Merkel cell carcinoma: treatment and outcomes over a 10-year period at a high-volume academic center.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, highly aggressive malignancy which lacks high-level evidence-based treatment guidelines. METHODS: To determine outcomes of MCC patients and assess the role of radiation in treatment, we performed a retrospective chart review of patients treated for MCC between 2006 and 2016 at a single high-volume academic medical center. The primary outcome was overall survival (OS) for the entire population and for those populations receiving specific therapies. RESULTS: Forty-two patients were evaluable. OS for all patients was not reached since most remain alive at time of analysis. OS for the American Joint Committee on Cancer (AJCC) stage I was not reached. OS for stages II, III, and IV was 37.3 months (6.8, -), 49.5 months (14.2, 49.5), and 14.5 months (10.8, -), respectively. OS could not be reached in the high radiotherapy (RT) dose group (biologically equivalent dose [BED] ≥ 60) and was 49.5 months (10.8, -) in the low-dose group (BED < 60). For surgical margin status, OS was 14.9158 months (6.8008, -) for positive margins and 37.3 months (10.8, -) for negative margins. CONCLUSIONS: No conclusive findings for OS were identified; however, trends for improved OS were associated with lower AJCC staging, negative surgical margins, and high RT doses.

Effect of Serum Deprivation Stress on Signal Induction Regulatory Protein-Alpha (SIRP-Alpha)-Mediated Erythrophagocytosis by Macrophages.

BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome that involves loss of macrophages' self-cells recognition resulting in auto-phagocytosis of erythrocytes, leukocytes, and platelets and leading to multi-system effects. The pathogenesis of HLH is unclear but can be explained by malfunction of the physiologic inhibitory pathway through interaction between macrophage SIRP-alpha and erythrocyte CD 47. The goal of the present study was to evaluate if erythrocytes phagocytosis occurs as a result of altered macrophage SIRP-alpha expression during inflammatory/stressful conditions as seen in HLH. MATERIAL AND METHODS RAW264.7 macrophages were cultured in serum-free media (SFM) and complete media (CM) to simulate stressful and physiologic conditions, respectively. CD47+ mouse erythrocytes were used to test interactions with macrophages at different stages. SIRP-alpha expressions and phagocytosis assays were measured and analyzed at different steps. The study was in vitro and used murine cells to simulate in vivo human interactions. RESULTS SIRP-alpha expressions and phagocytosis rates were higher in SFM compared to CM. Interestingly, after adding SIRP-alpha blocking antibodies (Ab), phagocytosis rates significantly decreased. CONCLUSIONS Serum deprivation and LPS/INF-Gamma induction resulted in increased SIRP-alpha expression and erythrophagocytosis. Using SIRP-alpha Ab during this condition decreased the rate of erythrophagocytosis, which indicates that SIRP-alpha receptor can have pro-phagocytic activity.

Intravenous administration of multipotent stromal cells and bone allograft modification to enhance allograft healing.

Aim: This study investigated a coordinated strategy of revitalizing bone allograft with circulating multipotent stromal cells (MSCs). Materials & methods: After chemotactic and releasing assessments, stromal cell-derived factor 1 and platelet-derived growth factor BB in copolymers were coated on the bone allograft (AlloS-P). Allograft coated with copolymers alone (Allo), as controls, or AlloS-P was implanted into the femur of athymic mice, which received intravenous injections of human MSCs or saline at weeks 1, 2 and 3. Results: At week 8, the total callus volume (both cartilaginous and bony callus) around the allograft was the largest in the AlloS-P + MSC group (p < 0.05). Conclusion: Coating bone allograft with stromal cell-derived factor 1 and platelet-derived growth factor BB and intravenous injections of MSCs improved allograft incorporation.

The role of hydroxychloroquine in catastrophic antiphospholipid syndrome case: Series of two case reports and review of literature.

Catastrophic antiphospholipid syndrome is a rare disorder that remains under-recognized causing a high mortality rate even with treatment. Factors such as infections and systemic lupus erythematosus flare play as an inciting event in the thrombotic crisis which underlies catastrophic antiphospholipid syndrome. The use of plasmapheresis has improved the outcome of such cases with a reduction in mortality rate from over 50% to less than 30%, according to some studies. However, the definitive treatment of this disabling and fatal condition remains an area warranting research. Case 1. A case of 32-year-old female with a background of epilepsy and recurrent abortions who presented with difficulty in breathing, dry cough, and bilateral lower limb swelling. The patient initially received treatment with cyclophosphamide and systemic corticosteroids after being diagnosed with systemic lupus erythematosus. She also underwent plasmapheresis for suspected pulmonary hemorrhage as her condition deteriorated rapidly requiring intensive care. The diagnosis was revised as catastrophic antiphospholipid syndrome given the typical multi-organ involvement, namely, cerebritis, Libman-Sacks endocarditis, and nephritis apart from the pulmonary involvement. Eventually, hydroxychloroquine was added to the regimen which led to a remarkable improvement in her condition after a few days. Case 2. A case of 28-year-old female with history of recurrent abortions presented with abdominal pain and was admitted as a case of pancreatitis. The patient received intravenous fluids and analgesics with no significant improvement. Later, she developed multi-organ failure requiring critical care. Given her history and clinical presentation along with the multi-organ involvement in an acute setting, she underwent extensive workup that favored catastrophic antiphospholipid syndrome and she was started on Aspirin initially, and then, hydroxychloroquine was administered. Few days after initiation, her condition improved markedly and with complete resolution of her abdominal symptoms. Hydroxychloroquine's antithrombotic effect in synergy with other therapies has been observed in our cases. Yet, its role in the early course of catastrophic antiphospholipid syndrome merits further investigation.

Superior mesenteric venous thrombosis complicating acute appendicitis: A case report.

RATIONALE: Superior mesenteric venous thrombosis (SMVT) is a rare condition that carries high mortality. Very few cases have been reported of SMVT, complicating acute appendicitis. Early recognition requires a high index of suspicion and is crucial in successful treatment of such a life-threatening condition. PATIENT CONCERNS: A 33-year-old male presents with a 4-day history of right lower abdominal pain, nausea and subjective fever. CT scan showed acute appendicitis and a central filling defect in the superior mesenteric vein. DIAGNOSES: Acute appendicitis complicated by SMVT. INTERVENTIONS: Intravenous antibiotics, appendectomy, and anticoagulation. OUTCOMES: Repeat CT scan showed successful resolution of the SMVT at a 3-month follow up. LESSONS: Clinical awareness and high index of suspicion are essential to diagnose and manage SMVT, a serious complication of acute appendicitis.

Orthotopic Transplantation of Achilles Tendon Allograft in Rats: With or without Incorporation of Autologous Mesenchymal Stem Cells.

The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at -80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully appreciate the functional benefits of MSCs.

Case Report: A Case of Severe Cerebral Malaria Managed with Therapeutic Hypothermia and Other Modalities for Brain Edema.

Malarial infections are uncommon in the United States and almost all reported cases stem from recent travelers coming from endemic countries. Cerebral malaria (CM) is a severe form of the disease usually affecting children and individuals with limited immunity. Despite proper management, mortality from CM can reach up to 25%, especially when it is associated with brain edema. Inefficient management of the edema may result in brain herniation and death. Uniform guidelines for management of CM-associated brain edema are lacking. In this report, we present a case of CM with associated severe brain edema that was successfully managed using a unique combination of therapeutic hypothermia, hypertonic saline, mannitol, and hyperventilation along with the antimalarial drugs quinidine and doxycycline. Our use of hypothermia was based on its proven benefit for improving neurological outcomes in post-cardiac arrest patients and previous in vitro research, suggesting its potential inhibitory role on malaria growth.

Effect of Low-Intensity Pulsed Ultrasound on Joint Injury and Post-Traumatic Osteoarthritis: an Animal Study.

This study investigated the therapeutic potential of low-intensity pulsed ultrasound (LIPUS) in post-traumatic osteoarthritis (PTOA). Intra-articular fracture of the medial tibial plateau was surgically created in 30 rats. LIPUS was applied to the operated joints either for the first 2 wk (LIPUS1-2 group) or in weeks 4 and 5 after intra-articular fracture (LIPUS4-5 group). In controls, the operated knees were not treated with LIPUS (LIPUS0 group). The rats were monitored with weekly gait analysis and euthanized at week 8. Among the altered gait parameters, the maximal and average paw print areas in the LIPUS1-2 and LIPUS4-5 groups, but not the LIPUS0 group, had either reached baseline or significantly recovered (70%, p <0.05) by week 8. PTOA pathology in both the LIPUS1-2 and LIPUS4-5 groups was less severe than that in the LIPUS0 group (Mankin score: 5.4 and 4.5 vs. 8.8, p <0.05). In conclusion, LIPUS treatment partially improved the gait of the affected limbs and reduced cartilage degeneration in PTOA.

Outcomes After Interpositional Arthroplasty of the First Metatarsophalangeal Joint.

BACKGROUND: For patients with hallux rigidus seeking a motion-sparing procedure, interposition arthroplasty is an alternative to fusion. The purpose of this study was to report patient outcomes after interpositional arthroplasty for hallux rigidus. METHODS: All patients undergoing interpositional arthroplasty at our institution from 2001 to 2014 were identified and a retrospective chart review was performed. Follow-up was conducted through a telephone survey to obtain survivorship, satisfaction, and functional scores. Survivorship of the interpositional arthroplasty procedure was defined as no subsequent surgery on the hallux after the index procedure. Patients were excluded for incomplete records. Complications were recorded. From 2001 to 2014, 183 patients were identified. Of these, 14 were excluded for incomplete data, leaving 169 patients. Of these, 133 had an average follow-up of 62.2 months (range, 24.3 months to 151.2 months). RESULTS: The overall failure rate was 3.8% (5/133). Patient-reported outcome was rated as excellent in 65.4% (87/133) or good in 24.1% (32/133) of patients and fair or poor in 10.5% (14/133) of patients. Of 133 patients, 101 (76%) were able to return to fashionable or regular footwear. The infection rate was 1.5% (2/133). Patient-reported cock-up deformity of the first metatarsophalangeal joint (MTPJ) occurred in 4.5% (6/133) of patients. In addition, 17.3% (23/133) of patients reported metatarsalgia of the second or third MTPJ at the time of final follow-up, and there was no significant difference between interposition types ( P = .441). CONCLUSION: Interpositional arthroplasty for hallux rigidus was found to have excellent or good results in most patients at a mean follow-up of 62.2 months. LEVEL OF EVIDENCE: Level IV, retrospective case series.

A Surgical Model of Posttraumatic Osteoarthritis With Histological and Gait Validation.

BACKGROUND: Posttraumatic osteoarthritis (PTOA) is secondary to an array of joint injuries. Animal models are useful tools for addressing the uniqueness of PTOA progression in each type of joint injury and developing strategies for PTOA prevention and treatment. HYPOTHESIS: Intra-articular fracture induces PTOA pathology. STUDY DESIGN: Descriptive laboratory study. METHODS: Through a parapatellar incision, the medial tibial plateau was exposed in the left knees of 8 Sprague-Dawley rats. Osteotomy at the midpoint between the tibial crest and the outermost portion of the medial tibial plateau, including the covering articular cartilage, was performed using a surgical blade. The fractured medial tibial plateau was fixed with 2 needles transversely. The fractured knees were not immobilized. Before and after surgery, rat gait was recorded. Rats were sacrificed at week 8, and their knees were harvested for histology. RESULTS: After intra-articular fracture, the affected limbs altered gait from baseline (week 0). In the first 2 weeks, the gait of the operated limbs featured a reduced paw print intensity and stride length but increased maximal contact and stance time. Reduction of maximal and mean print area and duty cycle (the percentage of stance phase in a step) was present from week 1 to week 5. Only print length was reduced in weeks 7 and 8. At week 8, histology of the operated knees demonstrated osteoarthritic pathology. The severity of the PTOA pathology did not correlate with the changes of print length at week 8. CONCLUSION: Intra-articular fracture of the medial tibial plateau effectively induced PTOA in rat knees. During PTOA development, the injured limbs demonstrated characteristic gait. CLINICAL RELEVANCE: Intra-articular fracture represents severe joint injury and associates with a high rate of PTOA. This animal model, with histologic and gait validations, can be useful for future studies of PTOA prevention and early diagnosis.

Minimally Invasive Calcaneal Displacement Osteotomy Site Using a Reference Kirschner Wire: A Technique Tip.

As a standard open approach, the lateral oblique incision has been widely used for calcaneal displacement osteotomy. However, just as with other orthopedic procedures that use an open approach, complications, including wound healing problems and neurovascular injury in the heel, have been reported. To help avoid these limitations, a percutaneous technique using a Shannon burr for calcaneal displacement osteotomy was introduced. However, relying on a free-hand technique without direct visualization at the osteotomy site has been a major obstacle for this technique. To address this problem, we developed a technical tip using a reference Kirschner wire. A reference Kirschner wire technique provides a reliable and accurate guide for minimally invasive calcaneal displacement osteotomy. Also, the technique should be easy to learn for surgeons new to the procedure.

Influence of Bone and Muscle Injuries on the Osteogenic Potential of Muscle Progenitors: Contribution of Tissue Environment to Heterotopic Ossification.

UNLABELLED: : By using surgical mouse models, this study investigated how the tissue environment influences the osteogenic potential of muscle progenitors (m-progenitors) and potentially contributes to heterotopic ossification (HO). Injury was induced by clamping the gluteus maximus and medius (group M) or osteotomy of greater trochanter (group O) on the right hip, as well as combined muscle injury and osteotomy of greater trochanter (group M+O). The gluteus maximus and medius of the operated hips were harvested at days 1, 3, 5, and 10 for isolation of m-progenitors. The cells were cultured in an osteogenic medium for 3 weeks, and osteogenesis was evaluated by matrix mineralization and the expression of osteogenesis-related genes. The expression of type I collagen, RUNX2 (runt-related transcription factor 2), and osteocalcin by the m-progenitors of group M+O was significantly increased, compared with groups M and O. Osteogenic m-progenitors in group O increased the expression of bone morphogenetic protein 2 and also bone morphogenetic protein antagonist differential screening-selected gene aberrative in neuroblastoma. On histology, there was calcium deposition mostly in the muscles of group M+O harvested at day 10. CD56, representing myogenic progenitors, was highly expressed in the m-progenitors isolated from group M (day 10), but m-progenitors of group M+O (day 10) exhibited the highest expression of platelet-derived growth factor receptor α (PDGFR-α), a marker of muscle-derived mesenchymal stem cells (M-MSCs). The expressions of PDGFR-α and RUNX2 were colocalized in osteogenic m-progenitors. The data indicate that the tissue environment simulated in the M+O model is a favorable condition for HO formation. Most likely, M-MSCs, rather than myogenic progenitors, in the m-progenitors participate in HO formation. SIGNIFICANCE: The prevalence of traumatic heterotopic ossification (HO) is high in war injury. The pathogenesis of HO is still unknown. This study clarified the contribution of a tissue environment created by bone or muscle injury to the formation of HO. The study also found that muscle-derived mesenchymal stem cells, but not myogenic progenitors, are involved in the formation of HO. The findings of this study could be used to strategize the prevention and treatment of HO.

Topical Tranexamic Acid Use in Knee Periprosthetic Joint Infection Is Safe and Effective.

Tranexamic acid (TXA) has been shown to decrease hemoglobin loss and reduce the need for transfusions in primary hip and knee arthroplasty. Our study evaluated the safety and efficacy of topical TXA in revision TKA for periprosthetic joint infection (PJI). We performed a retrospective review of patients who underwent removal of hardware with antibiotic spacer placement (stage 1) and/or revision TKA (stage 2) for PJI at our institution between September 2007 and July 2013. During that time, 49 patients underwent stage-1 procedures (20 knees with TXA, 29 without TXA) and 47 patients underwent stage-2 revisions (28 with TXA, 19 without TXA). We evaluated hemoglobin loss, need for transfusion, reinfection rate, length of stay (LOS), complications, and mortality with and without the use of TXA in these patients. All data sets were analyzed with a two-sample t-test. Average follow-up was 3.15 years (range, 1-7 years). TXA use led to a significantly lower percentage drop in the postoperative lowest hemoglobin compared with the preoperative hemoglobin in stage-1 surgeries (19.8 vs. 30.05%, p = 0.0004) and stage-2 revisions (24.5 vs 32.01%, p = 0.01). In both groups, TXA use was associated with a significant reduction in transfusion rates (stage-1, 25 vs 51.7%, p = 0.04; stage-2, 25 vs. 52.6%, p = 0.05). There was a nonstatistical decreased LOS in both groups in which TXA was used (stage 1, 5.15 vs. 6.72 days, p = 0.055; stage 2, 5.21 vs. 6.84 days, p = 0.09). There was no difference in the reinfection rate (4 vs. 4, p = 0.56) or mortality rate between groups (0 vs. 2 non-TXA group). A single upper extremity deep vein thrombosis occurred in a stage-1 patient who received TXA, and no pulmonary embolism occurred. We show that topical TXA is safe and effective for use in both stages of revision TKA for PJI. Previous studies have shown TXA to aggravate a staphylococcal infection in mice; however, topical TXA doesn't appear to negatively effect on the treatment of PJI in our patients and did not increase the reinfection, complication, or mortality rate.