bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of combination of pasireotide (SOM 230) plus gemcitabine in metastatic pancreatic cancer (MPC).
Authors: Kim Richard D. , Jump Helen , Chen Dung-Tsa , Fulp William J. , Shibata David , Siegel Erin , Springett Gregory M.
Published: March 2020

e15075

Background: For the past decade, gemcitabine (GEM) has been considered the standard chemotherapeutic agent in the treatment of MPC. SOM-230 is a multi-targeted somatostatin (SST) receptor (sst1,2,3 and 5) analog with five times the affinity of other SST receptor analogs and a potent inhibitor of insulin growth factor -1(IGF-1). SST receptors and IGF receptors are highly expressed in pancreatic cancer therefore potentially making it a valuable target. Methods: Patients with previously untreated MPC and ECOG PS 0-1 were eligible for the trial. A 3+3 dose escalation design was used. Patients with MPC received GEM 1000 mg/m2 (30-min, once-weekly IV infusion for 3 out of 4 weeks) and SOM 230 according to dose escalation. 2 dose levels (DL) were planned. (40mg and 60 mg IM once a month). Following MTD determination the plan was to expand the cohort to 10 more patients to assess efficacy. In the expanded cohort plasma levels of IGF-I, IGFBP (insulin growth factor binding protein)-1, and IGFBP-3 were measured at baseline and with each restaging CT scan. Results: 20 patients were enrolled with 16 patients evaluable for safety and efficacy. 3 patients were each enrolled in DL1 and DL2. No dose limiting toxicities related to SOM 230 were observed at any dose level. MTD was not reached. Therefore cohort at 60mg was expanded to 10 patients to assess efficacy. Median age was 65.5 years; 6 males and 10 females. Most common grade 3 or 4 toxicities were hyperglycemia (n=5), increased bilirubin (n=2), neutropenia (n=1), thrombocytopenia (n=1) and fatigue (n=1). Two of 16 evaluable pts (12%) had confirmed partial responses (PR), and 9 had stable disease (56%) as best response. Median PFS for all pts was 4.1 months and overall survival was 8.0 months. As of Feb 2nd2013 there are 3 patients who are still actively receiving treatment on the trial. One patient still has stable disease after 11 months. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were measured and will be presented. Conclusions: SOM 230 (60 mg IM monthly) plus gemcitabine was well tolerated in pts with MPC. Preliminary efficacy in a cohort of 16 pts with MPC looks promising and warrants further evaluation Clinical trial information: NCT01385956.
Use of phosphoprotein profiling with high-density fluorescence protein microarray to reveal a response predictor to a multikinase inhibitor sorafenib.
Authors: Yamada Tesshi , Masuda Mari , Chen Wei-Yu , Chen Chi-Long , Honda Kazufumi
Published: March 2020

e15080

Background: The efficacy of sorafenib in patients with unresectable hepatocellular carcinoma (HCC) has been revealed in the recent phase III SHARP (Sorafenib HCC Assessment Randomized Protocol) clinical trial, but only a small proportion of patients achieved the anticipated therapeutic outcomes. It is essential to identify biomarkers that will discriminate such patients. Methods: We newly developed high-density fluorescence reverse-phase protein arrays and used them to profile the phosphorylation status of 180 signaling molecules in the 120 pathways registered on the NCI-Nature curated database in 23 HCC cell lines with different sensitivities to sorafenib. Results: Among the 180 signaling nodes, we found that the level of ribosomal protein S6 phosphorylated at serine residues 235/236 (p-rpS6 S235/236) was the most significantly correlated with the sensitivity of HCC cells to sorafenib. The high expression of p-rpS6 S235/236 was confirmed immunohistochemically in biopsy samples obtained from HCC patients who responded poorly to sorafenib. Sorafenib-resistant HCC cells showed constitutive activation of the mammalian target of rapamycin (mTOR) and/or the mitogen-activated protein kinase (MAPK) pathways downstream of c-RAF. Conclusions: The present results indicate that p-rpS6 S235/236 is a potential predictor of unresponsiveness to sorafenib. Cross-talk between the mTOR and MAPK signaling pathways in sorafenib-resistant HCC cell lines was also revealed. A combination of mTOR and MAPK inhibitors may improve the efficacy of molecular targeting therapy against HCC.
Resminostat in advanced hepatocellular carcinoma (HCC): Overall survival subgroup analysis of prognostic factors in the SHELTER trial.
Authors: Bitzer Michael , Ganten Tom M. , Woerns Marcus A. , Siveke Jens T. , Dollinger Matthias M. , Scheulen Max E. , Wege Henning , Giannini Edoardo G. , Cillo Umberto , Trevisani Franco , Santoro Armando , Montesarchio Vincenzo , Mais Anna , Hauns Bernhard , Asche Julia , Herz Thomas , Pegoraro Stefano , Ammendola Aldo , Henning Stefan W. , Hentsch Bernd ,   SHELTER Study Group
Published: March 2020

e15088

Background: Previously published results of the phase I/II SHELTER study demonstrated efficacy and safety of the novel pan-HDAC inhibitor resminostat in second-line treatment of HCC patients (pts) who had progressed under first-line sorafenib. As patient baseline characteristics might influence treatment outcome, an analysis of their potential influence on overall survival (OS) was performed. Methods: 45 pts with advanced-stage HCC and centrally confirmed radiologic progression under first-line sorafenib were included in a multi-center, two-arm trial. Resminostat was administered either alone or in combination with sorafenib. A Cox proportional-hazards model was used to evaluate the interaction between baseline characteristics and the effect of the two treatment groups on overall survival. Results: In the combination group, pts with Child-Pugh-A, ECOG 0 or absence of vascular invasion had a statistically significant lower risk of death compared to pts with Child-Pugh-B (HR 0.19, 95% CI 0.06-0.55), ECOG 1 (HR 0.15, 95% CI 0.05-0.44), or vascular invasion (HR 0.37, 95% CI 0.15-0.93), respectively. For pts with BCLC-B there was a strong trend, although not statistically significant, of a lower risk of death when compared to pts with BCLC-C (HR 0.43, 95% CI 0.13-1.49). Etiology, prior TACE therapy, extrahepatic spread and interval between first- and second-line treatment had no impact on overall survival in this study. Similar findings were observed in the monotherapy group. Comparing the impact of these baseline characteristics in the combination and monotherapy group, no statistically significant different influence on OS between both treatment groups was observed. Conclusions: Resminostat in combination with sorafenib provides a substantial OS benefit (median OS of 8.1 months) for advanced HCC patients who had developed progressive tumor disease under first-line sorafenib therapy. Subgroup analysis of patient baseline characteristics revealed a significant influence of Child-Pugh index, ECOG classification, and vascular invasion on overall survival, whereas e.g. the interval between first- and second-line treatment had no impact on overall survival. Clinical trial information: NCT00943449.
Recurrent anal squamous carcinoma: Is HPV a risk factor?
Authors: Letendre Caroline , Aubin Francine , Ayoub Jean-Pierre M. , Letourneau Richard , Lougnarath Rasmy , Richard Carole S. , Delouya Guila , Donath David , Lavertu Sophie , Campeau Marie-Pierre , Gorska Isabelle , Soucy Genevieve , Nguyen Bich , Tehfe Mustapha Ali
Published: March 2020

e15094

Background: Anal squamous carcinoma (ASC) is a rare cancer, representing only 1.5 to 2% of all gastrointestinal (GI) malignancies. Combined chemo-radiotherapy therapy (CRT) is the treatment of choice with a response rate of 80% and recurrence rate of 10 to 15%. HPV is a risk factor for anal cancer but its role in cancer recurrence is less clear. We conducted a retrospective study to analyze clinical outcome of ASC patients in function of their HPV status. Methods: Patients with non-metastatic ASC treated between 2005-2011 at the Centre Hospitalier de l’Université de Montréal were eligible. Patient characteristics, clinical outcomes, and tumoral HPV status were retrospectively identified. Results: Seventy patients (M:31; F:39) were included in the analysis. The median age of patients was 51 years. Patient and tumor characteristics are shown in the Table. CRT was done in 57 patients. Median follow-up was 37.6 months. Eleven patients had recurrence of whom 10 were HPV-positive. Median TTR was 13.2 months. The 3 deaths related to cancer occurred during the first year of diagnosis. The 3 year overall survival was 90.08%. In multivariate analysis neither the advanced stage of disease nor the HPV-positive status had a statistically significant impact on relapse. Conclusions: In this small cohort, we found a high prevalence of HPV positivity in ASC but HPV infection couldn’t be identified as a risk factor for ASC relapse. Inclusion of men in the HPV vaccination program may help in reducing HPV related ASC. [Table: see text]
Translational significance of a newly identified hepatocellular carcinoma tumor suppressor gene on chromosome 8p.
Authors: Toh Han Chong , Enane Francis , Teo Marissa , Makishima Hideki , Ng JoAnna , Chee Chit Lai , Ang Soo Fan , Lim Kiat Hon , Saunthararajah Yogen
Published: March 2020

e15097

Background: After deletion of 17p that removes the tumor suppressor gene (TSG) TP53, deletion of 8p is the next most common chromosome abnormality in hepatocellular carcinoma (HCC). However, 8p TSG are insufficiently defined. Methods: Integrated genomic analysis of HCC and non-malignant liver obtained at therapeutic segmentectomy from the same patients. Results: A minimally deleted region on 8p was identified by SNP array. This incorporated GATA4. Therefore, GATA4 was Sanger sequenced in paired HCC/non-malignant liver: recurrent somatic non-synonymous missense mutations were identified in exon 4 (V267M n=5) or exon 6 (S357T n=6, R362N n=2, T366R n=2). Biallelic abnormalities were deletion and mutation (n=6) or mutation and uniparental disomy (n=4), with mutation or deletion of at least one GATA4 allele in 29/47 (62%) of HCC cases. The other GATA4 exons were mutation free. Although missense mutation is not intrinsically expected to decrease GATA4 expression, GATA4 mRNA was significantly decreased in cases with mutation as well as deletion (p<0.01) compared to non-malignant liver or wild-type GATA4 HCC. GATA4 drives liver differentiation, and the biological significance of GATA4 deficiency was demonstrated by significant enrichment (49%) for liver differentiation genes (p<1.2exp-124, Benjamini corrected) amongst genes with decreased expression in HCC compared to non-malignant liver. From an oncogenesis perspective, the most important of these hepatocyte genes (e.g., HNF4A, CEBPD) antagonize MYC to terminate proliferation: GATA4 introduction (expression vector) into HCC cells containing mutated or deleted GATA4 (HepG2 and PLC respectively) restored HNF4A and CEBPD expression, suppressed MYC protein, upregulated p27/CDKN1B that mediates cell cycle exit by maturation and significantly decreased HCC proliferation without apoptosis. In objectively quantified immunohistochemical analyses (ImageIQ), HCC cases with GATA4 mutation/deletion had significantly increased MYC protein (p<0.05). Conclusions: 8p deletion/GATA4 mutation in HCC suppresses cell cycle exit by maturation, thus complementing 17p deletion that suppresses cell cycle exit by apoptosis.
Investigation of anaplastic lymphoma kinase (ALK) translocations in gastric and esophageal signet ring cell carcinomas.
Authors: Miller Jill , Peng Zhihua , Wilcox Rebecca , Evans Mark , Cooper Kumarasen , Ades Steven , Verschraegen Claire F.
Published: March 2020

e15106

Background: Anaplastic lymphoma kinase (ALK) fusion oncogenes are present in multiple cancer types. The inversion of echinoderm microtubule associated protein like 4 (EML4) and ALK genes on chromosome 2 is present in a subset of non-small cell lung cancer (NSCLC) patients. ALK mutated lung cancers demonstrate a significantly higher incidence of signet ring cell histology than compared to ALK-negative tumors. Based on the histological similarities of ALK positive NSCLC and signet ring cell carcinomas (SRCC) of the GI tract, we hypothesized that gastric and/or esophageal SRCC may also harbor ALK translocations. Methods: Thirty-five formalin-fixed, paraffin-embedded (FFPE) tissue specimens of SRCC originating from esophageal, GE junction or gastric locations were obtained from the Fletcher Allen Healthcare (Burlington, Vermont) tissue bank following Internal Review Board guidelines. Confirmation of SRCC or adenocarcinoma with signet ring cell features was confirmed by a board certified, gastrointestinal pathologist. SRCC specimens were analyzed by fluorescence in situ hybridization (FISH) analysis using an ALK (2p23) break-apart probe (Kreatech Diagnostics). Results: The FISH analysis revealed no evidence of ALK translocation: all thirty-five (100%) SRCC specimens showed intact (yellow) ALK FISH signals. Conclusions: These data indicate that despite histological similarities between SRCC of the GI tract and ALK positive NSCLC, ALK translocations are unlikely to be a significant contributor to gastric and esophageal SRCC molecular etiology. Further genomic investigations are on-going. This study was performed with funding received from the Lake Champlain Cancer Research Organization.
Randomized phase II study of gemcitabine monotherapy versus gemcitabine with an EPA-enriched oral supplement in advanced pancreatic cancer.
Authors: Ueno Makoto , Kobayashi Satoshi , Ohkawa Shinichi , Kameda Ryo , Andou Tomoko , Sugimori Kazuya , Miwa Haruo , Ko Ryonho , Tanaka Katsuaki , Taguri Masataka , Morita Satoshi
Published: March 2020

e15109

Background: Gemcitabine is one of the standard chemotherapeutic agents for pancreatic cancer. Pancreatic cancer is often associated with cachexia. It had been reported that eicosapentaenoic acid (EPA) reduces proinflammatory cytokines, leading to improvement of cachexia. This study aimed to evaluate the efficacy and safety of gemcitabine with an EPA-enriched oral supplement in patients with unresectable pancreatic cancer. Methods: This phase II study consisted of patients (pts) who were randomly categorized into Arm A (1000 mg/m2 gemcitabine was administered on days 1, 8, and 15, every 4 weeks while an EPA-enriched oral supplement (Prosure, EPA 1056mg per pack) was taken daily at the maximum of 2 packs) or Arm B (gemcitabine monotherapy) at a 2:1 ratio. The primary endpoint was the evaluation of the 1-year survival. The sample size of 66 pts was chosen based on the randomized phase II selection design by Simon et al. (1985). The design suggests a correct selection probability of 80% if 1-year survival probabilities are 35% and 25% for two treatment arms. Results: From May 2010 to Oct. 2011, randomized 66 pts were examined (Arm A: 43, B: 23). The 1-year survival probability of Arm A was 35% while Arm B was 19%. The median survival times were 8.2 and 9.7 months, respectively. The hazard ratio was 0.79 [95%CI 0.46-1.37]; (p=0.40). The toxicities were mild and insignificant in both arms. Grade 3/4 toxicities (A/B %) included: neutropenia, 20.9/13.0; leukocytopenia, 30.2/21.7; hemoglobin, 14.0/8.7; thrombocytopenia, 9.3/8.7; nausea, 11.6/0.0; and diarrhea, 0/4.3. Although survival curve did not show significant differences, delayed effect was observed in Arm A. According to subgroup analyses, more beneficial effects were observed in men and pancreatic body-tail patients who took a lot of supplements (Table). Conclusions: Gemcitabine with an EPA-enriched oral supplement in advanced pancreatic cancer may be effective, and further phase III trial is needed. Clinical trial information: UMIN000003658. [Table: see text]
Gastric cancer with synchronous hepatic metastases: A multicentric Italian survey.
Authors: Tiberio Guido Alberto Massimo , Ferrari Vittorio D. , Ministrini Silvia , Cipollari Chiara , Graziosi Luigina , Morgagni Paolo , Marrelli Daniele , Marchet Alberto , Baiocchi Luca , Coniglio Arianna , Donini Annibale , Roviello Franco , De Manzoni Giovanni ,   on behalf of the Italian Research Group on Gastric Cancer
Published: March 2020

e15148

Background: The treatment of these patients is controversial and influenced by personal, often passive, attitude. Knowledge of variables affecting outcome may promote clinical pragmatism.We surveyed the clinical approach to the subset of patients presenting with synchronous hepatic metastases as sole metastatic site at diagnosis of gastric cancer, focusing on the results achieved by different treatments and investigated the prognostic factors of major clinical relevance. Methods: Retrospective multi-centre chart review evaluating 210 patients admitted in surgical units. We studied how survival from surgery or diagnosis was influenced by different patient-related, gastric cancer-related, metastases-related and treatment-related candidate prognostic factors. Results: Seventeen patients received supportive care, 44 minor palliative surgery, 98 palliative gastrectomy in 16 cases associated to R+ hepatectomy, while 51 patients received both curative gastrectomy and hepatic resection/s (R0). Adjuvant chemotherapy was administered to 41 patients. Therapeutic approach was selected on the basis of stage of disease, patients’ general conditions and surgeon’s attitude toward the disease, without any pre-set common criteria, in absence of institutional protocols or guidelines. Surgical mortality was 4.6%, surgical morbidity 17.6%. Survival was independently influenced by the degree of hepatic involvement (p= 0.036) but therapeutic approach to the metastases was the principal prognostic variable (p<0.001): 1, 3, and 5 years survival rates were 48.3%, 11.8% and 7.1%, respectively, for patients submitted to curative surgery (R0), 16%, 4.3% and 2.1% after palliative (R+) gastrectomy, 6,8%, 0% and 0% after minor palliative surgery and 0%,0% and 0% with supportive care. Chemotherapy displayed a clear prognostic role (p< 0.001) with clear benefit for those receiving adjuvant treatment. Conclusions: Our data show that an aggressive multimodal approach offers the best survival chances, the best results being offered by the association of radical (R0) surgery and adjuvant chemotherapy. Upon these bases we conclude that this aggressive management must be pursued whenever possible.
Gflip/ox in the treatment of advanced pancreatic cancer.
Authors: Hirshaut Yashar , Khalil Daniel , Kramer Rachel V. , Helfgott Daniel
Published: March 2020

e15192

Background: GFLIP and GLIP/Ox (Bruckner et al. ASCO, 2008) are effective in the treatment of pancreatic cancer (Bruckner, et.al. ASCO, 2008). A similar regimen FOLFIRINOX proved successful in a Phase 3 trial (Conroy, T. et al. NEJM, 2011). However, these regimens are not widely used because of concerns about efficacy and/ or toxicity. Our experience suggests that with dose adjustment when necessary, GFLIP/Ox is both effective and well tolerated. Methods: This is a retrospective review of 24 patients (12 M, 12 F) with unresectable or recurrent pancreatic cancer. The drugs/doses used were leucovorin 300mg, gemcitabine 500mg/M2, irinotecan 80mg/M2, fluorouracil (FU) 400mg/M2 bolus, FU 600mg/M2 46 hr. infusion, oxaliplatin 35 mg/M2, bevacizumab 10mg/M2 +/- cetuximab 400mg/2 given q2 wks. Doses were reduced up to 50% for pts. >70 yrs. Results: 24 pts treated, 11 with cetuximab. Age range 44-87 yrs, mean 68.8 yrs. Response (RR) 38%, Disease Control (DC) 79%. PFS (19 pts) median 264 days (d). Median OS 382 d. Overall survival <70 yrs median 814 d. >70 yrs 304 d. With cetuximab (CTX) DC 91%, OS 512 d, without CTX DC 69%, OS 249 days. Side effects were fatigue, sensory neuropathy, anemia, neutropenia, generally grade 1-2. There was one case of grade 4 thrombocytopenia. There were no deaths attributable to chemotherapy. Conclusions: The median OS of this regimen is 12.7 mo. vs. 6.8 mo. for gemcitabine and 11.1 mo. for FOLFIRINOX. The RR of 38% compares favorably to the 31% RR for FOLFIRINOX. Taken together with the 27 month median overall survival among those under 70 (11 pts) makes GFLIP/Ox a regimen worth further study for this disease.
Chemotherapy (CT) for advanced biliary tract cancers (BTC): A retrospective analysis from UT Southwestern Medical Center (UTSW) and Parkland Hospital (PH).
Authors: Athar Mohammed Abdul Ahad , Karri Sirisha , Arriaga Yull Edwin , Verma Udit N.
Published: March 2020

e15200

Background: CT is the main treatment option for patients (pts) with advanced BTC. There is limited randomized data to guide treatment selection. Based on phase 3 data, gemcitabine (G)/cisplatin (C) is an acceptable 1st line CT, but 5-FU based regimens are also used. We reviewed data from our institution to elucidate treatment preferences and responses. Methods: This is a retrospective analysis of pts treated at UTSW and PH from Jan 2008 to Dec 2011. Patient lists were obtained from the tumor registry at each hospital from Jan 2008 to Dec 2011. Results: 60 pts had inoperable or metastatic disease. 26/60 pts did not receive CT due to poor functional status. 34/60 pts received 1st-line CT- 26 cholangiocarcinoma, 7 gall bladder cancer, 1 ampullary cancer. 10/34 pts were not evaluated for treatment response due to lack of follow-up. Of the remaining 24 pts, 12 received 2nd line CT. In combined analysis of 1st and 2nd line CT in pts with adequate clinic follow-up, G alone (n=10) or in combination (with C n=9, C+ Cetuximab (CX) n=1, Oxaliplatin n=5, Capecitabine (CAP) n=1, Docetaxel n=1) was the most frequently used CT. 2 pts received CAP with radiation. 6 pts received 5-FU based regimen (FOLFOX n=1, FOLFOX/CX n=1, FOLFIRI n=1, FOLFIRI/CX n=1, FOLFIRI/panitumumab n=2). In 1st line, best response (BR)—partial response (PR) 4 pts, stable disease (SD) 14 pts, progressive disease (PD) 6 pts. Response duration range (RDR) in 1st line was 2-22 months (m). In 2nd line, BR—PR 1 pt, SD 7 pts, PD 2 pts. RDR in 2nd line was 2-10 m. Of the 4 pts who received CT combined with an EGFR inhibitor (EGFRI), 2 had SD, 2 had PR; RDR 3-10 m. Disease control (DC) rate (PR+SD) from 1st line CT 53%, 2nd line CT 67%. All 4 pts who received EGFRI in combination with CT showed evidence of DC. Conclusions: CT is effective in BTC with benefit seen in the majority of treated pts. 43% of pts were unable to receive CT which underscores the poor outlook in this malignancy. Interestingly we noted that even in our small subgroup who received EGFRI based combination CT, there was clinical benefit even in 2nd line CT. There is some published data to support this finding. EGFRI based CT should be further studied in this population.
Rate of durable complete remission (CR) using two sequential, dose-dense regimens of cisplatin, gemcitabine, paclitaxel (CGP) followed by m-VAC in patients with metastatic urothelial cancer (mUC).
Authors: Brighenti Matteo , Panni Stefano , Perrucci Bruno , Maltese Mariangela , Liguigli Wanda , Tomasello Gianluca , Poli Rossana , Negri Federica , Ratti Margherita , Donini Maddalena , Toppo Laura , del Boca Carlo , Benecchi Luigi , Prati Andrea , Martens Daniel , Potenzoni Michele , Passalacqua Rodolfo
Published: March 2020

e15502

Background: mUC is a chemotherapy sensitive tumor. Currently, CGP and MVAC are the most active regimens in this setting. According to Norton and Simon hypothesis, the administration of two sequential non cross-resistant, dose-dense chemotherapy regimens may target different cancer cells, avoid drug resistance, improve response rate and CR. Methods: Patients with histological diagnosis of mUC, PS 0–2 (ECOG), adequate organ function and no previous systemic regimens were treated with 4 cycles of CGP dose-dense (Gemcitabine 1000 mg/m2 d 1, Paclitaxel 140 mg/m2 d 1, Cisplatin 70 mg/m2 d 2 plus PegFilgrastim 6 mg on day 3, every 2 weeks) followed by 4 cycles of M-VAC (Methotrexate 30 mg/m2 d 1,Vinblastine 3 mg/m2 d 2, Doxorubicin 30 mg/m2 d 2, Cisplatin 70 mg/m2 d 2 plus Pegfilgrastim 6 mg on day 3 every 2 weeks). All were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for two years and 6 months thereafter. Metastatic sites included retroperitoneal nodes, lung, liver and bone. Results: From January 2007, 35 consecutive pts followed in the same oncology institution were included. Male were 74%; median age 65 years; median PS ECOG was 1; Bajorin risk factors was 0 in 37%, 1 in 43%, 2 in 20%. All pts were hospitalized for three days and received chemotherapy with hydration and supportive therapy. After the first 4 cycles of CGP we observed 14.3% CR, 48.6% PR, 22.9% SD and 14.3% PD. After the 4 sequential cycles of M-VAC we observed a global 37.1% of CR, 25.7% of PR, 8.6% of SD and 28.6% of PD. Median TTP was 9.9 months ( 95 % CI, 7.53-14.83) and median OS was 24.27 months ( 95 % CI, 10.03-38.43). Main grade 3–4 toxicity included asthenia ( 27%), anemia (21%), neutropenia (12 %), febrile (9%), thrombocytopenia (9%) and peripheral neuropathy (6 %). After a median follow up of 33 months, 6 of 13 patients who obtained a complete response are free of disease. Conclusions: These data confirm that the sequential use of this two dose-dense regimens is very active and 17 % of patients maintained a CR status.
Stage I testicular seminoma: Results of adjuvant irradiation, detection of patients with relapsed disease and results of relapse therapy.
Authors: Gamulin Marija , Grgic Mislav
Published: March 2020

e15509

Background: Despite the successfulness of testicular seminoma therapy experience in treatment of cases with disease relapse are of great interest. In the current study the results of treatment and patterns of relapse in seminoma stage I patients (pts) treated by adjuvant radiation therapy (RT) was evaluated. Methods: Study follows up 141 pts with stage I seminoma treated by adjuvant RT of paraaortic lymph nodes with a dose of 24 Gy in 16 fractions (fr) during the period of 8 years. Median ages at diagnosis were 35 years (19-72 y). The median follow-up period for pts treated with adjuvant RT was 6.5 years (range 3-10 y). Results: Of the total of 141 pts treated by RT, 6 pts (4%) experienced a relapse (5 in the pelvic lymph nodes, 1 in the mediastinal lymph nodes). Relapse occurred in the period of 3-21 months after RT. Three pts were treated with 4 cycles (cy) of BEP, one with a PE 4 cy, and one with relapse in the pelvis with 2 cy of BEP chemotherapy, later pelvic area was irradiated with a dose of 40Gy in 20 fr because he developed acute cerebral infarction. One patient with relapse in the pelvic lymph nodes measuring 4 cm refused chemotherapy and was treated to the pelvic area with a dose of 40Gy in 20 fr. Of the 6 pts who had a relapse, four had stage I B tumors, tumor sizes 4.5-8 cm, vascular and/or lymphatic invasion, 2 had positive rete testis (all had negative tumor markers). The 2 remaining pts had seminoma stage I A, one patient had tumor size of 6.5 cm (HCG 356 IU/L before orchiectomy), and the other patient had tumor size of 2 cm (LDH 669 U/L). Conclusions: All of 141 followed up pts are currently disease free. Disease relapse occurred in 4% of pts. The riskiest relapse time in our study is period 6-25 months after orchiectomy in pts who had (a) stage I B tumors and tumor size greater than 4 cm with vascular and/or lymphatic invasion (b) stage I A with elevated tumor markers LDH and bHCG before orchiectomy no matter on size of testicular tumors.
Targeted therapies (TT) in metastatic renal cell carcinoma (mRCC): An Italian survey of 902 pts.
Authors: Pasini Felice , Fraccon Anna Paola , Barile Carmen , Sacco Cosimo , Sava Teodoro , Valduga Francesco , Basso Umberto , Vattemi Emanuela , Rosti Giovanni , Durante Emilia , Nicodemo Maurizio , Lo Re Giovanni , Cengarle Rita , Bertocchi Paola , Bernardi Daniele , Sartori Donata , Donati Donatella , Pegoraro Cristina , Inno Alessandro , Bassan Franco
Published: March 2020

e15514

Background: TT have improved the outcome in mRCC; however, definite data regarding their efficacy when used in the community setting are still insufficient. This survey was aimed to evaluate survival in subsequent lines of treatment (tx) in mRCC pts treated outside clinical trials. Methods: Individual data from the clinical records of 902 pts treated with TT from mid 2007 to December 2012 were obtained from 28 Italian Institutions, through a questionnaire sent after approval by local ethical committees. Results: Median follow up was 26 mo (range 1-85), median age was 60 yrs (range 25-89), 75% were male. At onset metastatic sites were lung (62%), lymph nodes (38%), bone (31%); each of the other sites <10%. Median overall survival (mOS) was 24 mo (range 1-85) without statistical difference among the various centres. Sunitinib was the 1stline tx in 693 pts (76.6%), sorafenib in 124 (13.7%) , temsirolimus in 35 (4%), bevacizumab in 26 (3%), pazopanib in 19 (1.5%), others 5. Median PFS of 1stline (mPFS1) sunitinib was 11 mo and that of sorafenib 7 mo. Type of response: CR 32 (3.5%), PR 274 (30%), SD 275 (30%); PD 265 (29%), not evaluable 33 (3.5%), tx ongoing 23 (2.5%). Dose reduction of sunitinib and sorafenib was required in 49% and 39% of the cycles administered, respectively; 137 pts (15%) received only 1 cycle of sunitinib mostly for rapid progression and/or deterioration. 2ndline tx was performed in 46% of the pts: sorafenib 143 (16%), everolimus 121 (13%), sunitinib 100 (11%), temsirolimus 25 (3%), chemo-immunotherapy 26 (3%), others 1%. mPFS2 was 6 mo with sunitinib and about 4 mo with the other tx (p=0.001). 155 pts (17%) received 3 lines of tx: mOS of TKI-TKI-mTOR (A), TKI-mTOR-TKI (B) and other (C) triplets were 48, 37 and 33 mo, respectively; A vs B p= 0.06; A vs C p= 0.01. Overall PFS3 was 6 mo. Conclusions: i) This survey shows that data of clinical trials were reproduced in the real world setting; ii) a good proportion of pts achieved long OS after subsequent lines of tx; iii) on the other hand, a similar percentage of pts experienced rapid progression; iv) further studies are needed to better identify the different subsets of pts in order to improve the efficacy of TT.
Necessity of long follow-up schedule after surgery and partial nephrectomy for patients with T1 renal cancer.
Authors: Naya Yukio , Araki Kazuhiro , Sugiura Masahiro , Kojima Satoko , Sakamoto Shinichi , Suyama Takahito , Nihei Naoki , Ichikawa Tomohiko , Igarashi Tatsuo
Published: March 2020

e15521

Background: Almost renal cancers are renal cell carcinoma (RCC). Short term treatment results are excellent with 90% or more disease specific and overall survival at 5year. Follow up schedule of NCCN guideline for low risk group was up to 5 years after surgery. Although, we have experienced late recurrence in such a low risk cases. Therefore, we examined the recurrence of T1 and T2 renal carcinoma in our institute, retrospectively. Methods: Between March 1997 and September 2009, 580 patients with renal carcinoma were undergone surgical excision of renal tumor at Chiba University Hospital. In these cases,349 patients were T1 without metastasis. We analyzed the clinopathological deta of these 349 patents. Univariate and multivariate analysis were conducted to identify the prognostic factor of T1a or T1b patients with surgical excision. Results: During follow up, 5, 10, 15 and 20 years overall survival rate(OS) of T1a were 98.1%, 98.1%, 90.6% and 90.6%, respectively. Those of T1b were 95.8%, 92.7%, 90.2% and 90.2%, respectively. 5, 10, 15 and 20 years disease free survival rate (DFS) of T1a was 93.1%, 86.6%, 76.8%, 38.4%, respectively. 5, 10, 15 and 20 years DFS of T1b was 82.9 %, 66.5%, 58%, 50.8% ,respectively. 33% of metastasis was lung 10% of metastasis was contralateral kidney. Conclusions: 20 years OS of T1a was an excellent, however, 20 years DFS was 38.4%. Life expectancy of Japanese men and women in 2009 were 79.59 years old and 86.44 years old. Almost patients with T1a renal carcinoma might have a late recurrence. We think it is necessary to long follow p schedule for T1 cancer and partial nephrectomy is recommended.
MSKCC and Heng prognostic risk assessment for synchronous metastatic renal cell carcinoma (syncmRCC) and the tumor in place treated in the targeted therapy era.
Authors: Noe Allard , Blank Christian U. , Horenblas Simon , Haanen John B. A. G. , Bex Axel
Published: March 2020

e15525

Background: SyncmRCC is heterogenous and selection for cytoreductive nephrectomy (CN) and targeted therapy is required. MSKCC and Heng models for overall survival (OS) are validated for targeted therapy. However, they were developed from predominantly metachronous mRCC patients. It is unknown how they perform in syncmRCC and if they can be used to decide about CN. Methods: Retrospective study of pretherapeutic MSKCC and Heng scores and outcome from 146 patients with syncmRCC and the primary tumor in place treated at a single institute with targeted therapy since 2006. CN was performed in patients WHO 0-1 and low metastatic burden. Results: Table: distribution of risk and OS compared to Heng et al., JCO 27:5794, 2009 . Only n=2 were favorable risk. Overall, n=117 were treated by sunitinib, others by temsirolimus or sorafenib. CN was performed in n=94 (64.3%). Among Heng poor risk 46% (n=29) were intermediate risk by MSKCC. Of Heng poor risk n=37 (58.7%) had CN with a median OS of 8.5 months; 2y OS was 18.9% and higher than for MSKCC poor risk. Of Heng intermediate risk n=57 (69.5%) underwent CN (median OS 15.5 months (1-68); 2y OS 36.8%). Conclusions: In syncmRCC MSKCC and Heng intermediate risk patients have shorter OS than previously reported for each model in the targeted therapy era. However, 25-30 % of intermediate risk patients live >2 y and a potential benefit of CN may be apparent in this group. A discrepancy exists between Heng and MSKCC poor risk percentage. We speculate that the primary tumor in place may influence thrombocyte and neutrophile counts resulting in significantly more Heng poor risk among patients with MSKCC intermediate risk. Especially MSKCC poor risk carries a dismal median and 2y OS in syncmRCC. MSKCC risk assessment performs well in identifying poor risk patients unlikely to benefit from CN. [Table: see text]
Baseline high-sensitivity C-reactive protein to predict progression-free survival in metastatic renal cell carcinoma patients treated with first-line sunitinib.
Authors: Mizuno Ryuichi , Kimura Go , Kondo Tsunenori , Ueda Takeshi , Hara Hidehiko , Kishida Takeshi , Kume Haruki , Sohji Sunao , Hatano Takashi , Morita Jun , Kawata Nozomu , Matsumoto Kazuhiro , Ishida Masaru , Takahashi Shunji , Tanabe Kazunari , Nakazawa Hayakazu , Horie Shigeo , Oya Mototsugu ,   Tokyo Metropolitan Study Group
Published: March 2020

e15527

Background: Predicting the efficacy of tyrosine kinase inhibitors (TKI) would be of clinical value in patients with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that serum inflammatory markers are associated with clinical outcome in mRCC patients at favorable or intermediate prognostic risk treated with first-line sunitinib. Methods: Eighty-nine mRCC patients were prospectively monitored at baseline (day 0) during sunitinib treatment. Serum interleukin-6 and 8 levels were determined by CLEIA and ELISA, respectively. A high-sensitivity C-reactive protein (hs-CRP) levels were measured using laser nephelometry. Correlations between baseline interleukin-6, 8, hs-CRP levels and response to sunitinib, and progression-free survival (PFS) were examined. Results: Median PFS was 9.2 months. Clinical benefit rate (CBR; percent complete responses+partial responses +stable disease 24 weeks) was 57.3%. Baseline interleukin-8 (P=0.0240) and hs-CRP (P=0.0060) was associated with CBR. No association between baseline interleukin-6 and 8 with PFS was observed. However, baseline hs-CRP were associated with PFS (P=0.0016; unit risk 1.010; 95% CI 1.004 to 1.017). Conclusions: Baseline serum inflammatory markers could be of clinical interest in sunitinib-treated mRCC patiens to predict outcome. Baseline hs-CRP serum levels warrant further study. Clinical trial information: UMIN000009622.
Association between guideline-adherent imaging and overall survival following second-line targeted therapy for metastatic renal cell carcinoma.
Authors: Lin Peggy L. , Pal Sumanta Kumar , Jonasch Eric , Signorovitch James E. , Liu Zhimei , Culver Kenneth W. , Scott Jeffrey A. , Vogelzang Nicholas J.
Published: March 2020

e15538

Background: NCCN guidelines recommend imaging at 2-6 months after initiation of targeted therapy for metastatic renal cell carcinoma (mRCC). This study assessed the association between guideline-adherent imaging and overall survival in mRCC. Methods: Thirty-six community-based medical oncologists/hematologists reviewed charts for ≤ 15 mRCC patients each. Included patients were aged ≥ 18 years and initiated 2nd targeted therapy in 2010 or later. Patients alive up to month 6 were categorized into 3 groups based on time of first imaging test: early (0-60 days), guideline-adherent (61-180 days), and delayed(> 180 days). Overall survival (OS) was compared using multivariable Cox proportional hazards models adjusted for age, gender, duration of mRCC, prior treatments, comorbidities, metastatic sites, 1st targeted therapy, ECOG and MSKCC status, 2nd targeted therapy, and progression status (based on symptoms or imaging) in the first 6 months on 2nd line therapy. Reasons for imaging were also assessed. Results: Among the 192 patients included in the analysis, 25 received early imaging, 136 received guideline-adherent imaging, and 31 received delayed imaging. First imaging tests were more likely due to worsening symptoms or changes in a palpable mass, as opposed to routine monitoring, among patients with delayed vs. guideline adherent imaging (20.0% vs. 7.1%, P = 0.005). After adjusting for baseline characteristics, guideline-adherent imaging was associated with a 64% lower hazard of death compared to delayed imaging (hazard ratio (HR) = 0.36, 95% confidence interval (CI) 0.14 to 0.93, P = 0.035). Adjusted 1-year survival was 82% in the guideline-adherent compared to 67% in the delayed imaging group. The hazard of death did not differ between those with early vs. guideline-adherent imaging (HR = 1.05, 95% CI 0.35-3.12, P = 0.927). Conclusions: Among patients surviving 6 months after the initiation of 2nd targeted therapy for mRCC, timely first imaging within 2-6 months, consistent with guidelines, was associated with significantly prolonged overall survival compared to delayed imaging. Further investigation is warranted with larger samples.
A novel polymer-coated nanoparticle (NP) for urothelium penetration and drug delivery.
Authors: Hoimes Christopher J. , Martin Darryl T , Kaimakliotis Hristos K , Cheng Christopher J , Kelly William Kevin , Tew Gregory N , Wheeler Marcia , Weiss Robert M , Saltzman W. Mark
Published: March 2020

e15543

Background: Up to 40% of patients with non-invasive bladder cancer (BC) will develop invasive disease progression despite locally-directed therapy. Overcoming the urothelial barrier is a challenge for intravesical drug delivery. We designed a biodegradable poly(lactide-co-glycolide) (PLGA) NP coated with a novel cell penetrating polymer, poly (guanidinium oxanorbornene) (PGON) for testing against BC in vitro and in vivo. We chose to deliver the HDAC inhibitor belinostat (bel) for its BC cell cytotoxicity and inhibition of invasion & migration pathways; key mechanisms that enable progression of BC. Methods: Fluorophore (C6) or bel was encapsulated in PLGA using an oil/water nanoemulsion method, and surface coated with PGON, and then characterized for morphology, size, and loading. BC cell lines UM-UC-3 and T24 were treated with belinostat or NP-bel-PGON vs controls for assessment of cytotoxicity and acetyl-H4 histone expression over time. In vivo murine bladder and ex vivo human ureter were treated with NP-C6-PGON, and compared to NPs coated with chitosan or PEG for urothelial penetration using FACS analysis, tissue extraction, and fluorescence microscopy. UM-UC-3 murine flank xenografts were treated locally biweekly with NP-bel-PGON or controls and assessed for tumor size and acetyl-H4 expression. Results: C6 extraction of intravesically treated mouse bladder and ex-vivo human ureter showed uptake improved ten-fold in NP-C6-PGON compared to other NPs and corroborated by fluorescent microscopy. In vitro, NP-bel-PGON and bel had similar IC50 of ~2.0 μM in UM-UC-3 & T24 lines, and no effect from PGON. Significantly, the NP-bel-PGON treated groups retained 30% of max H4 hyperacetylation whereas bel groups declined to basal at 12hr post wash, which supports a mechanism of intracellular NP release and activity. In vivo, xenografts treated with NP-bel-PGON showed tumor volume reduced 70% and had 2.5 fold higher intratumoral acetyl-H4 expression compared to vehicle three days post final treatment. Conclusions: NP-bel-PGON penetrates the urothelium, is taken up by BC cells, sustains HDAC inhibition, and causes tumor regression. These data demonstrate the potential for NP-bel-PGON as an intravesical nanotherapy of BC.
A new equation to predict glomerular filtration rate one year after radical nephrectomy in Japanese patients.
Authors: Shimada Shuichi , Saito Hideo , Ito Akihiro , Ioritani Naomasa , Kawamura Sadafumi , Tochigi Tatsuo , Yamaguchi Takuhiro , Arai Yoichi
Published: March 2020

e15570

Background: Strong associations have been reported between chronic kidney disease (CKD) and outcomes such as the development of ischemic cardiovascular disease and heart failure, as well as all-cause mortality. In many patients, CKD develops immediately after radical nephrectomy (RN) for renal cortical tumors and the prevalence of CKD after RN increases steadily thereafter. Therefore, it is important to predict postnephrectomy renal function. To evaluate renal function one year after radical nephrectomy for renal cortical tumors (RCT), predictive factors for postnephrectomy renal function were investigated, and an equation to predict estimated glomerular filtration rate (eGFR) one year after RN was developed. Methods: A total of 525 patients who underwent RN between May 2007 and August 2011 at Tohoku University Hospital and its affiliated hospitals were prospectively evaluated. Overall, 429 patients were analyzed in this study, of whom 257 were randomly selected as the training dataset, and the remaining 172 patients constituted the validation dataset. The prediction equation was developed by stepwise regression applied to the training dataset. Results: Independent factors associated with postnephrectomy eGFR included tumor size (cm), preoperative serum creatinine (mg/dL), sex, and age (years), but body mass index (BMI) and body surface area (BSA) were not significant factors. An equation to predict eGFR one year after RN was developed: Predicted eGFR mL/min/1.73m2=211 × Age -0.454 × Pre SCr -0.841 × Tumor size 0.069 × 0.90 (if female). The equation was validated with the validation dataset (R2=0.55, P<0.0001). Conclusions: The equation developed provided predicted postnephrectomy GFR and will be helpful for preoperative patient counseling and selecting the type of surgical procedure, especially in elective partial or radical nephrectomy cases.
Prognostic factors in patients (pts) with mediastinal nonseminomatous germ cell tumors (MNGCT).
Authors: Bulanov Anatoly , Fedyanin Mikhail , Tryakin Alexey , Pokataev Ilya , Zakharova Tatiana , Polockii Boris , Garin August , Tjulandin Sergei
Published: March 2020

e15585

Background: According to IGCCCG, pts with MNGCT belong to poor prognostic group. But, there are no independent prognostic factors which could determine prognosis in this group of pts. We retrospectively studied prognostic factors in pts with MNGCT. Methods: We analyzed data on 61 pts with MNGCT, who were treated in our department during 1986-2011. Median age was 23 years (range: 18-44). Median follow-up time was 52 months (range 4-180). Biopsy was performed in 35/61 (57.4%) pts before treatment. At the beginning of therapy median AFP was 3,360 IU/ml (range: 1-300,000), HCG – 4.5 mIU/ml (range: 0.1 to 326210), LDH – 791 U/l (range: 249-4,475). Conventional induction chemotherapy (CT): classical BEP regimen – 23 (37.8%) pts, T-BEP – 17 (27.8%) pts, CPOB – 17 (27.8%) pts, accelerated (two-weekly) BEP – 4 (6.6%) pts. After CT, residual tumor was resected in 28 (45.9%) pts. Multivariate Cox regression analysis was performed to determine independent factors, which influenced on overall survival (OS). Results: Marker-negative objective response was revealed in 40/61 (65.6%). Progression disease during induction CT was detected in 21 (34.4%) pts. 5-years OS was 44% for all pts. Multivariate analysis revealed the following independent negative prognostic factors: age ≥ 24 (р=0.08, HR 1.9, 95%CI 0.92-4.1), size of the primary mediastinal tumor ≥ 19 cm (р= 0.03, HR 5.8, 96%CI 1.85-18.67). Median OS hasn’t been reached and 3-year OS was 62% in pts with good prognosis (age < 24 years and/or size of mediastinal tumor < 19 cm) vs. 15 months and 30% in pts with poor prognosis (р=0.02, HR 0.42, 95%CI 0.19-0.87) respectively. Conclusions: Age ≥ 24 and size of the primary mediastinal tumor ≥ 19 cm are independent negative prognostic factors in pts with MNGCT. These factors could be used as strata in clinical trials. However, this tendency has to be confirmed in large series of pts.
Adjuvant cancer peptide vaccine treatment with intravesical BCG therapy for non-muscle-invasive bladder cancer.
Authors: Obara Wataru
Published: March 2020

e15587

Background: We previously reported safety and high immunogenicity of peptide vaccine treatment using two novel peptides derived from oncoantigens, M phase phosphoprotein 1 (MPHOSPH1) and DEP domain containing 1 (DEPDC1), for patients with advanced bladder cancer. We further conducted a multi-center phase II clinical trial using the same peptides to investigate the effectiveness to prevent recurrence after TURBt for patients with non-muscle invasive bladder cancer (NMIBC). Methods: The key eligibility criteria were patients with intermediate or high risk for NMIBC, with tumors having expression of MPHOSPH1 and/or DEPDC1, and with HLA class I expression on tumor cells. HLA-A24-restricted MPH and/or DEP derived peptide were subcutaneously administered in combination with intravesical BCG therapy after TUR-Bt. All enrolled patients had received the vaccination without knowing HLA-A status, and the HLA genotypes were used for a key-open marker. The primary endpoint was to examine effect on recurrence free survival (RFS) and secondary endpoint was induction of peptide-specific CTL response, injection site of reaction (ISR) and adverse effect. Results: A total of 133 patients were enrolled. RFS rates at 2 years in all patients were 74.4 %. Although the difference in RFS between the A24(+) and A24(-) groups (77.2% vs. 70.4%) was not statistically significant (p=0.24), that in the ISR-positive group was significantly better than that in the ISR-negative group (81.6% vs. 54.3%, p=0.0004). The peptide vaccine treatment was well-tolerated without any treatment- associated severe adverse events, while the bladder irritability caused by BCG treatment was observed in 64 cases (48.1%). The MPHOSPH1 and DEPDC1 peptide-specific CTL responses in the 24(+) group were observed in 82 % and 83 % of patients, respectively. Four (7.4%) cases in the 24(-) group revealed the peptide-specific CTL response, indicating some cross-reactivity against the vaccinated peptides on other HLA allele(s). Conclusions: Combination immunotherapy of intravesical BCG and cancer peptide vaccine demonstrated the promising clinical effect on recurrence prevention for NMIBC as well as good immunogenicity and safety. Clinical trial information: 00633204.