bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostate cancer outcomes and polymorphism in LHRH and LH receptors and SHBG.
Authors: Liu S. , Pinski J. K. , Ingles S. A.
Published: February 2017

5

Background: The hypothalamic-pituitary-gonadal axis is integral to androgen synthesis and the management of prostate cancer (PC). Genetic variation in the receptors of this pathway may impact the efficiency of signal transduction and overall clinical course. We examined polymorphisms in four receptors central to this pathway: luteinizing hormone-releasing hormone receptor (LHRHR), luteinizing hormone receptor (LHR), androgen receptor (AR) and steroid hormone binding globulin (SHBG). We examined the association between these genotypes and survival.

Methods: Patients diagnosed with PC between 1999 and 2004 in Los Angeles County were identified using the Los Angeles County Cancer Registry as part of the California Collaborative Prostate Cancer study, a multiethnic, population based case-control study. Included in this analysis were 1232 men with PC: 631 with advanced stage PC at diagnosis and 430 with high-grade PC. The ethnic breakdown was 376 African-American, 355 Hispanic and 501 Caucasian. DNA was extracted from blood and genotypes for LHR, LHRHR, AR and SHBG were assayed using TaqMan or GeneScan methods. Vital status and cause of death was obtained by linking to the Cancer Registry records. Hazard ratios were estimated by fitting Cox proportional hazards models.

Results: As of September 2010, 396 (32%) had died and 122 (10%) had died of PC. In the multivariate model, there was a significant association between disease specific survival and genetic variation in LHRHR, LHR and SHBG. Hazard ratios (HR) for carriers (vs. non-carriers) of the LHR312 minor allele were 1.63 (95% CI: 1.08-2.45) among all cases and 2.04 (1.23-3.39) for high- grade cases. The LHRHR16 minor allele was rare among African Americans; the HR among Caucasians was 1.90 (1.15-3.13) and did not vary by disease grade. The SHGB356 minor allele was associated with survival only among high-grade cases with a HR of 2.38 (1.18-4.81). In addition, when comparing cases to controls, the LHR312 minor allele was inversely associated with PC incidence.

Conclusions: Genetic variation in the LHRHR, LHR and SHGB genes are associated with PC survival and warrant further analysis to define their role as prognostic and predictive markers.

No significant financial relationships to disclose.
Gastrointestinal toxicities following radiation therapy for localized prostate cancer.
Authors: Lu-Yao G. L. , Kim S. , Moore D. , Shih W. , Lin Y. , Shen S. , Li H. , Dolan M. , Shao Y.
Published: February 2017

64

Background: Radiation therapy (RAD) is commonly employed to treat localized prostate cancer; however, representative data regarding treatment related toxicities compared to conservative management (CM) is sparse.

Methods: We performed a population-based cohort study, using Medicare claims data linked to the Surveillance, Epidemiology, and End Results data, to evaluate gastrointestinal (GI) toxicities in men aged 65-85 years treated with either primary RAD or CM for T1-T2 prostate cancer diagnosed in 1992-2005. In this study, only GI toxicities requiring interventional procedures occurring after 6 months of cancer diagnosis were included. Competing risk models were used with the following covariates: year of diagnosis, comorbidity, age, tumor stage, cancer grade, hormone use within 1 year of diagnosis, region, race, poverty and marital status.

Results: Among 41,859 patients in this study, 28,021 patients received radiation therapy, 19,287 with external beam radiation therapy (EBRT) alone, and 5,138 with brachytherapy alone. The most common GI toxicity was GI bleeding or ulceration. GI toxicity rates were 6.1% after 3D-conformal therapy (3D-CRT), 2.8% after intensity modulated radiation therapy (IMRT), 2.6% after brachytherapy, 8.2% after proton therapy and 1.1% for CM patients. In the multivariate models, RAD group was associated with a higher hazard of GI toxicities (hazard ratio [HR] 4.68; 95% CI, 3, 93-5.58) than CM. Comparing to 3D-CRT, brachytherapy (HR 0.62; 95% CI, 0.51-0.75) and IMRT (HR 0.67; 95% CI, 0.55-0.82) are associated with a lower hazard of GI toxicities, while proton therapy is associated with a higher hazard of GI toxicities (HR 2.15; 95% CI, 1.45-3.17).

Conclusions: Radiation therapy is associated with a higher risk of GI toxicities than CM. Among different modalities of radiation therapy, protons therapy is associated with the highest risk of GI toxicities, followed by 3D-CRT, IMRT, and brachytherapy. The increased GI toxicities for patients with proton therapy may reflect a learning curve in the early years.

No significant financial relationships to disclose.
Radiation oncologist density and prostate cancer mortality.
Authors: Aneja S. , Yu J. B.
Published: February 2017

72

Background: There exists a geographic variation among the distribution of radiation oncologists (RO). The goal of this study was to determine the effect of RO density (ROD) on prostate cancer (PC) mortality (PCM).

Methods: Using county- level data from the 2008 Area Resource File, National Program for Cancer Registries, and US Centers for Disease Control, a multivariate regression model was constructed for PCM, controlling for county-level categorized ROD, demographics, socioeconomic status, and existing hospital facilities. Urologist and allergy/immunology density (UD and AID) were explored to assess whether the association with PCM was due to differences in regions with high medical specialist density or whether it was due to access to PC specific specialists.

Results: There was a statistically significant reduction in PCM (reduction ranging from 9% to 29% p<.001) associated with counties that possessed at least 1 RO. Moreover, increasing the county density to greater than 2 ROs per 100,000 people had a statistical significant reduction in PCM compared to having one RO (p<.001). UD and AID were also associated with a reduction in PCM.

Conclusions: The presence of a RO is associated with lowered PCM within that county, and increasing ROD does yield further improvements in PCM. Whether access to specialized medical care is an indicator of available health resources or directly influences PCM improvement is an important area of further study.

[Table: see text]

No significant financial relationships to disclose.
Predictors of outcome using salvage androgen deprivation therapy after radical prostatectomy.
Authors: Tollefson M. K. , Bergstralh E. J. , Rangel L. J. , Karnes R. J.
Published: February 2017

74

Background: Nearly all men that experience recurrence of prostate cancer after radical prostatectomy are placed on salvage androgen deprivation therapy (sADT) in an attempt to control the disease. Yet, little is known regarding the efficacy of the treatment, the therapeutic duration or the predictors of treatment failure. Therefore, we examined our experience with sADT after radical prostatectomy in a cohort of patients with no evidence of systemic disease.

Methods: We identified 1,373 patients that were treated with sADT after radical prostatectomy prior to the development of systemic disease. Clinical and pathologic variables predicting systemic progression and cancer death were evaluated using the Kaplan-Meier method and compared using the log rank test. Multivariate Cox proportional hazard regression models were used to analyze the impact of these variables on disease progression and survival.

Results: Patients were treated with sADT at a median of 4.2 years after surgery. The median PSA at initiation of sADT was 1.6 ng/mL. The majority (1,234, 90%) of patients had a calculable PSA doubling time prior to the initiation of sADT. 275 patients (20.0%) experienced systemic progression at a median of 3.1 years after the start of sADT. 175 patients (12.7%) died of prostate cancer at a median of 4.7 years after the start of sADT. Factors that predicted disease progression after sADT on multivariate analysis included either neoadjuvant or adjuvant ADT (HR - 2.0, p<0.0001), increasing pathologic Gleason Score (HR - 1.18, p=0.009), increasing pathologic stage (HR - 1.3, p<0.0001), PSA at start of sADT (HR - 1.3, p<0.0001) and PSA doubling time (1.65, p<0.0001).

Conclusions: Most men treated with sADT after radical prostatectomy prior to the development of systemic progression experience a lengthy disease-free interval. Multivariate predictors of treatment failure include prior adjuvant or neoadjuvant ADT, pathologic Gleason Score, pathologic stage, PSA level at initiation of sADT and PSA doubling time before sADT.

No significant financial relationships to disclose.
Quality of life after pelvic radiotherapy with hypofractionated IMRT boost and long-term hormone therapy for locally advanced prostate cancer.
Authors: Quon H. C. , Cheung P. , Loblaw D. A. , Morton G. , Szumacher E. , Danjoux C. , Choo R. , Thomas G. , Kiss A. , Deabreu A.
Published: February 2017

75

Background: Combined radiotherapy (RT) and long-term hormonal therapy (HT) is a standard treatment option for high-risk prostate cancer. Dose escalated RT alone has been shown to improve disease free survival. Increased sensitivity of prostate cancer to high doses per fraction has led to hypofractionation as a method to radiobiologically escalate dose.We report on the quality of life of patients treated with combined hypofractionated RT and HT.

Methods: A prospective phase I/II study enrolling patients with any of: clinical T3, PSA ≥20, or Gleason 8-10. Forty-five Gy (1.8 Gy/fraction) was delivered to the pelvic nodes with a concomitant 22.5 Gy intensity-modulated RT boost to the prostate, for a total of 67.5 Gy (2.7 Gy/fraction) in 25 fractions over 5 weeks. Hormonal therapy was administered for 2-3 years. Patient reported outcomes were measured at baseline and every 6 months using the validated Expanded Prostate Cancer Index Composite (EPIC) questionnaire, which measures urinary, bowel, sexual, and hormonal domains.

Results: Sixty patients with a minimum 24 months of patient-reported outcomes were analyzed. Mean scores comparing baseline to 24 month values are reported. There were no statistically significant changes in the urinary summary scores (86.3 vs. 86.0, p=0.45) or any of the urinary subscales (function, bother, incontinence, irritative/obstructive). Domain summary score decreases were observed in: bowel by 4.4% (94.7 vs. 90.3, p<0.01), sexual by 27% (44.5 vs. 17.5, p<0.01), and hormonal by 11.9% (93.1 vs. 81.2, p<0.01). Examining time trends in outcomes, most changes occurred within the first 6 months with smaller changes thereafter.

Conclusions: Hypofractionated RT combined with long-term HT is associated with good patient-reported urinary and bowel outcomes at 24 months. Sexual and hormonal summary scores are affected, largely due to continued androgen deprivation therapy. Further follow-up is needed to document patient reported outcomes after testosterone recovery.

No significant financial relationships to disclose.
Single fraction high-dose-rate brachytherapy and hypofractionated external beam radiation therapy in the treatment of intermediate-risk prostate cancer: Long-term results.
Authors: Cury F. L. , Duclos M. , Aprikian A. G. , Patrocinio H. , Kassouf W. , Shenouda G. , Faria S. , David M. , Souhami L.
Published: February 2017

83

Background: We present the long-term results of a cohort of patients with intermediate-risk prostate cancer (PC) treated with single fraction high-dose-rate brachytherapy (HDRB) combined with hypofractionated external beam radiation therapy (HRT).

Methods: Patients with intermediate-risk PC were treated exclusively with HDRB and HRT. HDRB delivered a dose of 10 Gy to the prostate gland and HRT consisted of 50 Gy delivered in 20 daily fractions. The planning target volume was the prostate gland with a 1 cm margin all around. The first 121 consecutive patients with a minimum of 2 years post-treatment follow-up were assessed for acute and chronic toxicity and disease control.

Results: The median follow-up was 62.8 months. No acute grade III or higher toxicities were seen. Grade II late GI toxicity was seen in 9 patients (7.4%) and grade III in 2 (1.6%). Grade 3 GU toxicity was seen in 2 patients (1.6%), both with urinary obstructive symptoms requiring catheterization. A repeat biopsy was offered to the first 58 consecutively treated patients, and 44 patients agreed with the procedure. A negative biopsy was found in 40 patients (91%). The biochemical relapse-free survival rate at 5 and 8 years were 90.7% and 81.4%, with 13 patients presenting biochemical failure. Among them, nine were diagnosed with distant metastasis. Prostate cancer-specific and overall survival rates at 8 years were 100% and 95.5%, respectively.

Conclusions: Our program of HDRB and HRT is well tolerated, with acceptable toxicity rates. Furthermore, results from re-biopsies revealed an elevated rate of local control. These results are encouraging and confirm that the use of conformal RT techniques, adapted to specific biological features, have the potential to improve the therapeutic ratio in intermediate risk PC patients.

No significant financial relationships to disclose.
Bowel morbidity after prostate brachytherapy with Cesium-131 assessed by longitudinal EPIC survey.
Authors: Beriwal S. , Smith R. , Vargo J. , Benoit R. M.
Published: February 2017

84

Background: Cesium-131 is a relatively new radioisotope for prostate brachytherapy (PB), with limited long- term data for toxicity profiles. Here we report our 1-year follow up for severity and time to resolution of bowel toxicity using Expanded Prostatic Cancer Index Composite (EPIC) scoring.

Methods: Longitudinal prospective study of 186 patients with prostate cancer treated with Cesium-131 PB at our institution were followed by EPIC recordings. The mean prostatic volume was 41.3 cm3 and the mean prostate D90 and V100 were 105.7% and 92.4%, respectively. Patients completed surveys preoperative and at 2 weeks, 4 weeks, 3, 6, 9, and 12 months post-operatively. Outcomes were analyzed using student t-tests, with an EPIC score drop of > 10 points considered clinically significant.

Results: For all patients (n=186), the mean EPIC bowel summary score at baseline was 90.1 ± 11.7 compared to 72.0 ± 21.8 [mean difference 19.0 ± 1.7, p<0.0001], 69.7 ± 21.4 (21.1 ± 2.0, p<0.0001), 87.0 ± 13.7 (3.4 ± 1.0, p = 0.001), 90.2 ± 10.1 (0.6 ± 1.0, p = 0.508), 89.8 ± 12.8 (1.4 ± 1.1, p = .216), and 88.5 ± 13.5 (2.6 ± 1.2, p = .031) at 2 weeks, 4 weeks, 3, 6, 9, and 12 months, respectively. For patients treated with PB alone (n=128), the mean EPIC bowel summary score at baseline was 91.6 ± 10.3 compared to 70.7 ± 23.2 (20.9 ± 2.1, p<0.0001), 66.1 ± 22.1 (25.3 ± 2.6, p<0.0001), 86.7 ± 13.8 (4.9 ± 1.2, p<0.0001), 91.4 ± 8.3 (0.8 ± 0.9, p = 0.396), 91.9 ± 10.8 (0.8 ± 1.3, p = 0.545), and 91.6 ± 10.5 (1.4 ± 1.3, p = 0.266), at 2 weeks, 4 weeks, 3, 6,9, and 12 months, respectively. For patients treated with external beam radiation therapy (EBRT) + PB (n=58), the mean EPIC bowel summary score at baseline was 89.6 ± 14.2 compared to 74.7 ± 18.6 (14.9 ± 2.6, p<0.0001), 77.2 ± 17.8 (12.3 ± 2.5, p<0.0001), 87.5 ± 13.7 (0.4 ± 1.8, p = 0.823), 87.9 ± 12.9 (0.3 ± 2.2, p = 0.884), 85.8 ± 15.3 (2.6 ± 2.2, p = 0.243), and 82.9 ± 16.1 (4.8 ± 2.5, p = 0.060) at 2 weeks, 4 weeks, 3, 6, 9, 12 months, respectively.

Conclusions: For men undergoing PB with Cesium-131 both as monotherapy and in conjunction with EBRT, bowel symptoms returned to clinical baseline within 3 months and statistical baseline within 6 months. These results remained non-significant relative to pre-operative values up to 1-year post-PB.

No significant financial relationships to disclose.
Signet ring cell cancer: Harbinger of doom?
Authors: Taghavi Sharven , Jayarajan Senthil N. , Davey Adam , Willis Alliric Isaac
Published: February 2017

10

Background: Signet ring cell cancer (SRC) is associated with worse prognosis. However, studies in Asia have questioned this idea. Our aim is to determine differences in presentation and outcomes between SRC and gastric adenocarcinoma (AC) to establish if SRC conveys worse prognosis in the U.S.

Methods: NCI SEER was used to analyze differences in presentation and outcomes of SRC and AC from 2004−2007.

Results: 10,886 gastric cancers included 2,872 SRC and 8,014 AC. SRC presented younger (62.0 vs 68.9 years, p<0.001) and less in males (53.7 vs 68.0%, p<0.001). SRC were more likely Asian (16.5 vs 13.5%) or Hispanic (23.3 vs 14.9%) and less Black (10.7 vs 11.5%) or White (71.8 vs 74.1%); p<0.001. SRC was more likely to be T-3 or T-4 (46.0 vs 33.8%), have nodal spread (72.5 vs 62.0%), and metastases (29.0 vs 24.1%); p<0.001. SRC was more likely lower stomach (30.6 vs 24.6%) or body (30.8 vs 21.6%) and less upper stomach (24.7 vs 46.9%); p<0.001. SRC more often overlapped regions (13.9 vs 6.9%, p<0.001). SRC was associated with mortality (HR 1.07, CI 1.01−1.14, p=0.017) and decreased median survival (12.0 vs. 13.0 months, p=0.034). Multivariate analysis stratified by AJCC stage and radiation found SRC was not independently associated with mortality (HR 1.04, CI 0.98−1.11, p=0.195). Mortality was associated with age (HR 1.01, CI 1.01−1.01, p=0.001), Black race (HR 1.11, CI 1.02−1.21, p=0.013), and tumor grade ( table ). Survival was associated with Asian race (HR 0.88, CI 0.81−0.95, p=0.001) and surgery (HR 0.21, CI 0.19−0.22, p=0.001).

Conclusions: In the U.S., SRC differs from AC in presentation with younger age, less male predominance, greater tumor extent, metastases, and Asian or Hispanic ethnicity. Survival for SRC is associated with Asian race and surgical resection. Overall, SRC survival is less than AC. However, adjusted for stage at presentation, SRC does not portend a worse prognosis.

[Table: see text]
Gastric leiomyosarcomas: A SEER analysis.
Authors: Moody John Scott , Kozak Kevin Robert
Published: February 2017

106

Background: Gastric sarcoma is an uncommon malignancy that represents approximately 1% of gastric malignancies. The presentation and outcomes of these patients remains poorly defined, and a dearth of information is available regarding the management of such patients.

Methods: Patients with primary gastric leiomyosarcoma, diagnosed between 1988 and 2008, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Clinical characteristics and outcomes of these patients were defined and compared with the characteristics of gastric adenocarcinoma patients.

Results: A total of 49,258 patients were identified for analysis, 574 with leiomyosarcoma. Gastric leiomyosarcomas were more likely to occur in younger patients, female patients, and were less likely to present with advanced disease. These tumors were more likely to occur in the gastric fundus or along the greater curvature of the stomach. The incidence of gastric leiomyosarcoma has dramatically decreased over the last decade, consistent with the likelihood that many of these tumors are now considered to represent GIST tumors with current pathologic techniques. Median overall survival for gastric leiomyosarcoma patients was 36 months whereas that for gastric adenocarcinomas was significantly shorter at 10 months (P < 0.001 on Kaplan-Meier analysis). For non-metastatic patients, the median survival of leiomyosarcoma patients was 72 months versus 22 months for gastric adenocarcinoma patients. Cox proportional hazards modeling similarly demonstrated a decreased mortality risk associated with leiomyosarcoma (HR 0.52, 95% CI 0.47-0.57). A multivariable Cox analysis that examined tumor, patient and treatment characteristics demonstrated that leiomyosarcoma was independently associated with improved survival (HR 0.64, 95% CI 0.54-0.76). A Cox analysis for leiomyosarcoma patients alone showed that surgery was associated with improved survival (HR 0.14, 95% CI 0.06 – 0.34).

Conclusions: Gastric leiomyosarcomas have been a distinct subset of gastric tumors with a superior prognosis than adenocarcinomas. Surgery has historically been a key component of successful management and is associated with improved survival.
Endoscopic resection as salvage treatment for patients with local failure after definitive chemoradiotherapy for stage II or III esophageal squamous cell cancer.
Authors: Makazu Makomo , Kato Ken , Takisawa Hajime , Yoshinaga Shigetaka , Oda Ichiro , Saito Yutaka , Mayahara Hiroshi , Ito Yoshinori , Itami Jun , Hamaguchi Tetsuya , Shimada Yasuhiro
Published: February 2017

109

Background: Local failure after definitive chemotherapy and/or radiotherapy for stage II or III esophageal cancer is one of the causes of poor outcome. Endoscopic resection (ER) is an effective treatment for superficial esophageal cancer. However, its curative potential and safety remain unclear for local recurrent or residual tumor.

Methods: Two hundred and sixty patients (pts.) who received definitive chemotherapy and/or radiotherapy for stage II or III esophageal squamous cell cancer between January 2000 and July 2007 were retrospectively reviewed.

Results: Characteristics of all patients were as follows: median age of 65 (range 35-86); male/female: 226/34; performance status 0/1/2:117/141/2; clinical stage IIA/IIB/III: 64/70/126; regimen of chemoradiotherapy/radiotherapy: 235/15; and radiation dose 50.4/60/>66 Gy: 31/218/10. Of 260pts, 170 (65%) achieved complete response after chemoradiotherapy. Median survival time was 38.5 months and 5-year survival rate was 43.5%. While 81 of them had recurrent disease, 39 had locoregional recurrence without distant metastasis. While 86 of 260 pts (33%) had residual disease after chemoradiotherapy, 68 had only locoregional disease. Of the 107 pts who had only locoregional recurrent or residual tumor, 15 (14%) underwent salvage ER (17 lesions in total). Tumor depth was limited in mucosal layer in 10 lesions and submucosal in 7 lesions. En bloc resection was performed in 9 lesions (52.9%). The vertical margin was free from cancer cells in 15 lesions (88.2%). No major complications, such as hemorrhage requiring blood transfusion and perforation, were experienced. Only one pt experienced minor hemorrhage 16 days after EMR, and was treated by endoscopic treatment. At a median follow-up period of 40.0 months (range, 0.7-94 months) after salvage ER, no recurrence was detected in 9 pts. (60%). Local recurrence was detected in 4 pts. (27%). The clinical courses of the remaining 2 pts were unknown. Three-year survival rate after salvage ER was 58%.

Conclusions: Salvage ER is feasible and one of the promising treatments for local recurrent or residual esophageal cancer after chemoradiotherapy or radiotherapy.
A phase I study of salvage photodynamic therapy (PDT) using talaporfin sodium and a diode laser for local failure of esophageal carcinoma (EC) after chemoradiotheapy (CRT).
Authors: Nagai Kengo , Muto Manabu , Ezoe Yasumasa , Yamamoto Takashi , Niimi Miyuki , Yoshimura Kenichi , Yoda Yusuke , Yano Tomonori , Higashino Koji , Iishi Hiroyasu , Yamamoto Yoshinobu , Nishizaki Hogara
Published: February 2017

123

Background: We recently reported that porfimer sodium (Photofrin)-based PDT was a less invasive, curative treatment option for carefully selected patients with locally residual EC after CRT (Endoscopy 2011:43:657-63). However, porfimer sodium-based PDT has some problems (long light shielding and skin phototoxicities). Conversely, talaporfin sodium (Laserphyrin)-based PDT using a diode laser system can overcome these problems. Therefore, we conducted a phase I study to establish the recommended dose of laser irradiation and to evaluate safety of talaporfin sodium-based PDT as a salvage treatment after CRT. (UMIN000003970).

Methods: We recruited patients with residual or recurrent EC at primary site and who were treated with more than 50 Gy of (chemo)radiotherapy. To determine the dose limiting toxicity (DLT) according to the energy of the diode laser, dose escalation was set at three energy levels (50,75 and 100J/cm2). The DLT was defined as follows; 1) severe pain, 2) ≥ grade 2 CTC-AE fever, 3) esophageal fistulae or stenosis, 4) ≥ grade 3 CTC-AE hemorrhage, and 5) ≥ grade 4 CTC-AE non-hematologic toxicity.

Results: Between Oct. 2010 and May 2011, a total of 9 patients (9 men, median age of 72 y-o) were recruited and were treated using up to the third energy level in groups of three individuals. The initial T stage was T1/T2/T3(4/2/3) and recurrent T stage was T1/T2(6/3). None of the patients experienced DLT at all energy levels. A complete response was achieved in 5 of 9 patients (56%).

Conclusions: Based on the results of our phase I study, we concluded that irradiation at 100J/cm2 appeared to be a recommended dose for talaporfin sodium-based PDT as a salvage treatment for locally residual esophageal carcinoma after CRT. We are currently running a phase II part of the study to investigate efficacy of salvage talaporfin sodium-based PDT.
Validation of a gastric cancer nomogram using a U.S. cancer registry.
Authors: McGhan Lee Joseph , Dueck Amylou C. , Pockaj Barbara A. , Gray Richard J. , Bagaria Sanjay Prakash , Wasif Nabil
Published: February 2017

13

Background: A Memorial Sloan Kettering Cancer Center (MSKCC) nomogram predicts disease−specific survival (DSS) following R0 resection for gastric adenocarcinoma using patient and tumor factors, with predictive ability superior to that of the current AJCC staging system. However, validation has only been performed in high−volume, specialized institutions. The goal of this study is to compare nomogram-predicted survival with actual survival by using a population database with the largest sample size reported to date.

Methods: A retrospective review of all gastric cancer patients from Surveillance, Epidemiology and End Results (SEER) registry data from 1988 to 2000 was conducted. Data for patient age, tumor size, gender, primary location of tumor, Lauren histology, depth of tumor invasion, and % (+) and (-) lymph nodes was entered into the nomogram calculator for each patient. Nomogram-derived 5−year DSS was compared with actual DSS survival using Cox proportional hazards regression and Kaplan-Meier estimates.

Results: 4,700 patients were identified. Mean patient age was 68.7 years (SD 12.3), and mean tumor size was 4.8 cm (SD 2.7). The commonest tumor location was the body/middle third of stomach (1519, 32%), followed by the gastro−esophageal junction (1381, 29%) and the antrum (1376, 29%). The majority of patients (76%) had intestinal histology. The estimated proportion of patients surviving 5 years was 23%, 48%, 58%, and 82% for survival groups defined by nomogram likelihoods of 5−year DSS of 0−25%, 26−50%, 51−75%, and 76−100%, respectively. Relative to patients in the 76−100% 5−year nomogram group, patients in the 0−25%, 26−50%, and 51−75% group had significantly higher likelihood of death with hazard ratios of 7.0 (95% CI 6.1−8.0), 3.3 (95% CI 2.8−4.0), and 2.6 (95% CI 2.2−3.0), respectively (all p<0.001). Median follow-up was 9.1 years (range, 0−18). The concordance index (c−index) for the 5−year nomogram score was 0.68 (95% CI 0.67−0.69).

Conclusions: There is good discrimination of survival between nomogram-predicted survival groups. Our results validate the use of the MSKCC nomogram in the setting of the general population, outside of specialized institutions, for predicting DSS following resection of gastric adenocarcinoma.
Standardized pathologic evaluation of the esophagus after neoadjuvant chemoradiation.
Authors: Muijs Christina T. , Smit Justin K. , Karrenbeld Arend , Beukema Jannet C , Langendijk Johannes A. , Plukker John Theodorus
Published: February 2017

136

Background: The main objective of this study was to develop and validate a method to reconstruct the gross and clinical tumor volume (GTV and CTV) on the esophageal specimen in order to facilitate a good pathologic examination of the original tumor area after neo-adjuvant chemoradiation (CRT).

Methods: The GTV and CTV borders of 25 patients were defined by a radiation oncologist on the planning CT in relation to 5 anatomical reference points. After CRT, the GTV and CTV borders were marked in vivo on the esophagus during surgical resection. Finally, the pathologist evaluated the presence of macroscopic and microscopic tumor in- and outside the GTV and CTV. The radiation tumor response was scored according to the standardized 5-tier Mandard classification. Radiation induced side effects were scored as well.

Results: The Mandard classification could be scored on basis of the GTV alone in 68% of the cases (N=17). For the other patients (N=8), the GTV and the CTV should both be incorporated for correct evaluation of the tumor response. Five patients (20%) showed complete tumor response (Mandard 1), 68% (N=17) showed partial response (Mandard 2-3) and 12% (N=3) showed hardly any response (Mandard 4-5). In the partial responders, macroscopic tumor was found within the delineated GTV and microscopic tumor remained within the CTV both in 100% of the cases. In two patients (40%) with hardly any response, microscopic tumor was also found outside the CTV. This might be caused by tumor growth during the neo-adjuvant treatment or by geographical miss. Nine patients turned out to have positive lymph nodes. On average 18 (range 8-30) lymph nodes were evaluated per patients. Giant cell reactions, lymphocyte infiltration, and fibrosis, which indicate tumor regression were seen in the CTV and GTV, and were most pronounced in the GTV.

Conclusions: This study suggested that demarcation of the GTV and CTV on the esophagus in vivo is important for standardized pathologic evaluation of the esophagus after neo-adjuvant chemoradiation. Furthermore using this method we determined microscopic tumor outside the CTV in 40% of the cases (N=2) of the bad responders (Mandard 4-5), illustrating the importance of our method in this patient category.
Clinical significance of obesity index (VFA versus BMI) as a risk factor for gastric cancer surgery.
Authors: Song Kyo Young , Shim Jung Ho
Published: February 2017

139

Background: Obesity is considered as a major perioperative risk factor in various cancer surgeries. We aimed to elucidate the effect of two different obesity index, such as VFA (visceral fat area) and BMI (body mass index), on gastrectomy.

Methods: From Mar 2009 to July 2010, 632 patients with diagnosed gastric carcinoma underwent curative gastrecomy at Seoul St. Mary’s hospital. We reviewed patients’ clinicopatholic data and collected 187 patients who had data including BMI, VFA and SFA. Patients with body mass index (BMI) ≥ 25 kg/m 2 were defined as obese and visceral fat area (VFA) ≥ 100 were defined as centrally obese.

Results: Out of a total 187 patients, eighty patients were in the high BMI group and 107 patients were in the low BMI group. We selected patients with high VFA and low BMI (group A) and compared to the patients with low VFA and low BMI (group B). Out of a total 107 patients in low BMI, seventy three patients were censored as high VFA, and age older than 60 and male patients were prevalent in this group (p=0.045 and 0.046). The operation time (OT) and estimated blood loss (EBL) were significantly higher in group A than group B (p=0.043 and p=0.05).

Conclusions: VFA and BMI are correlated each other and successfully represent patients’ obesity. However in selected patients, such as male patients with age older than sixty, VFA more practically represent their obesity.
HER2 status and histopathologic findings related to tumor regression in gastric carcinomas treated with preoperative chemotherapy.
Authors: Begnami Maria D. , Silva Milton Jose B , Costa Wilson L. , Coimbra Felipe José Fernandez , Chaves Marcos , Ribeiro Heber Salvador de Castro , Peresi Patricia , Mello Celso
Published: February 2017

145

Background: Neoadjuvant chemotherapy is now the standard of care of patients with resectable gastric carcinomas (GC). Predictive molecular markers and histopathological evidence of tumour response to chemotherapy are not widely available. In this study we evaluated HER2 status and histopathological features associated with tumor regression in 36 GC treated with neoadjuvant chemotherapy followed by surgery.

Methods: 36 patients had received ECF, DCF or ECX chemotherapy prior the surgery. The entire tumor beds of the specimens were histologically evaluated. HER2 expression by immunohistochemistry was detected in the biopsy and gastrectomy specimens.

Results: 46% of the cases were intestinal type, 40% were diffuse and 14% were unclassified. Nine patients had major clinical and radiological response (CRR) characterized by presence of viable tumor cells less than 50% of the tumor with increased fibrosis (>50%). Three cases had complete CRR showing tumor beds totally replaced by fibrosis. The remaining cases had minimal CRR characterized by viable tumor cells in more than 50% and minimal fibrosis. Necrosis was not found; mucinous metaplasia was observed in three cases of the major CRR. Inflammatory infiltrated was found in all cases. The downstaging of T-stage seems to be greater in the intestinal type than diffuse type (80% vs 44%). HER2+ (score 3) was detected in 16,6% of the biopsy specimen. Only 1 case was HER2+ in the biopsy and in the gastrectomy tissue. All the HER2+ GC showed minimal CRR.

Conclusions: The ratio of viable tumor cells and fibrosis is directly associated with tumor response to preoperative chemotherapy. The chemotherapy regimens seem to collaborate to downstaging rates; however the treatment of HER2+ GC group could be improved by the use of Ttrastuzumab.
What studies are appropriate and necessary for staging gastric cancer? Results of a RAND/UCLA expert panel.
Authors: Dixon Matthew , Cardoso Roberta , Tinmouth Jill , Helyer Lucy K. , Law Calvin , Swallow Carol Jane , Paszat Lawrence Frank , McLeod Robin S. , Seevaratnam Rajini , Mahar Alyson L. , Coburn Natalie G.
Published: February 2017

15

Background: The approach for staging gastric cancer (GC) patients has not been well defined, resulting in widespread heterogeneity in the application of pre-operative staging modalities.

Methods: A multi-disciplinary expert panel of 16 physicians from 6 countries scored 84 scenarios using the RAND/UCLA Appropriateness Methodology. Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) from 1-3 were considered inappropriate, 4-6 uncertain, and 7-9, appropriate. Agreement was reached when 11 of 16 panelists scored the scenario similarly. If a scenario was agreed to be appropriate, it was given a necessity score (NS) in the same manner. AS and NS are reported if agreed upon.

Results: TNM staging should be determined pre-operatively (AS 7.0-9.0; NS 7.0-9.0). Pre-operative radiological assessment should include a computed tomography (CT)−abdomen, CT−pelvis, and should be performed with a multi−detector CT scanner with 5 mm slices (AS 8.0−9.0; NS 7.0−9.0). A CT Chest may be performed (AS 7.5). The utility of a chest radiograph was indeterminate. All patients should have a pre-operative esophagogastroduodenoscopy (EGD). The endoscopist should biopsy the tumor; document its size, description, location, distance from the GE junction, and any GE junction, esophageal or duodenal involvement. If the EGD report is unclear, the surgeon should repeat it to confirm tumor location (AS 7.5-9.0, NS 7.0−9.0). Endoscopic ultrasound is appropriate prior to endoscopic resection, but not surgical resection (AS 9.0). Diagnostic laparoscopy (DL) should be performed prior to resection of cT3,4 lesions, or multi−visceral resections. DL should include visual inspection of the stomach, diaphragm, liver, and ovaries (AS 8.0−9.0, NS 7.0−9.0).

Conclusions: The Gastric Cancer Processes of Care expert panel has made recommendations regarding pre−operative staging modalities in an effort to standardize work up. Standardization could lead to more accurate staging and allocation towards optimal stage−specific treatments.
Low 18f-fluorodeoxyglucose uptake on positron emission tomography as a prognostic factor for stage I and II pancreatic cancer.
Authors: Pimiento Jose Mario , Boutrid Hinda , Weber Jill M. , Razzaque Saqib , Farma Jeffrey M. , Kim Richard D. , Hodul Pamela Joy , Shridhar Ravi , Hoffe Sarah E. , Almhanna Khaldoun , Chuong Michael D. , Chen Dung-Tsa , Springett Gregory M. , Eikman Edward , Klapman Jason , Jong Park , Karl Richard C. , Malafa Mokenge Peter
Published: February 2017

159

Background: Metabolic activity as defined by the uptake of 18F-fluorodeoxyglucose (FDG) on Positron Emission Tomography (PET) has proven beneficial as a prognostic marker for multiple malignancies; however, no study has examined the prognostic value of PET in stage I and II pancreatic cancer. We examined the value of PET FDG uptake in early pancreatic cancer.

Methods: Using a comprehensive pancreatic adenocarcinoma database, we identified patients with early stage pancreatic cancer (I-II) who underwent pancreatectomy for cancer and had PET scan performed as part of their preoperative evaluation from 2004 to 2010. Patients were divided by the median primary tumor standard uptake value (SUVmax) into two groups: high and low FDG uptake. The primary outcomes were overall survival (OS) and disease free survival (DFS). Kaplan-Meier estimate was used for survival analysis. Pathologic data were compared using Fisher's exact and chi-square.

Results: We identified 105 patients with resected stage I and II pancreatic cancer who had PET scans as part of their preoperative evaluation. 51 patients had low FDG uptake while 54 patients had high FDG uptake. The median age at diagnosis was 69 (24-89) years, 57% of the patients were male. 84 (81%) patients had PET avid tumors, while 20 (19%) patients did not. The median SUVmax was 5.1. High FDG uptake correlated with pathologic stage (p=0.012). Median follow-up was 12.3 (0-56) months. Patients with low FDG uptake had a significantly better median OS than patients with high FDG uptake (27 vs. 16 months; p=0.036). Recurrence occurred in 64 (60%) patients. Patients with low FDG uptake had significantly longer median DFS than patients with high FDG uptake (14 vs. 12 months; p=0.049).

Conclusions: Low 18F-fluorodeoxyglucose uptake in PET scans for stage I and II pancreatic cancer correlates with improved overall survival and disease free survival. This observation supports the concept that glucose metabolic pathways are important in pancreatic cancer biology, and that PET scan activity can be used as a prognostic biomarker after pancreatectomy for pancreatic cancer.
Utilization of hepatocellular carcinoma surveillance in the United States.
Authors: Harris Samar , Yopp Adam C. , Tiro Jasmin A , Beg Muhammad Shaalan , Skinner Celette Sugg , Lee William M , Singal Amit G
Published: February 2017

174

Background: Surveillance for hepatocellular carcinoma is recommended in high-risk patients, but several studies have suggested it is being underutilized.The aim of this study is to quantify utilization rates for HCC surveillance among patients with cirrhosis and summarize patterns of association between utilization rates and patient and clinic characteristics.

Methods: A systematic literature review using the Medline database and national meeting abstracts identified all cohort studies that described HCC surveillance rates among at-risk patients in the United States. Two investigators independently extracted data on patient populations, study methods, and results. A pooled surveillance rate with 95% confidence intervals was calculated. Pre-specified subgroup analysis was performed to find correlates of surveillance utilization.

Results: We identified 9 studies that met all inclusion criteria. There were a variety of definitions for surveillance among the studies, with only 4 assessing surveillance every 6-12 months as recommended by the AASLD guidelines. The pooled surveillance rate was 18.4% (95% CI 17.8% - 19.0%). Surveillance rates were significantly higher among patients followed in gastroenterology clinics compared to those followed in primary care clinics (51.7% vs. 16.9%, p< 0.001). Elderly, non-Caucasians, and people of low socioeconomic status had lower surveillance rates than their counterparts. Current studies fail to identify specific reasons for the underutilization of HCC surveillance.

Conclusions: Utilization rates for HCC surveillance are low, although they are significantly higher among patients followed in subspecialty clinics. Appropriate intervention targets to increase surveillance rates and reduce socio-demographic disparities have not been identified to date, and this should be a primary goal for future studies.
Value of preoperative biopsy and radiological assessment for the diagnosis of mixed hepatocellular cholangiocarcinoma (HCC-CC).
Authors: Bouattour Mohamed , Wassermann Johanna , Guedj Nathalie , Paradis Valerie , Dreyer Chantal , Castera Laurent , Vilgrain Valérie , Faivre Sandrine J. , Raymond Eric
Published: February 2017

176

Background: Mixed tumors with hepatocellular and cholangiocarcinoma component (HCC-CC) are rare variants of primary liver tumors. In this study, we aimed to describe clinical, radiological and histopathological features of patients with resected HCC-CC.

Methods: From 2000 to 2010, patients (pts) with diagnosis of mixed HCC-CC based on surgical specimen were identified from our database. Demographic, clinical, radiological and pathological data were analyzed retrospectively, along with outcome after resection.

Results: Among 18 pts, 6 men (33%) and 12 women (67%) were identified. The median age was 64 years (range 38- 75). Nine pts (50%) had at least one risk factor for chronic liver disease including alcohol consumption (6), NASH (3) and HBV infection (2). Twelve (67%) and 6 pts (33%) underwent major and minor hepatic resections respectively. The positive predictive value of radiological and pathological diagnosis was reviewed. Imaging by CT scan and/or MRI suggested characteristics of HCC and CC in 5 and 6 pts respectively. In 3 pts imaging showed combined features of HCC and CC while it was atypical in 4 cases. Preoperative biopsy was performed in 10 pts and analyzed using only morphological features. Biopsy sample was non contributive in 2 cases and concluded to CC, HCC and mixed HCC-CC in 5, 2 and 1 cases respectively. This contrasted with examination of resection specimen showing evidence of HCC combined with CC phenotype. Immunostaining on resection specimens showed the presence of differentiation markers for both hepatocytes and biliairy cancer cells (CK7 +, CK19 +, anti-hepatocyte +, and glypican +). Non tumor liver analysis showed normal underlying liver, non extensive fibrosis ≤ F2, extensive fibrosis > F2 without cirrhosis and cirrhosis in 2, 3, 7 and 6 specimens respectively. With more than 6 months follow-up (range 6 -59 months) the recurrence rate was higher than 50%.

Conclusions: Mixed HCC-CC are not accurately identified by preoperative biopsy using only morphological features and CT scan/MRI assessment. Following resection, mixed HCC-CC behave more like CC than HCC.
Relationship of STAT3-mediated treatment resistance on activated MAPK signaling in pancreatic cancer.
Authors: Nagathihalli Nagaraj S. , Beesetty Yugandhar , Shi Chanjuan , Merchant Nipun B.
Published: February 2017

181

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult human malignancies to treat due to its intrinsic (de novo) and extrinsic (acquired) chemoresistance. We have previously identified constitutively activated STAT3 as a mediator of treatment resistance. Src or EGFR activate STAT3 and promote STAT3 mediated tumor progression and mediate communication within the tumor microenvironment (TME). The purpose of this study was to further understand the molecular mechanisms of stromal-mediated chemoresistance in PDAC to generate new and promising targeted therapies.

Methods: We characterized the expression of total and activated STAT3 and MAPK proteins in human pancreatic tissues (n=106), PDAC cell lines (n=9) and in PanIn lesions, primary PDAC and liver metastasis cell lines generated from tumors established in genetically engineered mice. Effects of STAT3 and MAPK inhibition (drug or siRNA) were assessed for phosphorylation of STAT3, Src, MAPK, EGFR and GSK3β and expression of cyclin-D1, SPARC, VEGF, fibronectin, CD31 and tumorigenicity in vitro and in vivo.

Results: STAT3 activation is necessary for the malignant phenotype and affects survival in PDAC. In both human and mouse PDAC cell lines and tissues, there is an inverse correlation between activation of STAT3 on MAPK and GSK3β signaling. Inhibition of STAT3 reciprocally activated MAPK, GSK3β, Src and EGFR which led to subsequent reactivation of STAT3. Targeting both STAT3 and MAPK inhibited activation of STAT3, MAPK, GSK3β, Src, EGFR and cyclin-D1. Combined inhibition of STAT3 and MAPK overcame STAT3 mediated resistance and resulted in synergistic inhibition of tumorigenicity as well as inhibition of the tumor stroma, angiogenesis and hypoxia within the TME.

Conclusions: The mechanism of STAT3-mediated treatment resistance is dependent on activation of MAPK signaling which in turn leads to reactivation of multiple oncogenic signaling pathways. Combined inhibition of STAT3 and MAPK overcomes therapeutic resistance, targets the TME and reduces tumorigenicity in PDAC. Targeting STAT3 and MAPK is a potent treatment regimen and may be a novel approach to enhance drug delivery and improve therapeutic response in PDAC.
Prevalence of risk factors among patients with hepatocellular carcinoma (HCC) and the general population in an employer group database.
Authors: Doan QuynhChau Diem , Beiderbeck Annette , Qian Qingshan
Published: February 2017

190

Background: Most US studies evaluating risk factors for HCC have used data from hospitals, cancer registries, or Veterans Affairs database. These data sources have small patient populations and limited generalizability.

Methods: This study investigated the association between HCC and potential risk factors [hepatitis B and C virus (HBV, HCV), diabetes, alcoholism, cirrhosis, obesity, liver disease, dyslipidemia, hemochromatosis, and hypothyroidism] and compared to the general (non-HCC) population of ~60 million lives from an employer group database. A retrospective cohort analysis was conducted using the Marketscan Research Database from Thomason Reuters. Case patients had an ICD-9 diagnosis for HCC between 1/1/2001 – 12/31/2009 (index date) but no HCC diagnosis during 1-year prior to index date. Randomly selected control patients did not have HCC diagnosis, were matched 3:1 ratio and enrolled during same time period as matched case patients, and matched for age (+/− 1 year), gender, and geographical region. All patients were 18 - 65 years old and did not have any cancer diagnosis (except HCC for case patients). Data from 1-year prior to index date were used to identify risk factors. Demographic variables and prevalence of risk factors were analyzed using descriptive statistics. Multiple logistic regression was used to predict the odds of developing HCC compared to non-HCC patients for these risk factors.

Results: The study included 1,208 case and 3,624 control patients. Mean age of cases and controls was 54 years and 67% were male. In unadjusted multiple logistic regression models, the risk for HCC was 48-fold and 135-fold increased for patients with HBV and HCV, respectively [95% confidence interval (CI): 6.2 – 374.4 for HBV, 31.5 – 580.8 for HCV]. Diabetes increased the risk for HCC by 3.85 (95% CI 2.5 – 5.9). Alcoholic cirrhosis and nonalcoholic (NA) fatty liver disease/NA steatohepatitis increased the risk for HCC by nearly 200-fold.

Conclusions: Using a larger database, these study findings were consistent with previous research and provided further evidence that the risk of HCC is greatly increased in individuals diagnosed with hepatitis, diabetes, liver disease, and alcoholism.