to advanced stage at diagnosis and its increased mortality risk. Conclusions: Our data suggests that the risk factors of smoking, alcoholism, and diabetes mellitus alone do not explain African Americans’ propensity for pancreatic cancer. However, lack of health insurance does confer an advanced stage at diagnosis and increased mortality risk among African American females. Our data also suggests that other etiological factors such as genetics maybe be associated with the increased risk amongst African Americans. A further investigation is warranted into genetic etiologies since African American patients have higher incidence of K-ras mutations than Caucasians; and mutated K-ras has been associated with pancreatic cancer, which is a target for therapy.
Prognostic potential of tumoral FOXP3 expression in relation with tumor-infiltrating regulatory T cells in human gastric cancers.
Authors: Suh Jungho , EO Wankyu , Kim Si-Young
Published: March 2020

e15036

Background: Expression of the transcription factor FOXP3 is crucial for the regulatory T cells (Tregs) that engage in the maintenance of immunological self-tolerance and immune homeostasis. Recently, expression of FOXP3 in cancer cells and its association with prognosis have been shown in clinical studies. For gastric cancer, however, prognostic significance of the tumoral FOXP3 expression and its relationship with Tregs remains unknown. We observed the tumoral FOXP3 and Tregs from the 118 gastric cancer patients who underwent surgery to explore its relationships with the prognosis. Methods: Tissue samples from 118 cases of gastric cancer were used for the present study. We investigated the tumoral expression of FOXP3 and Tregs count in human gastric cancer tissue by the use of immunohistochemical analysis using a tissue microarray to explore the relation with clinicopathological variables by retrospective manner. Results: FOXP3-positive cancer cells were observed in 62 of 118 (52.5%) patients. Positive Tregs (Tregs≥10/HPF) were observed in 66 of 118 (55.9%) patients. There was significant positive relationship between positive Tregs count and the tumoral FOXP3 expression (P=0.006).Positive tumoral FOXP3 expression was significantly related with the better disease free survival but not with the overall survival. But increased Tregs count was significantly related with the better overall survival (P<0.01, P<0.01, respectively). When we divide the patients into four groups by the FOXP3 expression and the Tregs count, FOXP3/Tregs(+/+) group showed the best overall survival followed by FOXP3/Tregs(-/+) group, FOXP3/Tregs(+/-,) and FOXP3/Tregs(-/-), respectively. And the survival difference between the FOXP3/Tregs(+/+)-FOXP3/Tregs(-/+) group and the FOXP3/Tregs(+/-)-FOXP3/Tregs(-/-)group became more prominent by the Tregs count. Conclusions: These results suggest that positive tumoral FOXP3 expression in relation with the high Treg count is a new prognostic marker in gastric cancer. The combination of tumoral FOXP3 and Tregs enhanced its statistical power more than separated as a prognostic marker.
TP53 mutation and BUBR1 overexpression characterize the DNA aneuploidy of gastric cancer.
Authors: Oki Eiji , Ando Koji , Ida Satoshi , Kimura Yasue , Saeki Hiroshi , Morita Masaru , Kusumoto Tetsuya , Maehara Yoshihiko
Published: March 2020

e15039

Background: Gastric cancers show a high frequency of DNA aneuploidy, which is a phenotype of chromosomal instability. Gastric carcinomas with aneuploidy have been shown to have higher proliferative activity and metastatic or invasive potential than diploid tumors, which leads to a poor prognosis. It has been suggested that an abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. In this study, we focused on the TP53 gene and BUBR1 protein in gastric cancer to elucidate their relation with the features of DNA aneuploidy. Methods: The study included 178 unselected Japanese patients with primary gastric cancer who underwent gastrectomy between 1994 and 2006 at Kyushu University Hospital, Fukuoka. DNA ploidy status, TP53 gene status, and BUBR1 expression were analyzed. Nuclear DNA content was measured using laser scanning cytometry. The TP53 gene was amplified from exon 5 to exon 9, including exon-intron junctions, by PCR using p53 primers (Nippon Gene, Tokyo, Japan) and Ex Taq DNA polymerase (TaKaRa Bio Inc., Tokyo, Japan). Results: DNA aneuploidy was identified in 108 cases, and TP53 gene mutation was seen in 28 of 143 cases. Both DNA aneuploidy and TP53-mutated tumors correlated with high age and differentiated type tumors. BUBR1 aberrant expression, investigated using immunohistochemistry, was seen in 89 cases, and it correlated with malignant features such as deep invasion, and lymph node and liver metastases. DNA aneuploidy was significantly related to high BUBR1 expression (P = 0.0055), and a more significant relation was found between DNA aneuploidy and TP53mutation (P = 0.0032). Tumors with high BUBR1 expression showed poor prognosis. Conclusions: DNA aneuploidy is associated with the carcinogenesis and prognosis of gastric cancer. Therefore, there has been considerable interest in targeting cell cycle checkpoints, particularly in emerging and alternative anticancer strategies. The development of selection markers to aid in the selection of appropriate therapies for patients will be the primary focus of future research. TP53 mutation and BUBR1 expression may provide clinically useful diagnostic, therapeutic, and prognostic information.
Complications of thermal ablation of hepatic tumors: Comparison of radiofrequency and microwave techniques.
Authors: Jing Xiang , Ding Jianmin , Liu Jibin , Wang Yandong , Wang Fengmei , Wang Yijun , Du Zhi
Published: March 2020

e15040

Background: The efficacy and safety of radiofrequency ablation (RFA) have been reported in the literatures, which are considered as frontline choice for treatment of liver cancer. Recently, microwave ablation (MWA) has emerged and gained great attention over RFA. However, in comparison to RFA, the safety of MWA for treatment of liver cancer has not been fully reported in the literatures. Studies with large clinical data sets are still needed to understand the technique and avoid the complications. The objective of this study was to retrospectively investigate the common complications of thermal ablations of liver tumors using both RFA and MWA techniques, and compare the safety between these two procedures. Methods: This retrospective study protocol was approved by our institutional ethics committee to allow investigators to review the existing patient’s medical records. A total of 879 patients with hepatic tumors underwent thermal ablation. There were 323 cases having the RFA procedures and 556 cases having MWA procedures. The complications of thermal ablations of liver tumors were compared using both RFA and MWA techniques. Results: A total of 1,030 thermal ablation sessions was performed in 879 patients with a total of 1,652 tumors. There were 323 patients with 562 tumors received a total of 376 RFA with averaged 1.16±0.48 sessions per patient. The other 556 patients with 1,090 tumors received a total of 654 MWA with averaged1.18±0.51 sessions per patient. The mortality rates were 0.31% (1/323) and 0.36% (2/556) in RFA and MWA group. In RFA and MWA group, the major complication rates were 3.5% (13/376) and 3.1% (20/654) (Table 1), meanwhile the minor complication rates were 5.9% (22/376) and 5.7% (37/654). There was no statistical significant difference for the mortality rates, the major complications, the minor complications between the RFA and MWA groups (P>0.05). Conclusions: Thermal ablation therapy in the treatment of liver cancers is relatively safe with low mortality and low incidence of serious complications. The types and incidences of complications caused by RFA and MWA are similar and comparable for safety consideration in clinical settings.
Survival of patients receiving radiofrequency ablation or ethanol injection for early-stage hepatocellular carcinoma.
Authors: Lin Zhong-Zhe , Shau Wen-Yi , Shao Yu Yun , Yeh Yi-Chun , Kuo Raymond Nien-Chen , Hsu Chiun , Hsu Chih-Hung , Cheng Ann-Lii , Lai Mei-Shu
Published: March 2020

e15043

Background: Randomized trials suggest that radiofrequency ablation (RFA) may be more effective than percutaneous ethanol injection (PEI) in the treatment of hepatocellular carcinoma (HCC). However, the survival advantage of RFA need confirmation in daily practice. Methods: We conducted a population-based cohort study using the Taiwan Cancer Registry, National Health Insurance claim database and National Death Registry data from 2004 through 2009. Patients receiving PEI or RFA as first-line treatment for newly-diagnosed stage I-II HCC were enrolled. Results: A total of 658 patients receiving RFA and 378 patients receiving PEI treatment were included for final analysis. The overall survival (OS) rates of patients in the RFA and PEI groups at 5-year were 55% and 42%, respectively (p< 0.01). Compared to patients that received PEI, those that received RFA had lower risks of overall mortality and first-line treatment failure (FTF), with adjusted hazard ratios (HRs) [95% confidence interval (C.I.)] of 0.60 (0.50-0.73) for OS and 0.54 (0.46-0.64) for FTF. The favorable outcomes for the RFA group were consistently significant for patients with tumors > 2 cm as well as for those with tumors < 2 cm. Consistent results were also observed in other subgroup analyses defined by gender, age, tumor stage, and co-morbidity status. Conclusions: RFA provides better survival benefits than PEI for patients with unresectable stage I-II HCC, irrespective of tumors > 2 cm or ≤ 2 cm, in contemporary clinical practice.
Long-term survival and clinical efficacy in patients with advanced pancreatic and small bowel metastatic neuroendocrine tumors (GEP-NET) after I.V. 90Y DOTATATE.
Authors: Rogowski Wojciech , Wachula Ewa , Zok Jolanta , Lewczuk Anna , Cwikla Jaroslaw , Wysocki Piotr
Published: March 2020

e15045

Background: Current therapeutic options for patients with progressive metastatic gastroenteropancreatic neuroendocrine tumour/neoplasm (GEP-NET/NEN) are limited. Treatment with SST analogues is method of choice, due to good symptoms control. [DOTA0, D-Phe1,Tyr3] octreotate[DOTATATE] has a higher affinity for SST2 receptors and thus is able to achieve longer disease control. The aim of this study was to evaluate long term radiological and clinical therapeutic effect of 90Y-DOTATATE in patients with progressive somatostatin receptor–positive small bowel and pancreatic neuroendocrine tumour/neoplasm (GEP-NET/NEN).The primary end point was assessing OS and PFS in long term follow-up. Methods: 67 patients progressing after treatment with SST analogues were inlcuded in the study. The mean treatment activity was 3.8GBq. The mean interval between therapies was 7 weeks (range 6 -9 weeks). Patients were treated up to mean a cumulative activity of 11.2 GBq. Due to pure beta emission (90Y) internal dosimetry was evaluated. Results: Median overall survival (OS) and progression-free survival (PFS) are shown in the Table. In univariate analysis Ki-67 (p=0.048) was the only significant factor influencing OS in pancreatic tumors. That was not confirmed in multivariate analysis. In small bowel tumors we defined three factors influencing survival in univariate analysis. These were: female gender (p=0.023), performance status at the beginning of therapy (p=0.031) and presence of liver metastases (p=0.026). Female gender (HR=0.30, 95% CI 0.11-0.81; p=0.018) was confirmed as positive prognostic factor in multivariate analysis. Factos influencing PFS were also assessed and will be presented as well. Conclusions: 90Y DOTATATE PRRT is effective in long term outcome (OS and PFS) in patient with advances progressive pancreatic and small bowel GEP-NET. This therapy is relatively safe as initial systemic therapy and after previous treatment with chemotherapy or somatostatine analogues as well. [Table: see text]
MET amplification occurrence and prediction of unfavorable clinical outcomes in patients with recurrent/metastatic gastric cancer after chemotherapy.
Authors: Li Yu-hong , An Xin , Wang Fang , Shao Qiong , Wang Feng-Hua , Wang Zhiqiang , Chen Cui , Li Cong , Luo Huiyan , Zhang Sheng Dong , Xu Rui-hua
Published: March 2020

e15047

Background: Several large studies have reported an extremely low incidence of MET gene amplification (GA) in patients with radically resected gastric cancer. The aim of our study was to evaluate the prevalence and prognostic role of MET GA and protein expression in recurrent/metastatic gastric cancer patients who received chemotherapy. Methods: This retrospective study included 232 recurrent/metastatic gastric cancer patients. MET GA and protein expression were evaluated by fluorescent in-situ hybridization (FISH) and immunohistochemistry (IHC), respectively.Results: MET GA and strong protein expression were observed in 8.3% and 9.6% of patients, respectively. MET IHC 3+ was significantly correlated with GA. Patients with MET GA more frequently had a poor performance status (P < 0.001) and poorly differentiate tumors (P = 0.015) than those without MET GA. Both MET GA and IHC 3+ expression were associated with substantially shorter median progression free survival (PFS) and overall survival (OS). The median OS and PFS for patients with MET GA positive vs. MET GA negative were 5.7 vs. 15.5 months (P < 0.001) and 3.6 vs. 6.9 months (P < 0.001), respectively.The median OS and PFS for patients with MET IHC 3+ vs. IHC (0 to 2+) were 6.3 vs. 15.1 months (P < 0.001) and 3.6 vs. 7.0 months (P < 0.001), respectively. Conclusions: In recurrent/metastatic gastric cancer, MET amplification and strong protein expression are not rare and significantly associated with unfavorable clinical outcomes.
Low levels of radiofrequency electromagnetic fields and cancer cell proliferation in vivo.
Authors: Pasche Boris , Zimmerman Jacquelyn W. , Jimenez Hugo , Pennison Michael J. , Brezovich Ivan , Yi Nengjun , Kuster Niels , Costa Frederico , Barbault Alexandre
Published: March 2020

e15049

Background: The incidence of hepatocellular carcinoma (HCC) is increasing but five-year survival remains dismal. Intrabuccal administration of amplitude-modulated radiofrequency electromagnetic fields (RF EMF) is a novel, non-invasive treatment modality resulting in whole body absorption of very low levels of RF EMF. Recent studies show that this approach elicits radiological responses in patients with HCC and breast cancer (J Exp Clin Cancer Res, 2009, 28:51; Br J Cancer, 2011, 105:640). Using an in vitro exposure system replicating the levels of exposure achieved in humans, we have shown that HCC cells and breast cancer cells are growth inhibited by HCC-specific and breast cancer-specific frequencies, respectively. Additionally, RF EMF exposure causes modulation of gene expression and disruption of the mitotic spindle (Br J Cancer 2012, 106:307). Methods: HCC cells were exposed to radiofrequency electromagnetic fields modulated at specific frequencies previously identified in HCC patients. MicroRNA arrays compared exposed and control groups of HCC cells. HCC cells were injected subcutaneously in NOD SCID mice. Following palpable tumor establishment, mice were exposed to HCC-specific RF EMF at a specific absorption rate of 0.4 W/kg and euthanized following excessive tumor burden. Results: We identified increased levels of miRNAs targeting proteins belonging to the PI3K pathway, specifically IP3/DAG signaling and intracellular calcium release, a pathway frequently disrupted in HCC and breast cancer. While HCC xenografts grew in control mice, we observed significant tumor shrinkage in mice exposed to HCC-specific modulation frequencies and residual xenograft tumor cells were infiltrated with fibrous tissue and showed significantly decreased proliferation and increased apoptosis. There was no evidence of altered cell proliferation or fibrosis in other organs. Conclusions: These findings are the first in vivo evidence of the efficacy of RF EMF in HCC and uncover a novel mechanism that targets cancer cell growth at specific modulation frequencies, by means of changes in PI3K signaling and release of intracellular calcium.
Activity of nab-paclitaxel (nab-P) monotherapy in heavily pretreated pancreatic cancer (aPDAC) patients (pts): A multicenter retrospective analysis.
Authors: Vaccaro Vanja , Bria Emilio , Reni Michele , Sperduti Isabella , Gelibter Alain , Nuzzo Carmen , Torsello Angela , Garufi Carlo , Lucchini Eleonora , Frizziero Melissa , Melisi Davide , Belli Carmen , Cereda Stefano , Tortora Giampaolo , Cognetti Francesco , Milella Michele
Published: March 2020

e15057

Background: No standard treatment exists in pretreated aPDAC pts, who have already received available active drugs. nab-P has shown to improve survival in combination with GEM in first line and to be active in GEM-resistant aPDAC pts. Methods: aPDAC pts who received off-label single agent nab-P (125 or 100 mg/m2 over 30 minutes on days 1, 8, and 15 of a 28- day cycle) as 2nd or further line of treatment for metastatic disease in three Italian centers were retrospectively reviewed. Results: 29 pts were identified (M/F: 16/13; median age: 66 yrs, range: 39-83); >50% of pts had an ECOG PS 2; median number of previous treatment lines: 2 (range 1-5); 7 pts had received Folfirinox as first line. nab-P starting dose was 125 mg/m2 in 5 pts and 100 mg/m2 in the others. A median of 2 cycles (range 1-10) were administered. Two partial responses (44 and 46-wk duration) were observed; 4 pts had stable disease SD (9, 16, 23, 28-wk duration, respectively); 5 pt are presently not evaluable. Median and mean progression free survival (PFS) were 8 (95% CI: 5-11) and 13 (95% CI: 7-18) wks, respectively; median and mean overall survival (OS) were 13 (95% CI: 9-17) and 25 (95% CI: 15-35) wks, respectively. Three- and 6-month PFS rates were 33% and 15%, respectively; 6- and 12-month OS rates were 36% and 22%, respectively. Toxicity was mild with G4 neutropenia in 1 pt and G3 neuropathy in 1 pts. With at least 10 out of 29 pts free from progression at 3 months (3-month PFS rate: 35%), our results satisfy the following post-hoc statistical hypothesis: p0: 15%, p1: 35%, a: 5%, 1-b: 80%, according to A’Hern exact single stage phase II design. Conclusions: nab-P is well tolerated and moderately active, even in heavily pretreated aPDAC pts. Further analyses are warranted, especially to identify the small proportion of pts who derive exceptionally prolonged benefit from nab-P monotherapy.
Correlation of loss of spinophilin expression with increased proliferation and viability as a prognostic factor in patients with hepatocellular carcinoma.
Authors: Ress Anna Lena , Aigelsreiter Ariane , Schauer Silvia , Eisner Florian , Samonigg Hellmut , Lackner Carolin , Haybaeck Johannes , Bauernhofer Thomas , Pichler Martin
Published: March 2020

e15064

Background: A loss of the putative tumorsuppressor protein spinophilin has been recently involved in the pathogenesis of lung and other carcinoma types. However, a detailed study of the clinical significance and functional cellular effects of spinophilin in hepatocellular carcinoma (HCC) has never been performed. Methods: In this study, we determined for the first time the expression pattern of spinophilin and some of it´s known interacting/down-stream genes (p53, p14ARF, pRB) and proliferation markers (MIB-1 and Cyclin D) in human hepatocellular carcinoma (HCC). The prognostic relevance of spinophilin expression was determined on a cohort of 104 HCC patients who underwent primary tumor resection, followed by functional gene silencing studies. Results: Reduced spinophilin expression was detected by three independent methods (Western blot, RT-PCR and IHC) in a substantial number of patients (70%, p<0.05). Loss of spinophilin expression in HCC tissue was correlated with increased MIB-1 proliferation marker (p=0.01). In terms of clinical outcome, the disease-free survival (DFS) rate was 14.8% and 39.1% (p=0.010) and the cancer-specific survival (CSS) rate was 23.5% and 43.5% (p=0.006) for patients with low and high spinophilin expression, respectively. Multivariate Cox regression analysis identified low expression of spinophilin as an independent poor prognostic factor with respect to DFS (HR=1.8, CI=1.04-3.40, p=0.043) and CSS (HR=2.0, CI=1.1-3.8, p=0.025). Silencing of spinophilin expression in HepG2 cells was associated with increased cellular growth rate (p<0.05). Conclusions: According to our data, the loss of this putative tumor suppressor protein is an independent negative prognosticator for the clinical outcome of HCC patients. Reduced levels of spinophilin expression are associated with higher proliferation rates of HCC cells.
The impact of body mass index dynamics on survival of patients with advanced pancreatic cancer receiving chemotherapy.
Authors: Choi Younak , Oh Do-Youn , Kim Tae-Yong , Lee Kyung-Hun , Han Sae-Won , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue
Published: March 2020

e15066

Background: The obesity is increasing worldwide. High body mass index (BMI) is linked with an increased risk of developing pancreatic cancer (PC). However, in patients with advanced PC (APC), especially those are receiving palliative chemotherapy (the majority of all PC patients), the impact of BMI and its change during disease course on survival has not been fully investigated. Methods: Consecutive patients with APC were enrolled during years 2003-2010, all treated with palliative chemotherapy. The BMI measured at the point of starting the first cycle of palliative chemotherapy was called as “BMI at diagnosis”. “Pre-cancer weight” which means the weight in good health was the sum of “weight at diagnosis” and “weight loss at diagnosis” that the patients’ self- reported at the first visit. “Pre-cancer BMI” was calculated using pre-cancer weight. We got weight data measured at every visit during chemotherapy to investigate BMI change during chemotherapy period. Clinical characteristics and outcomes were analyzed. Results: A total of 425 patients were enrolled (median age, 60.1 years). At diagnosis of APC, the BMI distribution of patients was as follows: <18.5 (45, 10.6%); 18.5-19.9 (67, 15.8%); 20.0-22.4 (156, 36.7%); 22.5-24.9 (107, 25.2%); 25.0-29.9 (49, 11.5%); and ≥30.0 (1, 0.2%). Clinical characteristics were balanced across BMI groups. Median overall survival (OS) was 8.1 months (95% CI, 7.2-9.1). Pre-cancer BMI and BMI at diagnosis had no impact on OS (p = 0.488, p = 0.348, respectively), although patients at BMI range of 22.5-24.9 achieved the longest OS (9.9 months; 95% CI, 8.5-11.3). BMI loss at diagnosis (pre-cancer BMI minus BMI at the diagnosis) and BMI loss during chemotherapy (both stipulated as BMI change ≥1) were associated with shortened OS (HR, 1.300; p = 0.012 and HR, 1.367; p= 0.010, respectively). Conclusions: In patients with APC undergoing palliative chemotherapy, both declines in BMI at diagnosis of APC and during chemotherapy are more hazardous for OS than pre-cancer BMI or BMI at diagnosis itself as absolute values. Further research evaluating strategies to maintain BMI during chemotherapy in this setting is thus warranted.
Comparing recist and Choi’s criteria to evaluate radiological response to chemotherapy in patients with advanced pancreatic cancer.
Authors: Vecchiarelli Silvia , Macchini Marina , Grassi Elisa , Ferroni Fabio , Ciccarese Federica , Calculli Lucia , Ricci Claudio , Casadei Riccardo , Pezzilli Raffaele , Biasco Guido , Di Marco Mariacristina
Published: March 2020

e15069

Background: Assessment of response after chemotherapy (CTH) for pancreatic cancer (PC) is currently based on RECIST criteria. In 2007 Choi et al. published a new classification system.The purpose of this study was to evaluate the accuracy of these classification systems for radiological response to CTH in patients with advanced PC. Methods: From 2006 to 2012, 66 untreated patients with advanced PC underwent palliative CTH. Fourty (60 %) had a locally advanced PC and 26 (40%) a metastatic disease. All patients were treated with a GEM-based CTH or FOLFIRINOX. We assessed radiological response after three months of first-line therapy applying both RECIST criteria, which evaluate differences in CT size, and Choi’s criteria, which consider changes both in size and in density at CT. We evaluated the accuracy in restaging, comparing the class of response with overall survival (OS). OS was calculated with Kaplan-Meier method. The accuracy in restaging was assessed through log rank test and multivariate analysis with Cox Regression. Results: At restaging, using RECIST criteria, we registered 7 (10.6 %) patients with partial response (PR), 32 (48.5 %) with stable disease (SD), and 27 (40.9 %) with disease progression (PD). Instead Choi’s criteria assessed 19 PR (28.8 %), 12 SD (18.2%) and 35 PD (53.0%). Comparing each classification with OS, we observed that patients with different prognosis were better stratified with Choi’s criteria. Using RECIST criteria we found a borderline significant difference in OS between patients with PR (13.47 months), SD (13.67 months) and PD (9.97 months) (p=0.05). Instead we found a significant statistical difference in OS using Choi’s criteria between patient with PR (14 months), SD (16.37 months), PD (9.7 months; p=0.004). Multivariate analysis showed a statistically significant difference in OS between Disease Control Rate (DCR, PR+SD) and PD patients (14.47 vs. 9.67 months, p=0.02), only using Choi’s criteria. Conclusions: In our experience, Choi’s criteria seem to better assess radiological response of CTH in PC patients than RECIST criteria. Due to the small number of patients, larger prospective studies are needed.
Effect of the combination of the dual mTOR/pI3K inhibitor NVP-BEZ235 with gemcitabine on growth inhibition in pancreatic cancer cells in vitro and in vivo.
Authors: Maute Luise , Wicht Johannes , Zoernig Martin , Niederhagen Manuel , Bergmann Lothar
Published: March 2020

e15070

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumours and is still associated with a very poor prognosis. Therefore new treatment strategies are needed. The PI3K/AKT and mTOR signaling pathways are frequently dysregulated in PDAC. Thus we investigated the effects of NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, alone or in combination with gemcitabine first in vitro and after promising results also in vivo. Methods: We examined the effect of gemcitabine and NVP-BEZ235 (kindly provided by Novartis Pharma) on cell viability as single agents and in combination with sequential administrations in the four human pancreatic cancer cell lines MiaPaCa-2, Panc-1, AsPC-1 and BxPC-3. For in vivo experiments we used NOD SCID Mice, which were injected with BxPc3 into the right flank. Treatments consisted of Gemcitabine alone, NVP-BEZ235 alone, simultaneous application of both, first application of Gemcitabine followed by NVP-BEZ235 and NVP-BEZ235 followed by Gemcitabine. Results: Simultaneous incubation of gemcitabine and NVP-BEZ235 affected the PDAC cell lines significantly better than the single agent administration. But most effective was a sequential administration of gemcitabine followed by NVP-BEZ235. In vivo Gemcitabine and NVP-BEZ235 as single agents showed a slightly reduced tumor growth and the treatment in the sequence NVP-BEZ235 first, followed by Gemcitabine resulted in only a minimal reduction of tumor growth. The most effective results were obtained by simultaneous and even better in the sequence of Gemcitabine followed by NVP-BEZ235, respectively. Conclusions: The combination of gemcitabine with the dual PI3k/mTOR inhibitor NVP-BEZ235 enhanced the efficacy of PDAC treatment via down-regulation of the DDR related gene Survivin in vitro. This combination seems to be significantly more effective than single agent use in vitro and also in vivo. Furthermore we demonstrated that the sequence of administration of these agents could be a relevant issue. These promising results might offer a new and effective option for the treatment of pancreatic cancer in the future.
Association of decline in serum Ca19-9 after neoadjuvant therapy with improved survival among borderline resectable pancreatic cancer patients.
Authors: Tsai Susan , Mahmoud Anna , George Ben , Kelly Tracy R. , Ritch Paul S. , Erickson Beth , Evans Douglas B. , Christians Kathleen K.
Published: March 2020

e15082

Background: Serum Ca19-9 (19-9) decline in response to therapy has been associated with an increased overall survival in metastatic pancreatic cancer patients (pts). However, the prognostic value of a 19-9 decline after neoadjuvant therapy in pts with localized disease is less well defined. Methods: We evaluated 73 pts with NCCN defined BRPC who received neoadjuvant therapy with induction chemotherapy (CRX) followed by chemoradiation (CRT). Staging with CT and 19-9 was obtained at three defined time points: baseline (bilirubin normal), after CRX, and following CRT (pre-surgical). Change in 19-9 (δ19-9) was defined as: (baseline 19-9- pre-surgical 19-9)/baseline 19-9. δ19-9 was classified as: absent (δ19-9<0) or minimal (0 <δ19-9<0.25), low (0.25<δ19-9<0.50), moderate (0.50<δ19-9<0.75), high (δ19-9> 0.75). Results: Of the 73 pts, 20 pts had normal/undetectable 19-9 and were excluded from the analysis. Of the remaining 53 pts, mean 19-9 levels at baseline, after CRX, and after CRT were 956, 164, and 139 U/mL, respectively. The mean change in 19-9 after CRX was 44%. Changes in 19-9 after CRX correlated with continued decline in 19-9 after CRT (Spearman rho = 0.81, p<0.001). δ19-9 was high in 38 (71%), moderate in 9 (17%), min/low in 1 (2%), and absent in 5 (9%). Of the 53 pts, 49 (92%) were considered for surgery after neoadjuvant therapy and 38 (72%) underwent pancreatectomy. In a multivariate logistic regression, higher δ19-9 was associated with a 5.4 fold increased odds of completing all neoadjuvant therapy including surgery as compared to pts with no change in 19-9 (absent δ19-9; HR 5.4, p=0.12). Patients with absent δ19-9 had a worse overall survival than pts with minimal to high δ19-9 (median survival 11.5 mo vs. 30.1 mo, p = 0.0002). In a multivariate Cox proportional hazard, a decline in pre-surgical 19-9 from baseline was associated with improved survival (HR 0.21, p =0.02). Conclusions: Following neoadjuvant therapy, a decline in 19-9 is associated with surgical resection and improved overall survival. An increase in 19-9 above baseline (the absent δ19-9 group) prior to surgery is a poor prognostic marker and such patients may benefit from additional systemic therapy.
Differences in the survival rate between premenopausal and post menopausal women with gastric cancer: U.S. SEER database.
Authors: Yousif Nasser Ghaly
Published: March 2020

e15092

Background: Gastric cancer is the fourth most common malignancy in the world, The presence of estrogen receptor alpha (ER a) and estrogen receptor beta (ER b) have been reported in cell and tissue level in gastric cancer, but its impact on patients' survival remains unclear. The male predominance of gastric cancer suggests that female sex hormones may have a protective effect against gastric cancer. To understand the clinical impact of the estrogen pathway, we analyzed the national SEER database to compare the outcomes for gastric cancer in premenopausal vs.postmenopausal women. Methods: Data from the national SEER registry between the years of 1985-2009 was analyzed. Women between the ages 31-50 were chosen as representative of the pre-menopausal group (n=1291) and 51-70 year-old women represented the post-menopausal group (n=3089) as defined by the American College of Obstetricians and Gynecologists. To control the effect of age alone as a determinant of outcome, we compared the survival between men were similarly divided into two categories: younger men (n = 2114) aged 31- 50 years and older men (n = 5102) aged 51 - 70 years. Survival rates were analyzed by Kaplan-Meier method and compared by Z-test through SEER*Stat software version 7.0.9. Results: The cardiac gastric cancer site type and diffuse histological subtype had statistical significance difference between premenopausal and postmenopausal groups (49% vs.72%), (44% vs. 692%) respectively. The Kaplan-Meier curve shows the survival rate in premenopausal superior to postmenopausal women in diffuse gastric cancer P=0.01, while no statistically significant difference regarding mixed sub-types P>0.05 and control groups. Conclusions: The results suggest varying estrogen effects between localization and histological subtype of gastric cancer, the presence of estrogen in gastric cancer could have a protective effect against gastric cancer and support clinical strategies need to stimulate the ER pathway or use estrogen for the treatment of gastric cancer, and additional studies are warranted as well as experimental studies that can shed light on the mechanism underlying this potentially protective action.
Paclitaxel, carboplatin, and etoposide (TCE) in advanced poorly differentiated neuroendocrine carcinoma.
Authors: Mantovani Loeffler Luisa , Mauersberger Elias , Weimann Arved , Kuerschner Dorit , Schimmelpfennig Christoph , Wiechmann Volker , Bisanz Heike , Zeissig Gisela , Zeynalova Samira , Schmoll Hans-Joachim
Published: March 2020

e15096

Background: Only limited data are available on treatment outcomes in poorly differentiated neuroendocrine carcinomas. We evaluated retrospectively a complete series of consecutive patients with poorly differentiated neuroendocrine carcinoma treated with a regimen containing TCE in a single center. Methods: 50 new consecutively diagnosed patients were treated between 01/2000 and 04/2012 at St. Georg Hospital Cancer Center Leipzig. Dosing: paclitaxel (175-200mg/m² d1), carboplatin (AUC 6 d1) and etoposide (50/100mg d1-10) q3w (Hainsworth et al. JCO 2006, 22, 3548-3554). In cases of response after three cycles patients have been treated until progression or toxicities. Patient initial characteristics: age 61 years (range 23-85); 34 male, 16 female; 8/50 limited disease, 29/50 liver metastases, 13/50 only extra hepatic metastasis; 12/50 hormon active tumors. Histological confirmation, immunhistochemical staining (synaptophysin, chromogranin A) and proliferationsrate were performed in all cases. Resection of primary tumor was performed in 20/50 pts. Median no. of cycles was 4 (range 1-12 courses). CT-Scans of all patients were reviewed according to RECIST to detect maximal response. Results: 7/50 (14%) had CR, 20/50 PR (with a median reduction of the sum of diameters to 49%); 12/50 (24%) had no change; 7/50 PD (14%); 4/50 (8%) were not evaluable for response because of early death (3 sepsis, 1 liver failure). Median progression free survival time was 4.0 months (95% CI 2.9-5.1). The median overall survival time was 14,8 months (95% CI 9,5 -20,3). Major toxicity was myelosuppression. As a consequence paclitaxel dose was reduced to 175 mg/m² in the last 40 pts of this series (80%). Conclusions: TCE treatment is effective and induces tumor control in a substantial subgroup of patients. This analysis confirms the data of Hainsworth et al. and shows in an unselected population nearly the same encouraging results. [Table: see text]
Impact of the 92-gene assay on cost of diagnosis of tumor type in metastatic cancer of uncertain origin.
Authors: Bentley Tanya G. , Schroeder Brock , Schnabel Catherine A. , Ortendahl Jesse , Hsiao Wendy C. , Erlander Mark G. , Broder Michael S.
Published: March 2020

e15104

Background: Molecular classification of tumors has been incorporated into clinical algorithms for patients with metastatic cancers of uncertain origin. This study is a comprehensive cost analysis—characterizing standard of care for metastatic disease, cost implications of correct vs incorrect diagnosis, and cost effectiveness of implementing molecular classification into the diagnostic paradigm. Methods: A deterministic model was developed to project the cost and effectiveness of standard care for metastatic tumors of uncertain origin, compared with incorporating use of the 92-gene assay at 3 points: before immunohistochemical (IHC) analysis, or after 1, or 2 sets of IHC stains. For each strategy, total and incremental costs, life-years (LYs), quality-adjusted life years (QALYs), and incremental cost effectiveness ratios (ICERs) were projected, as well as the % of patients treated correctly vs incorrectly. Model inputs and costs were based on published literature, analyses of the SEER database, the Physicians’ Fee and Coding Guide 2012, and interviews with disease experts. Sensitivity analyses were performed on key inputs. Results: When standard care was compared with each 92-gene assay strategy, costs increased between $4,804 and $6,038 and QA-survival by 1.03-1.15 months. Using the 92-gene assay after 1 set of IHC stains was the most cost effective strategy ($50,273/QALY). Overall, the 92-gene assay increased the % of patients treated correctly and decreased the % of patients treated with empiric therapy compared with standard care. When compared with incorrect treatment, correct treatment provided an additional 5.4 QA-months of survival. Sensitivity analyses identified that costs of empiric treatment, the 92-gene assay, and lung cancer treatment had the greatest effect on outcomes. At a societal willingness-to-pay (WTP) threshold of $100,000, the 92-gene assay was cost effective 94% to 99% of the time. Conclusions: Use of the 92-gene assay is considered cost effective using current societal WTP thresholds, represents an efficient use of economic resources that improves patients' survival and quality of life, and could contribute to standardization of the costs of diagnosis.
EGFR family and c-Met expression profiles and prognostic significance in esophagogastric adenocarcinoma.
Authors: Chan Ellie , Alkhasawneh Ahmad , Duckworth Lizette Vila , Zuluaga-Toro Tania , Lu Xiaomin , Hughes Steven J. , George Thomas J.
Published: March 2020

e15108

Background: Targeted therapy of HER2 overexpression in patients with esophagogastric adenocarcinoma (EGA) improves survival; however, the effect is transient due to the development of resistance. Targeting of EGFR alone in EGA was not active. cMet overexpression is suggested to be a possible resistance pathway for EGFR and HER-2 inhibition. We characterized the expression profile of the EGFR family of receptors and cMet as well as their prognostic significance in EGA. Methods: This retrospective analysis included all patients (pts) with EGA who underwent primary resection at the University of Florida from 2001 to 2011 without neoadjuvant therapy. Demographics, risk factors, tumor features, and outcome data were analyzed. Central blinded immunohistochemistry (IHC) was performed on paraffin embedded tumor specimens with EGFR, HER2, HER3, HER4 and cMet expression scored as low (0, 1+) or high expression (2+, 3+). Descriptive statistics, Fisher exact test, Cox regression and Kaplan-Meier methods were used for statistical analyses. Results: 52 pts (42 M/10 F) were analyzed with median age 66 years (37-83). Most tumors (58%) were stage I (T1N0). Receptors expression profiles and their associations are presented in the Table. High HER3-HER4 co-expression was found in 35% of cases (p = 0.002). Univariate analysis did not show significant correlation of age, tumor differentiation, BMI, tobacco use and receptor expression with survival. Stage was the only variable that correlated significantly with survival (p=0.02). Conclusions: This is the first study to our knowledge examining the EGFR family expression relationships and cMet in treatment naïve resected EGA tumors. Associations between receptor expression patterns are of clinical interest for rational development of multi-targeted inhibition. Although our data do not significantly show receptor status as a prognostic factor, some receptor expression associations suggest trends towards worse survival. Larger studies are warranted for further investigation. [Table: see text]
Salvage gastrectomy for unresectable advanced gastric cancer after combination chemotherapy with docetaxel, cisplatin, and S-1.
Authors: Hosoda Kei , Yamashita Keishi , Sakuramoto Shinichi , Mieno Hiroaki , Higuchi Katsuhiko , Moriya Hiomitsu , Katada Natsuya , Kikuchi Shiro , Watanabe Masahiko
Published: March 2020

e15113

Background: The prognosis for patients with unresectable advanced gastric cancer treated with chemotherapy alone is extremely poor. We have evaluated the safety and efficacy of salvage gastrectomy following chemotherapy with docetaxel, cisplatin, and S-1 (DCS) in patients with unresectable advanced gastric cancer. Methods: We evaluated 30 patients with unresectable advanced gastric adenocarcinoma whose lesions were down-staged by DCS chemotherapy and who underwent salvage gastrectomy with lymph node dissection from 2006 to 2012, when visible lesions were judged resectable. We retrospectively reviewed their medical records to identify factors that would influence overall survival. Results: Of the 30 patients, 17 had extra-regional lymph node metastases, 5 had liver metastases, 9 had peritoneal dissemination and 6 had pancreatic head invasion prior to DCS chemotherapy. Of the 30 patients, 23, 3, and 4 underwent R0, R1, and R2 resection, respectively. No in-hospital deaths or reoperations occurred. Pathological evaluation of primary tumors revealed grades 3, 2, 1b, 1a, and 0 tumor regression in 4, 9, 7, 7, and 2 patients, respectively. Median progression-free survival was 19 months.Two-year progression-free survival and overall survival rates were 45% and 65%, respectively. Of 17 patients with target tumors, 15 had partial responses, making the overall response rate 88%. The most common grade 3/4 hematologic toxicity was neutropenia (56%); all treatment-related toxicities were resolved, and no patient died of toxicity-related causes. Univariate analysis showed that R1/2 surgery (p<0.001), diffuse type histology (p=0.054), histological grade 0/1a/1b following chemotherapy (p<0.033), ypN3 (p<0.001) and yply2/3 (p=0.003), were significantly prognostic of reduced overall survival. A multivariate proportional hazard model found that ypN3 (p=0.003) was the sole independent prognostic factor. Conclusions: Salvage gastrectomy after DCS chemotherapy was safe and effective in patients with unresectable advanced gastric cancer. Lymph node metastasis after chemotherapy was significantly prognostic of poor prognosis, suggesting the need for further treatment.
Expression of cyclin D1 and p21(WAF1/CIP1) in human gastric carcinoma and its clinicopathologic significance.
Authors: Michalaki Vasiliki , Theodosopoulos Theodosios , Kondi- Pafiti Agathi , Gennatas Constantine G.
Published: March 2020

e15114

Background: The deregulation of cyclin, cyclin-dependent kinases (CDKs) and their inhibitors could have a crucial role in the development of diverse human cancers. Alterations in cell cycle regulators and subsequent deregulation of the cell cycle are frequently involved in tumorigenesis and/or tumor progression. The aim of our study was to detect the abnormal expression of cyclin D1 and p21(WAF1/CIP1)in gastric carcinoma and investigate its clinicopathologic significance. Methods: Proteins of cyclin D1 were detected by immunohistochemistry in 80 cases of advanced gastric carcinoma, and 30 cases of benign gastric diseases (chronic gastritis, atrophic gastritis, gastric metaplasia, and gastric dysplasia). From each patient formaldehyde–fixed paraffin sections were stained and examined by immunohistochemistry using monoclonal antibodies.All tumor cells with distinct nuclear staining were considered positive. Results: Sixty-five patients were male and forty five female. Normal gastric epithelium showed consistently positive immunostain for p21WAF1/CIP1. Loss of p21WAF1/CIP1 expression was noted in 65% of intestinal type adenocarcinoma and in 90% of diffuse type adenocarcinoma. Overexpression of cyclin D1 was detected in 90% of advanced gastric carcinomas. Among the various clinicopathological findings, overexpression of cyclin D1 was associated with lymph-node metastasis (P=0.003) and recurrence (P=0.044). Loss of p21WAF1/CIP1 expression was more frequent in diffuse type cancers (P=0.005) and was correlated with recurrence (P=0.002) and death (P=0.001). Conclusions: These findings suggest that overexpression of cyclin D1 is a frequent finding in gastric cancer and immunohistochemical analysis for cell cycle regulators, might be a useful prognostic indicator in gastric cancer.