Virtual Surgical Planning: The Pearls and Pitfalls.

OBJECTIVE: Over the past few years, virtual surgical planning (VSP) has evolved into a useful tool for the craniofacial surgeon. Virtual planning and computer-aided design and manufacturing (CAD/CAM) may assist in orthognathic, cranio-orbital, traumatic, and microsurgery of the craniofacial skeleton. Despite its increasing popularity, little emphasis has been placed on the learning curve. METHODS: A retrospective analysis of consecutive virtual surgeries was done from July 2012 to October 2016 at the University of Montreal Teaching Hospitals. Orthognathic surgeries and free vascularized bone flap surgeries were included in the analysis. RESULTS: Fifty-four virtual surgeries were done in the time period analyzed. Forty-six orthognathic surgeries and 8 free bone transfers were done. An analysis of errors was done. Eighty-five percentage of the orthognathic virtual plans were adhered to completely, 4% of the plans were abandoned, and 11% were partially adhered to. Seventy-five percentage of the virtual surgeries for free tissue transfers were adhered to, whereas 25% were partially adhered to. The reasons for abandoning the plans were (1) poor communication between surgeon and engineer, (2) poor appreciation for condyle placement on preoperative scans, (3) soft-tissue impedance to bony movement, (4) rapid tumor progression, (5) poor preoperative assessment of anatomy. CONCLUSION: Virtual surgical planning is a useful tool for craniofacial surgery but has inherent issues that the surgeon must be aware of. With time and experience, these surgical plans can be used as powerful adjuvants to good clinical judgement.

Analysis of Human Papillomavirus Infection in 16,320 Patients From a Gynecology Clinic in Central South China.

OBJECTIVE: This study aimed to investigate the relationship between persistent human papillomavirus (HPV) infection and cervical lesion. METHODS: Clinical data of 16,320 patients who visited our clinic between January 2009 and December 2013 were collected. Retrospective analysis was performed to analyze the overall HPV infection and compare the infection rates of different subtypes among different age groups, to reveal the relationship between persistent HPV infection and cervical cytology. RESULTS: The overall prevalence of HPV was 26.54%. The most common genotypes were HPV 52, HPV 16, HPV 58, CP8304, and HPV 53. The highest overall high-risk HPV prevalence was found in women older than 60 years, and the lowest prevalence was found in women between the ages of 30 and 39 years. There was no significant difference in low-risk HPV prevalence among different age groups (p = .693). The HPV clearance rate after 1 year among those with initial positive test was 87.65%. The constituent ratios of high- or low-risk HPV subtypes were not significantly different (p = .545) between nonpersistent-positive and persistent-positive (PP) groups. Conversely, the constituent ratios of singe- or multi-type HPV infection were significantly different (p < .05) between these 2 groups. The most common subtypes in PP group were HPV 16, 52, 58, CP8304, and 33. The occurrence rates of atypical squamous cells of undetermined significance, high-grade squamous intraepithelial lesion, and squamous cell carcinoma in the PP group significantly increased (p < .05). CONCLUSIONS: Persistent HPV infections are mainly caused by multiple types of HPV and high-risk HPV. Our region should particularly pay attention to the prevention and treatment of HPV 16, 52, and 58.

[Viability of extended distal pancreatectomy for pancreatic adenocarcinoma of the body or tail].

OBJECTIVE: To analyze the viability of extended distal pancreatectomy and the associated prognostic factors. METHODS: The data of 57 patients with pancreatic adenocarcinoma who underwent standard distal pancreatectomy(DP) or extended distal pancreatectomy(EDP) from January 2011 to December 2014 were reviewed retrospectively. Thirty-five patients were performed with DP and 22 with EDP. Operation safety and survival benefit between DP and EDP were compared by t-test or χ(2) test.Cox regression analysis was used to explore the prognostic indicators. RESULTS: Compared to DP group, operation time((255±91)min vs.(208±80)min)(t=2.066, P=0.044) and ratio of blood transfusion (50.0% vs.17.1%)(χ(2)=12.836, P=0.008) were greater in EDP group, respectively.There were no significant differences in amount of intraoperative blood loss and postoperative duration of hospitalization. Delayed gastric emptying was greater in EDP(22.7% vs.2.9%)(Z=-2.251, P=0.027), while other complications had no differences. Mortality and ratio of relaparotomy also showed no differences. Median survival following DP was 13.1 months compared to 8.2 months following EDP. There was no difference in survival between DP and EDP. According to the results of multivariate analysis, tumor size(RR=1.275, P=0.03)and perioperative blood transfusions(RR=2.673, P=0.04) were independent prognostic factors. CONCLUSIONS: Though patients with pancreatic adenocarcinoma who undergo EDP have a worse pathologic staging, they will gain a comparable long-term survival to the patients undergo DP. Tumor size and perioperative blood transfusions are independent prognostic factors.

Meta-analysis of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy.

BACKGROUND: Surgical reconstruction following pancreaticoduodenectomy (PD) is associated with significant morbidity and mortality. Because of great variability in definitions of specific complications, it remains unclear whether there is a difference in complication rates following the two commonest types of reconstruction, pancreaticogastrostomy (PG) and pancreaticojejunostomy (PJ). Published consensus definitions for postoperative pancreatic fistula (POPF) have led to a series of randomized clinical trials (RCTs) uniquely placed to address this question. METHODS: A literature search was carried out to identify all RCTs comparing postoperative complications of PG versus PJ reconstruction following PD published between January 1995 and December 2013. Pooled odds ratios (ORs) with 95 percent confidence intervals (c.i.) were calculated using fixed-effect or random-effects models. RESULTS: In total, seven RCTs with 1121 patients were included. Four of these trials applied definitions as published by the International Study Group on Pancreatic Fistula (ISGPF). Using ISGPF definitions, the incidence of POPF was lower in patients undergoing PG than in those having PJ (OR 0·50, 95 per cent c.i. 0·34 to 0·73; P < 0·001). Using definitions applied by each individual study, PG was associated with significantly lower rates of POPF (OR 0·51, 0·36 to 0·71; P < 0·001), intra-abdominal fluid collection (OR 0·50, 0·34 to 0·74; P < 0·001) and biliary fistula (OR 0·42, 0·18 to 0·93; P = 0·03) than PJ. CONCLUSION: Meta-analysis of four RCTs based on ISGPF criteria, and seven RCTs using non-standard criteria, revealed that PG reduced the incidence of POPF after PD compared with PJ.

Systematic review and meta-analysis of outcomes after intraoperative pancreatic duct stent placement during pancreaticoduodenectomy.

BACKGROUND: Postoperative pancreatic leakage after pancreaticoduodenectomy is often serious. Although some studies have suggested that stenting the anastomosis can reduce the incidence of this complication, the value of stenting in the setting of pancreaticoduodenectomy remains unclear. METHODS: Studies comparing outcomes of stent versus no stent, and internal versus external stent placement for pancreaticoduodenectomy were eligible for inclusion. Pooled odds ratios (ORs) with 95 per cent confidence intervals were calculated using fixed- or random-effects models. RESULTS: From a search of the literature published between January 1973 and September 2011, five randomized clinical trials (RCTs) and 11 non-randomized observational clinical studies (OCS) involving 1726 patients were selected for inclusion in this review. Meta-analysis of RCTs revealed that placing a stent in the pancreatic duct did not reduce the incidence of postoperative pancreatic fistula. External stents had no advantage over internal stents in terms of clinical outcome. Subgroup analyses revealed that use of an external stent significantly reduced the incidence of pancreatic fistula (RCTs: OR 0·42, 0·24 to 0·76, P = 0·004; OCS: OR 0·43, 0·27 to 0·68, P < 0·001), delayed gastric emptying (RCTs: OR 0·41, 0·19 to 0·87, P = 0·02) and postoperative morbidity (RCTs: OR 0·55, 0·34 to 0·89, P = 0·02) compared with no stent. CONCLUSION: Pancreatic duct stenting did not reduce the incidence of pancreatic fistula and other complications in pancreaticoduodenectomy compared with no stenting. Although no difference was found between external and internal stents in terms of efficacy, external stents seemed to reduce the incidence of pancreatic fistula compared with control.

Selective anticancer strategies via intervention of the death pathways relevant to cell transformation.

Apoptosis is an important physiological process that promotes tissue homeostasis by eliminating unnecessary or malfunctioning cells. Abnormality in this process contributes to tumorigenesis, as well as the resistance to cancer treatment by radiation and chemotherapy. Restoration of normal apoptosis would not only promote cancer cell death and halt tumor progression, but also increase the response to many current cancer therapies. Although apoptosis induction is an important principle of currently used radiation and chemotherapy treatment, uncovering the mechanisms that govern this process, and which are lost during transformation, represents an important direction for realizing improved therapies for the future. This article first briefly reviews aspects of current discovery strategies for new anticancer therapeutics based on intervening in cell death pathways, and then discusses in more detail several cancer-relevant death pathways, which are disabled during transformation and which can be targeted therapeutically. These include anoikis/cell adhesion; energy metabolism and the unfolded protein response. Finally, we introduce a new concept, which utilizes cancer-specific apoptosis induced by oncolytic viruses. The discussion of these topics involves novel targets, compounds and virotherapy.

NR4A1, 2, 3--an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis.

Three members of the NR4A1/Nur77/ NGFIB orphan nuclear hormone receptor subfamily (NR4A1, NR4A2, and NR4A3) belong to the steroid nuclear hormone receptor superfamily. They share similar structural features and have no known natural ligand. They constitute immediate early genes that are induced by serum, growth factors and receptor engagement and are thus implicated in cell mitogenic responses. These nuclear receptors are transcription factors that exert their functions through activation and subsequent induction of the downstream pathways. They have been shown to play a role in complex pathways of cell survival and apoptosis. Although the expression of these genes have been shown to be pro-survival, it has also been reported that NR4A1 expression can cause apoptosis. These two opposite effects apparently result from distinct mechanisms: either transcriptional activation of genes responsible for cell survival or cell apoptosis, or translocation into the cytoplasm where they target the mitochondria and cause cell apoptosis via Bcl-2 binding. The latter mechanism constitutes a new paradigm of cellular apoptosis. In vitro functional studies using over-expression (gain of function) or gene inactivation (loss of function) type assays, combined with transgenic or knockout animal data in vivo, have revealed these effects and their physiological roles, including thymocyte development for NR4A1/3 and pro-survival in CNS for NR4A2. Recent studies have also suggested an important role of these receptors in cell transformation and tumorigenicity via both their anti-apoptotic and pro-apoptotic functions. In particular, the recent identification of a functional ligand for NR4A1 suggests that these members could potentially serve as drug targets for disease indications such as cancer. While many aspects of these receptors have been previously reviewed, this article focuses on new experimentation and discovery of their apoptotic and carcinogenic roles, and discusses their potential roles as therapeutic targets.

Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak.

A novel human member of the Bcl-2 family was identified, Bcl-B, which is closest in amino acid sequence homology to the Boo (Diva) protein. The Bcl-B protein contains four Bcl-2 homology (BH) domains (BH1, BH2, BH3, BH4) and a predicted carboxyl-terminal transmembrane (TM) domain. The BCL-B mRNA is widely expressed in adult human tissues. The Bcl-B protein binds Bcl-2, Bcl-X(L), and Bax but not Bak. In transient transfection assays, Bcl-B suppresses apoptosis induced by Bax but not Bak. Deletion of the TM domain of Bcl-B impairs its association with intracellular organelles and diminishes its anti-apoptotic function. Bcl-B thus displays a unique pattern of selectivity for binding and regulating the function of other members of the Bcl-2 family.

Drosophila pro-apoptotic Bcl-2/Bax homologue reveals evolutionary conservation of cell death mechanisms.

Genetic analysis of programmed cell death in Drosophila reveals many similarities with mammals. Heretofore, a missing link in the fly has been the absence of any Bcl-2/Bax family members, proteins that function in mammals as regulators of mitochondrial cytochrome c release. A Drosophila homologue of the human killer protein Bok (DBok) was identified. The predicted structure of DBok is similar to pore-forming Bcl-2/Bax family members. DBok induces apoptosis in insect and human cells, which is suppressible by anti-apoptotic human Bcl-2 family proteins. A caspase inhibitor suppressed DBok-induced apoptosis but did not prevent DBok-induced cell death. Moreover, DBok targets mitochondria and triggers cytochrome c release through a caspase-independent mechanism. These characteristics of DBok reveal evolutionary conservation of cell death mechanisms in flies and humans.

The pheromone response pathway activates transcription of Ty5 retrotransposons located within silent chromatin of Saccharomyces cerevisiae.

The Saccharomyces retrotransposon Ty5 integrates preferentially into transcriptionally inactive regions (silent chromatin) at the HM loci and telomeres. We found that silent chromatin represses basal Ty5 transcription, indicating that these elements are encompassed by silent chromatin in their native genomic context. Because transcription is a requirement for transposition, integration into silent chromatin would appear to prevent subsequent rounds of replication. Using plasmid-borne Ty5-lacZ constructs, we found that Ty5 expression is haploid specific and is repressed 10-fold in diploid strains. Ty5 transcription is also regulated by the pheromone response pathway and is induced approximately 20-fold upon pheromone treatment. Deletion analysis of the Ty5 LTR promoter revealed that a 33 bp region with three perfect matches to the pheromone response element is responsible for both mating pheromone and cell-type regulation. Transcriptional repression of Ty5 by silent chromatin can be reversed by pheromone treatment, which leads to transcription and transposition. Ty5 replication, therefore, is normally repressed by silent chromatin and appears to be induced during mating. This is the first example of transcriptional activation of a gene that naturally resides within silent chromatin.

The Saccharomyces retrotransposon Ty5 integrates preferentially into regions of silent chromatin at the telomeres and mating loci.

The nonrandom integration of retrotransposons and retroviruses suggests that chromatin influences target choice. Targeted integration, in turn, likely affects genome organization. In Saccharomyces, native Ty5 retrotransposons are located near telomeres and the silent mating locus HMR. To determine whether this distribution is a consequence of targeted integration, we isolated a transposition-competent Ty5 element from S. paradoxus, a species closely related to S. cerevisiae. This Ty5 element was used to develop a transposition assay in S. cerevisiae to investigate target preference of de novo transposition events. Of 87 independent Ty5 insertions, approximately 30% were located on chromosome III, indicating this small chromosome (approximately 1/40 of the yeast genome) is a highly preferred target. Mapping of the exact location of 19 chromosome III insertions showed that 18 were within or adjacent to transcriptional silencers flanking HML and HMR or the type X subtelomeric repeat. We predict Ty5 target preference is attributable to interactions between transposition intermediates and constituents of silent chromatin assembled at these sites. Ty5 target preference extends the link between telomere structure and reverse transcription as carried out by telomerase and Drosophila retrotransposons.

Destabilization of rbcS sense transcripts by antisense RNA.

Steady-state rbcS mRNA levels are drastically reduced in transgenic tobacco plants that express rbcS antisense RNAs. We have found that these reductions are not due to an effect of the antisense RNA at the level of rbcS transcription; rather, the sense mRNAs are more actively degraded in the mutant than wild-type plants. We have examined the kinetics of this turnover process by inhibiting transcription with cordycepin, and have found that rbcS sense mRNA decay is accelerated about five-fold in the antisense plants. This provides direct evidence that antisense RNAs can serve to destabilize sense transcripts in plants.