Progressive Improvement in 5-Year Survival Rates for Extremity Soft Tissue Sarcomas from 1999 to 2019.

Background: Extremity soft-tissue sarcoma (ESTS) is a group of rare, heterogeneous malignancies. Previous studies have demonstrated a progressive improvement in 5-year survival rate over time, but recent trends are unknown. Therefore, this study aimed to provide an update on the clinical characteristics and 5-year survival rate of ESTS from 1999 to 2019. Methods: This retrospective cohort study used the Surveillance, Epidemiology, and End Results (SEER) database. Overall, 5,654 patients over the age of 15 years with primary ESTS diagnosed between 1999 and 2019 were included. Data on patient demographics, clinical characteristics, and survival were extracted. Patients were grouped by year of diagnosis: 1999-2005, 2006-2012, and 2013-2019. Kaplan-Meier and Cox proportional hazards regression analyses were performed. Results: ESTS occurred primarily in the lower extremity (76.1%) and was frequently grade III (58.3%), >5 cm in size (69.9%), and without metastasis (77.9%) at diagnosis. Furthermore, there was a significant increase in the proportion of patients over age 60 (p < 0.001) and without metastasis (p < 0.001) over the study period. The 5-year survival rate successively improved, from 47% in 1999-2005, to 61% in 2006-2012, to 78% in 2013-2019. Similarly, in multivariate analysis, the mortality rate progressively declined from a hazard ratio (HR) of 3.4 in 1999-2005 to an HR of 2.1 in 2006-2012, with the 2013-2019 group having the best overall survival (p < 0.001). Age, tumor size, grade, and metastasis were negative prognostic factors for survival; radiation and surgery were positive prognostic factors. Conclusions: The 5-year overall survival rate for ESTS progressively improved over the 20-year study period, perhaps due to an increasing proportion of older patients diagnosed with local disease. These findings may also be related to earlier detection or more effective treatment over the study period.

Birth elicits a conserved neuroendocrine response with implications for perinatal osmoregulation and neuronal cell death.

Long-standing clinical findings report a dramatic surge of vasopressin in umbilical cord blood of the human neonate, but the neural underpinnings and function(s) of this phenomenon remain obscure. We studied neural activation in perinatal mice and rats, and found that birth triggers activation of the suprachiasmatic, supraoptic, and paraventricular nuclei of the hypothalamus. This was seen whether mice were born vaginally or via Cesarean section (C-section), and when birth timing was experimentally manipulated. Neuronal phenotyping showed that the activated neurons were predominantly vasopressinergic, and vasopressin mRNA increased fivefold in the hypothalamus during the 2-3 days before birth. Copeptin, a surrogate marker of vasopressin, was elevated 30-to 50-fold in plasma of perinatal mice, with higher levels after a vaginal than a C-section birth. We also found an acute decrease in plasma osmolality after a vaginal, but not C-section birth, suggesting that the difference in vasopressin release between birth modes is functionally meaningful. When vasopressin was administered centrally to newborns, we found an ~ 50% reduction in neuronal cell death in specific brain areas. Collectively, our results identify a conserved neuroendocrine response to birth that is sensitive to birth mode, and influences peripheral physiology and neurodevelopment.

5-Aminolevulinic acid tumor paint and photodynamic therapy for myxofibrosarcoma: an in vitro study.

BACKGROUND: 5-Aminolevulinic acid (5-ALA), a fluorescent contrast agent, has been used for tumor paint and photodynamic therapy (PDT) for various tumors, but its use with soft tissue sarcomas is not well documented. Myxofibrosarcoma, a subtype of soft tissue sarcoma with a high local recurrence rate, may benefit from similar types of treatment. The purpose of this study was to analyze the effects of 5-ALA tumor paint and PDT on a myxofibrosarcoma cell line. METHODS: Tumor paint was assessed by exposing micromass pellets of human adipose-derived stromal (ADS) cells or myxofibrosarcoma (MUG-Myx1) cells to 5-ALA. Cell pellets were then visualized using a microscope at established excitation and emission wavelengths. Corrected total cell fluorescence was calculated per accepted protocols. Photodynamic therapy was similarly assessed by exposing ADS and MUG-Myx1 cells to 5-ALA, with subsequent analysis via flow cytometry and real-time confocal microscopy. RESULTS: The use of 5-ALA tumor paint led to a selective fluorescence in MUG-Myx1 cells. Findings were confirmed by flow cytometry. Interestingly, flow cytometry results showed progressive selective cell death with increasing 5-ALA exposure as a result of the PDT effect. PDT was further confirmed using confocal microscopy, which revealed progressive cellular bubble formation consistent with advancing stages of cell death-a finding that was not seen in control ADS cells. CONCLUSIONS: 5-ALA tumor paint and PDT were successfully used on a human myxofibrosarcoma cell line (MUG-Myx1). Results from this study showed both selective fluorescent tagging and selective cytotoxicity of 5-ALA toward malignant myxofibrosarcoma cells, while sparing benign adipose control cells. This finding was further confirmed in a dramatic time-lapse video, visually confirming active, targeted cell death. 5-ALA's two-pronged application of selective tumor identification and cytotoxicity may transform surgical and medical approaches for treating soft tissue sarcomas.

Microglial Depletion Causes Region-Specific Changes to Developmental Neuronal Cell Death in the Mouse Brain.

Developmental neuronal cell death has been characterized as a cell autonomous "suicide" program, but recent findings suggest that microglia play an active role in determining the survival of developing neurons. Results have been contradictory, however, with some studies concluding that microglia promote cell death, while others report that microglia are neuroprotective. Here, we depleted microglia throughout the newborn mouse brain using intracerebroventricular injections of clodronate liposomes, and examined effects on naturally occurring cell death across multiple brain areas. Microglial density varied significantly by brain region, and clodronate liposome treatment at birth reduced the number of microglia in all regions examined. The effect of microglia reduction on cell death, however, varied by region: the number of dying cells was reduced in the medial septum and medial amygdala in clodronate treated animals, but was increased in the oriens layer of the hippocampus, and unchanged in several other brain regions. In most brain regions, the average size of microglia was greater in microglia-depleted than in control animals, suggesting that the remaining microglia compensate to some extent for a reduction in microglial number. The hippocampal oriens was exceptional in this regard, in that microglial size was reduced following treatment with clodronate. Microglia produce cytokines which mediate many of their effects, and we found higher expression of inflammatory cytokines in the hippocampus than in the septum, independent of clodronate treatment. Thus, microglial depletion has opposite effects on cell death in different brain regions of the newborn brain, which may be related to regional heterogeneity in microglia.

Birth delivery mode alters perinatal cell death in the mouse brain.

Labor and a vaginal delivery trigger changes in peripheral organs that prepare the mammalian fetus to survive ex utero. Surprisingly little attention has been given to whether birth also influences the brain, and to how alterations in birth mode affect neonatal brain development. These are important questions, given the high rates of cesarean section (C-section) delivery worldwide, many of which are elective. We examined the effect of birth mode on neuronal cell death, a widespread developmental process that occurs primarily during the first postnatal week in mice. Timed-pregnant dams were randomly assigned to C-section deliveries that were yoked to vaginal births to carefully match gestation length and circadian time of parturition. Compared with rates of cell death just before birth, vaginally-born offspring had an abrupt, transient decrease in cell death in many brain regions, suggesting that a vaginal delivery is neuroprotective. In contrast, cell death was either unchanged or increased in C-section-born mice. Effects of delivery mode on cell death were greatest for the paraventricular nucleus of the hypothalamus (PVN), which is central to the stress response and brain-immune interactions. The greater cell death in the PVN of C-section-delivered newborns was associated with a reduction in the number of PVN neurons expressing vasopressin at weaning. C-section-delivered mice also showed altered vocalizations in a maternal separation test and greater body mass at weaning. Our results suggest that vaginal birth acutely impacts brain development, and that alterations in birth mode may have lasting consequences.

Synovial Sarcoma Is Not Associated With a Higher Risk of Lymph Node Metastasis Compared With Other Soft Tissue Sarcomas.

BACKGROUND: Reported rates of the incidence of lymph node metastasis in soft tissue sarcoma vary considerably. Many are based on single-institution series and small patient populations. Certain sarcoma subtypes, including synovial sarcoma, have been associated with a higher risk of lymph node involvement. Most single centers have insufficient numbers of patients to assess lymph node metastasis accurately, but larger national databases may allow a more accurate estimation. QUESTIONS/PURPOSES: We queried a large national database and asked the following questions: (1) What proportion of patients with soft tissue sarcoma have lymph node metastasis and distant metastasis? (2) What histologic subtypes are associated with increased risk of nodal metastasis? (3) What is the impact of lymph node metastases and histologic subtype on survival? (4) Does lymph node excision improve survival of patients with soft tissue sarcoma? METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program is a national database that covers a geographic cross-section representing approximately 28% of the US population across demographic groups. Using the SEER database, we identified 15,525 adults diagnosed with histologically confirmed soft tissue sarcoma from 2004 to 2013. Proportions of patients with lymph node or distant metastases were calculated using descriptive statistics. Overall survival was computed using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazard regression to calculate the association of lymph node metastasis with overall survival while controlling for patient age, sex, race, tumor size, and tumor location. RESULTS: A total of 820 of 15,525 patients had lymph node metastasis at the time of diagnosis, yielding an overall proportion of 5.3% (95% confidence interval [CI], 4.9%-5.6%). Histologic subtypes that most frequently developed nodal metastasis were rhabdomyosarcoma, clear cell sarcoma, epithelioid sarcoma, and myxoid/round cell liposarcoma. Despite frequent reports regarding its association with lymph node metastasis, the proportion of patients with lymph node metastasis among 885 patients with synovial sarcoma (4.2%) was not different from the proportion with nodal metastasis in the overall soft tissue sarcoma population. For all soft tissue sarcomas, distant metastatic disease was present at diagnosis in 1869 (12%) patients (95% CI, 11.5%-12.6%). After controlling for relevant covariates, lymph node metastasis was associated with poorer overall survival (hazard ratio [HR], 1.34; 95% CI, 1.22-1.48; p < 0.001) as was distant metastasis (HR, 2.87; 95% CI, 2.66-3.09; p < 0.001). When comparing the subgroup of patients with positive lymph nodes, lymphadenectomy in conjunction with local excision/limb salvage was associated with the highest overall 5-year survival (HR, 0.46; 95% CI, 0.31-0.67; p < 0.001). CONCLUSIONS: In clarifying the overall proportion of patients with soft tissue sarcoma with nodal metastases, the current study indicates that lymph node metastases occur at a higher proportion than previous studies have suggested and that synovial sarcoma is not associated with a higher risk of lymphatic spread compared with soft tissue sarcoma overall. Patients with lymph node metastases are associated with poorer survival than those without metastases. Further investigation is needed to clarify the apparent improved overall survival after lymphadenectomy in the setting of nodal metastasis from soft tissue sarcoma. LEVEL OF EVIDENCE: Level II, prognostic study.

The microbiota influences cell death and microglial colonization in the perinatal mouse brain.

The mammalian fetus develops in a largely sterile environment, and direct exposure to a complex microbiota does not occur until birth. We took advantage of this to examine the effect of the microbiota on brain development during the first few days of life. The expression of anti- and pro-inflammatory cytokines, developmental cell death, and microglial colonization in the brain were compared between newborn conventionally colonized mice and mice born in sterile, germ-free (GF) conditions. Expression of the pro-inflammatory cytokines interleukin 1ß and tumor necrosis factor α was markedly suppressed in GF newborns. GF mice also had altered cell death, with some regions exhibiting higher rates (paraventricular nucleus of the hypothalamus and the CA1 oriens layer of the hippocampus) and other regions exhibiting no change or lower rates (arcuate nucleus of the hypothalamus) of cell death. Microglial labeling was elevated in GF mice, due to an increase in both microglial cell size and number. The changes in cytokine expression, cell death and microglial labeling were evident on the day of birth, but were absent on embryonic day 18.5, approximately one-half day prior to expected delivery. Taken together, our results suggest that direct exposure to the microbiota at birth influences key neurodevelopmental events and does so within hours. These findings may help to explain some of the behavioral and neurochemical alterations previously seen in adult GF mice.

Racial and ethnic disparities in treatment and survival of pediatric sarcoma.

BACKGROUND: Childhood sarcomas are rare and require complex interdisciplinary care including surgery, chemotherapy, and radiation. The goal of this study was to determine if racial or ethnic disparities exist for pediatric sarcoma patients in the United States. METHODS: The United States' National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify patients aged 0-21 diagnosed with primary sarcomas from 1973 to 2012. Patients were considered by race and ethnicity. Survival curves were computed using the Kaplan-Meier method and the log-rank test. RESULTS: A total of 11,502 patients were included in this study. When stratified by race, non-Hispanic black and Hispanic patients were significantly more likely to present with advanced stage disease than white patients. White patients were more likely to receive radiation therapy than black and Hispanic patients (P = 0.01). There was no significant difference between patients who underwent surgery (P = 0.21). Overall survival was better for white patients than black or Hispanic ones. Despite the overall 5-year survival improvement during the study period (56.2%-70.3%), survival disparities between race and ethnicity have grown. CONCLUSIONS: Racial and ethnic disparities do exist with respect to stage, treatment, and survival of these rare tumors. Black and Hispanic patients are presenting at more advanced stage and have overall worse survival. This survival disparity has widened over the past 4 decades.

Chest wall Ewing sarcoma: a population-based analysis.

BACKGROUND: The globally low incidence of pediatric chest wall Ewing sarcoma (CWES) has limited prior studies of this disease to mostly small, single-institution reviews. Our objective was to assess incidence, demographics, treatment patterns, and long-term survival of this disease through a population-based analysis. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was used to identify patients aged 0-21 y diagnosed with CWES from 1973 to 2011. Patients were grouped by decade to assess changes in treatment patterns and outcomes. The effects of clinical, demographic, and treatment variables on overall survival (OS) were assessed by the computation of Kaplan-Meier curves and the log-rank test, with Cox proportional hazard regression used for multivariable analysis. RESULTS: A total of 193 pediatric patients with histologically confirmed CWES were identified. The disease was more common in men (61%), whites (92%), and 11- to 17-y olds (49%). It was metastatic at presentation in 37% of patients. When grouped approximately by decade, 10-y OS improved progressively from 38% in 1973-1979 to 65% in 2000-2011 (P = 0.033). The use of radiation decreased from 84% in the earliest period to 40% in the most recent, whereas the proportion of patients receiving surgery increased from 75% to 85%. When controlling for covariates in multivariable analysis, male patients were found to have a higher mortality than female patients (hazard ratio: 2.4; confidence interval: 1.4, 4.4; P = 0.0028). CONCLUSIONS: This population-based analysis of CWES demonstrated an impressive trend of improving OS, with increasing use of surgery and decreasing use of radiation therapy. Our study demonstrated a gender difference in survival of CWES, with females having a better prognosis. The presence of metastatic disease is a very important prognostic factor for this illness.

Socioeconomic and demographic factors contributing to outcomes in patients with primary lymphoma of bone.

BACKGROUND: Primary lymphoma of bone (PLB) is a rare disease, comprising a malignant lymphoid infiltrate of bone. The goal of this study was to identify socioeconomic, demographic, and anatomic factors as prognostic indicators of survival for this disease using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The SEER database was used to identify a study population of 692 patients diagnosed with PLB in the United States from 1989 to 2003. Survival was analyzed using the Kaplan-Meier method, with effects of potential prognostic factors on survival analyzed using the log-rank test. Multivariable analysis was performed by Cox proportional hazards regression. RESULTS: The overall 5-year survival rate was 49.6%, with a 10-year survival rate of 30.2%. Median overall survival was 4.9 years (95% CI: 3.9, 6.1). In multivariable analysis, age (p<0.0001), marital status (p=0.006), and appendicular vs. axial tumor location (p=0.004) were found to be independent predictors of survival. CONCLUSIONS: This population-based study of PLB identified age, marital status, and tumor location as independent indicators of prognosis. This finding supports the clinical suspicion that an appendicular tumor location confers a better prognosis than an axial tumor location.

Improvement in Overall Survival from Extremity Soft Tissue Sarcoma over Twenty Years.

Several patient demographic factors, including marital status, have been demonstrated to have prognostic significance for survival in extremity soft tissue sarcoma (ESTS). A study population of 12,546 adult patients diagnosed with ESTS from 1991 to 2010 was identified from the SEER database, a large population-based registry, in order to determine whether overall survival had changed over this recent 20-year period. The study population was divided into three groups by year of diagnosis: 1991-1996, 1997-2003, and 2004-2010. We used the Kaplan-Meier method and Cox proportional hazards regression to assess survival differences between different demographic groups and prognostic clinical characteristics. Over the course of time, the 5-year overall survival rates have increased from 28% in the earliest time period to 62% in the latest (P < 0.0001). On multivariate analysis, the mortality rate progressively declined from the 1991-1996 group (HR: 3.02, CI: 2.78-3.29) to the 1997-2003 group (HR: 2.21, CI: 2.06-2.37), with the 2004-2010 group having the best overall survival, despite increases in the proportion of patients with tumors greater than 5 cm in size (P < 0.0001), and those presenting with metastasis (P < 0.0001).