bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of irinotecan, 5-fluorouracil (5-FU) and leucovorin combination chemotherapy in taxane and cisplatin-based chemotherapy-refractory metastatic gastric cancer
Authors: Yoon J. , Cho S. , Bae W. , Hwang J. , Shim H. , Chung I.
Published: August 2020

e15599

Background: The role of the second line chemotherapy in advanced gastric cancer was not clear, but possibility of prolongation of survival is open question. Irinotecan is promising agents in gastric cancer and this phase II study evaluated the efficacy and safety of combination chemotherapy with irinotecan, high dose of 5-fluorouracil (5-FU) and leucovorin in taxane and cisplatin based chemotherapy refractory metastatic gastric cancer. Methods: Eligible criteria were as followed; histologic confirmed adenocarcinoma of stomach, previously treated with taxane and cisplatin, age≥18, Eastern Clinical Oncology Group (ECOG) performance status of 1 or less, adequate organ function. Irinotecan (150 mg/m2) as a 30-min infusion and leucovorin (200 mg/m2) as a 15-min infusion were given on day 1, followed by 5-FU 400 mg/m2bolus infusion then 5-FU 2,400 mg/m2 as a 48-hour continuous infusion. This cycle was repeated every 2 weeks until disease progression or unacceptable toxicities. Results: Thirty-four patients were enrolled. The median age was 57 years (range 27–73 years), and the ECOG performance status of all patients was 1. All patients were evaluable for safety and survival and twenty seven patients (79.4%) were evaluable for tumor response. The overall response rate was 18.5% (95% CI: 3.9–33.1). The median progression free survival and overall survival were 4.6 (95% CI: 2.4–6.9) and 9.3 months (95% CI: 5.2–13.4), respectively. Greater than grade 3 haematological toxicities were neutropenia in nine (26.5%), febrile neutropenia in one (2.9%) and thrombocytopenia in one patient (2.9%). The major non-haematological toxicity was asthenia, but most of patients showed grade 1 or 2. Greater than grade 3 non- haematological toxicities were elevated AST/ALT in four (11.8%), hyperbilirubinemia in two (5.9%), nausea in two patients (5.9%). Conclusions: This results showed that the combination chemotherapy with irinotecan, 5-FU and leucovorin was well tolerated and active in taxane and cisplatin refractory patients.

No significant financial relationships to disclose.
Phase II study of S-1 in combination with paclitaxel as a first-line treatment for patients with advanced/recurrent gastric cancer
Authors: Toh U. , Yamana H. , Koufuji K. , Mine T. , Aoyagi K. , Miyagi M. , Imaizumi T. , Shirouzu K.
Published: August 2020

e15615

Background: Taxanes and S-1 have been shown to be effective in patients with advanced gastric cancer and they have a considerable single-agent activity, respectively. We evaluated the combination of paclitaxel and S-1 as first-line chemotherapy for advanced or recurrent gastric cancer (AGC). Methods: All patients with histologically confirmed AGC with unresectable or metastatic diseases, measurable lesions, PS 0–2, age between 18 and 75, and no contraindication to chemotherapy were eligible in this study. Prior adjuvant chemotherapy finished at least 6 months before enrollment was allowed. Treatment included S-1 80 mg/m2 p.o. twice daily on days 1–14 and paclitaxel 60 mg/m2 i.v. on day 1, 8, 15 with a 2-week interval until disease progression or unacceptable toxicities. Results: Between MAY 2004 and Match 2008, total 20 pts were enrolled in this study. The median age was 56.5 years (range, 38–73). Nine pts had recurrent disease after previous curative gastrectomy and 8 had previous adjuvant chemotherapy. After a median 4 (range, 1–9) cycles of chemotherapy, 12 pts were evaluable for toxicity and 20 pts for response. In intention-to-treat analysis, the overall response rate was 62.9% (95% C.I., 36.2–69.6%), including 0 CR, 6 PRs, 8 SDs, and 6 PDs. After a median follow-up of 8.6 months (range, 0.9–17.9), median time to progression was 6.3 months (95% C.I., 3.6–6.9) and median overall survival was 11.6 months (95% C.I., 8.5–20.7). Commonly observed grade 3/4 adverse events were neutropenia (40% of patients), anemia (10%). There was no neutropenic fever or treatment-related death. Conclusions: The combination of paclitaxel and S-1 appear to have well efficacy, manageable toxicity and is well tolerated in patients with AGC. Further studies of this combination should be considered.

No significant financial relationships to disclose.
KRAS mutations and relation to prognosis in patients operated for localized pancreatic cancer and other periampullary cancers
Authors: Schultz N. A. , Roslind A. , Christensen I. J. , Gaustadnes M. , Johansen J. S. , Kruhøffer M. , Horn T. , Wøjdemann M.
Published: August 2020

e15618

Background: Prognostic biomarkers in patients with pancreatic cancer might direct patients to optimal treatment. We studied the prognostic value of KRAS mutations in patients operated for pancreatic and other periampullary cancers. Methods: Retrospective study of 328 patients who were operated with a Whipples procedure at a single HBP-center during the period August 1976 to May 2008. For the present pilot study cancer tissue blocks were collected from 58 patients (31 men, 27 women, median age 64, range 33–81 years, ASA 1–3). All had localized pancreatic (n=26), ampullary (n=26) or duodenal cancer (n=6) and were operated during the period June 2001 to May 2008. 32 patients died (3 within the first month after operation and were excluded). Median follow-up time was 41 months (range 7–90). KRAS mutations in exon 1 and 2 were determined by LightScanner analysis (Idaho Technology). Results: KRAS mutations were found in 32 (55%) of the patients; 16 (62%) patients with pancreatic cancer, 13 (50%) with ampullary cancer and in 3 (50%) with duodenal cancer. KRAS status was neither associated with type of cancer (p=0.68), TNM stage (T stage p=0.64, N stage p=0.31). The median survival time for all patients was 22 months (KRAS mutation: 21, 95% CI: 10–40; Wildtype: not reached yet). Univariate Cox analysis showed that T stage (TNM) (1: HR=0.09, 95% CI: 0.02–0.48 p=0.004; 2: HR=0.18, 0.06- 0.51, p=0.0013; 3: HR=0.26, 0.09–0.71, p=0.0089) was a prognostic factor of OS. KRAS status (HR=0.70, 0.33–1.49, p=0.36) and N stage (TNM) (HR=0.53, 0.25–1.11, p=0.09) were not significant factors of OS, but there is a strong tendency for both factors. Conclusions: KRAS mutations are frequent in patients with localized pancreatic, ampullary and duodenal cancers. Preliminary analysis of 58 patients out of our cohort of 328 patients indicate that KRAS mutations may be a marker of overall survival and time to progression.

No significant financial relationships to disclose.
A single institution experience with neoadjuvant chemoradiation (CRT) with irinotecan (I) and cisplatin (C) in locally advanced esophageal carcinoma (LAEC)
Authors: Sharma R. , Yang G. Y. , Nava H. R. , Demmy T. L. , Nwogu C. E. , Yendamuri S. S. , Lamonica D. , Tan W. , Iyer R. V. , Khushalani N. I.
Published: August 2020

e15619

Background: Multimodal therapy is considered standard for LAEC with cisplatin and 5FU-based CRT being commonly used, though with significant toxicity. Novel agents are needed to improve pathologic response (pCR) which predicts for better prognosis. We analyzed our experience with CRT using I + C in LAEC. Methods: LAEC patients (PTS) who underwent surgery preceded by CRT with I + C were identified from the Roswell Park tumor registry. Treatment consisted of Day 1,8 of C 30mg/m2 and I 65mg/m2in a 21 day cycle. PTS concurrently received 45–50.4 Gy radiation in1.8Gy fractions. Data retrieved included toxicity, pCR rate and survival. Results: 44 eligible PTS, median age 61 yr, 43 males and 1 female. Histology included adenocarcinoma (n=38), squamous cell (n=4), mixed (n=2); 12 PTS had signet-ring cell features. 29 PTS had poorly differentiated tumors. Clinical stage was II (n=5), III (n=24), IVa(n=6), IVb(n=1), not available (n=8). ECOG PS was 0 (n=34) and 1 (n=10). Most common toxicities observed were fatigue (n=24), diarrhea (n=19), vomiting (n=15), hematologic (n=11), constipation (n=11) and neurologic (n=7). Dose delay or reduction was required in 10 PTS, usually from hematologic toxicity. Of these,1 week delay in 45% and 2 weeks in 36%; 1 PT discontinued treatment due to toxicity. There was no CRT-related mortality. 2 PTS died post-operatively (anastamotic leak and sepsis). Dyphagia improved in 33/35 (94%) PTS following CRT. All PTS underwent R0 resection and pCR rate was 25% (11/44). 15 PTS have experienced recurrence. The median disease-free and overall survival is 24 months and 34 months, respectively; 3-yr overall survival is 46%. Available pre- and post-CRT FDG uptake on PET imaging in 28 PTS did not correlate with pCR status (p=0.77). Conclusions: Neo-adjuvant CRT with I + C has modest efficacy in the treatment of LAEC and can be given safely in the out-patient setting. PTS should be monitored closely for toxicity, specifically diarrhea that requires prompt intervention. Efficacy results appear better than those reported in ECOG 1201. This regimen is being evaluated in CALGB 80302 and results are awaited.

No significant financial relationships to disclose.
Pharmacokinetics of intraperitoneal docetaxel and S-1 in patients with gastric cancer with peritoneal carcinomatosis
Authors: Kamikozuru H. , Hayashi K. , Kuramochi H. , Nakajima G. , Yamamoto M.
Published: August 2020

e15626

Background: One of the most causes of death from gastric cancer is peritoneal cartinomatosis. Intraperitoneal docetaxel infusion is expected to be a new strategy for a treatment of peritoneal carcinomatosis. The purpose of this study is to evaluate the plasma and peritoneal pharmacokinetic of intraperitoneal docetaxel infusion in combination with oral administration of S-1. Methods: Eight patients with peritoneal carcinomatosis of advanced gastric cancer were enrolled. Docetaxel was dissolved in an isotonic saline to a final 1 liter solution and administered in 2 hour via an implanted intraperitoneal catheter at dosage of 40mg/m2. Five of eight patients were administered S-1 orally at dosage of 80mg/m2. Blood and peritoneal fluid were collected before administration, on completion of the docetaxel infusion(hour 0) and at hours 1,2,4,6,12,24,48,and 72 after completion of the infusion of the docetaxel. Plasma and peritoneal fluid concentrations of docetaxel and 5FU were evaluated. Results: The mean peak peritoneal and plasma concentrations of docetaxel were 18.6×103 ng/ml (at hour 0) and 45 ng/ml (at hour 0 to 2), respectively. The peritoneal concentrations of docetaxel were remained even after 24 and 72 hours (24 hours: 1150ng/ml, 72 hours: 74ng/ml). In seven out of eight patients, plasma concentrations of docetaxel were disappeared after 24 hours, but in only one patient with severe ascites, concentration of plasma docetaxel at hour 24 could be obtained (20 ng/ml). The mean peritoneal and plasma areas under the curves (AUC) of docetaxel were 141×103 ng/ml×hr and 480 ng/ml×hr, respectively. The mean peritoneal concentrations of 5FU kept over 60% of plasma concentrations (plasma: 164.3ng/ml, peritoneal: 105ng/ml). Conclusions: Intaperitoneal docetaxel kept relatively high concentrations even after 72hours. 5FU concentrations were well transfered in peritoneal fluid from plasma via oral S-1 administration. Intraperitoneal docetaxel in combination with S-1 orally may be a useful regimen to the patients with carcinomatosis of advanced gastric cancer.

No significant financial relationships to disclose.
Chemotherapy for patients with advanced gastric cancer with performance status 2
Authors: Muro K. , Shitara K. , Ura T. , Takahari D. , Yokota T. , Sawaki A. , Kawai H. , Munakata M. , Sakata Y.
Published: August 2020

e15627

Background: S-1 plus cisplatin is considered to be the standard chemotherapy for Japanese patients with advanced gastric cancer (AGC) according to the results of three phase III trials (JCOG9912/SPIRITS/TOP-002). However, since few patients with poor performance status (PS2) were included in these phase III trials (27 of 1317; 2%), the standard treatment of patients with PS2 has not been established yet. In also, the characteristics and prognosis of AGC patients with PS2 has not been reported in detail. Methods: We retrospectively analyzed 545 patients with AGC treated by chemotherapy during the period from January 2003 to June 2008. Patients characteristic and treatment results were compared between PS0–1 and PS2. Results: At the beginning of 1st-line chemotherapy, PS0–1/2/3–4 was 454/69/22 cases respectively. Patients with peritoneal/pleural dissemination was more common in PS2 than PS0–1 (75% vs. 43%, p<0.001). Patients with multiple metastatic places was more common in PS2 (62% vs. 43%; p=0.007). Fewer patients in PS2 were registered in clinical trial (1.4% vs. 25%, p<0.001). First-line chemotherapy using oral drug (S- 1/capecitabine) was significantly fewer in PS2 (43% vs. 75%, P<0.001). Median time to treatment failure was significantly shorter in PS2 (2.3 months vs. 4.2 months, p<0.001). Patients who could receive second-line chemotherapy were significantly fewer in PS2 (50% vs. 75%, p<0.001). With the median follow up time of 42 months, median survival time of patients with PS0–1 was 14.8 months (95% CI;13.1–16.5) and that of patients with PS2 was 6.1 months (4.3 to 7.4 months; hazard ratio for death 3.0: 95% CI2.3–4.0; p<0.001). Mortality rate within 30 days was higher in PS2 (3% vs. 0.2%; p<0.001). Conclusions: AGC patients with PS2 had not only had poor prognosis compared with PS0–1 but also had fewer chance of registration in the clinical trial, shorter time to treatment failure, and higher mortality rate within 30 days. Considering these different characteristics and treatment results of PS0–1 and PS2, clinical trial especially targeting AGC patients with PS2 is necessary to evaluate optimal chemotherapeutic regimens for PS2 patients.

No significant financial relationships to disclose.
Use of partial liver resection according to carcinologic procedures as an alternative to liver transplantation for HCC
Authors: Herrero A. , Pulitano C. , Dondero F. , Dokmak S. , Aussilhou B. , Sauvanet A. , Farges O. , Faivre S. , Belghiti J.
Published: August 2020

e15628

Background: There are some arguments showing that anatomic resection, anterior approach and preoperative transarterial chemoembolization (TACE) with portal vein embolization (PVE) before major resection improves long term survival after partial liver resection for HCC. This oncologic approach could compete with liver transplantation (LT) which remains poorly accessible in western countries and inaccessible in the greatest part of the world.The aim of this study was to evaluate in patients with good liver function.the result of partial liver resection with an intended carcinologic approach. Methods: Between 1998 and 2007, among 210 patients resected for HCC, we selected a subgroup of 36 patients with single and small HCC (< 6 cm) developed on chronic liver disease (CLD) who underwent anatomic partial resection and anterior approach and TACE and PVE in case of major resection. Results: These 36 patients aged 37 to 76 years included 26 males (72%). Underlying CLD included hepatitis C in 16 (44%); hepatitis B in 8 (22%); alcohol in 9 (25%) and other in 3 ( 8%). The mean size of the tumor was 5.2 cm and 86% (n=31) had major resection. Operative mortality was 2.7% (n=1) and the overall 1-, 3- and 5-year survival rate were 92%,85%,73% while the disease free 1-, 3-, 5-year survival was 80%, 74%, 58%. Tumor recurrence occurred in 16 cases( 44%) after a mean delay of 21 months (ranging from 5 to 58 months). Recurrence was located out of the resected location in 6 cases. Conclusions: Partial liver resection for small tumors in patients with good liver function according to carcinologic procedures allow an excellent overall and disease free survival which can challenge LT. In the case of single HCC <6cm on chronic liver disease, this surgical approach may therefore be considered as a valuable alternative to LT within a curative intent.

No significant financial relationships to disclose.
The analysis of EGFR expression and EGFR mutations in advanced pancreatic cancer
Authors: Ueno M. , Ohkawa S. , Sakamoto Y. , Miyakawa K. , Miyagi Y.
Published: August 2020

e15629

Background: The standard chemotherapy of advanced pancreatic cancer is still gemcitabine and recently gemcitabine + EGFR tyrosine kinase inhibitor (TKI)is noted to be positive on Phase III study. In lung cancer, EGFR mutations (the deletion of exon 19, the point mutation of exon 18, 21) have been reported to be correlated with the effect of EGFR TKI. On the other hand, such EGFR mutations were not reported to be recognized by the direct sequencing method in pancreatic cancer. This time we examined EGFR expressions and EGFR mutations in advanced pancreatic cancer. Methods: We examined EGFR expressions immunohistochemically and EGFR mutations by Loop-Hybrid Mobility Shift Assay (LH-MSA) which is more sensitive than the direct sequencing method in the tissue obtained from percutaneous biopsies in advanced pancreatic cancer patients. In addition we examined the correlation between EGFR expressions and survivals by the log-rank test. Results: The subjects were 31 inoperable pancreatic cancer patients. Patients received chemotherapy (gemcitabine: 10, S-1: 8, gemcitabine+S-1: 12, no treatment: 1).The UICC stages were as follows:stage II; 2, stage III; 6, stage IV; 23. The tissues were obtaind from liver; 12, pancreas; 19. EGFR expressions were positive; 15, negative; 16. EGFR expressions were not correlated with survival (p=0.386). Although LH-MSA were performed successfully in all patients, the same EGFR mutations as lung cancer were not detected. Conclusions: EGFR expressions were not correlated with survivals and the same EGFR mutations as lung cancer were not detected in inoperable advanced pancreatic cancer.

No significant financial relationships to disclose.
Gastric submucosal tumors: Lessons learned from 10-year follow-up
Authors: Sawaki A. , Mizuno N. , Takagi T. , Hara K. , Nakamura T. , Tajika M. , Kawai H. , Matsumoto K. , Kobayashi Y. , Yamao K.
Published: August 2020

e15631

Background: Gastric Submucosal tumors (SMTs) were incidentally discovered esophagogastroduodenoscopy (EGD). However, they have not been studied in detail of epidemiology. Furthermore, no treatment strategy for SMTs has been established with few studies looking into long-term outcomes. The aim of this study is to clarify the clinical features and long-term outcomes of gastric SMT at a single institute for 10-year period. Methods: We performed a total of 5307 EGDs and detected 188 gastric SMTs during 1998. All clinical data including incidence, size and location in stomach were analyzed for the medical records. A retrospective review was conducted for 10-year period for 109 patients and 79 patients were excluded because of simultaneous surgery (3), disappear in follow- up EGD (27), lost of follow-up (49). Results: Gastric SMTs were detected 188 (81 males, 107 females) of 5307 patients (3.5%). Majority size of SMTs was less than 1cm (64%) and SMTs<2cm were 91%. 56% of SMTs located middle one third of stomach, and half (22%) of the remaining SMTs were detected at upper and lower one third, respectively. In 10-year follow-up, 83 of 109 patients were alive at December 2008. One patient was dead of SMT and the remaining 25 patients were dead of other disease till December 2008. Enlargement of SMT was observed in 2 of 109 SMTs (1.8%). Both of them underwent surgical resection and diagnosed as gastrointestinal stromal tumors (GIST). One patient was annually monitored by endoscopy, from 0.6cm to 1.5cm during 4 years, without recurrence for 6 years after surgical intervention. Another didn't undergo regular endoscopy, from 1.8cm to 8cm during 2 years, with recurrence, and consequently died of SMT. Conclusions: The incidence of SMTs is 3.5%, majority (91%) is small (<2cm), and frequent location is middle one third of stomach. Most of SMTs might be managed conservatively, but regular endoscopy is required.

No significant financial relationships to disclose.
A phase II study of Halichondrin B analog eribulin mesylate (E7389) as second-line therapy for patients with advanced pancreatic cancer
Authors: Moore M. J. , Tang P. , Renouf D. , Major P. , Hedley D. , Paterson V. , Wang L. , Dhesy-Thind B. , Southwood B. , Doyle L.
Published: August 2020

e15634

Background: Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics by a mechanism that is distinct from other tubulin-targeted agents. Preclinical studies suggest that Eribulin may be effective in pancreatic cancer. The primary objective of this study was to determine the objective response rate (complete and partial) to Eribulin in patients with advanced, pancreatic adenocarcinoma that had progressed after gemcitabine based therapy. Methods: Eligibility criteria included histologically confirmed pancreatic adenocarcinoma; measurable locally advanced, or metastatic disease; disease progression after gemcitabine; and ECOG performance status 0–2. Patients (pts) received Eribulin mesylate 1.4 mg/m2 IV on days 1 and 8. Treatment was repeated every 3 weeks in the absence of disease progression or unacceptable toxicity. Response was assessed by CT scans every 6 weeks while on treatment. Initially 12 pts were to be accrued, if 1 or more pt(s) had an objective response the accrual would increase to a total of 37. Results: 15 pts were accrued,14 received treatment and 12 were evaluable for response. Median age 61; M:F = 8:7; ECOG 1:2 = 11:4; Median number of cycles 2 (1–15). Grade 3+ adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses, and therefore the study was closed at the first accrual cut off. The best response was stable disease (SD) in 5/12 (42%) pts. Of these 5 pts, 3 (42%) had SD for 12 cycles or greater. Survival data is pending. Conclusions: Eribulin was well tolerated and did not result in any objective responses in refractory pancreatic cancer. However, 42% of pts had stable disease and for 3 pts this was maintained for more than 9 months. Further studies of eribulin in pancreatic cancer may be warranted.

No significant financial relationships to disclose.
Is there still place for endoscopic mucosal resection in patients with early oesophageal carcinomas?
Authors: Bogoevski D. , Schurr P. G. , Koenig A. M. , Busch P. , Kutup A. , Izbicki J. R.
Published: August 2020

e15640

Background: The objective of this study was to investigate whether limited resection of the oesophagogastric junction can be successfully used in the treatment of the patients with early oesophageal carcinomas. Methods: A total of 111 patients with early oesophageal cancer (57 adenocarcinomas, 54 squamous cell carcinomas) had surgical resection with systematic lymphadenectomy (41 thoracoabdominal-TA, 52 transhiatal-TH and 18 with limited resection of the oesophagogastric junction- LROGJ). Results: In all patients, regardless from the surgical procedure, a complete resection (R0) was achieved. The median lymph node yield was significantly higher (p=0.0001) in TA patients (24 LN), compared with TH (14LN) and LROGJ (16LN). The median in hospital and ICU stay were shorter in patients with the LROGJ (12 and 2 days, respectively) compared with the TA (24 and 8 days) and TH patients (23 and 4 days). None of the 43 patients with high grade intraepithelial neoplasia (HGIEN) or oesophageal carcinoma limited to the mucosa had lymphatic spread, as compared with 15 of 68 (22.1%) with affection of the submucosa. Although lymph node metastases were usually limited to locoregional lymph node stations, two patients had metastases in distant lymph nodes (pM1a) The infiltration of the submucosa was accompanied with significant worsening of the overall survival (pT1a vs. pT1b; p=0.002). Multifocal neoplasia was detected in three patients with SCC HGIEN (30%) but not in AC HGIEN! Nine out of 44 (20.4%) patients with early SCC had multifocal neoplasia, compared to 6 out of 53 (11.3%) patients in AC (p=0.322). The sensitivity of the preoperative tumour dept staging (endoscopic ultra sound - EUS; and CT) was astonishing low (only 50% for cT1b), as was the specificity (66.7% for cT1a and only 87.5% for cT1b). On multivariate analysis, only histological tumor type (AC) was independent predictor of survival. Conclusions: Considering the limitations and pitfalls of endoscopic and classical resectional procedures, the quest for alternative and “patient tailored” treatment in patients with early oesophageal carcinoma carries on. A valuable alternative can be the limited resection of the oesophago-gastric junction under sparing of the healthy oesophagus and stomach.

No significant financial relationships to disclose.
Differential expression of human telomerase reverse transcriptase β-site remaining alternative splicing variants (hTERT β+ ASV) in gastric carcinogenesis
Authors: Geng X.
Published: August 2020

e15641

Background: To investigate the changes of hTERT alternative splicing variants pattern in gastric cancer, precancerous lesions and normal gastric mucosa tissue. Methods: Three alternative splicing sites (α, β, γ) were selected and designed PCR primer. The expression of 8 hTERT alternative splicing variants (ASVs) in gastric cancer, precancerous lesions and normal gastric mucosa were detected by Semi-nested RT-PCR. The expression of β-site remaining ASV (β+ASV) in specimens of gastric cancer and specimens of precancerous lesions was detected by SYBER Green real-time PCR. Telomerase enzyme activity was evaluated associated with the different hTERT ASVs. Results: The positive rate of active full-length (α+β+γ+ ) ASV was significantly higher in gastric cancer than in precancerous lesions and normal mucosa (94.7% vs. 40.0% and 0, P<0.05). The positive rates of other ASVs were not different among the 3 groups(P>0.05). The positive rates of β+ ASVs (including α+β+γ+ASV, α-deletion ASV, γ-deletion ASV, αγ-deletion ASV) were 11.1% in normal mucosa,40.0% in precancerous lesions and 94.7% in gastric cancer (P<0.05). SYBR Green real-time RT-PCR showed that the expression level of β+ASV was 6.99 times higher in gastric cancer than in precancerous lesions. Further, increased telomerase enzyme activity was only associated with expression of the full-length hTERT isoform. Conclusions: hTERT alternative splicing pattern is different during gastric carcinogenesis. β+ASV was widely expressed in gastric carcinogenesis and may provide some information for diagnosis of gastric cancer or precancerous lesions. The gene expression patterns of hTERT alternative splicing variants may provide some useful information for diagnosis of gastric cancer and precancerous lesions.

No significant financial relationships to disclose.
The role of S-1 in gemcitabine-refractory pancreatic cancer: A retrospective single-institution study
Authors: Nakai Y. , Isayama H. , Sasaki T. , Sasahira N. , Hirano K. , Tsujino T. , Tada M. , Kawabe T. , Omata M.
Published: August 2020

e15648

Background: S-1 was reported to be active against gemcitabine (Gem)-refractory pancreatic cancer (PaC) in Japan and was introduced in February 2005 in our institution. The aim of this study was to elucidate the impact of S-1 on prognosis of patients with Gem- refractory PaC. Methods: A total of 108 patients (pts) with advanced PaC who were treated with Gem and had disease progression (PD) at the University of Tokyo Hospital were analyzed. The introduction rates of second-line chemotherapy and the causes of introduction failure were assessed. Prognostic factors for residual survival (RS) for Gem-refractory PaC were analyzed by the Cox proportional hazard model. Results: Of 108 pts with Gem-refractory PaC, 47 pts (PreS-1 Group) had PD before February 2005, the time of S-1 introduction in our institution, and 61 pts (PostS-1 Group) after February 2005. There were no differences in baseline characteristics at PD for Gem between PreS-1 and PostS-1 Groups, except for metastasis to peritoneum more prevalent in PreS-1 Group (44.7% in PreS-1 Group and 23.0% in PostS-1 Group, p=0.023). The introduction rate of second-line chemotherapy increased from 12.8% in PreS-1 Group to 45.9% in PostS-1 Group. Second-line chemotherapy was administered in 34 pts, 29 by S-1, 4 by 5-FU-based chemoradiation, and 1 by 5-FU. The causes of introduction failure of second line chemotherapy were poor PS in 64.9%, patients’ refusal in 16.2%, infection in 2.7%, adverse effects of Gem in 1.4% and jaundice in 1.4%. RR, PFS, and OS for second-line S-1 were 17.2%, 2.5 Mo, and 7.8 Mo, respectively. PFS for Gem was not prognostic of PFS for S-1 (2.5 Mo both in pts with PFS >6Mo and in pts with PFS <6Mo for Gem). RS after PD for Gem was prolonged from 3.1 Mo in PreS-1 Group to 6.5 Mo in PostS-1 Group (p<0.001). The Cox hazard model revealed PreS-1 Group (HR2.42, p=0.001) in addition to male gender (HR1.83, p=0.019), poor PS (HR3.52, p<0.001), liver metastasis (HR2.36, p=0.037), elevated LDH (per 100U/L increase) (HR 1.30, p=0.046), elevated CRP (HR 1.14, p=0.023) at PD for Gem as poor prognostic factors of RS for Gem-refractory PaC. Conclusions: Introduction of S-1 might lead to improvement of prognosis in patients with Gem-refractory PaC.

No significant financial relationships to disclose.
Retrospective analysis of salvage percutaneous cryoablation of hepatocellular cancer (HCC) in liver
Authors: Daniels J. R. , Katz M. D. , Hart M. , Fong T. , Donovan J. A. , El-Khoueiry A. B. , Wallman M. A.
Published: August 2020

e15649

Background: We report our initial experience with percutaneous cryoablation of HCC in liver. Prior published series are limited. Methods: We treated 30 lesions in 23 patients (pts): Child-Pugh class A, 13 pts; B, 8 pts.; C, 2 pts Candidate pts had residual disease after intra-arterial chemotherapy. Probe placement (2.4 mm, Endocare) occurred under general anesthesia with restricted tidal volume to facilitate computer tomographic (CT) localization. An average 2.7 probes (range 1- 5) achieved an estimated margin of 0.5 cm visualizing the ice ball after two 10 min freeze cycles. Median follow-up was 342 days (range 30–947) Results: Tumors ranged from 1.3 to 5.8 cm. Three pts died within 30 days: 2 following intra-peritoneal hemorrhage despite control of bleeding and 1 from ischemic liver injury following a TIPSS for hydrothorax in a pt with refractory ascites. Two additional pts had hemorrhage with recovery. Risk of bleeding was associated with ascites (P = 0.013). One pt had cutaneous needle tract tumor seeding caused by needle repositioning prior to freezing. Survivors remained clinically stable at the 2–3 month follow-up. At the 2 month evaluation 29 lesions had no residual enhancement by CT. One lesion required a second cryoablation procedure.There were no recurrences in any target lesion (30–947 days). Thirteen pts are alive without recurrence of whom 6 had liver transplant with no (4) or < 5% (2) residual disease. Three pts have had recurrence in non-target liver and have died. Multiple tumors at baseline predicts for hepatic recurrence. Two pts have died from complications of cirrhosis, and 2 are lost to follow-up. Conclusions: Percutaneous cryoablation effectively manages selected hepatic HCC tumors. Cirrhotic pts with ascites have significant risk for hemorrhage. We recommend peri-procedure paracentesis and an immediate post-procedure CT.

[Table: see text]
Lapatinib and gemcitabine for metastatic pancreatic cancer: A phase II study
Authors: Safran H. , Miner T. , Bahary N. , Whiting S. , Lopez C. , Sun W. , Charpentier K. , Charpentier K. , Shipley J. , Anderson E. , McNulty B.
Published: August 2020

e15653

Background: To determine the overall survival for patients with metastatic pancreatic cancer treated with lapatinib and gemcitabine. Methods: Patients with metastatic pancreatic cancer received lapatinib, 1,500 mg/day, and Gemcitabine, 1 gm/m2/week for 3 weeks followed by 1 week off, until disease progression. This multicenter phase II study was planned to enter 125 patients to evaluate if the treatment regimen could achieve a 1-year survival of 30% and a median survival of 7 months. An additional subset of 20 patients were to receive 2 months of single agent lapatinib followed by lapatinib and gemcitabine. Results: At a planned 6 month analysis, the Brown University Oncology Group Data Safety Monitoring Board terminated accrual after 29 patients due to futility analysis. The median survival was 4 months (95% CI, 2.0–5.5 months). The four patients who received single agent lapatinib all progressed at 1 month. Conclusions: Lapatinib is not effective in pancreatic cancer. Evaluation of HER2 inhibitors in pancreatic cancer is not warranted.

[Table: see text]
TIP regimen in metastatic or recurrent esophageal cancer: An Indian experience
Authors: Batra U. , Doval D. C. , Talwar V. , Sharma J. B. , Sherali R.
Published: August 2020

e15664

Background: Currently, there is no standard regimen for metastatic or recurrent upper or middle squamous cell esophageal cancer. Multiple agents including Taxanes, Ifosfamide have shown significant single agent efficacy in this subset of patients. We therefore undertook this study to test the first-line combination of TIP regimen (Paclitaxel, Ifosfamide and cisplatinum) in patients with metastatic carcinoma of the esophagus. Methods: This study evaluated the efficacy, tolerability and toxicity profile of the TIP regimen in patients with metastatic or recurrent carcinoma of the upper or middle squamous cell carcinoma of esophagus. Patients received Paclitaxel 135 mg/m2, Ifosfamide 1.3 gm/m2 day1–3, CDDP 75 mg/m2( split in day 1–2). Granulocyte Colony stimulating factors were not administered until the patient had prolonged Gr IV neutropenia or febrile neutropenia. Patients were evaluated after 3 cycles and at completion of treatment. Results: A total of 32 patients were treated with TIP regimen. 24 patients completed a median of 4 cycles of which 21 were evaluable for response assessment. 13 patients achieved a major response of which 5 patients had complete response. The median time to tumor progression was 7 months and the median survival was 13 months (range 2–36 months). The regimen was well tolerated with only 1 patient requiring dose reduction.Febrile Neutropenia occurred in 8 patients, all of whom recovered after treatment with antibiotics. There were no reported events of Gr IV peripheral neuropathy or mucositis. There were no treatment related deaths. In addition to the radiological responses, patients who responded had a significant better quality of life. Conclusions: The combination of Paclitaxel, Ifosfamide and Cisplatinum has significant activity in metastatic or recurrent esophageal cancer. This regimen is well tolerated with a high response rate. The ease of administration, cost effectiveness and suitable safety profile makes it an ideal first line regimen in metastatic esophageal cancer.

No significant financial relationships to disclose.
Survival time and its prognostic factors in advanced unresected cholangiocarcinoma without chemoradiation
Authors: Park J. , Kim M. , Kim J. , Lee J.
Published: August 2020

e15681

Background: To evaluate survival time and its prognostic factors contributing to survival of advanced unresected cholangiocarcinoma. Methods: We reviewed the experience of 330 patients with histologically proven unresected advanced intrahepatic and hilar cholangiocarcinoma and evaluated their survival time and significant prognostic factors. They did not receive any surgery, chemotherapy and radiotherapy and they underwent only palliative nonsurgical biliary drainage if it was needed to relieve biliary obstructive symptom. Results: Survival time of overall cholangiocarcinoma (median±SD) was 3.9±7.8 months; 3±5.3 months for intrahepatic cholangiocarcinoma, 5.9±10.1 months for hilar cholangiocarcinoma. By Kaplan-Meier survival analysis, intrahepatic cholangiocarcinoma patients survived significantly shorter than hilar cholangiocarcinoma patients. By multivariate analysis for intrahepatic cholangiocarcinoma, distant metastasis was independently associated with shorter survival time. Multivariate analysis for hilar cholangiocarcinoma showed initial CEA > 30 ng/dl were independent predictors of shorter survival. Conclusions: Patients with unresectable cholangiocarcinoma who do not undergo surgery, chemotherapy and/or radiotherapy have a dismal prognosis. We hope that the outcome of our study would help clinicians better predict the prognosis of cholangiocarcinoma patients not receiving such aggressive treatments. These data would be used as the comparable data for control groups of future studies to assess the outcome of newly designed or developed treatment method.

No significant financial relationships to disclose.
Prospective cardiotoxicity screening during tyrosine kinase inhibitor therapy for renal cell carcinoma: An institutional experience
Authors: Witteles R. M. , Harshman L. C. , Telli M. , Srinivas S.
Published: August 2020

e16003

Background: Tyrosine kinase inhibitors (TKI) can lead to cardiotoxicity either directly by causing left ventricular dysfunction, or indirectly by increasing blood pressure. In light of prior studies at our institution documenting a high rate of symptomatic heart failure in patients with renal cell carcinoma undergoing treatment with sunitinib, we instituted a prospective screening protocol to characterize the incidence and natural history of TKI-associated cardiotoxicity. Methods: From March-December 2008, patients receiving TKI therapy for renal cell carcinoma received cardiac biomarker screening (NT- BNP and Troponin I at baseline and after week 4 of each cycle) and transthoracic echocardiography (baseline, 1 month, 3 months, and every 3 months thereafter). If biomarkers were elevated or a decline in ejection fraction was observed, patients were referred for cardiology evaluation. Results: Twenty-six patients have been included since the protocol's initiation. No elevations in cardiac troponin I have been observed to date. Eight patients (31%) had elevations in NT-BNP (a sensitive marker for heart failure). The TKIs involved included sunitinib (5 patients), sorafenib (2 patients), and bevacizumab (1 patient). One patient who was treated with sunitinib had frank left ventricular systolic dysfunction. Seven of the eight patients with elevated NT-BNP values had baseline hypertension, and five patients had significant increases in blood pressure during TKI treatment. In all patients with follow-up biomarkers, NT-BNP levels fell after initiation of heart failure therapy. TKI treatment appeared to ‘unmask’ previously subclinical cardiac injury, including prior silent myocardial infarction (one patient), left ventricular hypertrophy (four patients), and valvular disease (three patients). Updated data from the ongoing screening protocol will be presented. Conclusions: The Stanford TKI screening protocol identified a high rate of subclinical cardiotoxicity and allowed for early initiation of heart failure therapy. Further studies are needed to determine if this approach can decrease cardiac morbidity and improve oncologic outcomes by preventing discontinuation or dose interruption of TKI therapy.

[Table: see text]
Changes in circulating endothelial cells (CECs) during treatment with cisplatin-based chemotherapy for testicular cancer
Authors: Altena R. , De Haas E. C. , Tibbe A. G. , Smit A. J. , van Roon A. , Meijer C. , Boezen M. H. , van der Meer J. , Sleijfer D. T. , Gietema J. A.
Published: August 2020

e16009

Background: Chemotherapy (CT)-induced endothelial damage is an important pathogenic factor for cardiovascular morbidity in testicular cancer (TC) patients (pts). Therefore, we studied early markers of endothelial damage as predictors of cancer treatment-related cardiovascular morbidity. Methods: We prospectively assessed markers of endothelial damage in TC pts treated at the University Medical Center Groningen, before, during, 4 weeks and one year after completion of standard CT (3 or 4 three weekly cycles with bleomycin, etoposide and cisplatin). The number of circulating endothelial cells (CECs), identified by CD146+, CD105+ and CD45− using the CellSearch system, and plasma levels of von Willebrand Factor (vWF) were measured. Results: 30 TC pts were included (median age 34 years, range 20–47). Before start of CT, CECs were not associated with disease stage or leukocyte count. The number of CECs progressively increased over the 9–12 week CT period [baseline: median (range) 25/mL (6–137); maximum number during CT: 134/mL (28–320; p<0.001); 4 weeks after completion of CT: 66/mL (18–316; p=0.005)]. One year post treatment, CECs were not different from baseline [N= 10; 13/mL (6–31; p=0.263)]. vWF levels also progressively increased during CT [baseline: median 105% (range 50–377); maximum level during CT: 289% (175–464; p<0.001); 4 weeks after completion of CT: vWF 124% (56–274; p=0.149)]. One year after CT, vWF levels were 115% (61–184; p=0.285). During CT, numbers of CECs and vWF levels correlated positively (r=0.283; p<0.001), whereas maximum CECs increase and maximum vWF increase were not associated (r=0.098; p=0.605). Two pts had a cerebral infarction during CT. In one pt, vWF increased before the event; in both pts CECs increased directly afterwards. Conclusions: During CT for disseminated TC, CECs and vWF progressively increased during consecutive cycles. CECs remained increased 4 wks after completion of CT, whereas vWF returned to baseline levels. The magnitude of changes was not equal in every pt. Therefore, both CECs and vWF might be early predictive markers for chemotherapy-induced cardiovascular toxicity, and may serve as intermediate endpoint in intervention studies.

[Table: see text]
Expression and activation of ADAM15 in bladder cancer
Authors: Bucheit A. , Day K. , Day M. L. , Chadwick W. A. , Liebert M. , Hussain M.
Published: August 2020

e16010

Background: ADAM15 is a member of the disintegrin family of metalloproteinases. These molecules function as membrane-bound proteases, and, when activated, cleave important membrane anchored growth factors such as heparin binding epidermal growth factor and cell adhesion molecules such as E-cadherin. This proteolysis may contribute to bladder cancer growth through release of growth factors and progression by altering cell adherence. We evaluated ADAM15 expression in bladder cancer cell lines and tissues. Methods: ADAM15 expression was assessed in human bladder cell lines, normal bladder and bladder cancer tissues. A datamining program (Oncomine) was used to evaluate previous array studies in bladder cancer. ADAM15 activation results in the release of a prodomain fragment. Expression and activation of ADAM15 in bladder cancer cell lines were monitored by enzyme-linked immunosorbent assay and western blotting using ADAM15 antibody (Millipore). Staining was performed on formalin-fixed, paraffin-embedded human tissues using ADAM15 antibody (Millipore) and the peroxidase- avidin-biotin complex (ABC) method. Results: Of 7 bladder cancer cell lines, 6 demonstrated expression of full length (100 kD) and “active” (90kD) ADAM15 molecules. Four of these cell lines showed release of the ADAM15 prodomain fragment, and 5 cell lines provided evidence for proteolytic activity, indicated by release of 80kD soluble E-cadherin molecule. Immunostaining of a bladder cancer tissue microarray revealed that normal urothelium expressed low levels of ADAM15, but focal overexpression of ADAM15 was observed in 17/29 bladder cancer specimens. Datamining of independent microarray analysis revealed that ADAM15 mRNA is upregulated in bladder cancer. Conclusions: ADAM15 is expressed in the majority of human bladder cancer specimens. Cell line studies indicate that ADAM15 can be activated, as indicated by release of the ADAM15 prodomain fragment. These results suggest that ADAM15 may be a therapeutic target to modulate bladder cancer growth and progression. Future studies will continue evaluation of the biology of ADAM15 in bladder cancer and evaluate if the soluble ADAM15 prodomain can be detected in plasma, serum or urine from patients with bladder cancer.

No significant financial relationships to disclose.
Dose intensity of cisplatin and gemcitabine (CG) for muscle invasive urothelial bladder cancer (MIUBC) in the neoadjuvant versus adjuvant settings: The Fox Chase Cancer Center (FCCC) experience
Authors: Hoffman-Censits J. H. , Wong Y. , Li T. , Boorjian S. , Giri V. N. , Uzzo R. , Greenberg R. E. , Hudes G. , Chen D. Y.
Published: August 2020

e16012

Background: Despite radical cystectomy (RC), subjects with MIUBC remain at risk of recurrence and optimal timing of chemotherapy remains unclear. Historically, we offered adjuvant (ADJ) CG to patients (pts) with T≥3 or node positive tumors. Since Dec 2005, neoadjuvant (NEO) CG treatment has been our preferred approach for pts with ≥T2 tumors. We compare our results with NEO and ADJ CG, including pathologic response after NEO CG. Methods: We reviewed records of patients who underwent RC for MIUBC and received at least 2 cycles of perioperative CG between Jan 2002 and Dec 2008at FCCC. We used Fisher's exact and Wilcoxon tests, as well as Generalized Estimating Equations (GEE), to compare baseline patient characteristics, dose intensity, completion, and complication rates in the ADJ and NEO groups. Results: Results of 22 ADJ and 17 NEO patients are shown below. Characteristics of age, gender, race, preop T stage and ECOG performance status (PS) ≤1 were similar. There was no significant difference in preoperative T stage between groups (p=0.2). The delivery of full doses (C 70mg/m2,G 1000 mg/m2) of GC were similar in the NEO vs the ADJ group. The delay between RC and chemotherapy may be shorter in the patients treated preoperatively, and trended toward significance (p=0.06). Reasons for dose modifications and delays are also shown in the Table . Of pts treated with NEO CG, 10/17 (55.7%) were ≤pT1 with 9 of those 10 pts also pN0 (52.9% of 17 pts) . 5/17 (29.4%) had positive lymph nodes at RC. Conclusions: CG for MIUBC is well tolerated in the NEO setting, with dose intensity comparable to that delivered adjuvantly. NEO pathologic downstaging with CG appears comparable to historical results with MVAC, and should be confirmed in larger, prospective studies. [Table: see text]

No significant financial relationships to disclose.