bluuebunny/crossref_metadata_2025 huggingface dataset:
R0 resection of locally advanced pancreatic cancer encasing major visceral arteries using arterial reconstruction: Short- and long-term results.
Authors: Genyk Yuri , Matsuoka Lea , El-Khoueiry Anthony B. , Iqbal Syma , Buxbaum James , Selby Rick , Vandam Jacquez , Lenz Heinz-Josef
Published: March 2020

e14679

Background: Locally advanced disease is found in about 40% of patients with pancreatic cancer at initial presentation. Tumors involving major visceral arteries are commonly deemed unresectable. In this study we analyzed the feasibility of R0 resection of locally advanced pancreatic cancer encasing major visceral arteries using arterial reconstruction. Methods: The following data were collected: age, gender, operative details, post-operative complications, chemotherapy and/or radiation therapy and overall and disease free survival. Patient survival was calculated utilizing Kaplan-Meier survival probability estimates. Results: From Dec., 2002 to Jan., 2012, 13 patients underwent pancreatic resection with concomitant resection and reconstruction of major visceral arteries for pancreatic cancer (9 males and 4 females, median age 63 yrs (range: 50–82 yrs)). The arterial involvement included celiac artery (n=6), superior mesenteric artery (n=4) and hepatic artery (n=3). Resections included pancreatico-duodenectomy (n=9), distal pancreatectomy (n=3), and total pancreatectomy (n=1). Management of the arterial involvement included: resection of celiac axis without reconstruction (n=2), reconstruction of one artery (n=6), two arteries (n=4) and three arteries (n=1). Nine of the 13 patients underwent simultaneous venous reconstruction. R0 resection was accomplished in 11, R1 in 1, and R2 in 1 patient. Ten of the 13 patients received neoadjuvant and/or adjuvant chemo- or chemo-radiation therapy outside protocols. To date, 4 patients are alive and disease free at 1, 4, 15 and 111 months, and 1 patient is alive with recurrence at 100 months. Six-month patient survival was 65% and median overall survival was 17 months. The probability of 5-year survival was 22%. Conclusions: Our study indicates that in select patients with locally advanced pancreatic cancer with involvement of major visceral arteries R0 resection is feasible by performing pancreatic resection with arterial reconstruction. The survival data in this group of patients are encouraging and provide the opportunity to reconsider the contraindications to surgical management of such patients.
HER2 positive gastroesophageal cancer in an Irish population.
Authors: Jayaram Anuradha , Battley Jodie E , O'Connor Kate , Bennett Michael WIlliam , Jamaluddin Muhammad Faisal , Boychak Oleksandr Volodymyrovych , Sheehan Margaret , Power Derek Gerard , Leonard Gregory
Published: March 2020

e14687

Background: Gastroesophageal cancer is a major cause of cancer-related mortality. HER2 is overexpressed in ~ 7-34% of gastroesophageal (GE) adenocarcinomas. The ToGA study, established the benefit of trastuzumab in combination with chemotherapy in HER2 positive metastatic GE tumours. In this study, 22% of patients were HER2 positive {immunohistochemistry (IHC)3+ or fluorescence insitu hybridization (FISH)(+)}. Potential heterogeneity of HER2 amplification, overexpression, and incomplete membrane staining of HER2 by IHC leaves some ambiguity in HER2 testing and definition of HER2 positive GE tumours. We report a multi-center Irish experience by examining HER2 status by IHC and FISH in GE tumours. Methods: HER2 testing was performed on adenocarcinoma biopsy or resection specimens of patients with early stage and metastatic GE tumors between 2008 - 2011. We defined HER2 positive as IHC3+ or FISH(+) {HER2:17ch ≥ 2}. In addition, age, gender, smoking history, histology, stage of disease, treatment, and survival data were recorded. Results: A total of136 Caucasian patients with early stage and metastatic GE cancers were identified. Median age was 69 yrs (ranging from 25 – 96). Data available for analysis was conducted from 111 patients with 10% FISH(+). There are 73 patients with early stage and 38 with metastatic disease. Five metastatic cases (13%) were FISH(+) (of whom 3 IHC3+, 1 IHC2+, 1 IHC1+), 33 cases were FISH(-). Sites of metastatic disease in the FISH(+) cohort were liver, peritoneal, and bone metastasis. In the FISH(-) group, sites of metastatic disease were predominantly liver. Interestingly CNS disease is seen exclusively in the FISH(-) cohort. Of the early stage patients, only 6 patients (8.2%) were FISH(+) (of whom 3 IHC3+, 2 IHC2+, 1 IHC1+). With respect to tumour heterogeneity of HER2 amplification, in IHC3+, 82% were FISH(+), IHC2+, 17% were FISH(+) and IHC1+, 6% were FISH(+). There was 100% concordance between IHC0 and FISH(-). Conclusions: HER2 positive GE adenocarcinomas in the analyzed cohort displays similar pattern of heterogeneity in IHC staining and FISH positivity but with lower incidence (10%) of HER2 amplification than was reported in the ToGA study. Further data on location, histological pattern and survival will be reported.
Evaluation of proteomic profiles of normal mucosa, Barrett’s esophagus (BE), and esophageal adenocarcinoma (EAC) obtained from humans and the Levrat’s rat model of BE/EAC.
Authors: Gibson Michael K. , Zaidi Ali H , Zeng Xuemei , Davison Jon M. , Foxwell Tyler , Hoppo Toshitaka , Komatsu Yoshihiro , Nason Katie Sue , Rotoloni Christina , Bhatt Astha , Kosovec Juliann , Smith Cornelia , Bigbee William L , Luketich James D. , Jobe Blair A
Published: March 2020

e14689

Background: EAC from BE is increasing, and prognosis is poor. Representative models are critical to understanding BE/EAC and developing therapies. We refined the Levrat’s model of BE/EAC and showed that a SMO inhibitor prevented BE/EAC (Proc ASCO 2012). To validate the rat model as representative of human and explore differentially expressed proteins/pathways, we evaluated the proteomic profiles of nl/BE/EAC from humans and rats. Methods: GE reflux was induced in 6-8 wk old male Sprague–Dawley rats by the Levrat’s procedure--approved by the IACUC. Incidence of BE/EAC at 28 wks was 90%/70%. Human nl/BE/EAC samples were obtained from the PENG database--IRB approved. Histology confirmed by a single pathologist (JD). Following LCM from paraffin, digests were analyzed in triplicate by nanoflow LC-MS/MS with a hybrid linear ion trap-Orbitrap Velos mass spectrometer followed by online nanoflow LC. Mass spectral data representing ~ 20-30,000 CID spectra were searched, and a quantitative estimate of relative abundance was obtained. Kruskal-Wallis non-parametric ANOVA was employed, and clusters were compared within and between humans and rats. Results: Data is available for rat tissues, 10 samples each for nl/BE/EAC. Heirarchical clustering of 410 features yielded 3 statistically significantly distinct groups corresponding to normal, BE and EAC (ANOVA p < 0.001). Pair-wise comparison between groups yielded statistically significant (p < 0.05) differential protein expression as follows: nl vs BE~550; nl vs EAC~450; BE vs EAC~150. For EAC, proteins were differentially expressed in pathways including: protein degradation/synthesis, cell death, growth and proliferation (NF-kB, EIF4A, Akt, b-tubulin). Analysis of human tissues and comparison to rat will be presented at the meeting. Conclusions: Proteomic evaluation of normal/BE/EAC tissues from the Levrat’s model of BE/EAC yielded distinct protein patterns for nl/BE/EAC. Proteins differentially expressed in EAC vs normal/EAC are involved in cancer related pathways. Differentially expressed proteins may provide targets for therapy, which could be tested in the Levrat’s model.
Practice patterns in the treatment of locally advanced resectable esophageal carcinoma: A national survey of Canadian thoracic surgeons.
Authors: Buduhan Gordon
Published: March 2020

e14695

Background: Many institutions have adopted a multimodality strategy for treating locally advanced resectable esophageal cancer including surgery, chemotherapy and radiation. While many neoadjuvant protocols have been studied, there is no well defined standard treatment. In order to determine current practices and clinician opinions regarding treatment of esophageal cancer, a survey study of practicing Canadian thoracic surgeons was performed. Methods: Members of the Canadian Association of Thoracic Surgeons were contacted by email; those who currently treat esophageal cancer were asked to complete an online survey. Three separate emails were sent to maximize participation. Results: The response rate was 54% (56 /104). Of the respondents, 85% exclusively practiced general thoracic surgery, 87% worked at a University-affiliated hospital. We presented a hypothetical patient with bulky, resectable distal esophageal adenocarcinoma with enlarged paraesophageal lymph nodes (T3N1M0). 54% stated that neoadjuvant chemoradiation followed by surgery was their institution’s treatment of choice, while 33% used neoadjuvant chemotherapy plus surgery. When asked to choose the best treatment for this patient based on available evidence, 33% chose neoadjuvant chemoradiation, 33% favored neoadjuvant chemotherapy, 31% were undecided. Regarding neoadjuvant chemotherapy vs. chemoradiation, 63% strongly agreed or agreed there was insufficient evidence to decide whether or not one treatment was superior to the other. 73% strongly agreed or agreed to support a future randomized trial of preoperative chemotherapy vs. preoperative chemoradiation for esophageal cancer patients. Conclusions: Most Canadian thoracic surgeons use either neoadjuvant chemotherapy or chemoradiation followed by surgery for locally advanced resectable esophageal cancer. There is wide variation in practice patterns with no clear standard approach. 63% feel there is insufficient evidence to decide whether or not one treatment is superior to the other, and the majority support a future trial of neoadjuvant chemotherapy vs. chemoradiation. A pilot study is being planned to determine feasibility.
Role and strategies of radiofrequency ablation in treating advanced hepatocellular carcinoma.
Authors: Chen Min Hua , Yang Wei , Wu Jie , Wu Wei , Yan Kun
Published: March 2020

e14701

Background: To investigate the application value and strategies of ultrasound-guided percutaneous radiofrequency ablation (RFA) in treating advanced hepatocellular carcinoma (HCC) which is common in china. Methods: A total of 655 patients with unresectablely advanced HCC underwent percuatenous RFA therapy and 92 patients with 136 tumors among them were enrolled into the study. According to the 6th UICC/AJCC-TNM system, 82 and 10 patients were in stage III and IV, respectively. The tumor size ranged from 1.5 to 8.0 cm (mean±SD, 4.5±1.6 cm). 59 patients had solitary tumor and the remaining 33 patients had multiple tumors. The Child-Pugh classification of A, B and C were 58,32 and 2 patients, respectively. Established strategies included: (1) select RFA indications based on the contrast-enhanced ultrasound (CEUS) results; (2) design radical protocols based on invasive range showed by CEUS; (3) multiple overlapping ablations based on mathematical protocol; (4) two or three bipolar RFA electrodes with three dimensional localization; (5) color US guided percutaneous ablation of tumor feeding artery (including TACE) + RFA for HCC with rich supply. The patients underwent follow-up using enhanced CT at one month, and then every three months after RFA. The ablation was considered a success if no abnormal enhancement or wash-out was detected in the treated area on the CT scan at one month. All patients after RFA received liver protection treatments. Overall survival was estimated by Kaplan-Meier analysis. Results: Early complete tumor necrosis rate after initial RFA was 90.4% (123/136 tumors). Serious complications were developed in two patients (2.2%) and no treatment-related death occurred. 3~129 months were followed up. Local recurrence rate was 15.4 %(21/136 tumors). The 1-, 3-, 5-year overall survival rates were 83.3 %, 48.3 %, 21.9%, respectively, and the median survival time was 35 months. Conclusions: RFA treatment of advanced HCC proved to be feasible. Paying attention to apply treatment strategies and liver protection therapies in RFA can effectively improve the survival.
Single institutional series of neuroendocrine tumours managed in the Australian capital territory.
Authors: Malik Laeeq , Chua Yu Jo , Butt Nadeem , Yip Desmond
Published: March 2020

e14703

Background: Neuroendocrine tumours (NETs) have been regarded as indolent tumors with significantly variable clinical behavior. Limited information is available on long-term clinical outcome and clinically applicable prognostic factors.We performed a retrospective review of NETS managed in the Australian Capital Territory (ACT) over a 12-year period,with examination of epidemiology and various prognostic clinicopathologic factors. Methods: This multicenter analysis included patients in ACT and surrounding New South Wales treated with histologically proven neuroendocrine tumor (lung carcinoids excluded). The cases were identified from hospital databases. Data was analysed according to epidemiological, clinical and histopathological characteristics. Results: The cohort of 107 patients showed slight male predominance. Median age at diagnosis was 62 years and tumour size of 1.2 cm. The most common primary tumour site was jejunum/ileum (32%) followed by rectum (22%) and pancreas (11.2 %). Most patients had localised disease at initial diagnosis (n- 73/107 (68%). Distant metastases were seen in 32% (n-34/107) on initial staging with liver being most common site. Most patients were symptomatic at diagnosis while 22.4% cases were found incidentally. Second malignancies in particular of gastrointestinal origin were diagnosed in 33.6% (n-36/107). Surgical debulking was the most common treatment (59.8%) while 18% had multi-modality therapy. At a median followup of 25 months from diagnosis, 76 patients (78%) were still alive. Median time to first relapse was 15 months. 5 year survival rate was 75% for NETs originating from jejunum/ilieum on Kaplan-Meier analysis. Increasing age, tumor size, male gender, high histological grade, high Ki 67 index, raised plasma chromogranin A and urine 5 HIAA at the time of diagnosis were associated with shorter 5-year survival. Conclusions: The epidemiologic characteristics and long-term outcome in our series was comparable to reported studies from other centers. This analysis confirmed some important prognostic factors that could be considered for risk stratification and therapeutic management in patients with NETs.
Efficacy and tolerability of FOLFOX6 as first-line treatment for advanced gastric and esophagogastric junction cancers (AGC): A single-center experience.
Authors: Abdul Rahman Rozana , Teo MinYuen , McDonnell Felicity , McDermott Raymond S.
Published: March 2020

e14705

Background: There are a number of options for first line treatment for AGC. We sought to review the efficacy and tolerability of FOLFOX (F) in AGC, and compare outcomes with anthracycline-based (A) ctx-treated patients (pts). Methods: Pts with AGC treated with F and A (EOX and ECF) were identified from institutional database. Pt. demographics, disease characteristics and treatment details were extracted from medical charts and pharmacy database. Progression-free survival (PFS) and overall survival (OS) were calculated from commencement of ctx to radiographic evidence of progression and death, respectively, estimated with the Kaplan-Meier method. Comparisons were made via log-rank method. Other descriptive statistics calculated via t-test or chi-square methods as appropriate. Results: Between July 05 and December 11, 27 pts were treated with F. Twenty-one (77.8%) were male and median age was 68yrs (range: 42 – 77). ECOG performance status was 0 -1 in 24 pts (88.9%) and 2 in 3 (11.1%). Median Charlson score prior to metastatic disease was 2 (range: 0 – 3). Three had relapsed disease and another three had locally-advanced disease. Sites of metastatic disease were liver (12), peritoneum (12), non-regional nodes (2) and lungs (2). Median number of cycles of F was 5 (range: 1 - 12), 51.8% of pts completed ≥10 cycles, while the rest discontinued treatment due to disease progression (33%) and toxicities (14.8%). 21 pts (77.8%) required dose reduction and 17 (63%) experienced treatment delay. Fourteen (51.8%), 6 and 2 pts had 2nd, 3rd and 4th line of ctx, respectively. Median PFS was 7.2 mos and median OS is 9.7 mos. Sixteen pts were treated with A. Pts were significantly younger (p=0.002) but other characteristics were similar. Median PFS with A was 6.6 mos and median OS was 9.2 mos. The hazard ratio (F vs A) for PFS was 1.11 (95% CI 0.56 to 2.18, p = 0.77) and for OS was 0.73 (95% CI 0.36 to 1.51, p = 0.40). Conclusions: Despite an older pts cohort with co-morbidities, high percentage of treatment delays and dose reductions, our data suggest that significant percentage of pts were able to complete ≥10 cycles of F and subsequent therapies. Outcomes are comparable to our A cohort and published data.
Evaluation of neoadjuvant chemotherapy for esophageal cancer.
Authors: Kawasaki Hitoshi , Hakamada Kenichi
Published: March 2020

e14709

Background: Neoadjuvant chemotherapy (CT) followed by surgery has become the standard treatment in patients with clinical stage II/III thoracic esophageal cancer. This study evaluated our experience with this treatment approach. Methods: We evaluated 39 patients that underwent an esophagectomy after neoadjuvant concurrent 5-fluorouracil/cisplatin CT, and investigated the clinical and pathological results of neoadjuvant CT. Results: The 3-year overall survival (OS) rate was 70%. Clinical CR, PR, SD and PD were observed in 0, 22, 14 and 3 patients, respectively, and response rate was 56.4%. The 3-year OS of clinical CR group was significantly better than that of clinical PD group. The OS of clinical CR group was not significantly different from that of clinical SD group. Down-staging was observed in 13 cases (33%), but OS was not significantly different between down-staging group and non-down-staging group. Pathological complete response was observed in 1 case (3%). According to lymph node metastasis, down-grading was observed in 11 cases (28%) (responder). The OS was significantly better in responders compared with those in non-responders (100% vs. 50%, p=0.024). Conclusions: Neoadjuvant chemotherapy can be a good option in treatment of clinical stage II/III thoracic esophageal cancer. Especially in this study, the patients with pathological lymph node response are expected to have better outcome in survival.
The prognostic significance of Cerb-B2 determination in gastric cancer.
Authors: Fradique Antonio CALDEIRA
Published: March 2020

e14713

Background: The Cerb-B2/HER2 marker, is a glycoprotein encoded by the ERBB2 oncogene, belongs to the family of epidermal growth factor receptors (EGFR), which has based its application on tests of new therapeutic modalities (target therapy). Apart from this interest has been invoked its value as a marker of tumor aggressiveness, due to his role as a regulator of cell proliferation and migration and consequent invasiveness and metastization. However, the results as to the meaning prognosis of this molecular marker are controversial and with variations depending on the geographical zone. Results: From a total of 50 pts. with advanced resectable gastric cancer that underwent surgery with D2 lymphadenectomy, 38 pts. had a total gastrectomy, and 12 pts. had subtotal gastrectomy. A mean of 35.7 lymph nodes/pt were resected at surgery. In 68% of pts. positive lymph node metastases were present. Tumor HER2-neu overexpression was observed in 16 pts (32%), several other parameters of tumor aggressiveness were also present, without any statistical significance or relevance. Methods: To determine if the Cerb-B2 played a prognostic role in gastric cancer, a total of 50 pts. with advanced resectable gastric cancer, were submitted to gastrectomy with D2 lymphadenectomy. In all cases assessment for tumor HER2-neu overexpression was performed using immunohistochemistry (IHC). FISH was used as a confirmation method in tumors with 2+ expression by IHC. A correlation was made between the tumor HER2-neu expression and the following parameters: tumor location, size, histological type, depth of invasion, lymph node metastases and clinical staging. Results: From a total of 50 pts. with advanced resectable gastric cancer that underwent surgery with D2 lymphadenectomy, 38 pts. had a total gastrectomy, and 12 pts. had subtotal gastrectomy. A mean of 35.7 lymph nodes/pt were resected at surgery. In 68% of pts. positive lymph node metastases were present.Tumor HER2-neu overexpression was observed in 16 pts (32%), several other parameters of tumor aggressiveness were also present, without any statistical significance or relevance. Conclusions: The determination of Cerb-B2 / HER2 expression has not shown prognostic significance in this study.
Effect of nab-paclitaxel combination chemotherapy on response and survival in pancreatic cancer.
Authors: Dean Andrew Peter , Cooray Prasad
Published: March 2020

e14718

Background: Pancreatic cancer has traditionally had few effective chemotherapy options. Recent discovery of the over-expression of SPARC (Secreted Protein Acidic Rich in Cysteine) on the majority of pancreatic cancers suggests possible utility of nab-paclitaxel, (a novel albumin-bound form of paclitaxel) as a treatment option. A small prospective study (ASCO 2009) supported this theory. We sought to retrospectively evaluate the treatment efficacy of nab-paclitaxel with gemcitabine or carboplatin in patients with pancreatic cancer to assess concordance with the previous small prospective study. Methods: Data was collected retrospectively from the medical records of pancreatic cancer patients who presented to the private clinic of two treating oncologists (n = 63) from June 2009 to December 2011 and were treated with nab- paclitaxel in combination with either gemcitabine or carboplatin. Patients were assessed on the basis of changes in serum tumour marker (CA19-9, CEA or CA15-3) and changes in tumour size on radiological imaging. Results: 39 (70%) patients had a biochemical response with a greater than 20% drop in tumour markers. Of these, 30 (94%) showed greater than 70% drop with all responders showing reduction in markers within 6 weeks of starting. The number of patients with biochemically defined disease control was 48 (86%). 36 patients were deceased by the end of the series with median overall survival being 12.9 months. The median survival time from starting nab-paclitaxel for these patients was 7.9 months. Very long survival times (up to 28.1 months following commencement nab-paclitaxel) were also observed in 2 patients at the time of data analysis. The overall disease control rate radiologically was 76.79% (43 of 56). Of the 43 responders, 10 were complete responders, 22 showed partial radiological response and 11 had stable disease. Conclusions: This retrospective case series demonstrates a near doubling of overall median survival time and also an improved response rate in patients on nab-paclitaxel treatment as compared to historical data of other treatment options for pancreatic carcinoma. It further supports Von Hoff’s data from ASCO 2010. Further prospective data is eagerly awaited.
Correlation of SMAD4 mutational status and local or metastatic progression in patients with pancreatic cancer.
Authors: Derbel Olfa , de la Fouchardière Arnaud , Peron Julien , Rivoire Michel , Desseigne Françoise , Meeus Pierre , Peyrat Patrice , Heudel Pierre , Stella Mattia , Racadot Severine , DE LA Fouchardiere Christelle
Published: March 2020

e14730

Background: Pancreatic cancer remains resistant to many key cytotoxic chemotherapeutic agents and novel targeted therapies. The molecular heterogeneity of this cancer may account for therapy failures to date, although the growing arsenal of novel targeted agents could translate into patient survival. A better understanding of the cellular and molecular features of advanced disease will afford new opportunities for investigation, therapeutic intervention and clinical management of patients afflicted with pancreatic cancer. Methods: This study examined the expression profiles of Smad4 in 45 samples of surgically resected pancreatic cancer. Of these 45 patients, 32 underwent pancreaticoduodenectomy. The clinicopathological parameters, the histologic features were determined and correlated to the stage at initial diagnosis, patterns of failure (locally advanced v metastatic disease) and the status SMAD4 genes. Results: Among the 45 patients, 40% of patients died with metastatic disease and 15 % died with locally advanced evolution. SMAD4 genetic status was determined in 25 patients and seems to be correlated with a high grade histologic features and progression to metastasis. Complementary data about correlation between the mutational status of SMAD4 and survival will be presented during congress. Conclusions: SMAD4 gene inactivation seems to be associated with poorer prognosis and disease progression. Prospective validation of SMAD4 as a predictive biomarker may personalize treatment strategies for patients with pancreatic cancer.
Survival outcomes of patients with unresectable hepatocellular carcinoma in a national population-based study: SEER versus tertiary cancer center.
Authors: Lawal Taoreed O. , El-Rayes Bassel F. , Kim Hyun Sik
Published: March 2020

e14736

Background: To evaluate long-term survival in patients with unresectable hepatocellular carcinoma (HCC) in large national population-based database and to assess the impact of subspecialized care on similarly matched patients at a tertiary cancer center. Methods: Using the Surveillance, Epidemiology and End Results (SEER) registry, patients diagnosed between 2004 and 2008 with advanced unresectable HCC not amendable to radiation therapy or cancer-directed surgery were extracted. Additionally, similar matched patients receiving drug eluting bead transarterial chemoembolizaton (DEB TACE) for unresectable HCC were included in the study. Demographic, clinical, and procedural data were collected. Patients were stratified based on Contract Health Service Delivery Areas (CHSDA) and the rural- urban continuum. The Kaplan Meier method was used for survival analysis, and survival curves were compared using the log rank test in SPSS. Results: 14,369 patients were studied and demographics were as follows: mean age at time of diagnosis was 63.97 years (SD 12.5); 76.1% were male; 66.7% were Caucasian; 13.3% were African-American; and 19.4% were Asian or American Indian. The overall median observed survival from diagnosis of the 136 patients receiving DEB TACE was significantly higher when compared to the 404 Atlanta patients and the 12,012 SEER patients (median OS = 22 vs 4 vs 4 months respectively, p< 0.05). When compared to CHSDA, the median overall survival for patients receiving DEB TACE was 5 times longer than all other geographical areas (22 months vs 3, 4, 3, 4, and 4 in Alaska, East, Northern Plains, Pacific Coast, and the Southwest, respectively, p<0.05). Metropolitan, urban, and rural areas demonstrated similar survival outcomes and patients receiving DEB TACE had superior survival (22 vs 3-4 months, p<0.05). Conclusions: This study suggests that DEB TACE is viable treatment option that confers significantly beneficial survival results when compared to similar patients nationwide diagnosed with advanced unresectable HCC in the same 5-year time frame regardless of population demographics and health service delivery area.
Single nucleotide polymorphisms as markers of bacillus Calmette-Guérin intravesical therapy response in non-muscle invasive bladder cancer.
Authors: Alanee Shaheen , Hamilton Robert James , Joseph Vijai , Ostrovnaya Irina , Garcia-Grossman Ilana Rebecca , Gallagher David J , Pendse Deepa , Regazzi Ashley Marie , Przybylo Jennifer A. , Gaudet Mia , Milowsky Matthew I. , Herr Harry W. , Offit Kenneth , Bajorin Dean F.
Published: March 2020

e15022

Background: A marker of response to Bacillus Calmette-Guérin (BCG) intravesical therapy in high-risk non-muscle invasive bladder cancer (NMIBC) could help avoid unsuccessful BCG treatment and potentially enhance care. This study examines germline single nucleotide polymorphisms (SNPs) as markers of BCG-refractory NMIBC. Methods: Saliva or blood was prospectively collected from patients treated with BCG for NMIBC between 1991 and 2010, treated either at MSKCC or referring centers prior to MSKCC registration. BCG-refractory disease was defined as the presence of pathologically documented tumor in the bladder six months after BCG administration. SNPs were selected based on either reported associations with BCG response or putative mechanisms of BCG activity. Eighty candidate SNPs were genotyped (using the Sequenom Mass ARRAY iPLEX platform) in a discovery set (n=158) and those significantly associated were analyzed in a validation set (n=168). Univariate logistic regression was used to test the association between refractory disease, selected clinical variables, and SNPs. Because center of treatment was found to be a confounding variable (p=0.02), primary analysis was limited to cases treated at a single center (MSKCC), consisting of 276 patients (108 from discovery set and 168 from validation set). Results: Median age of diagnosis of the 276 cases was 65.7 years, 94% diagnosed with high-grade superficial bladder cancer, 35% stage Ta, 30% stage T1, and 35% stage Tis. At six month follow-up, 37 (13.4%) had BCG–refractory disease. Nine SNPs showed significant associations with outcome in the discovery cohort (two SNPs failed genotyping). In primary analysis, One SNP, rs11615, an intronic variant within the ERCC1 gene, was associated with BCG-refractory disease. Patients with CC genotype were 3.6 times more likely to be refractory to BCG compared to TT genotype (OR for each C allele was 1.8: 95% CI 1.1-3; p=0.01). No other factors were found to be predictive. Conclusions: A single nucleotide polymorphism of ERCC1 may be associated with BCG-refractory disease. Validation in independent datasets is needed.
Complete disappearance of retroperitoneal lymph nodes after induction chemotherapy in advanced nonseminomatous germ cell tumors (NSGCT): Is there a place for adjunctive surgery?
Authors: Tryakin Alexey , Fedyanin Mikhail , Mitin Andrey , Sergeev Urii , Figurin Konstantin , Fainstein Igor , Zakharova Tatiana , Kanagavel Dheepak , Kostjakova Ljudmila , Titov Dmitry , Garin Avgust , Tjulandin Sergei
Published: March 2020

e15029

Background: The management of patients (pts) with a radiographic complete disappearance of retroperitoneal lymph nodes (CD-RPLN) metastases after chemotherapy (CT) remains controversial. Some authors recommend post-CT retroperitoneal lymph node dissection (PC-RPLND), whereas others omit surgery and observe these pts. In this retrospective study we analyzed outcome of pts with advanced NSGCT who achieved CD-RPLN and did not undergo PC-RPLND. Methods: From 1988 to 2008, 886 CT-naïve pts with advanced NSGCT were treated in our department with first-line cisplatin- and etoposide-based CT. All residual tumors >1cm were resected when it was feasible. Pts who had CD-RPLN (≤1cm by CT-scan) and normalized tumor markers after CT were included into the study. Results: One hundred thirty seven pts were identified. 30% pts had teratoma in primary tumor. Following CT 13 pts underwent resection of extra-retroperitoneal lesions, no viable carcinoma was found. Good, intermediate and poor IGCCCG prognosis had 87 (64%), 33 (24%) and 17 (12%) pts, respectively. After a median f.-up of 72 (6-193) months, 11 (8%) pts relapsed. All but one relapses occurred in the first two years. Only 4 (3%) relapses developed in RPLN and were treated with salvage CT and surgery, all 4 pts died. Relapse rate in RPLN was equal among prognostic groups (good 2(2%), intermediate 1(3%), poor 1(6%) pts). 5-years OS were 94%, 97% and 79%, respectively. Conclusions: Pts obtaining complete disappearance of RPLN after induction CT had low risk of relapse and can be safely observed without surgery.
Macrophage inhibitory cytokine 1 plasma levels in testicular cancer patients during cisplatin combination treatment and their relation to endothelial damage.
Authors: Altena Renske , Fehrmann Rudolf S. N. , Boer Hink , de Vries Elisabeth G. E. , Meijer Coby , Gietema Jourik A.
Published: March 2020

e15035

Background: Chemotherapy- (CTx) related endothelial damage contributes to cardiovascular morbidity in testicular cancer (TC) patients (pts). We used an unbiased translational approach to identify mechanisms of and potential biomarkers for this damage. Methods: During varying time periods human microvascular endothelial cells (HMEC-1) were in vitro exposed to bleomycin, cisplatin or left untreated. From 18k cDNA microarray expression signals were obtained, and quantified with an Affymetrix GMS428 scanner. Differences were analysed at single gene and pathway level, and validated by qRT-PCR. With ELISA, protein levels of 1 candidate biomarker were measured in TC pt plasma before, during and 1 month after bleomycin etoposide cisplatin CTx. Levels were related to endothelial damage plasma markers (von Willebrand Factor [vWF], high-sensitivity C-Reactive Protein [hs-CRP]). Results: Microarray data from 16k genes identified several genes with highly differential expression; Macrophage Inhibitory Cytokine 1(MIC-1), Activating Transcription Factor 3 (ATF3) and Amphiregulin (AREG) had strong differences in >1 experimental setting. We regarded these plausible candidates, and confirmed changes by qRT-PCR. Pathway analysis showed a strong association with ‘P53’ and ‘Diabetes Mellitus’ gene sets. Based on known function, we chose to validate MIC-1 protein levels in 41 TC pts. Pre-CTx MIC-1 levels did not differ from healthy controls (TC pts median 383 pg/mL [range 187-1935] vs 340 pg/mL [range 213-504], p=0.06). During CTx levels of MIC-1, vWF and hsCRP significantly increased. MIC-1 levels correlated with vWF and hsCRP at baseline (vWF rs= 0.35, P=0.03; hsCRP rs= 0.39, P=0.01), during (hsCRP at cycle 1d 8 rs= 0.44, P=0.01; vWF at cycle 3 d8 rs= 0.40, P=0.02) and after CTx (vWF rs= 0.56; P<0.01). Conclusions: An unbiased approach in a preclinical model revealed a set of genes related to bleomycin- and cisplatin-induced endothelial activation, such as MIC-1. The increases in plasma levels and the association with vWF and hsCRP suggest that MIC-1 may be a biomarker for CTx-related endothelial damage. Supported by Dutch Cancer Society grant 2009-4365.
Effects of nintedanib (BIBF 1120) on QTc interval in previously untreated patients with renal cell cancer (RCC): Results from an open-label, phase II study.
Authors: Eisen Tim , Shparyk Yaroslav , MacLeod Nicholas James , Wallenstein Gudrun , Temple Graham , Khder Yasser , Dallinger Claudia , Studeny Matus , Loembe Arsene Bienvenu , Bondarenko Igor N.
Published: March 2020

e15037

Background: Nintedanib (BIBF 1120), an angiokinase inhibitor of VEGFR 1–3, PDGFR-α/-β, and FGFR 1–3, has shown clinical activity with a good safety profile in patients (pts) with solid tumors in previous Phase II clinical trials. Several classes of targeted agents are associated with QT prolongation, including the multi-targeted tyrosine kinase inhibitors. Here, we prospectively evaluated the cardiac safety of nintedanib, specifically assessing the QT liability in an open-label, randomized, phase II efficacy and safety study of nintedanib vs sunitinib in pts with previously untreated RCC. Methods: Eligible pts (advanced, measurable, unresectable, recurrent RCC, ECOG PS 0–1, chemo-naïve, life expectancy >3 months) were randomized to receive either nintedanib 200 mg bid or sunitinib 50 mg od in a 2:1 ratio. Time-matched electrocardiograms of patients treated with nintedanib were collected over 12 hrs. Primary endpoint was the time-matched change from baseline (Day –1 prior nintedanib dosing) to Day 15 (steady-state) in the QTcF interval (QT interval corrected for heart rate dependency by the Fridericia formula) observed at each timepoint. PK parameters were determined and AEs were reported until Day 15. Results: 64 pts were treated with nintedanib. Estimated mean time-matched changes in the QTcF interval (ms) from baseline to Day 15 ranged from –1.7 (90% CI: –4.9, 1.6) at 2 hrs to 3.1 (90% CI: –0.2, 6.4) at 7 hrs. Upper CIs at all timepoints were <10 ms, the ICH E14 guideline threshold level of regulatory concern. Changes from baseline to Day 1 and changes in QT interval were also within the threshold of 10 ms. No pts showed a QTcF or a QT value >500 ms at baseline, Day 1 or Day 15, and no patient experienced an increase from baseline in QTcF >60 ms on Days 1 and 15. PK/QTc analyses did not indicate any relationship between exposure to nintedanib and a change from baseline in QTcF or the QT interval. The most frequently reported drug-related AEs were nausea (14.1%), diarrhea (12.5%) and vomiting (6.3%). Conclusions: Single and multiple doses of 200 mg nintedanib administered until steady-state did not prolong the QTcF interval compared with baseline in pts with RCC.
Oncologic kidney surgery in obese patients.
Authors: Safwat Mohab W. , O'Malley Rebecca , Kristopher Attwood , Mehedint Diana , Narayanan Ramkishen , Schwaab Thomas
Published: March 2020

e15039

Background: Obesity adds significant operative challenge to kidney surgery. Its impact on minimally invasive kidney surgery has not been well defined. We evaluated the impact of obesity on open and minimally invasive kidney surgery (MIS) for kidney tumors. Methods: Patients in our prospectively collected IRB-approved kidney database were divided into 5 groups as determined by the World health organization Body mass index (BMI) classification: less than 25.0, 25.0-30.0, 30.0-35.0, 35.0-40.0, and more than 40.0 Kg/m2. Patient characteristics, and peri-operative data were recorded and compared between the different groups and between surgical approches(open vs. MIS) using the Kruskal Wallis and Chi Square tests for continuous and categorical data, respectively. The potential association between BMI and the continuous measures of OR time, Post op stay and EBL were assessed using spearman Correlations. Results: Of the 620 patients identified, 142 (22.9 %) had healthy weight, 180 (29.0%) were overweight, and 298 (48.1%) were obese. Most had grade 1 obesity (BMI 30-34, 167, 26.9%), grade 2 obesity (BMI 35-40, 76, 12.3%), and grade 3 obesity (BMI > 40, 55, 8.9%). As expected, the ASA score rose with degree of obesity (p=<.001). EBL (estimated blood loss), OR (operative time) time, Room time and post-operative stay differed significantly in the 5 groups of patients (p=0.001, p=0.003, p=<0.002, p= <.001, p=.002), respectively. While intra-operative complications did not differ between the obesity groups, obese patients had a higher rate of high grade Clavien complications (p=0.026). Interestingly, the surgical approach (open vs. MIS) and type of nephrectomy ( radical vs. partial) did not correlate with degree of obesity or complications, even when adjusted for stage. Conversion rates for MIS did not correlate with degree of obesity. Conclusions: Nephrectomy in obese patients results in incresed high grade of postoperative complications. Surgical approach does not appear to have any impact on peri-operative outcomes.
Use of STAT3 polymorphisms to predict overall survival in patients treated with interferon-alpha for metastatic renal cell carcinoma.
Authors: Eto Masatoshi , Kamba Tomomi , Miyake Hideaki , Fujisawa Masato , Kamai Takao , Uemura Hirotsugu , Tsukamoto Taiji , Azuma Haruhito , Matsubara Akio , Nishimura Kazuo , Nakamura Tsuyoshi , Ogawa Osamu , Naito Seiji ,   Japan Immunotherapy SNPs-Study Group for Kidney Cancer
Published: March 2020

e15048

Background: We previously reported that the single nucleotide polymorphisms (SNPs) in signal transducer and activator 3 (STAT3) gene were most significantly associated with better response to interferon (IFN)-α in patients with metastatic renal cell carcinoma (mRCC) in our retrospective analysis (JCO 25:2785, 2007). We conducted this trial to prospectively confirm the results, and reported the significant association between the SNPs of STAT3-2 and clinical benefits (CR, PR, and SD more than 24 weeks) of IFN-α (p = 0.039) (ASCO 2011, abstract No. 4590). In this study, we have further analyzed the correlation between overall survival (OS), progression-free survival (PFS) and the 11 SNPs reported previously. Methods: In this multicenter, prospective study, patients with histologically confirmed RCC that was metastatic, measurable disease, age > 20 years, ECOG PS 0-1 and adequate organ function received 3 dosages of 5 million U per week of IFN-α treatment. We evaluated the correlation between OS, PFS and SNP allele frequencies of STAT3-2, STAT3-0, SOCS3-1, IL4R-34, PTGS1-3, PTGS1-4, PTGS1-5, PTGS2-12, IRF2-67, ICSBP-38, and TAP2-5 (JCO 25:2785, 2007) in mRCC patients treated with IFN-α. Association between OS, PFS and genetic polymorphisms was analyzed using Logrank test for trend. Results: Two hundreds three eligible patients were enrolled between December 2006 and October 2009. All patients had prior nephrectomy, and 88.7% had ECOG PS 0. Ninety-four percent of patients had clear cell RCC, and 5% had papillary RCC. At the time of this analysis the central review assessed response rate was 13.8% (28/203) (9 CR, 19 PR). CR rate of 4.4% (9/203) was more than we expected. PFS was not associated with any of the 11 SNPs examined. However, 2 SNPs of STAT3 gene, STAT3-2 and STAT3-0, were significantly associated with OS, and the correlation of STAT3-2 (p = 0.0347) was stronger than that of STAT3-0. Namely, C/C genotype of STAT3-2 was significantly associated with prolonged OS compared with the other genotypes (C/T and T/T). Conclusions: This is the first prospective study demonstrating that STAT3 polymorphisms can predict OS in mRCC patients treated with IFN-α.
RAD001 and zoledronic acid in renal cell carcinoma patients with bone metastases (RAZOR): A randomized phase II trial.
Authors: Broom Reuben James , Hinder Vicky , Sharples Katrina , Proctor Janie , Duffey Steven , Pollard Stephanie , Fong Peter C.C. , Forgeson Garry , Harris Dean Laurence , Jameson Michael B. , O'Donnell Anne , North Richard T. , Deva Sanjeev , Hanning Fritha J. , Grey Andrew , Findlay Michael P. N.
Published: March 2020

e15054

Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause major morbidity and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (ZOL) reduces skeletal-related-events (SRE’s) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving ZOL. We sought to evaluate the effect on BM of RAD001 (everolimus) alone compared to RAD001 plus ZOL in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to RAD001 10mg daily (Arm A) vs. RAD001 + ZOL 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl], Arm B). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates or radiotherapy within 4 weeks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, weeks 1,4,8 and12. Treatment was continued on the allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12-weeks. The primary endpoint was urine N-telopeptide (uNTX) levels with plasma C-telopeptide (CTX) being secondary. Secondary objectives include comparison of quality of life (QoL) and pain (FACT-BP, BPI scores), SREs, safety and efficacy (PFS, RR). Results: Heng prognostic group was poor, intermediate and favorable-risk in; 40.0%, 46.7%, 13.3% respectively in Arm A and 20.0%, 46.7%, 33.3% (Arm B). 53.3% (Arm A) and 60.0% (Arm B) of pts had prior nephrectomy. Over the first 12 weeks, the reduction in mean CTX on Arm B relative to Arm A was 77% (95% CI (68%, 83%); p<0.0001). Median PFS was 7.5mo (95% CI 3.5, 14.7) in Arm B and 5.5mo (95% CI 3.2, 7.2) in Arm A (p=0.11). Data on uNTX, QoL and SREs will be presented. At data cut off, 8 pts in Arm B had stopped ZOL before progression with either a drop in CrCl or hypocalcaemia. No cases of osteonecrosis of the jaw were seen. Conclusions: The addition of ZOL to RAD001 significantly reduced the bone resorption marker CTX in this treatment-naïve RCC population of pts with the adverse prognostic feature of BM.
Influence of risk factors for renal cell carcinoma (RCC) on outcome of patients (pts) with metastatic disease (mRCC) treated with sunitinib (Su).
Authors: Berger Raanan , Keizman Daniel , Ish-Shalom Maya , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Pili Roberto , Boursi Ben , Maimon Natalie , Gottfried Maya , Hayat Henry , Peer Avivit , Kovel Svetlana , Sella Avishay , Carducci Michael Anthony
Published: March 2020

e15058

Background: Obesity, smoking, hypertension (HTN) and diabetes (DM) are risk factors for RCC development. Their presence has been associated with a worse outcome of therapy (tx) in various metastatic cancers. We sought to determine their influence on the progression free survival (PFS) and overall survival (OS) of Su tx in mRCC. Methods: We performed an international multicenter retrospective study of pts with mRCC, who were treated with Su. We analyzed the pre-tx status of smoking (active vs past vs never), BMI (obese= BMI≥30 vs overweight=BMI 25-29.9 vs normal weight= BMI <25), HTN, DM, and known prognostic factors including past nephrectomy, clear cell vs non clear cell histology, initial diagnosis to Su tx initiation time, ≥ 2 metastasis (mets) sites, lung/liver/bone mets, ECOG performance status, anemia, calcium level > 10, elevated alkaline phosphatase (AP), pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su induced HTN, use of angiotensin system inhibitors (ASIs), past cytokines/targeted tx, and median Su dose/cycle. PFS and OS were determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed to determine their independent effect. Results: Between 2004-2011, 244 pts with mRCC were treated with Su. 51 pts were active smokers, 58 obese, 62 diabetic, and 145 had pre-tx HTN. In the entire pt cohort, median PFS was 9 months (mos) and OS 21 mos. Factors associated with PFS were active smoking (HR 2.29, p= 0.003, median PFS 4 vs 10 mos in past smokers vs 12 mos in never smokers), non clear cell histology (HR 1.7, p=0.042), pre-tx NLR >3 (HR 1.92, p<0.0001) and the use of ASIs (HR 0.58, p=0.03). Factors associated with OS were were active smoking (HR 1.85, p= 0.018, median OS 11 vs 25 mos in past smokers vs 27 mos in never smokers), AP (HR 1.9, p=0.017), pre-tx NLR >3 (HR 2.5, p<0.0001), and liver mets (HR 1.86, p=0.021). BMI, DM, and pre-tx HTN were not associated with PFS or OS. Conclusions: Active smoking may decrease the PFS and OS of pts with mRCC that are treated with Su. BMI, DM, and pre-tx HTN were not found to be associated with outcome. These results should be investigated prospectively, and if validated applied in clinical practice and clinical trials.