bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility study of postoperative management based on ERAS of patients with gastrectomy.
Authors: Sugiyama Y. , Hirabayashi N. , Taomoto J. , Mimura T. , Yoshimitsu M. , Murakami S. , Saeki S. , Mukaida H. , Takiyama W.
Published: February 2017

127

Background: Although the usefulness of the postoperative management based on Enhanced Recovery After Surgery (ERAS) program of patents with colectomy is shown, there are a few papers concerning ERAS program for gastric cancer patients. The aim of the present study was to examined whether a new postoperative management based on ERAS was feasible for pts with gastrectomy.

Methods: From September 2009 to April 2010, we have adopted the new clinical pathway (CP) based on ERAS and oral rehydration therapy (ORT) for 30 consecutive gastric cancer patients who underwent curative gastrectomy. These pts began a oral rehydration solution (ORS) on the first postoperative day, and after the volume of ORS got 1,000 ml, we stopped intravenous transfusion. The incidence of adverse events, postoperative pt's activity score, which pt's daily activity was evaluated with, and total infusion volume of these pts were compared with 30 pts with the previous CP that were enrolled as a control group.

Results: There were no significant differences in the clinical and operative factors between the two groups. The post operative patient's activity score of ERAS group was significantly higher up to 7th postoperative day (POD). Total infusion volume was significantly little besides, in most cases, infusion therapy was substituted for ORT with OS-1 within 2 POD. There was no difference in the hospitalized days, and the incidence of adverse events were statistically no significance between two groups.

Conclusions: Our CP based on ERAS and ORT is feasible for patients with gastrectomy.

No significant financial relationships to disclose.
Neoadjuvant radio chemotherapy in esophageal squamous cell carcinoma: Early results analysis of a 5-year experience.
Authors: Lima da Costa E. J. , Santos Sousa H. , Bouca-Machado T. , Caldeira B. , Paredes C. , Pinto-de-Sousa J. , Gouveia A. , Sousa Rodrigues J. , Costa-Maia J. ,   Unidade de Patologia Esofago-Gastro-Duodenal do Servico de Cirurgia Geral do Hospital de S. Joao
Published: February 2017

141

Background: Optimized survival in oesophageal squamous cell carcinoma (OSCC) depends on complete surgical resection: prognostic impact of well-standardized techniques and per operative management in experienced groups has proven to be a key aspect. Multimodal treatment (MT) options are still controversial but particularly important in locally advanced disease apparently allowing better resectability. We perform an early evaluation of a MT protocol in locally advanced OSCC.

Methods: Survival and clinical response analysis of a cohort of pts selected between 01/01/2002 and 31/12/2007. Criteria: Locally advanced OSCC (T3/4); No distant metastases; Negative bronchoscopy; Age under 76y; No other known cancer; Surgical feasibility. Pts underwent a 5 week MT: Chemo – taxotere 20 mg/m2 IV, cysplatin 20 mg/m2 IV, 5-FU 425 mg/m2 iv (days 1,8,14,22 and 29); Radio- 40 Gy (days 1-5, 8-12, 14-19, 22-26 and 29-34) followed by surgery within 4 weeks.

Results: 57 pts (38% of all admitted) 8 fem and 49 male, aged < 50y = 11, 51-65y = 30 and > 65y = 16. Response: Complete pathological remission = 13; Partial clinical response with downstaging = 15; Minimal / no clinical response = 14; Disease progression / no surgery: 15. From the 42 pts operated, an “en bloc” osophagectomy with extended lymphadenectomy was possible in 36. The overall mean follow-up for resected pts was 16.9 months (CI 95%: 10.9-22.8). The median survival was 18 months for resected patients (CI 95%: 8.7-27.3) in contrast with 7 for all candidates to MT. There was a statistically significant difference in the survival of the 4 groups divided according to their response to MT, with clear advantage of the complete pathological remission achievers.

Conclusions: Short follow-up and series size does not allow definite conclusions. It seems nevertheless that only the group of full pathological remission and probably those that obtain a downstaging of their disease benefit from MT. Histopathological or molecular markers are required to identify target pts for neoadjuvant radio chemotherapy.

No significant financial relationships to disclose.
The potential role of somatostatin analogues in the treatment of gastrointestinal (GI) cancers.
Authors: Hasskarl J. , Kaufmann M. , Schmid H. , Metz D. C.
Published: February 2017

150

Background: Somatostatin receptors (sstr) are expressed in various normal and malignant tissues, including non-neuroendocrine GI solid tumors. Gastric cancer (GC) cells mainly express sstr2 and sstr5, colorectal cancer (CRC) cells predominantly express sstr1 followed by sstr5 and sstr2, and hepatocellular carcinoma (HCC) cells express mainly sstr5 as well as sstr1,2,3. Somatostatin analogues (SAs) may have direct and indirect antitumor activity. Octreotide and lanreotide primarily target sstr2, whereas the new agent pasireotide has high affinity for sstr1,2,3 and sstr5.

Methods: Published data evaluating the antitumor properties of SAs in GI tumors were reviewed.

Results: The table lists the results of clinical studies in which SAs were evaluated as antitumor therapies in GI cancers.

Conclusions: Although octreotide and lanreotide are efficacious in the treatment of symptoms of neuroendocrine tumors, these agents have demonstrated mixed results in the antitumor treatment of non-neuroendocrine GI tumors. Data suggesting potential favorable outcomes with SAs alone or in combination with other agents have been seen in solid tumors with predominant sstr2 expression such as GC. Novel SAs such as pasireotide may have improved antitumor effects in non-neuroendocrine solid tumors expressing multiple sstr compared with octreotide and lanreotide.

[Table: see text]

[Table: see text]
Evaluation of the neutrophil-lymphocyte ratio as a predictor of survival after liver transplantation for hepatocellular carcinoma.
Authors: Limaye A. R. , Cabrera R.
Published: February 2017

170

Background: The Milan criteria are utilized to predict outcomes in patients with hepatocellular carcinoma (HCC) who undergo liver transplantation (LT). Though the survival of these patients has significantly improved since the adoption of these criteria, the risk of recurrence after LT is as high as 20 percent. One limitation of the Milan criteria is the lack of any estimation of tumor biology. The neutrophil-lymphocyte ratio (NLR) has been proposed as a peripheral surrogate for tumor biology. The predictive power of the NLR has been demonstrated for several solid tumors, and early evidence points to a role in HCC. We hypothesize that the NLR is predictive of overall survival and recurrence-free survival in patients with HCC who undergo LT.

Methods: This is a retrospective analysis of adult patients undergoing LT for HCC between 2000 and 2008 at our institution. We defined an elevated NLR as a ratio of five or greater.

Results: We identified 160 patients who underwent LT for HCC, 28 of whom had an elevated NLR. Seventeen subjects experienced recurrent HCC during the study period. The cumulative survival for subjects with an elevated NLR (1-year cumulative survival 70% ± 0.08, 3-year cumulative survival 48% ± 0.09, 5-year cumulative survival 38% ± 0.11) was significantly lower than for subjects with a normal NLR (1-year survival 80% ± 0.04, 3-year survival 75% ± 0.04, 5-year survival 68% ± 0.06). On univariate analysis, seven factors (including an elevated NLR) predicted decreased overall and recurrence-free survival. However, after multivariate analysis, only three factors (including elevated NLR) remained significant as predictors of overall survival. Additionally, multivariate analysis revealed that an elevated NLR was the only significant independent predictor of recurrence-free survival.

Conclusions: Preoperative NLR is a powerful independent predictor of overall survival and recurrence-free survival in patients undergoing LT for HCC. Measurement of NLR could serve as a useful and easily obtained adjunct to the MELD score and Milan criteria when evaluating this patient population and determining which patients will gain the most survival benefit from transplant.

No significant financial relationships to disclose.
Impact of diabetes mellitus on risk of major vessel invasion and distant metastasis in hepatocellular carcinoma.
Authors: Connolly G. C. , Safadjou S. , Kashyap R. , Chen R. , Ndauguba A. , Dunne R. , Maliakal B. , Khorana A. A. , Orloff M. , Hezel A. F.
Published: February 2017

174

Background: Diabetes mellitus (DM) is identified as a negative prognostic indicator in hepatocellular carcinoma (HCC), though the basis for this is unknown.

Methods: We conducted a retrospective review of 279 advanced and 191 transplanted HCC patients diagnosed between 1998 and 2008. Logistic regression analyses were conducted to assess the effect of clinical DM on clinical outcomes including distant metastasis and vascular invasion.

Results: Eighty- four of 191 (44%) transplanted patients had DM at time of transplantation and 97 of 279 (34%) nontransplanted patients had DM at the time of diagnosis. The presence of DM was associated with an older age at time of diagnosis and a higher prevalence of hepatitis C virus (HCV) and nonalcoholic steatohepatitis (NASH). Also 30% (30/97) of diabetics compared to only 9.3% (17/182) of nondiabetics (p<0.0001) among the cohort with advanced disease had distant metastasis at the time of initial diagnosis, and this difference remained significant when adjusting for CLIP stage, age, and etiologic risk factors in a multivariate logistic regression analysis (OR=8.3, p<0.0001). The association of DM with invasive disease was echoed among early stage transplanted HCC patients in whom histologically confirmed macrovascular invasion was higher among patients with DM compared to those without (20.5% vs. 9.5%, p=0.032). The association of DM with increased risk of macrovascular invasion remained significant in a multivariate logistic regression analysis when adjusting for tumor size, number of nodules, age, obesity and etiologic risk factors (OR=3.2, p=0.025).

Conclusions: DM was associated with significantly higher incidence of histological macrovascular invasion in a large cohort of HCC patients receiving liver transplantation and a significantly higher rate of distant metastatic disease at diagnosis in a large cohort of HCC patients with advanced disease.

No significant financial relationships to disclose.
Clinical significance of serum alkaline phosphatase level in advanced pancreatic cancer.
Authors: Ohno I. , Mitsunaga S. , Nakachi K. , Shimizu S. , Takahashi H. , Okuyama H. , Kojima Y. , Ochiai A. , Okusaka T. , Ikeda M.
Published: February 2017

183

Background: Alkaline phosphatase (ALP) is an enzyme that is elevated by various hepatobiliary diseases. Generally its elevation is thought to indicate bile stasis. There are some reports that show ALP is an important prognostic factor for several cancers such as colon, lung, and gastric cancer. Often it is speculated that ALP elevation indicates bile stasis caused by liver metastasis. However, the significance of ALP elevation in advanced pancreatic cancer (APC) patients is not well evaluated. The aim of this study was to determine the significance of elevated serum ALP as a prognostic factor in patients with APC even without jaundice and liver metastasis.

Methods: Serum ALP levels were measured in 393 patients with APC receiving gemcitabine monotherapy before treatment, and according to those levels, patients were subgrouped (ALP<upper normal limit (UNL), UNL-500 U/L, 501-700 U/L, 701-1000 U/L, 1000U/L < ALP). The clinical data of each group were analyzed to see characteristics of elevated ALP patients. The relationship between ALP level and survival, response were also examined.

Results: The elevated ALP group included poor performance status (PS>1) patients (41.3%, p=0.001), and associated with low serum albumin (3.31±0.38, p<0.01). The elevated ALP group (median survival time (MST) 112 days) showed significantly worse prognosis and lower disease control rate compared to the normal ALP group (MST 217days) (p<0.001, p<0.001). Multivariate analysis revealed ALP (p<0.001), CRP (p<0.001), ascites (p<0.001), distant metastasis (p=0.003), white blood cell count (p=0.005), PS (p=0.020), AST (p=0.020), and ALT (p=0.020) were independent prognostic factors. Similar results were seen in liver metastasis free patients without jaundice.

Conclusions: Elevated serum ALP level correlated with poor performance status and low serum albumin. ALP was also the independent prognostic factor in liver metastasis free APC patients without jaundice.

No significant financial relationships to disclose.
Bioluminescence image-guided irradiation and tumor monitoring in a preclinical pancreatic cancer mouse model.
Authors: Tuli R. , Surmak A. , Ford E. C. , Tryggestad E. , Wong J. , DeWeese T. L. , Herman J. M.
Published: February 2017

192

Background: Preclinical pancreatic cancer animal models for radiation research are far from optimal because they utilize nonlocalized, single-beam irradiation of large fields due to lack of accurate targeting and delivery. We report on a novel preclinical pancreatic cancer research model that utilizes bioluminescence imaging (BLI)-guided irradiation (RT) of orthotopic xenograft tumors, sparing of surrounding normal tissues and quantitative, noninvasive longitudinal assessment of treatment response.

Methods: In accordance with institutional guidelines, luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were used to generate orthotopic pancreatic tumors in nude mice. BLI of tumors were correlated to PET/CT and necropsy specimens using Pearson correlation. BLI was compared to cone-beam CT (CBCT) to determine the location of the tumor centroid and estimate an appropriate margin for radiation planning. Off-line fusion of BLI with CBCT was performed to guide radiation delivery to tumors using our small animal radiation research platform (SARRP). RT-induced DNA damage was assessed by γ-H2Ax and p-ATM foci. BLI was used to longitudinally monitor radiation treatment response and was correlated to necropsy specimen.

Results: BLI accurately predicted tumor volume (R2 = 0.9961) and correlated well with PET/CT imaging of tumors (R2 = 0.97). BLI centroid accuracy was 3.5 mm relative to that of the CBCT. Irradiated pancreatic tumors stained positively for γ-H2Ax and p-ATM, while surrounding organs were spared. Longitudinal assessment of irradiated (5 Gy) tumors with BLI revealed a significant tumor growth delay of 20 days relative to untreated controls. This was also confirmed pathologically as mean tumor volume of irradiated mice was 30.2% that of unirradiated mice (p < 0.05).

Conclusions: We have developed a bioluminescent, orthotopic preclinical pancreas cancer model that allows noninvasive 1) normalizing of pretreatment tumor burden; 2) treatment planning and image-guided focal RT therapy; and 3) longitudinal assessment of treatment response. This unique translational model offers a means to investigate targeted and systemic agents with focused RT for pancreatic cancer.

No significant financial relationships to disclose.
Quantification of hypoxia-inducible factor-1α, vascular endothelial growth factor, and angiopoietin-2 expression in hepatocellular carcinoma using a real-time quantitative reverse transcription polymerase chain reaction.
Authors: Sharma B. , Srinivasan R. , Chawla Y. K. , Chakraborty A. , Kapil S. , Singla B. , Duseja A. , Dhiman R. K. , Kalra N.
Published: February 2017

223

Background: Hepatocellular carcinoma (HCC) is characteristically a hypervascular tumor and its progression is closely related to angiogenesis. Hypoxia inducible factor-1α (HIF-1 α), vascular endothelial growth factor (VEGF), and angiopioetin-2 (Ang-2) are key angiogenic factors in HCC. In this study, expression of HIF-1α, VEGF, and Ang-2 were analyzed and correlated with clinicopathologic features of HCC.

Methods: Expression of HIF-1α, VEGF, and Ang-2 were analyzed by real-time quantitative reverse transcription polymerase chain reaction in 67 HCC patients (23HBV, 22HCV, 22NBNC) with mean age 59.09 ± 11.13 years (60 M: 7 F), 9 cirrhosis patients (2HBV, 2HCV, 5ALD) with mean age 48.33 ± 11.31 years (8 M:1 F), and 14 chronic hepatitis patients (7HBV, 7HCV) with mean age 48.33 ± 7.17 years (10 M: 4 F), respectively. HCC was diagnosed on the basis of EASL (European Association for the Study of the Liver) criteria.

Results: Expression of HIF-1α and VEGF were found to be significantly higher in patients with HCC compared with cirrhosis and chronic hepatitis. Although Ang-2 expression was higher in HCC compared to cirrhosis and chronic hepatitis but the difference was not statistically significant. The difference in the expression of HIF-1α, VEGF, and Ang-2 in cirrhosis and chronic hepatitis were not significant. Tumor size was positively correlated with HIF-1 α(p = 0.268, p = 0.030)and VEGF (p = 0.546, p = 0.0001). A positive correlation was also seen between the HIF-1α and VEGF expression (p = 0.347, p = 0.0001). However no correlation of HIF-1α, VEGF and Ang-2 was seen with portal vein thrombosis, cirrhosis, etiology, AST, ALT, and platelets.

Conclusions: HIF-1α and VEGF were highly expressed in HCC patients and may be responsible for the HCC growth. Further studies with a larger number of patients need to be done.

No significant financial relationships to disclose.
The reality of pancreas cancer care from access to delivery.
Authors: Abraham A. A. , Al-Refaie W. B. , Parsons H. M. , Dudeja V. , Vickers S. M. , Habermann E. B.
Published: February 2017

241

Background: Prior literature has identified significant demographic differences in surgically treated patients with pancreas cancer (PC). Therefore, we hypothesized that disparities in socio-demographics exist in critical parameters throughout the continuum of PC care.

Methods: We compiled a retrospective cohort of AJCC Stage I-IV PC from the California Cancer Registry. We used logistic regression to study sociodemographics as predictors of: 1) resectability at diagnosis or treatment (defined as absence of pre- or postoperative features of advanced or metastatic disease), 2) undergoing pancreatectomy, and 3) receipt of adjuvant chemotherapy (with/without radiotherapy) after surgery, while adjusting for confounders.

Results: Of 20,312 patients with PC (1994-2008), 37% presented with resectable disease. Of those, only 40% received pancreatectomy. At multivariate analysis, race did not predict resectability, yet independently predicted undergoing pancreatectomy and receiving adjuvant therapies. Whites were 1.5 times as likely as blacks to undergo pancreatectomy and, following surgery, were more likely to receive chemotherapy with or without radiotherapy (for all, p <0.01). Blacks were more likely to carry Medicaid than whites (10% vs. 5%, p<0.01). Compared to those with other insurances, Medicaid recipients showed lower odds of undergoing pancreatectomy (Table).

Conclusions: Our results suggest that race and insurance continue to influence the continuum of optimal PC care. Going forward, further policies and research should identify effective strategies to neutralize disparities in PC care.

[Table: see text]

No significant financial relationships to disclose.
Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: A phase II study of the Belgian Group of Digestive Oncology.
Authors: Borbath I. , Ceratti A. , Verslype C. , Demols A. , Delaunoit T. , Deleporte A. , Laurent S. , Vergauwe P. , Van Cutsem E. , Van Laethem J. ,   Belgian Group of Digestive Oncology
Published: February 2017

245

Background: Cholangiocarcinomas (CCK) are uncommon tumors with an increasing incidence and a poor prognosis. Epidermal growth factor receptor (EGFR) expression and activation in CCK have been demonstrated.

Methods: We conducted a multicenter phase II trial combining cetuximab (Ctx), an anti-EGFR chimerized IgG1 monoclonal antibody, to gemcitabine (Gem). Patients with either locally advanced (LA) or metastatic (M) CCK (excluding gallbladder) were included; no prior systemic therapy was allowed. Ctx was administrated at the initial dose of 400 mg/m2 and further injections at 250 mg/m2 every 7 days, and Gem was administrated at 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. The primary endpoint was the progression-free survival (PFS) rate at 6 months. A Simon 2-stage design was used. We hypothesized that Gem/Ctx would improve 6 month-PFS rate from 20% to 40%. We needed 3 patients with PFS ≥ 6 months from the first 13 to further include a total of 43 patients.

Results: Forty-four patients with advanced CCK (41% LA/59%M) were enrolled from 09/2008 to 01/2010. Median age was 61.5 years (range 40-86) and baseline ECOG PS was 0 for 68% and 1 for 32% of the patients. Forty-three percent of the patients had prior surgery. Forty-six percent of the patients were free from progression at 6 months. Median PFS was 5.8 months (95% CI, 4.4-7.4 m) and median overall survival was 11.6 months (95% CI, 8.7-14.6 m). Nine patients (20.9%) had partial response with a median duration of 5 months (range 2-10 m). Disease control rate (PR + SD > 8 weeks) was 81.4%. The most common grades 3/4 related-toxicities were haematological abnormalities (47.7%), skin rash (13.6%) and fatigue (11.3%). Due to toxicity, 6 patients discontinued study treatment; 14 and 3 patients had a Gem and Ctx dose reduction respectively. Among the nine responders, 8 experienced a skin rash of at least grade 2, suggesting a relationship between skin toxicity and efficacy.

Conclusions: Our study met its endpoint, i.e., a PFS rate of 46% at 6 months, suggesting that Gem-Ctx combination had promising activity with a manageable toxicity profile in advanced CCK. Adding Ctx to the new standard of care Gem-cisplatin deserves further investigations in CCK.

[Table: see text]
Preoperative chemotherapy in patients undergoing resection of colorectal liver metastases: Assessment of pattern of tumor response using CT registration imaging.
Authors: Cai G. , van Vledder M. G. , Kamel I. R. , Diaz L. A. , Boctor E. , Pawlik T. M. , Choti M. A.
Published: February 2017

252

Background: A significant radiologic response from preoperative chemotherapy may successfully convert some unresectable colorectal liver metastases (CRLM) to resectable disease. Understanding the pattern of tumor shrinkage in relation to the hepatic structures such as the liver capsule and vascular pedicles is important. We sought to determine the spatial relationship between individual liver metastases before and after chemotherapy, as well as to adjacent intrahepatic structures.

Methods: Using nonrigid registration of temporally separated CT scans before and after preoperative chemotherapy, 42 CRLM were evaluated in 27 patients with radiologic partial response. The response pattern was determined by independent observers and scored as: (1) asymmetric toward the liver periphery, (2) asymmetric toward the liver center, and (3) symmetric response. In addition, the shrinking pattern was characterized in relation to the liver capsule and major vascular pedicles, as well as clinicopathologic features.

Results: Among the tumors evaluated, 38/42 lesions (90%) responded asymmetrically, with only 10% undergoing a symmetric contraction. 43% shrank toward the periphery and 47% centrally. Tumors in proximity to the liver capsule were more likely to respond peripherally compared to deeper lesions (p=0.013). Unexpectedly, R1 resection was more common in tumors with peripherally directed response vs. those with central or symmetric response (p=0.027). In addition, tumors within 5 mm of a single major vascular pedicle were more likely to shrink toward (59%) and not away from the vessel. No difference in response pattern was observed in relation to tumor size, chemotherapy regimen, or presence of steatosis.

Conclusions: Tumors were found to respond asymmetrically in the vast majority of cases, either toward or away from the liver center. In addition, tumors in proximity to major vascular pedicles less commonly move away from these structures. These findings may have important implications when planning curative-intent resection or anticipating the ability to convert patients to resectable disease using preoperative chemotherapy.

No significant financial relationships to disclose.
A phase I trial of the monoclonal antibody FG-3019 to connective tissue growth factor (CTGF) in locally advanced or metastatic pancreatic cancer.
Authors: Heestand G. M. , Pipas J. M. , Valone F. , McMullen A. D. , Gadea P. , Williams D. , Zhong M. , Neff T. , Fisher G. A. , Koong A.
Published: February 2017

269

Background: CTGF is highly expressed in pancreatic tumors and is thought to mediate local desmoplasia. FG-3019 is a fully human monoclonal antibody against CTGF. Studies using FG-3019 in murine xenograft models have shown reduced tumor growth and metastasis.

Methods: This open-label, dose escalation study assessed the safety and pharmacokinetics of FG-3019 (3, 10, 15, and 25 mg/kg q14D). FG-3019 was initiated on D1 to assess single-agent toxicity. Standard gemcitabine and erlotinib were added on D15. Chemotherapy-naive patients with locally advanced or metastatic adenocarcinoma were eligible. Seventeen subjects (median age 66 yrs) were enrolled: n=4, 3, and 10 at 3, 10, and 15 mg/kg respectively. Enrollment is ongoing in the 25 mg/kg cohort. Seven subjects were female; four were stage 3, and 13 were stage 4.

Results: No safety signals were detected with single-agent FG-3019. After beginning chemotherapy, four subjects experienced seven SAEs, which were deemed unrelated to FG-3019 including three deaths: sepsis, suicide, and disease progression. Nine subjects experienced grade 3 AEs, all of which were expected in patients with pancreatic cancer. There were no grade 4 hematologic abnormalities. AEs related to gemcitabine (hematologic, abnormal LFTs) and erlotinib (rash) occurred at a rate and severity consistent with the prescribing information (preliminary data). Steady-state Cmax (median 428, range 236-455 μg/mL), and T1/2 (median 6.6, range 6.3-6.7 days) at the 10 mg/kg dose level were comparable to PK data from subjects in non-oncological trials who received FG-3019 at the same dose level. One subject had a partial response by RECIST criteria for 9.7+ months. Another subject had a minor response for 7.7 months. Three of five subjects with PET scans at baseline and D15 experienced stable to reduced PET activity before starting chemotherapy. The median TTP across all cohorts was 3.7 months (95% CI 1.9-6.2), and the median OS was 9.4 months (95% CI 1.9-10.6).

Conclusions: FG-3019 is well tolerated and dose escalation continues. Reduced PET activity after treatment with single-agent FG-3019 may indicate a biological effect of the agent.

[Table: see text]
Outcomes of continuously infused 5-fluorouracil, doxorubicin, and mitomycin-C (iFAM) as salvage regimen in patients with biliary tract cancer.
Authors: Lim K. , Han S. , Oh D. , Im S. , Kim T. , Bang Y.
Published: February 2017

282

Background: In advanced biliary tract cancer, after failure of first-line chemotherapy, salvage chemotherapy has not yet been established and the prognostic factors in salvage setting have not been widely known. The purpose of this study was to evaluate the efficacy and safety of iFAM as salvage chemotherapy in biliary tract cancer and to reveal the prognostic factors.

Methods: Eligibility included: 1) age 18-75, 2) histologically confirmed biliary tract cancer, 3) previously treated with palliative first-line chemotherapy, 4) ECOG PS 0-2, 5) adequate organ function. iFAM consisted of 5-FU 800 mg/m2 over 12 hour on days 1-5, doxorubicin 30 mg/m2 on day 1, and mitomycin-C 8 mg/m2 on day 1, every 4 weeks.

Results: Between February 2003 and August 2009, 50 patients (pts) were enrolled. The median age was 57.3 yrs (range: 26.0-71.5 yrs), and there were 33 men (66%). 32 pts (64%) had ECOG PS 0-1 and 18 pts (36%) had PS 2. Biliary tract cancers were extrahepatic cholangiocarcinoma (30%), intrahepatic cholangiocarcinoma (30%) and gallbladder cancer (40%). Previous chemotherapy mainly consisted of gemcitabine-based and 5-FU-based regimens. Median cycles of iFAM were 2 (range: 1-6). Best responses to iFAM were PR in 2 (4%) pts and SD in 9 (18%), that is response rate was 4% and disease control rate was 22% (95% CI: 7.35-28.65). The median PFS and OS were 2.2 (95% CI: 2.0–2.4) months and 5.0 (95% CI: 3.3–6.7) months, respectively. Grade 3/4 hematologic toxicities were neutropenia (10%), anemia (2%), and thrombocytopenia (8%). Frequent nonhematologic toxicities were alopecia (34%), stomatitis (28%), vomiting (24%), and diarrhea (12%), which were grade 1/2. ECOG PS (0-1 vs 2) was significant prognostic factor for both PFS (p=0.029) and OS (p=0.025). Poor response to previous chemotherapy (p=0.031) were poor prognostic factors for OS.

Conclusions: iFAM is an effective and safe treatment option in refractory biliary tract cancer and can be considered as salvage regimen, especially for patients with good PS and good response to previous chemotherapy.

No significant financial relationships to disclose.
Neoadjuvant stereotactic body radiation therapy (SBRT) for borderline resectable pancreas cancer: Moffitt Cancer Center initial experience.
Authors: Chuong M. D. , Shridhar R. , Patel M. , Klapman J. , Barthel J. S. , Vignesh S. , Hodul P. J. , Springett G. M. , Malafa M. P. , Hoffe S. E.
Published: February 2017

302

Background: Our institution has reported a strategy of using neoadjuvant GTX (gemcitabine, docetaxel, and capecitabine) chemotherapy followed by 5FU-based intensity-modulated radiation therapy (IMRT) for borderline resectable pancreas cancer. We now report our early experience with induction chemotherapy followed by stereotactic body radiation therapy (SBRT).

Methods: This retrospective review evaluates our initial 5 fraction SBRT experience in 15 patients following induction chemotherapy for borderline resectable pancreatic cancer. Staging included pancreatic protocol CT, endoscopic ultrasound, and PET/CT scan. Induction regimens consisted of GTX for 3 cycles in 12 patients and gemcitabine alone in 3. Daily SBRT was delivered to the pancreas at least 1 week after completing systemic chemotherapy. Endoscopically implanted fiducial markers and daily cone beam CT were used for image guidance. Treatment was delivered on a Varian Trilogy unit using 6-15 MV photons. Doses were selected based on dose painting the portion of tumor adjacent to the vasculature to a higher dose while meeting normal tissue constraints. The entire gross tumor received a dose of 5-6 Gy per fraction while the portion of the tumor adjacent to the vasculature resulting in the borderline designation received up to 8 Gy per fraction. Patients were re-imaged 3-4 weeks after SBRT for consideration of surgery.

Results: There were no acute or late grade 3 toxicities. At the time of this analysis, not all treated patients have reached the restaging time point, but 9 of 15 (60%) were candidates for resection. Six patients have gone to resection with negative margins and without any increased complications. Two patients were found to have disease surrounding the vasculature preventing resection. One patient had cardiac issues at surgery and resection was aborted. One patient was explored and found to have liver metastases.

Conclusions: Integration of SBRT in conjunction with systemic therapy is well-tolerated and appears to facilitate margin-negative resection in borderline resectable pancreatic cancer.

No significant financial relationships to disclose.
Incidence and risk factors for cholangitis during systemic chemotherapy among patients with advanced biliary tract cancer.
Authors: Hashimoto J. , Morizane C. , Kondo S. , Ueno H. , Mitsunaga S. , Nakachi K. , Ikeda M. , Arai Y. , Okusaka T.
Published: February 2017

313

Background: Patients with biliary tract cancer (BTC) have a high risk of developing cholangitis. In patients with advanced BTC receiving systemic chemotherapy, cholangitis might interfere with the execution of the treatment. Furthermore, cholangitis during severe immunosuppression might develop into lethal complications such as sepsis or shock. Purpose: To determine the incidence of cholangitis among patients with advanced BTC undergoing systemic chemotherapy and to identify risk factors for the development of cholangitis.

Methods: We reviewed the records of 301 patients with advanced BTC who received systemic chemotherapy at our hospital between February 2002 and July 2009. The clinical data of patients treated with gemcitabine monotherapy (GEM) as a first-line chemotherapy was retrieved.

Results: One hundred and thirty-one patients were successfully followed up throughout the entire GEM treatment. Forty-three patients had intrahepatic BTC (32.8%), 28 had extrahepatic BTC (21.4%), 11 had hilar BTC (8.4%), 7 had ampullary cancer (5.3%), and 42 had gallbladder cancer (32.1%). Interventional radiological treatment or biliary reconstruction for biliary obstruction was performed in 50 patients (37.9%) prior to the start of chemotherapy. The median time to GEM treatment failure was 126 days. Cholangitis developed in 30 patients (22.9%) during GEM, and severe cholangitis developed in 10 patients (7.6%). The median time to the first episode of cholangitis from the start of chemotherapy was 65 days. Chemotherapy was discontinued because of cholangitis in 4 patients (3.1%), but no deaths as a result of cholangitis occurred. A multivariate analysis using a logistic regression model demonstrated that the presence of hilar obstruction (p=0.0002, OR: 10.748), the loss of sphincter of Oddi function (p=0.0005,OR: 8.960), and the presence of internal biliary drainage (p=0.007, OR: 4.472) were independent risk factors of cholangitis.

Conclusions: The incidence of cholangitis during GEM treatment was 22.9% among the advanced BTC patients in this study. Hilar obstruction, the loss of sphincter of Oddi function, and internal biliary drainage may be risk factors of cholangitis.

No significant financial relationships to disclose.
The potential of shape-based treatment plan optimization for pancreatic IMRT treatments to spare organs at risk and allow for dose escalation to the tumor PTV.
Authors: Petit S. F. , Wu B. , Kazhdan M. , Dekker A. , Simari P. , Kumar R. , Taylor R. H. , Herman J. M. , McNutt T.
Published: February 2017

316

Background: Due to the low dose tolerance of the organs at risk (OARs) in the abdomen the tumor dose for pancreatic cancer patient is restricted to 50-60 Gy in 1.8-2.0 Gy fractions when combined with chemotherapy. The goal of this study was to develop a system that can determine the minimal radiation dose to the OARs of each individual patient that is achievable while maintaining adequate tumor coverage. This could guide treatment planners to spare the OARs to the fullest extent. When the minimal doses to the OAR are achieved, the total plan can be upscaled until the normal tissue dose constraints are met, allowing for an increase in tumor dose without increased normal tissue toxicity.

Methods: The minimal achievable dose to the OARs depends on its proximity to the planning target volume (PTV). The overlap volume histogram (OVH) was used to describe the spatial relation of each OAR to the PTV. A database of 33 patients, treated with IMRT, was queried to find the lowest achieved dose to an organ for any of the prior patients with less favorable PTV-OAR configurations than the current patient. This minimal dose must also be achievable for the OAR of the new patient. For 25 randomly chosen patients the lowest achievable dose to the liver and kidneys was predicted this way. Then the patients were replanned to verify if this dose could be achieved. The new plans were compared to the original clinical plans.

Results: After replanning the predicted achievable dose to the liver was realized within 1 and 2 Gy for more than 86% and 96% of the patients respectively. For the kidneys these numbers were 83% and 96%. The average improvement in terms of mean dose was 1.4 Gy (range 0 – 4.6 Gy) for the liver and 1.7 Gy (range 0 – 6.3 Gy) for the kidneys. This would have allowed an increase in PTV dose of on average 5 Gy (range 0-13 Gy) based on the liver and 8.5 Gy (range 0-38 Gy) based on the kidneys compared to the original plan, without an increase in dose to the bowel, cord, and stomach.

Conclusions: The lowest achievable dose to the OARs could accurately be predicted for pancreatic cancer patients within seconds. This can guide dosimetrists to spare the OARs or increase the PTV dose by 5 Gy without increased toxicity.

[Table: see text]
Early experience of combination treatment of sorafenib and radiotherapy in patients with advanced hepatocellular carcinoma (HCC).
Authors: Seong J.
Published: February 2017

320

Background: Although sorafenib has been recognized as a standard therapy for advanced HCC, its antitumor effect as a single modality seems unsatisfactory. In this study, we report our early experience of combination treatment of sorafenib and radiation in locally advanced or metastatic HCC.

Methods: From 2007 to 2009, a total of 22 HCC patients were treated with concurrent sorafenib (400 mg/day) and radiation. Nine patients received local radiotherapy 45-54 Gy in 1.8-5 Gy/fraction on the primary tumor with sorafenib (primary group). In the primary group, number of patients in stage III, IVA, and IVB was 1, 4, and 4, respectively. The remaining 13 patients received local radiotherapy 30-58.4 Gy in 1.8-6 Gy/fraction on the metastatic tumor with sorafenib (metastatic group). The metastatic sites involved bones (8 patients), lymph nodes (3 patients), chest wall (1 patient) and pelvic cavity (1 patient). Toxicity and tumor response were evaluated.

Results: In toxicity, the primary group presented hand-foot syndrome in 3 patients, grade 2 GI toxicity in 1 patient, and grade 2 thrombocytopenia in 1 patient. The metastatic group showed hand-foot syndrome in 2 patients and grade 1-2 GI toxicity in 4 patients. Grade 3 thrombocytopenia was observed in 2 patients, in whom the initial platelet count was less than 100,000/mm3. In tumor response, the primary group presented partial response and stable disease in 6 patients and 1 patient, respectively, among 8 assessable patients (PR rate; 6/8, 75%). Tumor marker AFP decreased from pretreatment 9,710±19,208 ng/mL to post- treatment 1,410±2,866 ng/mL. In the metastatic group, significant pain palliation was shown in 7 among 8 patients (87.5%) in Visual Analogue Scale. In the remaining 5 patients, tumor response was shown as partial response and stable disease in 4 patients and 1 patient, respectively (PR rate; 4/5, 80%).

Conclusions: In combination treatment of sorafenib and radiation, toxicity was acceptable. The substantial tumor response was also observed. Although this is the limited experience, the results of this study urge the initiation of a controlled clinical trial to verify the effect of combination treatment of sorafenib and radiotherapy.

No significant financial relationships to disclose.
Risk of metastatic spread in patients with early-stage, surgically resected pancreatic neuroendocrine tumors.
Authors: Strosberg J. R. , Cheema A. , Weber J. , Kvols L. K.
Published: February 2017

338

Background: The risk of metastatic spread among patients with early-stage surgically resected pancreatic neuroendocrine tumors has not been well established.

Methods: Patients with surgically resected localized or locally advanced pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I-III) based on the new AJCC classification. Recurrence-free survival was measured for each stage. A separate analysis was performed excluding patients who had been referred to Moffitt Cancer Center after metastatic recurrence.

Results: 123 patients with nonmetastatic, surgically resected pancreatic neuroendocrine tumors were identified. 5-year recurrence-free survival correlated with AJCC stage (p=0.01; Table).

Conclusions: The novel AJCC 7th edition TNM classification for pancreatic neuroendocrine tumors is highly prognostic for recurrence in patients with surgically resected nonmetastatic tumors.

[Table: see text]

No significant financial relationships to disclose.
Effect of bridging therapy for hepatocellular carcinoma prior to orthotopic liver transplantation on disease control and response.
Authors: Chuy J. W. , Kinkhabwala M. , Reinus J. , Tanaka K. , Kaubisch A.
Published: February 2017

343

Background: Orthotopic liver transplantation (OLT) is curative for both hepatocellular carcinoma (HCC) and underlying cirrhosis, but this option is limited by lengthy waiting times and donor organ shortages. Various bridging therapies have been employed to slow tumor progression, with reported results radiographically confirming local control with variable rates of tumor necrosis on pathologic examination of explants.

Methods: We retrospectively studied 11 patients who underwent a total of 26 locoregional therapies prior to OLT for HCC. One patient was also maintained on sorafenib. The effectiveness of bridging therapies was assessed by radiologic response and histopathological examination of the explanted livers.

Results: Sixteen tumor nodules identified in liver explants were evaluated. Pretransplant treatments included: TACE alone (5), TACE + sorafenib (2), RFA alone (1), TACE + RFA (6), or TACE + alcohol ablation (2) prior to OLT. Two nodules (13%) achieved complete tumor necrosis on explant analysis; these had been treated with TACE + RFA. Among 11 patients who underwent bridging therapies, 5 patients (45%) had no radiologic evidence of viable tumor prior to OLT. Among these patients, explant examination showed 2 patients with partial necrosis, 2 patients with at least 90% necrosis, and one patient with no evidence of viable tumor. Three patients with enhancing lesions on imaging prior to OLT had 100% concordance rate on pathological examination of the liver explant with respect to number of nodules identified.

Conclusions: Although bridging therapy prior to OLT is effective in achieving disease control, most patients have viable tumor present upon assessment of explanted livers. Absence of viable tumor by radiologic evaluation following bridging therapy does not correspond to complete tumor necrosis.

[Table: see text]

No significant financial relationships to disclose.
Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: The NORDIC VII study (NCT00145314), by the Nordic Colorectal Cancer Biomodulation Group.
Authors: Tveit K. , Guren T. , Glimelius B. , Pfeiffer P. , Sorbye H. , Pyrhonen S. , Kure E. , Ikdahl T. , Skovlund E. , Christoffersen T.
Published: February 2017

365

Background: The role of anti-EGFR therapy in first-line treatment of metastatic colorectal cancer (mCRC) is not established. In the present study pts were randomized to FLOX or FLOX + cetuximab until progression or FLOX intermittently + cetuximab continuously.

Methods: Treatment arm A: Nordic FLOX (q2w): oxaliplatin 85 mg/m2day 1, 5-FU bolus 500 mg/m2 and FA 60 mg/m2 day 1-2; B: FLOX + cetuximab, initial dose 400 mg/m2, then 250 mg/m2/week; C: FLOX for 16 weeks + cetuximab continuously, with FLOX added at progression. Primary endpoint was progression-free survival (PFS).

Results: Between May 05-Oct 07, 571 pts were randomized, 566 pts evaluable in intention to treat (ITT) analyses. Median age was 61 (24-74). ECOG status: 0=67%, 1=29%, 2=4%. KRAS and BRAF mutation (mut) analyses were obtained in 498 (87%) and 457 pts (81%), respectively. 40% of tumors had KRAS mut, 12% had BRAF mut. Cetuximab combined with Nordic FLOX did not significantly improve RR, PFS or OS compared to FLOX. KRAS mutation was not predictive for cetuximab effect. OS was similar for patients treated with FLOX intermittently and cetuximab continuously as for patients treated until progression. BRAF mutation was a strong negative prognostic factor (median OS 7.6 vs. 20.4 mo).

Conclusions: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC, irrespective of KRAS-mut.

[Table: see text]

[Table: see text]
Analysis of preoperative CT and peroperative evaluation as predictors of involvement of hepatic pedicle LN in patients operated for CRLM.
Authors: Belghiti J. , Rau C. , Blanc B. , Ronot M. , Dokmak S. , Fuks D. , Paradis V. , Vilgrain V. , Faivre S. J.
Published: February 2017

375

Background: Approximately 20% of patients who undergo resection for colorectal liver metastases (CLM) have additional metastases present in hepatic pedicle lymph nodes (HPLN). Although LN status is a major prognostic factor, routine LN dissection is controversial. We evaluated the accuracy of preoperative CT scans and peroperative surgical assessment to determine if these methods could help determining which patients are at high risk for nodal metastases and should undergo lymphadenectomy.

Methods: Between 01-2008 and 06-2010, 76 consecutive patients who underwent liver resection and lymphadenectomy for CLM after neoadjuvant chemotherapy were enrolled in a prospective study. All patients had recent (<1 month) preoperative CT to evaluate their liver metastases and the presence, location, size and radiologic characteristics of LN were assessed. Peroperatively, the size and consistency of LN were evaluated by the surgeon. Surgeons and radiologists independently assessed LN involvement. Results were compared to the definitive pathologic examination.

Results: Among the 76 patients, 241 nodes were analyzed with a mean number of 3 (± 2) nodes removed per patient. Lymphadenectomy increased the surgical procedure by 20 minutes (12-25 min) and there was no specific morbidity or mortality related to LN clearance. Pathologic HPLN involvement was observed in 15 (20%) patients with a median number of 2 (1-6) metastatic nodes per patient. Peroperative assessment had a high negative predictive value (NPV) = 91% with a low positive predictive value (PPV) = 43%. CT scan assessment had also a NPV and PPV of 85% and 56%, respectively. When considering both peroperative and radiologic data, 27% of patients with pathologic LN involvement were not anticipated and 25% of patients who were node negative on pathologic examination had suspected LN involvement.

Conclusions: A selective strategy limiting HPLN clearance to high risk patients relies on information from preoperative CT scans and eroperative surgical assessment. Given that both modalities cannot accurately predict nodal pathologic status, routine HPLN dissection should be performed in patients who undergo resection of CRLM.

No significant financial relationships to disclose.