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Background MicroRNAs are small (18–22 nucleotides) noncoding RNAs involved in posttranscriptional modification of many target genes. One of these, microRNA-21 (miR-21), has been shown to play a role in multiple hematologic and solid organ malignancies. We sought to determine the expression pattern of miR-21 in pancreatic cancers and its impact on clinicopathologic characteristics. Methods Eighty resected pancreatic cancer specimens were microdissected and tissue microarrays (TMA) created in duplicate. TMAs were also created for benign pancreas ( N  = 12) and chronic pancreatitis ( N  = 45). In situ hybridization (ISH) was undertaken utilizing locked nucleic acid probes for miR-21. RNA U6 and scrambled RNA served as positive and negative control, respectively. ISH was scored as 0 (absent), 1+ (faint/focal expression), or 2+ (strong expression). Kaplan–Meier survival curves were constructed and compared by log-rank analysis. Results MiR-21 expression was demonstrated in 63 (79%) pancreatic cancers (1+ in 49, 2+ in 14) compared to one of 12 (8%, p  < 0.0001) benign pancreas and 12/45 (27%, p  < 0.0001) chronic pancreatitis. None of the benign tissues demonstrated strong miR-21 expression. Although miR-21 expression did not correlate with tumor size, differentiation, nodal status, or T stage, strong miR-21 expression was predictive of poorer outcome compared to absent or faint/focal miR-21 expression in patients with node-negative disease (median 27.7 months vs. 15.2, p  = 0.037). Nodal status was also predictive of survival ( p  = 0.029). Conclusions MicroRNA-21 is significantly overexpressed in pancreatic cancers as detected by in situ hybridization. Its strong expression predicts limited survival in patients with node-negative disease and may be an important biologic marker for outcome.

Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.

Introduction Colorectal liver metastases develop in 50% of patients diagnosed with colorectal cancer. Surgical resection for colorectal liver metastasis typically involves either anatomical resection (AR) or parenchymal-sparing hepatectomy (PSH). The objective of the current study was to analyze data on parenchymal versus non-parenchymal-sparing hepatic resections for CLM. Methods A systematic review of the literature regarding parenchymal-sparing hepatectomy was performed. MEDLINE/PubMed, Cochrane, and EMBASE databases were searched for publications containing the following medical subject headings (MeSH): “Colorectal Neoplasms,” “Neoplasm Metastasis,” “Liver Neoplasms” and “Hepatectomy”. Besides, the following keywords were used to complete the literature search: “Hepatectomy,” “liver resection,” “hepatic resection,” “anatomic/anatomical,” “nonanatomic/ nonanatomical,” “major,” “minor,” “limited,” “wedge,” “CRLM/CLM,” and “colorectal liver metastasis.” Data was reviewed, aggregated, and analyzed. Results Two thousand five hundred five patients included in 12 studies who underwent either PSH ( n  = 1087 patients) or AR ( n  = 1418 patients) were identified. Most patients had a primary tumor that originated in the colon (PSH 52.2–74.4% vs. AR 53.9–74.3%) ( P  = 0.289). The majority of studies included a large subset of patients with only a solitary tumor with a reported median tumor number of 1–2 regardless of whether the patient underwent PSH or AR. Median EBL was no different among patients undergoing PSH (100–896 mL) versus AR (200–1489 mL) for CLM ( P  = 0.248). There was no difference in median length-of-stay following PSH (6–17 days) versus AR (7–15 days) ( P  = 0.747). While there was considerable inter-study variability regarding margin status, there was no difference in the incidence of R0 resection among patients undergoing PSH (66.7–100%) versus AR (71.6–98.6%) ( P  = 0.58). When assessing overall survival, there was no difference whether resection of CLM was performed with PSH (5 years OS: mean 44.7%, range 29–62%) or AR (5 years OS: mean 44.6%, range 27–64%) ( P  = 0.97). Conclusion PSH had a comparable safety and efficacy profile compared with AR and did not compromise oncologic outcomes. PSH should be considered an appropriate surgical approach to treatment for patients with CLM that facilitates preservation of hepatic parenchyma.

The efficacy of neoadjuvant therapy (NT) versus surgery first (SF) for pancreatic ductal adenocarcinoma (PDAC) remains controversial. A random-effects meta-analysis of only prospective randomized controlled trials (RCTs) comparing NT versus SF for potentially resectable (PR) or borderline resectable (BR) PDAC was performed. Among six RCTs including 850 patients, 411 (48.3%) received NT and 439 (51.6%) SF. In all included trials, NT was gemcitabine-based: four using chemoradiation and two chemotherapy alone. Based on an intention-to-treat analysis, NT resulted in improved overall survival (OS) compared to SF (HR 0.73, 95% CI 0.61–0.86). This effect was independent of anatomic classification (PR: hazard ratio (HR) 0.73, 95% CI 0.59–0.91; BR: HR 0.51 95% CI 0.28–0.93) or NT type (chemoradiation: HR 0.77, 95% CI 0.61–0.98; chemotherapy alone: HR 0.68, 95% CI 0.54–0.87). Overall resection rate was similar (risk ratio (RR) 0.93, 95% CI 0.82–1.04, I2 = 39.0%) but NT increased the likelihood of a margin-negative (R0) resection (RR 1.51, 95% CI 1.18–1.93, I2 = 0%) and having negative lymph nodes (RR 2.07, 95% CI 1.47–2.91, I2 = 12.3%). In this meta-analysis of prospective RCTs, NT significantly improved OS in an intention-to-treat fashion, compared with SF for localized PDAC. Randomized controlled trials using contemporary multi-agent chemotherapy will be needed to confirm these findings and to define the optimal NT regimen.

Introduction Biliary tract cancers (BTC) are aggressive malignancies that require complex surgical procedures. Patients with BTC can present with skeletal muscle depletion, yet the effects of muscle wasting (sarcopenia) on outcomes have not been well studied. The objective of the current study was to define the impact of sarcopenia on survival among patients undergoing resection of BTC. Methods Patients who underwent exploration for BTC who had a pre-operative CT scan available for review were identified. Body composition variables including total and psoas muscle area (cm 2 ), muscle density (Hounsfield units), visceral fat area, subcutaneous fat area, and waist-to-hip ratio were analyzed at the level of L3. Outcomes were assessed according to the presence or absence of sarcopenia defined using sex- and BMI-specific threshold values for Psoas Muscle Index (PMI, cm 2 /m 2 ). Results Among 117 patients with BTC, 78 (67%) underwent curative-intent resection and 39 (33%) were explored but did not undergo resection due to metastatic/locally advanced disease. Tumor type included distal cholangiocarcinoma ( n  = 18, 15.4%), hilar cholangiocarcinoma ( n  = 27, 23.1%), gallbladder carcinoma ( n  = 52, 44.4%), and intrahepatic cholangiocarcinoma ( n  = 20, 17.1%). Median patient age was 65.6 years and 43.6% were male. Mean patient BMI was 26.1 kg/m 2 among men and 27.5 kg/m 2 among women. Overall, 41 (35.0%) patients had sarcopenia. Sarcopenia was associated with an increased risk of death among patients who underwent resection (HR 3.52, 95%CI 1.60–7.78, p  = 0.002), which was comparable to patients with unresectable metastatic disease. Other factors such as low serum albumin (HR 3.17, 95% CI 1.30–7.74, p  = 0.011) and low psoas density (HR 2.96, 95% CI 1.21–7.21, p  = 0.017) were also associated with increased risk of death. Survival was stratified based on sarcopenia, psoas density, and serum albumin. The presence of each variable was associated with an incremental increased risk of death (0 variables ref.; 1 variable HR 3.8, 95% CI 1.0–14, p  = 0.043; 2 variables HR 13.1, 95% CI 3.0–57.7, p  = 0.001; 3 variables HR 14.6, 95% CI 2.5–87.1, p  = 0.003). Patients who had no adverse prognostic factors had a 3-year OS of 67% versus no survival among patients with all 3 factors. Conclusions Sarcopenia was common among patients undergoing resection of BTC, occurring in 1 of every 3 patients. Sarcopenia was associated with poor survival after resection, particularly among patients who experienced a recurrence. Body composition metrics such as sarcopenia and low psoas muscle density in addition to low albumin level were able to stratify patients into different prognostic categories.

Background Pancreatic cancer (PC) remains one of the most fatal forms of cancer worldwide with incidence nearly equal to mortality. This is often attributed to the fact that diagnosis is often not made until later disease stages when treatment proves difficult. Efforts have been made to reduce the mortality of PC through improvements in early screening techniques and treatments of late-stage disease. Exosomes, small extracellular vesicles involved in cellular communication, have shown promise in helping understand PC disease biology. Methods In this review, we discuss current studies of the role of exosomes in PC physiology, and their potential use as diagnostic and treatment tools. Results Exosomes have a role in diagnosing pancreatic cancer and in understanding tumor biology including migration, proliferation, chemoresistance, immunosuppression, cachexia and diabetes, and have a potential role in therapy for pancreatic cancer. Conclusions Exosomal analysis is beneficial in demonstrating mechanisms behind PC growth and metastasis, immunosuppression, drug resistance, and paraneoplastic conditions. Furthermore, the use of exosomes can be beneficial in detecting early-stage PC and exosomes have potential applications as therapeutic targets.

Background Surgical management of intrahepatic cholangiocarcinoma routinely includes resection of the hepatic parenchyma, yet the role of lymphadenectomy (LND) is more controversial. The objective of the current study was to define overall utilization, as well as temporal trends, in the utilization of LND among patients undergoing curative-intent hepatectomy for ICC using a nationwide database. Materials and Methods One thousand four hundred ninety-six patients who underwent curative-intent resection for ICC were identified using the SEER database from 2000 to 2013. The utilization of LND was assessed over time and by geographic region. LND utilization and the incidence of lymph node metastasis (LNM) were evaluated relative to AJCC T categories. Results At the time of surgery, slightly over one-half of patients ( n  = 784, 52.4%) had at least one LN evaluated. Specifically, 613 (41.0%) patients had 1–5 LNs evaluated, whereas 171 (11.4%) patients had ≥ 6 LNs evaluated. The proportion of patients who had at least one LN evaluated at the time of surgery did not change with time (2000–2004: 50.5% vs. 2005–2009: 52.0% vs. 2010–2013: 53.7%) ( p  = 0.636). In contrast, the proportion of patients who had ≥ 6 LNs examined did increase (2000–2004: 6.9% vs. 2005–2009: 10.6% vs. 2009–2013: 14.3%) ( p  = 0.003). The risk of LNM was higher among patients with advanced T category tumors (Referent T1; T2a: OR 4.2, 95% CI 2.0–8.8, p  < 0.001; T2b: OR 2.4, 95% CI 1.1–4.9, p  = 0.018; T3: OR 3.6, 95% CI 1.6–7.9, p  = 0.001; T4: OR 2.2, 95% CI 1.0–4.9, p  = 0.049). In addition, the portion of patients with LNM varied among the different T categories (T1, 23.2%, T2a, 55.3%, T2b, 42.0%, T3, 51.4%, and T4, 39.5%; p  = 0.001). Conclusions Utilization of LND in the surgical management of ICC across the USA remained relatively low and did not change over the last decade. Selective utilization of LND may be problematic as T-stage was not a reliable predictor of nodal status with almost a quarter of patients with early stage disease having LNM.

Background Cancer‐associated wasting, termed cancer cachexia, has a profound effect on the morbidity and mortality of cancer patients but remains difficult to recognize and diagnose. While increases in circulating levels of a number of inflammatory cytokines have been associated with cancer cachexia, these associations were generally made in patients with advanced disease and thus may be associated with disease progression rather than directly with the cachexia syndrome. Thus, we sought to assess potential biomarkers of cancer‐induced cachexia in patients with earlier stages of disease. Methods A custom multiplex array was used to measure circulating levels of 25 soluble factors from 70 pancreatic cancer patients undergoing attempted tumour resections. A high‐sensitivity multiplex was used for increased sensitivity for nine cytokines. Results Resectable pancreatic cancer patients with cachexia had low levels of canonical pro‐inflammatory cytokines including interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), interferon‐γ (IFN‐γ), and tumour necrosis factor (TNF). Even in our more sensitive analysis, these cytokines were not associated with cancer cachexia. Of the 25 circulating factors tested, only monocyte chemoattractant protein‐1 (MCP‐1) was increased in treatment‐naïve cachectic patients compared with weight stable patients and identified as a potential biomarker for cancer cachexia. Although circulating levels of leptin and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) were found to be decreased in the same cohort of treatment‐naïve cachectic patients, these factors were closely associated with body mass index, limiting their utility as cancer cachexia biomarkers. Conclusions Unlike in advanced disease, it is possible that cachexia in patients with resectable pancreatic cancer is not associated with high levels of classical markers of systemic inflammation. However, cachectic, treatment‐naïve patients have higher levels of MCP‐1, suggesting that MCP‐1 may be useful as a biomarker of cancer cachexia.

Background The objective of the current study was to characterize the association between travel distance/hospital volume relative to outcomes following resection of cholangiocarcinoma. Methods Patients were identified using the 2004–2015 National Cancer Database and stratified into quartiles according to travel distance/hospital volume. Multivariable regression models were utilized to examine the impact of travel distance and hospital volume on quality-of-care metrics and overall survival. Results Among 5125 patients, the majority of patients had T1/2 ( N  = 2006, 41.1%) and N0 disease ( N  = 2498, 50.9%). Median hospital quartile surgical volumes in cases/year were low volume (LV) 6, intermediate low volume (ILV) 7, intermediate high volume (IHV) 12, and high volume (HV) 24 cases/year. Median travel distance quartiles in miles were short travel (ST) 2.7, intermediate short travel (IST) 7.9, intermediate long travel (ILT) 18.9, and long travel (LT) 84.7. Longer travel distances were associated with better overall survival, as every 10 miles was associated with a 2% decrease in mortality ( p  = 0.02). Differences in quality-of-care metrics were largely mediated through travel distance. Conclusions Travel distance and hospital volume were associated with certain quality-of-care metrics among patients with cholangiocarcinoma. After controlling for hospital volume and travel distance simultaneously, only travel distance was associated with decreased risk of mortality.