Epidemiology of bone metastases.

BACKGROUND: This study evaluated the incidence of de novo bone metastasis across all primary cancer sites and their impact on survival by primary cancer site, age, race, and sex. QUESTIONS/PURPOSES: Our objectives were (I) characterize the epidemiology of de novo bone metastasis with respect to patient demographics, (II) characterize the incidence by primary site, age, and sex (2010-2015), and (III) compare survival of de novo metastatic cancer patients with and without bone metastasis. METHODS: This is a retrospective, population-based study using nationally representative data from the Surveillance, Epidemiology, and End Results program, 2010-2015. Incidence rates by year of diagnosis, annual percentage changes, Kaplan-Meier, univariate and multiple Cox regression models are included in the analysis. RESULTS: Of patients with cancer in the SEER database, 5.1% were diagnosed with metastasis to bone, equaling ~18.8 per 100,000 bone metastasis diagnoses in the US per year (2010-2015). For adults >25, lung cancer is the most common primary site (2015 rate: 8.7 per 100,000) with de novo bone metastases, then prostate and breast primaries (2015 rates: 3.19 and 2.38 per 100,000, respectively). For patients <20 years old, endocrine cancers and soft tissue sarcomas are the most common primaries. Incidence is increasing for prostate (Annual Percentage Change (APC) = 4.6%, P < 0.001) and stomach (APC = 5.0%, P = 0.001) cancers. The presence of de novo bone metastasis was associated with a limited reduction in overall survival (HR = 1.02, 95%, CI = [1.01-1.03], p < 0.001) when compared to patients with other non-bone metastases. CONCLUSION: The presence of bone metastasis versus metastasis to other sites has disease site-specific impact on survival. The incidence of de novo bone metastasis varies by age, sex, and primary disease site.

Resident Training and the Assessment of Orthopaedic Surgical Skills.

Medical knowledge and technical skills are foundations of surgical competency. The American Board of Orthopaedic Surgery (ABOS) and the Resident Review Committee for Orthopaedic Surgery recently mandated simulation training to improve surgical skills, listing 17 surgical skills modules to improve residents' technical skills. However, there is no established tool to measure the effectiveness of these modules. The Global Index for Technical Skills (GRITS) tool has been previously validated for evaluating general surgery residents. The aim of this study was to determine whether the GRITS tool is valid, practical, and reliable in evaluating the skills of orthopaedic residents in a simulation setting, whether the outcomes correlate to performance in the operating room, and to what extent these simulation modules are valued by residents. METHODS: Simulation performance was assessed longitudinally on 5 residents using the GRITS assessment through postgraduate years (PGY) 1 to 5 (n = 25 evaluations) in a simulated volar forearm approach using cadaveric specimens. An additional 20 PGY-1 residents were evaluated cross-sectionally in this same time frame. Written, open-ended feedback on the simulation experience was sought and analyzed via a thematic analysis. For correlative data, evaluations (n = 65 evaluations) of a variety of authentic surgical procedures were compiled on PGY-2 through PGY-5 orthopaedic residents and compared with the simulated experiences. RESULTS: GRITS scores were averaged for each group of residents, and validity and reliability were assessed using R-software. PGY-1 residents' mean GRITS evaluation score (expressed as a value from 1 to 5) was 3.4. Longitudinally, this mean score increased over the PGY years 2-5 to 4.4, 4.7, 4.9, and 4.8, respectively. Of the parameters measured by GRITS, the lowest average scores were "flow of operation" and "time and motion" across all levels, although these did improve over PGY years 2 to 5. Findings were consistent between simulation and "real-world" procedures. Open-ended responses evaluating the module were positive. CONCLUSIONS: Our study suggests that the GRITS tool shows promise as an effective and reliable method for assessing orthopaedic resident's technical skills based on an ABOS module system.

Novel fusion sarcomas including targetable NTRK and ALK.

BACKGROUND: Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up. METHODS: Fusion sarcomas (2020-2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS). RESULTS: Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases). CONCLUSIONS: Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.

Survival after palliative radiation therapy for cancer: The METSSS model.

BACKGROUND: We propose a predictive model that identifies patients at greatest risk of death after palliative radiotherapy, and subsequently, can help medical professionals choose treatments that better align with patient choice and prognosis. METHODS: The National Cancer Database was queried for recipients of palliative radiotherapy during first course of treatment. Cox regression models and adjusted hazard ratios with 95% confidence intervals were used to evaluate survival predictors. The mortality risk index was calculated using predictors from the estimated Cox regression model, with higher values indicating higher mortality risk. Based on tertile cutpoints, patients were divided into low, medium, and high risk groups. RESULTS: A total of 68,505 patients were included from 2010-2014, median age 65.7 years. Several risk factors were found to predict survival: (1) location of metastases (liver, bone, lung, and brain); (2) age; (3) tumor primary (prostate, breast, lung, other); (4) gender; (5) Charlson-Deyo comorbidity score; and (6) radiotherapy site. The median survival times were 11.66 months, 5.09 months, and 3.28 months in the low (n=22,621), medium (n=22,638), and high risk groups (n=22,611), respectively. A nomogram was created and validated to predict survival, available online, https://tinyurl.com/METSSSmodel. Harrel's C-index was 0.71 and receiver operator characteristic area under the curve was 0.76 at 4 years. CONCLUSION: We created a predictive nomogram for survival of patients receiving palliative radiotherapy during their first course of treatment (named METSSS), based on Metastases location, Elderly (age), Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy.

Vitamin D, smoking, EBV, and long-term cognitive performance in MS: 11-year follow-up of BENEFIT.

OBJECTIVE: To investigate whether vitamin D, smoking, and anti-Epstein-Barr virus (EBV) antibody concentrations predict long-term cognitive status and neuroaxonal injury in multiple sclerosis (MS). METHODS: This study was conducted among 278 patients with clinically isolated syndrome who participated in the clinical trial BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) and completed the 11-year assessment (BENEFIT-11). We measured serum 25-hydroxyvitamin-D (25(OH)D), cotinine (smoking biomarker), and anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) at baseline and at months 6, 12, and 24 and examined whether these biomarkers contributed to predict Paced Auditory Serial Addition Test (PASAT)-3 scores and serum neurofilament light chain (NfL) concentrations at 11 years. Linear and logistic regression models were adjusted for sex, baseline age, treatment allocation, steroid treatment, multifocal symptoms, T2 lesions, and body mass index. RESULTS: Higher vitamin D predicted better, whereas smoking predicted worse cognitive performance. A 50-nmol/L higher mean 25(OH)D in the first 2 years was related to 65% lower odds of poorer PASAT performance at year 11 (95% confidence intervals [95% CIs]: 0.14-0.89). Standardized PASAT scores were lower in smokers and heavy smokers than nonsmokers (p trend = 0.026). Baseline anti-EBNA-1 IgG levels did not predict cognitive performance (p trend = 0.88). Associations with NfL concentrations at year 11 corroborated these findings-a 50-nmol/L higher mean 25(OH)D in the first 2 years was associated with 20% lower NfL (95% CI: -36% to 0%), whereas smokers had 20% higher NfL levels than nonsmokers (95% CI: 2%-40%). Anti-EBNA-1 antibodies were not associated with NfL. CONCLUSIONS: Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS.

Long-term causes of death among pediatric patients with cancer.

BACKGROUND: The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death. METHODS: This retrospective, population-based study used the Surveillance, Epidemiology, and End Results database (1980-2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed. RESULTS: There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person-years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100-50,000; P < .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR, >100; P < .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87-76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28-181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82-620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89-102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51-57.09). CONCLUSIONS: The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

A Multidisciplinary Approach to Expedite Surgical Hip Fracture Care.

INTRODUCTION: In 2014, we implemented a geriatric hip fracture patient care pathway at our institution which was designed to improve outcomes and decrease time to surgery. MATERIALS AND METHODS: We analyzed retrospective data from 463 patients, aged greater than 50, who had surgical treatment for a closed hip fracture due to a low-energy injury between 2013 and 2016 at an academic institution. Objective outcome measures included time to surgery, mortality rate, and total hospital length of stay. Our primary goal was to decrease the time to surgery for definitive fracture fixation to within 24 hours of admission to the hospital for patients who were medically fit for surgery. RESULTS: We implemented a multidisciplinary, collaborative approach to address the needs of this specific patient population. Prior to implementing the pathway in 2013, our baseline time to surgery within 24 hours was 74.67%. After implementation, we had incremental yearly increases in the percentage of patients operated on within 24 hours, 82.31% in 2014 (P = .10) and 84.14% in 2015 (P = .04). During the study period, our overall time to surgery was reduced by 27% with an initial average of 20.22 hours in 2013, decreasing to 15.33 hours in 2014, and 14.63 hours in 2015. Our mortality rate at 1 year was 16% in 2013, 17% in 2014, and 15% in 2015. CONCLUSION: With implementation of the pathway, we were able to expedite surgical care for our patients and demonstrate a 10% improvement in the percentage of patients able to have surgery within 24 hours over a 3-year period. Our mortality and hospital length of stay, however, remained the same. Through this collaborative process and system standardization, we believe we have significantly improved not only direct patient care but their overall hospital experience. We continue to make improvements in our pathway.

Zoledronic Acid Improves Muscle Function in Healthy Mice Treated with Chemotherapy.

Carboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone-muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti-TGFß antibody (1D11) to prevent carboplatin-induced bone loss and showed similar results to ZA-treated mice. We found that atrogin-1 mRNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin-induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy. © 2019 American Society for Bone and Mineral Research.

Mutational spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma.

Aflatoxin B1 (AFB1) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB1-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C→T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Responding to a need for early-onset evidence predicting disease development, highly accurate duplex sequencing was used to monitor acquisition of high-resolution mutational spectra (HRMS) during the process of hepatocarcinogenesis. Four-day-old male mice were treated with AFB1 using a regimen that induced HCC within 72 wk. For analysis, livers were separated into tumor and adjacent cellular fractions. HRMS of cells surrounding the tumors revealed predominantly G:C→T:A mutations characteristic of AFB1 exposure. Importantly, 25% of all mutations were G→T in one trinucleotide context (CGC; the underlined G is the position of the mutation), which is also a hotspot mutation in human liver tumors whose incidence correlates with AFB1 exposure. The technology proved sufficiently sensitive that the same distinctive spectrum was detected as early as 10 wk after dosing, well before evidence of neoplasia. Additionally, analysis of tumor tissue revealed a more complex pattern than observed in surrounding hepatocytes; tumor HRMS were a composite of the 10-wk spectrum and a more heterogeneous set of mutations that emerged during tumor outgrowth. We propose that the 10-wk HRMS reflects a short-term mutational response to AFB1, and, as such, is an early detection metric for AFB1-induced liver cancer in this mouse model that will be a useful tool to reconstruct the molecular etiology of human hepatocarcinogenesis.

Exploring the implications of distinct mutational signatures and mutation rates in aging and cancer.

Signatures of mutagenesis provide a powerful tool for dissecting the role of somatic mutations in both normal and pathological processes. Significantly, cancer genomes are dominated by mutation signatures distinct from those that accumulate in normal tissues with age, with potentially important translational implications.

Gastrointestinal Tolerability of Delayed-Release Dimethyl Fumarate in a Multicenter, Open-Label Study of Patients with Relapsing Forms of Multiple Sclerosis (MANAGE).

BACKGROUND: In phase 3 trials, delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) demonstrated efficacy in relapsing-remitting multiple sclerosis (MS). Gastrointestinal (GI) events were associated with DMF treatment. The single-arm, open-label MANAGE study examined the incidence, severity, duration, and management of GI events in adults with relapsing MS initiating DMF treatment in clinical practice in the United States shortly after marketing approval. PATIENTS AND METHODS: Patients (N = 233) took DMF for up to 12 weeks and recorded information regarding GI events using an eDiary and numerical rating scales. RESULTS: Overall, 54.1% of patients used symptomatic therapy and had GI symptoms. The incidence of GI events was highest in the first month of treatment. The duration of GI events varied by event type, and severity was generally mild to moderate. Decreased severity was seen in patients treated with antacids, bismuth subsalicylate, acid-secretion blockers, antidiarrheals, and antiemetics. Less than 10% of patients were using symptomatic therapy for GI events by week 12 of DMF treatment. A modest reduction in severe GI events was observed in patients who regularly took DMF with food compared with patients who did not. The incidence of GI-related events was comparable in patients with or without a history of GI abnormalities and in patients who did or did not use alcohol or tobacco. CONCLUSIONS: Gastrointestinal events associated with DMF are generally transient, mild to moderate in severity, and manageable. Symptomatic therapy and dosing with food may mitigate these events.

Evaluation of Patients' Response Toward Osteoporosis Letter Intervention Versus Phone Call Plus Letter Intervention.

INTRODUCTION: The aim of this study was to compare the effectiveness of 2 interventions in prompting patients to obtain osteoporosis follow-up after a fracture. Our hypothesis was that a phone call plus letter would yield greater response toward osteoporosis evaluation versus a letter alone to patients after sustaining a fragility fracture. MATERIALS AND METHODS: Prospective study randomized 141 patients age 50 years and older with a fragility fracture into 3 groups for comparison. Group 1 (letter only) patients received a letter 3 months after their diagnosis of fracture indicating their risk for osteoporosis and urging them to follow-up for evaluation. Group 2 (phone call plus letter) patients were contacted via phone 3 months after their diagnosis of fracture. A letter followed the phone call. Group 3 (control) patients were neither contacted via phone nor sent a letter. All groups were contacted via phone 6 months after their initial visit to determine if they followed up for evaluation. RESULTS: In group 1, 23 (52.27%) of 44 had follow-up, and 21 (47.73%) of 44 did not follow-up. In group 2, 30 (62.5%) of 48 had follow-up, and 18 (37.50%) of 48 did not follow-up. In group 3, 6 (12.24%) of 49 had some sort of follow-up, and 43 (87.76%) of 49 did not have any follow-up. A statistical significance was achieved between group 3 (control) and both groups 1 and 2 with regard to follow-up (P < .0001). The results did not show a statistically significant difference between Groups 1 and 2, however, there was a trend toward improved response with a phone call plus letter (P = .321). CONCLUSION: A more personalized approach with a phone call plus follow-up letter to patients increased osteoporosis follow-up care by an additional 10%, however, this was not a statistically significant difference from just sending out a letter alone.

Detection of Ultra-Rare Mitochondrial Mutations in Breast Stem Cells by Duplex Sequencing.

Long-lived adult stem cells could accumulate non-repaired DNA damage or mutations that increase the risk of tumor formation. To date, studies on mutations in stem cells have concentrated on clonal (homoplasmic) mutations and have not focused on rarely occurring stochastic mutations that may accumulate during stem cell dormancy. A major challenge in investigating these rare mutations is that conventional next generation sequencing (NGS) methods have high error rates. We have established a new method termed Duplex Sequencing (DS), which detects mutations with unprecedented accuracy. We present a comprehensive analysis of mitochondrial DNA mutations in human breast normal stem cells and non-stem cells using DS. The vast majority of mutations occur at low frequency and are not detectable by NGS. The most prevalent point mutation types are the C>T/G>A and A>G/T>C transitions. The mutations exhibit a strand bias with higher prevalence of G>A, T>C, and A>C mutations on the light strand of the mitochondrial genome. The overall rare mutation frequency is significantly lower in stem cells than in the corresponding non-stem cells. We have identified common and unique non-homoplasmic mutations between non-stem and stem cells that include new mutations which have not been reported previously. Four mutations found within the MT-ND5 gene (m.12684G>A, m.12705C>T, m.13095T>C, m.13105A>G) are present in all groups of stem and non-stem cells. Two mutations (m.8567T>C, m.10547C>G) are found only in non-stem cells. This first genome-wide analysis of mitochondrial DNA mutations may aid in characterizing human breast normal epithelial cells and serve as a reference for cancer stem cell mutation profiles.

Sequencing small genomic targets with high efficiency and extreme accuracy.

The detection of minority variants in mixed samples requires methods for enrichment and accurate sequencing of small genomic intervals. We describe an efficient approach based on sequential rounds of hybridization with biotinylated oligonucleotides that enables more than 1-million-fold enrichment of genomic regions of interest. In conjunction with error-correcting double-stranded molecular tags, our approach enables the quantification of mutations in individual DNA molecules.

dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants.

Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Δ but not rad9Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy.

A rapid assay for measuring nucleotide excision repair by oligonucleotide retrieval.

Nucleotide excision repair (NER) excises bulky DNA lesions induced by mutagens and carcinogens. The repair process includes recognition of DNA damage, excision of a short patch of nucleotides containing the damaged base, re-synthesis of a new DNA strand and ligation of the nicks to restore the sequence integrity. Mutation or aberrant transcription of NER genes reduces repair efficiency and results in the accumulation of mutations that is associated with the development of cancer. Here we present a rapid, sensitive and quantitative assay to measure NER activity in human cells, which we term the Oligonucleotide Retrieval Assay (ORA). We used oligonucleotide constructs containing the UV-damaged adduct, cyclobutane pyrimidine dimer (CPD), to transfect human cells, and retrieved the oligonucleotides for quantification of the repaired, CPD-free DNA by real-time quantitative PCR. We demonstrate that ORA can quantify the extent of NER in diverse cell types, including immortalized, primary and stem-like cells.

Palliative effect of capecitabine and cetuximab for refractory metastatic squamous cell carcinoma of the perineum in epidermodysplasia verruciformis.

A teenage girl presented with multiple warty skin lesions and had a diagnosis of epidermodysplasia verruciformis made several years later. Later in life she presented with an extensive SCC in situ in her gluteal crease that was surgically resected with wide margins. Despite this treatment, the lesion recurred with extension onto her lower back. Biopsies at the time confirmed SCC in situ of the perianal tissue and invasive SCC above her gluteal cleft.

Oxidative stress is not a major contributor to somatic mitochondrial DNA mutations.

The accumulation of somatic mitochondrial DNA (mtDNA) mutations is implicated in aging and common diseases of the elderly, including cancer and neurodegenerative disease. However, the mechanisms that influence the frequency of somatic mtDNA mutations are poorly understood. To develop a simple invertebrate model system to address this matter, we used the Random Mutation Capture (RMC) assay to characterize the age-dependent frequency and distribution of mtDNA mutations in the fruit fly Drosophila melanogaster. Because oxidative stress is a major suspect in the age-dependent accumulation of somatic mtDNA mutations, we also used the RMC assay to explore the influence of oxidative stress on the somatic mtDNA mutation frequency. We found that many of the features associated with mtDNA mutations in vertebrates are conserved in Drosophila, including a comparable somatic mtDNA mutation frequency (∼10(-5)), an increased frequency of mtDNA mutations with age, and a prevalence of transition mutations. Only a small fraction of the mtDNA mutations detected in young or old animals were G∶C to T∶A transversions, a signature of oxidative damage, and loss-of-function mutations in the mitochondrial superoxide dismutase, Sod2, had no detectable influence on the somatic mtDNA mutation frequency. Moreover, a loss-of-function mutation in Ogg1, which encodes a DNA repair enzyme that removes oxidatively damaged deoxyguanosine residues (8-hydroxy-2'-deoxyguanosine), did not significantly influence the somatic mtDNA mutation frequency of Sod2 mutants. Together, these findings indicate that oxidative stress is not a major cause of somatic mtDNA mutations. Our data instead suggests that somatic mtDNA mutations arise primarily from errors that occur during mtDNA replication. Further studies using Drosophila should aid in the identification of factors that influence the frequency of somatic mtDNA mutations.

Patients' response toward an automated orthopedic osteoporosis intervention program.

Osteoporosis is overshadowed in an era of chronic illnesses, and a care gap exists between physicians and patients. The aim of this study was to determine the effectiveness of implementing an automated system for identifying and sending a letter to patients at high risk for osteoporosis. Patients 50 years of age and older were tagged with an International Classification of Diseases, Ninth Revision, diagnostic code upon initial visit to the emergency department (ED), identifying potential fragility fractures. Automatically generated letters were sent via our osteoporosis database system to each patient 3 months after the initial visit to the ED. The letter indicated that he or she was at risk for osteoporosis and suggested that the patient schedule a follow-up appointment with a physician. Patients were subsequently telephoned 3 months after receiving the letter and asked about their current plan for follow-up. The control group did not receive a letter after departure from the ED. In the control group, 84 (85.71%) individuals of the total 98 did not have any follow-up but the remaining 14 (14.29%) sought a follow-up. In the intervention group, 62 (60.19%) individuals of 103 did schedule a follow-up, while the remaining 41 (39.81%) did not seek a follow-up. Thus, the patient follow-up response rate after fracture treatment improved with intervention (P < .0001). Current literature has demonstrated the low rate of follow-up care addressing osteoporosis in patients experiencing fragility fractures (1%-25% without intervention). Research has shown the effectiveness of various types of intervention programs for improving the continuum of care for these high-risk patients. Nonautomated intervention programs can have a multitude of human-related system failures in identifying these patients. Our study successfully implements an automated system that is able to be applied to most hospitals with minimal cost and resources.