bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes in pancreatic adenocarcinoma (PAC) associated with a known BRCA mutation.
Authors: Lowery M. A. , Stadler Z. K. , Ludwig E. , Salo-Mullen E. , D'Adamo D. R. , Allen P. J. , Kurtz R. C. , Kelsen D. P. , O'Reilly E. M.
Published: February 2017

268

Background: BRCA1 and -2 germ-line mutations are associated with increased risk of PAC; approximately 5% of all cases of PAC are estimated to be due to an inherited genetic mutation (Lynch, HT, et al. Pancreatology, 2001;1(5):466-471). Other BRCA-associated cancers have demonstrated increased sensitivity to platinum chemotherapy and PARP inhibitors (PARPi) with improved clinical outcomes compared to sporadic cases (J Clin Oncol, 2008 Dec 1;26(34):5530-6). Outcomes in BRCA-associated pancreatic cancer are unknown.

Methods: Patients with a known BRCA1 or -2 mutation and a diagnosis of PAC were retrospectively identified from the MSKCC Familial Pancreas Cancer Registry and via institutional database review. Outcomes and clinical characteristics were reviewed. 7 patients (1 male) with BRCA2 mutation and PAC, 4 patients (1 male) with BRCA1 mutation and PAC, were identified. Two further cases of BRCA mutation and cholangiocarcinoma were identified.

Results: See Table for patient demographics. Treatment for advanced disease included a PARP inhibitor (PARPi) in 2 cases; both pts had a radiologic partial response (PR) to therapy. Five patients received platinum-based chemotherapy for advanced disease, 4 of whom had a PR. Median survival for all patients was 27.6 months.

Conclusions: The use of platinum- containing chemotherapy, radiation therapy, and PARPi to target the BRCA-associated defective DNA repair mechanism is deserving of further investigation in these patients. PARPi have demonstrated promising efficacy in patients with BRCA-mutated breast and ovarian cancer and are undergoing prospective evaluation in PAC. Genetic testing in patients presenting with a personal history or strong family history of BRCA associated cancers may help to guide choice of therapy.

[Table: see text]

No significant financial relationships to disclose.
FOLFIRI regimen as second-/third-line chemotherapy in patients with advanced pancreatic adenocarcinoma refractory to gemcitabine and platinum salts: A retrospective series of 70 patients.
Authors: Neuzillet C. , Hentic O. , Rousseau B. , Rebours V. , Bengrine-Lefèvre L. , Raymond E. , Ruszniewski P. , Louvet C. , Hammel P.
Published: February 2017

272

Background: Gemcitabine-based regimen is a standard of first-line chemotherapy in patients with advanced pancreatic adenocarcinoma (PAC) and 5-FU/oxaliplatin combination is an option for second line (Oettle, 2009). Some data suggest a potential efficacy of 5-FU/irinotecan regimen (FOLFIRI) as first-line treatment (Taïeb, 2007)or in patients with gemcitabine/platinum-refractory advanced PAC (Yoo, 2009; Gebbia, 2010).

Methods: All consecutive patients with unresectable advanced PAC (01-2005/05-2010) and OMS≤2 received FOLFIRI-1 (irinotecan 180 mg/m2 D1, n=60) or FOLFIRI-3 regimen (irinotecan 100 mg/m2 D1/D3 n=10) after failure of gemcitabine- and platinum-based chemotherapies as a systematic policy in two institutions. Following data were analyzed: tumor response, progression free survival (PFS), overall survival rate (OS), and grade 3-4 toxicities.

Results: Seventy patients were studied. Median age was 60 years (range: 24-81); 37 (52.9%) were male; 30 (42.9%) were PS 0, 27 were PS 1 and 13 were PS 2. Cancer was locally advanced in 15.7% and metastatic in 84.3% of patients. Before FOLFIRI regimen, patients received 1 line (n=24, 34.3%), 2 lines (n=40, 57.1%) or ≥ 3 lines (n=6, 8.8%) chemotherapy. PFS with previous line was less than 3 months in most patients. Tumor control was achieved in 31 (44.3%) patients (partial response: 5, stable disease: 26). PFS was 17% at 12 months and 3% at 24 months. Median PFS was 23 weeks (range: 2-147). OS was 24% at 12 months and 9% at 24 months. Median OS was 24 weeks (range: 2-147). From the initial diagnosis, 1-year and 2-year survivals were 79% and 32%. Dose adaptation was required in 21 (30.0%) patients. Eighteen (25.7%) patients had grade 3-4 toxicities, mainly hematologic (n=13) or digestive (n=6). Febrile neutropenia occurred in 3 patients without death.

Conclusions: FOLFIRI regimen after failure of gemcitabine- and platinum-based regimens for advanced PAC in our study had an acceptable toxicity and a surprising efficacy in patients OMS 0-2. These results suggest that FOLFIRI regimen should be further tested as first-line chemotherapy in patients with advanced pancreatic cancer.

No significant financial relationships to disclose.
High-dose remote afterloading intraluminal brachytherapy in the treatment of unresectable hilar or upper bile duct carcinoma.
Authors: Andoh H. , Shindo Y.
Published: February 2017

273

Background: To evaluate intraluminal brachytherapy (ILBT) for the treatment of unresectable hilar or upper bile duct carcinoma.

Methods: Between 1992 and 2005, 48 patients were identified who were not indicated for surgical resections. Among them, 22 patients received only biliary drainage (group I) and 26 patients received ILBT (group II). Expandable metallic stents (EMSs) were used in 17 patients and ILBT was delivered using the Varisource 200 remote afterloading unit with a 10 Ci 192Ir or 60Co. Each treatment of ILBT delivered 6 Gy at a 1-cm depth, and was repeated weekly for 5 weeks. A total of 30 Gy was administered to each patient. Survival rates between the groups were compared using Kaplan-Meier survival curves.

Results: In group I, survival rates at 6 and 12 months were 9% and 0%, respectively. Median survival was only 2 months. In contrast, group II survival rates at 6, 12, and 24 months were 77%, 54%, and 9%, respectively, and the median survival of this group was 13 months. Improved survival with the use of ILBT was significant, particularly in clinical stages III, IVa (p<0.01), and IVb (p<0.05). ILBT helped keep the bile duct lumen patent for a long period, but was not effective for the treatment of patients with positive lymph node metastasis.

Conclusions: Although randomized controlled studies will be necessary, the results of the present study are encouraging for using high-dose ILBT in the treatment of unresectable hilar or upper bile duct carcinoma without lymph node metastasis.

No significant financial relationships to disclose.
Clinical update on the SHELTER study: A phase I/II trial of the HDAC inhibitor resminostat in patients with sorafenib-resistant hepatocellular carcinoma (HCC).
Authors: Bitzer M. , Horger M. , Ganten T. , Ebert M. P. , Woerns M. A. , Dollinger M. M. , Mais A. , Hauns B. , Hentsch B. , Lauer U. ,   Shelter Study Group
Published: February 2017

275

Background: Resminostat (4SC-201) is a novel oral pan-HDAC inhibitor in clinical development in a variety of cancer indications. The aim of the SHELTER study is to evaluate safety, tolerability, and efficacy in patients (pts) with HCC exhibiting progressive disease under sorafenib first-line therapy.

Methods: Sorafenib-refractory pts with advanced HCC, BCLC B or C are included in a multicenter, open-label, two-arm parallel group trial. Resminostat is administered orally on three dose levels of 200 (DL1), 400 (DL2), and 600 mg (DL3) once daily, in combination with 400 mg sorafenib (arm A) or as mono therapy (600 mg, arm B). For arm A, a precedent dose escalation of resminostat and sorafenib is performed to determine the MTD. Resminostat is administered in a “5+9” dosing schedule, consisting of 5 consecutive treatment days (D1-5) followed by a 9-day rest period resulting in 14 day cycles. In arm A sorafenib is given twice daily throughout the treatment period. Primary objective is to determine progression-free survival rate after 12 weeks (6 cycles). Secondary objectives include safety and tolerability, tumor response, estimation of TTP, OS, assessment of PK, and biomarkers.

Results: To date, 14 pts were treated either with 600 mg resminostat alone or on DL1-3 in combination with 400 mg sorafenib. The majority of AE observed so far include gastrointestinal disorders such as nausea and vomiting. Plasma exposure to resminostat increased dose-dependently on D1 (cycle 1) with mean AUC 0-6 h values of 10.5 h*mg/L (600 mg mono) and 9.01 h*mg/L (DL3). No major changes in PK characteristics of resminostat were found with or without co-administration of sorafenib. A considerable portion of patients showed stabilization of their disease (SD): 9 out of 12 pts and 4 out of 5 pts examined after 6 and 12 weeks, respectively, displayed SD. In one patient treated on DL2, SD persisted for 36 weeks along with good long-term tolerability.

Conclusions: Preliminary clinical data confirmed the favorable oral drug profile of resminostat either in mono or in combination treatment with sorafenib. Initial data on therapeutic activity to overcome resistance to sorafenib are promising.

[Table: see text]
Neoadjuvant therapy for adenocarcinomas of the duodenum and ampulla of Vater.
Authors: Manoukian G. , Lal A. , Wen S. , Jiang Z. , Shroff R. T. , Wolff R. A. , Overman M. J.
Published: February 2017

279

Background: Adenocarcinomas of the ampulla of Vater and duodenum are both rare periampullary tumors with limited data regarding the use of neoadjuvant therapy. We sought to better define the role of neoadjuvant therapy as compared to adjuvant therapy in patients with high-risk disease.

Methods: Retrospective review of the M. D. Anderson Cancer Center (MDACC) tumor registry from 5/1990 to 1/2009 identified 66 cases of ampullary (26 neoadjuvant, 40 adjuvant) and 41 cases of duodenal adenocarcinoma (18 neoadjuvant, 23 adjuvant). Only patients who received adjuvant or neoadjuvant therapy and underwent surgical resection at MDACC where included. High-risk factors were defined as T3 or T4, poor differentiation, or lymph node involvement. Relapse-free survival (RFS) and overall survival (OS) were calculated from the start of surgical resection.

Results: Median age was 61 yrs (range 30-82) and 39% were female. Neoadjuvant (n=44) and adjuvant therapy (n=63) consisted of 5-FU chemoradiation in 93% and 65%, systemic 5-FU based chemotherapy only in 5% and 24%, and gemcitabine or irinotecan based therapy in 2% and 11%, respectively. Pathological high-risk factors were seen in 77% and 95% of neoadjuvant and adjuvant patients, respectively. Indications for neoadjuvant therapy were high risk disease (70%), poor surgical candidate (16%), and concern for possible metastatic disease (14%). In the neoadjuvant group T and N downstaging were observed in 25% and 32% of patients, respectively; 3 patients (7%) had a pathological complete response. Neoadjuvant as compared to adjuvant therapy had similar 5-year OS (66% vs. 59%, p =0.8) and 5-year RFS (54% vs. 59%, p=0.4). Variables significant (p <0.05) in the multivariate analysis for OS were age >60 yrs, lymph node involvement, and margin positivity; and for RFS were lymph node involvement and margin positivity. Neither tumor type (duodenal vs. ampullary; OS HR: 1.6, p =0.2; RFS HR: 0.9, p=0.8) nor treatment type (neoadjuvant vs. adjuvant; OS HR: 1.2, p =0.6; RFS HR: 1.1, p=0.7) were significant for OS or RFS in the multivariate model.

Conclusions: Neoadjuvant therapy appears to be a viable approach for high-risk duodenal and ampullary adenocarcinomas. Further investigation of this treatment approach is needed.

[Table: see text]
Early gastric cancer: The importance of early diagnosis on prognosis of gastric carcinoma.
Authors: Bouca-Machado T. , Santos Sousa H. , Lima-da-costa E. , Pinto-de-Sousa J. , Preto J. , Sousa-Rodrigues J. , Costa-Maia J.
Published: February 2017

29

Background: The aim of this study was to evaluate the characteristics of early gastric cancer (EGC) in comparison to advanced tumors and its role in patient's prognosis.

Methods: This study was related to 1,272 patients admitted with gastric or gastroesophageal junction carcinoma in our department, between January 1988 and December 2008. During this period the incidence of EGC was 12.68% (3.62% T0, 42.75% T1a and 53.62% T1b). Several clinical, pathological and staging parameters were evaluated according to classification in EGC and advanced tumors.

Results: Significant differences were observed in location (p<0.001); type of resection surgery (p<0.001) and of lymphadenectomy (p=0.008 for Siewert and p<0.001 for Japanese classifications) with less radical surgery in EGC patients. This type of tumors presented characteristics associated with a better prognosis in the following pathological parameters: tumor dimensions (p<0.001), macroscopic form (p<0.001), Ming's classification (p<0.001), venous invasion (p<0.001) and lymphatic permeation (p<0.001). The 5-year survival rate of this series was 33.7%. There were significant differences in survival curves according to classification in EGC and advanced tumors (73% at 5 years and 26% at 5 years, respectively). Cox-regression analysis identified age, T and lymph node ratio as independent prognostic factors. There was no significant differences in age (cut-off 45 years), but there was significant differences in lymph node metastasis (p<0.001). In 23.87% of EGC there was lymph node involvement, with significant differences (p=0.002) according to the depth wall invasion [T0 (100% N0), T1a (91.5% N0, 8.5% N1), T1b (60.8% N0, 21.6% N1, 13.5% N2, 4.1% N3a)].

Conclusions: The EGC percentage in our series was lower in comparison with other countries with high incidence of gastric cancer. The prognosis of the patients with gastric carcinoma continues to be gloomy mainly due to the late diagnosis and, given that the surgical treatment doesn't seem plausible of achieving a margin of significant additional progression, the need for an early diagnosis emerges if an improvement in patient survival is desired.

No significant financial relationships to disclose.
Biliary tract cancer (BTC) in the older adult: Complex decisions for complex patients.
Authors: Horgan A. M. , McKeever E. , Knox J. J.
Published: February 2017

295

Background: BTC is an uncommon malignancy. Complex patient (pt) factors potentially determine treatment choices in older pts and may independently impact outcomes.

Methods: Between 2000 and 2010, 133 pts aged ≥ 75 years with BTC were evaluated at Princess Margaret Hospital. Clinical and histopathological characteristics, geriatric-specific factors, and survival outcomes were studied in a retrospective analysis.

Results: Median age was 79 years (range 75-93). Predominant histology was adenocarcinoma (95%). 31 pts (23%) had curative surgery, 4 (13%) had additional (neo)adjuvant chemotherapy (CT) ± radiation therapy (RT). Pathological staging included: I/II: 20 (65%); III: 6 (19%); IV: 5 (16%). 25 pts (19%) received CT ± RT alone, 4 (15%) had stage I/II and 21(84%) stage III/IV disease. 77 pts (58%) received best supportive care (BSC) alone. Radiological complete or partial response was noted for 33% of pts treated with CT [gemcitabine (gem) alone 48%; gem doublet 52%]. 24% pts discontinued CT with toxicity. Untreated pts had greater degrees of functional dependence and poorer social supports. Of those untreated, the risk of treatment was felt to outweigh potential benefit given age ± comorbidities in 17%. In 22%, the pt opted not to receive treatment. Median overall survival was 19.7 months for the surgical group, 12.3 mths for the CT ± RT group and 4.37 mths for the BSC group.

Conclusions: Untreated BTC has a poor prognosis. Factors other than clinicopathological features may impact treatment decisions. Integrating geriatric assessements into the evaluation of this vulnerable patient group may help better guide treatment choices.

[Table: see text]

No significant financial relationships to disclose.
Primary pancreatic lymphoma: A population-based analysis using the Surveillance, Epidemiology and End Results database.
Authors: Mishra M. V. , Keith S. W. , Shen X. , Biswas T.
Published: February 2017

303

Background: Primary pancreatic lymphoma (PPL) is a rare disease, accounting for only 0.5% of all pancreatic masses. The clinical presentation of PPL is similar to that of pancreatic adenocarcinoma and the two are difficult to distinguish radiographically. A paucity of literature exists on the epidemiology and outcomes of PPL. Given the limited case reports published on PPL, a comparison of the different treatment modalities has previously not been possible. Here, we present a series of 523 cases of PPL obtained from the Surveillance, Epidemiology, and End Results (SEER) database to investigate the tumor characteristics and compare the different treatment modalities.

Methods: Patients diagnosed with a primary pancreatic lymphoma from 1973-2007 were identified. Data on patient and tumor characteristics as well as initial treatment with surgery or radiation was extracted. Chemotherapy information is not available through SEER. Overall survival was calculated using the Kaplan-Meier method. A multivariate analysis was performed to determine independent prognostic factors predicting for survival using a Cox proportional hazards model.

Results: Fifty-eight percent of patients identified were male. The median age range at diagnosis was 65-69 years (range, 10-14 years – greater than 85 years). The most common histologic subtype in the present series was diffuse large B-cell lymphoma (DLBCL), which accounted for 71% of all patients. The 5-year overall survival for the group was 47%. Multivariate analysis indicates that age >60 and a marital status of single were predictive of a decreased cause-specific and overall-survival specific survival (p<0.05). Radiation therapy, but not surgery, was predictive of an improved overall survival (p<0.05).

Conclusions: PPL is a rare form of extra-nodal NHLs of the GI tract. Adjuvant radiation therapy for patients with a PPL should be strongly considered and a surgical treatment should be avoided if an early diagnosis is established. A prospective study evaluating this patient population will be difficult given the rarity PPL. We hope that this case series will provide a context in evaluating and treating patients with PPL.

No significant financial relationships to disclose.
Gemcitabine (G) fixed-dose-rate infusion (FDR) plus erlotinib (E) in patients with advanced pancreatic cancer (APC).
Authors: Munoz Llarena A. , Mane J. , Lopez-Vivanco G. , de Lobera A. Ruiz , Sancho A. , Iruarrizaga E. , Arruti M. , Marrodan I. , Fuente N. , Ballesteros D.
Published: February 2017

304

Background: G (30-minute infusion) plus E improves survival in patients with APC compared with G alone. In a recent phase III trial, G-FDR showed a trend to better OS compared with standard G (6.2 vs. 4.9 months, HR 0.83, p=0.04), although the study was underpowered to detect great difference in OS. Based on our previous experience with G-FDR, we decided to evaluate the combination of G-FDR plus E, after E approval for APC.

Methods: Patients with previously untreated pathologically confirmed APC, locally advanced (LAPC) or metastatic (MPC), and ECOG PS 0-2 were included. G 1500 mg/m2 was given by 150-min infusion (10 mg/m2/min) on days 1, 8, and 15 every 28 days combined with E 100 mg/day orally. Treatment modifications for G-FDR were planned according with previously Tempero's phase II trial, and as described in prescribing information for E.

Results: 62 pts were included (36M/26F), with a median age of 63 y-o (range 37-78). ECOG PS 0/1/2: 19/40/3. LAPC/MPC: 16/46. All except one had measurable disease. ORR was 13% (8 PR), 95% CI: 4.7-21.3, and there were 34 (55%) SD. Mean relative dose intensity for G was 0.76 and 0.90 for E. Main hematologic toxicities 3/4 per pt: anaemia 12/0, thrombocytopenia 7/4, neutropenia 18/7. Acneiform rash 1/2/3 occurred in 16/16/3 pts. Other relevant adverse events were (grade 2/3/4): diarrhoea 18/3/0, mucositis 5/1/0, infection 9/8/1, thrombosis 1/4/1 and vomiting 6/4/0. There were three treatment-related deaths (septic shock, cholangitis, and bilateral pulmonary embolism). Ten pts (all LAPC) received RT after ≤ 6 cycles, all with concomitant capecitabine 825 mg/m2 bid. In 4 pts salvage surgery were performed: 2 R0, 1 R1 and 1 R2. Median PFS was 4.9 months (95% CI: 3-6.7), 7.9 m for LAPC and 2.5 m for MPC (p = 0.004). Median OS was 10 months (95% CI: 7.1-12.9), 17.5 m for LAPC and 7 m for MPC (p = 0.019). OS was significantly shorter in males (p = 0.01) and in pts taking major opioids (p = 0.027). There was a trend to better OS in pts who developed skin rash grade ≥ 2 (p = 0.078).

Conclusions: In this noncomparative study, G-FDR plus E is a feasible regimen in APC with an acceptable toxicity and notable activity. G-FDR seems to increase hematologic toxicity compared with standard infusion.

No significant financial relationships to disclose.
Effect of blood transfusion on early outcome of liver resection for colorectal hepatic metastases.
Authors: Gruttadauria S. , Saint Georges Chaumet M. , Pagano D. , Marsh J. W. , Bartoccelli C. , Gridelli B. G.
Published: February 2017

314

Background: The useof intraoperative blood transfusions (IBT) has been associated with worse surgical outcome in patients undergoing liver resection for malignancy. However, detailed analyses are required to define clinical findings impacting short-term outcome in this scenario.The aim of this study is to evaluate whether IBT are associated with a worse short-term outcome of liver resection in patients with colorectal hepatic metastases, and to assess whether certain patient characteristics and/or surgical variables affect the need for IBT.

Methods: In a series of 127 consecutive patients who underwent partial liver resection for colorectal metastases, between July 1999 and March 2010, we studied postoperative 90 days surgical outcome relative to IBT, and the effect of a variety of factors, including type of resection, surgical technique used, concomitant colo-rectal resection, non-tumoral hepatic histological findings, site of primary tumor, and comorbidities, on the incidence of IBT.

Results: Patients who received IBT during their liver resection were more likely to have a longer postoperative length of stay (p = 0.02), to experience complications (p = 0.0003), and to experience a Clavien Grade IIIa or worse complication (p = 0.003). Furthermore, undergoing a major resection, and the presence of portal fibrosis in the non-tumoral liver were both correlated with an increase in IBT (respectively, p = 0.003 and p = 0.049), while the surgical technique used (Kellyclasia or TissueLink), the presence of steatosis, undergoing a concomitant major colonic or rectal resection, and having a major comorbidity had no effect on the incidence of IBT (p ≥ 0.05).

Conclusions: This study confirmed that receiving IBT during partial liver resection for colorectal hepatic metastases is associated with a worse short-term surgical outcome. These clinical findings suggest that although several significant factors (surgical technique chosen, comorbidities present, etc.) do not seem to influence the short-term outcome of surgery, it is important to be aware of the deleterious effects of the type of resection performed and the presence of portal fibrosis on blood loss during partial liver resection.

No significant financial relationships to disclose.
Mixed photon and neutron radiotherapy given concurrently with chemotherapy in unresectable pancreatic cancer.
Authors: Christensen M. E. , Paximadis P. , Shields A. F. , Philip P. A. , Weaver D. W. , Konski A. A.
Published: February 2017

328

Background: Unresectable tumors of the pancreas remain difficult to treat despite the advent of targeted radiotherapy and modern chemotherapy. Randomized trials exploring the efficacy of chemotherapy and radiation have demonstrated median survival of 9 to 11 months. These survival times have not improved appreciably in the modern era. The purpose of this study was to retrospectively review our institutional experience with unresectable pancreatic cancer treated with mixed photon-neutron radiotherapy given concurrently with chemotherapy.

Methods: Thirteen patients with unresectable tumors of the pancreas were treated between 1993 and 2001. All patients were treated with mixed photon-neutron radiotherapy given concurrently with chemotherapy. Median photon dose was 39.6 Gy (30.6-45Gy) and median neutron dose was 8 nGy (7-9 nGy). 12 of 13 patients were treated with neoadjuvant chemotherapy, followed by 5-FU given concurrently with radiotherapy. Median survival, overall survival, and local control were calculated for all patients.

Results: The median age of all patients was 65 years (46-75 years). Twelve patients had histologic diagnosis of adenocarcinoma, with the other having an islet cell carcinoma. All patients are now deceased. Median survival for all patients was 11.5 months (3.0-25.6 months). The 1 and 2- year overall survival was 46.2% and 7.7%, respectively. Local control of the primary tumor was excellent at 92.3%. The rate of distant metastasis was 76.9%. One patient experienced decline without documented recurrence. No grade ≥3 acute toxicities were reported. However, there were 2 grade 5 late toxicities, both caused by gastrointestinal bleeding.

Conclusions: Our experience demonstrates that treatment of unresectable pancreatic tumors with mixed photon-neutron radiotherapy given concurrently with chemotherapy results in excellent local control, with survival time equivalent to or exceeding that demonstrated in previous series. With the added capability of intensity modulated neutron radiation therapy (IMNRT), the incidence of treatment-related morbidity may be improved while taking advantage of the superior tumor control that high-LET radiation may impart.

No significant financial relationships to disclose.
Sorafenib for the treatment of patients with advanced hepatocellular carcinoma and alcoholic cirrhosis.
Authors: Giovanis P. , Vincenzi V. , Manuppelli C. , Berletti R. , Marcante M. , Ricagna F. , Pinto F. , Giusto M.
Published: February 2017

352

Background: Hepatocellular carcinoma (HCC) from alcoholic cirrhosis, associated or not with chronic hepatitis C virus (HCV) infection, is a particularly severe liver disease. Scanty and inconsistent data concerning the efficacy of sorafenib in patients (pts) with this disease are available.

Methods: Since February 2009 we screened 26 Child-Pugh liver function class A pts bearing the above characteristics. Sixteen of them (61.5%), 15 males and 1 female with median age of 69 years (range 54-79), received 400 mg sorafenib b.i.d. Predominant cause of HCC was alcohol consumption in 13 pts (81.2%), associated with chronic HCV infection in 2 pts (12.5%), and hemosiderosis in 1 pt (6.2%). All pts suffered from multiple comorbidities, and 3 had been previously treated for Burkitt lymphoma, bladder and breast cancer. One pt with prostate cancer was on treatment with androgen blockade. Median number of concomitant medications was 4 (range 2-9). Four pts never received locoregional treatment, and none had received previous antineoplastic therapy.

Results: Twelve pts (73%) discontinued sorafenib after a median time of 2 months (range 2-6). The reasons for treatment discontinuation were disease progression (4 pts), liver function deterioration (5 pts), and mild gastrointestinal adverse events (2 pts): 1 pt refused sorafenib treatment after 15 days. 2/4 patients still on treatment with sorafenib at 7, 8, 11, and 18 months showed partial response (RECIST criteria). Seven pts (40%) died because of disease progression at a median time of 5.5 months (range 2-9) and at a median overall survival time of 36 months from diagnosis (range 2-84).

Conclusions: Treatment with sorafenib in pts affected by HCC and alcoholic cirrhosis seems effective and well tolerated with high-level compliance. The most common cause of discontinuation was progression of disease and liver function deterioration.

No significant financial relationships to disclose.
Evaluation of esophageal carcinoma for a radioresistant subpopulation with cancer stem cell characteristics.
Authors: Smit J. K. , Niemantsverdriet M. , van Os R. P. , Hollema H. , Plukker J. T. , Coppes R. P.
Published: February 2017

36

Background: Neo-adjuvant chemoradiation is considered as standard treatment in esophageal cancer (EC). However, a significant proportion of these tumors do not respond well to radiotherapy. Here, we investigated the presence of radioresistant cells in EC with cancer stem cell characteristics.

Methods: EC OE-33 adenotype and OE-21 squamous cell carcinoma cell-lines and fresh tumor material of EC patients were analyzed for common CSC-markers with Fluorecence Activated Cell Sorting (FACS) and immunohistochemistry. Subpopulations were tested for clonogenic survival to determine radioresistance. Non-adherent 3D sphere-cultures and xenograft tumors generated in NOD/SCID mice were performed to investigate stem cell properties.

Results: Both cell lines lacked expression of CD133 and CD90, whereas the expression of EpCam overlapped with CD44 in OE-33. In sub-confluent cultures the expression of CD44+/CD24- was 5.6% SD ± 2.3 and 35.1% SD ± 1.3 in OE-33 and OE-21, respectively. In a clonogenic survival assay the CD44+/CD24- cells showed up to a 2-fold lower radiosensitivity compared to CD44+/CD24+ cells in both the OE-33 (p = 0.02) and the OE-21 cell line (p = 0.01). The CD44+/CD24- subpopulation had a 2.2-fold higher sphere-forming capacity compared to the CD44+/CD24+ subset (p = 0.01) in OE-33. Analysis of the spheres showed an enrichment in the CD44+/CD24- phenotype from 5.6% to 56.4% (p = 0.01) after 4 days of culturing as measured by FACS, but differentiated to a higher percentage of CD44+/CD24+ in time. Furthermore, CD44+/CD24- cells exhibited a greater in vivo tumor initiating capacity, shorter latency time and faster growth speed compared with unsorted or CD44+/CD24+ cells. Importantly, a clear CD44+/CD24- population could be identified in fresh EC biopsies of patients.

Conclusions: EC appear to contain a radioresistant CD44+/CD24- subpopulation. This phenotype displays some CSC characteristics in vitro and in vivo and is present in human EC tumors. This marker could be used in future trials to predict tumor response.

No significant financial relationships to disclose.
sFRP-1: A functional prognostic marker for gastric cancer?
Authors: Moran C. J. , Ray P. S. , Bagaria S. P. , Qu Y. , Fleisig A. J. , Sim M. , Turner R. R. , Cui X.
Published: February 2017

37

Background: Despite being a leading cause of cancer-related death world wide, gastric adenocarcinoma (GA) lacks distinctive biomarkers and targeted therapies. Underexpression of the E-cadherin gene in GA is associated with an aggressive phenotype and a poor prognosis but the mechanisms of this difference are poorly understood. Developing effective therapies for GA requires identification of critical functional markers and deeper understanding of its pathophysiology.

Methods: Unsupervised hierarchical clustering analysis of a publicly available 230-sample GA microarray dataset identified a prominent cluster (21.7%) associated with underexpression of E-cadherin and overexpression of a Wnt-family protein: secreted frizzled-related protein 1 (sFRP-1). Archival GA specimens were then assessed for the expression of sFRP-1 by immunohistochemistry. Prognostic significance was assessed using univariate and multivariate analyses. GA cell lines transfected with sFRP-1 were used to determine the role of sFRP-1 in gastric cancer.

Results: 85 patients with GA underwent surgery with curative intent; 39 stained positive for sFRP-1 (46%). In this positive group, sFRP-1 staining was focal; was commonly found on the leading edge of the infiltrating tumor mass; and was not restricted to one histopathologic group, grade, or clinical stage. On univariate analysis T stage, nodal involvement, pathologic stage, nuclear grade, E-cadherin status and sFRP-1 status were predictive of overall survival. In a multivariate model, T stage (p < 0.001), nuclear grade (p < 0.001), E-cadherin status (p = 0.031) and sFRP-1 status (p = 0.0097) were predictive of overall survival. Overexpression of sFRP-1 in GA cell lines induced mesenchymal phenotype, enhanced growth and stem cell-like properties. sFRP-1 also attenuated Wnt signaling and E-cadherin expression, but potentiated Notch and Hedgehog signaling known to be involved in GA progression. These findings suggest a Wnt-independent mechanism mediated by sFRP-1.

Conclusions: The aggressive biological subtype of gastric cancer may be linked to overexpression of sFRP-1. Our findings identify sFRP-1 as a functional prognostic biomarker for gastric cancer, which may serve as a potential therapeutic target.

No significant financial relationships to disclose.
Association of use of bisphosphonates with risk of colorectal cancer.
Authors: Rennert G. , Pinchev M. , Rennert H. S. , Gruber S. B.
Published: February 2017

371

Background: Bisphosphonates are commonly used for the treatment of osteoporosis and of bone metastases due to breast cancer and were recently reported to be associated with reduced risk of breast cancer, but their association with risk of other cancers is unknown.

Methods: The Molecular Epidemiology of Colorectal Cancer (MECC) study is a population-based case-control study in northern Israel of colorectal cancer cases and age/sex/clinic/ethnic-group matched controls. Use of bisphosphonates prior to diagnosis was assessed in a subset of 933 pairs of post-menopausal female cases and controls, enrolled in Clalit Health Services (CHS), using computerized pharmacy records.

Results: The use of bisphosphonates for more than one year prior to diagnosis, but not for less than a year, was associated with a significantly reduced relative risk of colorectal cancer (odds ratio=0.50, 95% CI: 0.35-0.71). This association remained statistically significant after adjustment for, vegetable consumption, sports activity, family history of colorectal cancer, , BMI, use of low-dose aspirin, statins, vitamin D and post-menopausal hormones (OR=0.40, 0.24-0.64). Concomitant use of bisphosphonates and statins did not further reduce the risk.

Conclusions: The use of oral bisphosphonates for more than 1 year was associated with a 60% relative reduction in the risk of colorectal cancer similar to the recently reported association of this drug class with reduction in breast cancer risk.

No significant financial relationships to disclose.
The added value of diffusion-weighted magnetic resonance imaging (DW-MRI) in the local staging of advanced colorectal pelvic cancer.
Authors: Georgiou P. A. , Tekkis P. P. , Patel U. , Antoniou A. , Darzi A. W. , Cunningham D. , Koh D. , Brown G.
Published: February 2017

378

Background: Surgeons rely on imaging to plan exenterative pelvic surgery for locally advanced primary and recurrent rectal cancer. Accurate local staging is vital in this process, as it provides information about the extent of the disease, facilitating the planning of the operation required to achieve complete resection. DW-MR imaging is a functional radiological modality that can provide indirect informationabout the water proton mobility within biologic tissue, without the need of a contrast agent. The aim of the present study was to assess the diagnostic accuracy and added value of diffusion DW-MRI in detecting colorectal tumor invasion into seven intrapelvic compartments for planning exenterative pelvic surgery.

Methods: Thirty three consecutive patients were preoperatively staged using DW-MRI to undergo exenterative surgery for locally advanced primary (n=12) and recurrent (n=21) colorectal pelvic cancer. Two radiologists reported tumor invasion for each of the seven anatomic surgical resection compartments and were blinded to histopathology and intraoperative reference standards. Accuracy, sensitivity, specificity and predictive values were calculated for the seven intrapelvic compartments. Interobserver agreement was assessed using Cohen's Kappa (k) coefficient for each compartment.

Results: The sensitivity of DW-MRI when used alone was low for all the compartments except the central (92%). Its specificity was very high for all the compartment (≥89.5%). Combining DW-MRI with conventional MRI increased the sensitivity for the lateral compartment by 8.3% to 100% and the specificity for the anterior compartment below the peritoneal reflection by 9.1% to 90.9%. The overall incremental value for the lateral compartment was 3%. The interobserver agreement was either good or very good (k≥0.669; p<0001) for all the compartments.

Conclusions: DW-MRI can improve the diagnostic accuracy of conventional MRI when staging patients with advanced colorectal pelvic cancer. Diffusion images are cheap and easy to obtain. Therefore DW-MRI should always be used in combination with conventional MRI when considering patients for exenterative pelvic surgery.

No significant financial relationships to disclose.
Clinicopathologic and genetic features of Chinese hereditary nonpolyposis colorectal cancer (HNPCC).
Authors: Liu F. , Wei W. , Nan P. , Li X. , Xu Y.
Published: February 2017

382

Background: Hereditary non-polyposis colorectal cancer (HNPCC) is the most common hereditary colorectal cancer (CRC). At least five mismatch repair genes, majorly hMLH1and hMSH2 gene mutations, are associated with this syndrome. Given the geographical and racial differences, Chinese HNPCC patients have some special characteristics compared with patients in West countries. Based on our former studies, we developed a criteria, the Fudan Criteria, for clinical diagnosis of Chinese HNPCC. The aim of this study is (1) to understand the relationship between genotype and phenotype in Chinese HNPCC; and (2) to investigate the clinical value of Fudan Criteria.

Methods: 116 unrelated probands of HNPCC or suspected HNPCC families from the Fudan Colorectal Registry were studied. 32 families fulfilled the Amsterdam criteria (AC group), 28 families fulfilled the Fudan Criteria (FD group). 56 families met the revised Bethesda guideline (BG Group). Direct DNA sequencing of all exons of hMSH2 and hMLH1 genes were performed. Mutation and clinicalpathological features were compared between the groups.

Results: 32 pathological germline mutations were identified. 16/32 mutations were located at hMLH1 and 16/32 located at hMSH2. The sensitivity of Amsterdam Criteria was 50%, specificity was 81% and Youden's index was 31%. The sensitivity of Fudan Criteria was 75%, specificity was 58% and Youden's index was 33%. In AC group, there were no significant clinicopathological differences in patients with or without mutation. However, families with hMSH2 mutation had a higher ratio of synchronous and metachronous CRC than families with hMLH1 mutation (33% vs. 6%; P=0.04). Families in AC group share the same clinicopathological features with families in FD group, except multiple relative tumors (21.6% vs.6%; P=0.001).

Conclusions: There seems no close relation between genotype and phenotype, except patients with hMSH2 mutation more frequently harbor synchronous and metachronous CRC. Fudan Criteria had a little higher sensitivity and accuracy than Amsterdam Criteria for identification of Chinese HNPCC.

No significant financial relationships to disclose.
Profile of the colorectal (CRC) cancer (Ca) patients (PTS) in Turkey: A cross-sectional disease registry study—A Turkish Oncology Group trial.
Authors: Aykan N. , Demir G. , Disci R. , Yalcin S. , Turhal N. S. , Ozdogan M. , Ozkan M. , Yaren A. , Camci C. , Akbulut H. ,   Turkish Oncology Group
Published: February 2017

394

Background: CRC Ca is one of the most common Ca worldwide. This study was designed to determine the profile of recently diagnosed CRC Ca pts in Turkey.

Methods: In this national, multicenter cross-sectional disease registry study, data for 968 pts diagnosed CRC Ca were analyzed. This non-interventional study was supported by sanofi-aventis.

Results: From October 2008 to October 2009, 662 colon (68%), 306 rectum (32%) Ca pts were registered from 21 centers in 7 geographic regions of Turkey. Characteristics are as follows. Male 61%, mean age was 60±12 for colon and 57±13 for rectum Ca. The ratio of colon and rectum Ca were equal in the Black Sea region, colon Ca was higher in the other 5 regions except Eastern Anatolia where the highest percentage of rectum Ca was observed (55% vs 45%). Red meat consumption was significantly high only in Eastern Anatolia (p<0.001). The consumption of alcohol, fruit and vegetables didn't show any difference. The percentage of smoking was slightly higher in the rectum Ca group (21% vs 16%, NS). The CRC family history was a risk factor in 7.4% colon, and in 5.6% rectum Ca pts. Among all pts, 1.5% had familial poliposis and only 0.4% had Lynch syndrome. Hypertension (29%) and diabetes mellitus (15%) were the most frequent concomitant diseases. Mean body mass index was 26 ± 4 in colon and 26 ± 5 in rectum Ca pts. Median time between the onset of symptoms and diagnosis was 3 months (mo) for colon and 4 mo for rectum Ca pts. For 46% of pts this time was longer than 4 mo. The mean weight loss in last 6 mo was slightly higher in colon Ca pts (3.9 vs 3.4 kg). Anemia was more frequent in colon Ca pts (p<0.05). Primary tumor location: sigmoid 37% for colon Ca, distal rectum 61% for rectum Ca. In total, 86% of pts were operated (88% of colon, 80% of rectum Ca). In 26% of pts emergency surgery was performed. AJCC staging at diagnosis: I-7%, II-26%, III-35%, IV-32% in colon and I-14%, II-22%, III-39%, IV:25% in rectum.

Conclusions: This study showed that colon Ca was more frequent and most of the cases were operated. Data also revealed that pts were diagnosed at considerably later stages. The role of the consumption of red meat, obesity and smoking should be evaluated in larger trial in the future.

[Table: see text]
Impact of early tumor shrinkage on long-term outcome in metastatic colorectal cancer (mCRC) treated with FOLFOX4 with or without cetuximab: Lessons from the OPUS trial.
Authors: Piessevaux H. , Bokemeyer C. , Schlichting M. , Heeger S. , Tejpar S.
Published: February 2017

398

Background: The measurement of tumor shrinkage at the first evaluation (8 weeks) was reported to predict long-term outcome in mCRC treated with irinotecan-based chemotherapy (CT) + cetuximab (cet) in first-line and chemorefractory patients (pts). The predictive power of early tumor measurements was restricted to pts treated with CT + cet compared with CT alone but isn't known for cet with other CT regimens. This was investigated in pts treated with the FOLFOX4 regimen ± cet in the OPUS trial.

Methods: Based on the 8-weekly radiological assessments reported by the investigator and reviewed by an independent review committee, relative changes in tumor size from baseline were computed and dichotomized using a 20% relative decrease cut-off value. Kaplan-Meier curves were constructed for progression-free survival (PFS) and overall survival (OS), stratified by treatment arm and KRAS status.

Results: Tumor measurements at week 8 with KRAS status were available in 297 pts. Tumor shrinkage ≥20% was associated with significantly better PFS and OS in KRAS wild-type (wt) pts treated with FOLFOX4 + cet but not in those treated with CT alone (Table).

Conclusions: When combining cet with FOLFOX4 in first-line KRAS wt mCRC, early tumor shrinkage is associated with long-term outcome. This finding is specific for the effect of cet, confirming this drug to have distinctive and rapid effects on tumor size leading to long-term outcome measures unrelated to the effect of CT.

[Table: see text]

[Table: see text]
Clinicopathological features in metastatic colorectal cancer patients with KRAS wild type compared with codon 12 and codon 13 mutant: Results from a multicenter, cross-sectional study by the Japan study group of KRAS mutation in colorectal cancer.
Authors: Yoshino T. , Watanabe T. , Yamazaki K. , Uetake H. , Ishiguro M. , Sugihara K. , Ohashi Y. ,   Japan Study Group of KRAS Mutation in Colorectal Cancer
Published: February 2017

407

Background: The KRAS mutation mainly located in the codon 12 and 13 indicates unresponsiveness of patients with metastatic colorectal cancer (CRC) to anti-epidermal growth factor receptor (EGFR) antibodies. Many studies have reported that approximately 30%-40% of CRC patients have KRAS mutations. However, the clinicopathological features of KRAS mutant CRC have not been fully clarified, especially in Asian populations. This study aimed to clarify the clinicopathological features of KRAS mutant CRC in comparison with KRAS wild type in large-scale Japanese population.

Methods: The key eligibility criteria included histologically confirmed colorectal adenocarcinoma with adequate tumor samples. Formalin-fixed paraffin-embedded tumor blocks or thinly sliced tumor sections from 389 centers were sent to commercial laboratories. Almost all KRAS point mutations in the codon 12 and 13 were investigated by direct sequencing (96%). The logistic regression analysis was used to estimate the odds ratios (ORs) and compute 95% confidential intervals (CIs).

Results: Of 5,887 registered tumor samples between Oct. 2009 and Mar. 2010, the KRAS testing were performed for 5,790 samples. As of the cut-off date, Sep. 2010, we have successfully determined the KRAS mutational status of 5,732 samples (99%).The median age was 65 years old, and 61% were male. The primary tumor site was right colon, left colon, and rectum in 30, 38, and 32% patients, respectively. The frequency of KRAS mutation was 37.6% (2,155/5,732), of which the 80% (1,714/2,155) mutations were located in codon 12. On logistic regression analysis, female gender (OR=1.212, 95% CI=1.083-1.356), older age > 50 years (OR=1.312, CI=1.056-1.628) and right colon (versus left: OR=2.177, CI=1.905- 2.489; versus rectum: OR=1.500, CI=1.308-1.720) were independent risk factors of KRAS mutant CRC. Clinicopathological features were similar between codon 12 and 13 mutant CRC.

Conclusions: This study disclosed that KRAS mutant CRC was different from KRAS wild type CRC in terms of clinicopathological features.

No significant financial relationships to disclose.
Use of genetic variations to predict toxicity associated with neoadjuvant chemoradiation for AJCC stage II/III rectal cancer.
Authors: Ho J. , Li W. , Duldulao M. P. , Chen Z. , Kim J. , Garcia-Aguilar J.
Published: February 2017

411

Background: Genetic polymorphisms have been associated with toxicity from chemotherapeutic agents for colon cancer, but none has been identified for rectal cancer. We examined the association between polymorphisms in genes for DNA repair, cell cycle progression, angiogenesis, and drug metabolism with toxicity from neoadjuvant chemoradiation treatment (CRT) for rectal cancer.

Methods: Patients with AJCC stage II/III rectal adenocarcinoma were enrolled in a phase II multicenter trial examining timing of rectal cancer response to neoadjuvant CRT. There were two treatment arms: (I) radiation (XRT) and 5-FU followed by surgery and (II) XRT/5-FU and FOLFOX followed by surgery. Treatment toxicity, classified by the NCI Common Terminology Criteria guidelines as grade 3 and above, was recorded. DNA was extracted from normal rectal mucosa and analyzed for 22 polymorphisms in 17 genes.

Results: We evaluated 110 patients (group I, n = 52; group II, n = 58). A total of 19 patients experienced grade 3+ adverse events (AE) [group I, n = 10 (19%); group II, n = 9 (16%)]. Gastrointestinal symptoms were the most common AE [group I, n = 5 (10%); group II, n = 4 (7%)]. The detection of lys allele (lys/lys or lys/gln genotypes) at codon 751 of the Xeroderma pigmentosum group D (XPD) gene was associated with increased toxicity in group II (p = 0.03), whereas homozygosity for the arg allele (i.e., arg/arg genotype) at codon 399 of the X-ray cross-complementing protein 1 (XRCC1) gene was associated with a significant increase in toxicity in both treatment groups (p = 0.009).

Conclusions: Genetic polymorphisms in DNA damage repair genes XPD and XRCC1 are associated with toxicity in rectal cancer patients receiving CRT. The identification of gene polymorphisms that predict adverse events may help to optimize patient therapy while minimizing morbidities.

No significant financial relationships to disclose.