The Impact of Epidural Analgesia on Immobility and extended Hospital Stay After Periacetabular Osteotomy.

AIMS: Early mobilisation after periacetabular osteotomy (PAO) represents an important goal after surgery. The purpose of this study was to determine whether the use of epidural aznalgesia (EA) is associated with prolonged immobility and an increased length of stay (LOS) after PAO surgery. METHODS: From January 2022 to July 2023, the study included a cohort of 150 PAO procedures all performed by the same surgeon (SSA). Patients were categorized into two distinct groups: those who received epidural analgesia (EA) (79 PAOs) and those who did not receive EA (71 PAOs). "Ready for discharge" was defined as the ability to ascend and descend a standardized flight of stairs independently. Multivariable linear regression was used to identify additional factors influencing LOS after PAO. RESULTS: Patients in the EA group were ready for discharge 5.95 ± 2.09 days after surgery which was significantly longer than in the No EA group´s average of 4.18 days ± 2.5, (p < 0.001). While the reduction in the number of patients experiencing pulmonary embolism in the No EA group did not reach statistical significance, it still demonstrated a relevant decrease from two patients within the EA group (2.53%) to 0 (0%) in the No EA group. The active engagement of the surgeon in mobilising patients led to a substantial reduction in LOS, decreasing it from 5.81 ± 2.18 days to 2.2 ± 0.77 days (p < 0.001). Multivariable analysis revealed five independent factors influencing the LOS following PAO which included absence of EA, surgeon-led mobilisation within 24 h after surgery, postoperative hemoglobin levels, BMI, and prior experience with PAO surgery on the contralateral side. CONCLUSIONS: Opting against the use of EA in patients undergoing PAO is advisable, as it will result in extended postoperative immobility and the associated risks. Additionally, the active participation of the surgeon in the mobilisation process is strongly recommended.

Unveiling the learning curve of periacetabular osteotomy.

Aims: Periacetabular osteotomy (PAO) is widely recognized as a demanding surgical procedure for acetabular reorientation. Reports about the learning curve have primarily focused on complication rates during the initial learning phase. Therefore, our aim was to assess the PAO learning curve from an analytical perspective by determining the number of PAOs required for the duration of surgery to plateau and the accuracy to improve. Methods: The study included 118 consecutive PAOs in 106 patients. Of these, 28 were male (23.7%) and 90 were female (76.3%). The primary endpoint was surgical time. Secondary outcome measures included radiological parameters. Cumulative summation analysis was used to determine changes in surgical duration. A multivariate linear regression model was used to identify independent factors influencing surgical time. Results: The learning curve in this series was 26 PAOs in a period of six months. After 26 PAO procedures, a significant drop in surgical time was observed and a plateau was also achieved. The mean duration of surgery during the learning curve was 103.8 minutes (SD 33.2), and 69.7 minutes (SD 18.6) thereafter (p < 0.001). Radiological correction of acetabular retroversion showed a significant improvement after having performed a total of 93 PAOs, including anteverting PAOs on 35 hips with a retroverted acetabular morphology (p = 0.005). Several factors were identified as independent variables influencing duration of surgery, including patient weight (ß = 0.5 (95% confidence interval (CI) 0.2 to 0.7); p < 0.001), learning curve procedure phase of 26 procedures (ß = 34.0 (95% CI 24.3 to 43.8); p < 0.001), and the degree of lateral correction expressed as the change in the lateral centre-edge angle (ß = 0.7 (95% CI 0.001 to 1.3); p = 0.048). Conclusion: The learning curve for PAO surgery requires extensive surgical training at a high-volume centre, with a minimum of 50 PAOs per surgeon per year. This study defined a cut-off value of 26 PAO procedures, after which a significant drop in surgical duration occurred. Furthermore, it was observed that a retroverted morphology of the acetabulum required a greater number of procedures to acquire proficiency in consistently eliminating the crossover sign. These findings are relevant for fellows and fellowship programme directors in establishing the extent of training required to impart competence in PAO.

Development of early complications after treatment of trochanteric fractures with an intramedullary sliding hip screw in a geriatric population.

PURPOSE: Although trochanteric fractures (TF) are a frequent event in the geriatric population, studies reporting on complication rates associated with surgical treatment are sparse. Thus, this study investigated the relevance of fracture-, implant-, and surgery-associated complications in TF. Furthermore, the role of possible risk factors for the before mentioned complications was investigated. METHODS: A consecutive series of patients with TF treated by intramedullary nailing with a sliding screw device was evaluated. Data were sampled retrospectively from the hospital patient information system and anonymized at the source. Demographic data and information regarding fracture pattern, the treatment performed, hospital stay, and evaluation of operative and follow-up radiographs were analyzed. Intraoperative problems (i.e., technical problems with the implant, intraoperative fracture) and postoperative complications were investigated. RESULTS: Postoperative surgical complications were noted in 11.7%. The most frequent surgical problem was a difficult fracture reduction (13%) and intraoperative fracture dislocation (3.6%). The most frequent postoperative complication was intra-hospital mortality (3.6%), delayed/non-union (2.7%), and a cut-out of the lag screw in the femoral head (2.3%). Implant failure (1,4%) was significantly associated with morbid obesity while cut-out (2,3%) correlated with a higher tip-apex distance (TAD). A complex fracture type and a suboptimal screw position significantly increased the cut-out rate to 5% (p = 0.018). CONCLUSION: Complications after TF treatment occur frequently. While patient-associated variables such as morbid obesity cannot be influenced by the surgeon, correct fracture reduction and implant positioning remain to be of highest importance.

Effect of Injury Patterns on the Development of Complications and Trauma-Induced Mortality in Patients Suffering Multiple Trauma.

Patients that suffer from severe multiple trauma are highly vulnerable to the development of complications that influence their outcomes. Therefore, this study aimed to evaluate the risk factors that can facilitate an early recognition of adult patients at risk. The inclusion criteria were as follows: admission to a level 1 trauma center, injury severity score (ISS) ≥ 16 (severe injury was defined by an abbreviated injury score (AIS) ≥ 3) and ≥18 years of age. Injury- and patient-associated factors were correlated with the development of four complication clusters (surgery-related, infection, thromboembolic events and organ failure) and three mortality time points (immediate (6 h after admission), early (>6 h-72 h) and late (>72 h) mortality). Statistical analysis was performed using a Chi-square, Mann-Whitney U test, Cox hazard regression analysis and binominal logistic regression analysis. In total, 383 patients with a median ISS of 24 (interquartile range (IQR) 17-27) were included. The overall mortality rate (27.4%) peaked in the early mortality group. Lactate on admission significantly correlated with immediate and early mortality. Late mortality was significantly influenced by severe head injuries in patients with a moderate ISS (ISS 16-24). In patients with a high ISS (≥25), late mortality was influenced by a higher ISS, older age and higher rates of organ failure. Complications were observed in 47.5% of all patients, with infections being seen most often. The development of complications was significantly influenced by severe extremity injuries, the duration of mechanical ventilation and length of ICU stay. Infection remains the predominant posttraumatic complication. While immediate and early mortality is mainly influenced by the severity of the initial trauma, the rates of severe head injuries influence late mortality in moderate trauma severity, while organ failure remains a relevant factor in patients with a high injury severity.

Fifty percent of patients undergoing periacetabular osteotomy for hip dysplasia showed normal findings upon neonatal ultrasound screening : Symptomatic hip dysplasia in adulthood despite inconspicuous neonatal hip ultrasound.

Developmental dysplasia of the hip (DDH) is characterized by the pathomorphology of inadequate acetabular coverage of the femoral head leading to increased loading of the articular surface and acetabular rim. If left untreated, this ultimately leads to osteoarthritis. Germany introduced a nationwide universal ultrasound screening program for all newborn infants in 1996. Subsequently, the incidence of undiagnosed hip dislocation was significantly reduced. In this consecutive series of patients who underwent periacetabular osteotomy for the treatment of symptomatic dysplasia of the hip between October 2014 and October 2022 data regarding the U3 screening examination were analyzed. The data included whether the examination was performed, whether the findings were positive or negative, whether the patients underwent any form of treatment in the case of a positive finding and whether a control X­ray was performed. This study provides evidence that acetabular undercoverage cannot be ruled out based on a normal finding in ultrasonography screening. Furthermore, the study also shows that residual dysplasia may persist despite attempts of conservative treatment.

CycleFlow simultaneously quantifies cell-cycle phase lengths and quiescence in vivo.

Populations of stem, progenitor, or cancer cells show proliferative heterogeneity in vivo, comprising proliferating and quiescent cells. Consistent quantification of the quiescent subpopulation and progression of the proliferating cells through the individual phases of the cell cycle has not been achieved. Here, we describe CycleFlow, a method that robustly infers this comprehensive information from standard pulse-chase experiments with thymidine analogs. Inference is based on a mathematical model of the cell cycle, with realistic waiting time distributions for the G1, S, and G2/M phases and a long-term quiescent G0 state. We validate CycleFlow with an exponentially growing cancer cell line in vitro. Applying it to T cell progenitors in steady state in vivo, we uncover strong proliferative heterogeneity, with a minority of CD4+CD8+ T cell progenitors cycling very rapidly and then entering quiescence. CycleFlow is suitable as a routine method for quantitative cell-cycle analysis.

Fate mapping of hematopoietic stem cells reveals two pathways of native thrombopoiesis.

Hematopoietic stem cells (HSCs) produce highly diverse cell lineages. Here, we chart native lineage pathways emanating from HSCs and define their physiological regulation by computationally integrating experimental approaches for fate mapping, mitotic tracking, and single-cell RNA sequencing. We find that lineages begin to split when cells leave the tip HSC population, marked by high Sca-1 and CD201 expression. Downstream, HSCs either retain high Sca-1 expression and the ability to generate lymphocytes, or irreversibly reduce Sca-1 level and enter into erythro-myelopoiesis or thrombopoiesis. Thrombopoiesis is the sum of two pathways that make comparable contributions in steady state, a long route via multipotent progenitors and CD48hi megakaryocyte progenitors (MkPs), and a short route from HSCs to developmentally distinct CD48-/lo MkPs. Enhanced thrombopoietin signaling differentially accelerates the short pathway, enabling a rapid response to increasing demand. In sum, we provide a blueprint for mapping physiological differentiation fluxes from HSCs and decipher two functionally distinct pathways of native thrombopoiesis.

Patient-specific risk factors for adverse outcomes following geriatric proximal femur fractures.

BACKGROUND: Proximal femur fractures (PFFs) occur frequently among geriatric patients due to diverse risk factors, such as a lower bone mineral density and the increased risk of falls. METHODS: In this review, we focus on recent literature of patient-specific risk factors and their impact on common complications and outcome parameters in patients with PFF. RESULTS: Patient- and treatment related factors have a significant impact on outcome and are associated with an increased risk of mortality, impairments in functional rehabilitation and complicative courses. CONCLUSION: Geriatric patients at high risk for complications are nursing home inhabitants suffering from severe osteoporosis, dementia and sarcopenia. The early and ongoing assessment for these individual risk factors is crucial. Strategies including interdisciplinary approaches, addressing comorbidities and facilitating an optimal risk factor evaluation result in a beneficial outcome. The ongoing ambulant assessment and therapy of complicating factors (e.g., malnutrition, sarcopenia, frailty or osteoporosis) have to be improved.

Early local neutralization of CC16 in sepsis­induced ALI following blunt chest trauma leads to delayed mortality without benefitting overall survival.

Blunt thoracic trauma (TxT) is a common injury pattern in polytraumatized patients. When combined with a secondary trigger, TxT often results in acute lung injury (ALI), which negatively affects outcomes. Recent findings suggest that ALI is caused by both local and systemic inflammatory reactions. Club cell protein (CC)16 is an anti­inflammatory peptide associated with lung injury following TxT. Recently, the anti­inflammatory properties of endogenous CC16 in a murine model of TxT with subsequent cecal­ligation and puncture (CLP) as the secondary hit were demonstrated by our group. The present study aimed to determine whether CC16 neutralization improves survival following 'double­hit'­induced ALI. For this purpose, a total of 120 C57BL/6N mice were subjected to TxT, followed by CLP after 24 h. Sham­operated animals underwent anesthesia without the induction of TxT + CLP. CC16 neutralization was performed by providing a CC16 antibody intratracheally following TxT (early) or following CLP (late). Survival was assessed in 48 animals for 6 days after CLP. Sacrifice was performed 6 or 24 h post­CLP to evaluate the anti­inflammatory effect of CC16. The results revealed that CC16 neutralization enhanced pro­inflammatory CXCL1 levels, thereby confirming the anti­inflammatory characteristics of CC16 in this model. Early CC16 neutralization immediately following TxT significantly prolonged survival within 60 h; however, the survival rate did not change until 6 days post­trauma. Late CC16 neutralization did not provide any survival benefits. On the whole, the present study demonstrated that neutralizing CC16 confirmed its anti­inflammatory potential in this double­hit ALI model. Early CC16 neutralization prolonged survival within 60 h; however, no survival benefits were observed after 6 days post­CLP in any group.

Lumbar puncture rapidly improves olfaction in patients with idiopathic intracranial hypertension: A cohort study.

BACKGROUND: A lumbar puncture constitutes an important diagnostic procedure in the evaluation of idiopathic intracranial hypertension. Chronic overflow of cerebrospinal fluid into the sheaths of the olfactory nerves appears to be related to olfactory impairment in these patients. Here, we asked whether cerebrospinal fluid drainage in idiopathic intracranial hypertension patients improves olfactory function. METHODS: Fourteen idiopathic intracranial hypertension patients and 14 neurologic control patients were investigated before and after lumbar puncture using the extended Sniffin' Sticks procedure. We assessed odor threshold, discrimination, and identification. In idiopathic intracranial hypertension patients, cerebrospinal fluid was drained until cerebrospinal fluid pressure had normalized. In addition, a third group of 14 healthy controls participated in the two smell tests at similar intervals. RESULTS: Relative to healthy controls, threshold, discrimination, and identification composite scores before lumbar puncture were significantly lower in idiopathic intracranial hypertension patients and also in neurologic controls. Following lumbar puncture, threshold, discrimination, and identification scores for neurologic controls remained unchanged whereas idiopathic intracranial hypertension patients showed robust improvement on the composite score as well as on all three subscores (all changes: p < 0.003), quickly regaining olfactory function in the normal range. Cerebrospinal fluid opening pressure was significantly correlated with improvement in threshold, discrimination, and identification score upon cerebrospinal fluid drainage (r = 0.609, p = 0.021). CONCLUSION: Olfactory impairment is an important, yet underappreciated, clinical feature of idiopathic intracranial hypertension. Lowering of increased intracranial pressure improves hyposmia. Our findings shed new light on the pathophysiology of cerebrospinal fluid circulation in idiopathic intracranial hypertension.

Hidden long-range memories of growth and cycle speed correlate cell cycles in lineage trees.

Cell heterogeneity may be caused by stochastic or deterministic effects. The inheritance of regulators through cell division is a key deterministic force, but identifying inheritance effects in a systematic manner has been challenging. Here, we measure and analyze cell cycles in deep lineage trees of human cancer cells and mouse embryonic stem cells and develop a statistical framework to infer underlying rules of inheritance. The observed long-range intra-generational correlations in cell-cycle duration, up to second cousins, seem paradoxical because ancestral correlations decay rapidly. However, this correlation pattern is naturally explained by the inheritance of both cell size and cell-cycle speed over several generations, provided that cell growth and division are coupled through a minimum-size checkpoint. This model correctly predicts the effects of inhibiting cell growth or cycle progression. In sum, we show how fluctuations of cell cycles across lineage trees help in understanding the coordination of cell growth and division.

Contributing factors in the development of acute lung injury in a murine double hit model.

OBJECTIVES: Blunt chest (thoracic) trauma (TxT) is known to contribute to the development of secondary pulmonary complications. Of these, acute lung injury (ALI) is common especially in multiply injured patients and might not only be due to the direct trauma itself, but seems to be caused by ongoing and multifactorial inflammatory changes. Nevertheless, the exact mechanisms and contributing factors of the development of ALI following blunt chest trauma are still elusive. METHODS: 60 CL57BL/6N mice sustained either blunt chest trauma combined with laparotomy without further interventions or a double hit (DH) including TxT and cecal ligation puncture (CLP) after 24 h to induce ALI. Animals were killed either 6 or 24 h after the second procedure. Pulmonary expression of inflammatory mediators cxcl1, cxcl5, IL-1ß and IL-6, neutrophil infiltration and lung tissue damage using the Lung Injury Score (LIS) were determined. RESULTS: Next to a moderate increase in other inflammatory mediators, a significant increase in CXCL1, neutrophil infiltration and lung injury was observed early after TxT, which returned to baseline levels after 24 h. DH induced significantly increased gene expression of cxcl1, cxcl5, IL-1ß and IL-6 after 6 h, which was followed by the postponed significant increase in the protein expression after 24 h compared to controls. Neutrophil infiltration was significantly enhanced 24 h after DH compared to all other groups, and exerted a slight decline after 24 h. LIS has shown a significant increase after both 6 and 24 h compared to both control groups as well the late TxT group. CONCLUSION: Early observed lung injury with moderate inflammatory changes after blunt chest trauma recovered quickly, and therefore, may be caused by mechanical lung injury. In contrast, lung injury in the ALI group did not undergo recovery and is closely associated with significant changes of inflammatory mediators. This model may be used for further examinations of contributing factors and therapeutic strategies to prevent ALI.

Endogenous Uteroglobin as Intrinsic Anti-inflammatory Signal Modulates Monocyte and Macrophage Subsets Distribution Upon Sepsis Induced Lung Injury.

Sepsis is a serious clinical condition which can cause life-threatening organ dysfunction, and has limited therapeutic options. The paradigm of limiting excessive inflammation and promoting anti-inflammatory responses is a simplified concept. Yet, the absence of intrinsic anti-inflammatory signaling at the early stage of an infection can lead to an exaggerated activation of immune cells, including monocytes and macrophages. There is emerging evidence that endogenous molecules control those mechanisms. Here we aimed to identify and describe the dynamic changes in monocyte and macrophage subsets and lung damage in CL57BL/6N mice undergoing blunt chest trauma with subsequent cecal ligation and puncture. We showed that early an increase in systemic and activated Ly6C+CD11b+CD45+Ly6G- monocytes was paralleled by their increased emigration into lungs. The ratio of pro-inflammatory Ly6ChighCD11b+CD45+Ly6G- to patrolling Ly6ClowCD11b+CD45+Ly6G- monocytes significantly increased in blood, lungs and bronchoalveolar lavage fluid (BALF) suggesting an early transition to inflammatory phenotypes during early sepsis development. Similar to monocytes, the level of pro-inflammatory Ly6ChighCD45+F4/80+ macrophages increased in lungs and BALF, while tissue repairing Ly6ClowCD45+F4/80+ macrophages declined in BALF. Levels of inflammatory mediators TNF-α and MCP-1 in blood and RAGE in lungs and BALF were elevated, and besides their boosting of inflammation via the recruitment of cells, they may promote monocyte and macrophage polarization, respectively, toward the pro-inflammatory phenotype. Neutralization of uteroglobin increased pro-inflammatory cytokine levels, activation of inflammatory phenotypes and their recruitment to lungs; concurrent with increased pulmonary damage in septic mice. In in vitro experiments, the influence of uteroglobin on monocyte functions including migratory behavior, TGF-ß1 expression, cytotoxicity and viability were proven. These results highlight an important role of endogenous uteroglobin as intrinsic anti-inflammatory signal upon sepsis-induced early lung injury, which modules the early monocyte/macrophages driven inflammation. Short Summary: Blunt chest injury is the third largest cause of death following major trauma, and ongoing excessive pro-inflammatory immune response entails high risk for the development of secondary complications, such as sepsis, with limited therapeutic options. In murine double hit trauma consisting of thoracic trauma and subsequent cecal ligation and puncture, we investigated the cytokine profile, pulmonary epithelial integrity and phenotypic shift of patrolling Ly6ClowCD11b+CD45+Ly6G- monocytes and Ly6ClowCD45+F4/80+ macrophages to pro-inflammatory Ly6ChighCD11b+CD45+Ly6G- monocytes and Ly6ChighCD45+F4/80+ cells in blood, lungs and bronchoalveolar lavage fluid (BALF). Pro-inflammatory mediators and phenotypes were elevated and uteroglobin neutralization led to further increase. Enhanced total protein levels in BALF suggests leakage of respiratory epithelium. In vitro, uteroglobin inhibited the migratory capacity of monocytes and the TGF-ß1 expression without affecting the viability. These results highlight an important role of endogenous uteroglobin as an intrinsic anti-inflammatory signal upon sepsis-induced early lung injury, which modulates the early monocyte/macrophages driven inflammation.

The effect of CSF drain on the optic nerve in idiopathic intracranial hypertension.

BACKGROUND: Elevation of intracranial pressure in idiopathic intracranial hypertension induces an edema of the prelaminar section of the optic nerve (papilledema). Beside the commonly observed optic nerve sheath distention, information on a potential pathology of the retrolaminar section of the optic nerve and the short-term effect of normalization of intracranial pressure on these abnormalities remains scarce. METHODS: In this exploratory study 8 patients diagnosed with idiopathic intracranial hypertension underwent a MRI scan (T2 mapping) as well as a diffusion tensor imaging analysis (fractional anisotropy and mean diffusivity). In addition, the clinical presentation of headache and its accompanying symptoms were assessed. Intracranial pressure was then normalized by lumbar puncture and the initial parameters (MRI and clinical features) were re-assessed within 26 h. RESULTS: After normalization of CSF pressure, the morphometric MRI scans of the optic nerve and optic nerve sheath remained unchanged. In the diffusion tensor imaging, the fractional anisotropy value was reduced suggesting a tissue decompression of the optic nerve after lumbar puncture. In line with these finding, headache and most of the accompanying symptoms also improved or remitted within that short time frame. CONCLUSION: The findings support the hypothesis that the elevation of intracranial pressure induces a microstructural compression of the optic nerve impairing axoplasmic flow and thereby causing the prelaminar papilledema. The microstructural compression of the optic nerve as well as the clinical symptoms improve within hours of normalization of intracranial pressure.

Stem cell homeostasis by integral feedback through the niche.

Hematopoiesis is a paradigm for tissue development and renewal from stem cells. Experiments show that the maintenance of hematopoietic stem cells (HSCs) relies on signals from niche cells. However, it is not known how the size of the HSC compartment is set. Competition by HSCs for niche access has been suggested, yet niche cells in the bone marrow outnumber HSCs. Here we propose a cooperative model of HSC homeostasis in which stem and niche cells mutually interact such that niche cells function as negative feedback regulators of HSC proliferation. This model explains puzzling experimental findings, including homeostatic recovery of the HSC compartment after irradiation versus apparent lack of recovery after HSC ablation. We show that bidirectional niche-stem cell regulation has properties of a proportional-integral feedback controller. Moreover, we predict that the outflux of differentiated cells from HSCs can be regulated by the affinity of HSCs for niche cells. Much effort has been devoted to elucidating niche cell signaling to stem cells; our theoretical insights indicate that studying the effect of stem cells on the niche may be equally important for understanding stem cell homeostasis.

Does IIH Alter Brain Microstructures? - A DTI-Based Approach.

INTRODUCTION: To investigate the correlation of microstructural parameters with CSF pressure and macroscopic changes assessed by diffusion tensor imaging (DTI) in patients with idiopathic intracranial hypertension (IIH). METHODS: Twenty-three patients with IIH as well as age-, sex-, and body mass index (BMI)-matched controls underwent high resolution MR imaging of the optic nerve sheaths (ONS), pituitary gland, and ventricles. For DTI data a voxelwise permutation analysis was performed for the whole brain and ROI analysis was performed for the optic nerve and optic radiation. DTI measurements were correlated to morphometric measurements, CSF opening pressure, and headache intensity. The reliability of diagnostic performance of DTI parameters was assessed using ROC analysis. RESULTS: Analysis of DTI metrics revealed a significant reduction in the fractional anisotropy (FA) of the optic nerve in patients with IIH. In contrast, systematic regional variations between IIH patients and controls were neither observed in the whole brain analysis nor in the optic radiation. FA values of the optic nerve show significant correlations with the optic nerve sheath diameter (P = .003, r = -.589). The correlation of the alterations of the FA values of the optic radiation and the whole brain do not show a significant association to morphometric alterations in the ONS diameter and hypophysis height as well as to CSF opening pressure and headache intensity. CONCLUSIONS: The results indicate that IIH is associated with microstructural changes in the optic nerve. These alterations may be the direct consequence of chronically elevated intracranial pressure.

Mucosal melanoma: correlation of clinicopathologic, prognostic, and molecular features.

Although the presence of the t(12;22)(q13;q12) translocation (the defining molecular feature of malignant melanoma of soft parts/clear cell sarcoma) in cutaneous melanoma has been investigated, no large-scale studies have been performed among mucosal melanoma (MucM). In this study we assessed the prevalence of the EWSR1 rearrangement in primary MucM, and analyzed gross and microscopic features with their potential impact on diagnosis and prognosis. Overall, 132 specimens from 84 patients were included. A total of 55 cases had an intramucosal component. Survival of MucMs of the head and neck was associated with two independent factors: size and histology. Tumors more than 3 cm in greatest dimension had an average survival of 12.75 months; those 3 cm or less had an average survival of 38.3 months (P=0.035). Purely epithelioid tumors had an average worse survival of 16.8 months (P=0.028). A cut-off value of 1 mm for Breslow depth provided a statistically significant difference in survival at both 3 and 5 years (P=-0.02) by multivariate analysis in the gynecologic tract. At the molecular level three cases had a EWSR1 rearrangement by fluorescent in-situ hybridization, but only one with an intramucosal component. None of the 58 cases tested by PCR showed the presence of the EWSR1 rearrangement. With the exception of vulvar melanomas, the prognosis of mucosal-associated melanomas was poor and there was a suggestion that spindle morphology may be more favorable. Our study also showed that the EWSR1 rearrangement was very uncommon among MucM. Though 'clear cell sarcoma' is embedded in the sarcoma literature, the synonym 'melanoma of soft parts' has considerable justification in light of our evolving understanding of the molecular genetics in the family of malignant melanomas.

Prognostic significance of ß-human chorionic gonadotropin and PAX8 expression in anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy with a median survival of five months. Multimodality treatment is associated with some improvement in survival, but patients are only infrequently curable. Although ß-hCG secretion has been reported in many neoplasms, it has never been described in ATC. The objectives of this study were to report a case of ß-hCG-secreting ATC and to study the expression and significance of ß-hCG and PAX8 in an institutional cohort of ATC. METHODS: The sentinel case was characterized and then immunohistochemistry was performed for ß-hCG and PAX8 on 30 ATC patients. Clinical follow-up was obtained by chart review. RESULTS: The sentinel patient with ß-hCG-secreting ATC had a dramatic response to chemotherapy and radiation. After surgical excision of residual disease, the patient developed a regional recurrence of differentiated thyroid carcinoma at 18 months. However, she is now, 30 months after initial therapy, with no evidence of disease and no detectable serum ß-hCG or thyroglobulin. Five of the 30 (17%) total ATCs were positive for ß-hCG and 18 (60%) for PAX8. Outcomes for the ß-hCG-positive cases were not significantly different from those for negative ones. However, none of the other four ß-hCG-positive ATC patients received treatment with either chemotherapy or radiation. Interestingly, PAX8 positivity correlated with statistically significantly better overall survival (p=0.019). CONCLUSIONS: ß-hCG is expressed in a minority of ATCs. Although only a single case in the study had diffuse immunohistochemical expression, the response it showed to aggressive multimodality therapy and the resulting favorable outcome suggest that ß-hCG-positive ATC may be a unique tumor subtype, or possibly even a unique entity. PAX8 is a useful marker of ATC and may be helpful in the differential diagnosis with other malignant neoplasms.