Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium.

Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.

Fibroblast growth factor receptor 1 gene mutation as a potential risk factor for spontaneous intracranial hemorrhage in pediatric low-grade glioma patients.

Background: Fibroblast growth factor receptor 1 (FGFR1) mutations have been associated with poorer prognoses in pediatric central nervous system tumor patients. A recent study highlighted a link between FGFR1 mutations and spontaneous intracranial hemorrhage (ICH), demonstrating that all patients with an FGFR1 alteration experienced hemorrhage at some point during their course of treatment. Methods: The current study examined 50 out of 67 pediatric patients with low-grade gliomas (LGGs) who had genomic testing between 2011 and 2022 at our institution to determine whether a correlation exists between FGFR1 mutations and spontaneous ICH. Results: We found that of the 50 patients with genomic data, 7 (14%) experienced ICH, and an additional spontaneous hemorrhage was recorded; however, no genomic testing was performed for this case. Five of the seven patients (71.4%) had an FGFR1 modification. In our patient population, 6 expressed a detectable FGFR1 mutation (66.7% [4/6] had N546K alteration, 16.7% [1/6] FGFR1 exons duplication, and 16.7% [1/6] had a variant of unknown significance [VUS]). The patient with the FGFR1 VUS had no reported spontaneous hemorrhage. Statistical analysis found a significant association between FGFR1 and spontaneous intracranial hemorrhage (P-value = < .0001). In the patient population, all cases of PTPN11 alterations (n = 3) co-occurred with FGFR1 mutations. Conclusions: Our case series highlights this link between the FGFR1 mutation and spontaneous intracranial hemorrhage in pediatric LGGs.

Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma.

BACKGROUND: Pediatric-type diffuse low-grade gliomas (pLGG) harboring recurrent genetic alterations involving MYB or MYBL1 are closely related tumors. Detailed treatment and outcome data of large cohorts are still limited. This study aimed to comprehensively evaluate pLGG with these alterations to define optimal therapeutic strategies. METHODS: We retrospectively reviewed details of pLGG with MYB or MYBL1 alterations from patients treated or referred for pathologic review at St. Jude Children's Research Hospital. Tumor specimens were centrally reviewed, and clinical data were collated. RESULTS: Thirty-three patients (18 male; median age, 5 y) were identified. Two tumors had MYBL1 alterations; 31 had MYB alterations, MYB::QKI fusion being the most common (n=10, 30%). Most tumors were in the cerebral hemispheres (n=22, 67%). Two patients (6%) had metastasis at diagnosis. The median follow-up was 6.1 years. The 5-year event-free survival (EFS) rate was 81.3±8.3%; the 5-year overall survival (OS) rate was 96.4±4.1%. Patients receiving a near-total or gross-total resection had a 5-year EFS of 100%; those receiving a biopsy or subtotal resection had a 5-year EFS rate of 56.6±15.2% (p<0.01). No difference in EFS was observed based on location, histology, or molecular alterations. However, the tumors that progressed or metastasized may have distinct methylation profiles with evidence of activation of the MAPK and PI3K/AKT/mTOR pathways. CONCLUSIONS: pLGG with MYB/MYBL1 alterations have good outcomes. Our findings suggest that surgical resectability is a crucial determinant of EFS. Further characterization is required to identify optimal treatment strategies for progressive tumors.

Clonal associations of lymphocyte subsets and functional states revealed by single cell antigen receptor profiling of T and B cells in rheumatoid arthritis synovium.

Rheumatoid arthritis (RA) is an autoimmune disease initiated by antigen-specific T cells and B cells, which promote synovial inflammation through a complex set of interactions with innate immune and stromal cells. To better understand the phenotypes and clonal relationships of synovial T and B cells, we performed single-cell RNA and repertoire sequencing on paired synovial tissue and peripheral blood samples from 12 donors with seropositive RA ranging from early to chronic disease. Paired transcriptomic-repertoire analyses highlighted 3 clonally distinct CD4 T cells populations that were enriched in RA synovium: T peripheral helper (Tph) and T follicular helper (Tfh) cells, CCL5+ T cells, and T regulatory cells (Tregs). Among these cells, Tph cells showed a unique transcriptomic signature of recent T cell receptor (TCR) activation, and clonally expanded Tph cells expressed an elevated transcriptomic effector signature compared to non-expanded Tph cells. CD8 T cells showed higher oligoclonality than CD4 T cells, and the largest CD8 T cell clones in synovium were highly enriched in GZMK+ cells. TCR analyses revealed CD8 T cells with likely viral-reactive TCRs distributed across transcriptomic clusters and definitively identified MAIT cells in synovium, which showed transcriptomic features of TCR activation. Among B cells, non-naive B cells including age-associated B cells (ABC), NR4A1+ activated B cells, and plasma cells, were enriched in synovium and had higher somatic hypermutation rates compared to blood B cells. Synovial B cells demonstrated substantial clonal expansion, with ABC, memory, and activated B cells clonally linked to synovial plasma cells. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate RA synovium.

Evaluation of the automated LIAISON® SARS-CoV-2 TrimericS IgG assay for the detection of circulating antibodies.

OBJECTIVES: COVID-19 has brought about tests from many manufacturers. While molecular and rapid antigen tests are targeted for early diagnosis, immunoassays have a larger role in epidemiological studies, understanding longitudinal immunity, and in vaccine development and response. METHODS: The performance of the LIAISON® SARS-CoV-2 TrimericS IgG assay was evaluated against the Beckman ACCESS SARS-CoV-2 IgG assay in New Mexico, and against the Siemens ADVIA Centaur COV2G assay in New York. Discordant samples were parsed using a microneutralization assay. RESULTS: A SARS-CoV-2 antibody positivity rate of 23.8% was observed in the samples tested in New York (September 2020), while in the same month the positivity rate was 1.5% in New Mexico. Positive and negative agreement were 67.6% (95% CI 49.5-82.6%) and 99.8% (95% CI 99.5-99.9%), respectively, with the Beckman test, and 98.0% (95% CI 95.7-99.3%) and 94.8% (95% CI 93.4-96.0%), respectively, with the Siemens test. Receiver operating characteristic analysis for the detection of SARS-CoV-2 antibodies discloses an AUC, area under the curve, of 0.996 (95% CI 0.992-0.999) for the LIAISON® SARS-CoV-2 TrimericS IgG assay. The criterion associated to the Youden Index was determined to be >12.9 kAU/L with a sensitivity of 99.44% and a specificity of 99.82%. CONCLUSIONS: The LIAISON® SARS-CoV-2 TrimericS IgG assay is highly sensitive and specific. The balance of these parameters, without emphasis on high specificity alone, is particularly important when applied to high prevalence populations, where a highly sensitive assay will result in reporting a lower number of false negative subjects.

Clinicopathologic Features and Survival Trends for Acinic Cell Carcinoma of the Major Salivary Glands: A Surveillance, Epidemiology, and End Results Population Analysis.

BACKGROUND: We analyzed a population-based national registry to identify the most influential patient pretreatment and treatment factors affecting overall survival (OS) and cause-specific survival (CSS) in patients diagnosed with acinic cell carcinoma (ACC) of the major salivary glands. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database of the US National Cancer Institute (NCI) related to survival, a total of 1,254 patients with diagnosed ACC of the major salivary glands from 1975 to 2016 met inclusion criteria. Factors significant for OS and CSS were determined using univariate and multivariate analysis with the Cox proportional hazards model. RESULTS: Univariate OS analysis demonstrated that surgery favorably influenced longer survival compared to no surgery (hazard ratio (HR) 2.35, P < 0.05). Patient age was found to be highly predictive of superior OS (divided into 10-year age bands, P < 0.0001, younger age better). In multivariate OS analysis, there were statistically significant worse outcomes for men (HR 1.54, P < 0.05), grades III/IV (HR 2.5, P < 0.05), and distant disease (HR 3.55, P < 0.05) or regional disease (HR 1.22, P < 0.05). Patients diagnosed during years 1996 - 2016 had better OS when compared to earlier decades 1975 - 1995 (HR 1.38, P < 0.05). In univariate analysis, the mean CSS for grades I, II, and III/IV were 429 months (95% confidence interval (CI), ± 38.39), 426 months (95% CI, ± 25.73) and 198 months (95% CI, ± 66.38). Multivariate analysis of CSS further demonstrated that there were statistically significant worse outcomes for men (HR 1.68, P < 0.05), grade III/IV (HR 3.2, P < 0.05), tumor size greater than 40 mm (P < 0.001), and distant disease (HR 4.48, P < 0.05) or regional disease (HR 1.84, P < 0.05). CONCLUSIONS: To our knowledge, this is the largest population-based study of OS and CSS of major salivary gland ACC. We found that the patient pretreatment and treatment factors including younger age at diagnosis, female sex, early stage, lower grade, surgical excision, and recent year of diagnosis are associated with improved survival in patients diagnosed with ACC of the major salivary glands. We hope that this information will aid in construction of further research projects that better refine optimal treatment protocol of individualized patient care.

Static Magnetic Fields within Spinal Interbody Cages for the Promotion of Spinal Arthrodesis: A Pilot Study.

BACKGROUND: Spinal arthrodesis is a commonly performed spinal operation. Spinal arthrodesis can be complicated by pseudoarthrosis and resultant hardware failure. Static magnetic fields (SMF) have the ability to improve bone fusion. We seek to assess the feasibility of the construction and implantation of a lumbar interbody cage equipped with a SMF in a caprine model. METHODS: Six skeletally mature female Boer goats underwent a lateral approach for placement of an interbody graft at lumbar (L) 1-2 and 3-4. The goats were divided into 2 groups of 3 animals. The interbody graft contained a neodymium iron boron magnet in the experimental group and a nonmagnetic titanium sham in the control group. Both groups contained a synthetic bone graft. Blinded radiographic and histologic evaluation was performed at predetermined timepoints to assess degree of bony fusion and osseointegration. RESULTS: All 6 goats underwent successful placement of lumbar interbody grafts. At the 1-month postoperative computed tomography, 1 goat in the experimental group and 1 goat in the control group were noted to have dislodged their intervertebral cage. Qualitative radiographic and histologic evaluation identified enhanced bone formation, bone density, and osteointegration of the graft in the experimental group. CONCLUSIONS: A spinal interbody cage containing a neodymium iron boron magnet for the production of a local SMF is feasible. Preliminary data suggests enhanced bone formation, bone density, and osseointegration of the graft.

Social distancing merely stabilized COVID-19 in the United States.

Social distancing measures have been imposed across the United States in order to stem the spread of COVID-19. We quantify the reduction in the doubling rate, by state, that is associated with this intervention. Using the earlier of K-12 school closures and restaurant closures, by state, to define the start of the intervention, and considering daily confirmed cases through April 23, 2020, we find that social distancing is associated with a statistically-significant (p < 0.01) reduction in the doubling rate for all states except for Nebraska, North Dakota, and South Dakota, when controlling for false discovery, with the doubling rate averaged across the states falling from 0.302 (0.285, 0.320) days-1 to 0.010 (-0.007, 0.028) days-1. However, we do not find that social distancing has made the spread subcritical. Instead, social distancing has merely stabilized the spread of the disease. We provide an illustration of our findings for each state, including estimates of the effective reproduction number, R, both with and without social distancing. We also discuss the policy implications of our findings.

Single Solitary Fibrous Tumor Brain Metastasis in a Patient with Simultaneous Adenocarcinoma of the Lung: Case Report and Review of the Literature.

We present a unique case of a patient simultaneously diagnosed with solitary fibrous tumor (SFT) and unrelated adenocarcinoma of the lung, both proven with separate pathology. It was subsequently found that the SFT had metastasized to the brain by additional pathology, and not the predicted adenocarcinoma. SFTs are a rare mesenchymal neoplasm that accounts for less than 2% of all reported soft tissue tumors. SFTs most commonly arise in the thoracic cavity, but are frequently found in various locations throughout the body, and rarely metastasize to the brain. This case highlights that rare neoplasms, such as SFT, should not be ruled out as a potential cause of metastasis. Due to the rarity of this clinical situation, we also provide a review and discussion of previously reported SFT cases and the use of postoperative radiation therapy. The optimal treatment for individual patients remains unclear in this unique situation. Surgical resection followed by adjuvant Gamma Knife radiation therapy to the surgical bed appears to be a safe option for local treatment of SFT in select patients. Further studies are needed of this rare clinical situation in order to better understand and optimize future treatments for patients with SFT and metastasis to the brain.

Overall and cause-specific survival for mucoepidermoid carcinoma of the major salivary glands: Analysis of 2210 patients.

BACKGROUND: Mucoepidermoid carcinoma (MEC) is a rare malignancy of the head and neck; however, it accounts for a majority of the tumors of the salivary glands. This study used a national population-based registry to describe the pre-treatment and treatment-related prognostic factors that influence survival in patients with MEC of the major salivary glands. To our knowledge, this is the largest population-based study examining predictors of both overall and cause-specific survival of MEC of the major salivary glands. AIM: To identify prognostic factors influencing overall survival (OS) and cause-specific survival (CSS) of patients with MEC of the major salivary glands. METHODS: We used the Surveillance, Epidemiology and End-Results Database of the National Cancer Institute to investigate a variety of factors that could influence survival of patients diagnosed with mucoepidermoid carcinoma of the major salivary glands. A total of 2210 patients diagnosed with MEC of the major salivary glands during the years of 1975-2016 were studied. The primary endpoints were OS and CSS. Cox regression analysis was used to perform univariate and multivariate analyses of clinical variables such as age at diagnosis, diagnosis year, sex, race, tumor size, stage, grade, treatment with or without surgical excision, and adjuvant radiotherapy treatment. RESULTS: A total of 2210 patients diagnosed with MEC of the major salivary glands met inclusion criteria. In this study, 95% of patients underwent surgical excision and 41% received adjuvant radiation therapy. Median OS time for Grade I, II, and III/IV was 401 mo (± 48.25, 95%CI), 340 mo (± 33.68, 95%CI) and 55 mo (± 11.05, 95%CI), respectively. Univariate analysis revealed that lack of surgical excision was associated with decreased OS [hazard ratio (HR) 4.26, P < 0.0001] and that patients with localized disease had improved OS compared to both regional and distant disease (HR 3.07 and 6.96, respectively, P < 0.0001). Additionally, univariate analysis demonstrated that male sex, age over 50 at diagnosis, Grade III tumors, and increasing tumor size were associated with worsened OS (P < 0.0006). Univariate analysis of CSS similarly revealed that lack of surgical excision and Grade III carcinoma conferred decreased CSS (HR 4.37 and 5.44, respectively, P < 0.0001). Multivariate analysis confirmed that increasing age, in 10-year age bands, advanced tumor stage, increasing tumor size, Grade III carcinoma, male sex, and lack of surgical excision were associated with a statistically significant decrease in OS and CSS (P < 0.04). Of note, multivariate analysis revealed that the use of adjuvant radiation therapy was not associated with improved OS or CSS. CONCLUSION: Multivariate analysis demonstrated increasing age, advanced tumor stage, increasing tumor size, Grade III carcinoma, male sex, and lack of surgical excision were associated with decreased OS and CSS (P < 0.04).

Molecular point-of-care testing for influenza A/B and respiratory syncytial virus: comparison of workflow parameters for the ID Now and cobas Liat systems.

AIMS: Point-of-care (POC) tests for influenza and respiratory syncytial virus (RSV) offer the potential to improve patient management and antimicrobial stewardship. Studies have focused on performance; however, no workflow assessments have been published comparing POC molecular tests. This study compared the Liat and ID Now systems workflow, to assist end-users in selecting an influenza and/or RSV POC test. METHODS: Staffing, walk-away and turnaround time (TAT) of the Liat and ID Now systems were determined using 40 nasopharyngeal samples, positive for influenza or RSV. The ID Now system requires separate tests for influenza and RSV, so parallel (two instruments) and sequential (one instrument) workflows were evaluated. RESULTS: The ID Now ranged 4.1-6.2 min for staffing, 1.9-10.9 min for walk-away and 6.4-15.8 min for TAT per result. The Liat ranged 1.1-1.8 min for staffing, 20.0-20.5 min for walk-away and 21.3-22.0 min for TAT. Mean walk-away time comprised 38.0% (influenza positive) and 68.1% (influenza negative) of TAT for ID Now and 93.7% (influenza/RSV) for Liat. The ID Now parallel workflow resulted in medians of 5.9 min for staffing, 9.7 min for walk-away and 15.6 min for TAT. Assuming prevalence of 20% influenza and 20% RSV, the ID Now sequential workflow resulted in medians of 9.4 min for staffing, 17.4 min for walk-away, and 27.1 min for TAT. CONCLUSIONS: The ID Now and Liat systems offer different workflow characteristics. Key considerations for implementation include value of both influenza and RSV results, clinical setting, staffing capacity, and instrument(s) placement.

Ultrasensitive Detection of Clostridioides difficile Toxins in Stool by Use of Single-Molecule Counting Technology: Comparison with Detection of Free Toxin by Cell Culture Cytotoxicity Neutralization Assay.

Laboratory tests for Clostridioides difficile infection (CDI) rely on the detection of free toxin or molecular detection of toxin genes. The Singulex Clarity C. diff toxins A/B assay is a rapid, automated, and ultrasensitive assay that detects C. difficile toxins A and B in stool. We compared CDI assays across two prospective multicenter studies to set a cutoff for the Clarity assay and to independently validate the performance compared with that of a cell culture cytotoxicity neutralization assay (CCCNA). The cutoff was set by two sites testing fresh samples from 897 subjects with suspected CDI and then validated at four sites testing fresh samples from 1,005 subjects with suspected CDI. CCCNA testing was performed at a centralized laboratory. Samples with discrepant results between the Clarity assay and CCCNA were retested with CCCNA when the Clarity result agreed with that of at least one comparator method; toxin enzyme immunoassays (EIA), glutamate dehydrogenase (GDH) detection, and PCR were performed on all samples. The cutoff for the Clarity assay was set at 12.0 pg/ml. Compared to results with CCCNA, the Clarity assay initially had 85.2% positive agreement and 92.4% negative agreement. However, when samples with discrepant results between the Clarity assay and CCCNA in the validation study were retested by CCCNA, 13/17 (76.5%) Clarity-negative but CCCNA-positive samples (Clarity+/CCCNA-) became CCCNA-, and 5/26 (19.2%) Clarity+/CCCNA- samples became CCCNA+, resulting in a 96.3% positive agreement and 93.0% negative agreement between Clarity and CCCNA results. The toxin EIA had 59.8% positive agreement with CCCNA. The Clarity assay was the most sensitive free-toxin immunoassay, capable of providing CDI diagnosis in a single-step solution. A different CCCNA result was reported for 42% of retested samples, increasing the positive agreement between Clarity and CCCNA from 85.2% to 96.3% and indicating the challenges of comparing free-toxin results to CCCNA results as a reference standard.

Laboratory comparison between cell cytotoxicity neutralization assay and ultrasensitive single molecule counting technology for detection of Clostridioides difficile toxins A and B, PCR, enzyme immunoassays, and multistep algorithms.

Diagnostic tests for Clostridioides difficile infection (CDI) lack either specificity (nucleic acid amplification tests) or sensitivity (enzyme immunoassays; EIAs). The performance of the Singulex Clarity® C. diff toxins A/B assay was compared to cell cytotoxicity neutralization assay. Testing was also performed using an EIA for glutamate dehydrogenase (GDH) and C. difficile toxins A and B (C. Diff Quik Chek Complete®), polymerase chain reaction (PCR) (BD MAX™ Cdiff Assay), and 2 multistep algorithms: algorithm 1 (discordant GDH/toxin results arbitrated by PCR) and algorithm 2 (PCR-positive samples tested with toxin EIA). The Clarity assay and PCR both had 97% sensitivity, while specificity was 100% for Clarity and 79% for PCR. Algorithm 1 yielded 41% discordant results, and both toxin EIA and algorithm 2 had 58% sensitivity. Median toxin concentrations, as measured by the Clarity C. difficile toxin assay, were 3590, 11.5, 0.4, and 0 pg/mL for GDH+/toxin+, GDH+/toxin-/PCR+, GDH+/toxin-/PCR-, and GDH-/toxin- samples, respectively (P < 0.001). The Clarity assay may offer a single-test solution for CDI.

Concordance of PD-L1 Expression Detection in Non-Small Cell Lung Cancer (NSCLC) Tissue Biopsy Specimens Between OncoTect iO Lung Assay and Immunohistochemistry (IHC).

OBJECTIVES: We report on the validity of a fully quantitative technology to determine tumor cells' PD-L1 expression compared with a standard immunohistochemical (IHC) assay in non-small cell lung cancer. METHODS: Nineteen fresh tissue specimens were processed into single-cell suspensions using the IncellPREP Kit. Cells were treated with the OncoTect iO Lung Assay, which quantitatively assessed tumor-infiltrating lymphocytes (TILs), DNA content, and PD-L1 expression on diploid and aneuploid tumor populations. RESULTS: Comparison of the OncoTect iO Lung Assay with IHC revealed a concordance of 95% overall (negative percent agreement, 97%; positive percent agreement, 89%). PD-L1 expression varied depending on the DNA content. The number of TILs and antigen-presenting cells (APCs) was significantly decreased in tumor compared with normal lung tissue. CONCLUSIONS: The nonsubjective OncoTect iO Lung Assay has been shown to be at least as accurate and sensitive as IHC for the detection of PD-L1 expression while providing additional information to guide treatment.

Primary Epithelioid Sarcoma of Orbit: A Case Report and Review of the Literature.

Epithelioid sarcoma is a rare high-grade malignancy identified by Enzinger in 1970. It accounts for 1% of all reported soft tissue sarcomas and presents most commonly in distal upper extremities in young adults with a male predominance. At this time, there are only 5 previously reported cases of primary epithelioid sarcoma of the orbit. We present a primary orbital epithelioid sarcoma case of a patient who underwent orbital exenteration followed by external beam radiation treatment. Because the literature is limited, this is to our knowledge the largest descriptive analysis of cases of orbital epithelioid sarcoma. We also provide a detailed review of all the previously reported primary orbital epithelioid sarcoma cases, as well as a discussion on the use of postoperative radiation therapy for patients with epithelioid sarcoma. Surgical resection followed by adjuvant radiation therapy appears to be a safe option for local treatment of this rare malignancy, but further future studies are needed of this rare clinical situation in order to better understand and optimize treatment for patients with orbital epithelioid sarcoma.

Microsite and elevation zone effects on seed pilferage, germination, and seedling survival during early whitebark pine recruitment.

Tree recruitment is a spatially structured process that may undergo change over time because of variation in postdispersal processes. We examined seed pilferage, seed germination, and seedling survival in whitebark pine to determine whether 1) microsite type alters the initial spatial pattern of seed caches, 2) higher abiotic stress (i.e. higher elevations) exacerbates spatial distribution changes, and 3) these postdispersal processes are spatially clustered. At two study areas, we created a seed distribution pattern by burying seed caches in microsite types frequently used by whitebark pine's avian seed disperser (Clark's nutcracker) in upper subalpine forest and at treeline, the latter characterized by high abiotic environmental stress. We monitored caches for two years for pilferage, germination, and seedling survival. Odds of pilferage (both study areas), germination (northern study area), and survival (southern study area) were higher at treeline relative to subalpine forest. At the southern study area, we found higher odds of 1) pilferage near rocks and trees relative to no object in subalpine forest, 2) germination near rocks relative to trees within both elevation zones, and 3) seedling survival near rocks and trees relative to no object at treeline. No microsite effects were detected at the northern study area. Findings indicated that the microsite distribution of seed caches changes with seed/seedling stage. Higher odds of seedling survival near rocks and trees were observed at treeline, suggesting abiotic stress may limit safe site availability, thereby shifting the spatial distribution toward protective microsites. Higher odds of pilferage at treeline, however, suggest rodents may limit treeline recruitment. Further, odds of pilferage were higher near rocks and trees relative to no object in subalpine forest but did not differ among microsites at treeline, suggesting pilferage can modulate the spatial structure of regeneration, a finding supported by limited clustering of postdispersal processes.

Progressive hypoventilation due to mixed CD8+ and CD4+ lymphocytic polymyositis following tremelimumab - durvalumab treatment.

BACKGROUND: The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. CASE PRESENTATION: We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. CONCLUSIONS: This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.

Pretreatment clinical prognostic factors for brain metastases from breast cancer treated with Gamma Knife radiosurgery.

BACKGROUND: Brain metastases significantly affect morbidity and mortality rates for patients with metastatic breast cancer. Treatment for brain metastases lengthens survival, and options such as stereotactic radiosurgery (SRS) can increase survival to 12 months or longer. This study retrospectively analyzes the prognostic factors for overall survival (OS) for patients with one or multiple brain metastases from breast cancer treated with SRS. METHODS: Between December 2001 and May 2015, 111 patients with brain metastases from breast cancer were grouped by potential prognostic factors including age at diagnosis, Karnofsky Performance Status (KPS) score, number of brain metastases, and whether or not they received adjuvant treatments such as whole brain radiotherapy (WBRT) or surgical resection. Survival rates were determined for all groups, and hazard ratios were calculated using univariate and multivariate analyses to compare differences in OS. RESULTS: Median OS was 16.8 ± 4.22 months. Univariate analysis of patients with a KPS ≤60 and multivariate analysis of KPS 70-80 showed significantly shorter survival than those with KPS 90-100 (5.9 ± 1.22 months, 21.3 ± 11.69 months, and 22.00 ± 12.56 months, P = 0.024 and < 0.001). Other results such as age ≥65 years and higher number of brain metastases trended toward shorter survival but were not statistically significant. No difference in survival was found for patients who had received WBRT in addition to SRS (P = 0.779). CONCLUSION: SRS has been shown to be safe and effective in treating brain metastases from breast cancer. We found our median survival to be 16.8 ± 4.22 months, an increase from other clinical reports. In addition, 38.4% of our population was alive at 2 years and 15.6% survived 5 years. Significant prognostic factors can help inform clinical treatment decisions. This study found that KPS was a significant prognostic indicator of OS in these patients.

Whitebark pine facilitation at treeline: potential interactions for disruption by an invasive pathogen.

In stressful environments, facilitation often aids plant establishment, but invasive plant pathogens may potentially disrupt these interactions. In many treeline communities in the northern Rocky Mountains of the U.S. and Canada, Pinus albicaulis, a stress-tolerant pine, initiates tree islands at higher frequencies than other conifers - that is, leads to leeward tree establishment more frequently. The facilitation provided by a solitary (isolated) P. albicaulis leading to tree island initiation may be important for different life-history stages for leeward conifers, but it is not known which life-history stages are influenced and protection provided. However, P. albicaulis mortality from the non-native pathogen Cronartium ribicola potentially disrupts these facilitative interactions, reducing tree island initiation. In two Rocky Mountain eastern slope study areas, we experimentally examined fundamental plant-plant interactions which might facilitate tree island formation: the protection offered by P. albicaulis to leeward seed and seedling life-history stages, and to leeward krummholz conifers. In the latter case, we simulated mortality from C. ribicola for windward P. albicaulis to determine whether loss of P. albicaulis from C. ribicola impacts leeward conifers. Relative to other common solitary conifers at treeline, solitary P. albicaulis had higher abundance. More seeds germinated in leeward rock microsites than in conifer or exposed microsites, but the odds of cotyledon seedling survival during the growing season were highest in P. albicaulis microsites. Planted seedling survival was low among all microsites examined. Simulating death of windward P. albicaulis by C. ribicola reduced shoot growth of leeward trees. Loss of P. albicaulis to exotic disease may limit facilitation interactions and conifer community development at treeline and potentially impede upward movement as climate warms.

Retrospective Study of Metastatic Melanoma and Renal Cell Carcinoma to the Brain with Multivariate Analysis of Prognostic Pre-Treatment Clinical Factors.

Patients with brain metastasis from renal cell carcinoma (RCC) or melanoma have historically had very poor prognoses of less than one year. Stereotactic radiosurgery (SRS) can be an effective treatment for patients with these tumors. This study analyzes the effect of pretreatment prognostic factors on overall survival (OS) for RCC and melanoma patients with metastasis to the brain treated with SRS. A total of 122 patients with brain metastases from either RCC or melanoma were grouped by age at brain metastasis diagnosis, whether they received whole brain radiation therapy (WBRT) in addition to SRS, or they underwent surgical resection, Karnofsky Performance Score (KPS), number of brain metastases, and primary tumor. Median survival times for melanoma patients and RCC patients were 8.20 ± 3.06 and 12.70 ± 2.63 months, respectively. Patients with >5 metastases had a significantly shorter median survival time (6.60 ± 2.45 months) than the reference group (1 metastasis, 10.70 ± 13.40 months, p = 0.024). Patients with KPS ≤ 60 experienced significantly shorter survival than the reference group (KPS = 90-100), with median survival times of 5.80 ± 2.46 months (p < 0.001) and 45.20 ± 43.52 months, respectively. We found a median overall survival time of 12.7 and 8.2 months for RCC and melanoma, respectively. Our study determined that a higher number of brain metastases (>5) and lower KPS were statistically significant predictors of a lower OS prognosis.