bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment patterns, effectiveness, and safety of Trastuzumab in Chinese patients with metastatic gastric cancer: Interim analysis of the EVIDENCE registry study.
Authors: Qin Shukui , Lin Shen , Xu Ruihua , Su Wuyun , Tang Yong , Wang Xin , Xu Jian-ming , Zhou Weiping , Cui Tongjian , Luo Suxia , Wu Xiaohui , Ji Jiafu
Published: September 2018

e15595

Background: Trastuzumab (TRA) was approved for HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma (mGC) in China in August 2012. However, real-world data on the treatment patterns, effectiveness, and safety of TRA in Chinese patients (pts) with mGC are limited. Methods: EVIDENCE is a prospective, multicenter, non-interventional, registry study of 5 cohorts (NCT01839500). Cohort I enrolled pts with HER2-positive mGC (IHC3+ or IHC2+/ISH+) diagnosed up to 6 months previously. This interim analysis evaluated the effectiveness and safety of TRA in the first 95 pts of cohort I who were treated at 33 hospitals in China between April 2013 and August 15, 2016. Results: 71 of the 95 pts (74.7%) were male and the median age at diagnosis was 61 years (range 21-87 years). At the data cut-off date, the preliminary median PFS was 9.5 months (95% CI 7.6-11.8 months), and the preliminary median overall survival (OS) was 30.0 months (95% CI 18.6-38.7 months). 90 pts were treated with TRA + chemotherapy; XELOX (capecitabine + oxaliplatin) (28 pts, 31.1%) and capecitabine (20 pts, 22.2%) were the mostly commonly used regimens with TRA for first-line therapy, while paclitaxel was most commonly used with TRA for second-line (7.8%) and third-line (2.2%) therapy. TRA was also used in neoadjuvant (7 pts) and adjuvant (8 pts) settings prior to recurrence. During follow-up, 48 pts had progressive disease, and 21 (43.8%) received TRA beyond progression; 7 pts (14.6%) continued TRA after their 2nd disease progression. TRA-related adverse events (AEs) were observed in 26 pts (27.4%), including neutropenia in 10 pts (10.5%), thrombocytopenia in 9 (9.5%), and a decreased white blood cell count in 7 (7.4%). Only 6 pts (6.3%) experienced grade > = 3 TRA-related AEs (which included neutropenia and thrombocytopenia). Conclusions: In routine clinical practice in China, TRA combined with various chemotherapy regimens proved effective and well tolerated for treating mGC HER2+ pts. In addition to its use in palliative settings, TRA was also used as neoadjuvant/adjuvant treatment. Clinical trial information: NCT01839500.
Survival of elderly patients with advanced hepatocellular carcinoma with distant metastasis in pre- and post- sorafenib era: A population based study.
Authors: Budhathoki Nibash , Shah Binay Kumar
Published: September 2018

e15643

Background: Sorafinib was approved for advanced hepatocellular carcinoma in 2007. This study was conducted to study relative survival in elderly patients with advanced hepatocellular carcinoma in presorafinib and sorafinib era. Methods: We selected elderly patients (age ≥ 65 years) with advanced hepatocellular carcinoma (distant metastasis based on SEER’s LRD staging) from the Surveillance, Epidemiology, and End Results (SEER) database diagnosed during January 2000 to December 2013. We calculated one year and five year relative survival rates in pre- (2000-2006) and post- sorafinib (2008-2013) era by sex and ethnicity (Caucasians, African-Americans (AA) & Other) using SEER*Stat software. Results: There were total of 1533 patients in presorafinib era and 1694 patients in postsorafinib era. Of the total population, 71.30% were male and 28.70% female, 71% were Caucasian, 10% African-American and 19% were other race. Median age of patients was 73 years (65-99 years) and medial follow up period was 3 months (0-167 months) Survival rates improved significantly from pre- to post- sorafenib era (1 year RS: 10.60% ±0.80% vs 12.10±0.90%, p value = 0.001; 5 year RS: 1.10%±0.30% vs 1.8%±0.6%, p value = 0.001 ). The survival rate improved significantly for male (1 year RS: 11.60%±1.00% vs 12.30%±1.00%, p value = 0.006; 5 year RS: 1.00%±0.40% vs 1.3%± 0.6% , p value = 0.007) and Caucasian (1 year RS: 10.60%±1.00% vs 12.60%±1.10%, p value = 0.0008; 5 year RS: RS = 1.20%±0.40% vs 1.4%±0.7%, P value = 0.001) patients in post sorafenib era. There was no significant difference in the survival rates among any other cohorts examined.However in black (N = 153 vs 158 , RS = 6.80%±2.10% vs 7.80%±2.40% , p value = 0.77) or other races (N = 311 vs 311, RS = 12.20%±1.90% vs 12.80%±2.10%, p value = 0.30 ) , no significant improvement in survival was noted. Conclusions: Our study showed that relative survival rates of elderly patients with advanced hepatocellular carcinoma with distant metastasis has improved in the post-sorafenib compared to pre-sorafenib era. The improvement in survival is limited to male and Caucasian patients.
Down-regulation of neutral sphingomyelinase 1 to predict prognosis in hepatocellular carcinoma.
Authors: Lin Minglin , Liao Weijia , Jin Junfei
Published: September 2018

e15647

Background:Neutral sphingomyelinase 1 (NSMase1) catalyzes sphingomyelin to generate ceramide and mediates tumor cell apoptosis; however, the roles of NSMase1 in hepatocellular carcinoma (HCC) remain unclear. This study aims to evaluate the clinical value and prognostic significance of NSMase1 in HCC. Methods:A total of 142 patients who underwent radical hepatectomy were involved in this study. The expression of NSMase1 in HCC tissues and adjacent nontumorous liver tissues (ANLTs) was detected by quantitative real-time polymerase chain reaction and immunohistochemistry, and the association between NSMase1 expression and clinicopathologic features as well as prognosis of HCC patients was analyzed. Univariate and multivariate analyses were applied to identify independent prognostic factors. Results: NSMase1, at both mRNA and protein levels, was significantly decreased in HCC tissues compared to ANLTs. Low NSMase1 expression was associated with tumor size ( P= 0.029), TNM stage ( P= 0.040) and recurrence ( P= 0.006). Statistically, both the overall survival (OS) and disease-free survival (DFS) of low NSMase1 expression group were significantly shorter compared with high NSMase1 expression group ( p= 0.001; p= 0.001; respectively). Remarkably, the multivariate analysis showed that the low NSMase1 expression was an independent prognostic factor for OS (hazard ratio = 1.840; 95% confidence interval, 1.178-2.875, P= 0.007) and DFS (hazard ratio = 1.706; 95% confidence interval, 1.096-2.655, P= 0.018) in all enrolled HCC patients. Conclusions: NSMase1 down-regulation might actually serve as an independent prognostic factor for HCC patients. However, the roles of “NSMase1-ceramide” metabolic network in HCC deserve further studies.
Correlation of mesothelin expression and CD8 tumor infiltrating lymphocytes with prognosis in cholangiocarcinoma.
Authors: Kunk Paul Raymond , Obeid Joseph Mounir , Winters Kevin , Pramoonjago Patcharin , Brockstedt Dirk G. , Whiting Chan C. , Enstrom Amanda , Stelow Edward B , Bauer Todd W. , Slingluff Craig L. , Rahma Osama E.
Published: September 2018

e15650

Background: Cholangiocarcinoma (CC) is a rapidly progressing malignancy with an unmet treatment need. Little is known about the CC tumor immune microenvironment or about relevant antigenic targets. We hypothesized that lack of T cell infiltration or PD-L1 expression may identify patients at high risk of death, and that mesothelin may be a relevant antigenic target. Methods: A retrospective analysis was conducted of CC tumors at the University of Virginia from 2000-2014. TMAs were constructed of 3-4 cores from each tumor and were stained by IHC for CD4 and CD8 tumor infiltrating lymphocytes (TILs), mesothelin and PD-L1. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. TILs and protein expression were analyzed for association with overall survival, grouped as high or low expression based either on the median or the 33rdpercentile. Correlation with overall survival was assessed using a log rank test and a classification and regression tree with p-values < 0.05 being considered statistically significant. Results: Ninety-nine tumors were available for analysis: 26 intrahepatic, 37 hilar, and 36 distal. PD-L1 and mesothelin expression > 1% of tumor cells were found in 16% and 92% of tumors, respectively. CD4 and CD8 TILs were found in nearly all tumors (98% and 96%), with the majority showing intraepithelial CD4 and CD8 infiltration (73% and 68%). There were no significant associations between survival and PD-L1, mesothelin, or CD4 and CD8 infiltration. However when considered together, the group with low mesothelin/low CD8 (each below 33rdpercentile) had worse survival (9.1 months) compared to high mesothelin/high CD8 (25 months), high mesothelin/low CD8 (30.1 months) and low mesothelin/high CD8 (26.1 months), p = 0.015. Conclusions: CC tumors that lack CD8 infiltration and mesothelin expression have a poor prognosis. Mesothelin represents an attractive target in cholangiocarcinoma, opening the door for future immunotherapy for CC.
Efficacy and safety of vitamin K with sorafenib combination treatment against hepatocellular carcinoma: Open-label, randomized phase II study.
Authors: Haruna Yoshimichi , Inoue Atsuo , Kawamoto Seiichi
Published: September 2018

e15665

Background: Some animal studies showed that vitamin K enhances anti-cancer action of sorafenib for hepatocellular carcinoma (HCC). Our previous examination suggested that it might be because the vitamin K suppresses des-γ-carboxy prothrombin (DCP) production of tumor cells under ischemic status caused by sorafenib. The DCP is known as a tumor growth factor and a tumor angiogenesis factor. In order to clarify the efficacy and safety of vitamin K dosing in sorafenib treatment, we have performed a single center, open label, randomized, phase 2 study. Methods: Forty-four patients with advanced HCC were studied. They were randomly assigned in a 1:1 ratio, to receive vitamin K + sorafenib or to receive sorafenib alone, stratified according to macrovascular invasion and/or extrahepatic spread. The anti-cancer outcome was evaluated by modified RECIST. Results: There was no significant difference between the two groups in baseline characteristics (gender, age, Child-Pugh status and background liver disease). The progression-free survival (PFS) was significantly prolonged in the vitamin K + sorafenib group compared with sorafenib alone group (median time 3.7 months vs. 1.5 months, P = 0.001, hazard ratio 0.35). The disease control rates were 55% in vitamin K + sorafenib group and 18% in sorafenib alone group (P = 0.012). On the other hand, median overall survival (OS) times were 12 months in vitamin K + sorafenib group and 11.5 months in sorafenib alone group (P = 0.27, hazard ratio 0.67). However, 5 patients (23%) of 22 survived for more than 21 months in the vitamin K + sorafenib group, while one (5%) of 22 did in sorafenib alone group. There was no significant difference in incidence of adverse events between the two groups. Conclusions: The vitamin K dosing safely improved anti-cancer outcome of sorafenib treatment against advanced HCC. Clinical trial information: 000007855.
Metformin effects on clinical outcome in advanced HCC patients receiving sorafenib: Validation study.
Authors: Casadei Gardini Andrea , Faloppi Luca , De Matteis Serena , Foschi Giuseppe Francesco , Silvestris Nicola , Tovoli Francesco , Brunetti Oronzo , Umberto Vespasiani-Gentilucci , Ercolani Giorgio , Valgiusti Martina , Aprile Giuseppe , Fornaro Lorenzo , Saragoni Luca , Frassineti Giovanni Luca , Santini Daniele , Cascinu Stefano , Scartozzi Mario
Published: September 2018

e15684

Background: In 2015 we published a paper where we have assessed the outcome of patient with HCC treated with metformin(M)and sorafenib(S). The data show that the concomitant use of S and m was associated with a lower PFS and OS respect for patients receiving S alone. The aim of this study was to validate the prognostic significance of m in patients with HCC treated with S. Methods: 280 patients with HCC consecutively treated with S twice daily between March 2008 and August 2016 were included in the study. Patients who had been taking insulin (I) for at least 5 years at the time of the HCC diagnosis were considered “ patients with diabetes treated with I,” whereas those who had been on m at for at least 5 years when HCC was diagnosed were considered “ patients with diabetes treated with M.” Results: In patients treated chronically with m the treatment with S was associated with a median PFS of 1.9 months (95% CI 1.8-2.3) compared to 3.7 months (95% CI 3.1-4.6) for patients without DM2 and compared to 8.4 months (95% CI 5.3-11.4) for patients treatment chronically with I (P < 0.0001). In patients treated chronically with m the treatment with sorafenib was associated with a median OS of 6.6 months (95% CI 4.6-8.7) compared to 10.8 months (95% CI 9.0-13.1) for patients without DM2 and compared to 16.6 months (95% CI 14.5-25.5) for patients treatment chronically with I (P = 0.0001). Metformin effects on clinical outcome were also investigated in relation to ORR. Patients treated chronically with metformin showed a higher percentage of progression at the first CT re-evaluation than those patients treatment with I and patients without DM2 (75.8% vs. 14.7% vs 38,8%, respectively). Considering the overall population, the risk of progression, was higher in DM2 patients taking m compared with patients without DM2 (HR = 1.91, 95% CI 1.28-2.8,). Regarding the risk of survival, similar results were observed (HR = 1.70, 95% CI 1.14-2.55). Conclusions: These results confirm an increased tumor aggressiveness and resistance to S in patients treated with m cronicaly.Molecular alterations in transporter genes or transcription factors involved in m molecular action and pharmacokinetics could contribute to a different response to these drugs combination.
Outcomes of peptide receptor radionuclide therapy (PRRT) in metastatic grade 3 neuroendocrine tumors (NETs).
Authors: Lung Mei Sim , Hofman Michael , Kong Grace , Thang Sue-Ping , Michael Michael , Hicks Rodney J
Published: September 2018

e15694

Background:Grade 3 (G3) NETs have a poor prognosis and limited treatment options (usually chemotherapy). PRRT is a potential treatment option if all sites of disease demonstrate high uptake on somatostatin-receptor imaging (SSRI). We retrospectively evaluated the efficacy of PRRT in G3 NETs. Methods: We reviewed records of patients with metastatic G3 NETs (Ki-67 > 20%) who received PRRT at our institution. Patients were treated with up to 5 cycles of PRRT, predominantly 177Lu-DOTA-octreotate. Further maintenance PRRT was administered upon progression if deemed suitable on SSRI. Radio-sensitizing chemotherapy was administered unless contra-indicated. Kaplan-Meier estimate was used to determine median overall survival (OS) and median time to new treatment/death (TNTD) defined from start of PRRT. Subgroup-analysis was performed for patients with Ki67 < 55% and ≥55%. Results: 26 patients with metastatic G3 NET received PRRT; 22 combined with chemotherapy (capecitabine/temozolomide (n = 12), 5-fluorouracil or capecitabine (n = 8), other (n = 2)). 58% were male. The median age was 62 (range 16-78 years). 61% had pancreatic NET, 19% small bowel, 8% lung, 8% unknown primary, 4% rectal. 77% had received at least one line of prior chemotherapy. 54% received prior platinum-based chemotherapy. Median follow-up was 33 months (range 8-83 months). Patients received a median of 4 cycles of PRRT (range 1-15). The estimated median OS from start of PRRT was 18 months: for Ki-67 < 55% (n = 21), 20 months; and Ki-67≥ 55% (n = 5), 9 months. The estimated median TNTD was 12 months: for Ki-67 < 55%, 16 months; and Ki-67≥55%, 4 months. 31% of patients were alive without a change in treatment modality following PRRT. Conclusions: In thispoor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.
Influence of organ location and sex of patient on pancreatic neuroendocrine tumor 5-year survival.
Authors: Botta Gregory P. , Bhangoo Munveer Singh , Sigal Darren
Published: September 2018

e15713

Background: Pancreatic neuroendocrine tumors (PNET) represent a rare tumor histology among patients diagnosed with pancreatic cancer (less than 2% incidence). These tumors arise from the endocrine tissues of the pancreas and can present with a variable clinical course. We sought to examine the overall survival (OS) of patients based upon sex and anatomic location via the SEER database. Methods: Accessing the SEER-Medicare database, we identified 3,242 patients with both Pancreatic Cancer and Neuroendocrine Tumor (NET) histologic validation using ICD-O-3 Codes while excluding Large Cell, Small Cell, and Mixed Endocrine-Exocrine tumors. We then sub-stratified the data to male (N = 1816) and female (N = 1426) sex as well as pancreatic location: Head (Male = 831; Female = 657), Body (Male = 283; Female = 258), or Tail (Male = 701; Female = 510). We excluded PNETs of the pancreatic duct as there were only 2 cases (Male = 1; Female = 1). All comparison tests were run with SEER*STAT 8.3.2 via a Two-Sample t-Test Assuming Equal Variances. OS was analyzed using the Kaplan–Meier method. Results: Overall, both Male and Female patients with PNET have significantly improved 5-Year survival compared with those patients with Pancreatic Adenocarcinoma ((47.47% (n = 3242) vs 6.6% (n = 117,204), p < 0.05). There is no difference in 5-Year OS between Male (44.9%) and Female (50.5%) patients with PNET accounting for all locations. There is a trend towards significance in improved 5-Year OS in Female patients with Tail PNET versus Male patients with Tail PNET (55.8% (n = 510) vs 48.6% (n = 701), p < 0.06). Significantly, Female patients with Tail PNET have a significantly higher 5-Year OS compared to Female patients with Head PNET (55.8% (n = 510) vs 46.9% (n = 657), p < 0.05). There was a trend towards improved 5-Year OS in Female patients with Tail PNET versus those within the Body (55.8% (n = 510) vs 48.6% (n = 258), p < 0.01). Conclusions: Based upon this population study, Female patients with PNET localized to the Tail have a significantly higher 5-Year OS than Female patients with PNET localized to the Head of the Pancreas. These same patients trend towards improved survival when compared with Female patients with Body PNET as well as Male patients with Tail PNET.
A systematic review examining the relationship between progression-free survival and overall survival in adults with untreated metastatic pancreatic cancer.
Authors: Dabbous Omar , Wight Colin , Crathorne Louise , Qadan Ammar
Published: September 2018

e15724

Background: The majority of pancreatic cancers are diagnosed in advanced stages with a median survival of 3 to 5 months. From 2005 to 2012, the US Food and Drug Administration approved 41 oncology drugs; surrogate endpoints were used in 84% of the trials providing the basis of approval. The aim of this systematic review was to evaluate the relationship between PFS/TTP and OS in metastatic pancreatic cancer. Methods: A systematic literature review used the Centre for Reviews and Dissemination principles to identify studies that reported median PFS or TTP and OS. We searched Medline, Medline In-Process, and Embase, with the following additional limits: English language and published 1/1990 to 7/ 2016. Selection criteria, defined a priori, included chemo, immuno or targeted therapy, randomized controlled studies (Phase 2 or 3) in patients with metastatic pancreatic cancer. Studies were assessed for quality using the Cochrane Risk of Bias tool and the Jadad scale. Studies were excluded if full-text articles were not available, and if patients received chemotherapy plus radiotherapy or surgery. Correlation analyses and weighted linear regression were used to assess the association between median PFS/TTP and median OS. The distributions of median PFS/TTP and OS were examined using scatterplots. Results: 1,691 studies were identified. After screening by title and abstract, 212 full articles were assessed, of which 28 studies (evaluating 6,734 patients) met the selection criteria. The mean median PFS/TTP and OS were, respectively, 3.82 months (range 1.2 to 6.8 months), and 7.06 months (range 2.5 to 11.9 months). The correlation coefficient was 0.837; 95% CI (0.734-0.903) indicating a very strong positive correlation between median OS and median PFS/TTP. Regression analysis indicated that median PFS/TTP was a highly significant predictor of median OS = 2.177 + 1.247 * median PFS/TTP (p < 0.001). Conclusions: The analysis demonstrates a very strong positive correlation of median PFS/TTP with median OS for the treatment of metastatic pancreatic cancer, which reinforces the hypothesis that PFS or TTP is a useful surrogate endpoint for OS in this cancer setting.
Relationship between diagnostic interval and pancreatic ductal adenocarcinoma (PDAC) resectability: A single-center retrospective analysis.
Authors: Deshwar Amar , Torto Deirdre , Sugar Elizabeth , Laheru Daniel A. , Yarchoan Mark
Published: September 2018

e15738

Background: PDAC often presents with nonspecific symptoms and the workup for suspected PDAC is not standardized. While surgery remains the only curative therapy, only 20% of PDAC is resectable due to local extension or metastasis. We examined the relationship between diagnostic interval of PDAC and surgical resectability. Methods: We performed a retrospective chart review of patients evaluated for PDAC at the Center for Pancreas Cancer at Johns Hopkins in 2014. Data were collected on the patient, diagnostic, and treatment time intervals (defined as days between first symptoms to medical presentation, presentation to diagnosis, and diagnosis to treatment), diagnostic tests performed, and the type of initial treatment. Asymptomatic patients diagnosed incidentally, or those for whom initial medical presentation was unclear, were excluded from our analysis. Results: Of 453 charts reviewed, 116 patients met our inclusion criteria. The median patient interval was 14 days (IQR 6-30), the median diagnostic interval was 22 days (IQR 8-46), and the median treatment interval was 26 days (IQR 15-35). The median number of diagnostic tests performed was 8 (IQR 6-11). At the time of diagnosis, 7 patients (6%) had stage 1, 53 (46%) had stage 2, 24 (21%) had stage 3, and 32 (28%) had stage 4 disease. A total of 38 patients (33%) received upfront surgery for treatment of PDAC and 78 (67%) received nonsurgical treatment. Non-white individuals had lower odds of receiving surgery (Adjusted Odds Ratio [aOR]: 0.09, 95% Confidence Interval [CI]: 0.01, 0.74, p = 0.024). After adjusting for age, sex, race and diagnostic clinic, the odds of receiving surgery significantly increased for individuals with a patient interval of 1 month or less (aOR: 3.47, 95% CI: 1.003, 12.0, p = 0.010) and with a diagnostic interval of 2 months or less (aOR: 15.3, 95% CI: 1.90, 122, p = 0.019). Conclusions: A patient interval of less than 1 month and a diagnostic interval less than 2 months for symptomatic PDAC were associated with an increased probability of upfront surgical treatment. These data indicate that extended intervals prior to PDAC diagnosis may reduce the odds of obtaining a potentially curative treatment.
Effect of Redd1 loss on proliferation and metastasis of pancreatic cancer cells with KrasG12D-LOH by inhibiting glycolysis.
Authors: Hu Mingyue , Huang Peilin , Ma Yu , Ling Sunkai , Li Yuan , Chen Baoan , Xu Yueshuang
Published: September 2018

e15741

Background: Aerobic glycolysis, regulated by mammalian target of rapamycin (mTOR) pathway, plays an important role in pancreatic carcinogenesis. Regulated in development and DNA damage response (Redd1) constitutes an important regulator of mTOR signaling. Previously, we observed that the loss of heterozygosity (LOH) status of Kras mutations (e.g. KrasG12D) is associated with an increased Redd1 expression. Here, we investigated the functional relevance of Redd1 in the context of KrasG12D-LOH. Methods: Murine KrasG12D-LOH/KrasG12Dpancreatic cancer cells isolated from genetically engineered mice were used in this study. The glycolysis dependence was detected by CCK8 assays after treated by glycolysis inhibitor 2-Deoxy-D-glucose (2-DG). Redd1 expression was down-regulated using shRNA transfection. Cell proliferation was determined by CCK8 and colony formation assays. Cell invasion and migration was measured by transwell and wound-healing assays. The levels of lactic acid and ATP were tested by ELISA kit. Genes related to glycolysis and mTOR signal were evaluated by western-blot and quantitative RT-PCR. Results: Compared with KRASG12D pancreatic cancer cells, the viability of KRASG12D-LOH cells decreased significantly in the presence of 2-DG. After Redd1 suppression, the proliferative and invasive potentials of KRASG12D-LOH cells decreased significantly when compared with blank group and negative group. The levels of lactic acid and ATP were also reduced by Redd1 down-regulation. Furthermore, the signal activity of mTOR pathway and Pkm2 and Hk2 expression were reduced dramatically, while Tsc1 and Tsc2 expression were unaffected. Conclusions: The LOH status of KRASG12D renders the pancreatic cancer cells additive to glycolysis, which further affect the proliferative and invasive potentials via the function of Redd1/mTOR. These data underscore the importance of KRASG12D-LOH in regulating cancer glucose metabolism.
Phase two clinical trial of combination oxaliplatin, irinotecan, and cetuximab for patients with locally advanced or metastatic pancreatic cancer.
Authors: Abdou Yara , Friend Sarah Cooke , Patt Yehuda Z. , Gan Christine , Lee Fa-Chyi
Published: September 2018

e15781

Background: Pancreatic cancer remains a leading cause of cancer death with limited treatment options. After promising results from a retrospective chart review of the combination of irinotecan, oxaliplatin, and cetuximab (OIC), a prospective phase II trial was conducted to determine the efficacy and safety of this novel combination regimen in patients with advanced pancreatic cancer. Methods: Patients aged 18 and older, with a performance status of 0-2, and a life expectancy of minimum 12 weeks were eligible if they had confirmed locally advanced or metastatic pancreatic cancer. Patients were treated with intravenous irinotecan at 90 mg/m2, oxaliplatin at 60 mg/m2, and cetuximab at 250 mg/m2on day 1 of a 14-day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate (ORR) and disease control rate (DCR) per RECIST 1.1 criteria. The secondary endpoints included progression free survival (PFS), overall survival (OS), and tolerability of the regimen. Results: 60 patients were enrolled and 58 were evaluable; of these, 78% had metastatic disease and 22% had locally advanced cancer at time of enrollment. 41.4% of patients had received at least one prior line of cytotoxic chemotherapy. The ORR and DCR were 6.9% and 58.6%, respectively (complete response n = 1; partial response, n = 3; stable disease, n = 30). The median PFS was 3.6 months [95 % confidence interval (CI): 2.24-4.31], and median OS was 4.8 months [95 % CI: 3.68-6.25]. The most common grade 3 or 4 toxicities were hypokalemia (20.7%), fatigue (17.2%), abdominal pain (15.5%), hyperglycemia (13.8%) and dehydration (13.8%). Conclusions: OIC on a two-week regimen was well tolerated and demonstrated a high disease control rate, encouraging further investigation of this regimen in advanced pancreatic cancer. Clinical trial information: NCT00871169.
A pilot study of immune checkpoint inhibition in combination with radiation therapy in patients with metastatic pancreatic cancer.
Authors: Duffy Austin G. , Makarova-Rusher Oxana V. , Kleiner David E , Alewine Christine , Figg William Douglas , Steinberg Seth M. , Levy Elliot B , Krishnasamy Venkatesh P , Wood Bradford J. , Citrin Deborah E. , Jones Jennifer C , Greten Tim F.
Published: September 2018

e15786

Background: Durvalumab is a human IgG1 monoclonal antibody directed against PD-L1. Tremelimumab is a selective human IgG2 monoclonal antibody against CTLA-4. Several studies have documented an increase in peripheral antitumor immunity following radiation. The hypothesis of this study is that the effect of immune checkpoint inhibition (ICI) can be enhanced by radiation in pancreatic adenocarcinoma (PAC). Methods: Patients with histologically confirmed metastatic PC with primary in-situ or metastatic SBRT-amenable disease are being enrolled to this pilot study. Primary objective to determine safety, tolerability and feasibility of immune checkpoint inhibition [comprising either Durvalumab alone (Cohort A), or combined durvalumab and tremelimumab (Cohort B)] in combination with stereotactic body radiation therapy (SBRT) at two different schedules (8Gy/single fraction or 25Gy in 5 fractions). Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 accessible for biopsy. No limit to the number of prior chemotherapy regimens; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active autoimmune disorders. Results: N = 24 patients with chemorefractory metastatic PC have so far been enrolled; M/F = 13/11; Median age = 61. Treatment was well tolerated. No DLT encountered. The most common toxicity was fatigue (G1/2) in all patients in DL2. 5/24 pts had early discontinuation ( < 4 wks) due to rapid PD. No objective responses have been seen. 5 pts (21%) had SD as best response. Conclusions: Immune checkpoint inhibition in combination with SBRT in advanced pancreatic cancer is safe and feasible. Preliminarily no objective responses have been seen for these schedules of SBRT with durvalumab. The study is continuing with evaluation of SBRT with dual checkpoint inhibition (durvalumab and tremelimumab). Clinical trial information: NCT02311361.
Outcomes of elderly patients with muscle invasive bladder cancer (MIBC) treated with cystectomy or radiation therapy (RT): A surveillance epidemiology and end results (SEER) database analysis.
Authors: Tripathi Abhishek , Friderici Jennifer , Preston Mark A , Trinh Quoc-Dien , Mouw Kent , Beard Clair , Bellmunt Joaquim , Stewart James A. , Kibel Adam S. , Harshman Lauren Christine
Published: September 2018

e16001

Background: Cystectomy and RT are both utilized in the management of MIBC. Elderly pts are more likely to be treated with non-surgical approaches that include RT. Using the SEER database, we evaluated outcomes in elderly pts with MIBC. Methods: Inclusion required pts ≥75 years with MIBC (T2-4, N0-3, M0). Cohorts were based on treatment received: cystectomy; RT; TURBT or no treatment. A propensity score was developed to address differences in treatment allocation according to age, race, sex, T and N stage, tumor location, and year of diagnosis. Propensity-adjusted competing risks analysis compared cancer specific mortality (CSM) between cohorts. Results: We identified 8506 pts with MIBC treated from 2007-2012. Of the 8423 pts with adequate treatment data, 26% had cystectomy (2196), 21% underwent RT (1752), 49% received TURBT alone (4128), 3% (262) received no treatment, and 1% (85) received both RT and cystectomy. Compared to RT, cystectomy cohort had a significantly higher proportion of pts < 80 yrs (49% vs. 25%) and was surgically staged with a higher degree of node + (22% vs. 4%) and ≥T3 disease (58% vs. 17%; all P < 0.001). At median follow-up of 10 mo (0-71), 48% (1061) of cystectomy pts and 61% (1064) of RT pts had died. MIBC was the leading cause of death (31% cystectomy, 39% RT). On propensity adjusted analysis, RT was associated with significantly worse CSM (HR: 1.62; 95% CI: 1.45-1.82) compared to cystectomy. Patients treated with TURBT or no treatment had the worst outcomes (5 year CSM: 71% each). Conclusions: Even in elderly pts with competing morbidities, MIBC accounted for more deaths than other causes. In this SEER cohort, non-surgical approaches involving RT were associated with significantly worse outcomes compared to cystectomy. However, worse performance status, less concurrent chemotherapy use, discrepancies between pathologic and clinical staging, use of lower dose RT, or lack of completion TURBT could not be examined and could have contributed to worse outcomes in the RT cohort. These results highlight the need for aggressive management of fit elderly patients with cystectomy or multimodality BPT.
Frequent expression of androgen receptor (AR) on tumor cells of muscle-invasive (MIUC) and metastatic urothelial carcinoma (mUC): Insights for clinical research.
Authors: Colecchia Maurizio , Lo Vullo Salvatore , Giannatempo Patrizia , Raggi Daniele , Perrone Federica , Nicolai Nicola , Catanzaro Mario , Biasoni Davide , Torelli Tullio , Piva Luigi , Stagni Silvia , Salvioni Roberto , De Braud Filippo G. , Procopio Giuseppe , Mariani Luigi , Necchi Andrea
Published: September 2018

e16019

Background: Advanced UC treatment is being revolutionized by immunotherapy (IT). However, < 30% of patients (pts) will benefit from IT, and additional therapeutic targets are needed. Findings from analyses supporting an investigator-led, AR-based clinical research program are presented. Methods: From 09/2015, we collected the archival tissue blocks from pts who have been treated or consulted at our center and received platinum-based chemotherapy (CT) for MIUC or mUC. Immunohistochemistry (IHC) was performed on 3µm slides using mouse anti-human AR monoclonal Ab (Dako, clone AR441). ≥1% cutoff for AR+ IHC of tumor cells (TC) was used. AR-expressing pts were further stratified as follows: 1-5%, 5-25%, and 25-100%. Univariable (UVA) and multivariable (MVA) Cox models for overall survival (OS) were fitted, the latter adjusted for clinical stage (MIUC vs mUC), presence of visceral metastases, platinum CT type. OS was calculated from the date of first administration of CT. Exploratory PD-L1 co-expression, by TC or stroma (SP142 Ab, 1% cutoff), was analyzed in all pts. Results: 105 pts (46 MIUC and 59 mUC) had their tumor stained. 80 (76.2%) had bladder primary tumor, 85 (80.9%) had pure UC. 59 received cisplatin and 46 carboplatin. Overall, 37 pts (35.2%) had AR-expressing TC, 17 (16.2%) with ≥25% expression. Cox models were built on 93 pts with follow-up duration of ≥6 months. AR-expressing was equally distributed between MIUC and mUC pts (44.4% and 55.6%). On UVA, AR expression was not associated with OS, neither dichotomizing AR+/AR- pts (p = 0.477) nor after accounting for AR-positivity strata (p = 0.845). The same results were confirmed on MVA (p = 0.505 and p = 0.875). In AR+ vs. AR- pts, PD-L1 was equally expressed in the stroma (67.5 vs 57.9%) but less expressed by TC (39.4% vs 52%). Conclusions: AR is frequently expressed on TC of pts with MIUC and mUC, and AR expression does not seem to be associated with OS in these pts. AR pathway is worthy of clinical studies to synergistically act with anti-PD-L1 therapy. AR sequencing and FISH analysis in positive pts is ongoing, and a clinical program of a named-basis administration of antiandrogen therapy has started at our center.
Cisplatin and gemcitabine versus carboplatin and gemcitabine in metastatic bladder cancer: Survival analysis of veterans' health care data.
Authors: Kunthur Anuradha , Siegel Eric R , Govindarajan Rangaswamy
Published: September 2018

e16023

Background: Background: Cisplatin and gemcitabine combination chemotherapy is the standard regimen used for the treatment of metastatic bladder cancer. Most Veterans Administration (VA) patients with metastatic bladder cancer are elderly or with poor renal function, and are considered not good candidates for cisplatin administration. It is a common practice to substitute carboplatin for cisplatin in this population. Methods: Methods: We identified stage IV bladder cancer patients treated initially with cisplatin plus gemcitabine (Ci+G) or carboplatin plus gemcitabine (Ca+G) at VA medical centers from 2000 to 2010. The data was obtained via the VA central cancer registry from all VA medical centers across the country. Overall survival (OS) was summarized as Kaplan-Meier medians and compared for difference between platinum groups via Cox regression. Results: Results: 196 subjects () with stage IV bladder cancer were identified. There were 194 males , 78 received Ca+G, 118 received Ci+G. 149 deaths occurred during 197.49 person-years of follow up, for a median OS of 10.35 months. Median OS was 11.14 months with Ca+G versus 10.35 months with Ci+G. Cox regression revealed nearly equal group mortality rates, with Ca+G having a hazard ratio (90% confidence limits) of 1.02 (0.77–1.34) compared to Ci+G ( P= 0.93). Conclusions: Conclusion: Patients treated with Ca+G and Ci+G regimens had similar median OS, supporting the substitution of carboplatin for cisplatin with gemcitabine in this patient population.
Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and in vivo through induction of cell cycle arrest at the G2-M phase.
Authors: Li Qingdi Quentin , Hsu Iawen , Sanford Thomas , Railkar Reema S. , Agarwal Piyush K.
Published: September 2018

e16024

Background: Protein Kinase D (PKD) is implicated in tumor growth, death, invasion, and progression. CRT0066101 is an inhibitor of PKD and has antitumor activity in several types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer remain unknown. Methods: The MTS assay was used to evaluate the ability of CRT0066101 to inhibit cellular proliferation in bladder cancer cells. Cell cycle was analyzed by flow cytometry. Protein expression and phosphorylation were assessed by western blotting. Results: We showed that CRT0066101 suppressed the proliferation and migration of 4 bladder cancer cell lines in vitro. We also demonstrated that CRT0066101 inhibited tumor growth in an in vivo mouse model of bladder cancer. To verify the role of PKD in bladder tumor, we found that PKD2 was highly expressed in 8 bladder cancer lines and that RNA interference-mediated silencing of the PKD2 gene dramatically reduced bladder cancer growth in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was confirmed by demonstrating that the levels of PKD2 and phospho-PKD2 (Ser-876) were markedly decreased in CRT0066101-treated bladder cancer. In addition, our cell cycle analysis by flow cytometry revealed that CRT0066101 arrested bladder cancer cells at the G2-M phase. We further validated these data by immunoblotting showing that treatment of bladder carcinoma cells with CRT0066101 downregulated the expression of cyclin B1, cdc2 and cdc25C, but elevated the levels of p27kip1, gadd45a, chk1/2, and wee1. Finally, CRT0066101 was found to increase the phosphorylation of cdc2 and cdc25C, which lead to reduction in cdc2-cyclin B1 activity. Conclusions: These novel findings suggest that CRT0066101 inhibits bladder cancer growth through modulating the cell cycle G2 checkpoint and inducing cell cycle G2-M arrest, which lead to blockade of cell cycle progression. QQL and IH contributed equally to this work.
Health resource utilization and costs for stage IV bladder cancer in community oncology settings.
Authors: Shenolikar Rahul A. , Fisher Maxine D. , Miller Paul J. , Walker Mark Stephen , Fenton Moon Jung
Published: September 2018

e16032

Background: Current real-world data on patients with metastatic bladder cancer in the community setting are limited. This study describes patient characteristics, health resource utilization (HRU), and costs for this population. Methods: Medical records data from adults diagnosed with stage IV bladder cancer (T4b, node-positive, or distant metastatic disease) between 1/1/2008 and 6/1/2015 were retrospectively collected from a network of 10 US community oncology practices. Patient characteristics, HRU, and costs were assessed. Regression models were used to estimate group effects on utilization and costs through three progression-based lines. Results: Of 508 patients, 75% were male, 79% white, 15% African American, and 71.5% were aged ≥65 years (median age, 71 years; range 35-92 years). Overall, 76.4% were current or past tobacco users. The most prevalent comorbidities were diabetes (23.4%), renal disease (16.5%), and chronic obstructive pulmonary disease (COPD; 12.4%). Overall, 70.1% had distant metastases at diagnosis, including bone (24.0%), lung (23.4%), and liver (14.6%). Of 341 patients analyzed for HRU and cost, 58.9% had hospital visits and 11.7% had emergency department (ED) visits. Age, smoking history, and presence of diabetes were predictors of hospitalization (all P< 0.05). Overall mean monthly total healthcare cost was $18,778 ± $47,006 (median $6285), which was driven by hospitalizations ($14,660 ± 44,686, median $1717). Mean monthly ED cost was $776 ± $5530, median $0. Mean monthly cost for office visits was $186 ± $189, median $152. Procedures in the medical oncology setting had a mean monthly cost of $707 ± $1179, median $395. Other costs included systemic therapy ($267 ± $704, median $117), infused supportive care drugs ($758 ± $1458, median $0), and other drugs ($1422 ± $3745, median $136). Age, presence of diabetes, presence of any comorbidities, body mass index, and impaired composite performance status were predictors of healthcare costs (all P< 0.05). Conclusions: This study showed significant HRU and costs for metastatic bladder cancer patients suggesting high unmet need.
Correlation of tumor enhancement and imaging features on multiphasic multidetector CT with microvessel density as a step toward a minimally invasive method to predict Fuhrman nuclear grade in patients with clear cell renal cell carcinoma.
Authors: Coy Heidi , Young Jonathan , Douek Michael , Magyar Clara , Sisk Anthony , Brown Matthew S. , Sayre James , Raman Steven
Published: September 2018

e16049

Background: Clear cell renal cell carcinoma (ccRCC) is the most common tumor of the kidney. Up to 70% are incidentally detected on multiphasic CT. The prognosis for patients with ccRCC is related to Fuhrman grade (FG) and is diagnosed by biopsy or excision. There is a great need for a non-invasive method to assess tumor grade which may help inform clinical decision-making. The purpose of our study is to determine if contrast enhancement on CT predicts FG and microvessel density (MVD) of ccRCC lesions and to assess which combination of quantitative and qualitative radiological features and clinical features predict high FG ccRCC lesions. Methods: With IRB approval for this HIPAA-compliant retrospective study, our pathology and imaging databases were queried to obtain a cohort of ccRCC with a preoperative multiphasic (unenhanced (U), corticomedullary (C), nephrographic (N), and excretory (E)) CT scan. Tumors were stained with CD4 to quantify % MVD. Spearman’s rank correlation was calculated to test the strength of the association between CT enhancement, %MVD and FG. Stepwise logistic regression analysis was performed to determine the quantitative and/or qualitative feature with the highest performance in predicting high FG tumor. The multivariate logistic regression analysis was evaluated using ROC curves and AUCs. Results: Our cohort had 127 patients with 89 low-grade tumors and 43 high-grade tumors. The %wash-in of enhancement from the U to the C phase showed a significant correlation with %MVD of the tumor (R2= 0.181,p < . 001) as did enhancement of the tumor in the early C phase with %MVD (R2= 0.159,p < . 001). There was a significant inverse correlation with %MVD and FG (R2= 0.137,p < . 001). T-stage, tumor size, %MVD and presence of renal vein invasion were determined to be significant independent predictors of high grade lesions with an AUC of .838 (95% CI .748-.927). Conclusions: Lower grade ccRCC tumors have a higher MVD. Therefore, contrast material washes in at a faster rate from the UN to the CM phase, enabling low grade to be discriminated from high-grade tumors on CT.
The evolution of clinical trials in renal cell carcinoma: A status report for 2013-2016 from the clinicaltrials.gov website.
Authors: Ghatalia Pooja , Pisarcik David , Koenigsberg Rebecca , Handorf Elizabeth , Geynisman Daniel M. , Zibelman Matthew R.
Published: September 2018

e16050

Background: The treatment paradigm for renal cell carcinoma (RCC) continues to rapidly evolve. We previously published a snapshot analysis of clinical trials in RCC using the publicly available ClinicalTrials.gov registry. Here we present a 3 year update in order to understand the current trends in RCC clinical research, to identify opportunities for improvement, and to compare this data to the landscape in 2013. Methods: The Website’s advanced search function was used to search for the terms “renal cell carcinoma”, “kidney cancer”, “kidney neoplasm” or “renal neoplasm”. The search was further refined to “open studies”, “interventional” and “age ≥18”. Basket trials with ≥7 tumors with non-RCC tumor histologies, terminated studies and pediatric studies were excluded. The phase, stage, treatment setting, type of intervention, study design, histologies, use of biomarkers, studied outcomes, sponsors and location of the trials were recorded. Results: We locked our search on May 26, 2016 and 165 trials were eligible, compared with 169 trials on Sep 25, 2013. There were more phase I and I/II trials in 2016 compared to 2013 (p = 0.05): phase I (25.6% vs 15.4%) and phase I/II (15.2% vs 9.5%). More clinical trials in 2016 compared to 2013 used immunotherapy (IT) alone or in combination with other drugs (24.2 % vs 10.7%, p = 0.001), and the use of targeted therapy alone (TT) declined (32.9% vs 47.9%, p = 0.005). IT alone was used in 15.2% of current trials, compared to 5.96% in 2013. TT+IT combination trials more than doubled (6.7% vs 2.3%, p = 0.07). The number of trials with treatment in neoadjuvant/adjuvant settings in 2016 and 2013 were similar (9.7% vs 10.6%, p = 0.77), respectively. Compared to 2013, the number of trials with non-clear cell histology remained low (n = 10). Many more trials were sponsored by pharmaceutical industry in 2016 vs 2013 (41.5% vs 16.0%, p = < 0.001). Conclusions: More clinical trials included immunotherapy in 2016 compared to 2013, and there was a significant increase in industry sponsored trials. The increase in industry sponsored studies may reflect use of new expensive drugs. More studies in (neo)adjuvant settings and for non-clear cell histologies are needed.