Geographic variation in breast reconstruction surgery after mastectomy for females with breast cancer in Alberta, Canada.

BACKGROUND: Breast cancer is the most common cancer affecting females in Canada, and about half of females with breast cancer are treated with mastectomy. We sought to evaluate geographic variation in breast reconstruction surgery in Alberta, Canada. METHODS: Using linked population-based administrative databases, we extracted data on all Alberta females aged 18 years and older who were diagnosed with breast cancer and treated with mastectomy during 2004-2017. Analyses included regression modelling of odds of reconstruction at 1 year and a spatial scan to identify geographic clusters of lower numbers of reconstruction. RESULTS: A total of 16 198 females diagnosed with breast cancer were treated with a mastectomy, and 1932 (11.9%) had reconstruction within 1 year postmastectomy. Those with reconstruction were more likely to be younger (adjusted odds ratio [OR] 16.7, 95% confidence interval [CI] 13.7-20.3; aged 21-44 yr v. ≥ 65 yr) and were less likely to be from lower-income neighbourhoods. They were more likely to have at least 1 comorbidity and were more likely to have advanced stages of cancer and to require chemotherapy (adjusted OR 0.55, 95% CI 0.47-0.65) or radiotherapy after mastectomy (adjusted OR 0.59, 95% CI 0.39-0.87) than females without reconstruction. We identified rural northern and southeastern clusters with frequencies of reconstruction that were 69.6% and 41.6% of what was expected, respectively. CONCLUSION: We found an overall postmastectomy rate of breast reconstruction of 11.9%, and we identified geographic variation. Predictors of reconstruction in Alberta were similar to those previously described in the literature, specifically with patients in rural communities having lower rates of reconstruction than their urban counterparts. These results suggest that further interventions are required to identify the specific barriers to reconstruction within rural communities and to create strategies to ensure equitable access to all residents.

A Direct Comparison of Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interfaces to Prevent Neuroma Pain.

BACKGROUND AND OBJECTIVES: Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) surgeries manage neuroma pain; however, there remains considerable discord regarding the best treatment strategy. We provide a direct comparison of TMR and RPNI surgery using a rodent model for the treatment of neuroma pain. METHODS: The tibial nerve of 36 Fischer rats was transected and secured to the dermis to promote neuroma formation. Pain was assessed using mechanical stimulation at the neuroma site (direct pain) and von Frey analysis at the footpad (to assess tactile allodynia from collateral innervation). Once painful neuromas were detected 6 weeks later, animals were randomized to experimental groups: (a) TMR to the motor branch to biceps femoris, (b) RPNI with an extensor digitorum longus graft, (c) neuroma excision, and (d) neuroma in situ. The TMR/RPNIs were harvested to confirm muscle reinnervation, and the sensory ganglia and nerves were harvested to assess markers of regeneration, pain, and inflammation. RESULTS: Ten weeks post-TMR/RPNI surgery, animals had decreased pain scores compared with controls ( P < .001) and they both demonstrated neuromuscular junction reinnervation. Compared with neuroma controls, immunohistochemistry showed that sensory neuronal cell bodies of TMR and RPNI showed a decrease in regeneration markers phosphorylated cyclic AMP receptor binding protein and activation transcription factor 3 and pain markers transient receptor potential vanilloid 1 and neuropeptide Y ( P < .05). The nerve and dorsal root ganglion maintained elevated Iba-1 expression in all cohorts. CONCLUSION: RPNI and TMR improved pain scores after neuroma resection suggesting both may be clinically feasible techniques for improving outcomes for patients with nerve injuries or those undergoing amputation.

Current Concepts in the Management of Primary Lymphedema.

Primary lymphedema is a heterogeneous group of conditions encompassing all lymphatic anomalies that result in lymphatic swelling. Primary lymphedema can be difficult to diagnose, and diagnosis is often delayed. As opposed to secondary lymphedema, primary lymphedema has an unpredictable disease course, often progressing more slowly. Primary lymphedema can be associated with various genetic syndromes or can be idiopathic. Diagnosis is often clinical, although imaging can be a helpful adjunct. The literature on treating primary lymphedema is limited, and treatment algorithms are largely based on practice patterns for secondary lymphedema. The mainstay of treatment focuses on complete decongestive therapy, including manual lymphatic drainage and compression therapy. For those who fail conservative treatment, surgical treatment can be an option. Microsurgical techniques have shown promise in primary lymphedema, with both lymphovenous bypass and vascularized lymph node transfers demonstrating improved clinical outcomes in a few studies.

Recovering the regenerative potential in chronically injured nerves by using conditioning electrical stimulation.

OBJECTIVE: Chronically injured nerves pose a significant clinical challenge despite surgical management. There is no clinically feasible perioperative technique to upregulate a proregenerative environment in a chronic nerve injury. Conditioning electrical stimulation (CES) significantly improves sensorimotor recovery following acute nerve injury to the tibial and common fibular nerves. The authors' objective was to determine if CES could foster a proregenerative environment following chronically injured nerve reconstruction. METHODS: The tibial nerve of 60 Sprague Dawley rats was cut, and the proximal ends were inserted into the hamstring muscles to prevent spontaneous reinnervation. Eleven weeks postinjury, these chronically injured animals were randomized, and half were treated with CES proximal to the tibial nerve cut site. Three days later, 24 animals were killed to evaluate the effects of CES on the expression of regeneration-associated genes at the cell body (n = 18) and Schwann cell proliferation (n = 6). In the remaining animals, the tibial nerve defect was reconstructed using a 10-mm isograft. Length of nerve regeneration was assessed 3 weeks postgrafting (n = 16), and functional recovery was evaluated weekly between 7 and 19 weeks of regeneration (n = 20). RESULTS: Three weeks after nerve isograft surgery, tibial nerves treated with CES prior to grafting had a significantly longer length of nerve regeneration (p < 0.01). Von Frey analysis identified improved sensory recovery among animals treated with CES (p < 0.01). Motor reinnervation, assessed by kinetics, kinematics, and skilled motor tasks, showed significant recovery (p < 0.05 to p < 0.001). These findings were supported by immunohistochemical quantification of motor endplate reinnervation (p < 0.05). Mechanisms to support the role of CES in reinvigorating the regenerative response were assessed, and it was demonstrated that CES increased the proliferation of Schwann cells in chronically injured nerves (p < 0.05). Furthermore, CES upregulated regeneration-associated gene expression to increase growth-associated protein-43 (GAP-43), phosphorylated cAMP response element binding protein (pCREB) at the neuronal cell bodies, and upregulated glial fibrillary acidic protein expression in the surrounding satellite glial cells (p < 0.05 to p < 0.001). CONCLUSIONS: Regeneration following chronic axotomy is impaired due to downregulation of the proregenerative environment generated following nerve injury. CES delivered to a chronically injured nerve influences the cell body and the nerve to re-upregulate an environment that accelerates axon regeneration, resulting in significant improvements in sensory and motor functional recovery. Percutaneous CES may be a preoperative strategy to significantly improve outcomes for patients undergoing delayed nerve reconstruction.

Conditioning Electrical Stimulation Accelerates Regeneration in Nerve Transfers.

OBJECTIVE: Compared to the upper limb, lower limb distal nerve transfer (DNT) outcomes are poor, likely due to the longer length of regeneration required. DNT surgery to treat foot drop entails rerouting a tibial nerve branch to the denervated common fibular nerve stump to reinnervate the tibialis anterior muscle for ankle dorsiflexion. Conditioning electrical stimulation (CES) prior to nerve repair surgery accelerates nerve regeneration and promotes sensorimotor recovery. We hypothesize that CES prior to DNT will promote nerve regeneration to restore ankle dorsiflexion. METHODS: One week following common fibular nerve crush, CES was delivered to the tibial nerve in half the animals, and at 2 weeks, all animals received a DNT. To investigate the effects of CES on nerve regeneration, a series of kinetic, kinematic, skilled locomotion, electrophysiologic, and immunohistochemical outcomes were assessed. The effects of CES on the nerve were investigated. RESULTS: CES-treated animals had significantly accelerated nerve regeneration (p < 0.001), increased walking speed, and improved skilled locomotion. The injured limb had greater vertical peak forces, with improved duty factor, near-complete recovery of braking, propulsive forces, and dorsiflexion (p < 0.01). Reinnervation of the tibialis anterior muscle was confirmed with nerve conduction studies and immunohistochemical analysis of the neuromuscular junction. Immunohistochemistry demonstrated that CES does not induce Wallerian degeneration, nor does it cause macrophage infiltration of the distal tibial nerve. INTERPRETATION: Tibial nerve CES prior to DNT significantly improved functional recovery of the common fibular nerve and its muscle targets without inducing injury to the donor nerve. ANN NEUROL 2020;88:363-374.

Conditioning Electrical Stimulation Is Superior to Postoperative Electrical Stimulation in Enhanced Regeneration and Functional Recovery Following Nerve Graft Repair.

Background. Autologous nerve graft is the most common clinical intervention for repairing a nerve gap. However, its regenerative capacity is decreased in part because, unlike a primary repair, the regenerating axons must traverse 2 repair sites. Means to promote nerve regeneration across a graft are needed. Postoperative electrical stimulation (PES) improves nerve growth by reducing staggered regeneration at the coaptation site whereas conditioning electrical stimulation (CES) accelerates axon extension. In this study, we directly compared these electrical stimulation paradigms in a model of nerve autograft repair. Methods. To lay the foundation for clinical translation, regeneration and reinnervation outcomes of CES and PES in a 5-mm nerve autograft model were compared. Sprague-Dawley rats were divided into: (a) CES, (b) PES, and (c) no stimulation cohorts. CES was delivered 1 week prior to nerve cut/coaptation, and PES was delivered immediately following coaptation. Length of nerve regeneration (n = 6/cohort), and behavioral testing (n = 16/cohort) were performed at 14 days and 6 to 14 weeks post-coaptation, respectively. Results. CES treated axons extended 5.9 ± 0.2 mm, significantly longer than PES (3.8 ± 0.2 mm), or no stimulation (2.5 ± 0.2 mm) (P < .01). Compared with PES animals, the CES animals had significantly improved sensory recovery (von Frey filament testing, intraepidermal nerve fiber reinnervation) (P < .001) and motor reinnervation (horizontal ladder, gait analysis, nerve conduction studies, neuromuscular junction analysis) (P < .01). Conclusion. CES resulted in faster regeneration through the nerve graft and improved sensorimotor recovery compared to all other cohorts. It is a promising treatment to improve outcomes in patients undergoing nerve autograft repair.

Conditioning electrical stimulation is superior to postoperative electrical stimulation, resulting in enhanced nerve regeneration and functional recovery.

Postoperative electrical stimulation (PES) improves nerve regeneration by decreasing staggered regeneration at the coaptation site. By contrast, conditioning (preoperative) electrical stimulation (CES) accelerates axon extension. Given that both techniques can be delivered at the bedside, a direct comparison of outcomes is of significant clinical importance. In this study, we compared regeneration and reinnervation outcomes of CES, PES, a combination of CES and PES, and a no stimulation control. Sprague Dawley rats were randomly divided into i) CES, ii) PES, iii) CES + PES, and iv) no stimulation. CES was delivered one week prior to nerve cut/coaptation, and PES was delivered immediately following nerve repair. Length of nerve regeneration was assessed at 7 days post-coaptation (n = 6/cohort), and behavioral testing was performed between 6 and 8 weeks post-coaptation (n = 8/cohort). Animals treated with CES had significantly longer axon extension and improved sensorimotor recovery compared to all other cohorts. CES treated axons extended 8.5 ± 0.6 mm, significantly longer than PES (5.5 ± 0.5 mm), CES + PES (3.6 ± 0.7 mm), or no stimulation (2.7 ± 0.5 mm) (p < .001). Sensory recovery (von Frey filament testing, intraepidermal nerve fiber reinnervation) (p < .001) and motor reinnervation (horizontal ladder, gait analysis, nerve conduction studies, neuromuscular junction analysis) (p < .05 - p < .001) were significantly improved in CES animals. CES significantly improves regeneration and reinnervation beyond the current clinical paradigm of PES. The combination of CES and PES does not have a synergistic effect. CES alone therefore may be a more promising treatment to improve outcomes in patients undergoing nerve repair surgeries.

The nerve conditioning lesion: A strategy to enhance nerve regeneration.

By altering the intrinsic metabolism of the cell, including the upregulation of regeneration-associated genes (RAGs) and the production of structural proteins for axonal outgrowth, the conditioning lesion sets up an environment highly conducive to regeneration. In this review, we assess 40 years of research to provide a comprehensive overview of the conditioning lesion literature, directed at (1) discussing the mechanisms of and barriers to nerve regeneration that can be mitigated by the conditioning lesion, (2) describing the cellular and molecular pathways implicated in the conditioning lesion effect, and (3) deliberating on how these insights might be applied clinically. The consequential impact on regeneration is profound, with a conditioned nerve demonstrating longer neurite extensions in vitro, enhanced expression of RAGs within the dorsal root ganglia, early assembly and transportation of cytoskeletal elements, accelerated axonal growth, and improved functional recovery in vivo. Although this promising technique is not yet feasible to be performed in humans, there are potential strategies, such as conditioning electrical stimulation that may be explored to allow nerve conditioning in a clinically safe and well-tolerated manner. Ann Neurol 2018;83:691-702.

An appraisal of students' awareness of "self-reflection" in a first-year pathology course of undergraduate medical/dental education.

BACKGROUND: Self-reflection and reflective practice are increasingly considered as essential attributes of competent professionals functioning in complex and ever-changing healthcare systems of the 21st century. The aim of this study was to determine the extent of students' awareness and understanding of the reflective process and the meaning of 'self-reflection' within the contextual framework of their learning environment in the first-year of their medical/dental education. We endorse that the introduction of such explicit educational tasks at this early stage enhances and promotes students' awareness, understanding, and proficiency of this skill in their continuing life-long health professional learning. METHODS: Over two years, students registered in first-year pathology at the University of Saskatchewan were introduced to a self-reflection assignment which comprised in the submission of a one-page reflective document to a template of reflective questions provided in the given context of their learning environment. This was a mandatory but ungraded component at the midterm and final examinations. These documents were individually analyzed and thematically categorized to a "5 levels-of-reflection-awareness" scale using a specially-designed rubric based on the accepted major theories of reflection that included students' identification of: 1) personal abilities, 2) personal learning styles 3) relationships between course material and student history 4) emotional responses and 5) future applications. RESULTS: 410 self-reflection documents were analyzed. The student self-awareness on personal learning style (72.7% level 3+) and course content (55.2% level 3+) were well-reflected. Reflections at a level 1 awareness included identification of a) specific teaching strategies utilized to enhance learning (58.4%), b) personal strengths/weaknesses (53%), and c) emotional responses, values, and beliefs (71.5%). Students' abilities to connect information to life experiences and to future events with understanding were more evenly distributed across all 5 levels of reflection-awareness. CONCLUSIONS: Exposure to self-reflection assignments in the early years of undergraduate medical education increases student awareness and promotes the creation of personal meaning of one's reactions, values, and premises in the context of student learning environments. Early introduction with repetition to such cognitive processes as practice tools increases engagement in reflection that may facilitate proficiency in mastering this competency leading to the creation of future reflective health professionals.

Pulmonary lymphangitic carcinomatosis from squamous cell carcinoma of the cervix.

INTRODUCTION: Pulmonary metastasis presenting as lymphangitic carcinomatosis arising from squamous cell carcinoma (SCC) of the cervix is a rare event. Poorly represented in the literature, this event is associated with a) difficulty in accurate diagnosis, b) grave prognosis, and the c) lack of recognized predisposing risk factors. CASE REPORT: A 50 year-old female presented at our practice with a three-month history of a productive cough associated with dyspnoea and shortness of breath. A chest x-ray and computed tomography (CT) scan revealed multiple bilateral patchy areas with subsegmental atelectasis in both lungs which was investigated with a bronchoscopy, left thoracoscopy, and a left lung biopsy. Pathological examination of the wedge biopsy of the left upper lobe revealed neoplastic sheets of cell disturbed along the septal vessels, perivascular/peribronchial lymphatics, and the subpleural lymphatics. This lymphangitic carcinomatosis was confirmed to be metastatic from SCC of the cervix that had been diagnosed and treated two years ago. She was treated with systemic Carbo/Taxol chemotherapy and corticosteroids as a palliative measure. Despite temporary improvement, she died 13 months later. CONCLUSION: Pulmonary lymphangitic carcinomatosis is a rare manifestation of metastatic SCC of the cervix. As clinical presentations including radiographic imaging mimics other pulmonary entities, accurate diagnosis remains a challenge. Increased clinical awareness of such patterns of metastases in cervical cancer supported by accurate pathological diagnosis is imperative to guide appropriate therapy in these patients.

Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins.

AIM: The aim of our study was to evaluate survival outcomes in malignant mixed Mullerian tumors (MMMT) of the uterus with respect to the role of cell cycle and apoptotic regulatory proteins in the carcinomatous and sarcomatous components. METHODS: 23 cases of uterine MMMT identified from the Saskatchewan Cancer Agency (1970-1999) were evaluated. Immunohistochemical expression of Bad, Mcl-1, bcl-x, bak, mdm2, bax, p16, p21, p53, p27, EMA, Bcl-2, Ki67 and PCNA was correlated with clinico-pathological data including survival outcomes. RESULTS: Histopathological examination confirmed malignant epithelial component with homologous (12 cases) and heterologous (11 cases) sarcomatous elements. P53 was strongly expressed (70-95%) in 15 cases and negative in 5 cases. The average survival in the p53+ve cases was 3.56 years as opposed to 8.94 years in p53-ve cases. Overexpression of p16 and Mcl-1 were observed in patients with longer survival outcomes (>2 years). P16 and p21 were overexpressed in the carcinomatous and sarcomatous elements respectively. Cyclin-D1 was focally expressed only in the carcinomatous elements. CONCLUSIONS: Our study supports that a) cell cycle and apoptotic regulatory protein dysregulation is an important pathway for tumorigenesis and b) p53 is an important immunoprognostic marker in MMMT of the uterus.