Pancreatic fistula (PF) is common after pancreaticoduodenectomy (PD). Its effect on recurrence and survival is not known. Retrospective study of patients undergoing PD for periampullary adenocarcinomas (2000-2012). Standard statistical analyses were performed to determine the impact of PF on disease-free survival (DFS) and overall survival (OS). There were 634 PDs (pancreatic adenocarcinoma: 347, other periampullary adenocarcinomas: 287). Any-grade PF developed in 81/634 (13%). Perioperative mortality rate was 1.7 per cent (11/634), higher in patients with PF (10 vs 0.5%, P < 0.001). In multivariable analysis, PF significantly reduced DFS in pancreatic [hazard ratio (HR) = 1.6, 95% confidence-interval (CI): 1.1-2.6, P = 0.043] but not in other periampullary adenocarcinomas [HR = 1.3 (95% CI: 0.8-2.2), P = 0.45]. Positive lymph nodes, margins, and high-grade histology were associated with decreased DFS and OS. Adjuvant therapy was associated with improved OS in pancreatic [HR = 0.7 (95% CI: 0.5-0.9), P = 0.02] but not in other periampullary adenocarcinomas [HR = 1.14 (95% CI: 0.8-1.7), P = 0.49]. PF did not alter OS in either group. After PD, PF is associated with decreased DFS in pancreatic but not in other periampullary adenocarcinomas. This decrease DFS did not alter OS. Tumor grade, lymph nodes, and resection margin status are associated with DFS and OS.

Pancreatic cancer is a type of common malignant tumors with high occurrence in the world. Most patients presented in clinic had pancreatic cancer at advanced stages. Furthermore, chemotherapy or radiotherapy had very limited success in treating pancreatic cancer. Complementary and alternative medicines, such as natural products/herbal medicines, represent exciting adjunctive therapies. In this review, we summarize the recent advances of using natural products/herbal medicines, such as Chinese herbal medicine, in combination with conventional chemotherapeutic agents to treat pancreatic cancer in preclinical and clinical trials.

This study investigated the Trk receptor family as a therapeutic target in pancreatic ductal adenocarcinoma and assessed their prognostic significance. Global gene expression analysis was investigated in prospectively collected pancreatic ductal adenocarcinomas that had either undergone neoadjuvant chemoradiation or were treated by surgery. PANC-1 and MIA-PaCa-2 cell lines were investigated to establish whether fractionated radiation altered expression of four neuroendocrine genes and whether this resulted in subsequent changes in radiosensitivity. A specific inhibitor of TrkA, B, and C, AstraZeneca 1332, was investigated in vitro and in vivo in combination with radiation. A tissue microarray was constructed from 77 pancreatic ductal adenocarcinoma patients who had undergone neoadjuvant chemoradiation and the Trk receptor, and neurogenic differentiation 1 expression was assessed and correlated with overall survival. A total of 99 genes were identified that were differentially expressed in the chemoradiation patients with neuroendocrine genes and pathways, in particular the neurogenic differentiation 1 and Trk receptor family, being prominent. Fractionated radiation upregulated the expression of neuroendocrine genes, and AstraZeneca 1332 treatment in vitro enhanced radiosensitivity. No added effect of AstraZeneca 1332 was observed in vivo. Trk receptor expression varied between isoforms but did not correlate significantly with clinical outcome. Radiation treatment upregulated neuroendocrine gene expression but the Trk receptor family does not appear to be a promising treatment target.

In this study, the combined effect of doxorubicin with cucurbitacin B on survival of anaplastic thyroid carcinoma cells was evaluated. For experiments, 8505C and CAL62 human anaplastic thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, and cytotoxic activity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, multiplexed cytotoxicity assay, and cytotoxicity assay, respectively. Reactive oxygen species production was measured. In experiments, doxorubicin and cucurbitacin B reduced cell viability in a dose- and time-dependent manner. Cotreatment of doxorubicin and cucurbitacin B, compared with treatment of doxorubicin alone, decreased the percentage of viable cells and increased cytotoxic activity. All of the combination index values were lower than 1.0, suggesting the synergism between doxorubicin and cucurbitacin B in induction of cytotoxicity. In cells treated with both doxorubicin and cucurbitacin B, compared with doxorubicin alone, the protein levels of cleaved poly(adenosine diphosphate-ribose) polymerase and cyclooxygenase 2 and reactive oxygen species production were enhanced. In contrast, the protein levels of B-cell chronic lymphocytic leukemia/lymphoma 2 and survivin and B-cell chronic lymphocytic leukemia/lymphoma 2/B-cell chronic lymphocytic leukemia/lymphoma 2-associated x protein ratio were diminished. The protein levels of Janus kinase 2 and signal transducer and activator of transcription 3 were reduced, while phospho-extracellular signal-regulated kinase 1/2 protein levels were elevated without change in total extracellular signal-regulated kinase 1/2 protein levels. These results suggest that doxorubicin synergizes with cucurbitacin B in induction of cytotoxicity in anaplastic thyroid carcinoma cells. Moreover, synergistic cytotoxicity of doxorubicin with cucurbitacin B is mediated by B-cell chronic lymphocytic leukemia/lymphoma 2 family proteins, survivin, and reactive oxygen species and modulated by Janus kinase 2/signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 in anaplastic thyroid carcinoma cells.

Primary chemotherapy treatment response monitoring in advanced epithelial ovarian cancer (EOC) is currently based on CT-imaging and serum CA125 values. Serum HE4 profile during first line chemotherapy has not been previously studied. We evaluated the HE4 profile during first line chemotherapy after primary (PDS) and interval debulking surgery (IDS). In total, 49 FIGO stage III/IV EOC patients were included in the study. 22 patients underwent PDS and 27 patients neoadjuvant chemotherapy (NACT) followed by IDS. Serial HE4 and CA125 serum samples were taken during first line chemotherapy. The association of postoperative tumor markers to surgery outcome, primary therapy outcome and progression free survival (PFS) were determined. The lowest HE4 and CA125 values during chemotherapy were compared to primary therapy outcome and PFS. The postoperative HE4 was associated to residual tumor after surgery (p = 0.0001), primary therapy outcome (p = 0.004) and PFS (p = 0.03) in all patients (n = 40). The postoperative CA125 was associated to PFS after IDS (n = 26, p = 0.006), but not after PDS. In multivariate analysis with FIGO stage (III/IV), residual tumor (0/>0) and postoperative CA125, the postoperative HE4 was the only statistically significant prognostic variable predicting PFS. Both HE4 and CA125 nadir corresponded to primary therapy outcome (HE4 p < 0.0001, CA125 p < 0.0001) and PFS (HE4 p = 0.009, CA125 p < 0.0001). HE4 is a promising candidate for EOC response monitoring. In our study, the performance of HE4 in response monitoring of first line chemotherapy was comparable to that of CA125. Of the postoperative values, only HE4 was statistically significantly associated to primary therapy outcome.

Emerging evidence shows that microRNAs (miRNAs) play important roles in the regulation of various biological and pathologic processes in human cancers and the aberrant expression of miRNAs contributes to the tumor development. In this study, our findings indicate that miR-451 is significantly overexpressed in pancreatic cancer tissues and cell lines and elevated expression of miR-451 contributes to promoted cell viability (in vitro and in vivo). Moreover, overexpression of miR-451 is closely linked to poor prognosis and lymphatic metastasis. Inhibition of miR-451 dramatically suppresses cell viability and invasion, promotes cell apoptosis, and induces cell cycle arrest. Furthermore, miR-451 directly targets CAB39 and negatively regulates its expression and inhibition of CAB39 contributes to the promoted cell viability and invasion. Our findings improve our understanding of the function of miR-451 in the identification and therapy of pancreatic cancer.

Purpose. To determine if the MMP-9 genotype has an influence on development of pituitary adenoma (PA). Methodology. The study enrolled n = 86 patients with PA and n = 526 healthy controls (reference group). The genotyping of MMP-9 was carried out using the real-time polymerase chain reaction method. Results. Our data demonstrated that the MMP-9 (-1562) C/C genotype was more frequent in PA group than in healthy controls (81.4% versus 64.6%, p = 0.002); C/C genotype was more frequently present in PA females compared to healthy control females, 81.5% versus 64.6%, p = 0.018, as well. MMP-9 (-1562) C/C genotype was frequently observed for all subgroups: noninvasive and invasive, nonrecurrence, and inactive PA compared to healthy controls: 81.8% versus 64.6%, p = 0.021; 81.0% versus 64.6%, p = 0.041; 81.8% versus 64.6%, p = 0.005; 100.0% versus 64.6%, p < 0.001, respectively. MMP-9 (-1562) C/C genotype was more frequent in inactive PA compared to active PA: 100.0% versus 71.4%; p < 0.001. Conclusion. MMP-9 (-1562) C/C genotype plays a role in nonrecurrence, inactive, and invasive as well as in nonivasive PA development.

BACKGROUND: Adrenal corticomedullary mixed tumours are very rare. Its mechanism is rarely reported. Here we report the first case of a corticomedullary mixed tumour resembling a "small adrenal gland" with distinct arrangement of the cortical and medullary layers. We further hypothesize regarding the tumorigenic mechanism of this tumour.
CASE PRESENTATION: A 58-year man had been diagnosed with diabetes and hypertension for 3 years. His 24-h urine vanillylmandelic acid (VMA) levels were slightly elevated. An abnormal circadian cortisol rhythm was noted, and his cortisol levels were not suppressed by dexamethasone. Abdominal computed tomography (CT) revealed a right adrenal gland lesion (diameter, 30 × 38 mm), while an enhanced CT showed enhancement and hypervascularization. The tumour was positive for adrenocorticotropic hormone, chromogranin A (CGA), and steroidogenic factor-1 (SF-1) on the tumour surface. Acetaldehyde dehydrogenase 1(ALDH1), CD44, CD133, Nestin, Nerve growth factor receptor (NGFR), and Sex determining region y-box 9(SOX9) staining were positive. Although administration of medications for diabetes and hypertension was stopped until surgery was performed, the blood sugar level and blood pressure were maintained after surgery.
CONCLUSIONS: This is the first report about a possible mechanism by which cancer stem cells induce adrenal corticomedullary tumours.

Osteopontin (OPN) is a novel biomarker of various cancers including ovarian carcinoma. OPN is a promising adjunct to a major biomarker of ovarian cancer, CA125, in diagnosis, differential diagnosis and prognosis. The aim of our study was to measure the plasma level of OPN and CA125 in patients with borderline ovarian tumours (BOTs), serous ovarian carcinoma, and controls to determine its potential role in the differential diagnosis between serous ovarian carcinoma and BOT. The plasma samples of 66 women were analysed using Luminex technology, designed to simultaneously measure multiple specific protein targets. The mean OPN plasma level for the control group was 23.3 ng/ml; for BOT 26.3 ng/ml; and for patients with serous ovarian carcinoma 59.5 ng/ml. Specifically, there was a significant difference between the OPN levels in patients with ovarian carcinoma and BOT (P < 0.001) as well as controls (P < 0.001). There was no difference between the mean levels of OPN in patients with BOT and the control group (P = 0.286). Using the receiver operating characteristic (ROC), we determined the utility of OPN and CA125 to differentiate between BOT and serous ovarian carcinoma. The area under the ROC curve (AUC) for OPN was 0.793 (95% confidence interval (CI) 0.669-0.917, P < 0.001) and for CA125 0.766 (95% CI 0.626-0.907, P = 0.002). Based on our data, we suggest that OPN can be used as a possible differential diagnostic biomarker to distinguish between malignant serous ovarian carcinoma and BOT.

OBJECTIVE: Diffuse sclerosing variant papillary thyroid carcinoma (DSVPTC) is an uncommon variant of papillary thyroid carcinoma (PTC). The biological behaviors and prognostic outcomes of this variant, however, are still controversial. The aim of this systematic review and meta-analysis is to investigate the prognostic significance and outcomes of DSVPTCs in comparison with classical PTCs (cPTCs).
METHODS: An electronic search was performed in five libraries: PubMed, Scopus, ISI, World Health Organization Global Health Library (WHO GHL) and Virtual Health Library (VHL) in June 2016. Published data were extracted and were pooled into odds ratios (OR), mean differences and corresponding 95% confidence intervals (CI) using random-effect model. Publication bias was analyzed using Egger's regression test and funnel plot observation.
RESULTS: From 315 articles, we included 16 articles comprising 732 DSVPTCs for meta-analysis. Overall, DSVPTC manifested more aggressive clinicopathological behaviors than cPTC such as higher rate of vascular invasion (OR: 5.33; 95% CI: 3.08-9.23), extrathyroidal extension (OR: 2.96; 95% CI: 2.04-4.30), lymph node metastasis (OR: 5.40; 95% CI: 2.82-10.35), distant metastasis (OR: 3.61; 95% CI: 1.89-6.88) and were more likely to relapse (OR: 2.83; 95% CI: 1.59-5.05). DSVPTC patients were associated with a worsened overall survival (HR: 1.89; 95% CI: 1.36-2.62).
CONCLUSION: DSVPTCs should be considered high-risk PTCs because of high propensity for tumor invasion, metastasis, relapse and mortality. Aggressiveness of DSVPTCs might be related to a different molecular pathway than that in cPTCs.

BACKGROUND/AIM: The aim of this study was to investigate the safety and feasibility of neoadjuvant nab-paclitaxel plus gemcitabine therapy for patients with borderline resectable pancreatic carcinoma (BRPC).
PATIENTS AND METHODS: The study was a prospective single-center phase I trial for patients with BRPC. The primary endpoint was the toxicity, and secondary endpoints were the resection rate, the R0 resection rate and quality of life (QOL) regarding the peripheral sensory neuropathy (PSN). This trial was registered on the UMIN Clinical Trials Registry (UMIN000018382) and on ClinicalTrials.gov (NCT02506803).
RESULTS: The overall rate of any grade and grade 3-4 events (CTCAE ver. 4.0 criteria) were 100% and 90%. The majority of these adverse events represented expected neutropenia. The resection and R0 resection rates were 80% and 70%, respectively.
CONCLUSION: We found that neoadjuvant nab-paclitaxel plus gemcitabine therapy was safe and feasible without stringent selection of patients with BRPC.

BACKGROUND: A study of the computed tomography (CT) imaging related effective doses and radiation-related cancer death risk.
PATIENTS AND METHODS: Estimate effective doses were computed from CT scans of testicular cancer patients treated and followed-up in Turku University Hospital, South Western Finland. Association between effective doses from follow-up CT scans and radiation-induced cancer death was examined using United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 2008 formula.
RESULTS: Mean effective dose per CT abdomen was 9.32 (standard deviation, SD 3.89) mSv and for whole-body CT it was 14.24 (SD 6.84) mSv. During follow-up of 6 years, the patients were estimated to undergo 12 to 14 abdominal/whole-body CTs and the corresponding risk estimates were 0.11 and 1.14, respectively. The risk of estimated radiation-induced cancer deaths (RICD in %) computed for mean effective doses was lower in patients diagnosed at older age, being 0.61 for 10-19 years age and 0.04 for 40-49 years age at the diagnosis.
CONCLUSION: Patient radiation exposure in CT imaging is associated with the type of CT device and imaging protocols, which should be periodically updated and reviewed to minimize individual exposure. Using the UNSCEAR modelling 2 % risk for radiation related cancer death was attributed to diagnostic exposure of study patients. Age at the diagnosis was associated with CT imaging related radiation exposure. The highest exposure was estimated to the youngest patients.

BACKGROUND: The aim of this study was to evaluate a novel prognostic value of preoperative platelet-to-albumin ratio (PAR) in patients resected for pancreatic cancer.
PATIENTS AND METHODS: A total of 107 patients who underwent pancreatic resection for pancreatic cancer were studied. The patients were divided into two groups as PAR ≥46.4×10(3) or <46.4×10(3) Survival data were analyzed using the log-rank test for univariate analysis and Cox proportional hazards for multivariate analysis.
RESULTS: The PAR was a significant prognostic index on univariate analysis for disease-free survival (DFS) and overall survival (OS). The PAR retained its significance on multivariate analysis for OS (hazard ratio(HR)=2.344, 95% confidence interval(CI)=1.188-4.624, p=0.014) along with tumor differentiation and nodal involvement. PAR was a significant independent prognostic index for poor DFS on multivariate analysis (HR=1.971, 95% CI=1.128-3.444, p=0.017).
CONCLUSION: The preoperative PAR is a novel significant independent prognostic index for DFS and OS in patients after pancreatic resection with curative intent.

AIM: To analyze the outcomes in pancreatic cancer (PC) cases with a microscopically-positive resection margin (R1 resection) treated with postoperative radiotherapy (PORT).
PATIENTS AND METHODS: We retrospectively analyzed the outcomes in 62 patients who received PORT for PC with R1 resection between 2001 and 2012. All patients received three-dimensional conformal radiotherapy. Concurrent chemotherapy was administered to 58 patients.
RESULTS: The median follow-up was 20.1 months. The median survival was 22.0 months and the 3-year overall survival rate was 25%. The 3-year disease-free survival and local recurrence-free survival rates were 12% and 54%, respectively. Local recurrence occurred in 23 patients (44%), distant failure in 45 (87%), and both in 16 (31%). By multivariate analysis, the postoperative cancer antigen 19-9 (CA19-9) level and adjuvant chemotherapy were independent prognostic factors for survival.
CONCLUSION: PORT is associated with a relatively favorable survival outcome in PC with R1 resection. Chemotherapy and postoperative CA19-9 level were significant prognostic factors for survival.

BACKGROUND/AIM: The indication for resection of cystic pancreatic lesions is usually performed by sectional imaging criteria, such as the Sendai criteria. The aim of this study was to analyze a possible correlation between DNA cytometry and Sendai criteria for the differentiation between low-grade intraductal papillary mucinous neoplasms (IPMN-A) and medium-grade dysplasia (IPMN-B).
MATERIALS AND METHODS: Histopathological analysis, DNA index and preoperative Sendai criteria were determined in 16 patients who underwent pancreatic resection for IPMN.
RESULTS: All patients with IPMN-B showed aneuploid histograms with DNA indices ≥1.3, whereas three out of four patients with IPMN-A had diploid DNA indices ≤1.3. All 11 patients with one or more high-risk stigmata and aneuploid histograms had IPMN-Bs, whereas both patients who were Sendai-negative and diploid in the DNA analysis had an IPMN-A.
CONCLUSION: DNA index may be an important diagnostic tool for the differentiation of different IPMN types beyond the traditional Sendai criteria.

Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.
PATIENTS AND METHODS: Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.
RESULTS: Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.
CONCLUSION: Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.

BACKGROUND: Obesity is an established risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). However, the pathophysiology of how increased adiposity increases the risk for PDAC has not been fully elucidated. Adipose triglyceride lipase (ATGL) is a lipase that catabolizes triglyceride hydrolysis and has been implicated in the development of breast cancer. We hypothesized that overweight patients with PDAC would demonstrate higher tumor ATGL expression compared to non-overweight patients with PDAC.
MATERIALS AND METHODS: Immunohistochemical analysis for ATGL expression was performed on PDAC tissues from 44 patients after Whipple procedure or distal pancreatectomy. Correlation of ATGL expression with clinicopathological features was evaluated.
RESULTS: A total of 23/44 (52.2%) PDACs showed low level ATGL immunoreactivity, while 21/44 (47.8%) showed a high level, with moderate to strong positive ATGL immunoreactivity in more than 50% of the tumor cells. Chi-squared testing revealed a statistically significant association between high ATGL expression and both BMI >25 kg/m(2) (χ(2)=5.74, p=0.017) and increased tumor stroma (χ(2)=19.14, p<0.001). Chi-squared testing failed to reveal a statistically significant association when comparing ATGL expression by lymph node metastasis, histological grade, tumor size, patient age, patient sex and presence of fat invasion.
CONCLUSION: Our results suggest that increased ATGL expression is associated with increased adiposity and stromal proliferation in patients with PDAC, making it a possible key protein in how obesity increases the risk of PDAC.

Pancreatic cancer is highly malignant, characterized by aggressive proliferation, invasion, and metastasis. α-Bisabolol is an oily sesquiterpene alcohol derived from a variety of plants. We previously demonstrated that α-bisabolol is a potential therapeutic agent for pancreatic cancer. The aim of this study was to develop α-bisabolol derivatives which are more potent than the parent compound and may be clinically useful against pancreatic cancer. First, 22 derivatives of α-bisabolol were designed and synthesized. α-Bisabolol derivatives 4 and 5 had more potent inhibitory effects on the proliferation of pancreatic cancer cells than did α-bisabolol. Next, 15 additional α-bisabolol derivatives were designed and synthesized based on the structure of α-bisabolol derivatives 4 and 5 Among them, α-bisabolol derivative 5 had the strongest inhibitory effect on proliferation. This novel compound reduced the proliferation of various pancreatic cancer cell lines, such as KLM1, Panc1, and KP4. In addition, the compound induced higher levels of apoptosis in pancreatic cancer cell lines than did α-bisabolol. α-Bisabolol derivative 5 inhibited xenograft tumor growth and reduced dissemination of pancreatic cancer to peritoneal nodules. The compound strongly suppressed AKT expression in the peritoneal nodules. Reduced AKT expression in peritoneal nodules is consistent with an anticancer effect. These data indicate that α-bisabolol derivative 5 effectively prevents the progression of pancreatic cancer via inhibition of AKT. Taken together, the results showed that this compound has attractive therapeutic properties as a novel anticancer drug for pancreatic cancer.

BACKGROUND/AIM: Borderline ovarian tumors (BOTs) have a less aggressive behavior than invasive epithelial ovarian tumors. Still some patients relapse or succumb to disease. Molecular markers that reliably predict prognosis are lacking. Insulin-like growth factor II mRNA-binding protein (IMP3) has been suggested as a prognostic marker in colorectal, hepatocellular, and ovarian clear-cell carcinomas.
MATERIALS AND METHODS: We analyzed the expression of IMP3 by immunohistochemistry in a cohort of 140 BOT and its association with histopathological features.
RESULTS: We found no association of IMP3 expression with patients' age, FIGO stage, microinvasion, and presence of implants. In contrast, IMP3 expression correlated to mucinous subtype of BOTs (42.2% vs. 9.5% among other subtypes) (p<0.001). IMP3 expression was found to be associated with the presence of in situ carcinoma in MBOT, but not in other subtypes (p=0.021).
CONCLUSION: Expression of IMP3 in BOT is associated with the mucinous subtype and may serve as an early indicator for the development of malignant features.

Few data exist on the prognostic and predictive impact of erb-b2 receptor tyrosine kinase 4 (ERBB4) in ovarian cancer. Thus, we evaluated ERBB4 expression by immunohistochemistry in a tumor microarray consisting of 100 ovarian serous carcinoma specimens (50 complete responses [CRs] and 50 incomplete responses [IRs] to platinum-based therapy), 51 normal tissue controls, and 16 ovarian cancer cell lines. H scores were used to evaluate expression and were semiquantitatively classified into low, intermediate, and high categories. Category frequencies were compared between tumor specimens vs controls using an unpaired t test. Among tumors, category frequencies were compared between CR and IR to chemotherapy. Overall survival (OS) was stratified by category. In total, 74 ovarian serous carcinoma samples (32 CRs and 42 IRs), 28 normal controls, and 16 ovarian cancer cell lines were evaluable. High-level ERBB4 expression was observed at a significantly higher frequency in ovarian serous carcinoma compared with normal control tissue. Among tumor specimens, ERBB4 expression was significantly higher for those with an IR to chemotherapy compared with CR (P = .033). OS was inversely correlated with ERBB4 expression levels. Median rates of OS were 18, 22, and 58 months among high-, intermediate-, and low-expression tumors, respectively. Our results indicate that ERBB4 expression by immunohistochemistry may correlate with chemotherapy-resistant ovarian serous carcinoma and shortened OS.

Thrombotic microangiopathy syndromes consist of a collection of disorders with a varied etiology that share common clinical and pathological features. Although thrombotic microangiopathy is rare, it is associated with significant morbidity and mortality. Without early recognition and intervention, the prognosis of the disease is poor. This report illustrates the case of a 56-year-old man with advanced-stage metastatic pancreatic cancer who presented with hemolytic uremic syndrome associated with gemcitabine use. His condition was managed with eculizumab, a monoclonal antibody, although he was dependent on dialysis. This report reflects the importance of considering thrombotic microangiopathy syndromes in the differential diagnosis, because many malignancies and use of chemotherapeutic agents can trigger hemolytic uremic syndrome.

RATIONALE: Pancreatic neuroendocrine tumors (pNET) are rare slowly growing tumors with a high metastatic potential. Peptide receptor radionuclide therapy (PRRT) with radiolabeled analogues has been developed as a new tool for the management of metastatic well-differentiated (grade 1 and 2) neuroendocrine tumors expressing somatostatin receptor (SSTR2). Chemotherapy is the mainstay in the management of grade 3 (G3) unresectable pancreatic neuroendocrine carcinoma (pNEC). To date, no study has evaluated the efficacy of PRRT in such tumors.
DIAGNOSES AND INTERVENTIONS: We describe a case of a progressive G3 pNEC with huge liver metastases successfully treated with PRRT (Lu DOTATATE).
OUTCOMES: Complete remission was obtained for 3 years. Indeed, the mitotic index was low (as G2 tumors) but with a very high Ki-67 index (45%-70%). Such discordance between the proliferative markers should consider the use of PRRT before chemotherapy in unresectable metastatic G3 tumors expressing SSTR2.
LESSONS: This case supports the hypotheses highlighting the heterogeneity of G3 pNEC. The latter should be subdivided into 2 distinct categories: proliferation-discordant (well differentiated) and concordant (poorly differentiated) NEC. PRRT could be suggested for the former group before the conventional chemotherapy.

Ovarian cancer is one of the three most common gynecological malignant tumors worldwide. The prognosis of patients suffering from this malignancy remains poor because of limited therapeutic strategies. Herein, we investigated the role of a long noncoding RNA named MIR4697 host gene (MIR4697HG) in the cell growth and metastasis of ovarian cancer. Results showed that the transcriptional level of MIR4697HG in cancerous tissues increased twofold compared with that in adjacent noncancerous tissues. MIR4697HG was differentially expressed in ovarian cancer cell lines, with the highest levels in OVCAR3 and SKOV3 cells. MIR4697HG knockdown by specific shRNA significantly inhibited cell proliferation and colony formation in both OVCAR3 and SKOC3 cells. Consistently, in a xenograft model of ovarian cancer, MIR4697HG depletion also significantly restricted tumor volumes and weights. Furthermore, MIR4697HG knockdown inhibited cell migration and invasion capacities. Invasion ability was inhibited by 58% in SKOV3 cells and 40% in OVCAR3 cells, and migration ability was inhibited by 73% in SKOV3 cells and 62% in OVCAR3 cells after MIR4697HG knockdown. MIR4697HG knockdown also caused a decrease in matrix metalloprotease-9, phosphorylated ERK, and phosphorylated AKT. These data suggested that MIR4697HG promoted ovarian cancer growth and metastasis. The aggressive role of MIR4697HG in ovarian cancer may be related to the ERK and AKT signaling pathways.

INTRODUCTION: Although cytology and histopathology of thyroid lesions generally fall into common, well-defined categories, there are uncommon cases with unusual fine needle aspiration (FNA) findings or histology. Herein, we review the prevalence and characteristics of rare thyroid cytology and histopathology findings at a tertiary hospital.
METHODS: Institutional data from >31,000 patients with a thyroid pathology from 1995 to 2013 were queried. Both cytology and histology were available in 6,693 patients. After exclusion of the common cytological categories detailed by The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) and common histopathology categories, 90 patients with either an unusual FNA, histopathology, or both were identified.
RESULTS: A total of 90 cases were included (19: only unusual FNA; 25: only unusual histology; 46: both unusual cytology and histopathology). The positive predictive value of an unusual FNA for discovering an unusual lesion was 71% (95% CI: 58%-81%). The majority (66%) were females and median age was 59 years. On histopathology, 80 (88%) cases were malignant, 72 (90%) of which were initially diagnosed as malignant on FNA. Of the 10 benign lesions, 8 (80%) also had a benign FNA. Patients with unusual malignant lesions were significantly older than those with unusual benign lesions (62 vs. 44 years; P: 0.004).
CONCLUSION: Unusual cytopathological and histopathological findings in thyroid comprise a varied group of tumors that are individually rare but collectively common. A preoperative FNA with an unusual cytopathology is likely to lead to an unusual histopathological diagnosis; however, its diagnostic accuracy in differentiating benign from malignant is lower than the accuracy of cytopathology of conventional TBSRTC. Diagn. Cytopathol. 2017;45:185-190. © 2016 Wiley Periodicals, Inc.

We herein report the first case of a pancreatic fistula extending into the thigh caused by the rupture of an intraductal papillary mucinous neoplasm (IPMN) of the pancreas. An 80-year-old man was suspected to have necrotizing fasciitis because of right femoral pain. Computed tomography showed fluid retention from the pancreatic head to the right iliopsoas muscle and an IPMN at the pancreatic head. The findings of endoscopic retrograde pancreatography led to the suspicion of a minor leak and a pancreatic stent was placed. The patient died due to an uncontrollable infection. A pathological autopsy showed a pancreatic fistula extending into the thigh that had been caused by the rupture of the IPMN.

Pancreatic metastasis from colorectal cancer is rare, and there have been only a few reports of its preoperative diagnosis by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with immunohistochemical staining. We herein describe the case of a 77-year-old woman in whom a solitary mass in the pancreatic tail was detected 11 years after rectal cancer resection. The patient also had a history of pulmonary tumor resection. We performed EUS-FNA and a histopathological examination showed adenocarcinoma with CD20+, CD7-, and CDX2+ (similar to her rectal cancer). EUS-FNA enabled a histopathological examination, including immunohistochemical staining, which helped to confirm the diagnosis of pancreatic and pulmonary metastasis from rectal cancer.

The aim of this study was to evaluate whether the preparation for radioactive iodine (RAI) therapy by thyroid hormone withdrawal (THW) or a low-iodine diet (LID) can be risk factors for the development of hyponatremia in patients with differentiated thyroid cancer after thyroidectomy.We retrospectively reviewed the medical records and laboratory findings of 326 patients who underwent preparation for RAI therapy after thyroidectomy from 2012 to 2014. Demographic and clinical variables including the method of thyrotropin stimulation and duration of LID were assessed. Serum sodium was measured twice, before operation and before RAI therapy.Hyponatremia was detected in only 3 patients (0.9%) before operation, but in 15 patients (4.6%) before RAI therapy. None of the patients had severe hyponatremia after preparation for RAI therapy. Pre-RAI therapy serum sodium was correlated with the method of thyrotropin stimulation (TWH vs recombinant human thyroid stimulating hormone, P = 0.014) and duration of LID (r = -0.131, P = 0.018); however, the preparation of RAI therapy, THW and LID, did not affect the development of hyponatremia in logistic regression analysis. Preoperative serum sodium was a significant risk factor for hyponatremia during preparation for RAI therapy.Preparation for RAI therapy by THW or LID is not a risk factor for the development of hyponatremia in patients with thyroid cancer. The development of hyponatremia was neither frequent nor severe during preparation for RAI therapy. Physicians should not be greatly concerned about rare life-threatening hyponatremia during preparation for RAI therapy.

Several reports showed that interleukin-6 (IL-6) or -8 (IL-8) might be useful inflammatory biomarkers for pancreatic ductal adenocarcinoma (PDAC), although these clinical impact is still open to debate. The aim of this study was to elucidate whether serum levels of IL-6 and IL-8 at diagnosis could predict the tumor progression pattern of PDAC, especially in extensive hepatic metastasis.According to the tumor burden of hepatic metastasis at the last follow-up, tumor progression pattern was defined as follows: no or limited (unilobar involvement and 5 or less in the within liver, limited group) and extensive hepatic metastasis (bilobar or more than 5, progressed group). Fifty-three PDAC patients with initially no or limited hepatic metastasis were enrolled retrospectively.Around 42 (79.2%) were included in the limited and 11 (20.8%) in the progressed group. The median serum level of IL-6 in the progressed group was elevated significantly compared with the limited group. However, the median serum level of IL-8 was not. Furthermore, multivariate analysis revealed that the elevated serum level of IL-6 was an independent risk factor for progression to extensive hepatic metastasis (odds ratio 1.928, 95% confidence interval 1.131-3.365, P = 0.019), but IL-8 was not. However, higher IL-6 did not predict shorter survival.High serum IL-6 can be an independent risk factor for progression to extensive hepatic metastasis in PDAC patients.

BACKGROUND: Brachytherapy with iodine-labeled seeds (I-seeds) implantation is increasingly being used to treat tumors because of its positional precision, minimal invasion, least damage to noncancerous tissue due to slow and continuous release of radioactivity and facilitation with modern medical imaging technologies. This study evaluates the survival and pain relief outcomes of the I-seeds implantation brachytherapy in advanced pancreatic cancer patients.
METHODS: Literature search was carried out in multiple electronic databases (Google Scholar, Embase, Medline/PubMed, and Ovid SP) and studies reporting I seeds implantation brachytherapy in pancreatic cancer patients with unresectable tumor were selected by following predetermined eligibility criteria. Random effects meta-analysis was performed to achieve inverse variance weighted effect size of the overall survival rate after the intervention. Sensitivity and subgroups analyses were also carried out.
RESULTS: Twenty-three studies (824 patients' data) were included in the meta-analysis. I-seeds implantation brachytherapy alone was associated with 8.98 [95% confidence interval (CI): 6.94, 11.03] months (P < 0.00001) overall survival with 1-year survival of 25.7 ± 9.3% (mean ± standard deviation; SD) and 2-year survival was 17.9 ± 8.6% (mean ± SD). In stage IV pancreatic cancer patients, overall survival was 7.13 [95% CI: 4.75, 9.51] months (P < 0.00001). In patients treated with I-seeds implantation along with 1 or more therapies, overall survival was 11.75 [95% CI: 9.84, 13.65] months (P < 0.00001) with 1-year survival of 47.4 ± 22.75% (mean ± SD) and 2-year survival was 16.97 ± 3.1% (mean ± SD). I-seeds brachytherapy was associated with relief of pain in 79.7 ± 9.9% (mean ± SD) of the patients.
CONCLUSIONS: Survival of pancreatic cancer patients after I-seeds implantation brachytherapy is found to be 9 months, whereas a combined treatment with I-seeds brachytherapy and other therapies was associated with approximately 12 months' survival. The majority of patients who underwent I-seeds brachytherapy had their pain relieved.

BACKGROUND: Genomic instability caused by mutation of the checkpoint molecule TP53 may endow cancer cells with the ability to undergo genomic evolution to survive stress and treatment. We attempted to gain insight into the potential contribution of ovarian cancer genomic instability resulted from TP53 mutation to the aberrant expression of multidrug resistance gene MDR1.
METHODS: TP53 mutation status was assessed by performing nucleotide sequencing and immunohistochemistry. Ovarian cancer cell DNA ploidy was determined using Feulgen-stained smears or flow cytometry. DNA copy number was analyzed by performing fluorescence in situ hybridization (FISH).
RESULTS: In addition to performing nucleotide sequencing for 5 cases of ovarian cancer, TP53 mutations were analyzed via immunohistochemical staining for P53. Both intensive P53 immunohistochemical staining and complete absence of signal were associated with the occurrence of TP53 mutations. HE staining and the quantification of DNA content indicated a significantly higher proportion of polyploidy and aneuploidy cells in the TP53 mutant group than in the wild-type group (p < 0.05). Moreover, in 161 epithelial ovarian cancer patients, multivariate logistic analysis identified late FIGO (International Federation of Gynecology and Obstetrics) stage, serous histotype, G3 grade and TP53 mutation as independent risk factors for ovarian cancer recurrence. In relapse patients, the proportion of chemoresistant cases in the TP53 wild-type group was significantly lower than in the mutant group (63.6% vs. 91.8%, p < 0.05). FISH results revealed a higher percentage of cells with >6 MDR1 copies and chromosome 7 amplication in the TP53 mutant group than in the wild-type group [11.7 ± 2.3% vs. 3.0 ± 0.7% and 2.1 ± 0.7% vs. 0.3 ± 0.05%, (p < 0.05), respectively]. And we observed a specific increase of MDR1 and chromosome 7 copy numbers in the TP53 mutant group upon disease regression (p < 0.01).
CONCLUSIONS: TP53 mutation-associated genomic instability may promote chromosome 7 accumulation and MDR1 amplification during ovarian cancer chemoresistance and recurrence. Our findings lay the foundation for the development of promising chemotherapeutic approaches to treat aggressive and recurrent ovarian cancer.