bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.