Katherine Thornton

Circulating mutant DNA to assess tumor dynamics

The measurement of circulating nucleic acids has transformed the management of chronic viral infections such as HIV. The development of analogous markers for individuals with cancer could similarly enhance the management of their disease. DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. In this study, we applied a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in 162 plasma samples from 18 subjects undergoing multimodality therapy for colorectal cancer. We found that ctDNA measurements could be used to reliably monitor tumor dynamics in subjects with cancer who were undergoing surgery or chemotherapy. We suggest that this personalized genetic approach could be generally applied to individuals with other types of cancer (pages 914–915).

Management of Venous Thromboembolism: A Systematic Review for a Practice Guideline

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism, is a prevalent disease treated by internists. The incidence of VTE is about 7 per 10000 person-years among community residents (1, 2). The condition recurs in about 20% of patients after 5 years, but the rate varies depending on the presence of risk factors (3, 4). A community-wide study from the 1980s reported an incidence rate of pulmonary embolism, with or without DVT, of 2.3 per 10000 (5). Pulmonary embolism limits the short- and long-term survival of patients with VTE (6). Postthrombotic syndrome, another prevalent complication of DVT, may result in life-long morbidity with limb pain and edema (4). Treatment of VTE, with anticoagulants and thrombolytic therapies, is associated with its own risks. Given the prevalence of this condition and its associated morbidity, we reviewed the evidence on optimal treatment of VTE. We sought to summarize the evidence to inform the guidelines developed by the American Academy of Family Physicians and the American College of Physicians for management of patients with VTE. The foundation of this background paper was a previous systematic review of diagnosis and management of VTE (7). For this paper, we addressed the following questions: 1) Is heparin or low-molecular-weight heparin (LMWH) safer and more efficacious for initial treatment of VTE? 2) Is outpatient treatment of VTE safe and effective when compared with inpatient treatment? 3) Is LMWH cost-effective compared with heparin? 4) Does catheter-directed thrombolysis reduce VTE recurrences and the incidence of postthrombotic syndrome? 5) Does use of compression stockings reduce the incidence of postthrombotic syndrome? 6) Do vena cava filters alter the incidence of pulmonary embolism and recurrent DVT? 7) What is the optimal duration of therapy with vitamin K antagonists for VTE? 8) Does evidence support use of LMWH instead of vitamin K antagonists? 9) What is the best therapy for pregnant women with VTE? Methods The methods used in our systematic review are completely described in a detailed evidence report (7). The methods specific to this article are briefly described in the following section. Data Sources To identify relevant articles, we searched literature-indexing systems, including MEDLINE, MICROMEDEX, the Cochrane Controlled Trials Register, and the Cochrane Database of Systematic Reviews, beginning in the 1950s. We also examined reference lists from material identified through the electronic searching and from discussion with experts, and we reviewed recent tables of contents of the pertinent journals. For our previous report, we searched for citations through March 2002. For the current review, we extended the search through June 2006. Data Selection Our criteria for article inclusion are listed in Appendix 1. Two team members independently reviewed the titles and abstracts and excluded those that did not meet the eligibility criteria. For primary literature, the article must have been in English, addressed one of the chosen questions, not involved prevention only, included original human data, and not have been a single-patient case report. For our review of systematic reviews, we used these criteria but also stipulated that the article have included a systematic review, meta-analysis, or cost-effectiveness analysis. Data published only in abstract form were excluded. Each question had additional eligibility criteria. If both reviewers agreed about eligibility, we reviewed the article. In our previous review, we evaluated 64 systematic reviews and 148 primary studies. Of these, 16 systematic reviews and 32 primary studies were relevant to our questions about management of VTE. In our additional searching, we identified another 3 systematic reviews and 13 primary studies on the questions that were in the previous review. We also reviewed 515 additional abstracts to identify 46 primary studies on 5 additional questions covered in this review. Seven studies, previously included for question 7 above, were eliminated; they were published before 1995 and were inconsistent in their use of objective tests for diagnosing VTE. Data Extraction and Quality Assessment A single reviewer abstracted data, and a co-investigator did a secondary review to verify accuracy. We summarized data in evidence tables and assessed the quality of the article by using validated instruments, where appropriate (8). Two authors graded evidence according to the Strength of Recommendation Taxonomy (SORT) developed by a consortium of editors of U.S. family medicine and primary care journals (9). As shown in Table 1, level 1 indicates good-quality patient-oriented evidence, level 2 indicates limited-quality patient-oriented evidence, and level 3 indicates when there is other evidence. Table 1. Assessing Quality of Evidence* Data Synthesis and Analysis We pooled risk ratios across studies about duration of oral anticoagulation and generated CIs around the risk ratios with a random-effects model using the method of DerSimonian and Laird; the estimate of heterogeneity was taken from the Mantel-Haenszel model (Stata 9.0, StataCorp., College Station, Texas). The I2 statistic was calculated as 100%(Qdegrees of freedom)/Q, where Q is the measure of heterogeneity (10). Because the I2 statistic suggested heterogeneity between trials, we do not report pooled results. Role of the Funding Sources The initial systematic review was funded through a contract with the Agency for Healthcare Research and Quality. Members of the American College of Physicians/American Academy of Family Physicians guidelines committee for management of VTE reviewed drafts of this manuscript. Data Synthesis Is Heparin or LMWH Safer and More Efficacious for Initial Treatment of VTE? Numerous trials have compared the safety and efficacy of LWMHs to those of unfractionated heparin in the treatment of VTE. We report on 17 systematic reviews of these trials, published between 1994 and 2003, which reviewed rates of recurrent VTE, major bleeding, or death (1127). Five included only trials of patients with an isolated DVT, 1 review focused on patients with pulmonary embolism with or without concomitant DVT (23), and 1 evaluated the adequacy of dosing of unfractionated heparin (24). Thirteen LMWHs were compared with unfractionated heparin, almost always given intravenously. The LMWHs most often included were enoxaparin (13 reviews), dalteparin (12 reviews), nadroparin (11 reviews), tinzaparin (10 reviews), reviparin (9 reviews), and CY222 (8 reviews). The quality of the systematic reviews was generally good, although only 5 evaluated the quality of trials (14, 17, 23, 26, 28). Description of the search strategies and methods of combining results were weaker in the earlier reviews. Five reviews were descriptive and did not pool results (11, 18, 19, 22, 24). As expected, many of the same articles were included in multiple reviews. The reviews fell into 3 clusters depending on which trials they included. Table 2 summarizes the pooled trial results by these clusters. The cluster containing the most recent trials, cluster C, has odds ratios closer to 1.0 than the cluster containing only the earliest trials. Appendix Table 1 describes the individual trials within each review). Table 2. Systematic Reviews Comparing Low-Molecular-Weight Heparin with Unfractionated Heparin (n= 10)* Appendix Table 1. Individual Studies Included in Systematic Reviews The 5 descriptive reviews had discordant results (11, 18, 19, 22, 24). Among the 11 reviews that pooled trial results (with many trials in common), none showed heparin to be superior to LMWH in preventing recurrent DVT. In addition, patients treated with LMWH had fewer episodes of major bleeding than those treated with unfractionated heparin. All but 1 of 10 reviews showed that LMWH significantly reduced mortality during the 3 to 6 months of follow-up compared with unfractionated heparin (23). Only 4 reviews reported summary results separately for patients with pulmonary embolism; these reviews concluded that LMWH was as effective as unfractionated heparin in this population (16, 18, 23, 29). In summary, evidence is ample that LMWH is superior to unfractionated heparin for the treatment of DVT, particularly for reducing mortality and the risk for major bleeding during initial therapy. The magnitude of benefit from LMWH, while significant in many of these reviews, appears to be lower than was estimated in the earliest reviews. Additional trials are needed to examine the efficacy of LMWH for the treatment of pulmonary embolism, but reviews of existing trials indicate that LMWH is at least as effective as unfractionated heparin for these patients as well. This is level 1 evidence. Is Outpatient Treatment of VTE Safe and Effective When Compared with Inpatient Treatment? Thirteen studies compared the outcomes of patients with VTE treated with LMWH administered at home with outcomes of those treated with unfractionated heparin in the hospital (3042). Four of these were randomized trials (3032, 42); 9 were cohort studies. An additional 5 studies, including 2 randomized trials (43, 44), compared outcomes and costs for patients receiving LMWH at home with those for patients receiving LWMH in the hospital (4347). The studies used subcutaneous enoxaparin, nadroparin, tinzaparin, or dalteparin at varying dosages, and then an oral anticoagulant during follow-up. At least 8 studies allowed a brief inpatient admission for stabilization of patients randomly assigned to the outpatient group. Three studies permitted enrollment of patients with concomitant pulmonary embolism (38, 41, 47), while 1 prospective cohort study required stable patients with pulmonary embolism (45). The remaining studies excluded these patients. Inclusion criteria were restrictiveinvestigators screened far more patients than they enrolled. Most studies excluded patients with previous VTE, thrombophilic c

Predictors of survival after resection of retroperitoneal sarcoma: A population-based analysis and critical appraisal of the AJCC Staging system

Objective:To identify predictors of survival after resection of retroperitoneal sarcoma (RPS) and to evaluate the performance of the American Joint Committee on Cancer (AJCC) staging system for RPS. Summary Background Data:Previous studies of survival after RPS resection are restricted to at most several institutions, yet the current AJCC staging system for RPS is based entirely on these relatively small studies. Methods:Patients undergoing resection of primary RPS from 1988 to 2005 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazards models were used to analyze survival and evaluate AJCC staging. Results:In 1365 patient undergoing resection of primary RPS, the most prevalent histologies were liposarcoma (50%), leiomyosarcoma (26%), and malignant fibrous histiocytoma (11%). Median, 5-year, and 10-year survival after resection were 55 months, 47%, and 27%. Histological subtype (P < 0.001), histological grade (grade 3–4 vs. grade 1; HR, 2.42; P < 0.001), and tumor invasion of adjacent structures (HR, 1.37; P < 0.001) were associated with survival on multivariable analysis. However, tumor size had no prognostic value. Consequently, the AJCC T classification system demonstrated poor discriminatory ability (c = 0.50). The AJCC stage grouping system demonstrated moderate discriminatory ability (c = 0.66) but performed no better than a much simpler system that omits information on tumor size and lymph node metastasis (c = 0.67). Conclusions:Indicators of tumor aggressiveness (histological grade and invasion of adjacent structures) as well as histological subtype predict survival after RPS resection. Tumor size, however, does not impact survival. The AJCC staging system for RPS is in need of revision.

Imaging of Musculoskeletal Bacterial Infections by [124I]FIAU-PET/CT

Background Traditional imaging techniques for the localization and monitoring of bacterial infections, although reasonably sensitive, suffer from a lack of specificity. This is particularly true for musculoskeletal infections. Bacteria possess a thymidine kinase (TK) whose substrate specificity is distinct from that of the major human TK. The substrate specificity difference has been exploited to develop a new imaging technique that can detect the presence of viable bacteria. Methodology/Principal Findings Eight subjects with suspected musculoskeletal infections and one healthy control were studied by a combination of [124I]FIAU-positron emission tomography and CT ([124I]FIAU-PET/CT). All patients with proven musculoskeletal infections demonstrated positive [124I]FIAU-PET/CT signals in the sites of concern at two hours after radiopharmaceutical administration. No adverse reactions with FIAU were observed. Conclusions/Significance [124I]FIAU-PET/CT is a promising new method for imaging bacterial infections.

Pediatric Soft Tissue Sarcomas

Soft tissue sarcomas in children are rare. Approximately 850 to 900 children and adolescents are diagnosed each year with rhabdomyosarcoma (RMS) or a non-RMS soft tissue sarcoma (NRSTS). RMS is more common in children 14 years old and younger and NRSTS in adolescents and young adults. Infants get NRSTS, but their tumors constitute a distinctive set of histologies. Surgery is a major therapeutic modality and radiation plays a role. RMS is treated with adjuvant chemotherapy, whereas chemotherapy is reserved for the NRSTS that are high grade or unresectable. This review discusses the etiology, biology, and treatment of pediatric soft tissue sarcomas.

Evaluation of Clostridium novyi-NT spores in dogs with naturally occurring tumors

OBJECTIVE To establish the maximum tolerated dose of Clostridium novyi-NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. ANIMALS 6 client-owned dogs. PROCEDURES A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C. novyi-NT spores i.v.. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. RESULTS The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C. novyi-NT infection; both required surgical intervention. Clostridium novyi-NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that C. novyi-NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology.

Targeting Cancer with Bugs and Liposomes: Ready, Aim, Fire

One of the major challenges facing cancer therapy today is achieving specificity. Current efforts to meet this challenge are focused on developing targeted therapeutics specific to the cancer cell. An alternative approach is to selectively deliver cytotoxic agents to the tumor site. With this end in mind, liposomes optimized for physical robustness have been developed and used clinically as drug delivery vehicles. Paradoxically, the effectiveness of these liposomes is hampered by the suboptimal release of bioavailable drug. This article will highlight the recent advance in using a novel lipase secreted by the tumor-colonizing anaerobic bacterium Clostridium novyi-NT to induce the targeted release of liposomal payloads within tumors.

A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma.

There are few effective therapies for high‐risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, mammalian target of rapamycin (mTOR) inhibition potentiates the efficacy of chemotherapy on resistant sarcoma cells. Although sarcoma trials using mTOR inhibitors have been disappointing, these drugs were used as maintenance. We conducted a Phase I/II clinical trial to test the ability of temsirolimus to potentiate the cytotoxic effect of liposomal doxorubicin and present here the dose‐finding portion of this study. Adult and pediatric patients with recurrent or refractory sarcomas were treated with increasing doses of liposomal doxorubicin and temsirolimus using a continual reassessment method for escalation, targeting a dose‐limiting toxicity rate of 20%. Blood samples were drawn before and after the first dose of temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally tolerated dose combination was liposomal doxorubicin 30 mg/m2 monthly with temsirolimus 20 mg/m2 weekly. Hematologic toxicity was common but manageable. Dose‐limiting toxicities were primarily renal. Concurrent administration of liposomal doxorubicin resulted in increased exposure to sirolimus, the active metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients. Co‐administration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite.

Management of Extremity Soft Tissue Sarcomas

This article provides an understanding of the evaluation, staging, and management of patients with extremity soft tissue sarcoma. Although there are straightforward guidelines to the management of patients with extremity soft tissue sarcoma, each patient presents with a unique tumor, and considerations for tumor control, functional outcome, and the toxicity of therapy must be considered. As is true for patients diagnosed with sarcoma at other anatomic sites, a multidisciplinary team approach streamlines care with attention to the complexities and intricacies of choosing and delivering optimal therapy.

Chemotherapeutic management of soft tissue sarcoma.

Soft tissue sarcomas are a heterogeneous group of connective tissue tumors, with more than 50 different subtypes. Given the heterogeneity, and the relative small numbers of patients, performing large adequately powered clinical trials in which one can glean any overall broad treatment decisions based on outcome is difficult at best. There is controversy on which chemotherapeutic agents to use in the adjuvant and metastatic settings, or even if to use chemotherapy in the adjuvant setting. In the metastatic setting, doxorubicin and ifosfamide have remained the standards of care for more than 20 years. This review discusses the data on chemotherapy for treatment of metastatic sarcomas and the utility of chemotherapy in the adjuvant and neoadjuvant settings. In addition, the utility of newer biologic agents in the treatment for sarcomas is considered.