Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) myelodysplastic syndromes and impact of lenalidomide.

While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.

Causes and risk factors for same-day discharge failure after total hip and knee arthroplasty: a meta-analysis.

In recent decades, the trend toward early same-day discharge (SDD) after surgery has dramatically increased. Efforts to develop adequate risk stratification tools to guide decision-making regarding SDD versus prolonged hospitalization after total hip arthroplasty (THA) remain largely incomplete. The purpose of this report is to identify the most frequent causes and risk factors associated with SDD failure in patients undergoing THA and total knee arthroplasty (TKA). A systematic search following PRISMA guidelines of four bibliographic databases was conducted for comparative studies between patients who were successfully discharged on the same day and those who failed. Outcomes of interests were causes and risk factors associated with same-day discharge failure. Odds ratios (OR) were calculated for dichotomous variables, whereas mean differences (MD) were calculated for continuous variables. Meta-analysis was performed using RevMan software. Random effects were used if there was evidence of heterogeneity. Eight studies with 3492 patients were included. The most common cause of SDD failure was orthostatic hypotension, followed by inadequate physical condition, nausea/vomiting, pain, and urinary retention. Female sex was a risk factor for failure (OR 0.77, 95% CI 0.63-0.93), especially in the THA subgroup. ASA score IV (OR 0.33, 95% CI 0.14-0.76) and III (OR 0.72, 95% CI 0.52-0.99) were risk factors, as were having > 2 allergies and smoking patients. General anesthesia increased failure risk (OR 0.58, 95% CI 0.42-0.80), while spinal anesthesia was protective (OR 1.62, 95% CI 1.17-2.24). The direct anterior and posterior approaches showed no significant differences. In conclusion, orthostatic hypotension was the primary cause of SDD failure. Risk factors identified for SDD failure in orthopedic surgery include female sex, ASA III and IV classifications, a higher number of allergies, smoking patients and the use of general anesthesia. These factors can be addressed to enhance SDD outcomes.

Adjuvants influence the immune cell populations present at the injection site granuloma induced by whole-cell inactivated paratuberculosis vaccines in sheep.

Vaccination is the most effective tool for paratuberculosis control. Currently, available vaccines prevent the progression of clinical disease in most animals but do not fully protect them against infection and induce the formation of an injection site granuloma. The precise mechanisms that operate in response to vaccination and granuloma development, as well as the effect that adjuvants could trigger, have not been fully investigated. Therefore, this study aimed to investigate the injection site granulomas induced by two inactivated paratuberculosis vaccines, which differ in the adjuvant employed. Two groups of 45-day-old lambs were immunized with two commercially available vaccines-one (n = 4) with Gudair® and the other (n = 4) with Silirum®. A third group (n = 4) was not vaccinated and served as control. The peripheral humoral response was assessed throughout the study by a commercial anti-Mycobacterium avium subspecies paratuberculosis (Map) antibody indirect ELISA, and the cellular immune response was assessed similarly by the IFN-γ release and comparative intradermal tests. The injection site granulomas were measured during the experiment and sampled at 75 days post-vaccination (dpv) when the animals were euthanized. The tissue damage, antigen and adjuvant distribution, and the presence and amount of immune cells were then determined and assessed by immunohistochemical methods. Antibodies against Map antigens; a general macrophage marker (Iba1), M1 (iNOS), and M2 (CD204) macrophages; T (CD3), B (CD20), and γδ T lymphocytes, proteins MHC-II and NRAMP1, and cytokines IL-4, IL-10, TNF, and IFN-γ were employed. Silirum® elicited a stronger peripheral cellular immune response than Gudair®, while the latter induced larger granulomas and more tissue damage at the site of injection. Additionally, adjuvant and Map antigen distribution throughout the granulomatous inflammatory infiltrate, as well as the NRAMP1 cell expression, which is linked to antigen phagocytosis, were highly irregular. In Silirum® induced granulomas, a higher number of MHC-II and TNF-expressing cells and a lower number of M2 macrophages suggested an improved antigen presentation, which could be due to the better antigen distribution and reduced tissue damage induced by this vaccine.

Evaluation of Midodrine Utilization in Patients with Cancer and Heart Failure.

PURPOSE: The purpose of this study was to evaluate safety and cardiovascular outcomes as well as overall survival of cancer patients with concomitant heart failure (HF) treated with midodrine for hypotension. METHODS: Adult patients diagnosed with cancer and HF who were treated with midodrine at a tertiary cancer center from 03/2013 to 08/2021 were identified. Demographic and clinical parameters were collected retrospectively. RESULTS: A total of 85 patients were included with a median age of 68 years (IQR: 60, 74; 33% female and 85% White). Of those, 31% had HFpEF (EF ≥ 50%), 42% HF with mildly reduced EF (HFmrEF; EF 41-49%), and 27% HFrEF (EF ≤ 40%). The most common indication for midodrine use was orthostatic hypotension (49%). Midodrine was continued for at least one month in 57% of the patients. Supine hypertension was the only side effect reported in 6% of patients. No statistically significant changes in NYHA class, guideline-directed medical therapy, cardiac biomarkers (NT-proBNP or troponin T), echocardiographic findings or cardiovascular hospitalizations were observed between patients who continued treatment with midodrine compared to those who stopped using midodrine over a median follow-up of 38 months. In the multivariable cox regression analysis, continuation of midodrine, compared to discontinuation, and use of midodrine for orthostatic hypotension, as opposed to other causes of hypotension, were not associated with an increased risk of mortality (HR 0.41, 95% CI 0.24-0.69, p < .0001; HR 0.34, 95% CI 0.18-0.64, p < .001, respectively). In contrast, elevated creatinine (> 1.3 for males and > 1.1 for females) was associated with an increased risk of mortality (HR 1.83, 95% CI 1.07-3.14). LVEF was not significantly associated with lower or higher risk of mortality. CONCLUSIONS: In our study, midodrine use in patients with cancer and HF was not associated with significant adverse effects, worse cardiovascular outcomes, or increased risk of mortality. Larger, prospective studies are needed to confirm these findings.

Do Patients Treated With an Unplanned Resection for Small Superficial Soft Tissue Sarcomas Have Worse Long-term Survival Than Those Initially Treated With an Oncologic Resection?

BACKGROUND: Histologic grade, size, and depth are well-known prognostic factors in soft tissue sarcomas (STS). Small (< 5 cm) and superficial STS generally have an excellent prognosis when treated with appropriate surgery. However, they are often misdiagnosed and mistreated. We reported that in midterm follow-up (5 to 7 years), patients with unplanned resections of tumors with positive margins who immediately underwent a reoperation with margin-widening re-resection and postoperative radiotherapy had survival comparable to that of patients who were initially treated correctly. In that article, we included STS larger than 5 cm, deep STS, and individuals with local recurrence. However, we wanted to evaluate the impact of unplanned resection on the survival of patients who had STS with the best prognosis, small and superficial STS, with two groups that were as homogeneous as possible. QUESTION/PURPOSE: Do patients with small and superficial STS who underwent an unplanned resection have worse prognosis in the long term than those who were initially treated correctly? METHODS: We exclusively evaluated patients with small (< 5 cm) and superficial (to the deep fascia) STS. We systematically excluded deep STS. Among this subset, we identified 93 patients with superficial STS. We excluded patients with local relapse, metastatic disease, superficial STS of the head or neck, those with insufficient clinical or dosimetric information, and patients with follow-up of less than 2 years. Furthermore, our focus on investigating the most benign and homogeneous STS prompted us to exclude patients with superficial tumors greater than or equal to 5 cm. This selection was driven by the presumed better prognosis associated with smaller tumors, inevitably leading to a smaller pool of patients for direct comparison with patients who had unplanned resections. The initial expectation was to observe similar survival outcomes between cohorts. Between 1990 and 2019, a total of 17 patients underwent surgical treatment at our private, medium-size center. Of those, 29% (5 patients) were lost to follow-up before 2 years without meeting a study endpoint (relapse, metastasis or revision, reoperation, or death), leaving a total of 71% (12 patients) of the original group who had either follow-up of at least 2 years or who met a study endpoint before that minimum surveillance duration. They were treated with surgery alone. During that same period, another 51 patients were referred to us after undergoing an unplanned resection of a lesion that subsequently was determined to be a soft tissue malignancy. Of those, 18% (9 patients) were lost to follow-up before 2 years without meeting a study endpoint, leaving 82% (42 patients) of the original group who had either follow-up of at least 2 years or who met a study endpoint before that minimum surveillance duration. They were treated with re-excision and postoperative radiotherapy. Patients with unplanned resections had an older mean age (51± 5 versus 44 ± 7 years; p = 0.1) and a higher proportion of female patients (58% versus 38%; p = 0.07), but the groups did not differ in terms of largest diameter, histologic type, or tumor location. However, patients with planned resections had a higher proportion of high-grade STS (75% versus 55%; p = 0.07). No metastases were present in either group at diagnosis. We performed a univariate analysis of the groups. We could not perform a multivariate analysis because of the small sample. We compared the groups in terms of local recurrence and all-cause mortality using the Kaplan-Meier survivorship estimator. RESULTS: According to the Kaplan-Meier survivorship estimator, survivorship free from local recurrence at a mean of 20 years of follow-up was better in the planned resection group than in the unplanned resection group (92% [95% CI 63% to 100%] versus 69% [95% CI 54% to 81%]; p = 0.04). Furthermore, overall survivorship at 5 years was higher in the planned resection group than in the unplanned resection group (100% [95% CI 72% to 100%] versus 70% [95% CI 54% to 81%]; p = 0.04). Similarly, the planned resection group exhibited superior survivorship at 20 years of follow-up (100% [95% CI 72% to 100%] versus 62% [95% CI 47% to 75%]; p = 0.01). Metastatic disease was absent in the planned resection group, while it occurred in 12 patients in the unplanned resection group (28% [95% CI 17% to 44%]). CONCLUSION: Unplanned resection for patients with small and superficial STS was associated with a decrease in overall survival in the long term, despite the use of postoperative radiotherapy. An unplanned resection may be an important prognostic factor. Nevertheless, larger and prospective studies are needed to validate our findings. Although small and superficial lumps are usually benign, nonsarcoma surgeons should be aware that some masses may be malignant, and if in doubt, MR imaging, a biopsy before excision, or consultation with or referral to a sarcoma center should be considered before removing the mass. LEVEL OF EVIDENCE: Level III, therapeutic study.

Femoral Neck Preservation and Diaphyseal Invasion Comparing a Calcar-Metaphyseal Short Stem with its Homonymous Standard Femoral Stem. A Radiographic Study.

BACKGROUND: We aim to compare the preoperative planning radiographs of 50 patients in whom both a short stem and its homonymous standard version were programmed, focusing on the preservation of the neck and the invasion of the femoral shaft. The secondary objective was to evaluate the 50 preoperative radiographs with the 50 postoperative radiographs in which the short stem was implanted, measuring the real invasion of the diaphysis and the real preservation of the femoral neck. MATERIAL AND METHODS: We measured cut level at the femoral neck and diaphyseal invasion in 50 preoperative x-rays where an Alteon Neck Preserving Stem (ANPS) was templated and we compared it with 50 preoperative x-rays where an Alteon Taper Wedge Stem (ATWS) was templated. After surgery, we compared both parameters previously measured in the preoperative x-rays with the 50 postoperative radiographs where the short stem was implanted obtaining the real bone preservation at the femoral neck and the real diaphyseal invasion length. RESULTS: For templating comparison, mean bone preservation at the femoral neck was 14.87mm (SD 3.64) for the ANPS group and 9.94mm (SD 8.39) for the ATWS group (p <0.001). The mean diaphyseal bone invasion was 47.21mm (SD 5.89) and 76.77mm (SD 8.39) for ANPS and ATWS respectively (p <0.001). After surgery, the mean postoperative bone preservation at the femoral neck was 15.08mm (SD 3.1) with a mean of 0.17mm (SD 0.51) more preservation in the preoperative group. CONCLUSION: 1. ANPS allow bone preservation with limited diaphyseal invasion when compared with his homonymous ATWS in the preoperative templates. 2. ANPS showed a good correlation between preoperative radiographs and real bone preservation of the femoral neck and invasion of the femoral shaft.

Efficacy and safety of arthroscopy in femoroacetabular impingement syndrome: a systematic review and meta-analysis of randomized clinical trials.

This study aimed to compare the efficacy and safety of arthroscopy with physiotherapy or joint lavage in patients with femoroacetabular impingement (FAI). A meta-analysis using PubMed, Embase, Scopus, and the Cochrane Collaboration Library databases was performed in September 2022. We included studies focusing on patients with FAI who underwent arthroscopic surgery versus those who underwent physiotherapy or arthroscopic lavage. The outcomes were functional scores (iHOT-33 and HOS ADL) and adverse events. Randomized clinical trials were included in the study. The risk of bias in each study was assessed according to Cochrane guidelines for clinical trials. The data were combined using Review Manager version 5.4. (PROSPERO CRD42022375273). Six RCTs were included, from a pool of 839 patients (407 females). The iHOT-33 and HOS ADL scales showed significant differences at 12 months in favor of the arthroscopy group (MD, 10.65; 95% CI 6.54-4.76) and (MD, 8.09; 95% CI 3.11-13.07). MCID was not achieved through arthroscopy in functional variables. The rates of osteoarthritis (OR, 6.18; 95% CI 1.06-36.00) and numbness (OR, 73.73; 95% CI 10.00-43.92) were significantly higher in the arthroscopy group. Arthroscopic surgery showed statistical superiority over the control group without exceeding the MCID in most studies; however, the results might have been influenced by secondary variables. Finally, arthroscopic surgery results in a high rate of conversion to osteoarthritis.

Femoroacetabular Impingement and the Effect of Osteochondroplasty on Hip Osteoarthritis Prevention: The Pandora's Box Opening Process.

OBJECTIVE: This study was conducted to assess the effect of osteochondroplasty on osteoarthritis (OA) prevention, comparing radiological evolution between identical hips from the same patient who had undergone unilateral surgery. DESIGN: We retrospectively reviewed radiological evolution between hips with similar shape from the same patient who had undergone unilateral surgery. In all, 56 FAI patients (112 hips) with a mean age of 42.18 ± 9.16 years and had undergone unilateral arthroscopy treatment have been included. Four independent researchers measured Wiberg, Acetabular and Alpha angles, Extrusion index, and Tönnis classification preoperatively to verify that operated and non-operated hips had the same shape. OA evolution was assessed by joint space width (JSW) in 3 different articular points and Tönnis classification. RESULTS: No preoperative anatomical differences were present between groups (P > 0.05). At the end of follow-up (31.9 months), a decrease of JSW in the 3 points measured was found in OP hips (OP vs. N-OP; P < 0.01). These results were correlated with changes in the proportion of patients who progressed to grade III in Tönnis classification (from 1.3% preoperative to 23.2% at the end of follow-up). CONCLUSIONS: Osteochondroplasty and labrum procedures were not associated with OA prevention. The OP hips showed a faster OA degeneration, which was not seen in the N-OP. These results will encourage hip surgeons to perform further investigations to avoid the "Pandora's Box Opening Process."

Involvement of the PRL-PAK1 Pathway in Cancer Cell Migration.

Prolactin (PRL) is a polypeptide hormone synthesized in the lactotrophs of the adenohypophysis and in extrahypophyseal glands (such as the prostate and breasts) where it promotes their development. PRL is also involved in cancer development in these glands. It has been shown to stimulate cancer cell migration, suggesting its possible involvement in metastasis, in which cell migration plays an essential role. However, the role of PRL in cell migration is still unclear. Moreover, the intracellular mechanisms activated by PRL to carry out cell migration are less well understood. PRL exerts its effects via the PRL receptor (PRLR), which leads intracellularly to phosphorylation of Janus protein kinase 2 (JAK2), which in turn phosphorylates p21-activated protein kinase (PAK1), leading to an increase in cell migration. Although several studies have described the involvement of the PRL-PAK1 pathway in breast cancer cell migration, the molecular mechanisms have not been fully elucidated and there is no integration of these into signaling pathways. This study was conducted based on literature search of review articles and original research in the PubMed database, using the following keywords: PRL, cell migration, PRL and cell migration, PAK1 and signaling pathways. The aim of this review article was to describe the major signaling pathways controlled by PRL-PAK1 and propose a comprehensive model of the signaling pathways associated with PRL-PAK1.

Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution.

Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize an enriched population of human HSPCs obtained from young and elderly healthy individuals.Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain aging-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks (GRNs) and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and GRNs regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2, and RUNX1 suggesting a role of these transcription factors (TFs) in the pathogenesis of the disease.In summary, we demonstrate that the combination of single-cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in complex biological systems such as early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with perturbations such as aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients.

Our blood contains many different types of cells; red blood cells carry oxygen through the body, platelets help to stop bleeding and a variety of white blood cells fight infections. All of these critical components come from a pool of immature cells in bone marrow, which can develop and specialise into any of these. However, as we get older, these immature cells can accumulate damage, including mutations in specific genes. This increases the risk of diseases such as myelodysplastic syndromes (MDS), a type of cancer in which the cells cannot develop and the patient does not have enough healthy mature blood cells. The changes in gene activity in the immature cells have previously been studied using samples from young and elderly people, as well as individuals with MDS. These studies examined large numbers of cells together, revealing differences between young and elderly people, and individuals with MDS. However, this does not describe how the different types alter their behaviour. To address this, Ainciburu, Ezponda et al. used a technique called single-cell RNA sequencing to study the gene activity in individual immature blood cells. This revealed changes associated with maturation that may account for the different combinations of cell populations in younger and older people. The results confirmed findings from previous studies and suggested new genes involved in ageing or MDS. Ainciburu, Ezponda et al. used these results to create an analytical system that highlights gene activity differences in individual MDS patients that are independent of age-related changes. These results provide new insights that could help further research into the development of MDS and the ageing process. In addition, scientists could study other diseases using this approach of analysing individual patients' gene activity. In future, this could help to personalise clinical decisions on diagnosis and treatment.

Epiphyseal distraction prior to resection in paediatric bone sarcomas : four decades of experience.

Paediatric bone sarcomas are a dual challenge for orthopaedic surgeons in terms of tumour resection and reconstruction, as it is important to minimize functional and growth problems without compromising survival rates. Cañadell's technique consists of a Type I epiphysiolysis performed using continuous distraction by an external fixator prior to resection. It was designed to achieve a safe margin due to the ability of the physeal cartilage to be a barrier to tumour spread in some situations, avoiding the need for articular reconstruction, and preserving the growth capacity most of the times. Despite initial doubts raised in the scientific community, this technique is now widely used in many countries for the treatment of metaphyseal paediatric bone sarcomas. This annotation highlights the importance of Cañadell's work and reviews the experience of applying it to bone sarcoma patients over the last 40 years.Cite this article: Bone Joint J 2023;105-B(1):11-16.

The Year in Cardio-oncology 2022.

Cardiovascular disease and cancer are the leading causes of death worldwide. With advent of novel and improved cancer therapies, a growing population of cancer patients with cardiac complications is seen. Taking this into consideration, the clinical studies have also shifted their focus from the study of a single disease to the interdisciplinary study of oncology and cardiology. This current review article provides a comprehensive review of all major articles and guidelines from the year 2021-2022 in the field of cardio-oncology.

The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in older individuals. Here we analyze the transcriptome of human HSCs purified from young and older healthy adults, as well as MDS patients, identifying transcriptional alterations following different patterns of expression. While aging-associated lesions seem to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthy HSCs induces an MDS-like transcriptional state, and dyserythropoiesis, an effect associated with a failure in the activation of transcriptional programs required for normal erythroid differentiation. Moreover, DDIT3 knockdown in CD34+ cells from MDS patients with anemia is able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythroid differentiation characterizing MDS patients.

Local assessment of the immunohistochemical expression of Foxp3+ regulatory T lymphocytes in the different pathological forms associated with bovine paratuberculosis.

BACKGROUND: Mycobacterium avium subsp. paratuberculosis infected animals show a variety of granulomatous lesions, from focal forms with well-demarcated granulomas restricted to the gut-associated lymphoid tissue (GALT), that are seen in the initial phases or latency stages, to a diffuse granulomatous enteritis, with abundant (multibacillary) or scant (paucibacillary) bacteria, seen in clinical stages. Factors that determine the response to the infection, responsible for the occurrence of the different types of lesion, are still not fully determined. It has been seen that regulatory T cells (Treg) play an important role in various diseases where they act on the limitation of the immunopathology associated with the immune response. In the case of paratuberculosis (PTB) the role of Treg lymphocytes in the immunity against Map is far away to be completely understood; therefore, several studies addressing this subject have appeared recently. The aim of this work was to assess, by immunohistochemical methods, the presence of Foxp3+ T lymphocytes in intestinal samples with different types of lesions seen in cows with PTB. METHODS: Intestinal samples of twenty cows showing the different pathological forms of PTB were evaluated: uninfected controls (n = 5), focal lesions (n = 5), diffuse paucibacillary (n = 5) and diffuse multibacillary (n = 5) forms. Foxp3+ lymphocyte distribution was assessed by differential cell count in intestinal lamina propria (LP), gut-associated lymphoid tissue (GALT) and mesenteric lymph node (MLN). RESULTS: A significant increase in the number of Foxp3+ T cells was observed in infected animals with respect to control group, regardless of the type of lesion. However, when the different categories of lesion were analyzed independently, all individuals with PTB lesions showed an increase in the amount of Foxp3+ T lymphocytes compared to the control group but this increase was only significant in cows with focal lesions and, to a lesser extent, in animals with diffuse paucibacillary forms. The former showed the highest numbers, significantly different from those found in cows with diffuse lesions, where no differences were noted between the two forms. No specific distribution pattern was observed within the granulomatous lesions in any of the groups. CONCLUSIONS: The increase of Foxp3+ T cells in focal forms, that have been associated with latency or resistance to infection, suggest an anti-inflammatory action of these cells at these stages, helping to prevent exacerbation of the inflammatory response, as occurs in diffuse forms, responsible for the appearance of clinical signs.

Hip Preservation Surgery in Osteoarthritis Prevention: Potential Benefits of the Radiographic Angular Correction.

Objective: The aim of the study is to describe the morphology associated with the development of osteoarthritis (OA) in three different age groups. These data will contribute to defining the morphology associated with early and late hip OA. Methods: We studied 400 hips in 377 patients who had undergone primary THA due to idiopathic OA. Three groups were compared: group 1 (n = 147), younger patients, aged up to 60 years; group 2 (n = 155), patients aged between 61 and 74 years; and group 3 (n = 98), aged 75 or over. Five independent researchers measured the hip angles and the mean values were used to build a database. Results: No differences between groups in sex distribution and BMI were detected. Less coverage of the head (extrusion index), higher Tönnis angle, lower Wiberg and alpha angles characterized early OA hips. These differences increased with age, being greater between group 2 and group 3 (p < 0.01). However, significant differences were still present in the comparison between group 1 and group 2 (p < 0.01)). No differences were detected between group 2 and group 3. Conclusion: Elevated acetabular angle, head extrusion and decreased Wiberg angle characterize hip osteoarthritis at younger ages and should be the focus of hip preservation surgery in terms of osteoarthritis prevention. Pincer-type FAI (higher Wiberg and lower Tönnis angle) and higher alpha angle (CAM) are correlated with the development of later OA. These results shed doubt on applying the hip preservation surgery concept in terms of osteoarthritis prevention in FAI, especially in Pincer-type FAI patients.

Dose volume histogram constraints in patients with soft tissue sarcomas of the extremities and the superficial trunk treated with surgery and perioperative HDR brachytherapy.

BACKGROUND: Wound healing complications (WHC), osteoradionecrosis (ORN), and nerve damage (ND) are common adverse effects in adult patients with soft tissue sarcomas of the extremities and the superficial trunk treated with surgery and perioperative high dose rate brachytherapy (PHDRB) alone or combined with external beam radiotherapy (EBRT). RATIONALE: Analysis of the treatment factors contributing to these complications can potentially minimize their occurrence and severity. PATIENTS: A total of 169 patients enrolled in two parallel prospective studies were included in this analysis. Previously Unirradiated cases (Group 1; n = 139) were treated with surgical resection, 16-24 Gy of PHDRB and 45 Gy of EBRT. Adjuvant chemotherapy was given to selected patients with high-grade tumors. Previously irradiated cases (Group 2; n = 30) were treated with surgical resection and 32-40 Gy of PHDRB without further EBRT. METHODS: Patient factors, tumor factors, surgical factors, PHDRB factors and EBRT factors were analyzed using Cox univariate and multivariate analysis. RESULTS: In Previously Unirradiated cases, WHC, ORN and ND occurred in 38.8%, 5.0% and 19.4%. Multivariate analysis indicated that WHC increased with CTV size (p = 0.02) and CTV2cm3 Physical dose (p = 0.02). ORN increased with Bone2cm3 EQD2 ≥ 67 Gy(p = 0.01) and ND was more frequent in patients with TV100DVH-based dose (tissue volume encompassed by the 100% isodose) ≥ 84 Gy (p < 0.01). In Previously Irradiated cases, WHC, ORN and ND occurred in 63.3%, 3.3% and 23.3%. Multivariate analysis showed that WHC was more frequent in patients with Skin2cm3Lifetime EQD2 ≥ 84 Gy (p = 0.01) and ND was more frequent after CTVD90 Physical Doses ≥ 40 Gy (p < 0.01). CONCLUSIONS: WHC in Previously Unirradiated patients can be minimized by using a more conservative CTV definition together with a meticulous implant technique and planning aimed to minimize hyperdose CTV2cm3 areas. In Previously Irradiated patients WHC may be mimimized considering Lifetime EQD2 Skin2cm3 doses. ORN can be reduced by using the Bone2cm3 EQD2 constraint. ND occurs more frequently in patients with large tumors receiving high treated volume doses, but no specific constraints can be recommended due to the lack of peripheral nerve definition during brachytherapy planning.

A Reassessment of the Barrier Effect of the Physis against Metaphyseal Osteosarcoma: A Comprehensive Pathological Study with Its Radiological and Clinical Follow-Up Correlations.

Osteosarcoma is a primary malignant bone tumor usually arising at the metaphysis of long bones, particularly around the knee. The physis has been regarded as a barrier capable of blocking tumor extension, thus allowing it to preserve their epiphysis and therefore improve functional results. With the objective of clarifying how effective the physis is as a barrier to tumor spread, a large series of skeletally immature patients with osteosarcoma were reviewed. From 452 metaphyseal osteosarcomas a selection of 282 cases in which the tumor was close or crossing the physis were carried out. This sub-sample was split into two groups according to the surgical treatment (epiphyseal preservation or not). The specimens obtained by resection were studied, and the physeal and metaphyseal areas were studied by multiple sections. Immunostaining against VEGF of physis was obtained in selected cases. In about half of the patients affected by metaphyseal malignant bone tumors, the growth plate and epiphysis were not compromised by the tumor. Three sequential invasive growth patterns of an osteosarcoma in its relationship with the physis could be distinguished. An intense angiogenesis and osteoclastic reaction could be observed in the growth plate in the free zone between the tumor and the physis. The local recurrence incidence was lower in the epiphyseal preservation treated patients than it was in the conventional treatment (8% vs. 12%). Most local recurrences appeared in the first 2 years. The overall survival of patients treated with epiphyseal preservation was better than that of the patients treated without preserving the epiphysis (73% vs. 59%; p = 0.03) at a mean follow-up of 18 years. We have described an angiogenic and osteoclastic reaction in the base of the growth plate in the proximity of the advance front of the tumor, which could facilitate the osteosarcoma invasion. It is also shown that the preoperative imaging method for examination is a valid approach for the decision to carry out epiphyseal preservation. Finally, we concluded that epiphyseal preservation combined with protective chemotherapy is an excellent clinical approach for selected patients with metaphyseal osteosarcoma.

Risk Factors of DAIR Failure and Validation of the KLIC Score: A Multicenter Study of Four Hundred Fifty-Five Patients.

Background: Debridement, antibiotic agents, and implant retention (DAIR) is a currently accepted approach for the treatment of early prosthetic joint infections (PJI). The success of a DAIR procedure has shown variable results throughout the published literature. Scoring systems such as the Kidney, Liver, Index surgery, Cemented prosthesis, and C-reactive protein value (KLIC) score for the selection of patients that are likely to benefit from DAIR have proved to be helpful in decision making. Our study aims to further validate the KLIC score using a large external multicentric cohort and to evaluate other risk factors for failure. Patients and Methods: A retrospective analysis of patients with an early acute PJI who were treated with DAIR and recorded in a database of eight Spanish university hospitals was performed. According to pre-operative variables of the KLIC study, patients were categorized into five groups: group A, ≤2 points; group B, 2.5-3.5 points; group C, 4-5 points; group D, 5.5-6.5 points; and group E, ≥7 points. Failure rates were compared between groups at 60 days and after 60 days of DAIR. Further variables for risk of failure were also analyzed. Results: A total of 455 patients with early acute PJI were included in the analyses. At 60 days, patients presenting with pre-operative elevated C-reactive protein serum levels, Staphylococcus aureus, and polymicrobial infections were associated with failure. Failure rates recorded were 12% for group A (n = 210), 18% for group B (n = 83), 26% for group C (n = 89), 24% for group D (n = 66), and 0% for group E (n = 7). Univariable analysis between consecutive groups of the KLIC score showed no differences for failure before 60 days of the DAIR procedure. Scheduled surgery and having the procedure performed by a specialized unit were also identified as important factors for DAIR success. Conclusions: Our results suggest the KLIC score was not useful for predicting failure in our cohort. Furthermore, our results indicate a specialized unit should conduct DAIR procedures.

Preneoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma.

Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88L265P in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88L265P is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.