Outcomes after vascular resection during curative-intent resection for hilar cholangiocarcinoma: a multi-institution study from the US extrahepatic biliary malignancy consortium.

BACKGROUND: Surgical resection is the cornerstone of curative-intent therapy for patients with hilar cholangiocarcinoma (HC). The role of vascular resection (VR) in the treatment of HC in western centres is not well defined. METHODS: Utilizing data from the U.S. Extrahepatic Biliary Malignancy Consortium, patients were grouped into those who underwent resection for HC based on VR status: no VR, portal vein resection (PVR), or hepatic artery resection (HAR). Perioperative and long-term survival outcomes were analyzed. RESULTS: Between 1998 and 2015, 201 patients underwent resection for HC, of which 31 (15%) underwent VR: 19 patients (9%) underwent PVR alone and 12 patients (6%) underwent HAR either with (n = 2) or without PVR (n = 10). Patients selected for VR tended to be younger with higher stage disease. Rates of postoperative complications and 30-day mortality were similar when stratified by vascular resection status. On multivariate analysis, receipt of PVR or HAR did not significantly affect OS or RFS. CONCLUSION: In a modern, multi-institutional cohort of patients undergoing curative-intent resection for HC, VR appears to be a safe procedure in a highly selected subset, although long-term survival outcomes appear equivalent. VR should be considered only in select patients based on tumor and patient characteristics.

Apex posterior angulation of the humerus: A characterization of normal sagittal plane anatomy with implications for surgical fixation.

INTRODUCTION: An understanding of the sagittal plane morphology of the humerus is relevant during surgical fixation of humeral fractures but is not well described in the literature. The purpose of this study was to better characterize the native sagittal plane morphology of the humerus. MATERIALS AND METHODS: 170 patients with uninjured full length lateral humerus radiographs were retrospectively evaluated. The angle between the proximal humeral diaphyseal axis and the distal humeral diaphyseal axis was identified and measured. The proximal axis was defined by two points equidistant from the anterior and posterior cortex 10 mm and 100 mm distal to the metaphyseal flare, and the distal axis by two points at 10 mm and 50 mm proximal to the capitellum/trochlea. The relative location of the center of rotation of angulation (CORA) was calculated as a percentage of humeral length. RESULTS: 114 radiographs were included in the analysis (66 right humeri, 48 left humeri). The average apex posterior angulation was 6.5 +/- 2.9°. The CORA occurred at an average of 80% (SD+/-13%) of the length of the humerus (proximal to distal). Total humeral length and absolute distance to CORA were greater in males compared to females (364 ± 50 mm versus 326 ± 30 mm; p<0.001; 290 ± 68 mm versus 260 ± 48 mm; p=0.003), but there were no significant sex differences with respect to magnitude of the apex posterior angulation (p=0.077) or location of CORA as a percentage of total humeral length (p=0.916). There were no statistically significant associations between age and total humeral length (p=0.056), distance to CORA (p=0.130), location of CORA as percentage of total humeral length (p=0.753), or magnitude of angulation (p=0.075). CONCLUSION: An apex posterior bow consistently exists in the distal one-quarter of the humerus that is consistent across ages and between sexes. This normal anatomic bow is important to recognize to avoid an extension malreduction and has implications for implant fit and contouring.

Distal Tibia Apex Posterior Angulation: A Normal Anatomic Variant Related to Hindfoot Alignment With Side-to-Side Symmetry.

OBJECTIVES: The sagittal plane of the distal tibia has not been well-described. This study sought to characterize sagittal plane morphology, determine symmetry from side to side, and identify differences based on hindfoot alignment. METHODS: One hundred twelve bilateral lateral weight-bearing ankle radiographs were retrospectively evaluated (224 ankles). Hindfoot alignment was classified as neutral, planus, or cavus using the Meary angle. The angle between the diaphyseal and distal tibia axes was measured, and the apex location relative to the plafond was recorded. RESULTS: A mean distal tibia apex posterior angulation (DTAPA) of 2.0° (range -2° to 7°, SD = 2.06°) was located 8.0 cm proximal to the plafond. No difference was observed from side to side in DTAPA magnitude (P = 0.36) or location (P = 0.90). Planus alignment was associated with a significantly greater DTAPA (3.05°) as compared with neutral (1.89°) (P = 0.002) and cavus (1.25°) (P < 0.001) alignment. CONCLUSION: The distal tibia has an apex posterior angulation, suggesting that the true anatomic axis of the tibia terminates just posterior to the plafond center. Hindfoot alignment is related to distal tibia morphology. DTAPA symmetry indicates that contralateral imaging can be used to guide reconstruction of patient-specific anatomy and alignment. Knowledge of the DTAPA may help mitigate sagittal malalignment during distal tibia fracture surgery.

Long-Term Outcomes of Operatively Treated Medial Epicondyle Fractures in Pediatric and Adolescent Patients.

Purpose: Medial epicondyle fractures are among the most common pediatric elbow injuries. The management of these fractures continues to be debated. To better understand patient results with operative fixation, we reviewed the outcomes of operatively treated medial epicondyle fractures. Methods: A retrospective review was performed to identify all patients less than 18 years of age at the time of injury who were treated surgically for medial epicondyle fractures. Outcomes were assessed based on the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity and Pain Interference domains, Visual Analog Scale for pain, subjective range of motion, ulnar nerve function, and requirement for secondary surgery. Results: We identified a cohort of 95 patients treated for a medial epicondyle fracture with open reduction and screw fixation. Of these, 39 patients with a mean age of 12.2 years (SD, 2.2 years; range, 7.6-16.0 years) at surgery were assessed for an average follow-up of 6.3 years (SD, 3.2 years; range, 2.2-13.9 years). Outcome measures and pain scores were excellent. The mean PROMIS Upper Extremity score was 56.9, the mean Pain Interference score was 38.5, and the mean Visual Analog Scale score was 0.4.Sixteen patients (41%) required secondary surgery for symptomatic hardware removal. Seven patients (18%) developed sensory complaints and 2 (5%) developed motor complaints consistent with ulnar nerve irritability. Three patients (8%) reported dissatisfaction with elbow range of motion. Patients who required secondary surgeries had higher (worse) PROMIS Pain Interference scores. Conclusions: At an average of 6.3 years after surgery, the clinical outcomes for medial epicondyle fracture were excellent. While operative treatment for medial epicondyle fractures in children leads to excellent clinical outcomes, patients and surgeons should be aware of high rates of hardware removal. Type of study/level of evidence: Therapeutic IV.

Abductor Deficiency-Induced Recurrent Instability After Total Hip Arthroplasty.

¼ Operative intervention for deficient hip abductor muscles may require muscle transfer or the use of synthetic materials, possibly with biologic augmentation, to help stabilize the hip joint and prevent further dislocation following total hip arthroplasty (THA). ¼ Direct repair of the abductor mechanism onto the greater trochanter can be used in patients who present with instability <15 months following primary THA. ¼ Augmentation of soft tissue with acellular dermal allografts can be considered for patients with abductor avulsion that requires posterior capsular reconstruction. ¼ The Achilles tendon + calcaneal bone allograft is indicated for patients who have undergone multiple prior revision surgeries, who have experienced failure of nonoperative management, and have tissue inadequacy in the posterior wall of the hip joint. ¼ The gluteus maximus tendon transfer is indicated in patients with chronic abductor tears, limited or loss of function in the gluteus medius and minimus, and a fully functioning gluteus maximus. ¼ Vastus lateralis transfer may benefit patients with a history of multiple revision procedures, large separation between the gluteus medius tendon and the proximal part of the femur, and the ability to observe the postoperative protocol of splinting for 6 weeks. ¼ The latissimus dorsi tendon transfer should be reserved as a reconstructive procedure for patients with acute abductor insufficiency, such as those who have undergone extensive tumor resection. ¼ Synthetic mesh can be used to enable capsular reconstruction and prosthesis stabilization in patients undergoing salvage procedures for tumors of the hip and associated soft tissues. ¼ Synthetic ligament prostheses can be used in patients with recurrent posterior dislocations in the setting of normal components. ¼ The fascia lata plasty is indicated for patients with recurrent posterior instability without an identifiable cause. ¼ Although the quality of literature is limited, surgical interventions utilizing techniques of soft-tissue augmentation have shown promising outcomes with regard to pain relief, limping, ambulation, and the reduction of instability following THA.

Correction to: At the US Epicenter of the COVID-19 Pandemic, an Orthopedic Residency Program Reorganizes.

[This corrects the article DOI: 10.1007/s11420-020-09765-5.].

Arthroscopic treatment of triangular fibrocartilage complex injuries in paediatric and adolescent patients.

We assessed outcomes of 43 paediatric and adolescent patients (44 wrists) undergoing arthroscopic triangular fibrocartilage complex surgery by a single surgeon between 2003 and 2016. Medical records were reviewed for clinical, imaging, and operative data. Preoperatively, 49% of patients had additional diagnoses and mean QuickDASH was 47. Patients were telephoned to assess current wrist pain, subsequent treatment(s), satisfaction, and to complete QuickDASH and Patient-Rated Wrist Evaluation questionnaires. Twenty-five patients responded with mean follow-up of 70 months (minimum 13 months). In those patients not reached by telephone, mean clinical follow-up was 21 months. Seven patients had subsequent surgery (most commonly ulnar shortening osteotomy); this was associated with lower satisfaction scores. At final follow-up, mean QuickDASH was 4, Patient-Rated Wrist Evaluation 8 and patient and parent satisfaction scores were 9 and 9 out of 10, respectively. In conclusion, arthroscopic triangular fibrocartilage complex treatment in paediatric patients yielded favourable outcomes and patient/parent satisfaction. Level of evidence: IV.

Past matrix stiffness primes epithelial cells and regulates their future collective migration through a mechanical memory.

During morphogenesis and cancer metastasis, grouped cells migrate through tissues of dissimilar stiffness. Although the influence of matrix stiffness on cellular mechanosensitivity and motility are well-recognized, it remains unknown whether these matrix-dependent cellular features persist after cells move to a new microenvironment. Here, we interrogate whether priming of epithelial cells by a given matrix stiffness influences their future collective migration on a different matrix - a property we refer to as the 'mechanical memory' of migratory cells. To prime cells on a defined matrix and track their collective migration onto an adjoining secondary matrix of dissimilar stiffness, we develop a modular polyacrylamide substrate through step-by-step polymerization of different PA compositions. We report that epithelial cells primed on a stiff matrix migrate faster, display higher actomyosin expression, form larger focal adhesions, and retain nuclear YAP even after arriving onto a soft secondary matrix, as compared to their control behavior on a homogeneously soft matrix. Priming on a soft ECM causes a reverse effect. The depletion of YAP dramatically reduces this memory-dependent migration. Our results present a previously unidentified regulation of mechanosensitive collective cell migration by past matrix stiffness, in which mechanical memory depends on YAP activity.

Biosimilars from a practicing rheumatologist perspective: An overview.

The earliest experimental trials of monoclonal antibodies took place in the early 1980s using murine monoclonal antibodies directed at human lymphoma and leukemia cell antigens. Since those early trials, therapeutic advances have produced monoclonal antibodies and fusion proteins that are now used in multiple disease states including cancers, autoimmune diseases, inflammatory bowel disease, psoriasis, neurologic disorders and others. Modern techniques have led to the development of multiple chimeric or fully humanized immunoglobulin, receptor and fusion proteins targeting cell markers, interleukins or other target proteins involved in pathophysiologic disease processes resulting in marked improvements in many different disease states. As novel innovator patents are about to expire, commercial entities are actively involved in creating follow-on agents that are similar to these original biologic innovator compounds. The hope and promise of these "biosimilars" to society is increased access to more patients at lower costs. The desire of manufacturers is product development at lower cost (lower research and development) with great potential for widespread use and sales. The challenge for regulators and authorities is to develop strategies that do not overlook the safety concerns of physicians and patients by excessively streamlining approval processes and overlooking potential efficacy and immunologic differences compared to the original innovator compounds.

Disruption of the Cdc42/Par6/aPKC or Dlg/Scrib/Lgl Polarity Complex Promotes Epithelial Proliferation via Overlapping Mechanisms.

The establishment and maintenance of apical-basal polarity is a defining characteristic and essential feature of functioning epithelia. Apical-basal polarity (ABP) proteins are also tumor suppressors that are targeted for disruption by oncogenic viruses and are commonly mutated in human carcinomas. Disruption of these ABP proteins is an early event in cancer development that results in increased proliferation and epithelial disorganization through means not fully characterized. Using the proliferating Drosophila melanogaster wing disc epithelium, we demonstrate that disruption of the junctional vs. basal polarity complexes results in increased epithelial proliferation via distinct downstream signaling pathways. Disruption of the basal polarity complex results in JNK-dependent proliferation, while disruption of the junctional complex primarily results in p38-dependent proliferation. Surprisingly, the Rho-Rok-Myosin contractility apparatus appears to play opposite roles in the regulation of the proliferative phenotype based on which polarity complex is disrupted. In contrast, non-autonomous Tumor Necrosis Factor (TNF) signaling appears to suppress the proliferation that results from apical-basal polarity disruption, regardless of which complex is disrupted. Finally we demonstrate that disruption of the junctional polarity complex activates JNK via the Rho-Rok-Myosin contractility apparatus independent of the cortical actin regulator, Moesin.

Cell density and actomyosin contractility control the organization of migrating collectives within an epithelium.

The mechanisms underlying collective migration are important for understanding development, wound healing, and tumor invasion. Here we focus on cell density to determine its role in collective migration. Our findings show that increasing cell density, as might be seen in cancer, transforms groups from broad collectives to small, narrow streams. Conversely, diminishing cell density, as might occur at a wound front, leads to large, broad collectives with a distinct leader-follower structure. Simulations identify force-sensitive contractility as a mediator of how density affects collectives, and guided by this prediction, we find that the baseline state of contractility can enhance or reduce organization. Finally, we test predictions from these data in an in vivo epithelium by using genetic manipulations to drive collective motion between predicted migratory phases. This work demonstrates how commonly altered cellular properties can prime groups of cells to adopt migration patterns that may be harnessed in health or exploited in disease.

AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol.

The Hippo pathway controls organ growth and is implicated in cancer development. Whether and how Hippo pathway activity is limited to sustain or initiate cell growth when needed is not understood. The members of the AJUBA family of LIM proteins are negative regulators of the Hippo pathway. In mammalian epithelial cells, we found that AJUBA LIM proteins limit Hippo regulation of YAP, in proliferating cells only, by sequestering a cytosolic Hippo kinase complex in which LATS kinase is inhibited. At the plasma membranes of growth-arrested cells, AJUBA LIM proteins do not inhibit or associate with the Hippo kinase complex. The ability of AJUBA LIM proteins to inhibit YAP regulation by Hippo and to associate with the kinase complex directly correlate with their capacity to limit Hippo signaling during Drosophila wing development. AJUBA LIM proteins did not influence YAP activity in response to cell-extrinsic or cell-intrinsic mechanical signals. Thus, AJUBA LIM proteins limit Hippo pathway activity in contexts where cell proliferation is needed.

Ajuba proteins.

Schimizzi and Longmore summarise what we know about Ajuba LIM-domain proteins and their various subcellular roles.

The microtubule lattice and plus-end association of Drosophila Mini spindles is spatially regulated to fine-tune microtubule dynamics.

Individual microtubules (MTs) exhibit dynamic instability, a behavior in which they cycle between phases of growth and shrinkage while the total amount of MT polymer remains constant. Dynamic instability is promoted by the conserved XMAP215/Dis1 family of microtubule-associated proteins (MAPs). In this study, we conducted an in vivo structure-function analysis of the Drosophila homologue Mini spindles (Msps). Msps exhibits EB1-dependent and spatially regulated MT localization, targeting to microtubule plus ends in the cell interior and decorating the lattice of growing and shrinking microtubules in the cell periphery. RNA interference rescue experiments revealed that the NH(2)-terminal four TOG domains of Msps function as paired units and were sufficient to promote microtubule dynamics and EB1 comet formation. We also identified TOG5 and novel inter-TOG linker motifs that are required for targeting Msps to the microtubule lattice. These novel microtubule contact sites are necessary for the interplay between the conserved TOG domains and inter-TOG MT binding that underlies the ability of Msps to promote MT dynamic instability.

Expression levels of a kinesin-13 microtubule depolymerase modulates the effectiveness of anti-microtubule agents.

BACKGROUND: Chemotherapeutic drugs often target the microtubule cytoskeleton as a means to disrupt cancer cell mitosis and proliferation. Anti-microtubule drugs inhibit microtubule dynamics, thereby triggering apoptosis when dividing cells activate the mitotic checkpoint. Microtubule dynamics are regulated by microtubule-associated proteins (MAPs); however, we lack a comprehensive understanding about how anti-microtubule agents functionally interact with MAPs. In this report, we test the hypothesis that the cellular levels of microtubule depolymerases, in this case kinesin-13 s, modulate the effectiveness of the microtubule disrupting drug colchicine. METHODOLOGY/PRINCIPAL FINDINGS: We used a combination of RNA interference (RNAi), high-throughput microscopy, and time-lapse video microscopy in Drosophila S2 cells to identify a specific MAP, kinesin-like protein 10A (KLP10A), that contributes to the efficacy of the anti-microtubule drug colchicine. KLP10A is an essential microtubule depolymerase throughout the cell cycle. We find that depletion of KLP10A in S2 cells confers resistance to colchicine-induced microtubule depolymerization to a much greater extent than depletion of several other destabilizing MAPs. Using image-based assays, we determined that control cells retained 58% (+/-2%SEM) of microtubule polymer when after treatment with 2 microM colchicine for 1 hour, while cells depleted of KLP10A by RNAi retained 74% (+/-1%SEM). Likewise, overexpression of KLP10A-GFP results in increased susceptibility to microtubule depolymerization by colchicine. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that the efficacy of microtubule destabilization by a pharmacological agent is dependent upon the cellular expression of a microtubule depolymerase. These findings suggest that expression levels of Kif2A, the human kinesin-13 family member, may be an attractive biomarker to assess the effectiveness of anti-microtubule chemotherapies. Knowledge of how MAP expression levels affect the action of anti-microtubule drugs may prove useful for evaluating possible modes of cancer treatment.

A multicenter, randomized, open study to evaluate the impact of an electronic data capture system on the care of patients with rheumatoid arthritis.

OBJECTIVE: To examine the impact of an electronic data capture system on patient satisfaction and patient-physician interactions in a rheumatology clinical setting. STUDY DESIGN: In this multicenter study, 1079 patients with rheumatoid arthritis completed questionnaires quarterly about their health and satisfaction with care using a computer. At 6 months, 901 eligible patients were randomized 2:1 to receive or not to receive graphical summarized health information or Health Tracker (HT) reports. Data collected at each visit included patient satisfaction with care; patient-physician interaction assessments; a 56-joint self-assessment for patients; a 28-joint assessment for physicians; patient pain, fatigue, and global assessments (visual analogue scale, physician global assessment, Health Assessment Questionnaire, and Short Form-12) all of which were cumulatively recorded in the HT report. RESULTS: Patient demographics at baseline were similar between groups. Changes from baseline to 1 year showed that patients in the HT-viewers group were significantly more satisfied with their care (p < 0.001) than those in the HT-nonviewers group (p = 0.131). Physicians reported improved interactions with patients at 1 year in both the HT-viewers (p < 0.001) and HT-nonviewers groups (p = 0.002); however, the improvement was significantly larger for the HT-viewers group than for the HT-nonviewers group (p < 0.001). Adverse events were comparable between groups. CONCLUSIONS: Patient access to systematically collected patient data reports promoted self-involvement and improved patient satisfaction and patient-physician interactions more in the HT-viewers than in HT-nonviewers groups at 1 year (p < 0.001). This was an open, observational study; no formal hypothesis testing was conducted. The HT system was not validated and some bias may have existed with respect to patient comfort level with a computer, user error, and timing of data entry of the physicians' assessments.