bluuebunny/crossref_metadata_2025 huggingface dataset:
Antitumor efficacy and pharmacokinetics of a novel gemcitabine oral formulation (INNO-D07001) in xenograft animal models.
Authors: Hsu CS , Hao W-H , Wang J-J , Lin T-H , Kuo R-Y
Published: March 2020

e14699

Background: INNO-D07001 is a novel oral gemcitabine formulation which was developed to enhance the oral bioavailability of gemcitabine and it has been successfully demonstrated in both beagle dogs as well as nude mice. The objectives of this study were to examine the antitumor activity of this novel gemcitabine oral formulation in human xenograft models of pancreatic tumors with different daily doses as well as various dosing schedules. Methods: The INNO-D07001 dosing solutions (gemcitabine oral formulation) were formulated freshly before treatment and water for injection (USP) was used as the diluent. There were seven groups in the study and it was ten female NCr-nu/nu mice (with human CFPAC-1 pancreatic tumor) per group. Two doses (5 mg/kg and 10 mg/kg) and three dosing schedules (Q1D, Q2D, and Q3D) were examined. Water for injection (by oral administration) was used as the blank control and Gemzar (180 mg/kg by I.V.) was used as the active control. All INNO-D07001 dosing solutions were administered to mice by P.O. and, on the other hand, Gemzar was administered to mice by I.V. All animals were designed to receive doses for 12 days based on different doses and dosing schedules. Total body weights and tumor sizes were recorded continuously for evaluating the toxicity and antitumor activity, respectively, of INNO-D07001. Results: Oral administration of INNO-D07001 once daily at doses of 10 and 5 mg/kg/dose was not tolerated. In contrast, oral administration of INNO-D07001 on a Q2Dx6 schedule at a dose of 10 mg/kg/dose and on a Q3Dx4 schedule at doses of 10 and 5 mg/kg/dose was well tolerated. Moreover, the INNO-D07001 treatment at a dose of 10 mg/kg/dose on a Q2Dx6 schedule produced statistically significant inhibition of tumor growth (i.e. more than 60% inhibition rate comparing to the blank control) on the last treatment day. Conclusions: The novel gemcitabine oral formulation (INNO-D07001) is well tolerated and effective at a dose of 10 mg/kg/dose on a Q2Dx6 schedule to show the significant inhibition of pancreatic tumor growth. Future preclinical study in toxicity evaluation with repeating doses is ongoing in order to provide adequate safety information before entering phase I clinical study.
Gemcitabine (G) plus nab-paclitaxel (nab-P) plus chemoradiation (CRT) in locally advanced pancreatic cancer (LAPC).
Authors: Olowokure Olugbenga Olanrele , Bedoya Ivan Dario , Mierzwa Michelle Lynn , Torregroza Maria Patricia , Dwivedi Alok kumar , Wang Jiang , Smith Milton T , Schmulewitz Nathan , Kucera Stephen , Choe Kyuran Ann , Ristagno Ross , Rudich Steven , Sussman Jeffrey J. , Ahmad Syed A
Published: March 2020

e14714

Background: 30-40 % of PC pts present with LAPC. Optimal management remains controversial. Current NCCN guidelines, suggests clinical trial, FOLFIRINOX, G, G based combination therapy, chemo followed by CRT as options in pts with good PS. This single institution retrospective review, evaluated the UC experience of the impact of G+nab-p+/- CRT in LAPC. Methods: From 05/01/09-09/01/11,105 newly registered pts were identifiedusing ICD code 157, 13pts met inclusion criteria: ECOG PS 0-2, histologically proven LAPC, without prior therapy that received G + nab-P, pre or post radiation as part of their treatment. G+nab-p was given as cycles of G=1,000mg/m2 and nab-P=100mg/m2 weekly x3 every 4 weeks with appropriate modifications. CT scans and CA19-9 levels were followed. PFS was estimated from the date of diagnosis to date of progression or death if this occurred first and OS was estimated from date of diagnosis until date of death or loss to follow up. Kaplan Meier survival estimates were obtained with 95% confidence interval (CI). Log rank test was used to compare the PFS according to categorical variables. Results: Median duration of follow up was estimated to be 14.4 months (M) range(R) (5.8-19). CA19-9 data was available for 12 pts, 2 had baseline <1 (R<1-12,861), CA19-9 decrease > 50% from baseline was seen in 9/10. Mean # of G+nab-P cycles administered was 3, R (1-10). 77% received G based CRT with only 1pt receiving this post op. 38% (5/13) underwent resection, 4 post CRT with R0 margins and -ve LN’s and 1 pre CRT with R0 margins but 1/13 LN’s +ve. 11 pts were evaluable for response by RECIST (4PR, 6SD, 1PD). Disease control rate 91%. PFS 92% (CI: 57- 99%) at 6 M and 65% (CI: 31-85%) at 12 M. OS was 85% (CI: 51-96%) at 6M and 77 %(CI: 44-92%) at 12M. At 6M, 100% PFS was observed in resected group, whereas 88% PFS in non-resected group (p=0.12). There was no significant difference in PFS according to gender (p=0.44) and T lesion (p=0.49). Grade III/IV toxicity was mainly hematologic and gastrointestinal. (4/7) 57% received further therapy upon progression. Conclusions: Compared to contemporary G- based trials, the UC experience of G+ nab-P with CRT appears to be associated with improved survival in LAPC and warrants further study.
Single center experience of perioperative EOX in locally advanced resectable gastroesophageal cancer (GEC).
Authors: Djanani Angela , Pall Georg , Bechter Oliver Edgar , Kafka-Ritsch Reinhold , Zitt Matthias , Pratschke Johann , Kasseroler Marie-Therese , Eisterer Wolfgang
Published: March 2020

e14719

Background: Perioperative chemotherapy has shown to improve local control and survival in GEC (MAGIC, FFCD, EORTC40954) deploying 5-FU and cisplatin ± epirubicin. A triple chemotherapy with EOX (epirubicin, oxaliplatin, capecitabine) showed a promising response rate and an improved outcome in stage IV disease (REAL2). Methods: We analyzed 24 patients with locally advanced GEC (uT2N+, uT3N0-3, UICC II-IV) treated in our institution from 2008 to 2011 who received neoadjuvant EOX (epirubicin 50mg/qm iv d1 qd22, oxaliplatin 130mg/qm iv d1 qd22, capecitabine 1650mg/qm daily) followed by surgery followed by adjuvant EOX. The aim of this study was to retrospectively analyze the efficacy and toxicity of perioperative EOX and the treatment efficacy. Results: We treated 6 (25%) females and 18 (75%) male patients. Stage distribution was 42% UICC stage II, 50% stage III and 8% stage IV (cT1-4N3M0). All patients received neoadjuvant EOX. Dose reductions were necessary in 4/24 patients (17%). No treatment related deaths occurred. Main toxicities were grade 3/4 leucopenia 4/24 patients (17%), thrombopenia 2/24 patients (8%), diarrhea 3/24 patients (12%, CTC criteria 2.0). One patient suffered from a myocardial infarction after the third cycle of chemotherapy. Progression of disease was observed in 2 patients (8%). Surgery was performed in 21/24 patients (88%) with R0-resection rate of 100%. We recorded no major surgical complication. Downstaging assessed by histopathological response was achieved in 10 patients (48%) with complete pathological remission (CPR) in 2 patients (10%). 10 patients (42%) received adjuvant therapy. 54% of the patients are still alive and in complete remission. after a follow up period of 2 years. One patient died because of a cardiac arrest 2 weeks after surgery. Conclusions: Preoperative chemotherapy with EOX causes moderate toxicity and is associated with a meaningful clinical activity. The significant downstaging in locally advanced GEC suggests that this regiment is highly active in locally advanced gastric cancer. According to our experience EOX represents a valid alternative to cisplatin and 5FU ± epirubicin chemotherapy in curatively treated GEC.
Image-guided targeted intraarterial delivery of chemotherapy drug loaded iron oxide nanoparticles to rabbit liver cancer model.
Authors: Kim Hyun Sik , Lawal Taoreed O , Prieto Veronica E , Huang Jing , Wang Liya , Mao Hui
Published: March 2020

e14734

Background: To develop an enhanced drug delivery system to liver tumors using novel MRI traceable iron oxide nanoparticles (IONP) loaded with doxorubicin and to investigate biodistribution of deliverednanoparticle and by assessing intratumoral and normal liver tissue concentrations after targeted (IA) versus systemic (IV) administration. Methods: Paramagnetic IONP (core and hydrodynamic size of 10 nm and 23 nm, respectively) coated with amphiphilic polymers were non-covalently loaded with hydrophobic doxorubicin; whose presence was confirmed by optical absorption spectrum. VX2 liver tumors were induced in the left lobe of 12 rabbits, allowed to grow for 2 weeks to a size of 2 cm, and were subsequently divided into 2 treatment groups, each receiving 1 mg/kg body weight of doxorubicin via IONP. Group 1 received IA administration to the left hepatic artery under fluoroscopy, and Group 2 received IV administration via the marginal ear vein. Animals were sacrificed 24 hours after treatment. Tumor and liver sections were collected and iron concentrations of tumor and liver tissues were determined by the colorimetric method with iron binding 1,10-phenanthroline at 508 nm. Analysis of tissue iron concentrations in different groups was performed using a standard t-test, with p<0.05 considered significant. Results: Intratumoral and peritumoral concentrations of IONP were significantly higher 24 hours after IA administration than IV (1.54 vs 1.03 mg Fe/g , p=0.019), given at the same dosage. Additionally, 24 hours after treatment, the group receiving IA therapy showed significantly higher nanoparticle concentrations in the left hepatic lobe in comparison to the IV group (1.63 vs 1.34 mg Fe/g, p=0.0226). Conclusions: Targeted IA delivery significantly enhances intratumoral and peritumoral uptake of IONP when compared to IV. Targeted intraarterial delivery of IONP carrying doxorubincin can serve as a powerful tool in serving as a vehicle to deliver chemotherapy drugs to liver tumors. To further evaluate the potential of this drug delivery method, future studies will correlate the biodistrubution of the IONP to drug concentrations and findings on histology, imaging, tumor response.
Phase II trial of tamoxifen for progressive advanced urothelial carcinoma following prior chemotherapy.
Authors: Lerner Seth P. , Sternberg Cora N. , Younes Mamoun , Calabro Fabio , Cerbone Linda , Chandrashekar A , Mitchell Carmen , Shen Steven S. , Sonpavde Guru
Published: March 2020

e15003

Background: Urothelial carcinoma (UC) expresses estrogen receptor (ER)-β, which increases with stage and grade. The selective estrogen receptor modulators, tamoxifen and raloxifene have displayed anti-tumor activity in preclinical UC. Effective therapy for progressive UC following chemotherapy is lacking. A rationale can be made to evaluate the activity of tamoxifen following prior chemotherapy for advanced UC. Methods: A non-randomized two-center 2-stage phase II trial was planned. Eligible patients were required to have bladder or upper tract urothelial cancer, measurable metastatic disease, 1-2 prior chemotherapy regimens, adequate organ function and ECOG performance status (PS) 0-2. The primary endpoint was freedom from progression (FFP) at 4 months (mo), with secondary endpoints of response, survival, toxicities and association of tumor ER studies with FFP. FFP of ≥30% was considered important and ≤10% was felt to reflect poor activity. Twenty-five evaluable subjects were required, 15 during stage 1 and 10 during stage 2 for α=0.05 and power =0.8. If ≥2 patients attained FFP during stage-1, the trial proceeded to stage-2. Tamoxifen was administered as 20 mg orally once daily until progression by RECIST or intolerable toxicities. Clinical assessments were performed every 4 weeks and imaging every 8 weeks or earlier if indicated. ER isoforms were measured in archival formalin fixed tumor. Results: The trial has completed accrual with 28 patients enrolled of whom 18 are currently evaluable (16 male and 2 female). Number of prior chemotherapy regimens was 2 in 15, ≥3 in 2 and unknown in 1 patient. ECOG-PS was 0 in 9, 1 in 7 and 2 in 2 patients. Liver metastasis was present in 4 and anemia (Hb <10 gm/dL) in 7 patients. Four patients (22.2%) attained FFP at 4 mo. Minor tumor regression was seen in 1 patient. One grade 3 toxicity (deep vein thrombosis) possibly related to therapy was observed. Tumor ER isoform studies and correlation with FFP will be presented. Conclusions: Tamoxifen exhibited potential activity in a subset of patients with advanced UC following chemotherapy. Given the excellent tolerability, further study may be warranted to identify factors predictive of benefit in less heavily pretreated patients.
Urothelial cancer: Gender discrepancies and impact on overall survival.
Authors: du Manoir Jeanne Michelle , Richter Sue , Sridhar Srikala S.
Published: March 2020

e15020

Background: Gender differences for disease course and survival in various cancers exist. Gender disparity for both stage at diagnosis and overall survival (OS) has been observed in urothelial cancer (UC). We report a single institution analysis of UC patients treated with chemotherapy to further investigate gender differences in outcomes. Methods: We identified 190 bladder cancer pts treated with chemotherapy (adjuvant of palliative) since 2002. Age and stage at diagnosis, sex, smoking status, radiation/chemical exposures, bloodwork as a measure of organ dysfunction, ECOG performance status (PS), pathology, chemotherapies, presenting symptoms, other malignancies, and survival info was collected. Baseline demographics were compared by z test for significance and outcomes using chi square statistic. Survival was determined by censored Kaplan-Meier methods. Results: Average age and stage at diagnosis, and PS were similar for both genders. Males had significantly more exposure to smoking (58% vs 48%, p<0.05) and radiation/chemical exposures (28% vs 10%, p<0.05). Invasive urothelial carcinoma was the predominant histological diagnosis for both genders, but males were found to have significantly more subtypes or other pathologies (22.2% vs 14%, p<0.05). Males were found to have more malignancies diagnosed prior to or concurrently with their UC diagnosis (27.8% vs 20%, p<0.05). Standard Gem-Cis was given more often to males (70% vs 49%, p<0.01) despite no differences in age, organ dysfunction or PS between genders. Receiving alternative chemotherapy in the first-line setting was associated with a poorer 3-year OS (p<0.05) for either sex, as was stage of diagnosis, presence of visceral disease, creatinine, and ECOG PS (p<0.05). Conclusions: Our data suggests that poorer outcomes in females was associated with not receiving standard chemotherapy (Gem-Cis) as frequently as males, despite similar baseline characteristics. Both males and females had significantly improved OS when they received Gem-Cis as the first regimen of chemotherapy. This study reinforces the importance of administering cisplatin as initial chemotherapy to improve outcomes in UC.
Stage I seminoma: Treatment outcomes in a low-income country.
Authors: Abuodeh Yazan Asad , Abdelrahman Fadwa , Salem Ahmed Abdel-Fattah , Farah Naim , Al-Mousa Abdelatif , Khader Jamal
Published: March 2020

e15024

Background: The aim of this report is to address treatment outcomes of patients with early-stage seminoma in a developing country with special reference to patients with history of surgical violation of the scrotum and the potential predictors of disease relapse. Methods: Seventy four patients with pure seminoma were treated at King Hussein Cancer Center (Amman, Jordan) between 2003 and 2010. All patients underwent orchiectomy. All but 3 patients received adjuvant radiotherapy. Patients who underwent surgical violation of the scrotum prior to referral were managed by further excision or irradiation of the scrotal scar. The follow-up ranged from 1 to 200 months (mean, 33 months). Results: At the time of follow-up; all but one patient remain alive. The 3-year relapse-free survival for the entire cohort was 95.9%. Three patients were burdened by relapse, all of whom received adjuvant irradiation following inguinal orchiectomy and initially harbored tumors larger than 4cm upon pathological examination. Median time to relapse was 14 months (range, 8-25 months). None were associated with elevated tumor markers prior to detection of relapse. All but one patient were successfully salvaged by chemotherapy. Conclusions: Our results confirm the excellent prognosis for patients with early-stage seminoma treated by orchiectomy and adjuvant radiotherapy in a developing country. Although all patients burdened by relapse demonstrated adverse pathological findings upon initial assessment, no consistent predictor of relapse was found. Scrotal scar re-excision or irradiation in patients with prior history of surgical violation of the scrotum are effective in preventing local failure.
PAPR1 expression in testicular germ cell tumors.
Authors: Mego Michal , Cierna Zuzana , Svetlovska Daniela , Macak Dusan , Machalekova Katarina , Miskovska Viera , Chovanec Michal , Usakova Vanda , Babal Pavel , Mardiak Jozef
Published: March 2020

e15027

Background: Testicular germ-cell tumours (TGCTs) represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. PARP inhibitors represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate poly(ADP-ribose)polymerase-1 (PARP1) expression in TGCTs and to correlate expression patterns with clinico-pathological variables. Methods: In this translational study, tumor specimens from 124 patients with GCTs were identified. PARP1 expression was detected by immunohistochemistry using monoclonal antibody, scored by the multiplicative quickscore (QS) method and compared to PARP1 expression in testicular tissue of normal testis. The QS was calculated by multiplying the percentage score by the staining intensity score to yield a minimum value of 0 and a maximum value of 18. Based on the QS nuclear PARP1 expression was graded as low (0–9) or high (10–18). Results: We observed higher expression of PARP1 in testicular tumors compared to normal tissue of testis (mean QS = 10.04 vs. 3.60, p < 0.0000001). Mean QS ± SD for each histological subtype was following: intratubular germ cell neoplasia (ITGCN) = 18.00 ± 0.00, embryonal carcinoma = 9.62 ± 5.64, seminoma = 9.74 ± 6.51, yolc sac tumor = 7.8 ± 7.20, teratoma = 5.87 ± 5.34, and choriocarcinoma = 4.50 ± 8.33. The PARP1 overexpression (QS > 9) was most often detected in ITGCN (100% of specimen with PARP1 overexpression), seminona (52.6%), embryonal carcinoma (47.0%), yolc sac tumor (33.3%), teratoma (26.7%), and choriocarcinoma (25.0%), compared to 1.9% of normal testicular tissue specimen. There was no association between PARP1 expression and clinical variables. Conclusions: PARP1 overexpression is an early event in the development of TGCTs. We suggest that PARP1 could represent a novel treatment target in TGCTs and the assessment of PARP1 expression in tumor samples may lead to the consideration of TGCTs patients for PARP inhibitor therapy.
Carboplatin (carbo) AUC dosing and crude relapse rate (RelR) in stage I seminoma.
Authors: Decatris Marios P. , Charalambous Charis , Michaelides Ioannis , Zouvani Ioanna , Kitsios Petros
Published: March 2020

e15030

Background: Single-dose carbo is a treatment option in stage I seminoma. The MRC TE19 study update (2011) generated the hypothesis of a dose-response effect. Patients (pats) with similar creatinine clearance (CrCl) in TE19 had a higher RelR and lower relapse-free survival if treated with carbo AUC<7 than with AUC≥7. Methods: We compared the crude RelR of 40 consecutively treated pats at BoCOC, with that observed in the TE19 study cohorts and a previous large series (Dieckmann, 2000) dosing carbo in mg/m2. We determined CrCl (ml/min) with 24-hour urine collection (isotope method unavailable at our centre). Pats gave informed consent. Initially we used AUC≤7 and since 6/2008 AUC7.7. Follow-up CT scans were done annually to year 3. We compared RelR v actual mean carbo AUC between cohorts and between AUC<7 v ≥7. Results: After 3yrs median follow-up (IQR1.9-4.9), 1 pat relapsed 11months after carbo (AUC ≤7) and was salvaged with RT. Two pats were lost to follow-up at 30 and 52 months. There was a statistically significant negative correlation (Pearson coefficient) between crude RelR v actual mean carbo AUC (r2=0.91, p=0.012). The difference in frequency of relapse between cohorts treated at actual AUC<7 v AUC≥7 (24/322 v 13/370-7.5% v 3.5%) was significant (2-tailed p value for χ2 test 0.022, Fisher’s exact p=0.027). Conclusions: As the risk of relapse beyond 3yrs after carbo is very low (1/561 pats treated or 0.2% in TE19) significant number of further relapses is not expected. These results support an inverse dose-response association for carbo AUC and crude RelR. Follow-up is essential to confirm if these results are maintained. [Table: see text]
The burden of illness in metastatic renal cell carcinoma (mRCC) patients after two targeted therapies: A review of the literature.
Authors: Di Lorenzo Giuseppe , Coombs John , Casciano Roman , Stern Lee
Published: March 2020

e15043

Background: MRCC poses a substantial burden in terms of morbidity, mortality, impaired quality of life (QoL), and costs. Despite the emergence of targeted therapies (VEGF-TKIs and mTORs) in this setting, considerable unmet medical needs remain. Methods: A comprehensive literature search was performed to systematically review available data on the burden of mRCC. Included articles focused on the efficacy, toxicity, guidelines, therapy sequencing, and overall disease burden of mRCC patients who have failed multiple targeted therapies. Of the 933 articles mRCC articles identified, 83 met the criteria for data extraction. Results: An extensive amount of literature is published on targeted therapies in the treatment of patients with mRCC. Recently approved therapies report improved outcomes in 1st and 2nd line treatment; however, there are minimal data on the efficacy and safety of treatments following failure of 2 sequential targeted therapies. Specifically, two studies report OS in 2nd line failures: one prospective study of capecitabine as 3rd line treatment (OS: 7.2 months [CI: 4.6-8.8]) and one retrospective single arm study of 3rd line sorafenib use after failure of both VEGF-TKIs and mTORs (OS: 7 months [range: 6-10]). Consequently, of the six current practice guidelines, none recommend a specific treatment for patients who fail 2 targeted therapies. As highlighted in over 20 articles on therapy sequencing, the treatment population failing 2 targeted therapies represents an extremely heterogeneous group with a variety of prior therapies, for whom data are lacking. QoL and economic data focusing on patients in this setting were not identified. However, based upon evaluations in 1st and 2nd line patients, treatment toxicity and disease progression are expected to have a negative impact on QoL while increasing costs due to the associated need for additional treatment, hospitalizations, and other management. Conclusions: Despite significant advances in the treatment options for patients with mRCC, many patients inevitably progress and are left with few options. There is substantial unmet need for safe and effective 3rd line treatment options that can provide clinical benefit.
Second-line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients.
Authors: Levy Antonin , Menard Jean , Albiges Laurence , Di Palma Mario , Fizazi Karim , Escudier Bernard J.
Published: March 2020

e15049

Background: Sequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. Methods: Data from all mRCC patients treated at the IGR from 2005 to 2009 with first-line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mTOR)) were analyzed. Only patients with subsequent follow up have been included in this analysis. Patients were defined as “non eligible” for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response), or (iii) if they refused a second line treatment. Results: 251 patients, median age 60 years, median follow-up 20.2 months were treated with targeted therapy with a median OS of 25.8 months. Median OS with SU (127), SO (60) or B (61) were respectively 26.3, 16.4 and 32.5 months respectively. Only 3 patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n=61/103), 52% (n=30/58) and 79% (n=38/48) for Su, So and B, respectively. MSKCC classification (p = 0.02) and first line agent (p = 0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of PS = 0 compared to SO (53%) and SU (48%) (p = 0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8 months for a TKI (n=98; 75%) and 16.6 months for an mTOR (n=32; 42%) (p = 0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively. Conclusions: The median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2 years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for 2nd line treatment.
Cytogenetic changes in metastatic renal cell carcinoma: Basis for sensitivity and resistance to everolimus.
Authors: Caldwell Imogen Rose , Oei Paul , Ng Daniel , Caudwell Beth , Fong Peter C.C. , Broom Reuben James
Published: March 2020

e15050

Background: The mTOR inhibitors have improved outcomes for pts with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for pre-selecting pts who are likely to benefit from these agents. We undertook an exploratory translational study evaluating cytogenetic changes in the context of benefit from everolimus therapy. Methods: 10 pts with clear cell mRCC treated with everolimus therapy were enrolled. 2 pts had both primary & metastatic specimens. Pre-treatment paraffin-embedded tissue specimens were analysed for cytogenetic changes using fluorescence in situ hybridisation (FISH) & clinical data including Progression-free Survival (PFS) (RECIST 1.1) were obtained. The gene probes chosen for this analysis were: VHL, FHIT, PDGFβ, PDGFRβ, FGFR1, FGFR3, EGFR, MYC, PTEN & IGH@. Results: Results are displayed in the table. The median PFS was 7.5 months (mo), including 4 pts who remain on treatment. 8 pts were treated 1st-line, one 2nd-line & one 3rd-line. The longest responder (PFS 28 mo, 3rd-line) had a normal VHL status but loss of FHIT. 2 pts with the longest PFS had gain of both PDGFβ & PDGFRβ. Changes were observed between the primary & metastatic specimens including the acquisition of gain of PDGFβ & MYC (these pts remain progression-free on treatment). Conclusions: Loss of FHIT but a normal VHL status was seen in one pt with mRCC who had an enduring response to everolimus. Concomitant gain of PDGFβ & PDGFRβ was observed in 5 pts including 2 with prolonged benefit. Acquisition of gains in gene status suggests evolution of genetic changes between primary & metastatic specimens. [Table: see text]
Primary hypertension to predict progression-free survival of target therapy in patients with metastatic renal cell carcinoma.
Authors: Chi Zhi Hong , Mao Li Li , Si Lu , Cui Chuan Liang , Sheng Xi Nan , Li Si Ming , Tang Bi Xia , Guo Jun
Published: March 2020

e15052

Background: Primary Hypertension(PH) was identified as a risk factor for RCC(renal cell carcinoma) in previous studies, only one report showed history of hypertension predicted better survival in RCC patients. In recent years, treatment related hypertension (TRH) was found to be associated with clinical outcome of targeted therapy. However, little is known about whether primary hypertension had an effect on survival of mRCC patients treated with targeted therapy. The objective of this study was to investigate the effects of primary hypertension on treatment outcome in patients treated with targeted therapy for metastatic RCC (mRCC). Methods: We conducted follow-up on a cohort of consecutiave mRCC cases treated with sunitinib or sorafenib in our center. Baseline characters were recorded such as age, gender, blood pressure, stage, et al. All the patients were followed up for progression free survival (PFS), overall survival (OS), objective response rate(RR). Results: We studied a cohort of 77 cases, 58(24.7%) pts were male, 18(23.4%) pts were 65 years or older, and 47 (61%) pts received sunitinib. 28 pts(36.4%) had a history of PH and 19 pts (24.7%) developed TRH, which was more common in PH pts than pts with normal blood pressure(p=0.003). With a median follow-up time of 24 months (range: 1.5-36.2 months), 60 pts developed disease progression and 34 pts died. Patients with primary hypertension demonstrated longer median PFS than those with normal baseline blood pressure (14.0m vs 9.5m, 95%CI: 8.0-10.9m) (p=0.01). In multivariable analysis, primary hypertension was independent predictors of PFS (HR =0.51, 95% CI; 0.27-0.98). No significant differences were found between clinical outcomes and other factors such as gender, age. Conclusions: Data from this study suggested that primary hypertension may be an independent predictor of longer PFS in mRCC pts treated with targeted agents.
Allogeneic partially HLA-matched dendritic cells (DC) as a vaccine in metastatic renal cell cancer (mRCC): Final analysis of a clinical phase I/II study.
Authors: Flörcken Anne , Kopp Joachim , Movassaghi Kamran , van Lessen Antje , Takvorian Anna , Schönemann Constanze , Jöhrens Korinna , Möbs Markus , Sawitzki Birgit , Dörken Bernd , Pezzutto Antonio , Westermann Jörg
Published: March 2020

e15053

Background: Despite novel kinase inhibitors, prognosis of metastatic RCC remains poor and new experimental approaches are warranted. Our aim was to evaluate a DC-based vaccine, which exploits alloreactivity as a means to amplify specific anti-tumor immune responses. Methods: Allogeneic, partially HLA-matched DC were generated in our GMP facility. DC were loaded with autologous tumor lysate. 8 patients with progressive mRCC were included, 7 patients were immunized repetitively with 107 DC s.c. over 20 weeks. Low-dose IL-2 (3 Mio U s.c. qd) was used concomitantly. Endpoints of the study were feasibility, safety, immunological and clinical responses. T cell responses against HLA-A2-restricted RCC-associated antigens were evaluated by proliferation assays, ELISpot and cytokine bead array (CBA). T cell repertoire was analysed by T cell receptor γ and –β PCR. Results: Vaccination was feasible and safe, no treatment-related grade 3/4 toxicity or clinically relevant autoimmunity was observed. No objective responses were observed, however, 2/7 patients showed stable disease, one a minimal clinical response. The mean TTP was 24.6 weeks (range 5 to 96). Delayed-type hypersensitivity was detected in 3/7 and HLA antibodies were induced in 3/7 patients. In 3/7 patients T cell responses against RCC-associated antigens such as TYMS, G250, vimentin, surviving and cyclin-D1 were induced by vaccination. These antigen-specific T cells showed a predominant TH1-cytokine profile. Interestingly, a clonally expanded T cell population could be detected by γ- and –β PCR in one patient with both a minimal clinical response and a T cell response. This clone is currently persisting for more than 80 months, its specificity is under investigation. Conclusions: Vaccination with allogeneic tumor-lysate-loaded DC was feasible, safe and was able to induce TH1-polarized immune responses against RCC-associated antigens. Tumor vaccination might be a promising approach in minimal residual disease, possibly in combination with antibodies against CTLA-4 or PD-1.
Safety and efficacy of everolimus in Asian patients with metastatic renal cell carcinoma (mRCC) who failed previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy: A subanalysis of REACT.
Authors: Rha Sun Young , Lee Se-Hoon , Ou Yen-Chuan , Ahn Jin-Hee , Chang Yen-Hwa , Srimuninnimit Vichien , Lim Ho Yeong , Chung Ik-Joo , Pang See-Tong , Xue Hong-Ling , Panneerselvam Ashok , Chung Jooseop , Toh Chee-Keong
Published: March 2020

e15064

Background: Some targeted agents have shown variable safety profiles in Asian vs non-Asian patients with mRCC. A retrospective analysis of sunitinib in Korean patients with mRCC found increased incidence and severity of certain adverse events (AEs) compared with previous global trials (Hong et al. Cancer Res Treat. 2009;41:67-72). The open-label, expanded-access program REACT (RAD001 Expanded Access Clinical Trial in RCC; NCT00655252) provided everolimus, a mammalian target of rapamycin (mTOR) inhibitor, before its regulatory approval to 1367 patients with VEGFr-TKI refractory mRCC from 34 countries. Final results of REACT were recently published (Grünwald et al. Eur J Cancer. 2012;48:324-332). This analysis compared study end points in Asian patients with those in the total REACT population. Methods: The primary objective of REACT was to assess the safety of everolimus 10 mg/day, as determined by the overall occurrence of grade 3/4 AEs. Best overall tumor response was evaluated based on RECIST 1.0. Results: Baseline characteristics of Asian patients (n = 109; from South Korea, Taiwan, Thailand, and Singapore) were similar to those of the total study population. Median duration of everolimus exposure was longer in Asian patients than in the total population: 24.1 (range, 2.0-72.7) vs 14.0 (0.1-83.7) weeks. Overall incidence of grade 3/4 AEs was slightly higher in Asian patients than in the total population (70.6% vs 61.6%); common grade 3/4 AEs in Asian patients and the total population, respectively, included anemia (26.6% vs 13.4%), hyperglycemia (11.9% vs 5.5%), pneumonia (10.1% vs 4.2%), stomatitis (6.4% vs 5.4%), thrombocytopenia (3.7% vs 1.0%), and pneumonitis (3.7% vs 2.7%). More patients in the Asian population than in the total population had achieved disease control: partial response, 3.7% vs 1.7%; stable disease, 67.0% vs 51.6%. Conclusions: In this subanalysis of REACT, Asian patients treated with everolimus experienced a greater clinical benefit with a slightly higher incidence of AEs. These results are supportive of the use of everolimus in the Asian population.
The role of tumor vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFR) polymorphisms in the prediction of clinical outcome for advanced renal cell carcinoma patients receiving first-line sunitinib.
Authors: Bianconi Maristella , Scartozzi Mario , Faloppi Luca , Giampieri Riccardo , Maccaroni Elena , Bittoni Alessandro , Del Prete Michela , Loretelli Cristian , Belvederesi Laura , Conti Alessandro , Burattini Luciano , Minardi Daniele , Silva Rosa Rita , Montironi Rodolfo , Cascinu Stefano
Published: March 2020

e15074

Background: metastatic renal cell carcinoma (mRCC) still represents a medical challenge in cancer therapy. In recent years the introduction of new targeted therapies has radically changed the approach to the disease and patients outcome. Currently the therapeutic strongholds are TKIs directed against the VEGF family (sunitinib and sorafenib). The aim of our study is to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms, in determining the clinical outcome of mRCC patients receiving first-line sunitinib Methods: 41 histologic samples (biopsies and surgical specimens) of mRCC patients were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients progression free survival (PFS) and overall survival (OS) were analyzed for first line treatment. Results: VEGF A rs833061 C>T polymorphism was statistically significant in PFS (17 months for C vs 4 months for T; P = 0,0029) and OS (35,93 months for C vs 11 months for T; P = 0,0267). VEGF A rs699947 A>C was statistically significant for PFS (17 months for A vs 3,97 months for C; P = 0,0023) and OS (35,93 months for A vs 10,98 for C; P = 0,0272). VEGF A rs2010963 G>C was significant in PFS (16,98 months for G vs 4,65 for G/C vs 2,73 for C; P = 0,0188). VEGR3 rs6877011 C>G was significant in PFS (8,22 months for C vs 2,22 for C/G; P = 0,0361) and OS (35,93 months for C vs 12,08 for C/G; P = 0,0183). Conclusions: in our analysis patients with C polymorphism of rc833061, A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line. These polymorphisms of the VEGF-A gene are probably connected with a better control of the neoangiogenesis process during TKIs therapy, maybe leading to vasculature normalization. Patients with C polymorphism of rs6877011 and G polymorphism of rs307822 seem equally to have a favourable impact in first line therapy. VEGFR-3 role is still matter of debate but seems to be involved in vessels sprouting and architecture.
Plasma cytokines and angiogenic factors (CAFs) for evaluation of risk of recurrence and classification of patients (pts) with nonmetastatic renal cell carcinoma (RCC).
Authors: Khajavi Mehrdad , Jonasch Eric , Wang Xuemei , Wood Christopher G. , Matin Surena F. , Fiorentino Stefania , McKee Kathryn S. , Tran Hai T. , Heymach John , Zurita Amado J.
Published: March 2020

e15075

Background: Although recent years have brought great progress into understanding the pathogenesis of RCC and multiple promising biomarkers, no tumor tissue or blood-based test has yet been established to assist in the clinical determination of prognosis. Whether CAFs can be used to classify RCC pts and the set of CAFs that is host vs. tumor-dependent remain unclear. The main objectives of this exploratory analysis were to identify CAFs predictive of recurrence, and to gain insight into coordinated regulation and tumor dependency of individual factors by comparing CAFs pre- and post-nephrectomy (Nx) in RCC pts. Methods: Plasma samples were obtained before and up to 1 year after Nx from 52 pts with sporadic, non-metastatic RCC with dominant clear cell histology. Pts were categorized based on pathologic staging (pT1/pT2 as low-risk [LR] for recurrence, n=32; pT3/pT4 as high-risk [HR], n=20). Multiplex bead suspension arrays and ELISA were used to measure concentrations of 58 CAFs including angiogenesis and invasion mediators (VEGF, VEGF-C, soluble CAIX [sCA9], HGF and TGF-b1, among others), and multiple inflammatory and/or immunomodulatory chemokines and interleukins (IL). t-test and Wilcoxon signed rank or rank-sum tests were respectively used to assess changes in CAFs between pre- and post-Nx or to compare CAFs between subgroups of pts. Results: The concentrations of IL-8 and sCA9, among others, were significantly higher in HR vs. LR RCC pts pre-Nx (P<0.01). The pre-Nx concentrations of e-selectin were lower in RCC pts with eventual disease recurrence (P=0.027). Several CAFs decreased significantly post-Nx, including sCA9 and endoglin, whereas others increased, such as stem cell factor, IL-12, IL-18 and vascular cell adhesion molecule-1. Angiogenic and hypoxia-regulated CAFs such as OPN, sCA9, HGF, endoglin and collagen type IV grouped together using unsupervised hierarchical clustering. Conclusions: Pre-Nx CAFs associated with risk for recurrence could be useful in risk stratification of non-metastatic clear cell RCC pts. Some tumor-dependent angiogenic CAFs are coordinately regulated in these pts.
Impact of race and age on surgery and outcomes of renal cell carcinoma (RCC): A population based analysis.
Authors: Preet Mohan , Brar Amarpali , Surapaneni Aparna , Khillan Ratesh , Sidhu Gurinder Singh
Published: March 2020

e15097

Background: RCC is a surgically curable malignancy; the outcomes are typically based on tumor size/extent and histology. Partial nephrectomy (PN) is preferred as nephron sparing approach over radical nephrectomy (RN), especially in smaller tumors. Methods: We reviewed data from Surveillance, Epidemiology, and End Results (SEER) 17 Regs Research Data registry for adult patients (pts) with RCC who had data about age, race, pathology, surgery and survival outcome. Results: In all 84480 cases of pts: 31605 (37%) females (F) and 52875 (63%) males (M) were reviewed. There were 8663 (10%) African Americans (AA) and 70942 (84%) Caucasians (C). Of the AA pts, there were 3349(39%) AAF and 5314(61%) AAM. Of the C pts, there were 26412(37%) CF and 44530(63%) CM. Clear cell RCC (CRCC) was seen in 69336 (82%); AA pts with CRCC 6166 (71%) , AAF: 2588(77%) and AAM: 3578(67%). C pts with CRCC: 58936(83%) : CM 36443(82%), and CF-22493 (85%) were reviewed. In AA pts with CRCC PN was done 1282 (21%) and RN 4145 (67%)times. AA men had 818 (23%) PN and 2539 (71%) RN, where as AAF had 464 (16%) PN and 1606 (62%) RN. C pts with CRCC had PN 10402 (18%) and RN 37214 (63%) times. CM had PN 6692 (18%) and RN 23594 (65%) times; CF had PN 3710 (16%) and RN 13620 (61%) times. The median size of tumor in pts undergoing PN was 2-3 cm and independent of race or sex. In pts undergoing PN, the median survival for AAM, AAF, CM and CF was 22m, 18m, 23m and 23m respectively. In pts undergoing RN the median survival for AAM, AAF, CM and CF was 23m, 21m, 24m and 23m respectively. In pts over the age of 80, 8240 cases of CRCC were reviewed, and 3950 (48%) pts had no surgery, of pts having any surgery 376 (8%) and 2859 (68%) pts had PN and RN. Median survival of CRCC over 80 years old having no surgery, PN and RN was 5m, 27m and 29m. Race or sex made no impact on proportion of pts having no surgery. Conclusions: C pts esp. CF are more likely to have CRCC histology. The kind of surgery (PN vs. RN) and outcomes after that are similar across both ethnicities and sexes. Pts over 80 yr old are much less likely to have any surgery and have very poor outcomes, this is avoided if they have PN or RN.
Secondary chemoprevention using short period (3 months) of LHRHa as an option for men with low-risk localized prostate cancer (LRPC) before active surveillance (AS).
Authors: Cussenot Olivier , Drouin Sarah , Egrot Christophe , Cornu Jean-Nicolas , Sebe Philippe , Mozer Pierre , Conort Pierre , Vaessen Christophe , Haab Francois , Bitker Marc-Olivier , Roupret Morgan
Published: March 2020

e15105

Background: Definition of LRPC and candidates for AS remains problematic. Relevant markers that reflect tumor aggressiveness are still to be determined. When AS is used it can be difficult to assess disease progression despite surveillance with PSA and repeat biopsies. Moreover, 20-50% of patients on AS were over the windows of curability when radical treatment was triggered. The current knowledge of PC suggests that aggressiveness should be assessed not only in terms of clinical features but also in terms of response to Androgen Deprivation Therapy (ADT). Methods: 83 men with LRPC (T1c or T2a PC; PSA ≤10ng/ml; Gleason score ≤6) whom have chosen prostate cancer management without radical therapy were included. They then underwent AS after receiving one injection of ELIGARD-22.5. AS consisted of PSA every 3 months (mo) and biopsies (≥12 cores) every 12mo. Patients were stratified at diagnosis according to age at diagnosis, PSA, PSA density, PSA nadir, bio-testosterone, dynamic MRI staging, % positive cores and length of tumor on the diagnosis biopsy. Predictive factors of recurrent PC observed on biopsy were tested using a Cox regression and Markov models. Results: Mean age at diagnosis of LRPC was 64 years, (standard deviation, 6.2 years). Median time to follow-up after diagnosis biopsy was 31mo. Surveillance biopsies were positive for 37 men (44%) (7 with Gleason score>6). In the subgroup of insignificant PC according EPSTEIN criteria surveillance biopsies were positives for 17/48 men (35%) (2 with Gleason score>6). Expected results from literature on classical AS were 60-70% of positive biopsy and 10-21% of upgraded biopsy at the first repeat biopsy. Predictive factors of prostate cancer observed on biopsy were: PSA nadir at 3mo <0,1ng/ml (OR=1.8; 95%CI 1.0 to 3.3 p=0.04), positive core biopsy>1(OR=1.7; 95%CI 1.0 to 2.9; p=0,03), and >T1c detectable tumor on MRI (OR=2.9; 95%CI 1.4 to 5.9; p=0.003). Conclusions: Results obtained with 3mo of LHRHa for LRPC suggest that ADT response can be used firstly to reduce prevalence of primary PC lesions and secondly in order to identify PC able to castration resistance and consequently which require radical treatment.
Sentinel lymph node in prostate carcinoma: Methodology, feasibility, surgical, and oncological consequences, about 74 patients.
Authors: Soler Claude , Perraud Yves , Gremillet Eric , Armand Corine , Geissler Benjamin , Steiner Aline , Levigne Frederic
Published: March 2020

e15109

Background: There are few studies in the field of prostatic sentinel lymph node (SLN) procedure: in the international literature at the most 10 publications are found. However the interest of urological surgeons and oncologists is growing fast. Goals of our study were: on the first hand to evaluate the rate of SLN SPECT-CT detection and the rate of SLN involvement, on the other hand to evaluate the incidence of the SLN biopsy results on the surgical and oncological management. Methods: 74 patients with prostate cancer were included. All patients had a Gleason score between 6 and 8. All patients were elected for a radical laparoscopic prostatectomy. Nanocis-Tc 99m was intratumorally injected, guided by transrectal ultrosonography. 2 injections of 0.6 ml in each lobe of the prostate were performed, depending on the size of the prostate. Patient underwent planar imaging and SPECT-CT 2 hours after injections. Surgery was performed 18 hours after SPECT-CT lymphoscintigraphy. Results: A lymphatic pelvic drainage was seen in 94,6 % (70/74) by SPECT-CT. Lymphatic drainage was on the right side (23), on the left side (15), or bilateral (32). The radioguided lymphadenectomy was assisted by a laparoscopic gamma-probe, the SLN detection rate was 97% (68/70); the average number of resected radioactive nodes was 1.6 (range 1 to 5). By all the ways, a limited pelvic lymph node dissection was performed in all 74 cases. An SLN involvement was found in 5 cases (5/68= 7.35%); in these 5 cases and in the 63 cases without SLN involvement, no metastatic involvement was found in the other lymph nodes, as well as in the 6 patients for which no SLN could be selectively resected (4 with no drainage seen and 2 not detected intra-operatively although visualized on lymphoscintigraphy). Conclusions: The low rate of lymphatic involvement is not surprising considering the Gleason score range 6 to 8 (low metastatic risk). So, the preliminary results are very attractive, especially for these patients that could have been falsely considered as N0. Our study is still in progress, and if these results are confirmed on a larger scale, then SLN procedure could be considered in the routine management of low risk prostatic carcinomas.