bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival outcomes of neoadjuvant hormone therapy plus external-beam radiotherapy with relatively early initiation of salvage hormone therapy to patients with T3-4N0M0 prostate cancer.
Authors: Mizowaki T. , Norihisa Y. , Ogura M. , Kamba T. , Inoue T. , Shimizu Y. , Ogawa O. , Hiraoka M.
Published: February 2017

95

Background: Survival benefits of adding long-term adjuvant hormonal therapy (A-HT) on external beam radiation therapy (EBRT) had reported in patients with locally advanced prostate cancer. However, adverse effects of long-term hormonal therapy are also not negligible. If early initiation of salvage hormonal therapy (S-HT) to patents developed PSA failure after EBRT can realize comparable survival as to giving A-HT across the board, patients who maintain biochemical failure-free status after EBRT will receive hormonal-free benefit. We analyzed outcomes of EBRT combine with neoadjuvant hormonal therapy (NA-HT) to patients with T3-4N0M0 prostate cancer.

Methods: Between April 1998 and Mar 2006, consecutive 173 Japanese patients with T3-4N0M0 adenocarcinoma of the prostate were definitively treated by 3D-CRT / IMRT. The median age was 72 years old (range 48-80). Pre-treatment PSA values ranged between 3.7 and 430 ng/ml (mean: 45.3). T-stage was distributed as follows: T3a: 122, T3b: 50 and T4: 1 case. NA-HT (3–17 months, median: 5 months) was given to all cases. Mean delivered dose was 74 Gy in 2 Gy per fraction to the prostate and seminal vesicles (range: 60-78). A-HT was not given to any patients and PSA values were monitored with one to 6 months interval after the treatment. S-HT was essentially started when PSA value exceeded 4 ng/ml.

Results: Median follow-up period was 74 months (range: 8–152). So far, S-HT was initiated to 58 patients, and PSA values at the initiation of S-HT ranged 0.1 to 32.2 with a median value of 6.0 ng/ml. Biochemical relapse-free survival by the Phoenix definition and salvage hormonal therapy-free survival rates at 8 years were 60% (95% CI = 51-68) and 63% (95% CI = 56-71), respectively. Prostate cancer-specific and overall survival rates were 94% (95% CI = 89-99) and 85% (95% CI = 78-92), respectively.

Conclusions: Survival rates of this cohort of patients treated by EBRT combined with NA-HT were excellent despite no A-HT was given, and more than two thirds of patients maintained hormone-free status at 8 years. This approach may be an alternative to giving long-term A-HT.

No significant financial relationships to disclose.
Is it possible to get adequate dose coverage of a clinical target volume (CTV) to account for the possible extra capsular extension in early-stage prostate cancer by low dose rate (LDR) brachytherapy?
Authors: Saibishkumar E. P. , Iupati D. , Borg J. , Fernandes K.
Published: February 2017

98

Background: There is no consensus for the definition and evaluation of CTV in post-implant setting for LDR prostate brachytherapy to account for extra capsular extension in clinically localized prostate cancer. In this study, we defined a CTV and evaluated its dosimetry in the post implant CT/MR scans done at 1 month after the LDR brachytherapy procedure.

Methods: The initial consecutive 71 patients who underwent LDR brachytherapy under a single physician at Princess Margaret Hospital from June 2009 to July 2010 were included in this retrospective study. On the post implant MRI, the CTV was created by adding 3mm uniform margins around the prostate but respecting the anatomical boundaries like bone, bladder and rectum. Post implant dosimetry was based on CT/MR fusion using the dosimetric parameters V80, V90, V100, V150, V200, D80, D90 and D100. Implants were qualified as optimal if their V100 was >85% and D90 was >90% for both prostate and CTV. Univariate analysis was performed to evaluate associations of factors with V100 and D90 for the CTV using Wilcoxon rank sum test and Fisher's exact test.

Results: The mean (SD) prostate V100 and D90 were 95.5% (4.2) and 117% (10) respectively with only 1 patient having sub optimal implant (V100 <85% and D90 <90%). The mean (SD) V100 and D90 for the CTV were also acceptable at 90.6% (4.9) and 103% (9), respectively. Six patients had V100 <85% and 7 patients had D90 <90% for the CTV. On univariate analysis, edema and seed implantation technique correlated with sub-optimal implant for the CTV. The mean (SD) edema for patients with V100 <85% was 18% (10) and with D90 <90% was 15% (12). The corresponding values for the optimal implants both in terms of V100 and D90 were 3% (13). Patients implanted with exclusively loose seeds (15 patients only) had higher incidence of sub-optimal implants (26%) compared to patients who had strands on the antero-lateral margins (56 patients; 3.5%).

Conclusions: In this study, adequate dose coverage of CTV was achieved in most patients with current technique but implants with optimal dosimetry to prostate still may have sub-optimal D90 and V100 for the CTV.

No significant financial relationships to disclose.
Initial experience of focal therapy for prostate cancer using I-125 seed implantation: Unilateral ablation for patients selected by extended biopsy and MRI findings.
Authors: Saito K. , Kihara K. , Numao N. , Masuda H. , Kijima T. , Tatokoro M. , Koga F. , Fujii Y. , Hayashi K. , Shibuya H.
Published: February 2017

99

Background: Focal therapy for prostate cancer could be a minimally invasive therapeutic option with the preservation of genitourinary function to reduce treatment associated complication under the appropriate selection of patients. We have reported the good predict ability to unilateral prostate cancer by extended prostate biopsy combined with transperineal and transrectal approaches (Eur Urol supple, 2009). Among the candidate ablative, brachytherapy which has been proved as a definitive therapy and applied worldwide has been thought to have potential for focal ablation due to its ability of dose and location adjustment by seed implantation under real-time monitoring. Based on the findings, focal therapy with hemiablation using I-125 seed implantation has been started in our instituion. The aim of study is to describe the initial experience of focal therapy for patients selected by extended biopsy and MRI findings.

Methods: The eligible criteria for focal therapy to prostate cancer are as follows. Clinical stage is T2a or less. The positive cores of cancer are proven within unilateral lobe by extended prostate biopsy. There was no cancerous lesion in contralateral lobe by MRI. Gleason score in positive cores was 3 + 4 or less. Maximum cancer length was less than 5 mm. PSA value is less than 10 ng/mL. On the treatment, I-125 seeds were implanted to ablate the unilateral lobe with 160 Gy of the prescription dose. The protocol has been approved by the institutional ethics commit.

Results: At present, 3 patients were enrolled in this study and underwent focal therapy with written informed consents. In all three cases, I-125 seeds implanted (number od seeds: 43, 39, and 37) to unilateral lobe without severe acute complication such as acute urinary retention. In one case that has been followed over 3months among the initial three cases, PSA values decreased to 2.07 mg/ml at 3 months after the seed implantation.

Conclusions: To our knowledge, this is the first report about focal therapy by brachytherapy with hemiablative technique. In our initail experience, severe treatment associated complication has not been observed.

No significant financial relationships to disclose.
Randomized phase II multicenter study of the efficacy and safety of sunitinib on the 4/2 versus continuous dosing schedule as first-line therapy of metastatic renal cell carcinoma: Renal EFFECT Trial.
Authors: Motzer R. J. , Hutson T. E. , Olsen M. R. , Hudes G. R. , Burke J. M. , Edenfield W. J. , Wilding G. , Martell B. , Hariharan S. , Figlin R. A.
Published: February 2017

LBA308

Background: In a randomized phase III trial, sunitinib 50 mg/d on Schedule 4/2 (4 wk on treatment [Tx], 2 wk off) showed superior progression-free survival (primary endpoint) to IFN-α (11 vs. 5 mo; p<0.001) as first-line metastatic renal cell carcinoma (mRCC) therapy with a median overall survival (OS) of >2 yr (Motzer 2009). Continuous dosing of sunitinib 37.5 mg has demonstrated antitumor activity with a manageable safety profile in first- and second-line mRCC (Barrios; Escudier, 2009).

Methods: This randomized phase II trial compared sunitinib 50 mg/d on Schedule 4/2 (Arm A) vs. 37.5 mg continuous once-daily dosing (Arm B) in first-line mRCC. Eligible patients (pts) had clear cell locally recurrent or mRCC; measurable disease; and Karnofsky performance status ≥70%. Randomization (1:1) was stratified by MSKCC risk groups. Sunitinib was continued until progression, unacceptable toxicity, or up to 2 yr. The primary endpoint was time to tumor progression (TTP) by Kaplan-Meier estimate. Secondary endpoints included objective response rate (ORR), OS, and adverse events (AEs).

Results: Between January 2007 and June 2008, 292 pts were randomized. As of October 2010, 289 pts had received sunitinib, and all pts were off therapy. Median age was 62 yr. 65% were male. By MSKCC criteria, 28%, 61%, and 11% were favorable, intermediate, and poor risk, respectively. Pts received a median 4 and 5 Tx cycles in Arms A and B, respectively; median relative dose intensity was 90.8% and 77.5%. Dose delays, reductions, and interruptions occurred in 30% vs. 13%, 36% vs. 43%, and 65% vs. 62%, respectively; 11% and 15% discontinued due to Tx-related AEs. Median TTP was 9.9 vs. 7.1 mo in Arms A and B, respectively (HR=0.773, 95.1% CI, 0.572, 1.044; p=0.090). ORR was 32.2% vs. 28.1% (p=0.444). Median OS was 23.1 vs. 23.5 mo (p=0.615). The most common Tx-related AEs were fatigue (both 62%), nausea (56% vs. 49%), and diarrhea (56% vs. 64%).

Conclusions: In this randomized phase II mRCC trial, there was a trend toward inferior TTP with continuous dosing. ORR, OS, and AE profiles were similar for the approved sunitinib 50 mg/d dose on Schedule 4/2 vs. 37.5 mg continuous dosing.

[Table: see text]
Optimal indications for second-line chemotherapy in advanced gastric cancer.
Authors: Hasegawa Hiroko , Fujitani Kazumasa , Nakazuru Shoichi , Hirao Motohiro , Mita Eiji , Tsujinaka Toshimasa
Published: February 2017

105

Background: It remains uncertain whether every patient with advanced gastric cancer (AGC) who progresses after first-line chemotherapy should receive second-line chemotherapy. We conducted the present study to identify the optimal indications for second-line chemotherapy.

Methods: In this retrospective study, 101 patients were included in univariate and multivariate analyses to identify clinicopathological variables independently associated with longer survival post progression (SPP), defined as the time from recognition of disease progression on first-line chemotherapy to death from any cause or last follow-up.

Results: Median SPP of all patients was 340 days. On multivariate analysis, both performance status (PS) 2 (hazard ratio (HR), 14.234; 95% confidence interval (CI), 2.766–73.258), serum albumin (Alb) level < 3.5 g/dl (HR, 2.088; 95% CI, 1.047–4.060) at initiation of second-line chemotherapy, and time to progression (TTP) < 170 days on first-line chemotherapy (HR, 2.497; 95% CI, 1.227–5.083) were identified as independent prognostic factors for shorter SPP. Median SPP was 496, 375, and 232 days in patients with 0, 1, and 2 of these 3 negative prognostic factors, respectively (p = 0.0002).

Conclusions: The present study suggests that second-line chemotherapy would be less beneficial in patients with 2 or more of the following 3 negative prognostic factors: PS 2, Alb < 3.5 g/dl at initiation of second-line chemotherapy, and TTP < 170 days on first-line chemotherapy.
Effect of technologic advancements in radiotherapy on postoperative pulmonary complications after neoadjuvant chemoradiation in esophageal cancer.
Authors: Myles Bevan H. , Wei Caimiao , Komaki Ritsuko , Vaporciyan Ara A. , Mehran Reza J. , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A. , Liao Zhongxing X. , Cox James D. , Lin Steven H
Published: February 2017

110

Background: Although 3D conformal radiation therapy (3D-CRT) is currently the de facto standard for the treatment of esophageal cancers, technologies such as Intensity Modulated Radiation Therapy (IMRT) or Proton Beam Therapy (PBT) are increasingly being used, but the evidence for the clinical benefits of these technologies are lacking. We hypothesized that radiation technology influences perioperative complications in esophageal cancer patients treated with neoadjuvant chemoradiation.

Methods: We evaluated 423 patients (3D-CRT (n=208, 1998-2008), IMRT (n=165, 2004-2011), and PBT (n=50, 2006-2011)) treated with surgical resection after chemoradiation from 1998-2011 at M. D. Anderson Cancer Center. Postoperative complications (Pulmonary, GI, cardiac, wound healing) were recorded up to 30 days postoperatively. Kruskal-Wallis tests and Chi-square or Fisher’s exact tests assessed associations between continuous and categorical variables and the radiation technology, respectively. Logistic regression model tested the association between treatment technologies and complications adjusting for other significant patient characteristics.

Results: While radiation modality was not significantly associated with postoperative GI (leak, ileus, fistula), cardiac (MI, AF, CHF), and wound complications, there was a significant reduction in postoperative pulmonary complications (ARDS, pleural effusion, respiratory insufficiency, pneumonia) for IMRT compared to 3D-CRT (OR 0.46, 95%CI 0.25, 0.83) and PBT compared to 3D-CRT (OR 0.26, 95%CI 0.09, 0.70), but not when IMRT was compared to PBT (OR 1.74, 95%CI 0.66, 4.61) after adjusting for preRT DLCO level. The median length of hospital stay was also significantly different between treatment modalities (12, 10, and 8 days for 3D-CRT, IMRT, and PBT, respectively, p<0.0001). There was no significant association between treatment year with pulmonary complication rates.

Conclusions: Radiation technologies such as IMRT and PBT reduced postoperative pulmonary complication rates compared to 3D-CRT in esophageal cancer patients. This result needs to be confirmed in larger prospective studies.
Effect of online education on use of molecular markers to guide treatment selection for advanced gastric or gastroesophageal (GE) cancer.
Authors: Obholz Kevin , Van Cutsem Eric , Press Michael F. , Bowser Andrew , Mortimer Jim A. , Wasserstrom June , Grothey Axel
Published: February 2017

111

Background: Trastuzumab in combination with chemotherapy is recommended for advanced gastric cancer positive for human epidermal growth factor receptor 2 (HER2) overexpression. Despite this recommendation, an informal pilot survey suggested that many oncologists do not include HER2 testing as part of routine practice to identify patients most likely to benefit from adding trastuzumab to chemotherapy.

Methods: An interactive online educational activity was developed to provide expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer. Pre- and post-education surveys were administered as part of the activity to measure changes in participant competence. In addition, 3 months after completing the educational activity, participants were sent another follow-up survey by email to assess changes in practice.

Results: To date, pre-and post-education surveys have been obtained for 122 oncologists and 3-month follow-up surveys obtained from 14 oncologists. In the pre-education survey, only 46% said they were testing all of their patients with advanced gastric or GE cancer for HER2 overexpression. However, immediately after participating in the educational intervention, this proportion increased to 93%. Importantly, a follow-up survey indicated that HER2 testing of all patients with advanced gastric or GE cancer was now part of routine practice for 79% of those surveyed. A final analysis of pre- and post-education and 3-month follow-up surveys will be presented.

Conclusions: Expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer provided through an interactive online educational intervention substantially improved oncologist competence and practice patterns.
Cardiac toxicity associated with dose and gender in patients undergoing chemoradiation for esophageal carcinoma.
Authors: Tait Lauren Marie , Meyer Joshua E. , McSpadden Erin , Cheng Jonathan D. , Philip Philip Agop , Scott Walter J. , Baciewicz Frank , Meropol Neal J. , Shields Anthony Frank , Crawford Kevin , Cohen Steven J. , Wozniak Antoinette J. , Gadgeel Shirish M. , Choi Minsig , Konski Andre A.
Published: February 2017

112

Background: The purpose of this study was to identify factors associated with symptomatic cardiac toxicity in patients treated with chemoradiotherapy (CRT) for esophageal carcinoma.

Methods: One-hundred and forty-four patients with adenocarcinoma or squamous cell carcinoma were treated from 7/2002 - 6/2011 at 2 academic institutions with pre-operative, definitive or palliative CRT. Chemotherapy and radiation therapy was administered at the discretion of the treating oncologist. Altogether, 120 patients had sufficient dose volume histogram (DVH) data for analysis and ≥3 month follow up from treatment completion. Association of cardiac toxicity with a number of variables was investigated, including heart disease, cardiac bypass/angioplasty, diabetes, insulin use, smoking, and tumor location (upper/middle vs. lower/GE junction). T-test assessed risk of cardiac toxicity secondary to age. Percentage of heart volume receiving >20, 30, 40, and 50 Gy (V20-V50) and its association with cardiac toxicity was evaluated for each patient. Fisher’s exact test was used to test for an association between dose volume parameters and cardiac toxicity.

Results: Patient population included 93 males and 27 females with a mean age of 63 years. Any cardiac toxicity occurred in 27 patients, 8 of which were symptomatic. T-test comparing age to toxicity was not significant; however, female patients were 3.57 times more likely to have cardiac toxicity ([95% Confidence Interval 1.42-9.01], p=0.005). A significant difference in V40 existed between patients with cardiac toxicity and those without (p=0.05). Patients above the median cut-off for V40 (54%) had 2.48 increased odds of developing cardiac toxicity ([95% Confidence Interval 1.02-6.02], p=0.04). None of the other investigated variables were associated with an increased risk of developing cardiac toxicity.

Conclusions: Female patients were found to have an increased risk of cardiac toxicity subsequent to receiving CRT for esophageal carcinoma. V40 greater than 54% was associated with increased cardiac toxicity. These data suggest exercising increased care when designing radiation fields in women undergoing CRT for esophageal carcinoma.
Clinical availability of endoscopic submucosal dissection for patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma.
Authors: Inadomi Kyoko , Watanabe Masayuki , Nagai Yohei , Nonaka Koichi , Sakurai Koichi , Ida Satoshi , Iwagami Shiro , Iwatsuki Masaaki , Baba Yoshifumi , Miyamoto Yuji , Baba Hideo
Published: February 2017

118

Background: Local failure after chemoradiotherapy (CRT) remains a major problem for patients with esophageal squamous cell carcinoma (ESCC), and there are few curative treatment options available in such cases except salvage esophagectomy. The aim of this study is to demonstrate the clinical efficacy and safety of endoscopic submucosal dissection as a salvage therapy (salvage ESD) for local failure after CRT.

Methods: Between 2007 and 2011, 66 patients underwent ESD for superficial ESCC in our hospital. Five of these patients underwent salvage ESD for local failure after CRT, and were reviewed retrospectively. They were treated with CRT, consisting of 60 Gy irradiation and concurrent chemotherapy. The indications for salvage ESD were as follows: 1) absence of lymph-node or distant metastasis after CRT; 2) superficial and endoscopically resectable lesion after CRT; 3) refusal by patient to undergo salvage esophagectomy; 4) written informed consent. Salvage ESD was performed using a flush knife or hook knife with a hyaluronic acid injection into the submucosal layer.

Results: The baseline stage before CRT was as follows: T1b/T2/T3 in 3/1/1, N0/1 in 4/1, and M0/1 in 4/1 patients, respectively. These 5 patients had histologically proven local failure, and the stage after CRT was as follows: T1a/T1b in 1/4, N0/1 in 5/0, and M0/1 in 5/0 patients, respectively. Salvage ESD was performed in all patients who had en bloc resection with no complications and pathologically R0 resection. In 5 patients, 2 had a pT1a lesion, and 3 had a pT1b lesion. 1 lesion recurred in other site 3 months after salvage ESD, which was resected successfully by a second ESD procedure.

Conclusions: Salvage ESD is an available option for patients with local failure after CRT for ESCC.
Efficacy of weekly paclitaxel in patients with advanced gastric cancer with prior docetaxel-containing chemotherapy.
Authors: Ando Takayuki , Hosokawa Ayumu , Ogawa Kohei , Kajiura Shinya , Itaya Yuko , Ueda Akira , Tsukioka Yuji , Kobayashi Takashi , Horikawa Naoki , Sugiyama Toshiro
Published: February 2017

127

Background: Efficacy of paclitaxel for docetaxel-refractory gastric cancer is not known, although partial cross-resistance between docetaxel and paclitaxel has been demonstrated in breast and ovary cancers. Therefore, we retrospectively evaluated the efficacy of paclitaxel in gastric cancer patients who had been refractory to docetaxel-containing chemotherapy.

Methods: The patients who had received docetaxel-containing regimen were categorized as prior-docetaxel group, and the patients who had never received docetaxel were categorized as non-docetaxel group. Paclitaxel at 80 mg/m2 was administered by intravenous infusion in all patients, and this was repeated weekly for 3 weeks out of 4. The response rate (RR), median progression-free survival (PFS) and overall survival (OS) were evaluated in two groups.

Results: 65 patients were included between April 2006 and June 2011. Among them, 26 patients were prior-docetaxel group, and 39 patients were non-docetaxel group. The median age, gender, performance status, histology, history of gastrectomy, metastatic site, and the number of metastatic sites were not statistically different between two groups. In prior-docetaxel group, the RR was 14.2% (3/21) among the patients with measurable lesions, the median PFS was 79 days (95%CI, 47-135 days), and the OS was 123 days (95% CI, 90-215 days) from the initiation of paclitaxel administration. In non-docetaxel group, the RR was 11.5% (3/26) among the patients with measurable lesions, the PFS was 82 days (95% CI, 52-106 days), and the OS was 143 days (95% CI, 121-178 days). There were no significant differences in the RR (P = 0.78), PFS (P = 0.98), and OS (P = 0.51) between two groups.

Conclusions: Weekly paclitaxel was modestly active in gastric cancer patients who had been refractory to docetaxel containing chemotherapy. This represents that there was incomplete cross-resistance between docetaxel and paclitaxel in gastric cancer chemotherapy, as previously reported in other cancers.
The efficacy of gastrectomy plus chemotherapy for stage IV gastric cancer.
Authors: Muto Osamu , Kotanagi Hitoshi
Published: February 2017

132

Background: Metastatic gastric adenocarcinoma is an incurable condition. Despite the recently reported benefits of chemotherapies, the prognosis of advanced gastric cancer remains poor. The role of surgical resection is still debatable. Therefore, we investigated the efficacy of gastrectomy plus chemotherapy for stage IV gastric cancer.

Methods: We retrospectively evaluated the efficacy of gastrectomy plus chemotherapy for treating stage IV gastric cancer. Among the 753 patients with gastric cancer treated with gastrectomy at our institute between 2003 and 2010, a total of 70 patients classified into stage IV and underwent gastrectomy with perioperative chemotherapy were included in this study. In the analysis, particular attention was paid to the prognostic factors of age, gender, tissue type, metastatic site, pre or postoperative chemotherapy, single agent or combination chemotherapy and the reason for gastrectomy (palliative surgery due to stenosis, bleeding or perforation and reduction surgery). The survival rate was calculated by the Kaplan Meier method and a statistical analysis was performed using the log-rank test. Survival was calculated from the beginning of the treatment until the last follow-up or death from any cause.

Results: The median age was 65 years old. Peritoneal, lymph node and liver metastasis were 28, 23, and 13 patients respectively. Fifty-three patients had diffuse type. Gastrectomy followed by chemotherapy and chemotherapy were 53 patients. Single agent chemotherapy were 42 and combination were 28 patients. Thirty-one patients were underwent palliative surgery and 39 patients were reduction surgery. One-year survival rate of all patients was 43% and the median survival time was 19.9 months. In the statistical analysis, only reduction surgery plus chemotherapy demonstrated significant survival benefit. The median survival time was significantly greater in patients undergoing reduction gastrectomy group than in those undergoing palliative gastrectomy (25.3 versus 9.8 months; p=0.005).

Conclusions: Long-term survival for patients with stage IV gastric cancer who are managed with reduction surgery and chemotherapy is achievable. Further study with a larger number of patients is warranted.
5-FU induced encephalopathy during 5-FU containing regimen for esophageal squamous cell carcinoma.
Authors: Kato Ken , Akiyoshi Kohei , Hokamura Nobukazu , Igaki Hiroyasu , Tachimori Yuji , Honma Yoshitaka , Iwasa Satoru , Hamaguchi Tetsuya , Yamada Yasuhide , Shimada Yasuhiro
Published: February 2017

138

Background: 5-FU induced encephalopathy was known as uncommon toxicity during the treatment which contain with 5-FU. But there were few reports such as clinical feature and risk factors of 5-FU induced encephalopathy. We conducted retrospective case-control study to investigate the clinical feature and risk factor of them.

Methods: Data was collected by medical record. The selection criteria were as follows: Pathologically proven esophageal squamous cell carcinoma, patents who received 5-FU containing regimen in our hospital. The diagnostic criteria of the 5-FU induced encephalopathy includes: (i) development of encephalopathy during or shortly after completion of 5-FU administration; (ii) exclusion of other metabolic factors that may affect consciousness and (iii) exclusion of an adverse effect by concomitant medications. 5-FU containing regimens include that 5-FU+CDDP with or without radiation, 5-FU=Nedaplatin with or without radiation and 5-FU=CDDP=docetaxel.

Results: From January 2008 to March 2010, 317 patients were collected. Of 317 patients, the median age was 64 (range 36-79); male/female: 267/49; cStage I/IIA/IIB/III/IV: 63/19/53/91/85. Median and total course of 5-FU containing regimen and were 2 (range1-14) and 943. The object of first treatment was as follows; Neoadjuvant (n=114), definitive chemoradiotherapy (n=110), palliative chemotherapy (n=81) and others (N=24). Nine patients (2.8%) were diagnosed as 5-FU encephalopathy. The median course and time to onset of encephalopathy was 3 course (range1-4) and 5 days (range 3-6) from start of 5-FU. Five of 6 pts who examined NH3 were observed the elevation of NH3. All patients recovered within 1-2 days after stopping administration of 5-FU. Head CT or MRI showed no abnormality in all pts. Univariate analysis showed that only age (>60) was risk factor for encephalopathy. The other thing such as regimen and sex were not associated with encephalopathy.

Conclusions: This is the first report which described 5-FU induced encephalopathy in such large population. 5-FU encephalopathy was very rare but recovered with adequate treatment. In aged patients we should pay more attention about 5-FU encephalopathy than younger patients.
Retrospective cohort study on the risk factors of admission due to serious adverse events during S-1 (tegaful, gimeracil, oteracil potassium) containing chemotherapy for gastric cancer.
Authors: Kawamoto Yasuyuki , Yuki Satoshi , Kobayashi Yoshimitsu , Oba Koji , Hayashi Hideyuki , Nakatsumi Hiroshi , Komatsu Yoshito
Published: February 2017

141

Background: S-1 (tegaful, gimeracil, oteracil potassium) containing regimens are widely used as first line chemotherapy for metastatic or unresectable gastric cancer in Japan. Because patients often need admission due to serious adverse events (SAE) during chemotherapy, it is important to predict admission. We retrospectively investigated the risk factors of admission due to SAE during first line chemotherapy which contained S-1.

Methods: We retrospectively analyzed the patients who began to receive S-1 containing chemotherapy for the first line chemotherapy at our institution from January 2005 to December 2010 by medical records. Association between baseline characteristics and admission due to SAE were evaluated by Fisher’s exact test, t-test or Mann-Whitney test. Age, sex, S-1 dose (mg/m2) and other factors which significantly associated in the univariate analysis were evaluated in the multivariate logistic regression model.

Results: One hundred nine patients were assessed. Admission due to SAE were observed in 24 patients (34 times), and tended to occur before 2nd cycle had ended. Multivariate analysis suggested that hypoalbuminemia was a risk factor of admission due to all SAE (Odds ratio 0.15, 95% C.I. 0.05 - 0.44, P = 0.0005). It is suggested that S-1 dose was a risk for admission due to FU-induced colitis (Odds ratio 1.30, 95% C.I. 1.12 - 1.50, P=0.0004).

Conclusions: Hypoalbuminemia might constitute a marker of admission due to SAE. FU-induced colitis occurred in S-1 dose-related fashion, and the patients had lost their weight before appropriate course. It is suggested that clinicians should pay attention to patients’ weight loss during chemotherapy, notably time of initiation of chemotherapy.
Outcomes of adjuvant chemoradiotherapy after a radical gastrectomy and D2 node dissection for gastric adenocarcinoma in INEN (Lima, Peru).
Authors: Montenegro Paola Catherine , Lopez Lourdes , Quintana Shirley , Casanova Luis Augusto , Castro Victor , Mantilla Raul
Published: February 2017

150

Background: Adjuvant chemoradiotherapy is the standard treatment in Western countries in gastric cancer patients submitted to curative resection. INT 0116 pivotal trial established adyuvant chemoradiation as the standar care for resected high risk adenocarcionoma of the stomach in US however was hampered by suboptimal surgery. There is controversial data about efficacy of this adjuvant therapy in patients who have undergone D2 lymphadenectomy predominantly. In our hospital D2 lymphadenectomy is standar surgery for gastric cancer.

Methods: Retrospective study with gastric adenocarcinoma patients stage II to IV M0 who underwent curative resection at Instituto Nacional de enfermedades Neoplasicas Lima- Peru between 2001 and 2006 Standard treatment at institution is D2 lymphadenectomy. Chemoradiotherapy according to INT 0116 was given like adjuvant therapy. Survival curves were calculated according to Kaplan-Meier method and compared with log-rank test. Multivariate analysis of prognostic factors related to survival was performed by Cox proportional hazards model adjusted for age, stage and adjuvant chemoradiotherapy.

Results: 84 patients were included 60.3% male and 39.3% female. Median age was 40.5 years old. The patologic stage were T1-T2 (12.3%), T3-T4 ( 50% ), N0-N1 (10.7%), N2-N3 (89.3%). D2 lymphadenectomy was performed in all patients. The 3-year DFS was 17% and 3-year overall survivall was 23.9% years.However when we analized by subgroups the overal survival was significantly longer in group N1 ( 61%) and N2 (58.9%) that N3 (18.3%) and DFS were N1 (60%), N2 (55%) and N3 (16.3%).

Conclusions: Adjuvant chemoradiotherapy decreased risk of death and relapse in patients with node positive N1-N2 , who underwent curative resection with D2 lymphadenectomy, but recurrence was most frecuent in N3 node positive, maybe is necesary improve the chemotherapy in this group of patientes for dicrease the rate of relapse.
Biomarkers in pancreatic neuroendocrine tumors.
Authors: Alistar Angela Tatiana , Warner Richard , Moshier Erin , Kim Michelle , Holcombe Randall F.
Published: February 2017

166

Background: This study was designed to determine the role of Chromogranin A (CGA) and serotonin as prognostic biomarkers in relation with cytoreductive surgery for pancreatic neuroendocrine tumors (PNETs).The role of CGA and serotonin as biomarkers for PNETs is not fully established. Clinicians use CGA to monitor progression of disease and response to treatment; however this hasn’t been fully validated. There is no definitive data for serotonin as prognostic biomarker in PNETs.

Methods: A retrospective study of patients with PNETs seen at Mount Sinai from 1980 to 2011 was performed. All patients (142) that have had CGA and serotonin concentrations measured at least once were evaluated. Data relating to diagnosis, therapies and survival outcome were noted

Results: We evaluated the probability of survival post cytoreductive surgery among patients characterized by their postoperative CGA and serotonin values. 27 patients have had CGA level measured early post-op (0 to 3 months) and 30 patients have had CGA measurement late post-op (3-12 months). We identified no correlation between survival and a normal CGA early post-op (p = 0.5895). We identified a trend (p=0.1369) towards increase in survival for patients with a normal CGA late post-op with a probability in survival of 92.86% vs 65.12% at 3 years and median months to death of 80.265 for normal CGA vs 50.39 months for high CGA late post-op. For the 22 patients that had both a CGA early and late post-op the probability of survival by their change from early to late post- surgery CgA values was not statistically significant (p=0.2903). Serotonin did not correlate with survival in any of the 3 analyses: early post op, late postop or change in serotonin level.

Conclusions: The role of CGA as a predictive or prospective biomarker for PNETs is worth prospective investigation. Our study shows that late post-op CGA may predict clinical outocome while CGA early postop and serotonin early, late and change post op did not have value in predicting survival.
The impact of HER2 positivity on survival in metastatic gastric and GEJ cancer.
Authors: Kumar Aalok , Zhou Chen , Huntsman David , Kollmannsberger Christian K. , Gill Sharlene , Lim Howard John
Published: February 2017

17

Background: HER2 positive (+) gastric (GC) and GEJ adenocarcinoma (AC) has been associated with a worse survival outcome. This study examines the survival rate of patients (pts) with metastatic HER2 (+) GC and GEJ AC in the province of BC.

Methods: Formalin fixed embedded tissue from pts with resected GC or GEJ AC from 2004−2011 were identified retrospectively through the BC Cancer Agency registry and prospectively for pts with a new diagnosis of advanced disease. Biopsies and resection samples were analyzed via previously validated methods. IHC scores of 3 were considered (+), 2 were equivocal and 0/1 were negative (−). 10% cut-off was used to determine (+) samples. Equivocal staining was considered (+) via FISH or SISH with a ratio of > 2.2 considered amplified. Pt characteristics were abstracted to an anonymized database. Kaplan meier curves were calculated to evaluate overall survival from time of diagnosis or relapse to death for pts with Her 2 (+) or (-) disease.

Results: 164 of 294 pts were identified with metastatic or relapsed GC (49%) or GEJ (51%) AC without traztumumab treatment. 21 (13%) of pts were HER2 (+) either by IHC, FISH or SISH. See Table for pt characteristics. The HER2 (+) group was older (median age 68 yrs vs 60), more GEJ (62% vs 49% p=1.23), and a higher number of pts that did not receive treatment (52% vs. 27% p=5.09). Median survival was not significantly different among HER2 (+) and (−) disease (4.0 mo vs. 7.3 mo, p=0.089).

Conclusions: The rate of HER2 positivity is similar to that seen in trial data. HER2 positivity trends to a worse prognosis but was not significant in this study.

[Table: see text]
Candidate biomarkers identified in the saliva of patients with pancreatic adenocarcinoma.
Authors: Fleming Jason B. , Trajtenberg Cynthia
Published: February 2017

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Background: There is currently no simple test to identify patients with pancreatic ductal adenocarcinoma (PDAC). The goal of this research is to develop such a method. We hypothesized that the salivary proteome of patients with localized PDAC contains a protein set distinct from normal subjects.

Methods: We collected, processed and stored stimulated whole salivary gland secretions from patients with Stage I-II PDAC and aged-matched healthy volunteers. Fluorescently-labeled proteins were separated using 2D DIGE. Overlay imaging techniques compared 2D DIGE results, and spots representing individual proteins were quantified by signal, isolated from the gels, processed and protein identified using MALDI-TOF Mass Spectrometry. The SWISS-PROT database was used to identify proteins, and the ratio of signal in cancer versus normal samples was quantified and compared using Student’s t-test.

Results: Samples from 10 PDAC patients and 10 healthy subjects were compared. A total of 96 spots on the 2D-DIGE comparison were uniquely present or absent in PDAC patient saliva. MALDI-TOF Mass Spectrometry examination of these 96 characterized 53 unique proteins. After eliminating duplicates and proteins without significant differences (p-value <0.02), a total of 30 proteins were identified with levels higher (n=18) or lower (n=12) in saliva from PDAC patients versus normal subjects.

Conclusions: Examination of saliva from pancreatic cancer patients identified a set of proteins unique from normal subjects. These proteins represent targets for the development of biomarkers that could be used in early detection of pancreatic cancer.
Revisiting the prognostic significance of positive peritoneal cytology in pancreatic cancer.
Authors: Chen Kathryn T. , Singla Smit , Papavasiliou Pavlos , Devarajan Karthik , Hoffman John Parker
Published: February 2017

177

Background: Positive peritoneal cytology (PPC) in the setting of pancreatic cancer predicts a poor prognosis, such that it is considered metastatic disease in the American Joint Commission on Cancer staging guidelines. We re-evaluate the role of PPC, with particular attention to outcomes following neoadjuvant therapy.

Methods: We retrospectively identified 185 patients from January 1, 2000 to present with the diagnosis of pancreatic adenocarcinoma who had undergone peritoneal washings with cytology at the time of planned resection. Data regarding demographics, tumor stage, intraoperative cytology, surgical and chemoradiation therapeutics, and clinicopathological outcomes were analyzed, with the primary endpoints being disease-free and overall survival (DFS and OS).

Results: 20 patients (11%) had PPC at the time of planned resection; of these, 11 patients (55%) received neoadjuvant therapy prior to surgery. 165 patients (89%) had negative peritoneal cytology (NPC) at the time of planned resection; of these, 75 (45%) received neoadjuvant therapy prior to surgery. All patients proceeded with resection in the absence of visible metastatic disease. 42% of NPC reached 2-year survival compared to just 20% of patients with PPC. Overall, patients with PPC vs. NPC had significantly poorer DFS (p<0.0064) and OS (p<0.0135). When stratifying by neoadjuvant therapy, in those patients with stage II disease or higher who did not receive neoadjuvant therapy, multivariable CART analysis revealed that PPC predicted poorer DFS compared with NPC (p<0.004). However, among stage II or higher disease receiving neoadjuvant therapy, it failed to show a significant difference in DFS or OS between PPC and NPC.

Conclusions: Overall, patients with positive peritoneal cytology are shown to have worse DFS and OS compared to patients with negative peritoneal cytology in pancreatic adenocarcinoma. However, after multivariable analysis, the prognostic significance of positive peritoneal cytology disappears in those patients with stage II and higher disease receiving neoadjuvant therapy.
The incidence and preoperative detection of nodal metastases in resected pancreatic neuroendocrine tumors.
Authors: Lindberg James M. , Walters Dustin M , Stelow Edward B , Adams Reid B , Bauer Todd W.
Published: February 2017

178

Background: Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of rare malignancies in which surgical resection remains the only curative therapy. The optimal surgical approach (enucleation vs. pancreatectomy) is controversial. This study aims to determine the 1) incidence, 2) predictors, and 3) preoperative detection of lymph node (LN) metastases in resected pNETs to help guide surgical management.

Methods: A retrospective review of prospectively collected data was performed for all patients with pancreatic neuroendocrine tumors who underwent surgical resection at the University of Virginia between 1991 and 2010. The electronic medical record, radiology reports and pathology reports were used to identify patient demographics, surgical procedure, tumor functional status, type, size, location, and LN status.

Results: In all, 76 patients were identified. Most tumors were non-functioning (71%) with insulinomas (13%) and gastrinomas (5%) representing the largest groups of functioning pNETs. Nineteen tumors (25%) had LN metastases at the time of resection. LN-positive tumors were significantly larger than LN-negative tumors (4.0 ± 0.4 cm vs. 2.8 ± 0.2 cm, p=0.01). Five (11%) of 46 tumors ≤ 3 cm and one (14%) of 7 tumors ≤ 1 cm had LN metastases. There were no significant relationships between LN status and either tumor type or location (head/uncinate vs. body/tail). Of patients with LN-positive tumors, preoperative CT or MRI detected the LN metastases in only 19%.

Conclusions: Twenty-five percent of pNETs are associated with LN metastasis. The only predictor of LN metastasis was tumor size, but even smaller tumors were associated with LN metastasis. The sensitivity of preoperative CT and MRI is quite poor in detecting LN metastasis. Thus, formal resection with lymphadenectomy should be considered the standard of care for pNETs.

[Table: see text]
The metabolomic signature of pancreatic cancer in urine.
Authors: Davis Vanessa Wylie , Schiller Dan E. , Sawyer Michael B.
Published: February 2017

180

Background: Pancreatic cancer is one of the leading causes of cancer-related death, due partly to the lack of early detection and screening methods. Metabolomics, the newest of the “omics” sciences, provides a means for non-invasive screening of early tumor associated perturbations in cellular metabolism. We applied metabolomic techniques to identify urinary metabolites capable of facilitating diagnosis of pancreatic cancer.

Methods: Urine samples from pancreatic cancer patients (n=55) and healthy volunteers (n=25) were collected and examined using 1H-NMR spectroscopy. Targeted profiling of spectra using Chenomx NMR Suite 7.0 software permitted quantification of 66 metabolites. Unsupervised (PCA) and supervised (PLS-DA) multivariate pattern recognition techniques were applied to discriminate between sample spectra of pancreatic cancer patients and healthy volunteers using SIMCA-P (version 11, Umetrics, Umeå, Sweden).

Results: Significant differences were found when comparing concentrations of 66 metabolites in urines of healthy volunteers and pancreatic cancer patients. Those metabolites contributing the most class discriminating information included choline, 2-aminobutyrate, urea and 2-oxoglutarate. Clear distinctions between pancreatic cancer patients and healthy controls were noted when PLS-DA was applied to the data set. Model parameters for both goodness of fit R2, and predictive capability Q2, were high (R2 = 0.829; Q2 = 0.76). Model validity was tested using response permutation and results were suggestive of excellent predictive power. Application of PLS-DA to the data set also revealed clear discrimination of Stage I-III and Stage IV disease states, with the following model parameters, R2 = 0.62; Q2 =0.45.

Conclusions: Urinary metabolomics detected clear differences in metabolic profiles of pancreatic cancer patients and healthy volunteers. Early results presented here suggest that metabolomic approaches may facilitate discovery of novel biomarkers capable of early disease detection.
The role of NeuroD1 in the upregulation of SMYD3 by HBx.
Authors: Xu Junyao , Hong Qingqi , He Chuanchao , Wang Jie
Published: February 2017

183

Background: SET and MYND Domain-Containing Protein 3 (SMYD3) is frequently overexpressed in hepatocellular carcinoma (HCC) exhibiting increased malignant phenotypes. It has also been known that the hepatitis B virus x protein (HBx) is strongly associated with HCC development and progression. Although overexpression of both proteins is related to HCC, the relationship between the two has not been well studied.

Methods: Immunohistochemical staining was used to detect the expression of HBx and SMYD3 in HCC tumor tissues. HBx gene transfection, RNAi, and histone methyltransferase(H3-K4) activity assay were performed to reveal the transcrpitionally activation of HBx on functional SMYD3 gene expression. Chromatin immunoprecipitation (ChIP), Co-immunoprecipitation (Co-IP), Electrophoretic mobility shift assay (EMSA) were applied to investigate the underlying mechanism. Dual-luciferase reporter assay was used to search for the HBx responsive cis-element of SMYD3 gene.

Results: Immunohistochemistry identified the positive correlation between HBx and SMYD3 expression in 42 HCC tissues. Up-regulation of HBx on SMYD3 expression was validated through experiments involving overexpression or knock-down of HBx in different HCC cell lines. And up-regulated SMYD3 is functionally active as histone methyltransferase. Next we found that HBx transcriptionally regulated SMYD3 gene expression by interacting with RNA polymerase IIand altering its binding site to a proximal promoter region(SD2) from a distant promoter region(SD6) of SMYD3. Truncated and mutant reporter assays revealed that the cis-element mapped in -178~-203bp in SMYD3 promotor is responsive for HBx-transactivation. And this 25bp cis-element contains a E-box 3 unit, which is a binding site for the transcriptional factor Neurogenic differentiation 1(NeuroD1). EMSA and Chip showed that HBx increased NeuroD1 binding to SMYD3 proximal promotor, however transcient expression of antisense NeuroD1 abolished HBx-induced SMYD3 expression.

Conclusions: HBx transcriptionally up-regulates SMYD3 and that this process is mediated by NeuroD1 through binding to the E-box 3 site of SMYD3 promotor.