Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number ...alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplification (identified by whole-genome sequencing) and changes in gene expression as identified by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific SCNAs leads to significant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. SIGNIFICANCE: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specific dependencies could be identified within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for "genome-matched" therapies, demonstrating the utility of a targeted genome-informed approach.
.
Abstract Purpose To evaluate the effectiveness of home temperature monitoring to reduce the incidence of foot ulcers in high-risk patients with diabetes. Methods In this physician-blinded, 18-month ...randomized controlled trial, 225 subjects with diabetes at high risk for ulceration were assigned to standard therapy (Standard Therapy Group) or dermal thermometry (Dermal Thermometry Group) groups. Both groups received therapeutic footwear, diabetic foot education, regular foot care, and performed a structured foot inspection daily. Dermal Thermometry Group subjects used an infrared skin thermometer to measure temperatures on 6 foot sites twice daily. Temperature differences >4°F between left and right corresponding sites triggered patients to contact the study nurse and reduce activity until temperatures normalized. Results A total of 8.4% (n = 19) subjects ulcerated over the study period. Subjects were one third as likely to ulcerate in the Dermal Thermometry Group compared with the Standard Therapy Group (12.2% vs 4.7%, odds ratio 3.0, 95% confidence interval, 1.0 to 8.5, P = .038). Proportional hazards regression analysis suggested that thermometry intervention was associated with a significantly longer time to ulceration ( P = .04), adjusted for elevated foot ulcer classification (International Working Group Risk Factor 3), age, and minority status. Patients that ulcerated had a temperature difference that was 4.8 times greater at the site of ulceration in the week before ulceration than did a random 7 consecutive-day sample of 50 other subjects that did not ulcerate (3.50 ± 1.0 vs 0.74 ± 0.05, P = .001). Conclusions High temperature gradients between feet may predict the onset of neuropathic ulceration and self-monitoring may reduce the risk of ulceration.
OBJECTIVE:--To prospectively determine risk factors for foot infection in a cohort of people with diabetes. RESEARCH DESIGN AND METHODS--We evaluated then followed 1,666 consecutive diabetic patients ...enrolled in a managed care-based outpatient clinic in a 2-year longitudinal outcomes study. At enrollment, patients underwent a standardized general medical examination and detailed foot assessment and were educated about proper foot care. They were then rescreened at scheduled intervals and also seen promptly if they developed any foot problem. RESULTS:--During the evaluation period, 151 (9.1%) patients developed 199 foot infections, all but one involving a wound or penetrating injury. Most patients had infections involving only the soft tissue, but 19.9% had bone culture-proven osteomyelitis. For those who developed a foot infection, compared with those who did not, the risk of hospitalization was 55.7 times greater (95% CI 30.3-102.2; P < 0.001) and the risk of amputation was 154.5 times greater (58.5-468.5; P < 0.001). Foot wounds preceded all but one infection. Significant (P < 0.05) independent risk factors for foot infection from a multivariate analysis included wounds that penetrated to bone (odds ratio 6.7), wounds with a duration >30 days (4.7), recurrent wounds (2.4), wounds with a traumatic etiology (2.4), and presence of peripheral vascular disease (1.9). CONCLUSIONS:--Foot infections occur relatively frequently in individuals with diabetes, almost always follow trauma, and dramatically increase the risk of hospitalization and amputation. Efforts to prevent infections should be targeted at people with traumatic foot wounds, especially those that are chronic, deep, recurrent, or associated with peripheral vascular disease.
Poor balance control and increased fall risk have been reported in people with diabetic peripheral neuropathy (DPN). Traditional body sway measures are unable to describe underlying postural control ...mechanism. In the current study, we used stabilogram diffusion analysis to examine the mechanism under which balance is altered in DPN patients under local-control (postural muscle control) and central-control (postural control using sensory cueing). DPN patients and healthy age-matched adults over 55 years performed two 15-second Romberg balance trials. Center of gravity sway was measured using a motion tracker system based on wearable inertial sensors, and used to derive body sway and local/central control balance parameters. Eighteen DPN patients (age = 65.4±7.6 years; BMI = 29.3±5.3 kg/m2) and 18 age-matched healthy controls (age = 69.8±2.9; BMI = 27.0±4.1 kg/m2) with no major mobility disorder were recruited. The rate of sway within local-control was significantly higher in the DPN group by 49% (healthy local-controlslope = 1.23±1.06×10-2 cm2/sec, P<0.01), which suggests a compromised local-control balance behavior in DPN patients. Unlike local-control, the rate of sway within central-control was 60% smaller in the DPN group (healthy central-controlslope-Log = 0.39±0.23, P<0.02), which suggests an adaptation mechanism to reduce the overall body sway in DPN patients. Interestingly, significant negative correlations were observed between central-control rate of sway with neuropathy severity (rPearson = 0.65-085, P<0.05) and the history of diabetes (rPearson = 0.58-071, P<0.05). Results suggest that in the lack of sensory feedback cueing, DPN participants were highly unstable compared to controls. However, as soon as they perceived the magnitude of sway using sensory feedback, they chose a high rigid postural control strategy, probably due to high concerns for fall, which may increase the energy cost during extended period of standing; the adaptation mechanism using sensory feedback depends on the level of neuropathy and the history of diabetes.
A major component of cells in tenosynovial giant cell tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal ...translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here, we use single-cell RNA sequencing (scRNA-seq) to investigate cellular interactions in TGCT.
A total of 18,788 single cells from three TGCT and two giant cell tumor of bone (GCTB) samples underwent scRNA-seq. The three TGCTs were additionally analyzed using long-read RNA sequencing. Immunofluorescence and IHC for a range of markers were used to validate and extend the scRNA-seq findings.
Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to nonneoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping MAB features between the giant cells in TGCT and GCTB.
The neoplastic cells in TGCT are highly similar to nonneoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the platelet-derived growth factor receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.
Background:
As baby boomers age and their expected life span increases, there is an unprecedented need to better manage the health care of elders with diabetes who are at increased risk of falling ...due to diabetes complications, frailty, or other conditions. New clinical and research tools are needed to measure functioning accurately and to identify early indicators of risk of falling, thus translating into more effective and earlier intervention.
Methods:
The objective of this pilot study was to validate a significant change in hardware and algorithm to track activity patterns using a single triaxial accelerometer through validation of timed up and go and standard measures of balance and gait. We recruited a convenience sample of eight older adults with diabetes and peripheral neuropathy (age, 77 ±7 years old) who were asked to wear the sensor for imposed daytime activity performed in our gait laboratory. Subjects were stratified into risk of falling categories based on Tinetti scores. We examined the accuracy of the suggested technology for discrimination of high- versus low-risk groups.
Results:
The system was accurate in identifying the number of steps taken and walking duration (random error <5%). The proposed algorithm allowed accurate identification and stratification of those at highest risk of falling, suggesting that subjects with high risk of falling required a substantially longer duration for rising from a chair when compared with those with low risk of falling (p < .05).
Conclusions:
Our new single triaxial accelerometer algorithm successfully tracked postural transition, allowing accurate identification of those at high risk of falling, and could be useful for intermittent or even continuous monitoring of older adults with diabetes. Other potential applications could include activity monitoring of the diabetes population with lower extremity disease and of patients undergoing surgical procedures or as an objective measure during rehabilitation.
The initial management of desmoid tumors (DTs) is shifting from surgery towards active surveillance, with systemic and locally ablative treatments reserved for enlarging and/or symptomatic disease. ...However, it remains unclear which patients would benefit most from an initial conservative rather than interventional approach. To answer this question, we retrospectively analyzed adult and pediatric patients with DTs treated at a tertiary academic cancer center between 1992 and 2022. Outcomes measured were progression-free survival (PFS) and time to next treatment (TTNT) after first-line therapy. A total of 262 treatment-naïve patients were eligible for analysis with a median age of 36.5 years (range, 0−87 years). The 5-year PFS and the median TTNT (months) after first-line treatment were, respectively: 50.6% and 69.1 mo for surgery; 64.9% and 149.5 mo for surgery plus adjuvant radiotherapy; 57.1% and 44.7 mo for surgery plus adjuvant systemic therapy; 24.9% and 4.4 mo for chemotherapy; 26.7% and 5.3 mo for hormonal therapy; 41.3% and 29.6 mo for tyrosine kinase inhibitors (TKIs); 44.4% and 8.9 mo for cryoablation and high intensity focused ultrasound; and 43.1% and 32.7 mo for active surveillance. Age ≤ 40 years (p < 0.001), DTs involving the extremities (p < 0.001), a maximum tumor diameter > 60 mm (p = 0.04), and hormonal therapy (p = 0.03) predicted a higher risk of progression. Overall, our results suggest that active surveillance should be considered initially for patients with smaller asymptomatic DTs, while upfront TKIs, local ablation, and surgery achieve similar outcomes in those with more aggressive disease.
Background
Chondrosarcomas of bone traditionally have been treated by wide or radical excision, procedures that may result in considerable lifelong disability. Grade 1 chondrosarcomas have little or ...no metastatic potential and are often difficult to distinguish from painful benign enchondromas. Curettage with adjuvant cryosurgery has been proposed as an alternative therapy for Grade 1 chondrosarcomas given the generally better function after the procedure. However, because it is an intralesional procedure, curettage and cryosurgery may be associated with higher rates of recurrence.
Questions/purposes
We asked whether Grade 1 chondrosarcomas and enchondromas of uncertain malignant potential treated by curettage and cryosurgery are associated with low recurrence rates and high functional scores.
Patients and Methods
We retrospectively reviewed the records of 46 patients with Grade 1 chondrosarcomas and enchondromas of uncertain malignant potential treated by curettage and cryosurgery. Forty-one patients had tumors of the long bones. Patients were followed a minimum of 18 months (average, 47.2. months; range, 18–134 months) for evidence of recurrence and for assessment of Musculoskeletal Tumor Society (MSTS) functional score.
Results
Two of the 46 patients had recurrences in the original tumor site (4.3% recurrence rate), which subsequently were removed by wide excision, and both patients were confirmed to be disease-free 36 and 30 months, respectively, after the second surgery. The mean MSTS score was 27.2 of 30 points (median, 29 points).
Conclusions
Our observations show curettage with cryosurgery is associated with low recurrence of Grade 1 chondrosarcoma and high functional scores. Curettage with cryosurgery is a reasonable alternative to wide or radical excision as the treatment for Grade 1 chondrosarcomas, and allows for more radical surgery in the event of local recurrence.
Level of Evidence
Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic ...landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes.
Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model.
PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden.
The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.
Research on foot problems and frailty is sparse and could advance using wearable sensor-based measures of gait, balance, and physical activity (PA). This study examined the effect of foot problems on ...the likelihood of falls, frailty syndrome, motor performance, and PA in community-dwelling older adults.
Arizona Frailty Cohort Study participants (community-dwelling adults aged ≥65 years without baseline cognitive deficit, severe movement disorders, or recent stroke) underwent Fried frailty and foot assessment. Gait, balance (bipedal eyes open and eyes closed), and spontaneous PA over 48 hours were measured using validated wearable sensor technologies.
Of 117 participants, 41 (35%) were nonfrail, 56 (48%) prefrail, and 20 (17%) frail. Prevalence of foot problems (pain, peripheral neuropathy, or deformity) increased significantly as frailty category worsened (any problem: 63% in nonfrail, 80% in prefrail odds ratio (OR) = 2.0, and 95% in frail OR = 8.3; P = .03 for trend) due to associations between foot problems and both weakness and exhaustion. Foot problems were associated with fear of falling but not with fall history or incident falls over 6 months. Foot pain and peripheral neuropathy were associated with lower gait speed and stride length; increased double support time; increased mediolateral sway of center of mass during walking, age adjusted; decreased eyes open sway of center of mass and ankle during quiet standing, age adjusted; and lower percentage walking, percentage standing, and total steps per day.
Foot problems were associated with frailty level and decreased motor performance and PA. Wearable technology is a practical way to screen for deterioration in gait, balance, and PA that may be associated with foot problems. Routine assessment and management of foot problems could promote earlier intervention to retain motor performance and manage fear of falling in older adults, which may ultimately improve healthy aging and reduce risk of frailty.
PDF
