bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of chemotherapy on survival of patients with recurrent pancreatic ductal adenocarcinoma (PDAC) following surgical therapy.
Authors: Gbolahan Olumide B. , Tong Yan , O'Neil Bert H. , Shahda Safi
Published: September 2018

e15748

Background: Patients with recurrent PDAC are treated similarly to patients with de novo metastatic disease. The aim of this study is to report the outcome of patients with recurrent PDAC following initial definitive resection and adjuvant therapy. Methods: Patients were identified from an IRB approved, retrospective database at Indiana University that contained patient and tumor characteristics, adjuvant therapy and all treatment for metastatic disease. Follow-up was updated as of 6/2014. Overall survival (OS) from recurrence until death or last follow up was estimated using the Kaplan Meier method. Results: Between 2008-2014, 451 patients with resectable PDAC and available follow up data were identified, of whom 234 had documented relapse. Patient/tumor characteristics were as follows: median age: 64.2 years (25-89), 54% male, 76% LN+, 24% positive margins, 66% and 85% with lymphovascular and perineural invasion respectively. 69% of patients received adjuvant gemcitabine (GEM). Median time to relapse was 10 months. 60% of patients received at least 1 line of systemic therapy and 18% received 2 lines. Chemotherapy was GEM-based: 33%, 5FU-based 33%, or both 33% and 1% other treatment. Median OS from time of relapse was significantly improved following chemotherapy compared to no chemotherapy (10 months vs 3 months, P < 0.0001). Median OS for 5FU based and GEM based treatment was 6 and 8 months, respectively (P = 0.09). Those who received both had mOS of 14 months (95% C.I 10-17months, P < 0.0001). On univariate analysis, chemotherapy, regardless of type was associated with a survival benefit. Conclusions: Chemotherapy appears to be associated with survival benefit for patients with relapsed PDAC following initial curative therapy. Survival in our retrospective study appears similar to reported literature for de novo metastatic disease.
The effects of pioglitazone treatment on pancreatic cancer-related insulin resistance.
Authors: Stern Jennifer , Arriaga Yull Edwin , Gupta Arjun , Verma Udit N. , Karri Sirisha , Syed Samira K. , Khosama Leticia , Mansour John C. , Scherer Philipp , Beg Muhammad Shaalan
Published: September 2018

e15752

Background: Insulin resistance (IR) in pancreatic cancer (PC) patients is associated with cachexia and poor outcome. Pioglitazone (PIO) improves insulin sensitivity via activation of peroxisome proliferator-activated receptor (PPAR gamma). Effects of PIO on insulin sensitivity, glucose homeostasis, and circulating adipokine levels in PC have not been examined. Methods: Patients with metastatic PC were administered PIO 45mg/day orally for 8 weeks concurrent with chemotherapy. Patients with known DM at enrollment were identified Fasting plasma was collected at baseline, weeks 2, 4, 6, 8 of pioglitazone treatment and at 2 weeks-post treatment. The primary objective was to describe changes in indicators of IR, including glucoregulatory hormone levels, glucose tolerance, and inflammatory cytokines. Results: Fourteen patients (age 64y), with a mean BMI of 28 were enrolled. Mean adiponectin increased from baseline to week 8 of treatment (14.2± 3.3 and 46.9±11.4µg/ml, respectively, P ≤ 0.01), and returned to baseline levels at 2 weeks post-treatment (15.1±1.9 µg/ml). Markers of IR (serum glucose, insulin, glucagon, and response to an oral glucose bolus) did not correlate with tumor size, inflammatory cytokine levels, GM-CSF, or CA19-9. A dichotomous response to PIO treatment was observed between non-diabetic and T2DM patients. Fasting insulin increased 70.6±31.3% from baseline to treatment week 8 in patients with T2DM. In contrast, treatment of non-diabetic patients decreased fasting insulin by 40.2±6.3%, demonstrating a significant, P ≤ 0.01, difference in treatment response between PC patients with or without T2DM. Conclusions: We have demonstrated that PC patients respond to 8 weeks of PIO treatment with a significant rise in the insulin sensitizing adipokine, Adiponectin, with a complete wash-out after 2 weeks of cessation. PIO results in opposing fasting insulin responses in non-diabetic and DM patients suggests that diabetes status plays a significant role in the glucoregulatory effects of PIO treatment in PC patients. Clinical trial information Clinical trial information: NCT01838317.
Survival after recurrence following curative intent resection of pancreatic adenocarcinoma.
Authors: Ellsworth Susannah G. , Stanley Melissa , House Michael Garrett , Nakeeb Attila , Shahda Safi , Schmidt Christian , Zyromski Nicholas J , O'Neil Bert H. , Sehdev Amikar
Published: September 2018

e15760

Background: Limited data exist on outcomes after recurrence after curative intent resection for pancreatic adenocarcinoma (PC). We analyzed the prognostic significance of time to recurrence and associated factors in patients with post-pancreatectomy recurrence. Methods: Patients with a documented recurrence were identified from a prospectively maintained database of all patients undergoing pancreatectomy for PC between 2009-2015 at Indiana University Simon Cancer Center. Patients were divided into early (≤12 mos after surgery) and late recurrence ( > 12 mos after surgery) groups. Demographic (age, race, sex) and clinical (CA19-9, bilirubin, tumor location, diabetes at presentation, ECOG performance status, margin status, adjuvant radiation, and adjuvant and metastatic chemotherapy) data were obtained by manual chart abstraction and the IUSCC cancer registry. The primary outcome was survival after recurrence (SAR- time from recurrence to death). Chi-square was used for univariate analysis (except t-test for age). SAR was estimated with the Kaplan-Meier method and 95% CI. Cox proportional-hazard model was used for multivariate analysis (MVA). Results: Of 437 patients undergoing surgical resection for PC, 235 had documented recurrence. More patients had an early recurrence (ER) as compared to late recurrence (LR; 58.3% vs 41.7%). Median SAR was significantly shorter in ER vs LR patients (6.2 vs 8.6 months; HR, 0.71; 95% CI, 0.53-0.95; P = 0.02). Median age was higher in ER vs LR groups (64.7 and 64.2 years, P = 0.002). Diabetes at presentation was more common in ER vs LR group (42.3% vs 30.6%, P = 0.09). ER patients were significantly less likely to have received adjuvant chemotherapy (70.7% vs 84.7%, P = 0.02) or adjuvant radiation (17.8% vs 40%, P < .001). MVA showed a trend towards longer SAR in LR vs ER group (adjusted HR = 0.75, 95% CI, 0.55-0.1.03, p = 0.08) however age, adjuvant chemotherapy, adjuvant radiation and diabetes at presentation were not significant predictors of SAR. Conclusions: Early recurrence after resection of PC is associated with poor SAR. Patients with early recurrence tend to be older, diabetic at presentation and were less likely to have received adjuvant chemotherapy or adjuvant radiation.
Association between lymph node examination and nodal staging for pancreatic adenocarcinoma: A population-based analysis.
Authors: Xu Rui-hua , Wang Zi-Xian , Qiu Miaozhen , Jin Ying , He Ming-ming , Wang Feng , Wang Fenghua
Published: September 2018

e15772

Background: The minimum number of examined lymph nodes (ELNs) for accurate nodal staging remains controversial and has not been recommended by the NCCN guidelines for pancreatic adenocarcinoma (PADC). We aimed to evaluate the time trends in the ELN count and the proportion of node-positive PADC (N+%), as well as determine the minimal threshold for the ELN count. Methods: We analyzed 9258 patients with resectable PADC between 2000 and 2012 in the SEER database (18 registries). Changes in the ELN count and N+% over time were evaluated using the Spearman correlation analysis and the Cochran-Armitage test, respectively. Multivariable logistic and Cox models were used to evaluate the association between the ELN count and N+% and overall survival after adjusted for clinicopathologic features (i.e., race/ethnicity, sex, age, marital status, SEER region, year of diagnosis, tumor grade, tumor site, 8th AJCC T stage, and surgical type). Restricted cubic spline modeling was used to handle possible nonlinear effects of the ELN count as a continuous covariate in the multivariable models. Structural breakpoints, which were considered the threshold of clinical impact, were determined by the Chow test. Results: The median ELN count increased from 9 (interquartile range: 5−15) in 2000 to 16 (11−23) in 2012 ( Ptrend < 0.001), and the N+% increased from 61.1% to 67.2% ( Ptrend < 0.001). An increased ELN count was associated with a nonlinear increase in N+% ( P < 0.001), and the Chow test revealed a threshold ELN count of 8 (ORadjusted for ≥ 8 vs. < 8 ELNs, 2.42 [95% CI, 2.19−2.68]). The 8-ELN threshold was confirmed in patients with declared N0 disease: A larger number of ELNs was correlated with a nonlinear increase in overall survival among these patients ( P < 0.001), with the threshold ELN count also being 8 (HRadjustedfor ≥ 8 vs. < 8 ELNs, 0.79 [95% CI, 0.75−0.87]). Moreover, the 8-ELN threshold remained valid regardless of T stage and year of diagnosis. Conclusions: Lymph node examination has increased markedly over time and was associated with an overall shift toward higher-staged PADC. We recommend 8 ELNs as the cut point for improvement of prognostic accuracy and quality measurement of lymph node examination.
Chromogranin A levels to predict survival in resectable pancreatic neuroendocrine tumors.
Authors: Tariq Khurram Bilal , Roberts Brandon , Nayak Kapoor Asha
Published: September 2018

e15775

Background: To determine whether Chromogranin A (CGA) predicts outcome after Cytoreductive Surgery (CRS) for Pancreatic Neuroendocrine Tumors (PNETs). CGA is used by clinicians to monitor progression of disease and response to treatment, but has not been objectively evaluated. Methods: A retrospective study of patients with PNETs seen at the Georgia Cancer Center, formerly the Medical College of Georgia, from 1980 to 2011 was performed. All patients who had CGA concentrations measured were evaluated (n = 126). Data relating to diagnosis, therapies, and survival outcome were noted. Patients with resectable and unresectable disease were included. Those with unresectable disease where evaluated for receiving Octreotide treatment. Results: The initial patient pool yielded a group (n = 118) with 72% (n = 85) having undergone Cytoreductive Surgery (CRS). Within the CRS group decreased survival was noted in patients with an elevated CGA level 4 months post-operatively (p = 0.002) and an elevated median CGA level of > 224ng/ml correlated with a shorter survival time (p = < 0.005). Increased survival was seen in CRS patients with median CGA levels of < 200ng/ml between 4-12 months post-operatively with a 4 year survival of 91.08%. The median time to death was 80.27 months. Elevated CGA levels in CRS patients correlated with a survival probability of 63.25% at 4 years with a median death of 48.25 months. Overall 28% of the total patient group had unresectable disease (n = 33): 61% of this subgroup (n = 20) received Octreotide therapy and exhibited significant decrease in CGA level at a median of 3.6 months (p = < 0.024); no correlation existed between CGA levels and survival. Conclusions: PNETs amenable to resection by Cytoreductive Surgery (CRS) and had a median Chromogranin A (CGA) level < 200 ng/ml measured post-operatively after 4 months showed increased survival. No correlation existed between CGA levels and survival in patients with unresected disease despite Octreotide therapy lowering CGA levels. As such, CGA is predictive of survival in patients with resectable PNETs and worthy of prospective study.
A clinical prediction model to assess risk for pancreatic cancer among patients with new-onset diabetes.
Authors: Boursi Ben , Finkelman Brian S. , Giantonio Bruce J. , Haynes Kevin , Rustgi Anil K. , Rhim Andrew , Mamtani Ronac , Yang Yu-Xiao
Published: September 2018

e15780

Background: Approximately 50% of all patients with pancreatic ductal adenocarcinoma (PDA) develop diabetes mellitus (DM) prior to cancer diagnosis. Targeted screening for PDA among those with new-onset diabetes may allow earlier diagnosis. We sought to develop and validate a PDA risk prediction model to identify high-risk individuals among those with new-onset diabetes. Methods: We conducted a retrospective cohort study in a population representative database from the UK. Individuals with incident diabetes after the age of 35 and ≥3 years of follow-up after DM diagnosis were eligible for inclusion. Candidate predictors consisted of epidemiological and clinical characteristics available at the time of diabetes diagnosis. Variables with p-value<0.25 in the univariable analyses were further evaluated using backward stepwise approach. Model discrimination was assessed using ROC curve analysis. Calibration was evaluated using the Hosmer–Lemeshow test. Results were internally validated using a bootstrapping procedure. Results: The study included 109,385 patients with new-onset diabetes. Among them, 390 (0.4%) were diagnosed with PDA within 3 years. The final model (AUC 0.82, 95% CI: 0.75-0.89) included age, BMI, BMI change, smoking, HbA1C, cholesterol, hemoglobin, creatinine and alkaline phosphatase, and use of PPI and anti-diabetic medication. Bootstrapping validation showed negligible optimism. If the predicted risk threshold for definitive PDA screening was set at 1% over 3 years, only 6.19% of the new-onset diabetes population would undergo definitive screening, and the corresponding sensitivity, specificity and positive predictive value would be 44.7%, 94.0%, and 2.6% respectively. Conclusions: A risk model based on widely available clinical parameters can help target PDA screening in patients with new-onset diabetes.
Variations of circulating KRAS amount as a biomarker to monitor chemotherapy response in pancreatic cancer.
Authors: Del Re Marzia , Vivaldi Caterina , Rofi Eleonora , Vasile Enrico , Miccoli Mario , Fornaro Lorenzo , Restante Giuliana , Crucitta Stefania , Caparello Chiara , D'arienzo Paolo Davide , Falcone Alfredo , Danesi Romano
Published: September 2018

e15794

Background: Current treatment of pancreatic ductal adenocarcinoma (PDAC) is FOLFIRINOX or gemcitabine + nab-paclitaxel, and CA19-9 is the only approved biomarker to monitor tumor response. However, CA19-9 has several limitations (i.e. sensitivity and specificity), highlighting the need for new biomarkers. Being the majority of PDAC (75-95%) KRAS mutated (mutKRAS), the present study developed an analysis tool based on circulating tumor DNA (ctDNA) to monitor the variation of mutKRAS in PDAC undergoing first-line chemotherapy. Early variation of ctDNA mutKRAS after 15 days of treatment was correlated with response to therapy. Methods: Three ml of plasma were collected from patients with PDAC undergoing first-line FOLFIRINOX or gemcitabine + nab-paclitaxel. Patients underwent standard disease evaluation by imaging according to RECIST 1.1 criteria. Blood samples were drawn prior to cycle 1, after 14 days and at each radiological evaluation. ctDNA was extracted using a QIAmp Circulating nucleic acid Kit (Qiagen, Valencia, CA) and the KRAS codon 12 and p.G13D analysis was performed by digital droplet PCR (ddPCR, BioRad, Hercules, CA). Results: A total of 27 patients with locally advanced (15%) and metastatic (85%) PDAC were included in this study. mutKRAS in ctDNA was detected in 19 patients (70.3%) at baseline. There were no statistically significant differences in median PFS and OS in patients with baseline positive or negative ctDNA mutKRAS (p = 0.15). However, there was a statistically significant difference in PFS and OS between patients with increase vs. stability/reduction of ctDNA at the 14 day-evaluation (median PFS: 2.5 vs 7.5 months, p = 0.03; median OS: 9 vs 11.5 months p = 0.009). The imaging evaluation performed at 2 months after initiation of therapy demonstrated that all patients with an increase in ctDNA at 14 days had radiological progression of disease. Conclusions: The results of this pilot study support the use of ctDNA as a new marker for monitoring treatment outcome and disease progression in PDAC, suggesting that ctDNA mutKRAS is a non-invasive predictive factor of response in PDAC.
The prognostic value of baseline neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for predicting clinical outcome in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan (nal-IRI; MM-398) + 5-fluorouracil and leucovorin (5-FU/LV) vs 5-FU/LV.
Authors: Wang-Gillam Andrea , Chen Li-Tzong , Li Chung-Pin , Bodoky Gyorgy , Dean Andrew , Lee Kyung-Hun , Cunningham David , Hubner Richard , Braiteh Fadi S. , Pipas J. Marc , Belanger Bruce , de Jong Floris A. , Mody Purvi D. , Von Hoff Daniel D. , Siveke Jens T.
Published: September 2018

e15795

Background: Increased NLR and PLR have been associated with poor survival in several malignancies. Here we report the association of NLR and PLR with overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 trial (NCT01494506), which evaluated nal-IRI+5-FU/LV for the treatment of mPDAC patients (pts) after disease progression following gemcitabine-based therapy. Methods: Pts missing baseline NLR/PLR data were excluded. Medians reflect Kaplan-Meier estimates; hazard ratios (HRs) reflect Cox regression analysis. P values in this exploratory analysis are descriptive. Results: Of 116 evaluable pts in the nal-IRI+5-FU/LV arm, 82 (71%) had NLR ≤5 and 44 (38%) had PLR ≤150 (data cutoff: Nov 16, 2015). Of 105 evaluable pts in the 5-FU/LV control arm, 73 (70%) had NLR ≤5 and 36 (34%) had PLR ≤150. In pts with baseline NLR ≤5 or PLR ≤150, median OS and PFS were significantly longer in the nal-IRI+5-FU/LV treatment arm vs the 5-FU/LV control arm (Table). In pts with baseline NLR >5 or PLR >150, median OS and PFS were numerically longer in the treatment vs control arm, but differences were less compelling (95% CIs for HRs included 1). Conclusions: Median OS and PFS were improved with nal-IRI+5-FU/LV vs 5-FU/LV in pts with baseline NLR ≤5 or PLR ≤150. This exploratory analysis extends the prognostic significance of NLR and PLR to the post-gemcitabine setting. Clinical trial information: NCT01494506. [Table: see text]
Decision dissonance/alignment scale to promote patient-centered decisions about urinary diversion with cystectomy for bladder cancer.
Authors: Gilbert Scott Michael , Leo Michael C , Wendel Christopher , Krouse Robert S. , Grant Marcia , Danforth Kim N. , Kwan Marilyn L. , Harrison Teresa , Bulkley Joanna E , McMullen Carmit K.
Published: September 2018

e16010

Background: The choice of urinary diversion (UD) with cystectomy is an opportunity to provide preference-driven care. We adapted a decision dissonance scale to measure concordance of patient goals with choice of ileal conduit (IC) vs. neobladder (NB) UD. Methods: With patient and clinician input, we identified 6 IC- and 4 NB-aligned goals, each rated on an 11-point scale (0 = not at all important to 10 = very important). Kaiser Permanente members rated the importance of these goals in a comprehensive survey mailed 6 months post-op (71% response rate (269/381)). Excluding respondents (n=93) with contraindications to NB and missing data on goals, we examined structural validity with principal axis factor analysis and convergent validity using correlations with other decision-making measures. Results: Items aligned to IC vs. NB factored separately as hypothesized (Table 1). NB patients prioritized (p<.05) NB-aligned goals (M=8.8, SD=1.8) over NB-dissonant goals (M=4.3, SD=2.4). IC patients’ alignment (M=5.4, SD=2.7) and dissonance (M=5.6, SD=2.1) ratings were similar. Dissonance was negatively correlated with informed decision-making (r=-.27) and satisfaction with care (r=-.21), and positively correlated with decision regret (r=.28) (each p<.01), but not correlated with shared decision making or decision style preference. Alignment was not significantly correlated with decision-making measures. Conclusions: Our measure distinguished patient values that could guide shared decision-making about UD choice. Patients who chose a NB had strong preferences for maintaining body integrity and function. [Table: see text]
Combined FDG and NaF PET/CT study in patients (pts) with metastatic genitourinary tumors (mGU) treated with cabozantinib + nivolumab +/- ipilimumab (CaboNivo+/-Ipi).
Authors: Lin Jeffrey , Mortazavi Amir , Stein Mark N. , Pal Sumanta K. , Davarpanah Nicole N. , Nadal Rosa Maria , Francis Deneise C , Berniger Marilise Anne , Monk Paul , Kempf Jeffrey , Becker Murray , Sokol Levi , McKinney Yolanda , Knopp Michael V. , Wright Chadwick , Jung Alex , Choyke Peter L. , Mena Esther , Lindenberg Liza , Apolo Andrea B.
Published: September 2018

e16017

Background: The primary objective of the study is to assess the feasibility of obtaining combined FDG and NaF PET/CT in detecting soft-tissue and bone metastatic disease in mGU pts treated with CaboNivo+/-Ipi. Methods: Pts in this single-arm, multicenter, phase I trial had FDG PET/CT followed by NaF PET/CT within 1 hour, at baseline and 8 weeks. The number and location of metastatic lesions on FDG PET/CT and on NaF PET/CT were captured. Lesions were considered positive when there was focal abnormal radiotracer uptake with CT correlation. We analyzed soft tissue and bone lesions distribution and the concordance of baseline metastatic bone disease. Results: From 7/14/15 to 9/9/16, 27 pts (urothelial carcinoma N = 11, bladder squamous cell carcinoma N = 2, sarcomatoid renal cancer N = 1, sertoli cell N = 1, germ cell tumor N = 4, trophoblastic testicular cancer N = 1, urachal N = 4, castrate-resistant prostate cancer N = 2, prostate neuroendocrine N = 1) had scans. Median age was 55 (range 35-75 yr), 24 (89%) were male. Pts completed the dual PET/CTs on the same day (imaging time 3-4 hours) without complications. On FDG, the distribution of 340 lesions were lymph node 41%, bone 35%, lung 18%, liver 11%, soft tissue 4%, kidney 0.6%, adrenal 0.3%, spleen 0.3%, pancreas 0.3%. On NaF, the distribution of 130 lesions was spine 33%, rib 16%, pelvis 13%, femur 10%, scapula 9%, sacrum 8%, skull 5%, humerus 4%, sternum 3%, manubrium 2%, clavicle 2%. Of the 130 lesions on FDG/NaF PET/CT, 38% were not seen on initial FDG. The combination of the two tracers did not affect the quality of the PET/CTs given distinct radiotracer uptake in the anatomical locations with no distortions. Residual FDG activity on combined FDG-NaF images required background intensity to be adjusted to delineate focal radiotracer uptake. There was no difficulty in identifying metastatic lesions, and no instances of prior FDG uptake affecting the determination of metastatic disease. Conclusions: Combination FDG-NaF PET/CT is a feasible imaging modality that offers convenience to pts without compromising detection of metastatic disease in mGU pts. FDG alone detected fewer bone lesions than combined FDG-NaF PET/CT. Clinical trial information: NCT02496208.
Molecular features underlying response to neoadjuvant gemcitabine, cisplatin, and sorafenib (S-GC) in muscle-invasive urothelial bladder carcinoma (MIBC): Insights for trials of new agents combined with chemotherapy in the field.
Authors: Necchi Andrea , Raggi Daniele , Busico Adele , De Cecco Loris , Giannatempo Patrizia , Nicolai Nicola , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Calareso Giuseppina , Togliardi Elena , Colecchia Maurizio , Mariani Luigi , Salvioni Roberto , Paoli Alessandro , Daidone Maria Grazia , Sensi Marialuisa , Perrone Federica
Published: September 2018

e16018

Background: S-GC neoadjuvant chemotherapy (NACT) was active in a phase 2 trial in MIBC, showing a response rate (downstaging to pT < 2) of 54.3% in 46 pts within a single-arm, phase 2 trial ( Necchi et al, GU ASCO 2017). The addition of S to GC may help investigators unravelling key molecular features underlying response in MIBC. Methods: Analyses were made on pre- and post-treatment TURB and cystectomy (Cy) specimens (10µm sections) and matched germline DNA of 29/46 pts. Analyses included measurements of ERCC1 (by immunohistochemistry, IHC) on TURB specimens, baseline circulating VEGF levels (ELISA), copy number variations (CNV, Affymetrix), and next generation sequencing (NGS, custom gene panels through the Ion AmpliSeq Library Kit2.0™ and the Ion Torrent Personal Genome Machine™ platform). Results: We analyzed TURB samples from 15 responders (R) and 4 non-R (NR). An additional 10 Cy samples were used for NR. Baseline VEGF levels were not associated with PFS or OS on univariable analyses (p = 0.943 and p = 0.669, respectively). Differences in R vs. NR pts were found according to CNVs and NGS. CN gains on regions of chromosome (chr) 18 and 20 and loss in chr 5 were found in 56-60% of R and in none of the NR. Gains on regions of chr 3 and losses in chr 1 and 20 were more frequent in the NR ( > 50%) vs. R ( < 20%). The median number of somatic mutations (mut) per sample was 3 (range, 0-19). Missense mut in DNA-repair genes ( POLK; FANCM; PRKDC; BLM; MSH2; MSH6; RAD50) were found in 63.6% R vs 16.7% NR, in RAS-RAF pathway genes ( CDKN2A; RAC1; KRAS; NF1) in 45.4% vs 7.1%, in chromatin-remodelling genes ( ARID1A; ARID2; KDM5C; SMARCA4; ATRX; KMT2C; DAXX; SETD2) in 54.5% vs 16.7%, and in HER-family genes in R only (36.4%). ERCC1 IHC expression was found in 55.6% R vs 93.3% NR (p = 0.047). Conclusions: We identified distinct molecular features of R vs NR to S-GC in MIBC. These features may be linked to a potentially-additive effect of S and CT. The identification of the targets of CNVs will further elucidate the underlying biology. These results may help developing personalized medicine in MIBC with new more potent targeted agents with CT. Clinical trial information: NCT01222676.
Real world outcomes in advanced urothelial cancer and the role of neutrophil to lymphocyte ratio.
Authors: Yip Steven , Kaiser Jeenan , Li Haocheng , North Scott A. , Heng Daniel Yick Chin , Alimohamed Nimira S.
Published: September 2018

e16020

Background: Advanced urothelial carcinoma (UC) patients have a poor prognosis. In the first and second line UC treatment setting, we investigated real world outcomes and evaluated the prognostic role of the neutrophil to lymphocyte ratio (NLR). Methods: A retrospective analysis was performed on advanced UC patients treated with systemic therapy. Overall response rates (ORR), time to treatment failure (TTF) and overall survival (OS) were calculated. Cox regression analysis was performed to examine the association between baseline NLR (low NLR<3 vs high NLR≥3) and TTF and OS. Results: We evaluated 233 advanced UC patients. In the first line setting, the ORR was 25%. Median TTF and OS were 6.9 mo and 9 mo, respectively. Low baseline NLR was significantly associated with improved 8.3 mo median TTF, versus 5.8 mo for high NLR patients (p=0.05). Low NLR was significantly correlated with a longer median OS of 13.1 mo, in comparison to 8.2 mo in patients with high NLR (p=0.007). In the second line, an ORR of 22%, a median TTF of 4.1 mo and a median OS of 8 mo were observed. Low NLR in the second line was significantly associated with improved median TTF at 7.9 mo, versus 3.6 mo for patients with high NLR (p=0.03). Second line low NLR was also significantly associated with a longer median OS of 12.2 mo, in comparison to 6.8 mo in patients with high NLR (p=0.003). Conclusions: In this real world analysis of advanced UC patients, first line outcomes were lower than expected, while response rates in the second line compared favorably to the literature, suggesting a highly selected patient population actually receives second line treatment. A low baseline NLR in the first and second line is associated with improved TTF and OS and warrants further prospective evaluation. [Table: see text]
Association of muscle mass with pathologic response and toxicity in localized bladder cancer patients treated by neoadjuvant chemotherapy (NAC) and radical cystectomy (RC).
Authors: Fenioux Charlotte , Huillard Olivier , Xylinas Evanguelos , Tlemsani Camille , Boudou-Rouquette Pascaline , Carton Edith , Peyromaure Michael , Alexandre Jerome , Goldwasser Francois
Published: September 2018

e16022

Background: Sarcopenia, the condition of low muscle mass, is a prognostic factor across many cancer types including bladder cancer. Moreover, sarcopenia was shown to predict severe toxicity induced by many anticancer agents. Conversely, NAC may increase the prevalence of sarcopenia before surgery. This retrospective study aimed to investigate the association of sarcopenia with pathologic response and toxicity in localized bladder cancer patients treated by NAC and RC. Methods: Among the 52 patients who underwent RC after NAC between Jan 2010 and Dec 2016, the preoperative sarcopenia status could be determined for 39 patients. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured on CT scan images, and sarcopenia was defined as skeletal muscle index of < 43 cm2/m2 for men with body mass index (BMI) < 25 kg/m2, SMI < 53 cm2/m2 for men with BMI > 25 kg/m2, and SMI < 41 cm2/m2 for women. The criteria for efficacy was pathologic response defined by pathological down-staging to ≤ pT1N0. Patients were compared using χ2 or Fischer’s exact test when appropriate. Results: 48% of patients were sarcopenic before RC. A significant higher rate of pathological response was found in non-sarcopenic patients compared to sarcopenic patients (13/20 vs 5/19, P = 0.01). More severe chemotherapy related toxicity was found in sarcopenic patients compared to non-sarcopenic patients for neutropenia (P = 0.06), thrombopenia (P = 0.15), and neuropathy (P = 0.23). Among the 21 patients for whom sarcopenia status before chemotherapy was available, 3 patients became sarcopenic and 4 patients initially sarcopenic gained muscle mass on post-chemotherapy CT scan. Conclusions: Sarcopenia is frequent in localized bladder cancer patients. Muscle mass correlates with pathological response to NAC.
Clinical characterization of febrile neutropenia episodes in patients with testicular germ cell tumors.
Authors: Bezan Angelika , Posch Florian , Bauernhofer Thomas , Pichler Martin , Szkandera Joanna , Hutterer Georg C. , Pummer Karl , Partl Richard , Zurl Brigitte , Kapp Karin , Stoger Herbert , Gerger Armin , Stotz Michael
Published: September 2018

e16038

Background: Febrile neutropenia (FN) is a serious complication of chemotherapy (CTX). Here, we aim to characterize the clinical course of FN in patients (pts) with testicular germ cell tumors (TGCT). Methods: 413 TGCT patients who underwent at least one cycle of CTX in adjuvant or curative intent were studied within this single-center observational cohort study. Baseline characteristics of the subpopulation with FN are reported in Table 1. Results: During a total number of 1,196 CTX cycles in 413 patients, we observed 70 episodes of febrile neutropenia (16.9%). 55 (79%) of these episodes occurred during the 1stcycle of CTX. The median time between CTX start and FN onset was 14 days [IQR: 12-15, range: 7-18]. One (1%) FN episode was fatal, and 56 patients (80%) had to be hospitalized. Median time in hospital was 7 days [IQR: 6-8, range: 3-12], and the median number of days with an absolute neutrophil count below 0.5G/L was 2 [IQR: 2-3, range: 1-7]. Twelve (20%) FN episodes occurred in the 60 pts who received primary G-CSF support. There was very little treatment delay due to FN (median: 0 days [IQR: 0-0, range: 0-7]. 3 patients (4%) developed a second FN episodes. Conclusions: This study supports prior reports that FN is a relatively frequent complication of CTX in TGCT. However, the case-fatality-rate of FN in TGCT appears to be very low. [Table: see text]
Brachyury, a driver of epithelial mesenchymal transition, as an independent prognostic factor in high-grade testicular germ cell tumors.
Authors: Carcano Flavio Mavignier , Pinto Filipe , da Silva Eduardo CA , Vidal Daniel Onofre , Scapulatempo Neto Cristovam , Lopes Luiz Fernando , Reis Rui Manuel
Published: September 2018

e16039

Background: The T-box transcription factor Brachyury has been considered a cancer-specific marker and a novel oncotarget in solid tumors. Brachyury overexpression has been described in various cancers, being associated with epithelial-mesenchymal transition, metastasis and poor prognosis. However, its clinical association with testicular germ cell tumor (TGCT) is unknown. Methods: We analyzed the expression of Brachyury both at protein and transcript levels in a series of 96 TGCT samples and by in silico analysis, respectively. Additionally, we investigated the clinical significance of Brachyury in TGCT. Results: Brachyury protein showed to be over-represented in 89.6% (86/96) of TGCT cases with nuclear staining in 24% (23/96) of them. Microarray expression analysis in two independent cohorts of TGCTs showed similar results with increased levels of Brachyury in TGCTs and metastasis compared with normal testis. Clinically, Brachyury nuclear staining was statistically associated with event-free survival (p = 0.04) and overall survival (p = 0.01) in intermediate/high-risk TGCTs. Multivariate analysis showed that Brachyury nuclear subcellular localization was an independent predictor of poor prognosis (HR: 3.56, p = 0.06). Conclusions: These results indicate that Brachyury plays an oncogenic role in TGCTs and its subcellular localization in the nucleus is a potential novel biomarker of poor prognosis and an oncotarget for intermediate/high-risk TGCTs treatment.
Management of pure metastatic teratoma in chemotherapy naïve testis cancer patients.
Authors: Ahmed Shahid Sattar , Jacob Joseph , Cary Clint , Foster Richard , Einhorn Lawrence H.
Published: September 2018

e16043

Background: Management of metastatic testicular cancer often requires post-chemotherapy resection of teratoma. This is well known and described in literature. However, the ability of teratoma to metastasize independently is not as well appreciated, making chemotherapy futile in patients with pure metastatic teratoma. Methods: 15 patients with metastatic teratoma were identified of which 13 had only teratoma in the orchiectomy and 2 had predominantly teratoma. All 15 had normal serum hCG and AFP. Cases were derived from a retrospective review of patients seen from 1989-2016. Results: Mean age of patients was 27 years. 12 patients presented initially with Stage II disease and 2 presented with stage III disease. Median RP mass size was 6 cm with a range of 1.5-24 cm. 2 of 15 patients were treated initially with a single course of chemotherapy with BEP and showed no response. The remaining 13 patients only received resection(s). All 15 patients underwent RPLND with 2 patients requiring additional mediastinal and retrocrural resection and 1 requiring lobectomy. All surgical specimens showed pure teratoma on pathology with no other active germ cells. Patients were followed for a median duration of 5 years and all 15 remain with no evidence of disease at most recent follow up. However, 1 patient needed subsequent surgery for a late relapse of teratoma and 1 patient had a second extra-gonadal primary. Conclusions: Teratoma can metastasize in the absence of other germ cells. Surgical treatment alone for patients with pure metastatic teratoma of any stage can result in cure for the majority of patients and this approach can help avoid unnecessary chemotherapy.
Single institution experience on papillary renal cell carcinoma PD-1/PD-L1 expression, pathological analysis, and outcomes after nephrectomy.
Authors: Carthon Bradley Curtis , Tabba Manal , Harris Wayne , Kucuk Omer , Master Viraj A. , Ogan Kenneth , Osunkoya Adeboye O. , Ellis Carla
Published: September 2018

e16048

Background: The PD-1/PD-L1 pathway plays an important role in tumor growth and tolerance among renal cancer cells. Renal cell carcinoma (RCC) consists of several different histological subtypes, including clear cell and non-clear cell varieties. Papillary RCC is the most common non-clear cell type and accounts for almost 13% of RCC cases. Our center has a large volume of papillary RCC patients treated by nephrectomy or with systemic therapy. This retrospective study examines pathological criteria, outcomes, and PD-1/PD-L1 expression in a defined cohort. Methods: Institutional review board (IRB) approval was obtained to access and retrospectively review clinical and pathological data of patients that presented with papillary RCC and had a partial or radial nephrectomy during a 1 year duration at our institution. We collected data on survival, systemic treatments, and pathological staging. Tumor samples from the patients were also stained and analyzed for PD-1 and PD-L1 expression. Results: 31 patients were identified with papillary histology after nephrectomy. 45% (14/31) of the patients underwent a radial nephrectomy while 55% (17/31) underwent a partial nephrectomy. Of these 31 patients, 23 had tumor slides available for staining and review. 65% (15/23) of the tumor samples were type 1 papillary RCC, and 35% (8/23) were type 2. PD-L1 was expressed in 13% (3/23) of the cases and PD-1 was expressed in 52% (12/23) of the cases. 71% of the patients were pT1 and 84% of the patients were alive at 5 years. Only 1/31 patients required use of systemic therapy. 74% (17/23) of patients were African American. Conclusions: Patients undergoing nephrectomy for papillary RCC at our institution commonly had small primary tumors with excellent survival. 46% of the tumors expressed PD-1, whereas only 12% expressed PD-L1. Trials that study the inhibition of the PD-1/ PD-L1 pathway may be helpful in strategies for treating both localized and metastatic papillary RCC. Further genomic and pathological examination of additional samples is currently underway.
Establishment of patient-derived renal cell carcinoma (RCC) models based on orthotopic xenografts (PDX) and cancer stem cell (CSC) isolation to provide prognostic and predictive information.
Authors: di Martino Simona , de Luca Gabriele , Grassi Ludovica , Federici Giulia , De Salvo Laura , Di Pace Anna Laura , Addario Antonio , Muto Giovanni , Costantini Manuela , Biffoni Mauro , Signore Michele , Sperduti Isabella , Sentinelli Steno , Milella Michele , Cognetti Francesco , Gallucci Michele , De Maria Ruggero , Bonci Desiree
Published: September 2018

e16055

Background: The introduction of VEGF/VEGFR- and mTOR, and immune checkpoint-targeted agents has radically changed metastatic RCC treatment; however, predictive biomarkers are still lacking and the potential for curative impact of such treatments in earlier disease stages is hotly debated. To identify potential diagnostic, prognostic, and predictive biomarkers, we developed patient-derived preclinical RCC models based on PDX obtained from freshly dissociated cancer tissues and combining isolation of cell populations endowed with self renewal and multi-lineage differentiation abilities (CSC). Methods: 182 surgical RCC specimens (clear cell, n = 110; papillary type I/II, n = 23, chromophobe/oncocytoma, n = 26, other, n = 23; stage I-III, n = 124, stage IV, n = 28, n/a n = 30) were collected; tumor spheroids were obtained and characterized in 57 cases, using a stem-cell isolating medium supplemented with EGF/b-FGF; 30 cancer samples were orthotopically injected in immunocompromised mice and were able to engraft in 67% of cases (G3-G4 cases more frequently than G1-G2 cases, p = 0.04). Results: PDX tumors recapitulated histological appearance, sarcomatoid features when they were present, and tumor heterogeneity of their human counterpart; interestingly, PDX engraftment was significantly correlated with shorter DFS in the corresponding patient population (p = 0.12). We conducted proteomic analysis by Reverse Phase Protein Array (RPPA) in 21 patient-derived CSC models in vitro: a panel of established (HIF, VEGFR, mTOR) and novel (EGFR(Y1148)), AKT, PI3K) oncogenic signals were deregulated in our isolated cell populations; molecular endpoints were correlated with grading and with angiogenesis and mTOR pathways (p < 0.05). Data analysis is ongoing to ascertain whether specific RPPA-signatures can potentially complement clinical prognostic information and suggest candidate biomarkers and potential targets for therapy. Conclusions: In the era of personalized therapy, the combined use of PDX and RPPA from tumor specimens may be very useful for drug testing and patient stratification in RCC.
Renal cell carcinoma with perirenal fat invasion: Is partial nephrectomy as good as radical surgery?
Authors: Cordeiro Mauricio , Bastos Diogo Assed , Gallucci Fabio Pescarmona , Barbosa Joao Arthur Brunhara , Ilario Eder Nisi , de Carvalho Paulo Afonso , Nonemacher Henrique T. S. , Albuquerque George Lins , Mattedi Romulo Loss , Carvalho Arnaldo Fazoli , Nahas William Carlos
Published: September 2018

e16056

Background: Partial nephrectomy (PN) is the standard of care in the management of cT1a tumors, while radical nephrectomy (RN) is indicated in more advanced tumors. Recent studies provided evidence that PN could be performed in patients with tumors greater that 7 cm with complication rates and oncological outcomes comparable with those undergoing RN. This study compares the recurrence-free survival (RFS), overall (OS) and cancer-specific survival (CSS) of PN and RN in patients with non-metastatic pathological T3a renal cell carcinoma (RCC) with perirenal fat invasion only. Methods: We reviewed 1202 patients undergoing RN (n = 653) and PN (n = 549), at a oncological referral center, from January 2003 to June 2016. Of all patients, we identified 25 RN and 41 PN pT3a tumors with exclusively perirenal fat invasion. None had nodal or distant metastasis at pretreatment clinical staging. Patients characteristics were compared with Mann-Whitney U test and Student t-test for categorical and numeric variables with normal distribution, respectively. Both groups were compared for RFS, OS and CSS with a Kaplan-Meier survival analysis. Results: All patients included had pT3a stage with isolated perirenal fat invasion. Groups undergoing RN and PN were not significantly different regarding Charlson Comorbidity Index (Median 3 for RN vs 4 for PN, p = 0.24) or Age (Mean 65.3 for RN vs 62.0 for PN, p = 0.99). Patients undergoing RN had bigger tumors (7.9 cm vs 4.6, p < 0.001) and higher Fuhrman grade (p = 0.01). Median follow-up was 36 months for RN and 34 months for PN. At the end of follow-up, recurrence was seen in 3 patients undergoing RN (12%) and 2 undergoing PN (5%), p = 0.36. Mortality was similar across groups (16% for RN vs 15% for PN, p = 0.99) as well as Cancer-specific mortality (4% for RN vs. 5% for PN, p = 0.99). At the end of follow-up, RFS was 80% (20/25) for RN and 82% (34/41) for PN. Conclusions: In our data, renal cell carcinoma with T3 stage due to perirenal fat invasion exclusively had similar outcomes when treated with Radical or Partial Nephrectomy. OS as well as RFS were comparable for both surgical modalities, suggesting that, although RN is currently the gold standard for this staging, PN may provide similar oncologic results.
The impact of kidney function on the efficacy and safety of pazopanib in metastatic renal cell carcinoma (mRCC) patients: CORE-URO-01 study.
Authors: Vitale Maria Giuseppa , Masini Cristina , Procopio Giuseppe , De Giorgi Ugo , Buti Sebastiano , Rossetti Sabrina , Iacovelli Roberto , Mucciarini Claudia , Cosmai Laura , Vignani Francesca , Prati Giuseppe , Scagliarini Sarah , Berselli Annalisa , Pinto Carmine
Published: September 2018

e16063

Background: Pazopanibhas been approved for treatment of patients (pts) with mRCC based on the prospective randomized trial that enrolled only pts with adequate renal parameters. There are no data on the toxicity profile and efficacy of pazopanib in pts with renal insufficiency (RI).The aim of this study is to investigate the effect of renal function on treatment outcomes in pts treated with pazopanib for mRCC. Methods: We retrospectively analyzed the data of the mRCC pts treated with pazopanib with respect to renal function in eleven Italian institutions from January 2010 to June 2016. Baseline glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula at the time of therapy initiation. Pts with MDRD < 60 mL/min/1.73 m2 (group 1) were compared with pts with MDRD ≥60 mL/min/1.73 m2(group 2) in terms of response rates, progression free survival (PFS), overall survival (OS) and side effects. Results: One hundred and twenty-ninepts with mRCC were included in this study: 70 pts in group 1 and 59 pts in group 2. 67% of pts were male, median age was 66 years (34-83) and median CrCl was 49 ml/min (6.3-59.5) in group 1. In group 2, 64% of pts were male, median age was 65 years (38-80), and median CrCl was 64 ml/min (58.1-137.1) Pts with MDRD < 60 were more likely to have had a previous nephrectomy (84.3% vs 79.7%). No difference between the 2 groups was observed in terms of outcomes: PFS was 9.6 months (0.6–56.9) and 9.0 months (0.4–60.1), OS was 16.1 months (1.3–56.9) and 17.0 months (1.2–60.1), for MDRD < 60 group and MDRD ≥60 respectively. The disease control rate was 85.8% in group 1, and 72.9% in group 2. About grade 1-2 toxicity, no difference between the 2 groups was reported (67.1% vs 67.8%) while a higher incidence of grade 3-4 toxicity was evident in the group 1 (25.7% vs 18.6%). Conclusions: RI was commonly observed in pts with mRCC. Renal function at therapy initiation does not adversely affect the efficacy and safety of pazopanib. More frequent monitoring of side-effects in patients with RI is recommended.
Patients with advanced renal cell carcinoma: Immediate or delayed treatment? Study of a cohort of patients followed at Instituto Oncológico Henry Moore (IOHM).
Authors: Morgenfeld Eduardo L. , Gil Deza Ernesto , Martin Reinas Gaston , Acuna Claudia Lorena , Niewiadomski Dario , Rivarola Edgardo G. J. , Ares Sandra L. , Gercovich Felipe G.
Published: September 2018

e16073

Background: Most of the treatment guidelines for advanced renal cancer (RCC) agree about what drugs must be used, but don’t indicate when the treatment should be started. This decision is left to the desire of the patient (pt) and/or the common sense of the doctor. The aim of this paper is to study which could be the best time of initiation of systemic treatment (Tx) in advanced RCC. Methods: Between 1/1/2001 and 11/30/2016, 828 patients diagnosed with RCC were followed at IOHM. We selected all pt with clear cell or papillary stage IV RCC who received systemic Tx; 80 pt met this inclusion criteria. We reviewed all the clinical records of this population and separated two groups according to the time of initiation of systemic treatment: Group A (Immediate = within three months of diagnosis) or Group B (Delayed = beyond three months of diagnosis). We compared the population’s characteristics and outcome of each group. Results: The results are shown in the table. Conclusions: 1) In this cohort of 80 patients with advanced clear cell or papillary RCC, 47 pt (59%) received systemic treatment immediately after diagnosis and 33 pt (41%) postponed it at least three months. 2) Both groups were similar in age, surgical treatment, metastatic sites and systemic treatments. 3) There was no difference in survival rates with immediate or delayed treatments. [Table: see text]