The Liverpool duodenum-and spleen-preserving near-total pancreatectomy can provide long-term pain relief in patients with end-stage chronic pancreatitis.

PURPOSE: Total pancreatectomy may improve symptoms in patients with severe end-stage chronic pancreatitis. This might be achieved whilst preserving both the duodenum- and spleen-(DPSPTP). Mature clinical outcomes of this approach are presented. METHODS: Single-centre prospective cohort study performed between September 1996 and May 2016. Demographic, clinical details, pain scores and employment status were prospectively recorded during clinic attendance. RESULTS: Fifty-one patients (33 men, 18 women) with a median (interquartile range) age of 40.8 (35.3-49.4) years, a median weight of 69.8 (61.0-81.5) Kg and a median body mass index of 23.8 (21.5-27.8), underwent intended duodenum-and spleen-preserving near-total pancreatectomy for end-stage chronic pancreatitis. Aetiology was excess alcohol in 25, idiopathic (no mutation) in 15, idiopathic (SPINK-1/CFTR mutations) in two, hereditary (PRSS1 mutation) in seven and one each post-necrotising pancreatitis and obstructive pancreatic duct divisum in 1. The main indication for surgery was severe pain. Findings included parenchymal calcification in 79% and ductal calculi in 24%, a dilated main pancreatic duct in 57% and a dilated main bile duct in 17%, major vascular involvement in 27% and pancreato-peritoneal fistula in 2%. Postoperative complications occurred in 20 patients with two deaths. Median pain scores were 8 (7-8) preoperatively and 3 (0.25-5.75) at 5 years (p = 0.013). Opiate analgesic use was significantly reduced postoperatively (p = 0.048). Following surgery, 22 (63%) of 38 patients of working age re-entered employment compared with 12 (33%) working preoperatively (p = 0.016). CONCLUSION: Duodenum-and spleen-preserving near-total pancreatectomy provided long-term relief in adult patients with intractable chronic pancreatitis pain, with improved employment prospects.

Tumour stage and resection margin status are independent survival factors following partial pancreatoduodenectomy for duodenal adenocarcinoma.

INTRODUCTION: There is limited published evidence on duodenal carcinoma due to its rarity. This study aimed to evaluate gastric outlet obstruction and obstructive jaundice along with pathological variables as survival factors in patients with duodenal adenocarcinoma following resection. METHODS: Survival factor analysis was undertaken in patients undergoing duodenal cancer surgery from 1997 to 2015 in a single centre. RESULTS: There were 57 patients of whom 18 had gastric outlet obstruction and 14 had obstructive jaundice. Fifty-three had a partial pancreatoduodenectomy and four had palliative bypass. Perioperative mortality and morbidity were 4% (2/53) and 47% (25/53) respectively in resected patients. With a median (95% confidence interval, CI) follow-up of 72 (57-86) months, median overall and recurrence-free survival was 38 months (95% CI 28-113) and 27 months (95% CI 18-83) respectively. The 1 and 3-year overall survival rates were 84% (95% CI 74-95) and 52% (95% CI 39-69) respectively. Median overall survival was 19 months in patients with gastric outlet obstruction vs 53 months in those without (p = 0.026) and 28 months in patients with obstructive jaundice vs 38 months in those without (p = 0.611). Univariate analysis revealed that tumour stage, resection margin status, pre-operative albumin status, gastric outlet obstruction and age were associated with poorer overall and recurrence-free survival but multivariate analysis confirmed only tumour stage and resection margin status to be significant. CONCLUSION: Whereas gastric outlet obstruction in duodenal cancer appeared to be an important survival factor following partial pancreatoduodenectomy, multivariate analysis showed that only tumour stage and resection margin status were the key independent survival factors. Further multicentre studies are required to elucidate further characteristics of duodenal carcinoma and develop neoadjuvant/adjuvant management strategies.

Robot-Assisted Excision of Congenital Mega-Seminal Vesicle Associated with Zinner's Syndrome.

Background: Abnormalities of mesonephric ducts are rare congenital conditions, which can present with vague symptoms in otherwise healthy men. Zinner's syndrome is the association of an enlarged seminal vesicle cyst with ipsilateral renal agenesis, which can be symptomatic and require operative interventions. Case: We present the case of an otherwise healthy 24-year-old man who presented with a symptomatic 15 cm seminal vesicle cyst, which was completely excised using a robot-assisted approach. Conclusion: Use of robotic surgery for excision of large seminal vesicle cysts is a safe and effective operative procedure.

Differentiation of Autoimmune Pancreatitis from Pancreatic Cancer Remains Challenging.

BACKGROUND: Autoimmune pancreatitis (AIP) is an uncommon form of chronic pancreatitis. Whilst being corticosteroid responsive, AIP often masquerades radiologically as pancreatic neoplasia. Our aim is to appraise demographic, radiological and histological features in our cohort in order to differentiate AIP from pancreatic malignancy. METHODS: Clinical, biochemical, histological and radiological details of all AIP patients 1997-2016 were analysed. The initial imaging was re-reviewed according to international guidelines by three blinded independent radiologists to evaluate features associated with autoimmune pancreatitis and pancreatic cancer. RESULTS: There were a total of 45 patients: 25 in type 1 (55.5%), 14 type 2 (31.1%) and 6 AIP otherwise not specified (13.3%). The median (IQR) age was 57 (51-70) years. Thirty patients (66.6%) were male. Twenty-six patients (57.8%) had resection for suspected malignancy and one for symptomatic chronic pancreatitis. Three had histologically proven malignancy with concurrent AIP. Two patients died from recurrent pancreatic cancer following resection. Multidisciplinary team review based on radiology and clinical history dictated management. Resected patients (vs. non-resected group) were older (64 vs. 53, p = 0.003) and more frequently had co-existing autoimmune pathologies (22.2 vs. 55.6%, p = 0.022). Resected patients also presented with less classical radiological features of AIP, which are halo sign (0/25 vs. 3/17, p = 0.029) and loss of pancreatic clefts (18/25 vs. 17/17, p = 0.017). There were no differences in demographic features other than age. CONCLUSION: Despite international guidelines for diagnosing AIP, differentiation from pancreatic cancer remains challenging. Resection remains an important treatment option in suspected cancer or where conservative treatment fails.

Penetrating facial trauma from a Taser barb.

The Taser X26® (Axon) is a conducted energy device that is used by the police forces in the United Kingdom to deliver a high voltage shock that will disable a person. Injuries related to its use are uncommon but can be serious, the extent of the damage caused being related to the structures targeted and the length of deployment of the electrical charge. We describe a 15-year-old boy who had a penetrating midfacial injury after deployment of a Taser, the barb of which became embedded in the subtarsal region of his left cheek. Removal under general anaesthetic was uncomplicated, and exploration of the wound showed that there was no damage to adjacent structures. Case reports of this type are limited, and we know of none of a penetrating injury of the midface.

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy.

BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Postoperative pain and analgesia administration in children after urological outpatient procedures.

INTRODUCTION: There are limited data about pain patterns, analgesic requirements and factors predicting opioid requirements of children undergoing outpatient urologic surgery. This prospective study aimed to assess recovery profiles and pain medication requirements. METHODS: Patients between 6 months and 12 years of age were recruited prospectively between December 2013 and June 2014. Demographic and operative characteristics were collected. Following discharge home, the parents were asked to administer both acetaminophen and ibuprofen Q6H at a weight-adjusted dose, based on a schedule, until the end of postoperative day 2, and to administer the medication as required on postoperative day 3. Pain severity was recorded using validated pain scores (Face, Legs, Activity, Cry, Consolability/Parents' Postoperative Pain Measurement). A morphine prescription was provided for breakthrough pain. A Likert scale was used to assess parent's satisfaction with the pain management. RESULTS: A total of 249 patients were recruited, 111 patients (45%) returned appropriately completed surveys and were included in the final analysis. Mean age was 44.1 months (SD = 37.3). The performed procedures were orchidopexy (31), hypospadias repair (26), hernia/hydrocele repair (15), Fowler-Stephens procedure (13), meatoplasty (7), phalloplasty (4), scrotoplasty (1), circumcision (7), and diagnostic laparoscopy (5). After discharge home 17 patients (15.3%) received morphine. Mean utilization of non-opioid analgesia was 79% on postoperative day 1, 67% on day 2, 36% on day 3, and 2% on day 4. Parental satisfaction was high (92.0% satisfied/very satisfied). No patient, anaesthetic or surgical factors were associated with opioid use or prolonged need for postoperative analgesia. CONCLUSION: The combination of scheduled non-opioid medications for maintenance and opioids for breakthrough pain provided satisfactory pain control after outpatient urologic surgery in children. There were no specific patient, anesthetic or surgical factors that predicted postoperative opioid requirements.

Is there a relationship between surgical case volume and mortality in congenital heart disease services? A rapid evidence review.

OBJECTIVE: To identify and synthesise the evidence on the relationship between surgical volume and patient outcomes for adults and children with congenital heart disease. DESIGN: Evidence synthesis of interventional and observational studies. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Library and Web of Science (2009-2014) and citation searching, reference lists and recommendations from stakeholders (2003-2014) were used to identify evidence. STUDY SELECTION: Quantitative observational and interventional studies with information on volume of surgical procedures and patient outcomes were included. RESULTS: 31 of the 34 papers identified (91.2%) included only paediatric patients. 25 (73.5%) investigated the relationship between volume and mortality, 7 (20.6%) mortality and other outcomes and 2 (5.9%) non-mortality outcomes only. 88.2% were from the US, 97% were multicentre studies and all were retrospective observational studies. 20 studies (58.8%) included all congenital heart disease conditions and 14 (41.2%) single conditions or procedures. No UK studies were identified. Most studies showed a relationship between volume and outcome but this relationship was not consistent. The relationship was stronger for single complex conditions or procedures. We found limited evidence about the impact of volume on non-mortality outcomes. A mixed picture emerged revealing a range of factors, in addition to volume, that influence outcome including condition severity, individual centre and surgeon effects and clinical advances over time. CONCLUSIONS: The heterogeneity of findings from observational studies suggests that, while a relationship between volume and outcome exists, this is unlikely to be a simple, independent and directly causal relationship. The effect of volume on outcome relative to the effect of other, as yet undetermined, health system factors remains a complex and unresolved research question.

Severe testicular atrophy does not affect the success of microdissection testicular sperm extraction.

PURPOSE: Men with azoospermia and severe testicular atrophy may be counseled to avoid sperm retrieval due to perceived limited success. We evaluated the outcomes of microdissection testicular sperm extraction in men with severe testicular atrophy (volume 2 ml or less). MATERIALS AND METHODS: We reviewed the records of 1,127 men with nonobstructive azoospermia who underwent microdissection testicular sperm extraction followed by intracytoplasmic sperm injection. They were classified into 3 groups based on average testicular volume, including 2 ml or less, greater than 2 to less than 10 and 10 or greater. Sperm retrieval, clinical pregnancy and live birth rates were calculated. Clinical features evaluated included age, follicle-stimulating hormone level, cryptorchidism history, Klinefelter syndrome, varicocele and testicular histology on diagnostic biopsy. RESULTS: Testicular sperm were successfully retrieved in 56% of the men. The sperm retrieval rate in those with a testicular volume of 2 ml or less, greater than 2 to less than 10 and 10 or greater was 55%, 56% and 55%, respectively. Clinical pregnancy and live birth rates were similar in men in the 3 groups who underwent sperm retrieval (55.2%, 50.0% and 47.0%, and 47.2%, 43.0% and 42.2%, respectively). Of the 106 men with an average testis volume of 2 ml or less those from whom sperm were retrieved were younger (31.1 vs 35.2 years) and more likely to have a history of Klinefelter syndrome (82.2% vs 55.6%) than men in whom sperm were not found (p <0.05). Men in this group had a higher prevalence of Klinefelter syndrome than men with a testis volume of greater than 2 ml (72.6% vs 5.3%, p <0.0001). Men younger than 30 years with Klinefelter syndrome had a higher sperm retrieval rate than men older than 30 years without Klinefelter syndrome (81.8% vs 33%, p <0.01). There was no cutoff point for age beyond which sperm could not be retrieved in men with small testes. On multivariable analysis younger age was the only preoperative factor associated with successful sperm retrieval in men with small testes (2 ml or less). CONCLUSIONS: Testicular volume does not affect the sperm retrieval rate at our center for microdissection testicular sperm extraction. Of men with the smallest volume testes those who were younger with Klinefelter syndrome had the highest sperm retrieval rate. Severe testicular atrophy should not be a contraindication to microdissection testicular sperm extraction.

Rescue of glandular dysmorphogenesis in PTEN-deficient colorectal cancer epithelium by PPARγ-targeted therapy.

Disruption of glandular architecture associates with poor clinical outcome in high-grade colorectal cancer (CRC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN) regulates morphogenic growth of benign MDCK (Madin Darby Canine Kidney) cells through effects on the Rho-like GTPase cdc42 (cell division cycle 42). This study investigates PTEN-dependent morphogenesis in a CRC model. Stable short hairpin RNA knockdown of PTEN in Caco-2 cells influenced expression or localization of cdc42 guanine nucleotide exchange factors and inhibited cdc42 activation. Parental Caco-2 cells formed regular hollow gland-like structures (glands) with a single central lumen, in three-dimensional (3D) cultures. Conversely, PTEN-deficient Caco-2 ShPTEN cells formed irregular glands with multiple abnormal lumens as well as intra- and/or intercellular vacuoles evocative of the high-grade CRC phenotype. Effects of targeted treatment were investigated. Phosphatidinylinositol 3-kinase (PI3K) modulating treatment did not affect gland morphogenesis but did influence gland number, gland size and/or cell size within glands. As PTEN may be regulated by the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ), cultures were treated with the PPARγ ligand rosiglitazone. This treatment enhanced PTEN expression, cdc42 activation and rescued dysmorphogenesis by restoring single lumen formation in Caco-2 ShPTEN glands. Rosiglitazone effects on cdc42 activation and Caco-2 ShPTEN gland development were attenuated by cotreatment with GW9662, a PPARγ antagonist. Taken together, these studies show PTEN-cdc42 regulation of lumen formation in a 3D model of human CRC glandular morphogenesis. Treatment by the PPARγ ligand rosiglitazone, but not PI3K modulators, rescued colorectal glandular dysmorphogenesis of PTEN deficiency.

PTEN regulates colorectal epithelial apoptosis through Cdc42 signalling.

BACKGROUND: Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) regulation of the Rho-like GTPase Cdc42 has a central role in epithelial polarised growth, but effects of this molecular network on apoptosis remain unclear. METHODS: To investigate the role of Cdc42 in PTEN-dependent cell death, we used flow cytometry, in vitro pull-down assays, poly(ADP ribose) polymerase (PARP) cleavage and other immunoblots in isogenic PTEN-expressing and -deficient colorectal cells (HCT116PTEN(+/+), HCT116PTEN(-/-), Caco2 and Caco2 ShPTEN cells) after transfection or treatment strategies. RESULTS: The PTEN knockout or suppression by short hairpin RNA or small interfering RNA (siRNA) inhibited Cdc42 activity, PARP cleavage and/or apoptosis in flow cytometry assays. Transfection of cells with wild-type or constitutively active Cdc42 enhanced PARP cleavage, whereas siRNA silencing of Cdc42 inhibited PARP cleavage and/or apoptosis. Pharmacological upregulation of PTEN by sodium butyrate (NaBt) treatment enhanced Cdc42 activity, PARP cleavage and apoptosis, whereas Cdc42 siRNA suppressed NaBt-induced PARP cleavage. Cdc42-dependent signals can suppress glycogen synthase kinase-ß (GSK3ß) activity. Pharmacological inhibition of GSK3ß by lithium chloride treatment mimicked effects of Cdc42 in promotion of PARP cleavage and/or apoptosis. CONCLUSION: Phosphatase and tensin homologue deleted on chromosome 10 may influence apoptosis in colorectal epithelium through Cdc42 signalling, thus providing a regulatory framework for both polarised growth and programmed cell death.

Defining the endoscopic appearances of tylosis using conventional and narrow-band imaging: a case series.

Tylosis is an autosomal dominant skin disorder strongly associated with esophageal squamous cell cancer. We present a single-operator experience of utilizing conventional endoscopy and narrow-band imaging with magnification to characterize esophageal appearances in tylosis. Nineteen consecutive patients with tylosis attending for surveillance endoscopy were studied. White-light imaging (WLI) and narrow-band imaging (NBI) were undertaken, with magnification being performed as necessary. On WLI, we classified 12 patients as having mild change, 5 moderate change, and 2 severe change. WLI can define changes to the esophageal mucosa of variable hyperkeratosis and identify more significant focal abnormalities. NBI enhances these mucosal changes, and NBI with magnification can demonstrate intrapapillary capillary loop changes compatible with dysplasia, prompting consideration of surgery. This report is the first to characterize the endoscopic appearances in tylosis.

Enhanced lymphocyte interferon (IFN)-γ responses in a PTEN mutation-negative Cowden disease kindred.

Identification of immune modifiers of inherited cancer syndromes may provide a rationale for preventive therapy. Cowden disease (CD) is a genetically heterogeneous inherited cancer syndrome that arises predominantly from germline phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutation and increased phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) signalling. However, many patients with classic CD diagnostic features are mutation-negative for PTEN (PTEN M-Neg). Interferon (IFN)-γ can modulate the PI3K/mTOR pathway, but its association with PTEN M-Neg CD remains unclear. This study assessed IFN-γ secretion by multi-colour flow cytometry in a CD kindred that was mutation-negative for PTEN and other known susceptibility genes. Because IFN-γ responses may be regulated by killer cell immunoglobulin-like receptors (KIR) and respective human leucocyte antigen (HLA) ligands, KIR/HLA genotypes were also assessed. Activating treatments induced greater IFN-γ secretion in PTEN M-Neg CD peripheral blood lymphocytes versus healthy controls. Increased frequency of activating KIR genes, potentially activating KIR/HLA compound genotypes and reduced frequency of inhibitory genotypes, were found in the PTEN M-Neg CD kindred. Differences of IFN-γ secretion were observed among PTEN M-Neg CD patients with distinct KIR/HLA compound genotypes. Taken together, these findings show enhanced lymphocyte secretion of IFN-γ that may influence the PI3K/mTOR CD causal molecular pathway in a PTEN mutation-negative CD kindred.

Expression of osteopontin coregulators in primary colorectal cancer and associated liver metastases.

BACKGROUND: A transcription regulatory complex (TRC) that includes Ets1, Ets2, PEA3 and ß-catenin/T-cell factors regulates osteopontin (OPN) that is implicated in colorectal cancer (CRC) dissemination. The consistency of OPN transcriptional control between primary CRC and metastases is unclear. This study investigates expression and prognostic significance of the OPN-TRC in primary human CRC and associated colorectal liver metastases (CRLM). METHODS: Osteopontin-TRC factors were assayed by digital microscopy in 38 primary CRCs and matched CRLM specimens and assessed against clinical prognosis. RESULTS: In primary CRC, OPN expression intensity correlated with that of its co-activators, PEA3 (r=0.600; P<0.01), Ets1 (r=0.552; P<0.01), Ets2 (r=0.521; P<0.01) and had prognostic significance. Osteopontin intensity in primary CRC inversely correlated with the interval between diagnosis and resection of CRLM. Overall OPN intensity was lower in CRLM than primary CRC and correlations with co-activators were weaker, for example, Ets1 (P=0.047), PEA3 (P=0.022) or nonsignificant (Ets2). The ratio of OPN expression in CRLM vs primary CRC had prognostic significance. CONCLUSION: This study supports transcriptional control of OPN by known coregulators in both primary and secondary CRC. Weaker associations in CRLM suggest involvement of other unknown factors possibly from the liver microenvironment or resulting from additional genetic or epigenetic changes that drive tumour metastatic capability in OPN transcriptional control.

The mammalian target of rapamycin inhibitor everolimus (RAD001) in early breast cancer: results of a pre-operative study.

mTOR plays a key role in tumor cell cycle control, proliferation, and survival. RAD001 (everolimus) is a novel macrolide that inhibits mTOR and thus downstream signaling pathways. 31 post-menopausal women with early breast cancer were given 5 mg RAD001 once daily for 14 days prior to surgery. Biopsies were taken at diagnosis and at surgery (post 14 days of treatment) and assessed for immunohistochemical changes in proliferation (Ki67), apoptosis (active caspase-3), p-AKT (s473), p-S6 (s235/236 and s240/244), p-mTOR (s2448), ER, and PR. Five patients did not complete the 2-week treatment period due to adverse events. All adverse events were grade 1 or 2 (NCIC-CTC scale). RAD001 treatment significantly decreased proliferation (geometric mean reduction 74% from baseline (p = 0.019)), particularly in HER-2 positive tumors. High Ki67 pre-treatment correlated with reduction in Ki67, an increase in apoptosis, a reduction in p-AKT (cytoplasmic) and reduction in p-mTOR following treatment. Nuclear expression of p-AKT was significantly reduced with treatment. Tumors that had a reduction in Ki67 with treatment exhibited a significant reduction in cytoplasmic p-AKT. p-S6 staining was significantly reduced independently of Ki67 (p < 0.001 for two sites of phosphorylation). RAD001 5 mg/daily is safe and tolerable in postmenopausal early breast cancer patients and inhibits the mTOR pathway and its downstream effectors, significantly reducing tumor cell proliferation. Tumors with high Ki67, high p-AKT, and HER-2 positivity may be more responsive to mTOR inhibition with RAD001. This is the first study to report results of RAD001 5 mg as a single agent in early breast cancer.

Apical node metastasis independently predicts poor survival in Dukes C colorectal cancer.

AIM: The prognostic significance of apical node metastasis in node-positive colorectal cancer (CRC) is disregarded by the Fourth American Joint Committee on Cancer and the International Union Against Cancer (AJCC/UICC) TNM classification system. The influence of apical node metastases on overall 5-year survival among patients with Dukes stage C CRC was examined. METHOD: Patients who underwent operative resection for CRC between 1999 and 2003 were reviewed. RESULTS: Two-hundred and ninety patients were included in the study, including 203 with Dukes C apical node-negative cancers, 39 with Dukes C apical node-positive cancers and 48 with Dukes D cancers. The respective prevalence of extramural vascular invasion was 35%vs 64%vs 56% (P = 0.0005), T4-stage 24%vs 38%vs 48% (P = 0.013), positive resection margin 16%vs 41%vs 23% (P = 0.001), more than three positive nodes harvested 28%vs 85%vs 52% (P < 0.0001) and poorer tumour differentiation grade 9%vs 21%vs 23% (P = 0.009). Multivariate analyses of all Dukes C cancer patients (n = 242) showed a positive apical node to be a highly significant independent predictor of mortality (hazard ratio 2.281, 95% confidence interval 1.421-3.662, P = 0.0006). Extramural vascular invasion and a positive resection margin were also independent predictors of poor survival. Patients with Dukes C apical node-positive cancers had a significantly poorer overall 5-year survival compared to patients with Dukes C apical node-negative cancers (P < 0.0001) but survival was not significantly different compared to patients with distant metastases at initial presentation (P = 0.504). CONCLUSION: Apical node metastasis appears to be a strong independent, negative prognostic factor of poor survival in Dukes C CRC.

Considerations for the use of plasma cytokeratin 18 as a biomarker in pancreatic cancer.

BACKGROUND: Enzyme-linked immunoassays of full-length (M65) and/or caspase-cleaved (M30) cytokeratin 18 (CK18) released from epithelial cells undergoing necrosis and/or apoptosis, respectively, may have prognostic or predictive biomarker utility in a range of solid tumour types. Characterisation of baseline levels of circulating full length and cleaved CK18 specifically in patients with pancreatic cancer. METHODS: Plasma samples from 103 patients with pancreatic cancer stored at -80 degrees C were assayed for M65 and M30 levels. The median (inter-quartile range (IQR)) duration of plasma storage was 34 (23-57) months. Patients with metastatic disease (n=19) were found to have greater median (IQR) M65 levels (1145 (739-1698) U l(-1)) compared with the locally advanced (n=20; 748 (406-1150) U l(-1)) and resected (n=64; 612 (331-987) U l(-1)) patients (P=0.002). Elevated M65 levels were associated with poorer overall survival on univariate (P<0.001) but not multivariate (P=0.202) analysis. M65 concentrations also exhibited significant associations with concurrent serum-bilirubin levels (P<0.001) and the duration of plasma storage (P<0.001). CONCLUSIONS: Baseline plasma CK18 levels in pancreatic cancer are affected by the presence of obstructive jaundice and prolonged plasma storage. Clinical biomarker studies utilising serial CK18 levels are warranted in pancreatic cancer, provided consideration is given to these potentially confounding factors.

The yin and yang of vitamin D receptor (VDR) signaling in neoplastic progression: operational networks and tissue-specific growth control.

Substantive evidence implicates vitamin D receptor (VDR) or its natural ligand 1alpha,25-(OH)2 D3 in modulation of tumor growth. However, both human and animal studies indicate tissue-specificity of effect. Epidemiological studies show both inverse and direct relationships between serum 25(OH)D levels and common solid cancers. VDR ablation affects carcinogen-induced tumorigenesis in a tissue-specific manner in model systems. Better understanding of the tissue-specificity of vitamin D-dependent molecular networks may provide insight into selective growth control by the seco-steroid, 1alpha,25-(OH)2 D3. This commentary considers complex factors that may influence the cell- or tissue-specificity of 1alpha,25-(OH)2 D3/VDR growth effects, including local synthesis, metabolism and transport of vitamin D and its metabolites, vitamin D receptor (VDR) expression and ligand-interactions, 1alpha,25-(OH)2 D3 genomic and non-genomic actions, Ca2+ flux, kinase activation, VDR interactions with activating and inhibitory vitamin D responsive elements (VDREs) within target gene promoters, VDR coregulator recruitment and differential effects on key downstream growth regulatory genes. We highlight some differences of VDR growth control relevant to colonic, esophageal, prostate, pancreatic and other cancers and assess the potential for development of selective prevention or treatment strategies.