The impact of a new hepatopancreatobiliary surgery program on the management of pancreatic cancer at Health Sciences North

Background: Centralization of specialist services to urban centres presents a challenge to patients living in rural communities. The hepatopancreatobiliary surgery (HPB) program at Health Sciences North (HSN) is the tenth and newest HPB centre by Cancer Care Ontario and presents a unique opportunity to evaluate the barriers to delivering HPB cancer care to patients in northern Ontario. Methods: We retrospectively reviewed the cases of patients referred to the Northeastern Ontario Cancer Centre and HSN with a pancreatic cancer diagnosis between 2009 and 2015. July 2013 marked the inception of the HPB surgical program. Our primary outcome was time to HPB surgical consultation. Secondary outcomes included distance of travel and time to curative intent operation. Results: Our population consisted of 207 patients (98 pre-HPB v. 109 post-HPB). Median time to consultation with an HPB surgeon was decreased in the post-HPB group (43 v. 11 d, p < 0.001). An increased proportion of patients with pancreatic malignancies in the post-HPB group received HPB surgical consultations (34% v. 74%, p < 0.001), with decreased median distance travelled to surgical consultation (411 v. 79 km, p < 0.001). Time to curative intent operation or medical oncology consultation did not significantly increase. Conclusion: A new HPB program appears to have facilitated the proportion of patients with pancreatic malignancies at HSN receiving an HPB surgical consultation. Patients received complex surgeries, closer to their home regions. It is anticipated that these changes may affect overall outcomes and patient satisfaction and will be the focus of future investigations.

Contexte: La concentration des services spécialisés dans les centres urbains pose un défi pour les patients des communautés rurales. Le programme de chirurgie hépatopancréatobiliaire (HPB) d'Horizon Santé-Nord (HSN) est le 10e et plus récent centre HPB d'Action Cancer Ontario; il offre une occasion unique d'évaluer les obstacles à la prestation des soins oncologiques HPB aux patients du Nord de l'Ontario. Méthodes: Nous avons passé en revue de manière rétrospective les cas adressés au Centre de cancérologie du Nord-Est de l'Ontario et à HSN pour un diagnostic de cancer du pancréas entre 2009 et 2015. Le programme chirurgical HPB a été lancé en juillet 2013. Notre principal paramètre était le délai d'obtention d'une consultation pour une chirurgie HPB. Les paramètres secondaires incluaient la distance à parcourir et le délai d'obtention d'une intervention à visée curative. Résultats: Notre population comportait 207 patients (98 pré-HPB c. 109 post-HPB). Le délai médian d'obtention de la consultation en chirurgie HPB a diminué dans le groupe post-HPB (43 j c. 11 j, p < 0,001). Une proportion plus grande de patients atteints de cancer du pancréas dans le groupe post-HPB a obtenu une consultation pour chirurgie HPB (34 % c. 74 %, p < 0,001), et une diminution de la distance médiane à parcourir pour se rendre à la consultation a été constatée (411 km c. 79 km, p < 0,001). Le délai d'obtention de la chirurgie à visée curative ou de la consultation en oncologie médicale n'a pas augmenté significativement. Conclusion: Le nouveau programme HPB semble avoir permis d'accroître la proportion de patients atteints de cancer du pancréas ayant pu bénéficier d'une consultation pour chirurgie HPB. Les patients ont pu subir des chirurgies complexes plus près de chez eux. On prévoit que ces modifications auront une incidence sur les paramètres globaux et la satisfaction des patients et qu'elles feront l'objet d'études.

Predictive Power of the NSQIP Risk Calculator for Early Post-Operative Outcomes After Whipple: Experience from a Regional Center in Northern Ontario.

BACKGROUND: NSQIP Risk Calculator was developed to allow surgeons to inform their patients about their individual risks for surgery. Its ability to predict complication rates and length of stay (LOS) has made it an appealing tool for both patients and surgeons. However, the NSQIP Risk Calculator has been criticized for its generality and lack of detail towards surgical subspecialties, including the hepatopancreaticobiliary (HPB) surgery. We wish to determine whether the NSQIP Risk Calculator is predictive of post-operative complications and LOS with respect to Whipple's resections for our patient population. As well, we wish to identify strategies to optimize early surgical outcomes in patients with pancreatic cancer. METHODS: We conducted a retrospective review of patients who underwent elective Whipple's procedure for benign or malignant pancreatic head lesions at Health Sciences North (Sudbury, Ontario), a tertiary care center, from February 2014 to August 2016. Comparisons of LOS and post-operative complications between NSQIP-predicted and actual ones were carried out. NSQIP-predicted complications rates were obtained using the NSQIP Risk Calculator through pre-defined preoperative risk factors. Clinical outcomes examined, at 30 days post-operation, included pneumonia, cardiac events, surgical site infection (SSI), urinary tract infection (UTI), venous thromboembolism (VTE), renal failure, readmission, and reoperation for procedural complications. As well, mortality, disposition to nursing or rehabilitation facilities, and LOS were assessed. RESULTS: A total of 40 patients underwent Whipple's procedure at our center from February 2014 to August 2016. The average age was 68 (50-85), and there were 22 males and 18 females. The majority of patients had independent baseline functional status (39/40) with minimal pre-operative comorbidities. The overall post-operative morbidity was 47.5% (19/40). The rate of serious complication was 17.5% with four Clavien grade II, two grade III, and one grade V complications. One mortality occurred within 30 days after surgery. NSQIP Risk Calculator was predictive for the majority of post-surgical complication types, including pneumonia, SSI, VTE, reoperation, readmission, and disposition to rehabilitation or nursing home. Our center appears to have a higher rate of UTI than NSQIP predicted (O/E = 3.9), as well, the rate of cardiac complication (O/E = 3.1) also appears to be higher at our center. With respect to readmission rates (O/E = 0.6) and renal failure (O/E = 0), NSQIP provided overestimated rates. The average LOS was 11.9 ± 0.9 days, which was not significantly different from the average LOS of 11.5 ± 0.3 days predicted by NSQIP (p = 0.3). Overall, 80% of discharges occurred less than or within 3 days of that predicted by NSQIP. CONCLUSION: NSQIP Risk Calculator is predictive of post-operative complications and LOS for patients who have undergone Whipple's at our center. A more HPB-focused NSQIP calculator may accurately project post-operative complication in the pre-operative period. Nevertheless, the generic NSQIP has allowed us to examine our existing practice of post-operative care and has paved way to reduce cardiac and urinary complications in the future.

A Near-Infrared Dye That Undergoes Multiple Interconversions through Acid-Base Equilibrium and Reversible Redox Processes.

A near-infrared (NIR) polymethine dye (1), consisting of a cyclohepta[1,2-b;4,3-b']dithiophene and two phenol moieties, was synthesized. This dye exhibited pH-responsive changes in its photophysical properties due to a two-step acid-base equilibrium that produced a protonated cation (1H+ ) and an anion (1- ). While 1H+ showed an intense fluorescence in the red region of the visible spectrum, 1- exhibited a strong absorption in the NIR region. The tropylium ion character in 1H+ induces high pKa1 and pKa2 values for 1. Moreover, a stable radical (1. ) was prepared, which showed a NIR absorption band with a maximum at circa 1600 nm. The cyclic voltammogram of 1. revealed a two-step reversible redox process that produced 1- and the cation 1+ , which is different from 1H+ . These redox processes accompany drastic electrochromic changes in the vis-NIR region. Overall, 1 is susceptible to multiple interconversions between five forms, due to the multifaceted character of the cycloheptadithiophene skeleton.

Stable Red-Emissive Cationic Dithienotropylium Dyes.

A series of thiophene-fused tropylium ions, containing various electron-donating amino groups at the terminal positions, was synthesized. The fusion of the thiophene rings, as well as the presence of the terminal amino groups endows the cationic tropylium ion with excellent stability and high pKR+ values. X-ray crystallographic analysis of these compounds revealed a pronounced quinoidal character for the amino-substituted dithienotropylium skeletons. These compounds exhibit attractive photophysical properties such as strong absorption in the visible region combined with red fluorescence. Theoretical calculations suggested that the 3,3'-bithiophene substructure should be crucial for attaining these photophysical properties.

Management of a delayed post-pancreatoduodenectomy haemorrhage using endovascular techniques.

BACKGROUND: A delayed post-pancreatoduodenectomy haemorrhage is associated with a significant increase in peri-operative mortality. Endovascular techniques are frequently used for a delayed haemorrhage. However, limited data exists on the short- and long-term outcomes of this approach. A retrospective review over a 10-year period at a quaternary-referral pancreatic centre was performed. METHODS: Between 2002-2012, 1430 pancreatoduodenectomies were performed, and 32 patients had a delayed haemorrhage (occurring >24 h post-operatively) managed by endovascular techniques. The clinicopathological variables related to a haemorrhage were investigated. RESULTS: A total of 42 endovascular procedures were performed at a median of 25 days, with the majority of delayed haemorrhages occurring after 7 days. There were four deaths (13%) with three occurring in patients with a grade C haemorrhage. Seven patients (22%) experienced rebleeding, and two patients developed hepatic abscesses. CONCLUSION: A delayed haemorrhage post-pancreaticoduodenectomy can be managed by endovascular techniques with acceptable morbidity and mortality. Rebleeding and hepatic abscesses may occur and can be managed non-operatively in most cases. The association of a delayed haemorrhage with a pancreatic fistula makes this a challenging clinical problem.

A cyclic octithiophene containing ß,ß'-linkages.

A cyclic octithiophene containing two ß,ß'-linkages was synthesized. Due to the large structural change in the excited state, this compound exhibited bathochromically shifted fluorescence. It also showed a small difference between the first and second oxidation potentials, indicative of spin delocalization through the ß,ß'-linkage in the one electron-oxidized state.

hnRNP E1 and E2 have distinct roles in modulating HIV-1 gene expression.

Pre-mRNA processing, including 5' end capping, splicing, and 3' end cleavage/polyadenylation, are events coordinated by transcription that can influence the subsequent export and translation of mRNAs. Coordination of RNA processing is crucial in retroviruses such as HIV-1, where inefficient splicing and the export of intron-containing RNAs are required for expression of the full complement of viral proteins. RNA processing can be affected by both viral and cellular proteins, and in this study we demonstrate that a member of the hnRNP E family of proteins can modulate HIV-1 RNA metabolism and expression. We show that hnRNP E1/E2 are able to interact with the ESS3a element of the bipartite ESS in tat/rev exon 3 of HIV-1 and that modulation of hnRNP E1 expression alters HIV-1 structural protein synthesis. Overexpression of hnRNP E1 leads to a reduction in Rev, achieved in part through a decrease in rev mRNA levels. However, the reduction in Rev levels cannot fully account for the effect of hnRNP E1, suggesting that hmRNP E1 might also act to suppress viral RNA translation. Deletion mutagenesis determined that the C-terminal end of hnRNP E1 was required for the reduction in Rev expression and that replacing this portion of hnRNP E1 with that of hnRNP E2, despite the high degree of conservation, could not rescue the loss of function.

Q values of longitudinal leaky Saws propagating on rotated Y-cut LN substrates along the perpendicular to the X axis.

Longitudinal leaky SAWs (LLSAWs), which can be excited in a thick aluminum (A1) grating on a rotated Y-cut lithium-niobate substrate, were analyzed in a simulation that combined both FEM and BEM. The Q-value dependence of an LLSAW on the rotated angle and the Al-grating thickness was clear. The simulation results were confirmed experimentally. These SAWs have potential applications in high-frequency SAW devices because their velocities range from 6100 to 6500 m/s and their optimum Q values are theoretically larger than 4000.

NinR- and red-mediated phage-prophage marker rescue recombination in Escherichia coli: recovery of a nonhomologous immlambda DNA segment by infecting lambdaimm434 phages.

We examined the requirement of lambda recombination functions for marker rescue of cryptic prophage genes within the Escherichia coli chromosome. We infected lysogenic host cells with lambdaimm434 phages and selected for recombinant immlambda phages that had exchanged the imm434 region of the infecting phage for the heterologous 2.6-kb immlambda region from the prophage. Phage-encoded activity, provided by either Red or NinR functions, was required for the substitution. Red(-) phages with DeltaNinR, internal NinR deletions of rap-ninH, or orf-ninC were 117-, 12-, and 5-fold reduced for immlambda rescue in a Rec(+) host, suggesting the participation of several NinR activities. RecA was essential for NinR-dependent immlambda rescue, but had slight influence on Red-dependent rescue. The host recombination activities RecBCD, RecJ, and RecQ participated in NinR-dependent recombination while they served to inhibit Red-mediated immlambda rescue. The opposite effects of several host functions toward NinR- and Red-dependent immlambda rescue explains why the independent pathways were not additive in a Rec(+) host and why the NinR-dependent pathway appeared dominant. We measured the influence of the host recombination functions and DnaB on the appearance of orilambda-dependent replication initiation and whether orilambda replication initiation was required for immlambda marker rescue.

A novel function for Sam68: enhancement of HIV-1 RNA 3' end processing.

Both cis elements and host cell proteins can significantly affect HIV-1 RNA processing and viral gene expression. Previously, we determined that the exon splicing silencer (ESS3) within the terminal exon of HIV-1 not only reduces use of the adjacent 3' splice site but also prevents Rev-induced export of the unspliced viral RNA to the cytoplasm. In this report, we demonstrate that loss of unspliced viral RNA export is correlated with the inhibition of 3' end processing by the ESS3. Furthermore, we find that the host factor Sam68, a stimulator of HIV-1 protein expression, is able to reverse the block to viral RNA export mediated by the ESS3. The reversal is associated with a stimulation of 3' end processing of the unspliced viral RNA. Our findings identify a novel activity for the ESS3 and Sam68 in regulating HIV-1 RNA polyadenylation. Furthermore, the observations provide an explanation for how Sam68, an exclusively nuclear protein, modulates cytoplasmic utilization of the affected RNAs. Our finding that Sam68 is also able to enhance 3' end processing of a heterologous RNA raises the possibility that it may play a similar role in regulating host gene expression.

Control of HIV-1 env RNA splicing and transport: investigating the role of hnRNP A1 in exon splicing silencer (ESS3a) function.

The control of HIV-1 viral RNA splicing and transport plays an important role in the successful replication of the virus. Previous studies have identified both an exon splicing enhancer (ESE) and a bipartite exon splicing silencer (ESS3a and ESS3b) within the terminal exon of HIV-1 that are involved in modulating both splicing and Rev-mediated export of viral RNA. To define the mechanism of ESS3a function, experiments were carried out to better define the cis and trans components required for ESS3a activity. Mutations throughout the 30-nt element resulted in partial loss of ESS function. Combining mutations was found to have an additive effect, suggesting the presence of multiple binding sites. Analysis of interacting factors identified hnRNP A1 as one component of the complex that modulates ESS3a activity. However, subsequent binding analyses determined that hnRNP A1 interacts with only one portion of ESS3a, suggesting the involvement of another host factor. Parallel analysis of the effect of the mutations on Rev-mediated export determined that there is not a direct correlation between the effect of the mutations on splicing and RNA transport. Consistent with this hypothesis, replacement of ESS3a with consensus hnRNP A1 binding sites was found to be insufficient to block Rev-mediated RNA export.

Positive and negative modulation of human immunodeficiency virus type 1 Rev function by cis and trans regulators of viral RNA splicing.

Expression of the entire complement of human immunodeficiency virus type 1 (HIV-1) viral proteins depends on the competing activities of viral RNA splicing and export into the cytoplasm by Rev. To investigate the possibility that modulation of viral RNA metabolism may alter Rev function, we analyzed the impact of multiple SR proteins on both processes. While overexpression of several of the SR factors altered splicing of HIV-1 env mRNA, they had disparate effects on Rev function that varied with the cell line used. Subsequent examination of exon splicing enhancer (ESE) and/or silencer (ESS) deletions suggests that the effects of the SR proteins on Rev function are not mediated through interaction with these elements. However, analysis of the deletions did indicate that the ESE and/or ESS does have significant effects on Rev function, with deletion of the ESS augmenting the magnitude of the response to Rev and deletion of the ESE significantly reducing it. In situ hybridization and reverse transcription-PCR indicated that the loss of Rev response upon deletion of the ESE was due to a failure of Rev to induce transport of the unspliced RNA into the cytoplasm. Together, the data indicate that cellular splicing factors and viral regulatory elements can have significant stimulatory and inhibitory effects on Rev function, raising the possibility that cells can be rendered permissive or nonpermissive for virus replication by modulation of splicing activities.