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1.
Oncologist ; 29(4): e475-e486, 2024 Apr 04.
Article in English | MEDLINE | ID: mdl-38103030

ABSTRACT

PURPOSE: We examined the concordance of genetic mutations between pretreatment tumor tissue and posttreatment circulating tumor DNA (ctDNA) in patients with metastatic squamous cell carcinoma of the anal canal (SCCA) and assessed the impact of therapy on this concordance. METHODS: We analyzed next-generation sequencing reports from pretreatment tumor tissue and posttreatment ctDNA in 11 patients with metastatic SCCA treated at Vanderbilt University Medical Center between 2017 and 2021. RESULTS: Among the mutations identified in posttreatment ctDNA, 34.5% were also found in pretreatment tumor tissue, while 47.6% of pretreatment tumor tissue mutations were found in posttreatment ctDNA. Four patients had preservation of potentially actionable mutations in both pretreatment tissue and posttreatment ctDNA, while 7 patients had newly identified mutations in posttreatment ctDNA that were not present in pretreatment tumor tissue. CONCLUSION: Patients with SCCA demonstrate a high degree of temporal mutational heterogeneity. This supports the hypothesis that ctDNA can serve as a real-time tracking mechanism for solid tumors' molecular evolution in response to therapy. Our findings highlight the potential of ctDNA in identifying emerging actionable mutations, supplementing information from tissue-based genomic assessments. Further research, ideally with larger and multi-institutional cohorts, is needed to validate our findings in this relatively rare tumor type.


Subject(s)
Anus Neoplasms , Carcinoma, Squamous Cell , Circulating Tumor DNA , Humans , Anal Canal , Mutation , Circulating Tumor DNA/genetics , Carcinoma, Squamous Cell/genetics , Anus Neoplasms/genetics , Biomarkers, Tumor/genetics , High-Throughput Nucleotide Sequencing
2.
Front Oncol ; 13: 1176950, 2023.
Article in English | MEDLINE | ID: mdl-37409250

ABSTRACT

Colorectal cancer results in the deaths of hundreds of thousands of patients worldwide each year, with incidence expected to rise over the next two decades. In the metastatic setting, cytotoxic therapy options remain limited, which is reflected in the meager improvement of patient survival rates. Therefore, focus has turned to the identification of the mutational composition inherent to colorectal cancers and development of therapeutic targeted agents. Herein, we review the most up to date systemic treatment strategies for metastatic colorectal cancer based on the actionable molecular alterations and genetic profiles of colorectal malignancies.

3.
Clin Cancer Res ; 29(12): 2310-2323, 2023 06 13.
Article in English | MEDLINE | ID: mdl-37071497

ABSTRACT

PURPOSE: Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response. EXPERIMENTAL DESIGN: We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n = 16) or immunotherapy-containing (n = 17) regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL). Longitudinal dynamic changes in cfTL were monitored to determine circulating cell-free tumor DNA (ctDNA) molecular response during therapy. RESULTS: Combined tiered analyses of tumor-derived sequence alterations and plasma aneuploidy allowed for the assessment of ctDNA molecular response in all patients. Patients classified as molecular responders (n = 9) displayed sustained elimination of cfTL to undetectable levels. For 14 patients, we observed initial molecular responses, followed by ctDNA recrudescence. A subset of patients (n = 10) displayed a clear pattern of molecular progression, with persistence of cfTL across all time points. Molecular responses captured the therapeutic effect and long-term clinical outcomes in a more accurate and rapid manner compared with radiographic imaging. Patients with sustained molecular responses had longer overall (log-rank P = 0.0006) and progression-free (log-rank P < 0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging. CONCLUSIONS: ctDNA analyses provide a precise approach for the assessment of early on-therapy molecular responses and have important implications for the management of patients with SCLC, including the development of improved strategies for real-time tumor burden monitoring. See related commentary by Pellini and Chaudhuri, p. 2176.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Cell-Free Nucleic Acids , Circulating Tumor DNA , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Circulating Tumor DNA/genetics , Lung Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Prognosis , Neoplasm Recurrence, Local , Mutation
4.
JTO Clin Res Rep ; 3(8): 100361, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35814861

ABSTRACT

Lung cancer incidence is increasing in pregnancy due in part to advanced maternal age. A subset of patients with NSCLC during pregnancy harbor an ALK gene rearrangement. Although ALK inhibitors, such as alectinib, are routinely used to treat ALK-rearranged NSCLC, there are limited safety data regarding use during pregnancy and fetal effects. Here, we report the second case of a patient with metastatic ALK-rearranged lung adenocarcinoma treated with alectinib throughout pregnancy. Notably, the patient had two uncomplicated pregnancies with routine obstetrical and postnatal courses. In this case, alectinib did not seem to affect embryofetal or early childhood development. This does not exclude undetectable or delayed toxic effects, and additional studies are needed to further reveal the safety of alectinib treatment during pregnancy.

5.
Cancers (Basel) ; 14(15)2022 Jul 26.
Article in English | MEDLINE | ID: mdl-35892891

ABSTRACT

Background: Early-onset gastric cancer (EOGC), or gastric cancer in patients younger than 45 years old, is poorly understood and relatively uncommon. Similar to other gastrointestinal malignancies, the incidence of EOGC is rising in Western countries. It is unclear which populations experience a disproportionate burden of EOGC and what factors influence how patients with EOGC are treated. Methods: We conducted a retrospective, population-based study of patients diagnosed with gastric cancer from 2004 to 2018 using the National Cancer Database (NCDB). In addition to identifying unique demographic characteristics of patients with EOGC, we evaluated (using multivariable logistic regression controlling for year of diagnoses, primary site, and stage) how gender/sex, race/ethnicity, treatment facility type, payor status, and location of residence influenced the receipt of surgery, chemotherapy, and radiation. Results: Compared to patients 45−70 and >70 years of age with gastric cancer, patients with EOGC were more likely to be female, Asian/Pacific Islander (PI), African American (AA), Hispanic, uninsured, and present with stage IV disease. On multivariable analysis, several differences among subsets of patients with EOGC were identified. Female patients with EOGC were less likely to receive surgery and chemotherapy than male patients with EOGC. Asian/Pacific Islander patients with EOGC were more likely to receive chemotherapy and less likely to receive radiation than Caucasian patients with EOGC. African American patients were more likely to receive chemotherapy than Caucasian patients with EOGC. Hispanic patients were more likely to receive surgery and chemotherapy and less likely to receive radiation than Caucasian patients with EOGC. Patients with EOGC treated at community cancer centers were more likely to receive surgery and less likely to receive chemotherapy than patients with EOGC treated at academic centers. Uninsured patients with EOGC were more likely to receive surgery and less likely to receive chemotherapy than privately insured patients with EOGC. Patients with EOGC living in locations not adjacent to metropolitan areas were less likely to receive surgery compared to patients with EOGC who resided in metropolitan areas, Conclusions: Patients with EOGC are a demographically distinct population. Treatment of these patients varies significantly based on several demographic factors. Additional analysis is needed to elucidate why particular groups are more affected by EOGC and how treatment decisions are made for, and by, these patients.

6.
J Surg Oncol ; 125(7): 1151-1160, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35230696

ABSTRACT

Each year, gastric cancer claims the lives of hundreds of thousands of patients worldwide. Despite surgical resection, the risk of residual disease, micrometastatic disease, and disease recurrence remain elevated. Herein, we review systemic therapy strategies in the neoadjuvant, adjuvant, and metastatic settings, including novel uses of immunotherapy, targeted therapies and cytotoxic chemotherapies, for the treatment of gastric cancer.


Subject(s)
Stomach Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Adjuvant , Gastrectomy , Humans , Neoadjuvant Therapy , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery
7.
Br J Dermatol ; 187(3): 401-410, 2022 09.
Article in English | MEDLINE | ID: mdl-35293617

ABSTRACT

BACKGROUND: Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African. OBJECTIVES: To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups. METHODS: Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal. RESULTS: In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50-57% vs. 20%, 95% CI 13-28%; adjusted P < 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7-20·3 vs. 5·4 months, 95% CI 4·5-7·0; adjusted P < 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48-6·81; adjusted P < 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46-0·74; adjusted P < 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes. CONCLUSIONS: Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.


Subject(s)
Melanoma , Skin Neoplasms , Ethnicity , Humans , Melanoma/pathology , Retrospective Studies , Skin Neoplasms/pathology , Melanoma, Cutaneous Malignant
8.
Clin Cancer Res ; 27(21): 5993-6000, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34376536

ABSTRACT

PURPOSE: Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear. EXPERIMENTAL DESIGN: In this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed. RESULTS: Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort [irAE(+) n = 90], early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) [post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10-13.70; P < 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20-16.09; P < 0.001] compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort [irAE(+) n = 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04-2.76; P = 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15-3.39; P = 0.01]. Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results. CONCLUSIONS: Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.


Subject(s)
Glucocorticoids/administration & dosage , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Melanoma/drug therapy , Melanoma/mortality , Correlation of Data , Drug-Related Side Effects and Adverse Reactions/prevention & control , Humans , Melanoma/pathology , Neoplasm Staging , Survival Rate , Time Factors
9.
Oncologist ; 26(11): e1962-e1970, 2021 11.
Article in English | MEDLINE | ID: mdl-34390291

ABSTRACT

BACKGROUND: Over the past few years, tumor next-generation sequencing (NGS) panels have evolved in complexity and have changed from selected gene panels with a handful of genes to larger panels with hundreds of genes, sometimes in combination with paired germline filtering and/or testing. With this move toward increasingly large NGS panels, we have rapidly outgrown the available literature supporting the utility of treatments targeting many reported gene alterations, making it challenging for oncology providers to interpret NGS results and make a therapy recommendation for their patients. METHODS: To support the oncologists at Vanderbilt-Ingram Cancer Center (VICC) in interpreting NGS reports for patient care, we initiated two molecular tumor boards (MTBs)-a VICC-specific institutional board for our patients and a global community MTB open to the larger oncology patient population. Core attendees include oncologists, hematologist, molecular pathologists, cancer geneticists, and cancer genetic counselors. Recommendations generated from MTB were documented in a formal report that was uploaded to our electronic health record system. RESULTS: As of December 2020, we have discussed over 170 patient cases from 77 unique oncology providers from VICC and its affiliate sites, and a total of 58 international patient cases by 25 unique providers from six different countries across the globe. Breast cancer and lung cancer were the most presented diagnoses. CONCLUSION: In this article, we share our learning from the MTB experience and document best practices at our institution. We aim to lay a framework that allows other institutions to recreate MTBs. IMPLICATIONS FOR PRACTICE: With the rapid pace of molecularly driven therapies entering the oncology care spectrum, there is a need to create resources that support timely and accurate interpretation of next-generation sequencing reports to guide treatment decision for patients. Molecular tumor boards (MTB) have been created as a response to this knowledge gap. This report shares implementation strategies and best practices from the Vanderbilt experience of creating an institutional MTB and a virtual global MTB for the larger oncology community. This report describe a reproducible framework that can be adopted to initiate MTBs at other institutions.


Subject(s)
Neoplasms , Humans , National Cancer Institute (U.S.) , Neoplasms/genetics , Neoplasms/therapy , United States
10.
Eur J Cancer ; 148: 61-75, 2021 05.
Article in English | MEDLINE | ID: mdl-33735811

ABSTRACT

BACKGROUND: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. METHODS: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. RESULTS: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. CONCLUSIONS: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Melanoma/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Aged , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Male , Melanoma/immunology , Melanoma/pathology , Middle Aged , Prognosis , Retrospective Studies , Survival Rate
11.
JTO Clin Res Rep ; 1(2): 100024, 2020 Jun.
Article in English | MEDLINE | ID: mdl-34589931

ABSTRACT

INTRODUCTION: Most patients (70%) with limited-stage SCLC (LS-SCLC) who are treated with curative-intent therapy suffer disease relapse and cancer-related death. We evaluated circulating tumor DNA (ctDNA) as a predictor of disease relapse and death after definitive therapy in patients with LS-SCLC. METHODS: In our previous work, we developed a plasma-based ctDNA assay to sequence 14 genes (TP53, RB1, BRAF, KIT, NOTCH1-4, PIK3CA, PTEN, FGFR1, MYC, MYCL1, and MYCN) that are frequently mutated in SCLC. In this work, we evaluated 177 plasma samples from 23 patients with LS-SCLC who completed definitive chemoradiation (n = 21) or surgical resection (n = 2) and had an end-of-treatment blood collection (median 4 d, range 0-40 d from treatment completion) plus monthly surveillance blood sampling. Median overall survival (OS) and progression-free survival (PFS) were compared using a Wilcoxon test. RESULTS: The median OS among patients in whom we ever detected ctDNA after definitive treatment (n = 15) was 18.2 months compared with a median OS of greater than 48 months among patients in whom we never detected ctDNA after definitive treatment (n = 8; p = 0.081). The median PFS among patients in whom we ever detected ctDNA after definitive treatment was 9.1 months compared with a median PFS of greater than 48 months among patients in whom we never detected ctDNA after definitive treatment (p < 0.001). CONCLUSIONS: Detection of ctDNA in patients with LS-SCLC after curative-intent therapy predicts disease relapse and death. Prospective trials using ctDNA as an integral biomarker for therapeutic selection should be considered in SCLC.

12.
Oncologist ; 24(11): 1495-1496, 2019 11.
Article in English | MEDLINE | ID: mdl-31213499

ABSTRACT

BRAF and MEK inhibitors are highly active in the setting of BRAF V600 mutant melanoma. Rarely, patients without previous testing present with fulminant progression necessitating emergent treatment prior to BRAF testing results. The safety and efficacy of empiric treatment in this setting is unclear. Herein, we present two patients treated with empiric BRAF and MEK inhibitors, resulting in dramatic clinical improvement in one patient later found to have a BRAF mutation, and lack of improvement (but no accelerated progression) in a patient lacking this mutation. Empiric BRAF and MEK inhibitor treatment should not be routinely pursued but may be given safely in rare, emergent situations.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , MAP Kinase Kinase 1/antagonists & inhibitors , Melanoma/drug therapy , Molecular Targeted Therapy , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Adult , Humans , Imidazoles/administration & dosage , Male , Melanoma/pathology , Neoplasm Metastasis , Oximes/administration & dosage , Prognosis , Pyridones/administration & dosage , Pyrimidinones/administration & dosage
14.
PLoS One ; 9(3): e91904, 2014.
Article in English | MEDLINE | ID: mdl-24637515

ABSTRACT

Bone mineral density (BMD) estimates for the proximal femur using Dual Energy X-ray Absorptiometry (DXA) are currently considered the standard for making a diagnosis of osteoporosis in an individual patient using BMD alone. We have compared BMD results from a commercial Quantitative CT (QCT) BMD analysis system, "CTXA Hip", which provides clinical data for the proximal femur, to results from DXA. We have also used CTXA Hip to determine cortical and trabecular contributions to total BMD. Sixty-nine patients were scanned using 3D QCT and DXA. CTXA Hip BMD measurements for Total Hip and Femoral Neck were compared to DXA results. Twenty-two women were scanned at 0, 1, 2 years and CTXA Hip and DXA results analyzed for long-term reproducibility. Long-term reproducibility calculated as root-mean-square averages of SDs in vivo was 0.012 g/cm2 (CV = 1.8%) for CTXA Total Hip and 0.011 g/cm2 (CV = 2.0%) for CTXA Femoral Neck compared to 0.014 g/cm2 (CV = 2.0%) and 0.016 g/cm2 (CV = 2.7%), respectively, for DXA. The correlation of Total Hip BMD CTXA vs. DXA was R = 0.97 and for Femoral Neck was R = 0.95 (SEE 0.044 g/cm2 in both cases). Cortical bone comprised 62±5% (mean ± SD) of total hipbone mass in osteoporotic women. CTXA Hip provides substantially the same clinical information as conventional DXA and in addition provides estimates of BMD in separate cortical and trabecular bone compartments, which may be useful in evaluation of bone strength.


Subject(s)
Bone Density , Hip Joint/diagnostic imaging , Tomography, X-Ray Computed , Aged , Female , Femur Neck/diagnostic imaging , Humans , Middle Aged , Osteoporosis, Postmenopausal/diagnostic imaging
16.
J Bone Miner Res ; 20(6): 977-86, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15883638

ABSTRACT

UNLABELLED: Bisphosphonates have been widely administered to children with OI based on observational trials. A randomized controlled trial of q3m intravenous pamidronate in children with types III and IV OI yielded positive vertebral changes in DXA and geometry after 1 year of treatment, but no further significant improvement during extended treatment. The treated group did not experience significantly decreased pain or long bone fractures or have increased motor function or muscle strength. INTRODUCTION: Bisphosphonates, antiresorptive drugs for osteoporosis, are widely administered to children with osteogenesis imperfecta (OI). Uncontrolled pamidronate trials in OI reported increased BMD, vertebral coronal area, and mobility, and decreased pain. We conducted a randomized controlled trial of pamidronate in children with types III and IV OI. MATERIALS AND METHODS: This randomized trial included 18 children (4-13 years of age) with types III and IV OI. The first study year was controlled; 9 children received pamidronate (10 mg/m2/day IV for 3 days every 3 months). Four children in each group also received recombinant growth hormone (rGH) injections (0.06 mg/kg/day for 6 days/week). Seven children in the treatment group received pamidronate for an additional 6-21 months. All patients had L1-L4 DXA, spine QCT, spine radiographs, and musculoskeletal and functional testing. RESULTS: In the controlled phase, treated patients experienced a significant increase in L1-L4 DXA z score (p < 0.001) and increased L1-L4 mid-vertebral height (p = 0.014) and total vertebral area (p = 0.003) compared with controls. During extended treatment, DXA z scores and vertebral heights and areas did not increase significantly beyond the 12-month values. Fracture rate decreased significantly in the upper extremities (p = 0.04) but not the lower extremities (p = 0.09) during the first year of treatment. Gross motor function, muscle strength, and pain did not change significantly during the controlled or extended treatment phases. CONCLUSIONS: A controlled trial confirmed the spine benefits of short-term pamidronate treatment in children with types III and IV OI. Pamidronate increased L1-L4 vertebral DXA and decreased vertebral compressions and upper extremity fractures. Vertebral measures did not improve during the extended treatment phase. The treatment group did not experience decreased lower extremity long bone fractures, significant improvement in growth, ambulation, muscle strength, or pain. There was substantial variability in individual response to treatment.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Bone Development/drug effects , Diphosphonates/therapeutic use , Osteogenesis Imperfecta/drug therapy , Adolescent , Body Height , Bone Density , Bone and Bones/drug effects , Child , Child, Preschool , Densitometry , Fractures, Bone/prevention & control , Growth Hormone/therapeutic use , Humans , Pamidronate , Spine/drug effects , Treatment Outcome
17.
Bone ; 33(4): 744-50, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14555280

ABSTRACT

The correlation between bone mineral density and vertebral strength is not based on mechanical principles and thus the method cannot reflect the effects of subtle geometric features and densitometric inhomogeneities that may substantially affect vertebral strength. Finite element models derived from quantitative computed tomography (QCT) scans overcome such limitations. The overall goal of this study was to establish that QCT-based "voxel" finite element models are better predictors of vertebral compressive strength than QCT measures of bone mineral density with or without measures of cross-sectional area. QCT scans were taken of 13 vertebral bodies excised from 13 cadavers (L1-L4; age: 37-87 years; M = 6, F = 7) and used to calculate bone mineral density (BMD(QCT)). The QCT voxel data were converted into linearly elastic finite element models of each vertebra, from which measures of vertebral stiffness and strength were computed. The vertebrae were biomechanically tested in compression to measure strength. Vertebral strength was positively correlated with the finite element measures of strength (r(2) = 0.86, P < 0.0001) and stiffness (r(2) = 0.82, P < 0.0001), the product of BMD(QCT) and vertebral minimum cross-sectional area (r(2) = 0.65, P = 0.0008), and BMD(QCT) alone (r(2) = 0.53, P = 0.005). These results demonstrate that highly automated "voxel" finite element models are superior to correlation-based QCT methods in predicting vertebral compressive strength and therefore offer great promise for improvement of clinical fracture risk assessment.


Subject(s)
Models, Biological , Spine/physiology , Adult , Aged , Aged, 80 and over , Bone Density , Compressive Strength , Female , Finite Element Analysis , Humans , In Vitro Techniques , Linear Models , Male , Middle Aged , Radiographic Image Interpretation, Computer-Assisted , Spine/diagnostic imaging , Tomography, X-Ray Computed
18.
RPG rev. pos-grad ; 6(2): 103-10, abr.-jun. 1999. ilus, tab, graf
Article in Portuguese | LILACS, BBO - Dentistry | ID: lil-283526

ABSTRACT

A densidade mineral óssea foi determinada na regiäo posterior da maxila de 61 indivíduos total ou parcialmente desdentados, sendo eles 33 (trinta e três) homens, entre 28 e 50 anos (média de idade = 41,0), e 28 (vinte e oito) mulheres, no período de pré menopausa, entre 24 e 47 anos (média de idade = 38,8. Esses indivíduos foram examinados pela tomografia computadorizada, visando ao planejamento de cirurgias para colocaçäo de implantes osseointegrados. Os resultados näo mostraram diferença significativa para a densidade óssea média entre os grupos masculino e feminino. A média do coeficiente de atenuaçäo para ambos os gêneros foi de 373,22 H, mensuradas num tomógrafo GE 9800 QUICK. A densidade óssea média na regiäo posterior edêntula da maxila, de indivíduos caucasianos adultos, foi de 352,76 equivalente meneral (mg K²HPO4/ml). O coeficiente de atenuaçäo näo se correlacionou com a idade no grupo masculino. Para o grupo feminino, houve aumento dos valores dos coeficientes de atenuaçäo em funçäo, de porcentagens pouco expressiva (R²=0,351)


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Bone Density , Maxilla/anatomy & histology , Tomography, Emission-Computed , Dental Implantation, Endosseous , Sex Factors
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