bluuebunny/crossref_metadata_2025 huggingface dataset:
A pilot study of evaluation of a phosphorylation signature from pancreatic cancer tumors.
Authors: Wang-Gillam Andrea , Wani Sachin , Early Dayna S , Edmundowicz Steven Alphonse , Mullady Daniel , Murad Faris , Jonnalagadda Sreenivasa , Gao Feng , Hollander Thomas , Langley Emma J. , Meyer Gary , Singh Sharat , Kim Phillip Sangwook , Lim Kian-Huat , Linehan David , Azar Riad
Published: March 2020

e14584

Background: The development of targeted therapy in pancreatic cancer has been hindered by minimal material available for molecular analysis from diagnostic endoscopic ultrasound-guided fine-needle aspirations (EUS/FNA). Revealing the phosphorylation status of key pathway mediators would allow optimal selection of patients for kinase inhibitor clinical trials. We launched a pilot study to evaluate the feasibility of detecting phosphorylation signatures from FNA samples using an ultrasensitive multiplexed protein microarray platform (CEER, Prometheus). Methods: Patients who underwent routine diagnostic EUS/FNA for a suspicious lesion in the pancreas underwent two additional EUS passes. Mediators of multiple signaling pathways including HER1/EGFR, HER2, HER3, IGF-IR, and their downstream mediators, AKT, MEK, ERK, et al were evaluated by CEER. Circulating tumor cells (CTCs) and resected tumor specimens were collected as available from patients for comparison. Results: From January-September, 2011, 57 patients were enrolled with a planned final enrollment of 100. This is an interim analysis. Thirty-nine (68.4%) had carcinoma cytology, 9 had atypical and 9 had negative cytology. HER2 (median value of 18 CU vs. 2 CU, p = 0.021) and HER3 (median value of 547 CU vs. 168 CU, p = 0.008) showed significantly higher levels of phosphorylation in malignant FNAs over their counterparts with negative cytology. Robust levels of CK expression were also observed in FNAs with carcinoma cytology (median CK level 1030 CU vs. 106 CU, p = 0.007). The wide range of phosphorylation signatures detected indicates this is a feasible clinical approach. For example, the expression levels of phosphorylated PI3K were 16 (22.5% - low), 28 (39.4% - medium low), 23 (32.4% - medium high), and 2 (2.8% - high). The correlation of p PI3K between 2 passes was 0.59 (p = 0.018) based on the Spearman Correlation. A CEER comparison of FNA vs. surgical specimens and FNA vs. CTCs is forthcoming. Conclusions: Profiling the phosphorylation status of pancreatic cancer pathways from FNA samples is feasible. If further validated, patients with pancreatic cancer can be screened for targeted therapy by their phosphorylation signature.
Correlation between classical prognostic factors and overexpression of HER2 and HER3 in localized gastric cancer.
Authors: Perez-Fidalgo Jose Alejandro , Tarazona Noelia , Navarro Samuel , Lopez-Mozos Fernando , Marti Roberto , Rosello Keranen Susana , Roda Perez Desamparados , Mongort Cristina , Cervantes-Ruiperez Andres
Published: March 2020

e14589

Background: Although HER2 overexpression has been identified as a predictive factor for targeted therapy in advanced gastric cancer (GC), little is known about its role in localized GC. Recent studies suggest that not only HER2 but also HER3 might have a role in prognosis in GC. Our study aimed to identify the prevalence of HER2 and HER3 overexpression in a series of localized GC and to describe correlations of these with traditional prognostic factors Methods: We performed a retrospective analysis of HER2 and HER3 overexpression in archived tumour samples in pts diagnosed with GC at stage I-III. HER2 was assessed with herceptest, (negative if 0 or 1+, or positive with 2+ or 3+). Staining of HER3 was determined with the Rajkumar score (HER3+ when score > or = 8). Correlation between the HER receptors expression and the clinicopathologic parameters was statistically analyzed. Statistical analysis of the correlation of HER2 and HER3 with other variables was performed with chi-square test or with the Mann Witney U for continuous variables. Impact on survival was analysed with Kaplan-Meier and log-rank tests. Results: From Jan 2003 to Sep 2011, 125 patients with clinical stage I-III GC were included. Median age was 73 years (35-91) and most frequent location was antrum (47.2%). Up to 43.2% of the patients were treated with preoperative chemotherapy. HER2 was + in 18 patients (14.4%) and HER3 in 38 (30.4%). HER2 was more likely to be overexpressed in older patients (median age: 78.4 vs 68.4; p<0.0001) and in low grade adenocarcinomas (grade 1-2: 13.8% vs grade 3: 1.1%; p=0.006). HER3 was more frequently overexpressed at advanced stages (I and IIA: 10.3% vs IIB and III: 20.3%; p=0.004) and in adenocarcinoma with intestinal subtype (intestinal: 21.4% vs difuse/mixed: 8.5%; p=0.03) or without evidence of signet ring cells (absent: 26.8% vs present: 4.1%; p=0.03) . HER2 and HER3 were significantly related (p=0.0012) with an OR of 3,52 times more frequently HER3+, if HER2 was +. No significant impact was shown in survival for either HER2 or HER3. Conclusions: HER2 and HER3 overexpression seems to identify a particular subgroup of patients with favourable classical prognostic factors.
Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin-C for invasive anal carcinoma in HIV-positive patients receiving highly active anti-retroviral therapy versus non-HIV patients.
Authors: Rubinstein Paul G. , Sreenivasappa Shylandra B. , Gupta Shweta , Jain Shivi , Pattali Shinoj , Blumetti Jennifer , Mullane Michael Russell
Published: March 2020

e14590

Background: In the non-HIV population, radiotherapy (RT), fluorouracil (5FU) with mitomycin (MMC) has become the standard in the non-metastatic setting for anal carcinomas (AC). To date, most studies with AC in HIV patients (pts) are small case series where multiple chemoradiation (CRT) regimens were used and analyzed as one cohort. In addition, little data exists on the inner city HIV population. Cook County Hospital (CCH) is the largest health provider for HIV pts in Chicago and together with its outpatient clinic, the Ruth M. Rothstein CORE Center (CC) 5,500 HIV+ pts are treated per year. The County Hospital (CCH) AIDS Malignancy Project (CHAMP Study) is a retrospective study of all HIV cancer pts treated for the past 14 years. Methods: We identified all HIV+ pts with invasive AC in CHAMP cohort. We analyzed HIV characteristics, overall survival (OS), PFS and pt demographics and compared it to a HIV- cohort from the same institution. All AC treated without MMC/5FU/RT were excluded. Statistics: Time to local recurrence (TLR), time to distant metastasis (TDM), and OS data was analyzed using Kaplan-Meier analysis and a Cox Proportional Hazards model. Results: 35 HIV + and 52 HIV - pts were included. Of the HIV+ vs. HIV- pts, 89 vs. 52% were male, 82 vs. 48% were AA and the average age in HIV+ vs. HIV- was 44 vs. 52 yrs. 45 % of the HIV pts presented with stage IIIA or IIIB disease vs. 46% in HIV- pts. 15 % HIV- pts had stage IV vs. 0% HIV +. The median survival in the HIV+ vs. HIV- was 34 vs. 39 mo (p>0.5). In the HIV- population, 22% survived 120 months, while no HIV pt survived over 90 months. TLR was 20 months shorter in the HIV+ arm (p<0.5). OS based on CD4 count did not differ. Conclusions: HIV associated AC is an AA male disease compared to HIV- pts in the inner city. More stage IV disease was reported in the HIV- cohort, but the median survival was equal with no long-term survivors in the HIV+ arm, possibly due to TLR, which was 20 months shorter, implying more aggressive disease. Both inner city groups present late but tolerate chemotherapy equally well. Education is needed in both HIV+ and HIV- pts to diagnose the cancers early so the OS can match the national average.
Effect of BPM 31510 on survival outcomes when used in combination with gemcitabine in a preclinical model of pancreatic cancer.
Authors: Jimenez Joaquin J. , Mauro Lucia M , Akmaev Viacheslav R , McCook John , Du Min , Luan Shen , Song Paul Y. , Sarangarajan Rangaprasad , Narain Niven R
Published: March 2020

e14593

Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to create a hallmark shift from lactate dependency towards mitochondrial oxidative phosphorylation, reversing the Warburg effect. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. This study reports on the therapeutic benefit associated with BPM 31510 used in combination with gemcitabine in animal model of pancreatic cancer. Methods: The NGS mouse devoid of innate and adaptive immune system were implanted with human pancreatic cancer cells, Mia PaCa-2. The animals were randomized (n=30/group) to the following dose regiment cohorts: 50 mg/kg body weight (BW) once or twice daily ± gemcitabine (150 mg/kg BW once/week) for 3 weeks followed by one week rest. A group of animals received 75 mg/kg BW thrice daily ± gemcitabine (150 mg/kg BW once/week) for 3 weeks followed by one week rest. Untreated or group treated with gemcitabine alone with corresponding treatment regimen served as controls. The primary objective was to evaluate the difference in overall survival of the animals when treated with gemcitabine alone compared to combination regimens with BPM 31510. Results: All tumor bearing untreated animals (control arm) expired by Day 21 of the study. In contrast, the once daily BPM 31510 dose regimen was associated with significant increase in duration of overall survival (p<0.009) with all animals expiring by Day 142 compared to gemcitabine alone. The combination of BPM 31510 with gemcitabine was associated with significantly increase in overall survival compared to BPM 31510 (p=0.002) or gemcitabine (p = 7.3E-8) alone. This was associated with significant reduction in tumor size and weight (p<0.001). Increased frequency of BPM 31510 dosing alone or in combination with gemcitabine was associated with significant increases in survival rates. Conclusions: The data herein suggest that BPM 31510 may be a viable agent for combination therapy in pancreatic cancer via employment of a novel metabolic pathways.
Phase I trial of dose escalated whole liver irradiation (WLRT) with hepatic arterial (HA) fluorodeoxyuridine (FUDR)/leucovorin (LV)/streptozotocin (STZ) chemotherapy followed by chemoembolization with mitomycin C (MMC) for patients with neuroendocrine hepatic metastases.
Authors: Shilkrut Mark , Schipper Matthew J , Ensminger William D. , Ben-Josef Edgar , Lawrence Theodore Steven , Feng Mary Uan-Sian
Published: March 2020

e14603

Background: Phase I trial combining HA chemotherapy, chemoembolization and dose-escalated WLRT was conducted to determine if the maximum safe dose of 32 Gy in 2 Gy fractions could be delivered to patients (pts) with neuroendocrine (NE) hepatic metastases. Methods: Pts with symptomatic liver metastases from NE tumors who failed somatostatin analog therapy were eligible. HA FUDR (3 mg/m2/d) and LV (300 mg/m2/d) were given for 12 days; STZ (500 mg/m2/d) was given on days 5,8,10. Concurrent WLRT was prescribed in 2 Gy/day with doses escalated from 24 Gy to 32 Gy using the time-to-event continual reassessment method for dose allocation with a target rate of dose-limiting grade ≥3 radiation-induced liver disease (RILD) of 10%. 8 weeks later, for patients without RILD and other grade ≥4 toxicities, 72-h infusion with HA FUDR (3 mg/m2/d) and LV (300 mg/m2/d) was given, followed by chemoembolization with mitomycin C (20 mg) and polyvinyl alcohol. Results: 19 pts were enrolled in the trial, 11 pts completed the entire protocol. 7 pts received 24 Gy, 2 - 26 Gy, 1 - 28 Gy, 2 - 30 Gy and 6 - 32 Gy. One pt stopped at 14 Gy because of STZ-induced grade 4 renal failure. No pts developed RILD at any dose level; 4 - had grade 3-4 increased liver function tests, 4 - had other grade 4 toxicities during or after the first part of the treatment; 1 - had other grade 4 toxicity during the second part. Posterior estimates of probabilities of RILD were all <10% (table). Three pts (14%) had partial response, 16 (84%) - stable disease. Median freedom from local progression for all pts was 35.3 (9.3-58.9) months. Conclusions: The study showed that chemotherapy can be safely combined with a full dose of WLRT and subsequent chemoembolization without producing RILD. [Table: see text]
Survival outcomes in patients with early-stage, resectable pancreatic cancer: A comparison of gemcitabine and 5-fluorouracil based chemotherapy and chemoradiation regimens.
Authors: Kizilbash Sani Haider , Ward Kevin , Jaiyesimi Ishmael A. , Lipscomb Joseph
Published: March 2020

e14608

Background: Beyond curative surgery, the optimal treatment for early stage pancreatic cancer is still a matter of debate. We conducted a comparative survival analysis between patients with resectable pancreatic cancer who received adjuvant treatment with either gemcitabine or 5-fluorouracil based chemotherapy and chemoradiation regimens. Methods: The Surveillance, Epidemiology and End Results (SEER)-Medicare database was used to identify patients with pancreatic cancer diagnosed from 1998 to 2005 who received curative surgery and adjuvant chemotherapy with either 5-fluorouracil or gemcitabine. These groups were subdivided by treatment with radiotherapy. Patients were followed until death, study endpoint or a maximum of five years after diagnosis. Results: 359 patients received 5-fluorouracil and 346 received gemcitabine. Compared to chemoradiation with 5-fluorouracil, outcomes for patients who received chemoradiation with gemcitabine did not differ. Patients who received gemcitabine without radiation had increased hazards (hazard ratio (HR) = 1.50 for high grade tumors (HGT), HR = 1.32 for low grade tumors (LGT)). However, outcomes of patients who received 5-fluorouracil without radiation varied with tumor grade. In LGT, patients had better outcomes with 5-fluorouracil when compared with chemoradiation with 5-fluorouracil (HR = 0.43). In HGT, the opposite was true (HR 2.10). Conclusions: Patients with low grade resectable pancreatic cancer may have better outcomes with 5-fluorouracil based chemotherapy without radiation when compared to 5-fluorouracil with radiation.
Safety and efficacy of modified FOLFIRINOX in pancreatic cancer: A retrospective experience.
Authors: Mahaseth Hemchandra , Kauh John S. , Brutcher Edith , Hawk Natalyn Nicole , Kim Sungjin , Chen Zhengjia , El-Rayes Bassel F
Published: March 2020

e14614

Background: Conroy et al reported a significant improvement in overall survival of patients with metastatic pancreatic cancer treated with FOLFIRINOX compared to single agent gemcitabine. The regimen was associated with significant grade 3/ 4 toxicities, such as myelosuppression(46%), fatigue(24%), vomiting(15%) and diarrhea (13%). In order to improve the toxicity profile, we have modified FOLFIRINOX (mFOLFIRINOX) regimen by removing the bolus 5-FU and adding the routine use of growth factor prophylaxis. We present our experience with mFOLFIRINOX in patients with locally advanced or metastatic pancreatic cancer. Methods: After obtaining IRB approval, patients with a diagnosis of pancreatic cancer were identified from the Emory University tumor registry. Twenty eight patients who received at least one dose of mFOLFIRINOX (5-FU 2400 mg/m2 CIVI over 46 hours, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, irinotecan 180 mg/m2 and pegfilgrastim 6 mg every two weeks ) were selected and their charts were retrospectively reviewed for safety, response, and survival. Results: Of 28 patients, 14 (50%) were male, 18 (64%) white, 8 (29%) black and other 2(7%). Median age was 63 (50-75) and ECOG performance status 0-1. Nineteen (68%) patients had primary tumor located in head of pancreas. Eight patients (29%) experienced grade 3/4 toxicities, i.e., nausea/vomiting (11%), diarrhea (11%), fatigue (11%), neuropathy (4%), neutropenia (4%), thrombocytopenia(4%), and sepsis not-related to neutropenia (4%). No grade 3/4 anemia or febrile neutropenia was noted. mFOLFIRINOX controlled the disease in 20 patients (71%) with 2 CR, 4 PR and 14 SD. With a median follow up of 5.5 months, median overall or progression free survival is not reached. Two patients have died and six patients have progressed. Conclusions: Modified FOLFIRINOX is well tolerated in this US population. The clinical activity appears very promising with majority of patients being free of progression.
FOLFIRINOX in locally advanced and metastatic pancreatic cancer.
Authors: Faris Jason Edward , Hong Theodore S. , McDermott Shaunagh , Borger Darrell R. , Guimaraes Alexander R , Wo Jennifer Yon-Li , Sahani Dushyant , Dias Lauren Elizabeth , Allen Jill N. , Zhu Andrew X. , Murphy Janet E. , Kwak Eunice Lee , Ryan David P. , Clark Jeffrey W. , Blaszkowsky Lawrence Scott
Published: March 2020

e14615

Background: The phase III trial of 5-FU, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) demonstrated improved survival compared to gemcitabine in good performance status (PS) patients (pts) with metastatic pancreatic cancer (Conroy et al, NEJM 2011). Less is known about the efficacy and tolerability of FOLFIRINOX in the non-clinical trial setting. In this retrospective analysis, we report our institutional experience with FOLFIRINOX. Methods: 38 pts with locally advanced (LAPC) or metastatic pancreatic cancer (MPC) who began treatment with FOLFIRINOX between 7/2010 and 6/2011 were identified. Clinical characteristics, gradable toxicities, and molecular genotyping results were tabulated. Formal radiographic review was performed to determine best overall response rates (ORR). All pts receiving FOLFIRINOX were assessed for toxicities, while pts receiving ≥2 cycles were assessed for response. Results: 26 pts received FOLFIRINOX for MPC and 12 pts for LAPC. The median age was 60 (range 39-76). 29/38 pts were men, 26/38 had received no prior chemotherapy, and 11/38 had biliary stents. Overall, 12 partial responses (PR) were observed in 33 evaluable pts (ORR 36%); 11/12 partial responses were in chemo-naïve pts. In evaluable pts with MPC, there were 7 PR (ORR 33%), and 11 pts with stable disease (SD). In LAPC, there were 5 PR (ORR 42%), and 7 pts with SD. Following FOLFIRINOX, two pts with LAPC have subsequently undergone R0 resection. 18/38 pts required an ED visit or hospitalization during treatment. Grade 3/4 neutropenia was observed in 12 pts; 8/12 had not received prophylactic growth factor from the start of FOLFIRINOX. There were 6 pts with febrile neutropenia, 6 pts with grade 3/4 thrombocytopenia, and 5 pts with grade 3/4 anemia. 1 pt died with bacteremia in the setting of febrile neutropenia. 22 pts had molecular genotyping at multiple loci performed: 17/22 were KRAS mutation positive, and 3 pts with KRAS mutations also had TP53 mutations. 4 pts were wild-type at all loci tested, and 3 of these pts had a PR on FOLFIRINOX. Conclusions: In a non-clinical trial setting, FOLFIRINOX demonstrated activity in both LAPC and MPC, but is associated with significant toxicities, with nearly half of pts requiring an ED visit or hospitalization.
Combination of docetaxel, cisplatin, and capecitabine (DCX) as a first-line chemotherapy in patients with metastatic gastric carcinoma: A phase II study.
Authors: Narimanov Mekhty , Tryakin Alexey , Bazin Igor , Kanagavel Dheepak , Tjulandin Sergei
Published: March 2020

e14623

Background: Docetaxel is an active agent for treatment of metastatic gastric carcinoma. We launched this phase II trial to evaluate the efficacy and safety of docetaxel, cisplatin and capecitabine (DCX) combination in patients (pts) with metastatic gastric carcinoma. Methods: Pts with metastatic gastric carcinoma received docetaxel 75 mg/m2 i.v. day 1, cisplatin 75 mg/m2 i.v. day 1, capecitabine 1650 mg/m2 per os days 1-14 every 3 weeks. Up to 6 cycles were provided. G-CSF was not routinely used for primary prophylaxis. Results: From 2007 to 2011, 37 pts were included in the study, all pts were available for response. Pts characteristics and results are shown in the table. Median number of cycles delivered was 5 (range, 1-5). Grade 3-4 toxicity (per cycle) included: neutropenia – 24,9%, deep venous thrombosis – 2%, diarrhea – 6.2%, stomatitis – 3.8%, infection – 11%; anemia 14% pts. Six pts had dose reductions, 2 pts stopped chemotherapy due to toxicity. No toxic deaths were observed. Median progression-free survival (PFS) and median overall survival (OS) were 7,5 months (95% CI 6,076-8,857) and 14,5 months (95% CI 10,054-18,880), respectively. Conclusions: Compare with combination of docetaxel, cisplatin and 5-FU, evaluated in V325 study, our regimen had more favorable toxic profile with similar efficacy. Further investigation of this regimen in randomized controlled trials is warranted. [Table: see text]
Resource utilization among neuroendocrine tumor patients in the United States.
Authors: Casciano Roman , Chulikavit Maruit , Parikh Rohan , Stern Lee , Liu Zhimei , Wang Xufang , Grzegorzewski Kris , Strosberg Jonathan R.
Published: March 2020

e14627

Background: Neuroendocrine Tumors (NET) constitute over 100,000 prevalent cases in the United States (US), with predicted increase of incidence in the future. Advanced NET is associated with significant morbidity and mortality. Resource use was assessed for managing advanced NET. Methods: As part of a global study, an online survey was administered to US physicians to quantify resource use among advanced pancreatic (pNET) and lung/gastrointestinal (GI) NET patients. The study collected resource use data (treatments, visits with survey and other physicians, surgery and hospitalizations) for baseline (diagnosis to 1st progression of disease [PD]), 1st and 2nd PD periods. PD was defined as measurable/radiographic evidence of tumor progression. As patients with 2nd PD were likely to be less, resources were estimated in a hypothetical scenario. Results: 55 US physicians provided data on 110 NET patients (36.4% pNET, 63.6% Lung/GI NET). Average follow up in baseline was 14.0 and 13.3 months for pNET and Lung/GI NET, respectively; in 1st PD period, it was 5.7 and 7.9 months, respectively. For 2nd PD, it was assumed to be 12 months. Table 1 shows resource use for baseline and 1st PD. Increased use of chemotherapy, somatostatin analogs, hospitalization and other physician visits was observed during 1st PD, especially for pNET patients. Targeted therapy use was minimal at baseline and 1st PD; however it may increase in 2nd PD. Conclusions: Among advanced NET patients, resource use is generally high and there appears to be an increase in resource use upon PD, especially in patients with pNET. [Table: see text]
Perioperative management of patients with distal esophagus and gastroesophageal junction tumors: Three years of results.
Authors: Zemanova Milada , Pechacova Zdenka , Harustiak Tomas , Fencl Pavel , Vitek Pavel , Petruzelka Lubos B.
Published: March 2020

e14631

Background: In patients with operable gastroesophageal adenocarcinoma, a perioperative regimen ECF significantly improved survival (MAGIC trial - Cunnigham 2006) and has been accepted as standard treatment option. In our study we present experience with modified MAGIC protocol in patients with lower esophagus or GE junction tumors. Methods: 67 patients (pts) (60 men, 7 women), median age 59 years (37-74), with resectable adenocarcinoma in lower esophagus or gastroesophageal junction were included in period 01 Mar 2008 – 15 Jun 2010. Fifty one (76%) pts had clinical stage nodal positive. Chemotherapy (CT) consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg/m2) and cisplatin (60 mg/m2) on day 1, and a continuous infusion of fluorouracil (200 mg/m2 per day) for 21 days or oral capecitabine 1000 mg/m2 for 14 days. Postoperative radiochemotherapy (CRT) with fluorouracil or capecitabine after the end of CT was indicated in pts with two and more positive lymphnodes in surgical specimen if feasible. Results: Preoperative CT completed 64 (94%) pts, 52 (78%) had surgery, 46 (69%) had radical resection with 3 cases of complete pathological response, 22 pts had pN0 and 21 pts pN plus finding. Postoperative CT was started in 39 (58%) pts and was completed in 32 (48%) pts. 10 (22%) pts had postoperative CRT. Adverse events grade 3-4 were: neutropenia 10%, vomiting 8%, fatigue 5%, diarrhea 3%. Reasons for omitting surgery in 15 (22%) pts were: progression in 7 pts, medically unfit in 4 pts, other in 4 pts. With a median follow-up of 31 months (17-47) there were recurrences in 35 (52%) of all pts, in 5 (7%) pts locoregional only, in 7 (11%) distal plus locoregional and in 23 (34%) pts distal metastases. Recurrence rate in radically resected pts was 39%, in patients with pN0 28% and in pN1 86%, despite adding CRT. Thirty one patients are alive with 3-year survival 46%. Conclusions: Perioperative chemotherapy ECF/ECCap in our set was feasible and well tolerated. Patients with node positive postoperative stage had poor prognosis, despite completing adjuvant treatment including postoperative CRT. This work was supported by grant NO: IGA MZ(CR) NT/12331-5/2011.
Photodynamic therapy with temoporfin in combination with gemcitabine/capecitabine in biliary tract cancer: Feasibility and safety in a randomized phase II trial.
Authors: Hauge Truls , Warloe Trond , Hauge Petra Weber , Franco-Lie Isabel , Drolsum Anders , Johansen Cathrine , Viktil Ellen , Aabakken Lars , Buanes Trond , Konopski Zbigniew
Published: March 2020

e14637

Background: Patients whocannot be offered curative surgical treatment for biliary tract cancer (BTC) have a poor prognosis. Photodynamic therapy (PDT) has been shown to improve survival and quality of life in patients with unresectable BTC. A combination of treatment modalities might improve survival further, but such data are still lacking. Therefore we have performed the first randomized trial on the combination of temoporfin/PDT and chemotherapy. Here we report data on the feasibility and safety. Methods: Randomized phase II trial, planned to include 20 patients with time to progression as primary endpoint, feasibility and toxicity as secondary endpoints. Inclusion criteria were unresectable BTC confirmed by histology or cytology, need for biliary stent, bilirubin level < 50 mmol/L and no previous cancer disease. The treatment arms were: A: Stent, temoporfin / PDT followed by gemcitabin / capecitabin (GemCap). B: Stent, GemCap. Only one initial PDT treatment was given. Results: Twenty patients with locally advanced and metastatic disease were included, 10 patients in each arm. Two patients in arm B did not receive any treatment (thrombocytopenia, study withdrawal) and two patients in arm A did not receive chemotherapy (ECOG>2, infection). PDT was feasible in all 10 patients without any acute procedure-related complication. During the first 30 days, two cases of cholangitis in arm A and three in arm B were observed. Cutaneous erythema (grade 1-2) was observed after PDT in two patients. Conclusions: PDT using temoporfin in combination with chemotherapy in BTC was feasible. Restrictions to light exposure were well tolerated. PDT in combination with chemotherapy did not increase the complication rate during the first 30 days follow-up. Three months follow-up data will be available at the time for presentation. Larger prospective trials are warranted to assess the efficacy of this treatment combination.
Multispecialty care among hepatocellular carcinoma patients in SEER-Medicare.
Authors: Breunig Ian Michael , Shaya Fadia T. , Mullins C. Daniel , Chirikov Viktor , Seal Brian S. , Hanna Nader
Published: March 2020

e14638

Background: Multispecialty care has increased for many cancers yet little evidence exists for hepatocellular carcinoma (HCC). Methods: Medicare non-transplant patients with HCC 1ry diagnosis in 2000-07 were studied using SEER-Medicare data with HCC claims generated from Medicare parts A-B, including patients with >=1 claims for HCC-related physician visits post-diagnosis. Physician specialties were grouped as Gastroenterology (GE), General/Family/Geriatric/Internal (GF), Diagnostic/Intervention radiology (DIR), Hematology/Medical oncology (HMO), General surgery/Surgery oncology (GSO), Radiation oncology (RO), Multispecialty clinic/group practice (MG), or Others. Visits by specialty seen within 4 weeks, and trends, were explored by comparing distributions, using t-tests, of visits by specialty, from the 2000/01 diagnosis cohort and the 2006/07 cohort. Results: Out of 2284 HCC patients diagnosed in 2000/01, 1380 (60%) had at least one HCC-related physician visit post-diagnosis, and 1330 (58%) within 4 weeks. Excluding the “Others” category, 1015 (44%) visited within 4 weeks. Of 3155 patients diagnosed in 2006/07, 1782 (56%) had any HCC-related visit, 1689 (54%) within 4 weeks, and 1295 (41%) when excluding Others. Among patients with at least one post-diagnosis HCC-related visit ever, the percentage of patients who saw only 1 type of specialist within 4 weeks of diagnosis did not change (44% in 2000/01 vs. 43% in 2006/07; p=0.15); nor did the percentage visiting multiple specialists (52% vs. 53%; p=0.58). The percentage of patients visiting GE within 4 weeks went from 27% to 25% (p=.10), 11% to 10% (p=.41) for GF, 28% to 31% (p=.08) for HMO, 4% to 3% (p=.53) for RO, 65% to 67% (p=.33) for Others, and remained at 23% for DIR, 16% for GSO, and 1% for MG. Among patients who saw only 1 type of specialist within 4 weeks of diagnosis, the percentage visiting GE went from 14% to 12% (p=.29), 4% to 5% (p=.50) for GF, 11% to 10% (p=.55) for DIR, 11% to 12% (p=.36) for HMO, 4% to 3% for RO, 52% to 53% for Others, and remained at 5% for GSO, and <1% for MG. Results are robust when “Others” are excluded. Conclusions: Despite increased incidence of HCC since 2000, there was no significant trend toward multidisciplinary care.
Primary small cell carcinoma of the esophagus: Retrospective analysis of the Veterans Affairs Cancer Registry.
Authors: Abu Hazeem Mahmoud , Thota Ramya , Subbiah Shanmuga , Silberstein Peter T.
Published: March 2020

e14641

Background: Small cell carcinoma (SCC) of the esophagus is a rare aggressive and rapidly fatal neoplasm, often diagnosed in late stages. Hence no prospective studies evaluating the most effective treatment strategies have been done. We aim to describe the clinicopathological features and treatment outcomes of this rare entity. Methods: Retrospective analysis of 49 patients diagnosed with SCC of the esophagus from 1995 to 2009 was done via the Veteran's Affairs Central Cancer Registry. Demographics, staging, treatment, and outcomes data was recorded. Staging was classified as limited (no distant metastasis) or extensive stage (metastatic disease). Results: Out of 10,540 patients with esophageal cancer, 49 were diagnosed with SCC (0.005%) and were mainly located in the middle and lower thirds of the esophagus (84%). Median age of diagnosis was 64.1 yrs (range: 26-90). 19 patients had limited disease, 26 patients had extensive disease and four patients who were not staged adequately were excluded. Patients received a variety of treatments (Table) with different survival outcomes. Limited stage SCC patients had a median survival of 6.3 mos with patients who received combined modality therapy showing a trend towards improved outcomes. Extensive stage patients who received no therapy had very poor outcomes compared to patients who received any therapy. Conclusions: SCC of esophagus should be considered a systemic disease and like pulmonary SCC, it is an aggressive tumor associated with a poor prognosis. Patient numbers are too low to draw definitive conclusions regarding choice of therapy. Extensive disease patients benefit from chemotherapy and combined modality therapy should be considered in limited stage disease. [Table: see text]
Ascitic derived primary pancreatic cancer cell cultures from different patients as a platform for personalized medicine.
Authors: Golan Talia , Atias Dikla , Avivi Camila , Barshack Iris , Berger Raanan
Published: March 2020

e14646

Background: In Pancreatic Cancer (PC) challenges in drug development include: obtaining metastatic cancer tissue for research, developing and validating biomarkers predicative for personalized therapeutic decisions. We have recently developed a novel therapeutic model for PC to address these challenges based on the isolation of viable PC cells derived from ascitic fluid. Methods: Ascitic fluid was obtained from PC patients undergoing palliative paracentesis. In several patients ascites was obtained several times during the course of their disease. Ascitic-derived primary PC cells were isolated, cultured and identified for each patient in vitro. Informed consent was obtained for all patients. Results: We successfully established ascitic-derived primary cell cultures in 87% (53/61) of the ascites obtained. Homogeneous epithelial PC enriched cell cultures were identified; CK 7/8 (epithelial marker) staining by FACS in 90-95% of the cells, IHC strong staining of CK 7 and negative staining for CK 5/6 in the majority of cells in the cultures. We observed a wide range in doubling time and migration properties among the patients' cell cultures. The diverse nature of each individual patient's cell cultures were further demonstrated by varying chemo-sensitivity to gemcitabine and additional therapeutic agents. Morphological changes were observed at different stages of disease, most cells initially displayed a characteristic epithelial morphology. With more advanced disease a mixed morphological appearance "epithelial-mesenchymal" was seen and up regulation of various epithelial-mesenchymal-transition markers were observed by real-time PCR. Conclusions: We have developed a unique primary ascitic-derived PC cell culture model. These cell lines have the potential to serve as a relevant model to study signaling pathways in PC progression, and to assess the sensitivity to therapeutic agents in a short time frame, therefore supporting personalized treatment decisions.
Effect on survival of postoperative therapy in patients with primary small cell carcinoma of esophagus (SCCE): An analysis of multicenter clinical outcomes.
Authors: Wen Zou Bing , Tao Li , Yuan Ma Dai , Qiang Zhou , Xu Yong , Li Lu , Huang Meijuan , Zhu Jiang , Zhou Lin , Wang Jin , Zhang Yu , Lu You
Published: March 2020

e14648

Background: To retrospectively evaluate the therapy pattern and survival in patients with dissection of primary SCCE. Methods: This study included 89 patients from four centers in southwest China who underwent radical section of SCCE without any preoperative therapy. 36 were treated with postoperative chemoradiotherapy (POCRT), and 53 with postoperative chemotherapy (POCT) alone. The radiation dose to clinical target volume (CTV) was 50 Gy (varying between 44 and 52 Gy), while the cycles of platinum-based chemotherapy ranged from two to six with a median of four. Results: The 5-year overall survival rate (OS) and 5-year disease-free survival rate (DFS) were 16.4% and 14.3% for all patients,respectively. The 5-year overall survival rate was 21.5% in the POCRT group, and 12.9% in the POCT group (p=0.013). The 5-year DFS was 21.3% in POCRT group and 9.3% in POCT group (p=0.028). There was significant difference in 5-year local recurrence-free survival (LRFS) between POCRT and POCT (LRFS: 74.6% vs. 45.3%, p=0.022), while no difference for 5-year distant recurrence-free survival (DRFS: 37.3% vs. 17.4%, p=0.101). Subgroup analysis revieled that there were obvious difference in 5-year OS and DFS between patients received radiotherapy less than 75 days after surgery and ≥ 75 days (OS: 35.6% vs. 8.6%, p=0.046; DFS: 24.9% vs. 7.3%, p=0.020), while received radiotherapy less than 75 days after surgery have worse DRFS (p=0.041). In a multivariate analysis, age ≥59 years was associated with significantly worse OS while with lymph node involved infulence DFS. Tumor size more than 3cm, absence of radiotherapy and less than 4 cycles chemotherapy were poor prognostic factors for both overall survival and disease-free survival. Conclusions: Our analysis shows that postoperative chemotherapy improved OS and DFS in patients with dissection of SCCE, while radiotherapy was given less than 75 days after surgery may improve DRFS and OS. In those patients received postoperative chemotherapy less than 4 cycles is the most important characteristic associated with decreased survival.
MicroRNA-218: A potential regulator of lymphatic metastasis in pancreatic ductal adenocarcinoma.
Authors: He Hang , Di Yang , Liang Min Rui , Yang Feng , Yao Lie , Hao Si Jie , Li Ji , Jiang Yong Jian , Jin Chen , Fu De Liang
Published: March 2020

e14651

Background: Early lymph node metastasis is one of the most important characteristic features of pancreatic ductal adenocarcinoma (PDAC) with a dismal prognosis. MicroRNAs (miRNAs) have been shown to have a role in oncogenesis, invasion, and metastasis via epigenetic posttranscriptional gene regulation. However lymphatic metastasis related miRNAs of pancreatic cancer (PC) has not been well documented. Methods: Through microarray analysis aberrantly expressing miRNAs potentially regulating lymphatic metastasis in PC were gained from PDAC tissue specimens and cell lines. Candidate miRNAs were confirmed in total 40 resected PDAC cases and cell lines by quantitative reverse transcription-PCR (qRT-PCR). In situ hybridization was performed to elucidate the expression features of miRNA-218 in PDAC, precursor lesions, metastatic lymph nodes and cell lines. Results: MiRNA-218 and other five miRNAs were found aberrantly expressing both in PDAC and BxPC-3-LN5 (cell line with high-metastasis characteristics) by microarray analysis. Down-regulated expression of miRNA-218 was validated in PDAC tissue samples (4 fold decrease) compared to adjacent benign tissue (p=0.006) and cell line BxPC-3-LN5 (3 fold decrease) compared to BxPC-3 (p=0.01). Clinicopathological data demonstrated inverse correlation of miRNA-218 expression with lymph node metastasis (p=0.045). Expression of miRNA-218 was down-regulated in IPMN and even decreased in PDAC in a grade-dependent manner. Almost negative expression of miRNA-218 was revealed in metastatic lymph nodes. Conclusions: Down-regulated expression of miRNA-218 in PDAC and its expression features in precursor lesions suggests a tumor suppressor action of miRNA-218 in PDAC. Decreased expression of miRNA-218 may be associated with lymphatic metastasis of PDAC and interpret the high-metastasis ability of BxPC-3-LN5 cell line.
Survival analysis of maintenance therapy with capecitabine (Cape) in patients with resected pancreatic adenocarcinoma (PAC) after adjuvant therapy: A retrospective cohort study.
Authors: Yang Xuezhong , Weinberg Benjamin , Hwang Jimmy J. , Wu Christina Sing-Ying , Akram Madeeha , Pishvaian Michael J. , He Aiwu Ruth , Marshall John
Published: March 2020

e14658

Background: The 5-year survival of PAC with surgery alone is below 10%, and with adjuvant chemotherapy increases to about 20%. The original GITSG adjuvant study demonstrating a survival benefit compared to surgery could be attributed to the use of 2-years of weekly IV bolus 5FU, and not only chemoradiation. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that may remain in G0 arrest, by attacking them as they infrequently enter G1/S phase. To evaluate this hypothesis, we retrospectively evaluated our pts who were treated with or without maintenance Cape. Methods: Pts in the Georgetown/Lombardi Cancer Center EMR since Oct 2007 were sought for PAC that was resected with curative intent, received standard adjuvant chemotherapy with or without chemoradiation. The study group received maintenance cape for at least 2 months, and the control group was monitored until disease recurrence. Only pts with complete follow-up survival data were analyzed. Results: 20 pts met the criteria as study group, and 58 pts as the control group. In the study group, cape was usually given 1000mg orally twice a day, Monday through Friday following adjuvant therapy, for an indefinite period, up to 2 years. Pts received cape for median duration of 12.5 months (2 to 24 months), and the median follow-up duration was 33 months (16 to 78 months). The median overall survival (OS) for the study group was 48 months. The 2 year OS was 94%, and 5 year OS was 40%. The median recurrence free survival (RFS) was 39 months. The 2 year RFS was 67%, and the 5 year RFS was 25%. Common toxicities were mild hand-and-foot syndrome and fatigue. 4 pts discontinued cape due to toxicities: febrile neutropenia, severe fatigue, weight loss and diarrhea. The control group was of comparable staging, and the median OS was 22 months, 5 year OS rate was 16%, median RFS was 13 months, 2 year RFS was 19%. Conclusions: In this single institute retrospective controlled cohort study, Cape maintenance therapy following adjuvant therapy in resected PAC is associated with a significantly (p<0.05) higher OS and PFS compared to the control group. This approach should be studied in a RCT.
Chemoradiotherapy for locally advanced esophageal cancer using carboplatin, paclitaxel.
Authors: Battley Jodie E. , O'Keeffe Margaret , Mulvihill Erica , O'Reilly Seamus , Bennett Michael William , O Suilleabhain Criostoir , Flavin Aileen , Murphy Thomas J , Power Derek Gerard
Published: March 2020

e14666

Background: Localized esophageal adenocarcinoma is usually treated with multi-modality therapy, i.e., chemotherapy or chemoradiotherapy (CRT) followed by surgery. Standard treatment for localized squamous cell carcinoma is controversial as definitive CRT can offer the same overall survival as CRT followed by surgery. Cisplatin and infusional 5FU is the accepted chemotherapy in combination with RT. However this regimen is cumbersome to administer and is associated with significant toxicities. Based on recent data combining weekly paclitaxel with radiotherapy in both the neoadjuvant and definitive settings we report our early experience with this regimen. Methods: All patients (pts) were staged with CT, EUS and PET/CT. Pts with localized, operable or inoperable disease were included. CRT consisted of paclitaxel 50mg/m2 and carboplatin AUC = 2 on days 1, 8, 15, 22, 29, 35 with concurrent RT (5 days/wk, 41.4-50.4Gy). Results: From December 2010 to January 2012, 24 pts: male/female 20/4, median age 67 yrs (29-88), adeno/squamous carcinoma 14/10, lymph node involvement (21pts) were treated. 13 pts treated with neoadjuvant (NA) intent, 11 pts underwent definitive CRT. In the NA group grade 3/4 toxicities were non-hematologic: cardiac (1pt), fatigue (1pt), 2 pts died from progression of disease prior to surgery. Eight pts have undergone surgery (3 awaited). RO resection rate 87.5%, 1 pt had a pCR, 4 pts had a near pCR. At 3mth follow-up 3 pts had no clinical or radiological evidence of disease, 5 pts await repeat imaging. In the definitive group grade 3/4 toxicities included hematologic: neutropenic fever (1pt), non-hematologic: esophagitis (3pts). At 3mth follow-up 7 pts have stable disease, 4 pts await repeat imaging. Dysphagia improved in 21 pts, worsened in 3 pts, and 5 pts required a feeding tube (4 prior to CRT). Conclusions: Carboplatin and paclitaxel combined with radiotherapy is a tolerable regimen in either the neo-adjuvant or definitive setting for locally advanced esophageal cancer. Rates of toxicity compare favorably to standard cisplatin and infusional 5FU. Prospective data with long-term follow-up using this regimen have been reported in the neo-adjuvant setting and are awaited in the definitive setting.
Evaluation of safety and efficacy of somatuline autogel in combination with molecular targeted therapies (MTT) in patients with neuroendocrine tumors (NETs): Data from one Spanish cohort.
Authors: Capdevila Jaume , Sevilla Isabel , Alonso Vicente , Aparicio Luis Anton , Jimenez Paula , Grande Enrique , Reina Juan J , Manzano Jose Luis , Alonso-Guadalajara Juan Domingo , Garcia Alfonso Pilar
Published: March 2020

e14671

Background: Analysis of the mechanisms of action of somatostatin analogs (SSAs) and mTOR inhibitors or tyrosine kinase inhibitors suggest that they may provide synergistic effects when used in combination for the treatment of pts with NETs. Methods: This is a Spanish multicenter cohort of pts with NETs treated with the SSAs lanreotide (LAN) and MTTs at 35 Spanish referral centers. Data of 159 combined treatments (133 pts) was retrospectively collected in order to evaluate the efficacy and safety of such combinations. Results: 133 pts (52,6% M) with a median age of 59,9 years; ECOG 0/1/2/3: 34%/49%/16%/1%; Lung/Pancreas/Gastrointestinal//Unknown(UK) origin: 9%/48% /32%/11%; G1/G2/G3/UK: 41%/32%/1%/26%; Non Functioning/ Functioning (69%/31%) received treatment with MTT + LAN for synergistic antiproliferative purpose in 85% of the cases, hormonal control (13,5%) or both objectives (1,5%). 115 pts received one combination treatment and 18 pts received between 2 (12 pts) and 5 (1 pt). LAN was administrated in combination with sunitinib (61), everolimus (73), bevazucimab (9), sorafenib (8) and pazopanib (8). The reported toxicity was determined by the MTT profile with no significant additional severe adverse events related to the combination with LAN. The probability of progression-free survival (PFS) at 6, 12 and 18months was 89%, 73% and 67% respectively for those pts who received LAN and sunitinib (n=50) and 78%, 69% and 57%, respectively for those pts who received LAN and everolimus (n=56). Median PFS was not reached at the time of analysis. Conclusions: The combination of LAN and MTT, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities. Median PFS will be higher than data observed in phase III studies with sunitinib and everolimus, raising the hypothesis of enhanced efficacy combining SSAs and MTT that should be confirmed in randomized prospective clinical trials. [Table: see text]
HER2 amplification, HER2 overexpression,and TOP2A abnormalities in gastroesophageal cancers: Do they predict responsiveness to epirubicin-based chemotherapy?
Authors: Personeni Nicola , Bozzarelli Silvia , Spaggiari Paola , Rubino Luca , Giordano Laura , Roncalli Massimo , Santoro Armando
Published: March 2020

e14672

Background: Abnormalities of TOP2A, a major target of anthracyclines, have been reported as positive predictive markers of response to anthracycline-based therapy in breast cancer. We determined abnormalities of TOP2A and HER2, and HER2 protein expression, in a cohort of patients with gastric or gastro-oesophageal junction adenocarcinomas treated with epirubicin-based chemotherapy. Methods: We studied 50 patients that received either adjuvant (74%) or perioperative (26%) epirubicin, cisplatin and 5-fluorouracil. All patients were screened for TOP2A amplification/deletion by fluorescent in situ hybridization (FISH), and for HER2 protein expression by immunohistochemistry (IHC). For each patient at least two paired surgical samples were examined. Tumors exhibiting a HER2 score of 2+ were further screened for gene amplification by FISH. We studied the association of TOP2A abnormalities and HER2 amplification/expression with recurrence free survival (RFS) and overall survival (OS). Results: By IHC, HER2 overexpression (score 3+) was detected in 9 patients. Intra-tumor heterogeneity of HER2 staining, resulting in discrepant HER2 scores, was detected in 4 of 50 (8%) paired samples analyzed. HER2 amplification was detected in 1 of 8 tumors with a HER2 score 2+. TOP2A amplification was observed in 1 of 50 tumors; none exhibited TOP2A deletions. In patients whose tumors showed HER2 overexpression or gene amplification (HER2-positive) and in patients with HER2-negative tumors, median RFS was 11.0 and 13.9 months, respectively (p= 0.35); median OS was 28.8 and 29.9 months, respectively (p= 0.56). A pathological complete response was observed in 1 of 4 HER2-positive patients that underwent perioperative chemotherapy. Conclusions: In this cohort of patients with early-stage gastroesophageal cancers who were treated with epirubicin-based chemotherapy, neither HER2 amplification nor HER2 overexpression were associated with outcome. TOP2A abnormalities are rare and their putative role as a determinant of responsiveness to anthracycline-based chemotherapy in gastroesophageal cancers is not supported by our findings.