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PDF file - 981KB, Representative Immunohistochemistry for CHD7 Expression in Primary Tumor Tissue (S1). Network Analysis via MetaCore ExPlain Process Network Analysis for genes involved in CHK1, CDC25A, AURKB, PLK1, HUS1 pathway (S2). CHD7 Knockdown Causes Gemcitabine Sensitization (S3). Mice with Xenograft Tumors Showed No Significant Difference in Body Weight (S4). CHD7 Knockdown Effect on Cell Cycle (S5). Gemcitabine Does Not Significantly Change CHD7 Protein Levels in Cells (S6).

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XLS file - 675KB, Full Results of Primary Gemcitabine Sensitivity Screen (S1). Known DNA Damage Response Genes Identified as Hits in Gemcitabine Sensitivity Screen (S2). Dysregulation, Differential Expression, and Literature RNAi Cross-Reference for Known DDR Genes and Select Hits (S3). Selected Top 15% of Gemcitabine Sensitivity Genes Tested on Secondary Screen (S4).

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment. Cancer Res; 74(10); 2677–87. ©2014 AACR.

BACKGROUND. The optimal management of patients with stage IV soft tissue sarcoma of the extremity (STSE) with distant metastases at diagnosis is unclear due to limited evidence and heterogeneity of current practice patterns. National guidelines have recommended surgical management of the primary site (SP) with or without radiotherapy (R), chemotherapy (C), and metastasectomy (M). METHODS. In the National Cancer Database (NCDB), patients with initially metastatic STSE who received definitive SP from 2004 to 2014 were identified. Survival distributions were estimated and compared using the Kaplan–Meier method and log-rank tests, and covariates were compared using Chi-square tests or analysis of variance (ANOVA). Propensity score analysis using inverse probability of treatment weighting was used. RESULTS. Overall, 1124 patients were included, with a median age of 55 years (range 18–90). Utilization of SP+M increased over time from 18.8% in 2004–2006, to 33.3% in 2007–2009, to 47.9% in 2010–2014 (p = 0.024). The addition of M to SP was associated with superior 5-year overall survival (OS) at 30.8% (SP+M+/−C+/−R) compared with 18.2% for those treated with non-surgical adjuvant therapies (SP+/−C+/−R) and 12.6% for SP alone (p

Resistance of pancreatic ductal adenocarcinoma (PDAC) to radiotherapy and chemotherapy represents a significant clinical issue. Although the mechanisms of resistance are multi-faceted, client proteins of heat shock protein 90 (HSP90) such as hypoxia induced factor-1α (HIF-1α) have a central role in this process. The purpose of this investigation was to evaluate inhibition of HSP90 as a therapeutic strategy for radiosensitization in pancreatic cancer. Ganetespib, a selective inhibitor of HSP90, was evaluated as a radio-sensitizer in setting of PDAC. Inhibition of HSP90 by ganetespib potentiated the ability of radiation therapy to limit cell proliferation and colony formation in vitro. HIF-1α expression was upregulated by irradiation and HIF-1α-overexpressing stable cell lines were resistant to radiation. Inhibition of HSP90 with ganetespib reversed the effects of HIF-1α overexpression, by reducing signaling via proliferative, angiogenic and anti-apoptotic pathways. The potentiation of the antitumor effects of chemoradiotherapy by ganetespib and modulation of key pathways (e.g. HIF-1α, STAT3, and AKT) was confirmed in vivo in nude mice bearing HPAC xenograft tumors. These novel data highlight HIF-1α-mediated mechanisms of HSP90 inhibition that sensitize PDAC cells to chemoradiotherapy. This pathway and its pleiotropic effects warrant further evaluation in concert with conventional therapy in pancreatic cancer clinical trials.

The LAP07 randomized trial calls into question the role of radiation therapy (RT) in the modern treatment of locally advanced pancreatic cancer (LAPC). However, advances in chemotherapy and RT limit application of the LAP07 results to current clinical practice. Here we utilize the National Cancer Database (NCDB) to evaluate the effects of RT in patients receiving chemotherapy for LAPC. Using the NCDB, patients with American Joint Committee on Cancer (AJCC) clinical stage T2–4, N0–1, M0 adenocarcinoma of the pancreas from 2004 to 2014 were analyzed. Patients were stratified into chemotherapy only (CT) and chemoradiation (CRT) cohorts. Patients undergoing definitive RT, defined as at least 20 fractions or ≥ 5 Gy per fraction [i.e., stereotactic body radiation therapy (SBRT)] were included in the CRT cohort. Propensity-score matching (PSM) and landmark analysis were used to address selection bias and lead-time bias, respectively. 13,004 patients met inclusion criteria, of whom 7034 (54%) received CT and 5970 (46%) received CRT. After PSM, 5215 patients remained in each cohort. The CRT cohort demonstrated better overall survival (OS) compared with CT alone, with median and 1-year OS of 12 versus 10 months, and 50% and 41%, respectively (p

BACKGROUND Octogenarians and nonagenarians with stage II/III rectal adenocarcinomas are underrepresented in the randomized trials that have established the standard-of-care therapy of preoperative chemoradiation followed by definitive resection (ie, chemoradiation and then surgery [CRT+S]). The purpose of this study was to evaluate the impact of therapies on overall survival (OS) for patients with stage II/III rectal cancers and determine predictors of therapy within the National Cancer Data Base (NCDB). METHODS In the NCDB, patients who were 80 years old or older and had clinical stage II/III rectal adenocarcinoma from 2004 to 2013 were queried. Kaplan-Meier analysis, log-rank testing, logistic regression, Cox proportional hazards regression, interaction effect testing, and propensity score–matched analysis were conducted. RESULTS The criteria were met by 2723 patients: 14.9% received no treatment, 29.7% had surgery alone, 5.0% underwent short-course radiation and then surgery (RT+S), 45.3% underwent CRT+S, and 5.1% underwent surgery and then chemoradiation (S+CRT). African American race and residence in a less educated county were associated with not receiving treatment. Male sex, older age, worsening comorbidities, and receiving no treatment or undergoing surgery alone were associated with worse OS. There was no statistical difference in OS between RT+S, S+CRT, and CRT+S. Interaction testing found that CRT+S improved OS independently of age, comorbidity status, sex, race, and tumor stage. In the propensity score–matched analysis, CRT+S was associated with improved OS in comparison with surgery alone. CONCLUSIONS A significant portion of octogenarians and nonagenarians with stage II/III rectal adenocarcinomas do not receive treatment. African American race and living in a less educated community are associated with not receiving therapy. This series suggests that CRT+S is a reasonable strategy for elderly patients who can tolerate therapy. Cancer 2017;123:4325-36. © 2017 American Cancer Society.

BACKGROUND Patients with resectable esophageal cancer (rEC) are managed with either concurrent chemoradiotherapy followed by surgery (CRSx) or concurrent chemoradiotherapy alone (cCR). To the authors' knowledge, there is insufficient evidence comparing the overall survival of patients treated with these 2 options. METHODS The National Cancer Data Base was queried for rEC cases diagnosed from 2003 through 2011. Patients with previous cancers, cervical rEC, clinical stage T1N0 disease, or metastasis were excluded. cCR was defined as radiotherapy administered within 30 days of chemotherapy. CRSx was defined as cCR followed by esophagectomy within 90 days. Overall survival was compared using Kaplan-Meier methods, propensity score matching, and extended Cox proportional hazards models. RESULTS Of the 11,122 eligible patients, 8091 (72.7%) received cCR and 3031 (27.3%) received CRSx. The odds of receiving CRSx were higher among patients with American Joint Committee on Cancer stage II disease (vs stage III), adenocarcinoma (vs squamous cell carcinoma), lesions of the lower one-third of the esophagus, private insurance, and those living >25 miles from the treating facility or in areas with a higher median income or a greater percentage of high school-educated residents. Patients aged >70 years, female patients, African-American patients, those with ≥2 comorbidities, or those treated at community programs were more likely to receive cCR. After propensity score matching, the median and 10-year survival rates were found to be significantly better with CRSx (32.5 months [95% confidence interval (95% CI), 29.6-34.8 months] and 23.8% months [95% CI, 20.0-27.9 months], respectively) compared with cCR (14.2 months [95% CI, 13.4-15.5 months] and 6.1% months [95% CI, 3.9-9.0 months], respectively). CONCLUSIONS Data from the National Cancer Data Base support the inclusion of surgery after concurrent chemoradiotherapy for patients with locally advanced rEC. Cancer 2017. © 2017 American Cancer Society.

Objectives: Esophageal adenosquamous carcinoma (ASC) is a rare tumor with characteristics of adenocarcinoma (AC) and squamous cell carcinoma (SCC), the two most common esophageal cancers. Its behavior is aggressive but poorly understood. Using the National Cancer Database (NCDB), the clinical features and overall survival of ASC were compared with AC and SCC. Methods: The NCDB was queried for patients with esophageal ASC, AC, and SCC. Univariate association of histology with patient characteristics and overall survival were analyzed and socioeconomic characteristics were balanced. Results: Clinical M stage was 0 in a significantly lower proportion of ASC (69.0%) than in AC (70.9%) or SCC (75.6%) (p < 0.001). Median survival was lower in patients with ASC (9.6 months) than with AC (13.5) or SCC (9.7) and 2-year OS was lower in patients with ASC (23.8%) than with AC (34.6%) or SCC (26.5%) (p < 0.001). The OS hazard ratio for ASC was 1.14 when compared to AC (95% CI = 1.016-1.267, p = 0.025) and 1.10 when compared to SCC, but the latter was not significant (95% CI = 0.980-1.222, p = 0.111). Conclusion: ASC is a rare tumor among esophageal carcinomas with a greater burden of metastatic disease than AC or SCC and worse OS than AC.

BACKGROUND: Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard of care approach includes curative-intent surgery, often following preoperative (neoadjuvant) radiotherapy (RT) to increase rates of tumor downstaging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. METHODS: Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT utilizing immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. RESULTS: Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger-scale clinical trials. CONCLUSIONS: This review by the NCI’s Radiation Research Program Colorectal Cancer Working Group provides an updated comprehensive examination of the continuously evolving State of the Science regarding radiosensitizer drug development in the curative treatment of CRC.

Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation.Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used.Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively.The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.

Background: Hispanic patients with esophageal cancer (EC) have racially disparate survival outcomes compared with white patients. Objectives:We explored the impact on survival of racial differences in socioeconomic factors, tumor characteristics, and rates of surgical utilization in patients with EC. Method:Using the SEER (Surveillance, Epidemiology, and End Results) registry, we identified 22,531 cases of EC in Hispanic and white patients between the ages of 18 and 65 years in 2003–2014. Of these, 6,250 cases had locoregional EC. Patients were categorized according to age, gender, education, tumor grade, histology, primary tumor site, and surgical status. Postdiagnosis survival was examined over time and compared by race and stratified by surgical status. Results: Compared with whites, Hispanics with EC had significantly higher unadjusted mortality (hazard ratio [HR] 1.11; 95% confidence interval [CI] 1.06–1.17; p < 0.001) as did Hispanics with locoregional EC (HR 1.15; 95% CI 1.03–1.29; p = 0.01). In the multivariate analysis, several socioeconomic and tumor factors were found to be independently associated with survival by race, including county of residence income and prevalence of smoking, tumor grade, stage, and primary site, and surgical utilization. After adjusting for demographic and tumor characteristics, surgical utilization in patients with locoregional EC had a significant interaction with race on overall mortality (p = 0.01). Hispanics with locoregional EC were significantly less likely to receive surgery than whites (46 vs. 60%; p < 0.001) and not receiving surgery was associated with a significantly lower overall survival (HR 2.84; 95% CI 2.65–3.04; p < 0.001). Conclusions: A lower rate of surgery among Hispanics with potentially resectable esophageal cancer was associated with a decreased survival rate when compared to whites, even when adjusting for relevant socioeconomic and tumor factors. These data support the need to better address patient barriers to surgical treatment and the systemic biases present in medical care.

BACKGROUND Stage II and III rectal cancers have been effectively treated with neoadjuvant chemoradiotherapy (NCRT) followed by definitive resection. Advancements in surgical technique and systemic therapy have prompted investigation of neoadjuvant multiagent chemotherapy (NMAC) regimens with the elimination of radiation (RT). The objective of the current study was to investigate factors that predict for the use of NCRT versus NMAC and compare outcomes using the National Cancer Data Base (NCDB) for select stage II and III rectal cancers. METHODS In the NCDB, 21,707 patients from 2004 through 2012 with clinical T2N1 (cT2N1), cT3N0, or cT3N1 rectal cancers were identified who had received NCRT or NMAC followed by low anterior resection. Kaplan-Meier analyses, log-rank tests, and Cox-proportional hazards regression analyses were conducted along with propensity score matching analysis to reduce treatment selection bias. RESULTS The 5-year actuarial overall survival (OS) rate was 75% for patients who received NCRT versus 67.2% for those who received NMAC (P

Purpose A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

UNLABELLED Adenocarcinoma of the pancreas remains a highly lethal disease, with less than 5% survival at 5 years. Borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC) account for approximately 30% of newly diagnosed cases of PC. The objective of BRPC therapy is to downstage the tumor to allow resection; the objective of LAPC therapy is to control disease and improve survival. There is no consensus on the definitions of BRPC and LAPC, which leads to major limitations in designing clinical trials and evaluating their results. A multimodality approach is always needed to ensure proper utilization and timing of chemotherapy, radiation, and surgery in the management of this disease. Combination chemotherapy regimens (5-fluorouracil, leucovorin, irinotecan, oxaliplatin, and gemcitabine [FOLFIRINOX] and gemcitabine/nab-paclitaxel) have improved overall survival in metastatic disease. The role of combination chemotherapy regimens in BRPC and LAPC is an area of active investigation. There is no consensus on the dose, modality, and role of radiation therapy in the treatment of BRPC and LAPC. This article reviews the literature and highlights the areas of controversy regarding management of BRPC and LAPC. IMPLICATIONS FOR PRACTICE Pancreatic cancer is one of the worst cancers with regard to survival, even at early stages of the disease. This review evaluates all the evidence for the stages in which the cancer is not primarily resectable with surgery, known as borderline resectable or locally advanced unresectable. Recently, advancements in radiation techniques and use of better combination chemotherapies have improved survival and tolerance. There is no consensus on description of stages or treatment sequences (chemotherapy, chemoradiation, radiation), nor on the best chemotherapy regimen. The evidence behind the treatment paradigm for these stages of pancreatic cancer is summarized.

Background Pancreatic cancer (PC) is an aggressive malignancy characterised by chemoresistance. HSP90 is important for stabilisation of proteins, cell signalling and malignant growth. We hypothesised that ganetespib, an HSP90 inhibitor, can inhibit PC cell growth by interfering with multiple signalling cascades, including the Janus-activated kinase (JAK)-STAT pathway, and act synergistically with chemotherapeutic drugs. Methods The effects of ganetespib were evaluated in ASPC-1, HPAC, MIA PaCA-2 and PANC-1 cell lines using a cell proliferation assay. Effects on the expression of phosphoinositide 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK) and JAK-STAT pathways were examined by Western blot. JAK2 and STAT3 were knocked down by transient transfection with JAK2 or STAT3 small interfering RNA. ASPC-1 and HPAC cell lines were tested for sensitivity to ganetespib, 5-fluorouracil/oxaliplatin, and gemcitabine/paclitaxel, alone and in combination, using an in vivo tumour xenograft model. Results Ganetespib significantly decreased cell proliferation in all tested PC cell lines. Ganetespib decreased the activation of extracellular signal-related kinase (ERK), PI3K/AKT, and c-Jun NH2-terminal kinase (JNK) signalling molecules and diminished the activation of STAT3 in an additive manner with isolated downregulation of JAK2 expression. In animal models, ganetespib potentiated the effects of 5-fluouracil/oxaliplatin and gemcitabine/paclitaxel, as measured by tumour volume. Western blot analysis from tumours removed from animals confirmed the effects of ganetespib on PI3K/AKT, ERK and JNK pathways. Conclusions Ganetespib inhibits the growth of PC cells, an effect associated with downregulation of signalling through the JAK2-STAT3, PI3K/AKT and MAPK pathways. This provides preclinical proof-of-principle that ganetespib enhances the activity of chemotherapeutic agents and warrants further evaluation in PC clinical trials.

Background: This study was designed to investigate the impact of intensity modulated radiation therapy (IMRT) on overall survival (OS) in patients treated with chemoradiation (CRT) for anal cancer (AC). Methods: We performed a case-control, propensity score (PS) matched analysis of the National Cancer Data Base (NCDB) of patients diagnosed with non-metastatic AC from 2004 to 2013. Only patients receiving concurrent CRT were included. Patients were stratified into two groups based on the RT technique: IMRT vs . non-IMRT. Multivariate analysis (MVA) and Kaplan-Meier (KM) plots for OS were obtained for the matched and unmatched groups. Results: A total of 8,108 patients diagnosed between 2004 and 2013 were eligible for the study, of which 3,307 (40.8%) and 4,801 (59.2%) were in the IMRT and non-IMRT groups, respectively. Median follow-up for all patients was 54.4 months. After PS matching, MVA for OS showed that IMRT was associated with improved OS compared to non-IMRT (HR 0.83, 95% CI: 0.74–0.94; P=0.002). Adjusted KM analysis showed that the 5-year OS for patients treated with IMRT was 74.6% vs . 70.5% (P=0.0022). Conclusions: To our knowledge, this is the largest study to date that evaluates the impact of IMRT on OS for patients with AC. Our investigation shows that IMRT based concurrent CRT for non-metastatic AC is associated with improved survival when compared to similar patients treated with non-IMRT based therapy. In the absence of randomized evidence, our analysis might provide additional support for increasing the use of IMRT for patients with AC receiving concurrent CRT.

Scalp angiosarcomas (SA) are rare, representing1% of soft tissue sarcomas. The optimal management of these tumors is unknown, with management based on small case series. We sought to assess the impact of different therapies on overall survival (OS), the practice patterns nationally, and identify factors associated with OS for non-metastatic scalp angiosarcomas.A prospectively maintained database was used to identify non-metastatic scalp angiosarcomas who received some form of definitive therapy. Logistics regression, Kaplan-Meier, and Cox proportional-hazard models were utilized.A total of 589 patients met study entry criteria with a median follow-up of 4.2 years. The majority (482 patients, 81.8%) had upfront definitive resection and an additional 317 patients (65.8%) received postoperative radiation. Of the 107 patients who didn't have surgery, the majority (65 patients, 60.7%) received definitive radiation and 42 patients (39.3%) received radiation and chemotherapy. One-year and five-year survival estimates for patients not receiving definitive surgery were 68.0% (95%CI: 57.5-76.4) and 18.0% (95%CI: 10.2-27.5) respectively compared to 78.2% (95%CI: 74.0-81.9) and 34.1% (95%CI: 28.9-39.3) for patients receiving definitive surgery (p 0.01). On multivariable analysis, age ≥65 years, tumor size ≥5 cm, and not receiving definitive surgery was associated with worse OS.The majority of patients with non-metastatic scalp angiosarcomas had upfront definitive surgery, with a subsequent improvement in OS, including when accounting for other patient and tumor factors. Postoperative radiation was frequently given. Our large series confirmed age and tumor size as prognostic factors for this rare disease.

Background: To examine the prognostic relevance of human papillomavirus (HPV) infection for anal squamous cell carcinoma (ASCC) patients treated with chemoradiation (CRT) in the National Cancer Data Base (NCDB). Methods: The 2014 NCDB was queried for non-metastatic, histologically confirmed, ASCC patients diagnosed between 2004 and 2013. Patients were required to have HPV status documented in order to be eligible. Patients were then stratified into two groups: HPV+ and HPV−. Univariate analysis (UVA) was performed using the χ 2 test for categorical covariates and ANOVA for numerical covariates. Multivariable analysis (MVA) was performed using Cox proportional hazard model for overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated for each covariate. To minimize selection bias, propensity score (PS) weighting was implemented to balance OS related variables between the groups including: age, education level, stage, diagnosis year, insurance type, and agent of chemotherapy. Results: A total of 1,063 patients were eligible. Patients were stratified into HPV+ (n=498, 46.8%) and HPV− (n=565, 53.2%). After PS weighting, MVA for OS showed that for men, HPV infection was associated with better OS (HR: 0.60, 95% CI: 0.38–0.96; P=0.034). However, for women, HPV infection did not significantly influence survival (HR: 1.47, 95% CI: 0.96–2.25; P=0.074). Conclusions: To our knowledge, this is the largest patient series evaluating the impact of HPV infection on OS in patients with anal cancer. We found that HPV infection is associated with a statistically significant better survival for men with ASCC. In contrast, for women, HPV infection did not significantly influence survival.

To investigate the utility of quantitative PET analysis for early prediction of local control following stereotactic body radiation therapy (SBRT).An initial test cohort of fourteen cases and a validation cohort of twenty-three cases were analyzed. All patients had metastatic or recurrent cancer and underwent PET-CTs pre- and post- SBRT to a variety of sites. Local failure was defined as biopsy proven persistent/recurrent disease or progressive disease on radiologic imaging. Using deformable registration, radiation dose was transferred to the PET-CTs. Using the prescription isodose as the volume of interest (VOI), response was assessed by generating metabolic volume histograms (MVH). MVH curves examine metabolic heterogeneity in the VOI. Exploratory analyses of the test cohort evaluated the viability of multiple iso-SUV and iso-volumetric points selected from the MVH curves to serve as novel markers of response. Standard PET response markers (maximum/mean SUV and qualitative analysis) were also assessed.In the initial cohort, ten of fourteen patients achieved local control at last follow-up, a median of 225 days following post-SBRT PET. Three out of four local failures had an increase in max SUV, while all patients who achieved local control had a reduction in max SUV (p=0.01). Exploratory analyses using multiple iso-SUV and iso-volumetric points did not yield any factors associated with local control (p0.05). In the validation cohort, lower post- treatment max SUV (p=.03) and reduction in max SUV (p0.05) were significantly associated with local control.Reduction in max SUV following SBRT is associated with local control.

Background and Objectives Though necessary for improved outcomes, surgical resection is often limited in patients with locally advanced pancreatic cancers (LAPCs). We evaluated the efficacy of the approach adopted by our institution of using modified FOLFIRINOX chemotherapy followed by radiation with concurrent gemcitabine or capecitabine for patients with LAPCs, in an effort to enhance resectability while improving the toxicity profile compared with similar treatment regimens. Methods We included 29 consecutive patients with LAPC treated at our institution with the above approach in this review. We evaluated rates of resection, locol control, and survival outcomes in this cohort. Results The median follow up for this series of patients was 15.2 months. Approximately half the patients were unresectable at presentation. After neoadjuvant therapy, 41.3% of all patients were able to undergo resection of their tumors and 83% achieved an R0 resection. One-year local control for the entire cohort was 85%; one-year progression-free and overall were 49.2% and 65.5%, respectively. High rates of metastatic disease were seen regardless of resectability. There were minimal toxicities in this cohort. Conclusions Neoadjuvant therapy with induction modified FOLFIRINOX and chemoradiation presents a well-tolerated, promising treatment approach for patients with LAPC. High rates of metastatic disease highlight the need to optimize systemic and targeted agents for pancreatic adenocarcinoma. J. Surg. Oncol. 2015 111:1028–1034. © 2015 Wiley Periodicals, Inc.

Purpose To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. Methods and Materials Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. Results Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR ( P =.03), and low HIF-1α expression was significantly associated with isolated LR ( P =.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P =.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. Conclusions High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for adjuvant local radiation therapy and systemic chemotherapy.

Total mesorectal excision (TME) after neoadjuvant chemoradiotherapy (CRT) has offered superior control for patients with locally advanced rectal cancer, but can carry a quality of life cost. Fortunately, some patients achieve a complete response after CRT alone without the added morbidity caused by surgery. Efforts to increase fidelity of radiation treatment planning and delivery may allow for escalated doses of radiotherapy (RT) with limited off-target toxicity and elicit more pathological complete responses (pCR) to CRT thereby sparing more rectal cancer patients from surgery. In this review, methods of delivering escalated RT boost above 45–50.4 Gy are discussed including: 3D conformal, intensity-modulated radiotherapy (IMRT), and brachytherapy. Newly developed adaptive boost strategies and imaging modalities used in RT planning and response evaluation such as magnetic resonance imaging (MRI) and positron emission tomography (PET) are also discussed.

Octogenarians and nonagenarians with stage II/III rectal adenocarcinomas are underrepresented in the randomized trials that have established the standard-of-care therapy of preoperative chemoradiation followed by definitive resection (ie, chemoradiation and then surgery [CRT+S]). The purpose of this study was to evaluate the impact of therapies on overall survival (OS) for patients with stage II/III rectal cancers and determine predictors of therapy within the National Cancer Data Base (NCDB).In the NCDB, patients who were 80 years old or older and had clinical stage II/III rectal adenocarcinoma from 2004 to 2013 were queried. Kaplan-Meier analysis, log-rank testing, logistic regression, Cox proportional hazards regression, interaction effect testing, and propensity score-matched analysis were conducted.The criteria were met by 2723 patients: 14.9% received no treatment, 29.7% had surgery alone, 5.0% underwent short-course radiation and then surgery (RT+S), 45.3% underwent CRT+S, and 5.1% underwent surgery and then chemoradiation (S+CRT). African American race and residence in a less educated county were associated with not receiving treatment. Male sex, older age, worsening comorbidities, and receiving no treatment or undergoing surgery alone were associated with worse OS. There was no statistical difference in OS between RT+S, S+CRT, and CRT+S. Interaction testing found that CRT+S improved OS independently of age, comorbidity status, sex, race, and tumor stage. In the propensity score-matched analysis, CRT+S was associated with improved OS in comparison with surgery alone.A significant portion of octogenarians and nonagenarians with stage II/III rectal adenocarcinomas do not receive treatment. African American race and living in a less educated community are associated with not receiving therapy. This series suggests that CRT+S is a reasonable strategy for elderly patients who can tolerate therapy. Cancer 2017;123:4325-36. © 2017 American Cancer Society.

Patients with resectable esophageal cancer (rEC) are managed with either concurrent chemoradiotherapy followed by surgery (CRSx) or concurrent chemoradiotherapy alone (cCR). To the authors' knowledge, there is insufficient evidence comparing the overall survival of patients treated with these 2 options.The National Cancer Data Base was queried for rEC cases diagnosed from 2003 through 2011. Patients with previous cancers, cervical rEC, clinical stage T1N0 disease, or metastasis were excluded. cCR was defined as radiotherapy administered within 30 days of chemotherapy. CRSx was defined as cCR followed by esophagectomy within 90 days. Overall survival was compared using Kaplan-Meier methods, propensity score matching, and extended Cox proportional hazards models.Of the 11,122 eligible patients, 8091 (72.7%) received cCR and 3031 (27.3%) received CRSx. The odds of receiving CRSx were higher among patients with American Joint Committee on Cancer stage II disease (vs stage III), adenocarcinoma (vs squamous cell carcinoma), lesions of the lower one-third of the esophagus, private insurance, and those living25 miles from the treating facility or in areas with a higher median income or a greater percentage of high school-educated residents. Patients aged70 years, female patients, African-American patients, those with ≥2 comorbidities, or those treated at community programs were more likely to receive cCR. After propensity score matching, the median and 10-year survival rates were found to be significantly better with CRSx (32.5 months [95% confidence interval (95% CI), 29.6-34.8 months] and 23.8% months [95% CI, 20.0-27.9 months], respectively) compared with cCR (14.2 months [95% CI, 13.4-15.5 months] and 6.1% months [95% CI, 3.9-9.0 months], respectively).Data from the National Cancer Data Base support the inclusion of surgery after concurrent chemoradiotherapy for patients with locally advanced rEC. Cancer 2017;123:3476-85. © 2017 American Cancer Society.

Cell cycle progression and DNA synthesis are essential steps in cancer cell growth. Thymidylate synthase (TS) is a therapeutic target for 5FU. We tested the hypothesis that HSP90 transcriptional and functional inhibition can inhibit cell cycle progression, downregulate TS levels and sensitize colorectal cancer (CRC) cell lines to the effects of 5FU. Treatment with ganetespib (50 nM) for 24 hours inhibited cyclin D1 and pRb at the transcriptional and translational levels and induced p21, leading to G0/G1 cell cycle arrest in both CRC cell lines (HCT-116 and HT-29). This was associated with downregulation of E2F1 and its target gene TS. In addition, ganetespib inhibited PI3K/Akt and ERK signalling pathways. Similar effects were observed with HSP90 knockdown in both cell lines. Ganetespib sensitized CRC cell lines to the effects of oxaliplatin and 5FU. Similar effects were also observed in tumors from animals treated with ganetespib, oxaliplatin and 5FU. In this study, we present in vitro and animal data supporting that the targeting of HSP90 decreases CRC cell survival and proliferation. Ganetespib sensitizes CRC cell lines to the effects of 5FU-based chemotherapy. Combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in CRC.

Epithelial to mesenchymal transition (EMT), invasion, and motility are essential steps in colorectal cancer (CRC) metastasis regulated by HIF-1α and NF-κB. Since HSP90 activates HIF-1α and NF-κB, we hypothesized that inhibition of HSP90 leads to inhibition of HIF-1α and NF-κB resulting in inhibition of EMT, invasion, and motility. Treatment of colorectal cancer cell lines HT-29 and HCT-116 with ganetespib at 50 nM for 24 h inhibited EMT (downregulated vimentin and upregulated E-cadherin), matrigel invasion, and spheroid migration. Ganetespib treatment or HSP90 knockdown downregulated molecular pathways associated with EMT, invasion, and motility. The overexpression of HIF-1α or NF-κB resulted in increased EMT, invasion, and motility in both cell lines and these effects were inhibited by ganetespib. Similar effects were observed in animal xenografts treated with ganetespib. Taken together, our data demonstrate for the first time that inhibition of HSP90 downregulates both HIF-1α and NF-κB leading to inhibition of EMT, motility, and invasiveness in colorectal cancer. © 2014 Wiley Periodicals, Inc.

Purpose To assess a new method for generating patient-specific volumetric dose calculations and analyze the relationship between tumor dose and positron emission tomography (PET) response after radioembolization of hepatic melanoma metastases. Methods and Materials Yttrium-90 ( 90 Y) bremsstrahlung single photon emission computed tomography (SPECT)/computed tomography (CT) acquired after 90 Y radioembolization was convolved with published 90 Y Monte Carlo estimated dose deposition kernels to create a three-dimensional dose distribution. Dose-volume histograms were calculated for tumor volumes manually defined from magnetic resonance imaging or PET/CT imaging. Tumor response was assessed by absolute reduction in maximum standardized uptake value (SUV max ) and total lesion glycolysis (TLG). Results Seven patients with 30 tumors treated with 90 Y for hepatic metastatic melanoma with available 90 Y SPECT/CT and PET/CT before and after treatment were identified for analysis. The median (range) for minimum, mean, and maximum dose per tumor volume was 16.9 Gy (5.7–43.5 Gy), 28.6 Gy (13.8–65.6 Gy) and 36.6 Gy (20–124 Gy), respectively. Response was assessed by fluorodeoxyglucose PET/CT at a median time after treatment of 2.8 months (range, 1.2–7.9 months). Mean tumor dose ( P = .03) and the percentage of tumor volume receiving ≥ 50 Gy ( P max , whereas maximum tumor dose predicted for decrease in tumor TLG ( P Conclusions Volumetric dose calculations showed a statistically significant association with metabolic tumor response. The significant dose-response relationship points to the clinical utility of patient-specific absorbed dose calculations for radionuclide therapy.

BACKGROUND Pancreatic adenocarcinoma (PAC) has low overall survival (OS) rates and high recurrence rates following surgical resection. The role for preoperative radiation therapy (prRT) for PAC versus postoperative RT (poRT) remains uncertain. The authors used the National Cancer Data Base (NCDB) to report prRT outcomes for the largest multi-institutional patient cohort to date. METHODS NCDB data were obtained for all patients who underwent resection and external beam radiation (RT) for PAC from 1998 to 2002. Patients with metastatic (M1) disease, intraoperative RT, RT both before and after surgery, missing OS, or missing RT variables were excluded. Univariate (UV) and multivariate (MV) analysis were run using treatment characteristics, tumor characteristics, and patient demographics. The difference in patients' known characteristics was described by a chi-square test or analysis of variance. RESULTS A total of 5414 patients were identified. Of these, 277 received prRT and 5137 received poRT. Overall, 92.9% received chemotherapy and 7.1% received RT alone; 56% (2990 of 5307) of patients had stage III disease, according to American Joint Commission on Cancer (AJCC) staging manual, 5th edition. Median tumor size was 3 cm (range: 0-9.9 cm); 82% (199 of 244) of patients with prRT had negative surgical margins; 72% (3383 of 4699) of patients with poRT had negative margins. Forty-one percent (71 of 173) of patients with prRT were lymph node (LN)-positive; 65% (3159 of 4833) of patients with poRT were LN-positive. Median OS for patients with prRT was 18 months (95% CI = 18-19 months) and for patients with poRT, 19 months (95% CI = 17-22 months). CONCLUSIONS Receipt of prRT was associated with lower stage, higher rates of negative margins, and lower rates of lymph node positivity at resection. However, there was no significant difference in median OS versus that of the poRT group. Cancer 2014;120:499–506. © 2014 American Cancer Society.

Background Ampullary (AMP-A) and duodenal adenocarcinomas (DA) are rare tumors. The literature regarding treatment and outcome is very limited. The objective of this project is to compare the outcomes of AMP-A and DA. Methods The records for AMP-A and DA patients between July 1995 and July 2012 at Emory University were reviewed for demographics, pathology, treatment, and survival. Survival rates were estimated by Kaplan–Meier method and compared with log-rank test. A Cox proportional hazard model was fitted to estimate the adjusted effect of AMP-A versus DA on overall survival (OS). Results Ninety-five AMP-A and 66 DA patients were identified. No significant difference between patients with DA and AMP-A was observed for age, gender, or grade. DA presented with larger tumors and higher stages. Treatment included surgery, surgery followed by adjuvant therapy or chemotherapy alone. No OS difference was observed when controlled for stage. AMP-A was sub-classified into intestinal (IAMP), pancreaticobiliary (PBAMP), and unspecified types. IAMP tended to present at a higher grade (P = 0.045) than PBAMP. No OS difference between the IAMP and PBAMP was observed. Conclusions After accounting for stage, OS was not significantly different for AMP-A and DA patients. There was no OS difference comparing PBAMP with IAMP. J. Surg. Oncol. 2014 109:556–560. © 2013 Wiley Periodicals, Inc.

The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.

FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, and irinotecan) as compared with gemcitabine in pancreatic cancer (PC) has superior activity and increased toxicity. The bolus 5-FU contributes to the toxicity. We hypothesized that the elimination of bolus 5-FU and use of hematopoietic growth factor will improve the safety profile without compromising the activity of FOLFIRINOX.Sixty patients with PC treated with modified FOLFIRINOX (no bolus 5-FU) were reviewed. Patients were divided into metastatic or nonmetastatic (locally advanced or borderline resectable) disease. Toxicity, response rate, progression-free survival, and overall survival were evaluated.Nonmetastatic and metastatic disease were present in 24 (40%) and 36 (60%) patients, respectively. The incidence of grade 4 neutropenia, grade 3/4 diarrhea, and fatigue were 3%, 13%, and 13%, respectively. Response rate was 30%. The median progression-free survival for nonmetastatic disease was 13.7 months (95% confidence interval [CI], 9.6-24.6 months), and that for metastatic disease was 8.5 months (95% CI, 3.7-11.0 months), respectively. The median overall survival for nonmetastatic disease was 17.8 months (95% CI, 9.9 months to not estimable), and that for metastatic disease was and 9.0 months (95% CI, 7.1 months to not estimable), respectively.Modified FOLFIRINOX has an improved safety profile with maintained efficacy in metastatic PC. Modified FOLFIRINOX has promising activity in nonmetastatic disease.

The renin angiotensin system (RAS) is a network of enzymes and peptides that coalesce primarily on the angiotensin II type 1 receptor (AT1R) to induce cell proliferation, angiogenesis, fibrosis, and blood pressure control. Angiotensin-converting enzyme (ACE), the key peptidase of the RAS, is promiscuous in that it cleaves other substrates such as substance P and bradykinin. Accumulating evidence implicates ACE in the pathophysiology of carcinogenesis. While the role of ACE and its peptide network in modulating angiogenesis via the AT1R is well documented, its involvement in shaping other aspects of the tumor microenvironment remains largely unknown. Here, we review the role of ACE in modulating the immune compartment of the tumor microenvironment, which encompasses the immunosuppressive, cancer-promoting myeloid-derived suppressor cells, alternatively activated tumor-associated macrophages, and T regulatory cells. We also discuss the potential roles of peptides that accumulate in the setting of chronic ACE inhibitor use, such as bradykinin, substance P, and N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), and how they may undercut the gains of anti-angiogenesis from ACE inhibition. These emerging mechanisms may harmonize the often-conflicting results on the role of ACE inhibitors and ACE polymorphisms in various cancers and call for further investigations into the potential benefit of ACE inhibitors in some neoplasms.

The impact of adjuvant radiotherapy for pancreatic adenocarcinoma (PAC) remains controversial. We examined effects of adjuvant therapy on overall survival (OS) in PAC, using the National Cancer Data Base (NCDB).Patients with resected PAC from 1998 to 2002 were queried from the NCDB. Factors associated with receipt of adjuvant chemotherapy (ChemoOnly) versus adjuvant chemoradiotherapy (ChemoRad) versus no adjuvant treatment (NoAdjuvant) were assessed. Cox proportional hazard modeling was used to examine effect of adjuvant therapy type on OS. Propensity scores (PS) were developed for each treatment arm and used to produce matched samples for analysis to minimize selection bias.From 1998 to 2002, a total of 11,526 patients underwent resection of PAC. Of these, 1,029 (8.9 %) received ChemoOnly, 5,292 (45.9 %) received ChemoRad, and 5,205 (45.2 %) received NoAdjuvant. On univariate analysis, factors associated with improved OS included: younger age, higher income, higher facility volume, lower tumor stage and grade, negative margins and nodes, and absence of adjuvant therapy. On multivariate analysis with matched PS, factors independently associated with improved OS included: younger age, higher income, higher facility volume, later year of diagnosis, smaller tumor size, lower tumor stage, and negative tumor margins and nodes. ChemoRad had the best OS (hazard ratio 0.70, 95 % confidence interval 0.61-0.80) in a PS matched comparison with ChemoOnly (hazard ratio 1.04, 95 % confidence interval 0.93-1.18) and NoAdjuvant (index).Adjuvant chemotherapy with radiotherapy is associated with improved OS after PAC resection in a large population from the NCDB. On the basis of these analyses, radiotherapy should be a part of adjuvant therapy for PAC.

Background Mixed lineage kinase domain-like protein (MLKL) is a necrosome component mediating programmed necrosis that may be an important determinant of cancer cell death. The goal of the current study was to evaluate the prognostic value of MLKL expression in patients with pancreatic adenocarcinoma (PAC).

Purpose We assessed the accuracy of abdominal magnetic resonance imaging (MRI) for determining tumor size by comparing the preoperative contrast-enhanced T1-weighted gradient echo (3-dimensional [3D] volumetric interpolated breath-hold [VIBE]) MRI tumor size with pathologic specimen size. Methods and Materials The records of 92 patients who had both preoperative contrast-enhanced 3D VIBE MRI images and detailed pathologic specimen measurements were available for review. Primary tumor size from the MRI was independently measured by a single diagnostic radiologist (P.M.) who was blinded to the pathology reports. Pathologic tumor measurements from gross specimens were obtained from the pathology reports. The maximum dimensions of tumor measured in any plane on the MRI and the gross specimen were compared. The median difference between the pathology sample and the MRI measurements was calculated. A paired t test was conducted to test for differences between the MRI and pathology measurements. The Pearson correlation coefficient was used to measure the association of disparity between the MRI and pathology sizes with the pathology size. Disparities relative to pathology size were also examined and tested for significance using a 1-sample t test. Results The median patient age was 64.5 years. The primary site was pancreatic head in 81 patients, body in 4, and tail in 7. Three patients were American Joint Commission on Cancer stage IA, 7 stage IB, 21 stage IIA, 58 stage IIB, and 3 stage III. The 3D VIBE MRI underestimated tumor size by a median difference of 4 mm (range, −34-22 mm). The median largest tumor dimensions on MRI and pathology specimen were 2.65 cm (range, 1.5-9.5 cm) and 3.2 cm (range, 1.3-10 cm), respectively. Conclusions Contrast-enhanced 3D VIBE MRI underestimates tumor size by 4 mm when compared with pathologic specimen. Advanced abdominal MRI sequences warrant further investigation for radiation therapy planning in pancreatic adenocarcinoma before routine integration into the treatment planning process.

BACKGROUND Adjuvant radiotherapy (A-RT) for patients with resected pancreatic adenocarcinoma (PAC) is controversial. In the current study, the authors aim to determine whether there is an association between overall survival (OS) and A-RT dose. METHODS National Cancer Data Base (NCDB) data were obtained for all patients who received A-RT for resected PAC from 1998 through 2002. Univariate and multivariate survival analyses were performed along with Kaplan-Meier estimates for A-RT levels

BACKGROUND: Recent studies have demonstrated the feasibility of combining oxaliplatin with 5-fluorouracil (5-FU) or capecitibine and radiation therapy. The addition of bevacizumab to chemotherapy improves overall survival for metastatic disease. We initiated a phase 2 trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy followed by surgery and postoperative 5-FU, leucovorin, oxaliplatin (FOLFOX) and bevacizumab for locally advanced rectal cancer. METHODS: Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled. Preoperative treatment was capecitabine (825 mg/m2 twice daily from Monday to Friday), oxaliplatin (50 mg/m2 weekly), bevacizumab (5 mg/kg on days 1, 15, 29), and radiation therapy (50.4 Gy). Surgery was performed by 6 weeks after neoadjuvant therapy. Beginning 8 to 12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles. RESULTS: Fifty-four of 57 enrolled patients were eligible. Forty-nine (91%) patients completed preoperative therapy and underwent surgery. Nine patients (17%; 90% confidence interval, 9%-27%) achieved pathologic complete response. Thirty-two patients (59%) experienced pathologic tumor downstaging, and 53% and 15% of patients experienced worst grade 3 and grade 4 acute toxicity, respectively. Forty-seven percent of patients who underwent surgery experienced a surgical complication. CONCLUSIONS: The primary endpoint of a 30% pathologic complete response rate was not reached; however, the majority of patients experienced pathologic downstaging with this regimen. Increased wound-healing delays and complications may have been related to the addition of bevacizumab, oxaliplatin, or both. Continued observation of these patients will establish the long-term morbidity and efficacy of this combined modality approach. Cancer 2013. © 2012 American Cancer Society.

Genetic markers for distant metastatic disease in patients with colorectal cancer (CRC) are not well defined. Identification of genetic alterations associated with metastatic CRC could help to guide systemic and local treatment strategies. We evaluated the association of tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) copy number variation (CNV) with distant metastatic disease in patients with CRC using The Cancer Genome Atlas (TCGA).Genetic sequencing data and clinical characteristics were obtained from TCGA for all available patients with CRC. There were 515 CRC patient samples with CNV and clinical outcome data, including a subset of 144 rectal adenocarcinoma patient samples. Using the TCGA CRC dataset, CNV of TNFRSF10C was evaluated for association with distant metastatic disease (M1 vs. M0). Multivariate logistic regression analysis with odds ratio (OR) using a 95% confidence interval (CI) was performed adjusting for age, T stage, N stage, adjuvant chemotherapy, gender, microsatellite instability (MSI), location, and surgical margin status.TNFRSF10C CNV in patients with CRC was associated with distant metastatic disease [OR 4.81 (95% CI, 2.13-10.85) P0.001] and positive lymph nodes [OR 18.83 (95% CI, 8.42-42.09)]; P0.001) but not MSI (OR P=0.799). On multivariate analysis, after adjusting for pathologic T stage, N stage, adjuvant chemotherapy, gender, and MSI, TNFRSF10C CNV remained significantly associated with distant metastatic disease (OR P=0.018). Subset analysis revealed that TNFRSF10C CNV was also significantly associated with distant metastatic disease in patients with rectal adenocarcinoma (OR P=0.016).TNFRSF10C CNV in patients with CRC is associated with distant metastatic disease. With further validation, such genetic profiles could be used clinically to support optimal systemic treatment strategies versus more aggressive local therapies in patients with CRC, including radiation therapy for rectal adenocarcinoma.

Cholangiocarcinoma (CCA) is a bile duct tumor with a grim prognosis. The median survival after radiotherapy of unresectable disease is 9-12 months. The following is a review of our experience with neoadjuvant (NEO) chemoradiation followed by orthotopic liver transplantation (OLT) for CCA.Ten patients with CCAs were selected as candidates for NEO-OLT between 2008-2011. Patients with unresectable CCA above the cystic duct without intra or extrahepatic metastases were eligible. Primary sclerosing cholangitis (PSC) patients were included due to their poor resection response. Patients initially received external-beam radiation [via conventional fields or volumetric-modulated arc therapy (VMAT)] plus capecitabine (XEL) or 5-fluorouracil (5-FU), followed by either Iridium(192) (Ir(192)) brachytherapy high dose rate (HDR) or external boost. 5-FU or XEL was administered until OLT. Patients underwent periodic surveillance computed tomography (CT)/MRIs after OLT. Primary endpoints included actuarial rates (AR)/crude rates (CR) of overall survival (OS), and local control (LC) at 6, 12, and 24 months.Five males and five females were identified. Mean age was 58.3 years (range, 38-71 years). Mean composite radiation dose delivered was 59.0 Gy (range, 54-71.4 Gy). Forty percent of patients had an HDR boost. Fifty percent of patients received XEL during NEO. Two patients were excluded from the analysis as they did not go on to OLT due to metastases (n=1) and death due to GI bleed (n=1). Thirty-eight percent of the OLT patients had a pathological complete response (pCR) after NEO, while 25% required a Whipple due to positive margins. Median follow-up for the OLT group was 23 months (range, 6.5-37 months). Six, twelve, and twenty-four months LC AR was 100%. LC CR was 100% at longest interval (30 months). Six, twelve, and twenty-four months OS AR was 100%, 87.5%, and 87.5%, respectively. Mean OS AR was 30.2 months (95% CI: 22.8-37.7). OS CR was 75% at longest interval (37 months). Post OLT mortality resulted from (I) unknown causes (0.5 months), (II) allograft rejection (27.25 months). Other toxicities included: necrotic myelitis 12/10 months after NEO/OLT (n=1), post NEO biliary stricture requiring new stent (n=1); post Whipple bile leak repair (n=1), and post OLT fistula (n=1), cholangitis (n=1), and wound revision (n=2).Our outcomes using NEO-OLT for CCA are promising and comparable to other series. These results further justify (I) use of NEO and (II) prioritization of available transplant livers for CCA management.

Breast conserving therapy (BCT) that include breast conserving surgery followed by adjuvant radiation therapy has revolutioned medicine by allowing women to avoid mastectomy. Accelerated partial breast irradiation (APBI) has emerged as a valid alternative to whole-breast irradiation that requires a shorter time commitment. We report our novel experience with APBI at a large public hospital that serves low-income and potentially noncompliant patients. A retrospective chart review was conducted of women who underwent BCT for stage 0–IIA breast cancer from August 2007 to August 2010 treated with APBI with a brachytherapy catheter. Twenty-four patients (20 African American) were considered for APBI. Average age was 61 years. Four patients could not undergo APBI for technical reasons and completed whole-breast irradiation over a 5 week period. Median follow-up was 19 months. Nine patients (37.5 %) had ductal carcinoma-in-situ, and 15 patients (62.5 %) had invasive ductal carcinoma with an average tumor size of 1.1 cm. All patients had negative margins of >2 mm. Two patients (8 %) treated with the brachytherapy catheter had in-breast tumor recurrence. Thus, all 24 patients initially identified for APBI successfully completed adjuvant radiotherapy. Patient compliance with postoperative irradiation is key to minimize local recurrence after BCT for breast cancer. This success with a brachytherapy catheter in underserved women in a U.S. public hospital setting indicates that outcomes of compliance and complications are comparable to nationally published results.

To compare the biochemical outcome and toxicity scores of men with human immunodeficiency virus (HIV) and prostate cancer with a matched control population with negative or unknown HIV status when treated with external-beam radiotherapy (EBRT).A single-institution database of men with prostate cancer treated with EBRT from 1999 to 2009 was reviewed. Thirteen men with HIV were identified and matched to 2 control patients according to age, race, T stage, prostate-specific antigen level, Gleason score, RT dose, intensity-modulated RT vs. three-dimensional conformal RT, and whole-pelvis vs. prostate-only RT, for a total of 39 cases. The median follow-up time was 39 months (range, 3-110 months).The 4-year biochemical failure (BF)-free survival rate was 87% in the HIV-positive group vs. 89% in the controls (p = 0.94). Pre- and post-RT viral loads were found to be predictive of BF (p = 0.04 and p = 0.04, respectively). No men with HIV died, whereas 2 in the control group died of causes unrelated to prostate cancer. Acute and chronic genitourinary and gastrointestinal toxicity were less in the HIV-positive patients than in controls (p0.001, p0.001, p = 0.003, and p0.001, respectively). The HIV-positive men experienced an average decline in CD4 count of 193 cells/mm(3).Our findings suggest that men with HIV treated with EBRT have a similar risk of BF; however, high viral loads may contribute to an increased risk. This analysis supports that HIV-positive men with prostate cancer can be treated with definitive EBRT with similar disease control and toxicity outcomes as in the general population.

Purpose The indications for upfront laryngectomy in the management of laryngeal cancer are a functionless larynx and extralaryngeal extension. Practically, clinicians rely on imaging to predict which patients will have T4 disease. Our goal was to review the accuracy of preoperative computed tomography (CT) scanning in determining the necessity for initial laryngectomy for advanced laryngeal cancer. Patients and Methods In total, 107 consecutive untreated laryngectomy specimens with high-quality, preoperative CT imaging interpreted by our neuroradiologists were reviewed. Radiographic findings, including sclerosis, invasion, penetration, extralaryngeal spread, and subglottic extension were correlated with pathologic findings. CT images were not reinterpreted, since our purpose was to assess the original interpretations. Results CT imaging reported 23 cases of thyroid cartilage penetration and 27 cases of extralaryngeal spread. Pathology reported 12 cases of thyroid cartilage invasion, 29 cases of penetration, and 45 cases of extralaryngeal disease. CT imaging identified 17 (59%) of 29 cases of pathologically documented thyroid cartilage penetration and 22 (49%) of 45 cases of pathologically documented extralaryngeal spread. Pathologically proven extralaryngeal spread without thyroid cartilage penetration occurred in 18 (40%) of 45 cases. The positive predictive values for thyroid cartilage penetration and extralaryngeal spread were 74% and 81%. Sclerosis was of limited value in predicting thyroid cartilage invasion or penetration. Cricoid or arytenoid destruction predicted for thyroid cartilage penetration at rates of 57% and 63%. Conclusion CT imaging has clear limitations when deciding whether there is thyroid cartilage penetration or extralaryngeal spread of advanced laryngeal cancer. Extralaryngeal spread without thyroid cartilage penetration was more common than expected. Alternate methods of pretreatment assessment are needed.