Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted ...whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.
Abstract
Given its high population density and degree of urbanization, the eastern United States (US) is a region vulnerable to the impacts from hailstorms. Small changes in hail activity may ...indicate large impacts on the potential hail risks faced by the region. While contrasting hailstorm-favorable environmental changes between the northeastern and southeastern US have been documented, the meridional shift of hail activity in the eastern US has not been directly revealed based on observed hailstorm records. In this letter, using the official hailstorm database, we find a significant northward migration of hail activity (+0.33° N decade
−1
) in the eastern US since 2000, which is mainly contributed by the increasing proportion of large hailstorm events (hail size 0.75–2.0 inch) hitting the northeast in July and August (+0.93° N decade
−1
). The spatially inhomogeneous climatic mean state changes over the past two decades contribute a leading role: the intensified Bermuda High and the eastward shift of upper-level jet stream over the central US tended to moisten (dry) the atmosphere over the northeastern (southeastern) US by enhancing the low-level poleward moisture transport. This not only provides more moisture for hailstorm formation in the northeast but also destabilizes (stabilizes) the atmosphere in the northeast (southeast) under an overall increase in dry instability over the eastern US. These factors together lead to a northward shift of large hailstorms toward the northeastern US, where hailstorms were relatively seldom reported. Incorporating this shift in knowledge may improve contingency and risk management strategies of both the public and private sectors in the future.
Although the North Atlantic (NA) hurricane season has been reported to start increasingly early, historical long-term changes in NA spring tropical cyclone (TC) activity have not been examined in ...previous studies. We find that spring TCs have become more frequent and intense, and they have more closely approached the US coastline over the past four decades, thus increasing the probability of landfall. A long-term increase in the NA sea surface temperature (SST) and northward incursion of warm water may be responsible for the increasing number, intensity, and northward shift of spring TCs. In addition, the interdecadal winter NA SST tripole mode may induce a North Atlantic Oscillation (NAO)-like atmospheric response in the following spring, which controls spring TC tracks via modulating the strength and position of the NA subtropical high (or the Bermuda high). The superposition of the interdecadal positive winter SST tripole on the NA warming trend has contributed to the anomalous enhancement and northward shift of spring TC activity, increasing the spring TC risks in the US in the past six years.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Objectives
SATB2 is a transcriptional regulator that plays an important role in osteoblastic differentiation. We examined the prevalence and potential significance of SATB2 expression in ...undifferentiated pleomorphic sarcoma (UPS) of bone.
Methods
We examined 38 cases of bone UPS without osteoid. The male-to-female ratio was 1:1.4, with a median age of 48 years (range, 23-83 years). Tumors occurred primarily in the femur (n = 8) and ilium (n = 8), with a median tumor size of 9.5 cm (range, 1.8-27.0 cm). The median follow-up was 24.7 months (range, 2-82 months): 11 patients developed local recurrences, and 18 patients had metastases, mainly to lung and bone.
Results
SATB2 expression (nuclear labeling ≥5%) was seen in 21 of 38 (55%) cases: 5 with focal (nuclear labeling 5%), 11 with patchy (nuclear labeling 5%-50%), and 5 with diffuse (nuclear labeling ≥50%) staining. Among this group, diffuse SATB2 expression demonstrated superior metastasis-free survival (P = .036) and event-free survival (P = .024). For comparison, 100 soft tissue UPS were stained; the majority were negative (75/100 75%).
Conclusions
UPS of bone demonstrated more frequent SATB2 expression compared with its soft tissue counterpart. In this series, diffuse SATB2 expression in UPS of bone was associated with better outcomes. Additional studies are still needed to determine its significance.
Introduction
Biologic disease–modifying anti-rheumatic drugs (bDMARDs) interfere with the immune system and could theoretically increase risk of malignancies. However, recent evidence has not ...substantiated such concerns and physicians are less reluctant in treating patients with underlying cancer with such bDMARDs. We aimed to understand the current utilization patterns of bDMARDs for the treatment of rheumatoid arthritis (RA) in cancer patients.
Methods
We performed a retrospective cohort study of patients with prevalent RA and cancer initially seen at MD Anderson Cancer Center between 2002 and 2014. A cohort of cancer patients was identified from the tumor registry, and patients with RA were identified through ICD-9 codes, followed by review of electronic medical records. We included patients 18 years and older, with a cancer diagnosis, and a diagnosis of RA by a rheumatologist. Patients were followed until 2016.
Results
We identified 431 patients with RA and cancer that met our inclusion criteria. Overall, 111 (26%) received bDMARDs after their cancer diagnosis; of these, 60 (54%) had received bDMARDs prior to their cancer diagnosis and continued to receive this therapy following their diagnosis. Thirteen (22%) switched to a different bDMARD, and the rest continued to receive the same agent after their cancer diagnosis. Of all patients on a bDMARD, 91 (82%) received tumor necrosis factor inhibitors (TNFi).
Conclusions
The treatment landscape of patients with a history of cancer and RA is changing. Future studies evaluating the safety of bDMARDs in patients with a recent history of cancer or with active cancer are needed.
Prior abstract publication
Part of the data of this project was presented as a poster at the 2016 American College of Rheumatology annual meeting.
Zamora NV, Siddhanamatha H, Barbo A, Tayar J, Lin H, Suarez-Almazor M. Utilization of Biologic Therapy in Patients with Rheumatoid Arthritis and Cancer abstract.
Arthritis Rheumatol.
2016; 68 (suppl 10).
https://acrabstracts.org/abstract/utilization-of-biologic-therapy-in-patients-with-rheumatoid-arthritis-and-cancer/
. Accessed September 30, 2019.
Key Points
• One in four patients with RA and concomitant cancer received bDMARDs, including TNFi, after their cancer diagnosis, at our institution.
• Half of the patients with RA and cancer who received bDMARDs had initiated therapy prior to the cancer diagnosis, continuing thereafter.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This case report presents a rare occurrence of a single lung abscess caused by Panton-Valentine leukocidin (PVL)-producing methicillin-resistant Staphylococcus aureus (MRSA) in a 38-year-old ...immunocompetent man. The patient, of Southeast Asian origin, presented with symptoms of fever, chest pain, cough, and shortness of breath following a recent flu-like illness. Imaging indicated a cavitary lung lesion in the left lower lobe, suggestive of a lung abscess. Initial antibiotic treatment failed, and drainage of the abscess confirmed MRSA with the PVL gene, indicating a community-acquired MRSA infection. The patient received intravenous vancomycin followed by oral linezolid, leading to the resolution of the abscess. Contact tracing and decolonization measures were implemented. This case highlights the importance of considering PVL-producing S. aureus as a potential pathogen in severe necrotizing pneumonia or sepsis and underscores the need for prompt diagnosis, appropriate antibiotic therapy, and infection control measures in managing such infections.
Immunotherapy is an effective and generally well-tolerated treatment strategy for older adult patients (aged greater than or equal to70 years) with advanced non-small cell lung cancer (NSCLC). ...Unfortunately, most patients who receive immunotherapy eventually exhibit disease progression during treatment. The present study reports on a subset of older adult patients with advanced NSCLC who could effectively continue immunotherapy beyond rad iog raphic disease progression due to perceived clinical benefit. Local consolidative radiotherapy may be used in select older adult patients to prolong the duration of immunotherapy they receive, with a particular consideration of their preexisting co-morbidities, performance status and tolerance of potential toxicities associated with combined modality therapy. However, prospective research is needed to determine which patients benefit most from the addition of local consolidative radiotherapy, including whether type of disease progression (i.e., sites of progression, pattern of progression) and/or extent of consolidation offered (i.e., complete or incomplete) impact clinical outcomes. Further research is also warranted to determine which patients would most beneit from the continuation of immunotherapy beyond documented radiographic disease progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the ...rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma.
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•Upregulated PHGDH in osteosarcoma correlates with poor survival•Inhibiting PHGDH attenuates osteosarcoma proliferation without causing cell death•TCA cycle blockade and accumulation of metabolites results in mTORC1 activation•PHGDH inhibition combined with non-rapalog mTORC1 inhibition is synergistic
Rathore et al. identify 3-phosphoglycerate dehydrogenase (PHGDH) overexpression as a marker of poor prognosis in osteosarcoma. PHGDH inhibition causes decreased proliferation, inhibited TCA cycle, and accumulation of metabolites that drive the activation of mTORC1. Non-rapalog mTORC1 inhibition combined with PHGDH inhibition demonstrates a possible synergistic dual metabolic therapy for osteosarcoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
Metastatic phyllodes tumors of the breast (MPT) are rare breast neoplasms, limiting development of standardized treatment approaches. We sought to characterize the largest group of MPT thus ...far reported, evaluating systemic therapy outcomes.
Methods
Adult patients diagnosed with MPT between 1993 and 2015 and followed at MD Anderson Cancer Center were selected for retrospective chart review. Systemic therapy was sorted into: adriamycin/ifosfamide (AI), other anthracycline regimens, other ifosfamide regimens, gemcitabine-based regimens, and other. Given one patient may have received more than one regimen, we assumed that the effects of each regimen were independent from previous therapy. Median overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method. Log-rank test was performed to evaluate the difference in OS between patient characteristics groups, and the differences in PFS between the five chemotherapy regimens.
Results
We identified 50 MPT patients, with 31 patients receiving 61 systemic regimens. Median OS was 10.7 months (95% CI: 8.67, 16.5). AI had a PFS of 9.10 months (95% CI: 5.03, 14.2), other ifosfamide regimens had a PFS of 5.10 months (95% CI: 0.67, 12.1), other anthracycline regimens had a PFS of 3.65 months (95% CI: 1.17, 7.90), gemcitabine-based regimens had a PFS of 2.80 months (95% CI: 1.83, 4.60), and other regimens had a PFS of 1.67 months (95% CI: 1.13, 7.77).
Conclusion
MPT patients are a unique population with limited characterization to date. Our study demonstrates activity of multiple sarcoma-directed chemotherapy regimens, with ifosfamide-containing regimens having the longest PFS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Melioidosis is a rare but often fatal tropical infection caused by gram‐negative bacteria Burkholderia pseudomallei. It most commonly manifests as pneumonia and rarely presents as pericarditis. ...Melioidosis can be difficult to diagnose because of its diverse clinical manifestation and close resemblance to bacteria of the genus Pseudomonas. We report a rare case of melioidosis presenting as pericarditis and pneumonia in a 61‐year‐old male patient with poorly controlled diabetes mellitus. He was initially misdiagnosed with Pseudomonas aeruginosa infection and later treated empirically as tuberculosis pericarditis for 2 months, before reaching the diagnosis of melioidosis.
A rare case and diagnostically challenging case of melioidosis presenting as pericarditis and pneumonia in a patient with poorly controlled diabetes mellitus.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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