Current Concepts of Pathogenesis and Treatment of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms.

Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.

Human Amnion Chorion Membrane Allografts in the Treatment of Chronic Diabetic Foot Ulcers: A Literature Review.

OBJECTIVE: To discuss human amnion chorion (placental) membrane allograft (HACMA) use for the treatment of chronic diabetic foot ulcers (DFUs) and to evaluate the effectiveness, cost, and product waste of this therapy. DATA SOURCES: PubMed, Cochrane, and OVID databases. STUDY SELECTION: Twenty-four articles pertaining to HACMA and DFUs published from 2016 to 2020 were selected. DATA EXTRACTION: The data collected included type of wound care product, study design, study size, baseline size of DFU, cost, product wastage, number of applications, and wound healing outcomes. DATA SYNTHESIS: Human amnion chorion membrane allografts in the treatment of chronic DFUs have led to a reduction in healing time and increased the overall percentage of healing, making them more effective in treating DFUs compared with standard of care. These products are offered in multiple sizes with various shelf lives and methods of storage, making them accessible, easy to use, less wasteful, and lower in cost compared with other commercially available products. Promising evidence demonstrates that HACMAs are beneficial in treating complex, high-grade DFUs with exposed tendon or bone. CONCLUSIONS: Human amnion chorion membrane allografts are effective in treating chronic DFUs with a greater percentage of complete wound closure and a reduction in healing time versus standard of care.

A comparison of contiguous two-level anterior cervical discectomy and fusion using a structural allograft versus a Polyetheretherketone (PEEK) cage: the results of a three-year follow-up.

BACKGROUND: Allografts and polyetheretherketone (PEEK) cages are the two most commonly used materials in anterior cervical discectomy and fusion (ACDF). However, their effectiveness in two-level ACDF remains controversial. The primary aim of this retrospective study was to compare the clinical and radiological outcomes of two-level ACDF with plate fixation using either a structural allograft or a PEEK cage. METHODS: From 2010 to 2015, 88 consecutive patients underwent two-level ACDF, of whom 53 received an allograft and 35 patients received a PEEK cage. All PEEK cages were filled with local autografts. All clinical outcomes were prospectively collected before and six months and two years after surgery. Clinical efficacy was evaluated using a visual analogue scale for neck pain and limb pain, the Neck Pain and Disability Score, the Neck Disability Index, the Neurogenic Symptom Score, and the Japanese Orthopedic Association score. Radiological outcomes were assessed preoperatively, immediately after surgery, and at the final follow-up. RESULTS: A preoperative comparison revealed no difference between the two patient groups in terms of age, sex, body mass index, smoking status, preoperative symptoms, operation level, or follow-up (mean = 42.8 months). No differences in the improvements in clinical outcomes were observed between the two groups. Both groups showed significant improvement in mean disc height, segmental height, and segmental lordosis postoperatively. The fusion rate for the PEEK cage was 100% at both levels, while the fusion rate for the allograft group was 98.1% at the cephalad level and 94.2% at the caudad level (p > 0.05). Subsidence at the cephalad level occurred in 22.9% (8/35) of segments in the PEEK group and 7.7% (4/52) of segments in the allograft group (p = 0.057). At the caudal level, a higher incidence of cage subsidence was noted in the PEEK group than in the allograft group [37.1% (13/35) versus 15.4% (8/52)] (p = 0.02). Overall, subsidence was noted in 30% (21/70) of the PEEK group and in 11% (12/104) of the allograft group (p <  0.05). CONCLUSION: The use of PEEK cages resulted in a higher rate of subsidence in two-level ACDF than the use of allografts. Two-level ACDF using either allografts or PEEK cages resulted in similar clinical outcomes, radiological improvements in alignment and fusion rates.

Liver Transplantation with "Hors Tour" Allocated Versus Standard MELD Allocated Grafts: Single-Center Audit and Impact on the Liver Pool in France.

BACKGROUND: The French transplant governing system defined "Rescue" (the so-called "Hors Tour") livers as those livers which were declined for the five top-listed patients. This study compares the outcomes following liver transplantation (LT) in patients who received a donor liver through a rescue allocation (RA) procedure or according to MELD score priority (standard allocation, SA) and evaluates the impact on the graft pool of a proactive policy to accept RA grafts. METHODS: Data from all consecutive patients who underwent LT with SA or RA grafts from 2011 to 2015 were compared in terms of short- and long-term outcomes. RESULTS: The 249 elective first LTs were performed with 64 (25.7%) RA and 185 (74.3%) SA grafts. RA grafts were obtained from older donors and were associated with a longer cold ischemia time. Recipients of RA livers were older and had lower MELD scores. The rates of delayed graft function, primary nonfunction, retransplantation, complications, and mortality were similar between the RA and SA groups. At 1 and 3 and 5 years, graft and patient survival rates were similar between the groups. These results were maintained after matching on recipient characteristics. Our proactive policy to accept RA grafts increased the liver pool for elective first transplantation by 25%. CONCLUSIONS: RA livers can be safely transplanted into selected recipients and significantly expand the liver pool.

Association of baseline histopathology and kidney donor risk index with graft outcomes in deceased donor kidney transplantation
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BACKGROUND: Donor organ quality is a key determinant of graft outcomes in deceased donor kidney transplantation (DDKT). The predictive values of baseline histopathology and several clinical scoring systems for long-term graft outcomes have been evaluated, but the results remain controversial. MATERIALS AND METHODS: We screened 167 patients who underwent DDKT at Ulsan University Hospital from April 2003 to June 2016. Among them, 66 patients who underwent baseline kidney biopsy and whose kidney donor risk index (KDRI) was available were included in this analysis. All baseline biopsies were rescored according to the updated Banff classification. RESULTS: Median follow-up was 22 months. Mean age of recipients and donors was 51.4 and 44.7 years, respectively. Mean KDRI was 1.40 ± 0.44. During follow-up, delayed graft function and biopsy-proven acute rejection (BPAR) developed in 7 and 11 patients, respectively. Graft failure occurred in 2 patients. In Cox regression analysis, interstitial fibrosis/tubular atrophy (IFTA) (hazard ratio (HR) = 3.59; p = 0.049) was a significant risk factor for BPAR. In multivariate linear regression, age (standardized ß (SB) = -0.282; p = 0.002), BPAR (SB = -0.406; p < 0.001), KDRI (SB = -0.277; p = 0.003), and IFTA (SB = -0.298; p = 0.001) were significant predictors of last-visit estimated glomerular filtration rate (eGFR). CONCLUSION: Several clinical and pathologic parameters, such as KDRI and IFTA, may be helpful for predicting long-term graft outcomes, including BPAR and last-visit eGFR, in DDKT.
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Comparison of synthetic bone graft ABM/P-15 and allograft on uninstrumented posterior lumbar spine fusion in sheep.

BACKGROUND: Spinal fusion is a commonly used procedure in spinal surgery. To ensure stable fusion, bone graft materials are used. ABM/P-15 (commercial name i-Factor™ Flex) is an available synthetic bone graft material that has CE approval in Europe. This peptide has been shown to improve bone formation when used in devices with fixation or on bone defects. However, the lack of external stability and large graft size make posterolateral lumbar fusion (PLF) a most challenging grafting procedure. This prospective randomized study was designed to evaluate early spinal fusion rates using an anorganic bovine-derived hydroxyapatite matrix (ABM) combined with a synthetic 15 amino acid sequence (P-15)-ABM/P-15 bone graft, and compared with allograft in an uninstrumented PLF model in sheep. The objective of this study was to assess fusion rates when using ABM/P-15 in uninstrumented posterolateral fusion in sheep. METHODS: Twelve Texas/Gotland mixed breed sheep underwent open PLF at 2 levels L2/L3 and L4/L5 without fixation instruments. The levels were randomized so that sheep received an ABM graft either with or without P15 coating. Sheep were euthanized after 4.5 months and levels were harvested and evaluated with a micro-CT scanner and qualitative histology. Fusion rates were assessed by 2D sections and 3D reconstruction images and fusion was defined as intertransverse bridging. RESULTS: There was 68% fusion rate in the allograft group and an extensive migration of graft material was noticed with a fusion rate of just 37% in the ABM/P-15 group. Qualitative histology showed positive osteointegration of the material and good correlation to scanning results. CONCLUSIONS: In this PLF fusion model, ABM/P15 demonstrated the ability to migrate when lacking external stability. Due to this migration, reported fusion rates were significantly lower than in the allograft group. The use of ABM/P15 as i-Factor™ Flex may be limited to devices with fixation and bone defects.

The Impact of Renal Tissue Procurement at Bedside on Specimen Adequacy and Best Practices.

Objectives: Renal biopsy is the gold standard for the diagnosis of both native and allograft renal diseases. We studied the impact of tissue procurement at bedside (TPB) omission on the adequacy of renal biopsies. Methods: We compared 120 renal biopsies collected during 2015 using TPB with 111 renal biopsies collected during 2016 when TPB was discontinued. Adequacy criteria were applied as follows: by light microscopy, 10 glomeruli and two arteries for allograft biopsies and seven glomeruli for native biopsies. At least one glomerulus was considered adequate for immunofluorescence and electron microscopy in both groups. Results: The rate of inadequacies in allograft biopsies increased significantly, from 12.50% to 21.61% (P < .05), when TPB was discontinued. Conclusions: Elimination of TPB service had a negative impact on allograft specimen adequacy. Repeat biopsies add cost and delay patient care. Institutions should take this into consideration when considering omission of TPB.

The New Era of Transplant Oncology: Liver Transplantation for Nonresectable Colorectal Cancer Liver Metastases.

Colorectal cancer (CRC) is the third most incident cancer worldwide. Most of CRC patients will develop distant metastases, mainly to the liver, and liver resection is the only potential chance for cure. On the other hand, only a small proportion of patients with hepatic CRC metastasis are candidates for upfront liver resection. Liver transplantation (LT) is an attractive option for patients with nonresectable CRC liver metastases (NRCLM) without extrahepatic involvement. Initial experiences with LT for NRCLM achieved very poor outcomes, with a 5-year overall survival (OS) lower than 20%. However, these initial studies did not have a standardized patient selection or neoadjuvant or adjuvant therapies. With recent advances in the surgical and medical oncology fields, the landscape has changed. Recent studies from Norway have shown an encouraging 5-year OS of 50% when transplanting patients with NRCLM. Nevertheless, the main concern when expanding the indications for LT is organ shortage. To manage this organ shortage, strategies utilizing live donor liver transplantation are gaining favor. A few ongoing trials are assessing the impact of LT in NRCLM patient survival. Therefore, the aim of this paper is to review the current status of LT for NRCLM.

Testing feasibility of an accurate microscopic assessment of macrovesicular steatosis in liver allograft biopsies by smartphone add-on lenses.

Light microscopy is an essential tool in histological examination of tissue samples. However, the required equipment for a correct and rapid diagnosis is sometimes unavailable. Smartphones and mobile phone networks are widespread, and could be used for diagnostic imaging and telemedicine. Macrovesicular steatosis (MS) is a major risk factor for liver graft failure, and is only assessable by microscopic examination of a frozen tissue section. The aim of this study was to compare the microscopic assessment of MS in liver allograft biopsies by a smartphone with eyepiece adaptor (BLIPS device) to standard light microscopy. Forty liver graft biopsies were evaluated in transmitted light, using an Iphone 5s and 4 different mini-objective, add-on lenses. A significant correlation was reported between the two different approaches for graft MS assessment (Spearman's correlation coefficient: rs = 0.946; p < .001). Smartphone with eyepiece adaptor had similar discriminatory power to identify MS in liver grafts than standard light microscopy. Based on these findings, a smartphone integrated with a low-cost eyepiece adaptor can achieve adequate accuracy in the assessment of MS in liver graft, and could be used as an alternative to standard light microscope when unavailable.

Hematopoietic Cell Transplantation Comorbidity Index Predicts Outcomes in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Receiving CD34+ Selected Grafts for Allogeneic Hematopoietic Cell Transplantation.

To evaluate the association between the hematopoietic cell transplantation-comorbidity index (HCT-CI) and the recently developed age-adjusted HCT-CI (HCT-CI/age) and transplant outcomes in the setting of CD34-selected allogeneic HCT, we analyzed a homogeneous population of patients undergoing allogeneic HCT with CD34-selected grafts for acute myeloid leukemia and myelodysplastic syndrome (n = 346). Median HCT-CI and HCT-CI/age scores were 2 (percentile 25 to 75, 1 to 4) and 3 (percentile 25 to 75, 1 to 5), respectively. Higher HCT-CI and HCT-CI/age scores were associated with higher nonrelapse mortality (NRM) and lower overall survival (OS). The HCT-CI distinguished 2 risk groups (0 to 2 versus ≥3), whereas, with the HCT-CI/age, there was a progressive increase in NRM and decrease in OS with increasing scores in all 4 groups (0 versus 1 to 2 versus 3 to 4 versus ≥5). Higher scores in both models were associated with lower chronic graft-versus-host disease relapse-free survival but not with higher relapse. Both models showed a promising predictive accuracy for NRM (c- = .616 for HCT-CI and c- = .647 for HCT-CI/age). In conclusion, the HCT-CI and HCT-CI/age predict transplant outcomes in CD34-selected allo-HCT, including NRM, OS, and chronic graft-versus-host disease relapse-free survival and may be used to select appropriate patients for this approach.

An audit of consent for allograft use in elective orthopaedic surgery.

Introduction Patients receiving musculoskeletal allografts may be at risk of postoperative infection. The General Medical Council guidelines on consent highlight the importance of providing patients with the information they want or need on any proposed investigation or treatment, including any potential adverse outcomes. With the increased cost of defending medicolegal claims, it is paramount that adequate, clear informed patient consent be documented. Methods We retrospectively examined the patterns of informed consent for allograft bone use during elective orthopaedic procedures in a large unit with an onsite bone bank. The initial audit included patients operated over the course of 1 year. Following a feedback session, a re-audit was performed to identify improvements in practice. Results The case mix of both studies was very similar. Revision hip arthroplasty surgery constituted the major subgroup requiring allograft (48%), followed by foot and ankle surgery (16.3%) and revision knee arthroplasty surgery (11.4%) .On the initial audit, 17/45 cases (38%) had either adequate preoperative documentation of the outpatient discussion or an appropriately completed consent form on the planned use of allograft. On the re-audit, 44/78 cases (56%) had adequate pre-operative documentation. There was little correlation between how frequently a surgeon used allograft and the adequacy of consent (Correlation coefficient -0.12). Conclusions Although the risk of disease transmission with allograft may be variable, informed consent for allograft should be a routine part of preoperative discussions in elective orthopaedic surgery. Regular audit and feedback sessions may further improve consent documentation, alongside the targeting of high volume/low compliance surgeons.

A retrospective study on annual evaluation of radiation processing for frozen bone allografts complying to quality system requirements.

Bone allografts have been used widely to fill up essential void in orthopaedic surgeries. The benefit of using allografts to replace and reconstruct musculoskeletal injuries, fractures or disease has obtained overwhelming acceptance from orthopaedic surgeons worldwide. However, bacterial infection and disease transmission through bone allograft transplantation have always been a significant issue. Sterilization by radiation is an effective method to eliminate unwanted microorganisms thus assist in preventing life threatening allograft associated infections. Femoral heads procured from living donors and long bones (femur and tibia) procured from cadaveric donors were sterilized at 25 kGy in compliance with international standard ISO 11137. According to quality requirements, all records of bone banking were evaluated annually. This retrospective study was carried out on annual evaluation of radiation records from 1998 until 2012. The minimum doses absorbed by the bones were ranging from 25.3 to 38.2 kGy while the absorbed maximum doses were from 25.4 to 42.3 kGy. All the bones supplied by our UMMC Bone Bank were sterile at the required minimum dose of 25 kGy. Our analysis on dose variation showed that the dose uniformity ratios in 37 irradiated boxes of 31 radiation batches were in the range of 1.003-1.251, which indicated the doses were well distributed.

Potential lack of "standardized" processing techniques for production of allogeneic and xenogeneic bone blocks for application in humans.

In the present study, the structure of two allogeneic and three xenogeneic bone blocks, which are used in dental and orthopedic surgery, were histologically analyzed. The ultimate goal was to assess whether the components postulated by the manufacturer can be identified after applying conventional histological and histochemical staining techniques. Three samples of each material, i.e. allogeneic material-1 and -2 as well as xenogeneic material-1, -2 and -3, were obtained commercially. After decalcification and standardized embedding processes, conventional histological staining was performed in order to detect inorganic matrix, cellular or organic matrix components. Allogeneic material-1 showed trabecular bone-like structures, which were free of cellular components as well as of organic matrix. The allogeneic material-2 showed trabecular bone structures, in which connective tissue and cellular remnants were embedded. Additionally, some connective tissue, which resembled fat-like tissue, was found within this material. The xenogeneic material-1 showed trabecular bone-like structures and contained organic components comparable to that demonstrated for the allogeneic material-2. The xenogeneic material-2 showed trabecular bone structures with single cells located in lacunae. The xenogeneic material-3 also showed trabecular structures. Neither cellular nor organic matrix components were found within this material. According to the data of the present study, the allogeneic material-1 and the xenogeneic material-3 were the only investigated materials for which the obtained histological data were in accordance with the manufacturers advertised information. The remaining three materials showed discrepancies-although the manufacturers of all five bone substitute materials stated that their blocks were free of organic/cellular remnants. These data are of great clinical and material science interest. It seems that even patented processing techniques are not always able to deliver reproducible materials. Although the manufacturers of all five bone blocks stated that their blocks were free of organic/cellular remnants, our histological analysis revealed that three out of five bone blocks did contain such remnants. Such specimens might be able to induce an immune response within the recipient.

Aplicación clínica del aloinjerto de matriz dérmica acelular en cirugía plástica periodontal* / Clinical application of a cellular dermal matrix allograft in periodontal plastic surgery

Se han indicado diferentes procedimientos quirúrgicos para la preservación y aumento del reborde alveolar, así como para el tratamiento de recesiones gingivales e incremento de la amplitud de la encía adherida, alrededor de dientes naturales e implantes. Cuando se utilizan injertos autógenos en estas intervenciones se evidencian algunas desventajas que incluyen la inconformidad asociada con un sitio quirúrgico adicional y la disponibilidad limitada de tejido donante. Recientemente, se utilizan aloinjertos de matriz dérmica acelular como sustitutos de los injertos autógenos en cirugía plástica periodontal. La matriz dérmica es un aloinjerto libre de células obtenido de la piel humana, bioestructuralmente compuesto por membrana basal y matriz extracelular que actúa como una matriz que permite la neovascularización, y proliferación de fibroblastos y células epiteliales En esta serie de casos, se presentan tres aplicaciones quirúrgicas de la matriz dérmica: cubrimiento de recesiones gingivales, manejo de dehiscencias sobre implantes y aumento de reborde alveolar(AU)

Several surgical procedures have been indicated for the preservation and increase of the alveolar ridge, and for the treatment of gingival recessions so to increase the width of attached gingiva around natural teeth or implants. The disadvantages of harvesting autogenous grafts on these procedures lie in the postoperative discomfort associated with an extra surgical site, as well as the limitation of available donor tissues. Recently, an acellular dermal matrix allograft has been approved as substitutes for autogenous grafts in periodontal plastic surgery. Dermal matrix allograft are free cells obtained from human skin, bioestructuraly formed by basement membrane and extracellular matrix that act as a matrix that allow the revascularization and proliferation of fibroblasts and epithelial cells. In this series case, we present three surgical applications of the dermal matrix: coverage of gingival recessions, management of implant dehiscence and alveolar ridge augmentation(AU)