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BACKGROUND: Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. METHODS: Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. RESULTS: Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16(Ink4a) attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 (Cdkn1a) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. CONCLUSIONS: Maladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.

Background Accidental awareness during general anaesthesia (AAGA) is a complex and rare outcome to investigate in surgical patient populations, particularly obstetric patients. We report the protocol of the Direct Reporting of Awareness in Maternity patients (DREAMY) study, illustrating how the research was designed to address practical and methodological challenges for investigating AAGA in an obstetric cohort. Methods This is the trial protocol of a prospective, multicentre cohort study of patients undergoing obstetric surgery under general anaesthesia. Accidental awareness during general anaesthesia will be detected using three repetitions of standardised direct questioning over 30 days, with responses indicating memories during general anaesthesia verified using structured interviews. Reports will be adjudicated, then classified, in accordance with pre-defined and pre-validated structures, including the Michigan Awareness Classification tool. Quantitative data will be collected on general anaesthesia conduct for all participants. This descriptive study is being conducted in England and aims to recruit a minimum of 2015 patients. Results The DREAMY study was prospectively registered (ClinicalTrials.gov Identifier: NCT03100396) and ethical approval granted. Participant recruitment began in May 2017 and one year follow up concluded in August 2019. Publication of the results is anticipated in 2020. Conclusions The DREAMY study will provide data on incidence, experience and implications of AAGA for obstetric patients, using a robust methodology that will reliably detect and translate subjective AAGA reports into objective outcomes. In addition, the study is expected to improve vigilance for AAGA in participating hospitals and encourage adoption of recommendations for support of patients experiencing AAGA.

A key step in the clinical production of CAR-T cells is the expansion of engineered T cells. To generate enough cells for a therapeutic product, cells must be chronically stimulated, which raises the risk of inducing T-cell exhaustion and reducing therapeutic efficacy. As protocols for T-cell expansion are being developed to optimize CAR T cell yield, function and persistence, fundamental questions about the impact of in vitro manipulation on T-cell identity are important to answer. Namely: 1) what types of cells are generated during chronic stimulation? 2) how many unique cell states can be defined during chronic stimulation? We sought to answer these fundamental questions by performing single-cell multiomic analysis to simultaneously measure expression of 39 proteins and 399 genes in human T cells expanded in vitro. This approach allowed us to study – with unprecedented depth - how T cells change over the course of chronic stimulation. Comprehensive immunophenotypic and transcriptomic analysis at day 0 enabled a refined characterization of T-cell maturational states (from naïve to TEMRA cells) and the identification of a donor-specific subset of terminally differentiated T-cells that would have been otherwise overlooked using canonical cell classification schema. As expected, T-cell activation induced downregulation of naïve-associated markers and upregulation of effector molecules, proliferation regulators, co-inhibitory and co-stimulatory receptors. Our deep kinetic analysis further revealed clusters of proteins and genes identifying unique states of activation defined by markers temporarily expressed upon 3 days of stimulation (PD-1, CD69, LTA), markers constitutively expressed throughout chronic activation (CD25, GITR, LGALS1), and markers uniquely up-regulated upon 14 days of stimulation (CD39, ENTPD1, TNFDF10). Notably, different ratios of cells expressing activation or exhaustion markers were measured at each time point. These data indicate high heterogeneity and plasticity of chronically stimulated T cells in response to different kinetics of activation. In this study, we demonstrate the power of a single-cell multiomic approach to comprehensively characterize T cells and to precisely monitor changes in differentiation, activation and exhaustion signatures in response to different activation protocols.

INTRODUCTION The most common incision for total knee arthroplasty is the anterior midline incision; however, it is commonly associated with lateral knee numbness, kneeling difficulties and restricted flexion range. We sought to review the literature regarding the neurovascular supply and angiosomes over the anterior knee, and evaluate the anterolateral incision as a viable alternative for knee arthroplasty. METHODS A systematic review of the literature was performed searching PUBMED, MEDLINE and EMBASE to evaluate the incisions available for total knee arthroplasty with respect to neurological function, kneeling ability and complications. RESULTS Ten studies were identified evaluating midline or anterolateral incisions for total knee arthroplasty, with a total of 664 knees for analysis. Mean patient age was 68 years (45-88), and average length of followup was 1 year. A total of 586 had an anterior midline incision and 78 had an anterolateral incision. A total of 62% of anterior midline incisions sustained altered sensation compared to 15% (12/78) of anterolateral incisions (p

Another congress of the World Society for Reconstructive Microsurgery (WSRM) this past year in Bologna was magnificent not just for the presentation of so many keynote lectures by the giants of our field nor the novel and innovative ideas shown by those who will someday follow in those footsteps, but by making all of us realize how many capable microsurgeons there are now practically everywhere in this world, doing incredibly important surgical management of challenges that previously were unmet and resulted in sheer devastation for so many of our patients. How much we are the same in our goals, aspirations, and abilities could not be overlooked, but it is amazing how much we also want to learn more together—each relying on the other. To do so, we must not forget our origins as we appropriately plan for the future. All this we philosophized in our WSRM panel on lower extremity reconstruction, while emphasizing on the surface the perforator flap that at the least today has caught everyone's attention. In this overview to follow, we once again tell two stories, starting with the beginnings of the concept of flaps in showing how the nomenclature has evolved over time according to our various surgical manipulations. Often overlooked, though, is a parallel timeline by the anatomists who have better elucidated the circulation to these flaps, where it will become obvious that often long ago the existence of perforators was recognized by them long before known by the surgeons. At least today, these two paths have at least temporarily intersected. Our pursuit of the “perforator” in the perforator skin flap has come full circle, following the course of the history of the flap itself—a pursuit of excellence.

Background Blindness following facial filler procedures, although rare, is devastating, usually acute, permanent, and attributed to an ophthalmic artery embolus. However, blindness may be delayed for up to 2 weeks, sometimes following injection at remote sites, suggesting alternative pathways and pathogenesis. Methods Seeking solutions, fresh cadaver radiographic lead oxide injection, dissection, and histologic studies of the orbital and facial pathways of the ophthalmic angiosome, performed by the ophthalmic artery and vein, both isolated and together, and facial artery perfusions, were combined with total body archival arterial and venous investigations. Results These revealed (1) arteriovenous connections between the ophthalmic artery and vein in the orbit and between vessels in the inner canthus, allowing passage of large globules of lead oxide; (2) the glabella, inner canthi, and nasal dorsum are the most vulnerable injection sites because ophthalmic artery branches are anchored to the orbital rim as they exit, a plexus of large-caliber avalvular veins drain into the orbits, and arteriovenous connections are present; (3) choke anastomoses between posterior and anterior ciliary vessels supplying the choroid and eye muscles may react with spasm to confine territories impacted with ophthalmic artery embolus; (4) true anastomoses exist between ophthalmic and ipsilateral or contralateral facial arteries, without reduction in caliber, permitting unobstructed embolus from remote sites; and (5) ophthalmic and facial veins are avalvular, allowing reverse flow. Conclusion The authors' study has shown potential arterial and venous pathways for filler embolus to cause blindness or visual field defects, and is supported clinically by a review of the case literature of blindness following facial filler injection.

There is increasing evidence to suggest that leaders need to use a combination of leader behaviors to successfully improve safety, including both transformational and transactional styles, but there has been limited testing of this idea. We developed a leadership intervention, based on supervisor training in both transformational and active transactional behaviors, and implemented it with supervisors at a UK-based chemical processing company. The study found that the supervisory training intervention led to significant improvements in perceived employee safety climate, over an eight-week period, relative to the comparison group. Although we found no change in the frequency of leader behaviors, the intervention was effective in helping supervisors to apply active transactional leader behaviors in a safety-critical context. The results indicated that transformational leader behaviors were already at a high level and effectively linked to safety. Our findings suggest not only that employees may be receptive to safety-related active transactional behaviors within high-risk situations, but furthermore, leaders can be trained to adjust their behaviors to focus more on active transactional behaviors in safety-critical contexts.

Background: As we enter an age with new approaches to tissue reconstruction, the emphasis on the adage "like for like" has become even more relevant. This study illustrates the potential for several tailored vascularized composite allotransplantation reconstructive techniques and, in particular, for the management of Volkmann contracture. Methods: Twenty fresh cadaver dissections and 30 archival lead oxide radiographic studies were examined to (1) identify potential upper limb vascularized composite allotransplantation donor sites (i.e., elbow, forearm, and flexor tendon complex) and (2) demonstrate a "mock transplant" of the vascularized volar forearm allograft for a severe Volkmann ischemia defect. They were designed without skin to reduce antigenicity. Results: The elbow joint was supplied within the brachial angiosome and the flexor tendon complex of the flexor digitorum superficialis and flexor digitorum profundus by the superficial palmar arch of the ulnar angiosome. The forearm allograft of flexor muscles, median, ulnar, and anterior interosseous nerves, when harvested on the brachial vessels, was supplied within the radial, ulnar, and anterior interosseous angiosomes but could be based on the ulnar artery alone because of intramuscular connections with the other territories. A mock transplant was performed with a distal-to-proximal dissection of the allograft, facilitating the best and fastest technique. Conclusions: This application of the angiosome concept highlights the anatomical feasibility of the volar forearm vascularized composite allotransplantation donor site focusing on a complex subunit problem in the upper limb - severe Volkmann ischemic contracture. It demonstrates the potential use and immunologic advantage of subdivided and modified nonskin variations of vascularized composite allotransplantation in reconstructive transplantation surgery.

A package of biopsychosocial services for young adults experiencing psychological distress was evaluated and compared to usual outpatient psychiatric care. Young adults (18-25) with moderate-to-severe symptoms of depression and/or anxiety (n = 26) were enrolled in a 13-week intervention consisting of nutritional coaching and multi-vitamin supplements, weekly educational and peer support groups, and a modest financial stipend to engage with physical or expressive activities. A comparison group (n = 13) continued with their usual medication-based outpatient care. Program participants reported significantly improved depression, anxiety, severity of distress, overall quality of life, and empowerment over 4 months, with progress maintained or further improved at 2-month follow-up. No evidence of change on any outcome was observed for comparison group participants. Although long-term impacts on mental health trajectories and reliance on psychotropic medications remain unknown, a holistic self-learning approach is a viable alternative to standard outpatient psychiatric care for young adults.

Background: Vascularised composite allo-transplantation (VCA) is emerging as a tailored approach for complex tissue reconstruction. This study focuses on the quadriceps VCA as a potential solution for tissue repair, following trauma, necrotising fasciitis/myositis, or tumor ablation. Methods: Dissections were undertaken in 10 adult cadaveric lower limbs to characterize the blood supply to the quadriceps femoris for en bloc muscle allo-transplantation. A mock cadaveric transplantation was performed to (a) define the best neurovascular VCA design and (b) test the feasibility of the procedure. A review of 54 archival radiograph studies from the institution was also performed to further evaluate the muscle vasculature. Results: In two lower limbs, the quadriceps VCA was harvested designed on the common and superficial femoral vessels and nerve, which revealed a lengthy and bloody dissection, especially of the veins, which could increase clinically with the inability to use a tourniquet for most of the dissection. However, review of our previous archival studies showed that all four quadriceps muscles are supplied within the lateral circumflex femoral angiosome. In a further eight lower limbs, the quadriceps femoris muscle group consistently received its blood supply from the lateral circumflex femoral angiosome, verified by selective lead oxide injections of this artery. The vastus medialis appeared to have a more tenous blood supply distally based on this angiosome. A successful mock cadaveric transplant was performed based on this data. Conclusions: We suggest that the best neuromuscular quadriceps VCA should be (a) designed on the lateral circumflex femoral pedicle, (b) should be raised from distal to proximal, and (c) should include the descending genicular vessels as a potential supplemental supply to vastus medialis, should all four muscles be required.

With advancements in technology and microsurgical techniques, lymphovenous anastomosis has become a popular reconstructive procedure in the treatment of chronic lymphedema. However, the long-term patency of these anastomoses is not clear in the literature.A systematic review of the MEDLINE and EMBASE databases was performed to assess the reported long-term patency of lymphovenous anastomoses.A total of eight studies satisfied the inclusion criteria. Pooled data from four similar experiments in normal dogs showed an average long-term (≥5 months) patency of 52 percent. The only experiment in dogs with chronic lymphedema failed to show any long-term patency.The creation of peripheral lymphovenous anastomoses with a moderate long-term patency rate has become technically possible. However, the long-term results in chronic lymphedema are limited.

Over the past decade, lymph node transfer has rapidly gained popularity among plastic surgeons for the treatment of chronic lymphedema because of the initial promising results and its unique technical advantages compared with the other reconstructive options. However, its functional mechanism is still a matter of great debate, and some concerning reports have emerged regarding the safety of this procedure in patients with chronic lymphedema. The authors review the literature on the experimental and clinical evidence for lymph node transfer, discuss its proposed functional mechanisms, review the potential risk of iatrogenic lymphedema following this procedure, and discuss the suggested strategies to avoid this complication.

Background Most target areas for facial volumization procedures relate to the anatomical location of the facial or ophthalmic artery. Occasionally, inadvertent injection of hyaluronic acid filler into the arterial circulation occurs and, unrecognized, is irreparably associated with disastrous vascular complications. Of note, the site of complications, irrespective of the injection site, is similar, and falls into only five areas of the face, all within the functional angiosome of the facial or ophthalmic artery. Methods Retrospective and prospective studies were performed to assess the site and behavior of anastomotic vessels connecting the angiosomes of the face and their possible involvement in the pathogenesis of tissue necrosis. In vivo studies of pig and rabbit, and archival human total body and prospective selective lead oxide injections of the head and neck, were analyzed. Results were compared with documented patterns of necrosis following inadvertent hyaluronic acid intraarterial or intravenous injection. Results Studies showed that the location of true and choke anastomoses connecting the facial artery with neighboring angiosomes predicted the tissue at risk of necrosis following inadvertent intraarterial hyaluronic acid injection. Conclusion Complications related to hyaluronic acid injections are intimately associated with (1) the anatomical distribution of true and choke anastomoses connecting the facial artery to neighboring ophthalmic and maxillary angiosomes where choke vessels define the boundary of necrosis of an involved artery but true anastomoses allow free passage to a remote site; or possibly (2) retrograde perfusion of hyaluronic acid into avalvular facial veins, especially in the periorbital region, and thereby the ophthalmic vein, cavernous sinus, and brain.

BACKGROUND: The course of the cutaneous lymphatic collectors of the abdominal wall in relation to the Scarpa fascia is unclear in the literature. Preserving the Scarpa fascia in the lower abdomen to reduce the seroma rate following abdominoplasty has been suggested based on the assumption that the lower abdominal lymphatics run deep to this layer along their entire course. METHODS: Using the previously described technique, the superficial lymphatic drainage of eight hemiabdomen specimens from four fresh human cadavers was investigated. RESULTS: The upper and lower abdominal collectors originated at the umbilical and midline watershed areas in a subdermal plane by the union of precollectors draining the dermis. In the lower abdomen, the depth of the collectors gradually increased in the subcutaneous fat as they coursed toward the groin. They eventually pierced the Scarpa fascia before draining into the superficial inguinal nodes located deep to this layer. The transition from the supra- to the infra-Scarpa fascia plane occurred within 2 to 3 cm of the inguinal ligament in 95 percent of the collectors. CONCLUSION: In the four cadavers studied, preserving the Scarpa fascia during abdominoplasty would not preserve the lower abdominal collectors.

Background HER2 mutations and amplifications have been identified as oncogenic drivers in lung cancers. Dacomitinib, an irreversible inhibitor of HER2, EGFR (HER1), and HER4 tyrosine kinases, has demonstrated activity in cell-line models with HER2 exon 20 insertions or amplifications. Here, we studied dacomitinib in patients with HER2-mutant or amplified lung cancers. Patients and methods As a prespecified cohort of a phase II study, we included patients with stage IIIB/IV lung cancers with HER2 mutations or amplification. We gave oral dacomitinib at 30–45 mg daily in 28-day cycles. End points included partial response rate, overall survival, and toxicity. Results We enrolled 30 patients with HER2-mutant (n = 26, all in exon 20 including 25 insertions and 1 missense mutation) or HER2-amplified lung cancers (n = 4). Three of 26 patients with tumors harboring HER2 exon 20 mutations [12%; 95% confidence interval (CI) 2% to 30%] had partial responses lasting 3+, 11, and 14 months. No partial responses occurred in four patients with tumors with HER2 amplifications. The median overall survival was 9 months from the start of dacomitinib (95% CI 7–21 months) for patients with HER2 mutations and ranged from 5 to 22 months with amplifications. Treatment-related toxicities included diarrhea (90%; grade 3/4: 20%/3%), dermatitis (73%; grade 3/4: 3%/0%), and fatigue (57%; grade 3/4: 3%/0%). One patient died on study likely due to an interaction of dacomitinib with mirtazapine. Conclusions Dacomitinib produced objective responses in patients with lung cancers with specific HER2 exon 20 insertions. This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2-targeted agents in specific HER2-driven lung cancers. ClinicalTrials.gov NCT00818441.

OBJECTIVEThe Agency of Healthcare Research and Quality (AHRQ) has defined Patient Safety Indicators (PSIs) for assessments in quality of inpatient care. The hypothesis of this study is that, in the treatment of unruptured cerebral aneurysms (UCAs), PSI events are less likely to occur in hospitals meeting the volume thresholds defined by The Joint Commission for Comprehensive Stroke Center (CSC) certification.METHODSUsing the 2002–2011 National (Nationwide) Inpatient Sample, patients treated electively for a nonruptured cerebral aneurysm were selected. Patients were evaluated for PSI events (e.g., pressure ulcers, retained surgical item, perioperative hemorrhage, pulmonary embolism, sepsis) defined by AHRQ-specified ICD-9 codes. Hospitals were categorized by treatment volume into CSC or non-CSC volume status based on The Joint Commission’s annual volume thresholds of at least 20 patients with subarachnoid hemorrhage and performance of 15 or more endovascular coiling or surgical clipping procedures for aneurysms.RESULTSA total of 65,824 patients underwent treatment for an unruptured cerebral aneurysm. There were 4818 patients (7.3%) in whom at least 1 PSI event occurred. The overall inpatient mortality rate was 0.7%. In patients with a PSI event, this rate increased to 7% compared with 0.2% in patients without a PSI event (p < 0.0001). The overall rate of poor outcome was 3.8%. In patients with a PSI event, this rate increased to 23.3% compared with 2.3% in patients without a PSI event (p < 0.0001). There were significant differences in PSI event, poor outcome, and mortality rates between non-CSC and CSC volume-status hospitals (PSI event, 8.4% vs 7.2%; poor outcome, 5.1% vs 3.6%; and mortality, 1% vs 0.6%). In multivariate analysis, all patients treated at a non-CSC volume-status hospital were more likely to suffer a PSI event with an OR of 1.2 (1.1–1.3). In patients who underwent surgery, this relationship was more substantial, with an OR of 1.4 (1.2–1.6). The relationship was not significant in the endovascularly treated patients.CONCLUSIONSIn the treatment of unruptured cerebral aneurysms, PSI events occur relatively frequently and are associated with significant increases in morbidity and mortality. In patients treated at institutions achieving the volume thresholds for CSC certification, the likelihood of having a PSI event, and therefore the likelihood of poor outcome and mortality, was significantly decreased. These improvements are being driven by the improved outcomes in surgical patients, whereas outcomes and mortality in patients treated endovascularly were not sensitive to the CSC volume status of the hospital and showed no significant relationship with treatment volumes.

Latrodectism following Black Widow envenomation is rare in Canada. We present the case of a previously healthy 50 year old male who presented with an acute abdomen, hypertension, and urinary retention. After a thorough work up it was determined to be as a result of a Black Widow spider bite. Due to climate change we may see more cases of Latrodectism in the future and it should be considered as a differential diagnosis in anyone presenting with an acute abdomen after an insect bite.

OBJECTIVEAlthough the use of dual antiplatelet therapy with flow diversion is recommended and commonplace, the testing of platelet inhibition is more controversial.METHODSThe authors reviewed the medical literature to establish and describe the physiology of platelet adhesion, the pharmacology of antiplatelet medications, and the mechanisms of the available platelet function tests. Additionally, they present a review of the pertinent neurointerventional and interventional cardiology literature.RESULTSCompeting reports in the neurointerventional literature argue for and against the use of routine platelet function testing, with adjustments to the dosage or medications based on the results. The interventional cardiology literature has also wrestled with this dilemma after percutaneous coronary interventions, with conflicting reports of the benefits of platelet function testing.CONCLUSIONSDespite its prevalence, the benefits of platelet function testing prior to flow diversion are unproven. This practice will likely remain controversial until the level of evidence improves through more rigorous testing and reporting.

Background There are minimal data in the literature regarding the lymphatic drainage of the conjunctiva and lower eyelid and the relationship with postoperative chemosis and edema. Methods Injection, microdissection, and histologic and radiologic studies were conducted on 12 hemifacial fresh cadaver specimens. Indocyanine green lymphography was conducted in five volunteers. Results Histology identified lymphatic vessels superficial and deep to the orbicularis oculi. Cadaveric dissection, injection, and radiographic studies identified interconnecting superficial and deep facial lymphatic systems and a conjunctival lymphatic network draining through the tarsal plate to the deep lymphatic system. The superficial lymphatic collectors traveled in subcutaneous fat within the lateral orbital and nasolabial fat compartments. The lateral deep lymphatic collectors traveled beneath orbicularis oculi, then through the superficial orbicularis retaining ligament, and into the sub-orbicularis oculi fat in the roof of the prezygomatic space. These vessels descended to preperiosteal fat at the level of zygomaticocutaneous ligaments to travel adjacent to the facial nerve into preauricular nodes. Indocyanine green lymphography identified correlating draining pathways laterally to the parotid nodes and medially to submandibular nodes. Conclusions The authors have found that the lower eyelid and conjunctiva are drained by interconnecting superficial and deep lymphatic systems of the face. The superficial system is vulnerable to damage in incisions and dissection in the infraorbital area. The deep system is vulnerable to damage in dissection around the orbicularis retaining ligament and the zygomaticocutaneous ligaments. The authors suggest that concurrent damage to both the superficial and deep lymphatic systems, especially laterally, may be responsible for postoperative chemosis and edema.

Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9-13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer.In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [100 cigarettes per lifetime] or former light smokers [10 pack-years per lifetime] and ≥15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials.gov, number NCT00818441, and is no longer accruing patients.Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76·8% (95% CI 66·4-84·4) in the as-enrolled population, and was 95·5% (95% CI 83·2-98·9) in the EGFR-mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded.Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer.Pfizer.

Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study.In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554.Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib.Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations.Pfizer.

Introduction Dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non–small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib). Methods The phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of dacomitinib. In the phase II portion, patients received dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS 4m ). Results Twelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS 4m was 47.2% (95% confidence interval [CI], 31.6–61.3; one-sided p -value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7–17.6); median overall survival was 46.3 weeks (95% CI, 32.7–not reached); and the objective response rate was 17.1% (95% CI, 7.2–32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms "cough" and "pain" showed improvement within 3 weeks of initiating treatment. Conclusions Dacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor.

BACKGROUND This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health‐related quality of life of dacomitinib (PF‐00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild‐type non–small cell lung cancer (NSCLC). METHODS Patients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild‐type or known EGFR‐sensitizing mutant tumor, and Eastern Cooperative Oncology Group performance status of 0 to 2 received 45 mg of dacomitinib once daily continuously in 21‐day cycles. RESULTS A total of 66 patients enrolled (adenocarcinoma, n = 50; those without adenocarcinoma [nonadenocarcinoma], n = 16). The objective response rate (ORR) for patients with adenocarcinoma (primary endpoint) was 5% (2 partial responses; 1‐sided P = .372 for null hypothesis [H0]: ORR ≤ 5%) and 6% (1 partial response) for patients with nonadenocarcinoma. Responders included: 2 of 25 EGFR mutation‐positive tumors; 1 of 3 EGFR wild‐type with HER2 amplification. Median progression‐free survival was 12 weeks overall (n = 66) and 18 weeks (n = 26) for patients with EGFR mutation‐positive tumors. Common treatment‐related adverse events were of grade 1 or 2 severity, manageable with standard supportive care, and included diarrhea (grade 3 [G3], 12%), acneiform dermatitis (G3, 6%), exfoliative rash (G3, 3%), dry skin (G3, 0%), fatigue (G3, 3%), and stomatitis (G3, 2%). Six patients (9%) discontinued due to treatment‐related adverse events. By patient report, NSCLC symptoms of dyspnea, cough, and pain (chest, arm/shoulder) showed improvement first observed after 3 weeks on therapy. CONCLUSIONS Dacomitinib demonstrated preliminary activity and acceptable tolerability in heavily pretreated patients, and may offer benefit in molecularly defined patient subsets. Cancer 2014;120:1145–1154. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society., This study investigated the efficacy and safety of dacomitinib in advanced, refractory non–small cell lung cancer (NSCLC), selecting for patients with KRAS wild‐type tumors to exclude those least likely, and simultaneously enrich for those most likely, to benefit from therapy. Although the observed response rate was low, a number of patients experienced prolonged disease control accompanied by rapid and durable lung cancer symptom relief, suggesting that dacomitinib has relevant activity against KRAS wild‐type NSCLC.

Summary Background The recent advent in the surgical treatment of lymphedema necessitates a more detailed understanding of the anatomy of the lymphatic system. Lymphovenous anastomosis (LVA) requires a precise knowledge of the anatomy of the superficial lymphatic collectors in relation to the superficial veins. In vascularized lymph node transfer (VLNT), donor site lymphatic function must be preserved. Methods Using the previously described technique, the superficial lymphatic drainage of 8 anterior hemi-abdomen/upper thigh specimens from 4 fresh human cadavers was investigated. Results The upper and lower abdominal collectors were found above Scarpa's fascia immediately below the subdermal venules. They were thin-walled and translucent and their diameter ranged between 0.2 and 0.8 mm. In the upper thigh two distinct groups of superficial collectors were found. The collectors of the ventromedial bundle constituted the majority of the superficial collectors, were deep in the subcutaneous fat, measured 0.6–1 mm in diameter, had thick walls, and consistently drained into two large nodes inferolateral to the saphenous bulb. The local collectors of the thigh were immediately deep to the subdermal venules, measured 0.3–0.5 mm, had thin walls, and drained into the superolateral group of the superficial inguinal nodes which also drained the lower abdomen, the lower back and the upper gluteal region. Conclusions When raising the groin lymphatic flap for VLNT, the medial extent of the dissection should be limited to the lateral border of femoral artery. When following up patients after VLNT with a groin donor site, circumference measurements must include the upper thigh.

Migraine is a common neurological disorder characterised by temporary disabling attacks of severe head pain and associated disturbances. There is significant evidence to suggest a genetic aetiology to the disease however few causal mutations have been conclusively linked to the migraine subtypes Migraine with (MA) or without Aura (MO). The Potassium Channel, Subfamily K, member 18 (KCNK18) gene, coding the potassium channel TRESK, is the first gene in which a rare mutation resulting in a non-functional truncated protein has been identified and causally linked to MA in a multigenerational family. In this study, three common polymorphisms in the KCNK18 gene were analysed for genetic variation in an Australian case-control migraine population consisting of 340 migraine cases and 345 controls. No association was observed for the polymorphisms examined with the migraine phenotype or with any haplotypes across the gene. Therefore even though the KCNK18 gene is the only gene to be causally linked to MA our studies indicate that common genetic variation in the gene is not a contributor to MA.

Background The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. Methods The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. Results One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. Conclusions Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). Clinical trials number ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).

Background The first successful free vascularized bone flap was performed on June 1, 1974 (and reported in 1975), using the fibula. This was followed by the iliac crest based on the superficial circumflex iliac artery in 1975 and then the deep circumflex iliac artery in 1978. Methods A total of 384 transfers using fibula (n = 198), iliac crest (n = 180), radius (n = 4), rib (n = 1), and metatarsal (n = 1) were used between June of 1974 and June of 2014 for reconstruction of the mandible (n = 267), maxilla (n = 20), clavicle (n = 1), humerus (n = 8), radius and ulna (n = 21), carpus (n = 3), pelvis (n = 2), femur (n = 11), tibia (n = 47), and foot bones (n = 4). Indications were tumor ablation (n = 286), trauma (n = 84), osteomyelitis (n = 2), and the congenital deformities hemifacial microsomia (n = 2) and pseudarthrosis of the tibia (n = 9) and ulna (n = 1). Results Successful transfer was achieved in 95 percent of patients. Union varied with the recipient bone, from 6 to 8 weeks in the jaw, 2 to 3 months in the upper limb, and 3 to 4 months in the femur and tibia. Union was fastest with iliac crest. The fibula provided easier dissection; it could be raised on either peroneal or anterior tibial vessels; the skin flap could be designed distally; it could be placed centrally in the medullary cavity of long bones; and hairline stress fracture in the lower limb frequently preceded rapid subperiosteal hypertrophy. The fibula lacks sufficient height for osseointegration, whereas iliac crest is ideal. Osteotomies of either bone are possible to straighten or increase curvature. Conclusions The fibula is best for long bone or angle-to-angle jaw reconstruction, especially in edentulous patients. Iliac crest is best for hemimandible, curved bones (pelvis, carpus, and metacarpus), and as an alternative for short, straight, 6- to 8-cm-long bone defects.

Tumor metastasis to lymph nodes is a key indicator of patient survival, and is enhanced by the neo-lymphatics induced by tumor-secreted VEGF-C or VEGF-D, acting via VEGFR-3 signalling. These targets constitute important avenues for anti-metastatic treatment. Despite this new understanding, clinical observations linking metastasis with tumor depth or location suggest that lymphangiogenic growth factors are not the sole determinants of metastasis. Here we explored the influence of tumor proximity to lymphatics capable of responding to growth factors on nodal metastasis in a murine VEGF-D over-expression tumor model. We found that primary tumor location profoundly influenced VEGF-D-mediated lymph node metastasis: 89 % of tumors associated with the flank skin metastasised, in contrast with only 19 % of tumors located more deeply on the body wall (p

Purpose This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily. Results One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib. Conclusion Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.

The human EGF (HER) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies. Trastuzumab and lapatinib are standard treatments for HER2-amplified breast cancer, but a significant number of patients do not respond or develop resistance to these drugs. Here we evaluate the in vitro activity of dacomitinib (PF-00299804), an irreversible small molecule pan-HER inhibitor, in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands, and with variable sensitivity to trastuzumab and lapatinib. Forty-seven human breast cancer and immortalized breast epithelial lines representing the known molecular subgroups of breast cancer were treated with dacomitinib to determine IC50 values. HER2-amplified lines were far more likely to respond to dacomitinib than nonamplified lines (RR, 3.39; P < 0.0001). Furthermore, HER2 mRNA and protein expression were quantitatively associated with response. Dacomitinib reduced the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. Dacomitinib exerted its antiproliferative effect through a combined G0–G1 arrest and an induction of apoptosis. Dacomitinib inhibited growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab. Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. This study identifies HER2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in HER2-amplified breast cancers resistant to trastuzumab and lapatinib. Mol Cancer Ther; 11(9); 1978–87. ©2012 AACR.

Background Multiple factors contribute to muscle weakness and reduced muscle mass in chronic obstructive pulmonary disease (COPD) and this impacts patients’ quality of life. One factor implicated in this process is systemic inflammation, an accompaniment of acute exacerbations. Recurrent exacerbations are associated with lower health status. This study examines the relationship between muscle weaknesses, health status and exacerbation frequency in a cohort of patients with COPD. Methods This is an observational study of 188 (95 female) patients with COPD attending two hospital clinics in the northeast of England between 2004 and 2007. We measured spirometry, body mass index, health status (St George’s Respiratory Questionnaire) and grip strength and recorded Medical Research Council dyspnoea scores and the frequency of exacerbations in the previous year. Results Patients were aged 72.568.3 years (data expressed as mean6SD) with Medical Research Council score of 3.660.8, forced expiratory volume in one second (FEV1) of 49.2621.5 per cent predicted and a total St George’s Respiratory Questionnaire score of 72.2615.5. Grip strength, expressed as per cent predicted, was 72.0621.8 in men and 81.0618.2 in women. Exacerbations ranged from zero to five in the previous year and there were associations of reduced grip strength with exacerbation frequency (c 2 ¼9.634; p¼0.0019) and lower health status (c 2 ¼34.00; p

Background Island "perforator flaps" have become state of the art for free-skin flap transfer. Recent articles by Saint-Cyr et al. and Rozen et al. have focused on the anatomical and the clinical territories of individual cutaneous perforating arteries in flap planning, and it is timely to compare this work with our angiosome concept. Methods The angiosome concept, published in 1987, was reviewed and correlated with key experimental and clinical work by the authors, published subsequently at different times in different journals. In addition, new data are introduced to define these anatomical and clinical territories of the cutaneous perforators and to aid in the planning of safe skin flaps for local and free-flap transfer. Results The anatomical territory of a cutaneous perforator was defined in the pig, dog, guinea pig, and rabbit by a line drawn through its perimeter of anastomotic vessels that link it with adjacent perforators in all directions. The safe clinical territory of that perforator, seen not only in the same range of animals but also in the human using either the Doppler probe or computed tomography angiography to locate the vessels, was found reliably to extend to include the anatomical territory of the next adjacent cutaneous perforator, situated radially in any direction. Conclusion The data provided by Saint-Cyr et al. and Rozen et al., coupled with the authors' own original work on the vascular territories of the body and their subsequent studies, reinforce the angiosome concept and provide the basis for the design of safe flaps for patient benefit.

Summary Background An understanding of the vascular anatomy of the breast is paramount in breast reduction surgery in order to minimize vascular complications. While most vascular compromise in breast reduction is largely venous in nature, the venous anatomy of the breast has not been sufficiently explored in the literature, particularly the inferior pole of the breast. Developments in infrared photography have enabled the use of this noninvasive technique to evaluate the venous architecture of the breast. Methods 32 voluntary participants (26 female, 6 male) underwent infrared photography of the superficial veins of the breast. Using a modified technique, the venous architecture of the breast, with an emphasis on the inferior pole veins, was evaluated. Results Infrared photography was able to clearly demonstrate the superficial veins of the breast in all cases. The subareolar plexus and pattern of venous radiation from this plexus were evident, with a predominant pattern of superomedial and inferior pole drainage seen. Although the dominant drainage route was via the third and fourth intercostal spaces, two patterns of drainage were noted: superomedial drainage to the 2nd and 3rd intercostal spaces (29 out of 29 cases) and lower pole drainage to the 4th and/or 5th intercostal space (27 of 29 patients – 93.1%). Conclusion The venous architecture of the breast is demonstrated clearly with the techniques described, enabling the improved planning of breast reduction pedicles. Preservation of the superficial venous drainage as well as the arterial supply can help to mini mize the incidence of vascular complications.

Summary Background The pudendal thigh fasciocutaneous (PTF) flap is a useful flap in perineal reconstruction, that is reliable when small but is traditionally unreliable when large flaps are raised. Large flaps in particular, are associated with an increased incidence of apical necrosis. Thorough descriptions of the vascular anatomy of this flap have been lacking from the literature, with the current study evaluating this anatomy, aiming to provide the anatomical basis for vascular problems and for techniques to maximise its survival. Methods Five unembalmed human cadaveric pelvis specimens were studied. Lead oxide injectant enabled radiographic and dissection analysis of the arterial anatomy of the integument of the perineum. Results A consistent pattern of vascular supply was found in all specimens. 1: the blood supply to the pelvic floor was supplied sequentially by the posterior labial/scrotal arteries, cutaneous branches from the anterior branch of the obturator artery, and branches from the external pudendal arteries. 2: these vessels ran close to the midline, medial to the PTF flap. 3: the posterior labial/scrotal arteries were deep to the Colles' fascia and the branches from the obturator artery and external pudendal arteries were located superficial to the Colles' fascia. Conclusion This study has demonstrated that the PTF flap is a three vascular territory flap and that the pedicle is situated close to the midline. This may explain why regions of the PTF flap may have a potentially precarious blood supply, and suggests that the PTF flap should be designed more medially. Given the third territory of supply to the apex of the flap, a delay procedure may help to avoid flap necrosis.

The anterior abdominal wall integument is frequently used in a range of reconstructive flaps. These tissues are supplied by the deep and superficial inferior epigastric arteries (DIEA and SIEAs) and the deep and superficial superior epigastric arteries (DSEA and SSEAs). Previous abdominal wall surgery alters this vascular anatomy and may influence flap design. One hundred and sixty-eight patients underwent abdominal wall computed tomographic angiography (CTA) for preoperative imaging. Fifty-eight of these patients had undergone previous abdominal surgery, and were assessed for scar pattern and relationship to the course and distribution of all major axial vessels and perforators. Two cadaveric abdominal wall specimens with midline abdominal scars underwent contrast injection of the DIEAs and DSEAs, with subsequent CTA. The course and distribution of all cutaneous vessels were assessed. In all clinical and cadaveric cases, the vasculature of the abdominal wall had been altered by previous surgery. In the clinical cases, vascular architecture was universally altered in the region of the scar, often modifying the filling patterns of the abdominal wall and occasionally precluding the use of an abdominal wall flap. In both cadaveric specimens, regions of non-filling were evident upon contrast injection, highlighting the angiosomes not supplied by the DIEA or DSEA. Previous abdominal wall surgery necessarily alters the vascular architecture of the abdominal wall, and may alter the source vessels supplying cutaneous tissues. CTA was useful in identifying and delineating these changes, and may be used as a preoperative tool in this role.

Background: The lumbar region has been scarcely explored as a donor site for free tissue transfer or as a free flap recipient site. The lumbar integument provides a versatile prospective flap site, with a potentially well-concealed scar. Similarly, defects of this region can require recipient vessels that may be difficult to identify. Although lumbar artery perforators have been described, the reliability of perforators in this region remains questionable. Methods: An anatomical study was undertaken combining both cadaveric and in vivo analysis of the lumbar vessels. The cadaveric component comprised both dissection and angiographic studies in fresh and embalmed cadavers (36 lumbar regions in 18 cadavers), and the clinical study comprised a computed tomographic angiographic study (44 sides in 22 patients) and an operative case report. Results: Perforators were shown to arise from all eight lumbar arteries to enter the lumbar integument, with their size, location, and course described. Lower lumbar perforators were more often septocutaneous and of larger caliber. A case in which the fourth lumbar artery and concomitant vein were used as free flap recipient vessels is described, the first such reported case in the literature. Conclusions: Improving the incidence of identifying lumbar perforators of large caliber and with a septocutaneous course can be achieved by selecting lower lumbar vessels, or with the use of preoperative computed tomographic angiography. Computed tomographic angiography can successfully identify the location, size, and course of lumbar artery perforators and can aid flap design. Lumbar artery perforators are highly useful for both donor and recipient vessels in free flap surgery.

The sartorius muscle is a superficial muscle of the thigh that possesses highly suitable qualities for many uses in local transposition and free muscle transfer. However, a paucity of description of the neurovascular anatomy of the sartorius has contributed to its infrequent use in these roles.Both human and canine studies were undertaken to delineate the neurovascular anatomy of the sartorius and to determine the role for surgical delay clinically. Fifty-five human cadaveric sartorius muscles and 30 canine cadaveric sartorius muscles underwent angiographic and dissection studies, and the location and course of the vessels and nerves supplying sartorius are described. A subsequent study was undertaken in two live canines in which the vascular supply to the sartorius was evaluated before and after surgical delay.The sartorius is supplied by an average of six or seven vascular pedicles, the size, location, and course of which are described. The nerve supply to the sartorius enters at its proximal end and uniformly arises from a branch of the femoral nerve. Variations in branching patterns and course of nerves and vessels are described. Living canine studies demonstrated the dilatation of intramuscular vessels following surgical delay, with the contrast injection of a single remaining vascular pedicle shown to vascularize the entire length of the sartorius muscle.The sartorius is highly suitable for local transposition and free muscle transfer for facial reanimation. The neurovascular anatomy is reliable, and the use of surgical delay can augment its vascular supply and increase the arc of rotation for local transposition.

The deep inferior epigastric artery perforator (DIEP) flap aims to reduce donor-site morbidity by minimizing rectus muscle damage; however, damage to motor nerves during perforator dissection may denervate rectus muscle. Although cadaveric research has demonstrated that individual nerves do not arise from single spinal cord segments and are not distributed segmentally, the functional distribution of individual nerves remains unknown. Using intraoperative nerve stimulation, the current study describes the motor distribution of individual nerves supplying the rectus abdominis, providing a guide to nerve dissection during DIEP flap harvest.Twenty rectus abdominis muscles in 17 patients undergoing reconstructive surgery involving rectus abdominis (DIEP, transverse rectus abdominis musculocutaneous, or vertical rectus abdominis musculocutaneous flaps) underwent intraoperative stimulation of nerves innervating the infraumbilical segment of the rectus. Nerve course and extent of rectus muscle contraction were recorded.In each case, three to seven nerves entered the infraumbilical segment of the rectus abdominis. Small nerves (type 1) innervated small longitudinal strips of rectus muscle, rather than transverse strips as previously described. There was significant overlap between adjacent type 1 nerves. In 18 of 20 cases, a single large nerve (type 2) at the level of the arcuate line supplied the entire width and length of rectus muscle.Nerves innervating the rectus abdominis are at risk during DIEP flap harvest. Small, type 1 nerves have overlapping innervation from adjacent nerves and may be sacrificed without functional detriment. However, large type 2 nerves at the level of the arcuate line innervate the entire width of rectus muscle without adjacent overlap and may contribute to donor-site morbidity if sacrificed.

Institutional review board approval was obtained for this study, and all patients gave written informed consent. Autologous surgical breast reconstruction with use of abdominal wall donor flaps based on the deep inferior epigastric artery (DIEA) and one or more of its anterior musculocutaneous perforating branches (DIEA perforator flap) is being used with increasing frequency instead of breast reconstruction with use of traditional transverse rectus abdominus musculocutaneous and modified muscle-sparing flaps. Preoperative mapping of the DIEA perforators with abdominal wall computed tomographic (CT) angiography may improve patient care by providing the surgeon with additional information that will lead to optimization of the surgical technique, shorter procedure time, and reduction in the frequency of surgical complications. The branching patterns of the DIEA, the segmental anatomy of the anterior adipocutaneous perforating branches of the DIEA, and the importance of these features in pre- and intraoperative surgical planning necessitate a different approach to abdominal wall CT angiography than that used with other abdominal CT angiographic techniques. In abdominal wall CT angiography, the common femoral artery is used as the bolus trigger, CT scanning is performed in the caudocranial direction, the automatic exposure control feature is disabled, a scaled grid overlay tool is used to present information to the surgeons, and radiation dose is minimized (average dose, 6 mSv). The anatomic accuracy of abdominal wall CT angiography has been investigated in cadaveric and surgical studies, with sensitivity of 96%-100% and specificity of 95%-100%. This detailed description will allow other radiologists and surgeons interested in free DIEP flap surgery to incorporate this useful tool into their practice.

Background: The deep inferior epigastric artery (DIEA) perforator flap for breast reconstruction spares rectus abdominis muscle and has low donor-site morbidity. However, abdominal wall weakness and bulge remain significant complications, with damage to the motor innervation of the rectus abdominis postulated as a cause. This study describes the relationship between the nerves supplying rectus abdominis and perforators, based on a thorough cadaveric study and review of the literature. Methods: Twenty hemiabdominal walls from fresh and embalmed cadavers were dissected, mapping the course of the nerve and vascular supply of rectus abdominis. Results: The infraumbilical segment of rectus abdominis was innervated by T9-L1, with four to seven nerve branches entering rectus abdominis from its lateral border (12 cases) or posterior surface (93 cases). Each nerve entered a nerve plexus running with the most lateral branch of the DIEA, before running with arterial perforators into rectus abdominis. Nerves entered rectus muscle more medial than the lateral row perforators (83 percent of cases), with the medial branches of the DIEA devoid of these nerve branches. Conclusions: The nerves innervating rectus abdominis are at risk during the raising of a DIEA perforator flap. These nerves enter the posterior surface of rectus abdominis and run with the most lateral branch of the DIEA and its perforators. Damage to these nerves may denervate rectus abdominis muscle and contribute to donor-site morbidity. As medial row perforators were not related to these motor nerves, these perforators are ideal for inclusion in DIEA perforator and transverse rectus abdominis myocutaneous flaps.

Background: Lymphoscintigraphy has become a routine examination for identifying the sentinel lymph node in various cancer patients. Despite increasing clinical information, the basic anatomy of the superficial lymphatic system of the upper torso has not been fully elucidated. Methods: Five female breasts, three anterior chest walls, and three forequarter specimens from fresh nine cadavers (two male and seven female) were used for this study. Our original radiographic method for delineating the lymphatics was applied. The course of the lymph vessels was traced from the x-ray films and color coded in accordance with their sentinel lymph node to define the lymph territories of the upper torso. In addition, cross-sectional studies were performed on the female breasts to demonstrate the three-dimensional pathway and connections of the lymphatic vessels. Results: The lymphatic territories of the upper torso were divided by the mid-axillary line. The anterior side drained into the external mammary or axillary vein lymph nodes and the posterior side drained into the scapular nodes. There was no significant difference between sexes. In most cases, one sentinel lymph node in the axilla notably covered a large lymph territory in both the upper arm and the upper torso. Conclusions: The authors have demonstrated by radiography and dissection the superficial lymphatics of the upper torso in male and female cadavers. The lymph vessels originating in the lower region of the upper torso have close spatial association with the breast tissue and seemed to play a key role in the breast lymph drainage.

Breast reconstruction plays a significant role in the management of breast cancer. The removal of a breast has implications for the psychologic, social, and sexual well-being of the patient, establishing the need for discussion of postmastectomy breast reconstruction with suitable patients. However, operative morbidity and the potential for diminished oncologic safety are ongoing issues of contention. A Medline literature review was performed to evaluate the interplay between the psychosocial need for breast reconstruction in patients after mastectomy and the issues surrounding its oncologic safety. Immediate breast reconstruction does not impair the oncologic safety of breast cancer management, with no increase in local recurrence rates, and no delays in the initiation of adjuvant chemotherapy or radiation therapy (RT). Immediate breast reconstruction in the setting of chemotherapy is not associated with greater complication rates; however, there is some evidence for increased complications in the setting of adjuvant RT. Breast reconstruction has a positive effect on the psychosocial outcomes of mastectomy and is oncologically safe in the immediate and delayed settings. Ultimately, the decision-making process of whether to reconstruct, how to reconstruct, and when to reconstruct requires a multidisciplinary approach, with the patient, plastic surgeon, oncologic surgeon, medical oncologist, and radiation oncologist all contributing.

Current understanding of the pattern of lymph channels is largely dependent on the anatomical studies of Sappey performed in the nineteenth century, when mercury was injected into human cadavers and the lymphatics were dissected. These studies have not been repeated because the use of mercury is now prohibited as a result of its toxicity. The aim of this study was to reappraise the gross lymphatic anatomy and lymph node connections using a radiologic technique. A period of 3 years was required for development of a new method.The definitive technique used hydrogen peroxide to identify lymphatic vessels and to inflate them. The individual channels were injected with a radiopaque lead oxide mixture and recorded on x-ray film. Each channel was dissected meticulously under the surgical microscope and its course examined in relation to the regional lymph nodes. This method was then applied to 14 human cadaver upper limbs obtained from 10 different cadavers.The authors found that the superficial lymphatic vessels course within the subcutaneous fat in close proximity to the main subcutaneous veins. Communication between the superficial and the deep lymphatic systems was not identified in these studies.Most lymph vessels were seen to flow into one main (sentry) lymph node in the axillary region; however, some of the lymph vessels ran along the posterior forearm, bypassing the "sentry" node to reach other smaller nodes.

Muslim infants undergo circumcision for religious reasons and Bradford has a high Muslim population. The National Health Service in UK does not provide religious circumcision, so in 1996 a nurse-delivered circumcision service led by consultant urologists was set up at a no-profit and cost-only basis. Plastibell circumcision was offered to all infants between 6 and 14 weeks old and performed under local anaesthesia. Information leaflets and videotapes about the procedure were available to parents prior to the procedure. A three monthly audit of the service was undertaken. Between July 1996 and June 2005 (9 years) 1,129 circumcisions were performed. The common complications were problems with the ring (3.6%) and bleeding (3%). Overall, there was 96% satisfaction rate among the service users. The Plastibell technique for circumcision is a simple method and can be safely performed by trained nurses with acceptable complication rates.

Introduction It is now widely accepted that veterinary graduates should enter their profession with high-quality communication skills. Until recently, however, this has not been reflected in undergraduate training. Recently, the Veterinary Faculty at the University of Liverpool, in collaboration with the profession's indemnity insurers (the Veterinary Defence Society), has developed one of the first specific communication skills training courses for veterinary undergraduates. For the first three years it has been run, the aim of this course has been to increase students’ awareness of the importance of good communication in the veterinary profession. The course is based on best practice as currently defined in medical education, making extensive use of actors as simulated clients. As well as watching acted-out consultations, the students also role-play scenarios designed to expose them to all aspects of the veterinary consultation (including introductions, history taking, breaking bad news, fee issues, and dealing with anger). Feedback on the role plays is facilitated by members of stbio. Evaluation of the first year of this course has been published and has shown it achieves its aims of increasing the students’ awareness of the importance of good communication with their clients.1 However, regular facilitators became aware that the students’ learning experience was very variable and, perhaps more importantly, could not be defined. This was felt to be a critical limitation to further development of the course, particularly in the area of student learning and assessment. It was recognized that one of the major obstacles to further development was the lack of a teaching model suitable for the veterinary consultation. Such models are routinely used in medical education. However, their direct application to veterinary education is limited because they do not reflect the diversity of clients with whom the veterinarian/veterinary surgeon communicates (e.g., farmers, companion animal owners), nor do they take into account the two important, and often difficult, areas of euthanasia and finances. The aim of this project was to develop a consultation model for veterinary education based on the Calgary-Cambridge model of the medical consultation. The model was adapted, recognizing both the considerable overlap and also the likely differences between the veterinary and medical consultations. Subsequently, this model has been used to train communication skills facilitators and undergraduates. Here we present the model and provide results of evaluation of its use within the communication skills program for veterinary undergraduates at the University of Liverpool.

Studies of the gross anatomy of the lymphatic system are few and far between when compared with those of other vascular systems. Our knowledge of the anatomy of the lymphatic system is so limited that it seems vastly inadequate in explaining the clinical manifestations caused by its disorder. This study has developed an effective method to identify the lymphatics using hydrogen peroxide, to demonstrate the lymphatic vessels radiographically using a lead oxide suspension, and to dissect them out in adult human cadavers.