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Abstracts by Tom Swartz and Bruce Shriver
In this issue's column:
The Hazards of Biopsy in Patients with Malignant Primary Bone and Soft-Tissue Tumors The Musculoskeletal Tumor Society conducted this study to assess: (1) the accuracy of diagnoses made from the findings of biopsies; (2) the incidence of complications associated with the biopsy procedure; (3) the effects of errors in diagnosis and of complications on the patient's course; and (4) whether these problems occurred with greater frequency when the initial biopsy was performed in a referring institution or in a treating center. Using questionnaires, each member of the Society was asked to submit data on twenty sequential, unselected, newly diagnosed patients with malignant primary tumors of bone or soft tissue who had had a biopsy and a subsequent definitive procedure. Twenty orthopedic surgeons in sixteen treating centers submitted information on 329 patients with a wide range of diagnoses. The mean age of the patients was 36.5 years (range, two weeks to eighty-three years). Two hundred and twenty-two lesions were primary in bone and 107 arose in soft tissue. One hundred and forty-three of the tumors were biopsied in the referring institution and 171 in the treating center. Analysis of the results of the study showed sixty (18.2 per cent) major errors in diagnosis and thirty-four (10.3 per cent) non-representative or technically poor biopsies. Problems arose in the skin, soft tissue, or bone of the biopsy wounds of fifty-seven patients (17.3 per cent), and the optimum treatment plan had to be altered as a result of problems related to the biopsy in sixty patients (18.2 per cent). In fifteen patients (4.5 per cent) an unnecessary amputation was performed as a result of problems with the biopsy, and in twenty-eight patients (8.5 per cent) the prognosis and outcome were considered to have been adversely affected. The biopsy-related problems occurred from three to more than five times more frequently when the biopsy was performed at a referring institution rather than in a treating center.
On the basis of these observations, the Society suggests the following. The biopsy should be planned as carefully as definitive surgery and that careful attention should be paid to asepsis, skin-handling, hemostasis, and wound closure. The skin incision should be placed in such a manner so as not to compromise subsequent surgery. The tissue obtained should be sufficient in amount and sufficiently representative of the lesion so that the pathologist can provide a definitive diagnosis. If the surgeon or the institution is not prepared to perform accurate diagnostic studies or proceed with definitive treatment for these patients, the patients should be referred to a treating center prior to biopsy. The full text of the article is available by subscription.
Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate In this article which appeared in the May 11, 2006 issue of The New England Journal of Medicine, Dr. Berman and her co-authors summarized their results in the following way, "In summary, although imatinib inhibits tyrosine kinases associated with specific diseases, our data suggest that in vivo inhibition of the PDGF receptor may also occur and may have clinical consequences. If this is confirmed, routine monitoring of serum phosphate and vitamin D during imatinib therapy may be advisable so that prompt phosphate replacement can be initiated. Chronic, untreated hypophosphatemia can result in impaired bone mineralization, rickets, and osteomalacia. Further study in this area is important, since other tyrosine kinase inhibitors that act on the PDGF receptor are now in clinical use in patients with renal adenocarcinoma and other forms of cancer." An interview with Dr. Robert Maki, on of the co-authors of the study, can be found on the GIST Support International website by clicking here. NEJM. 2006 May 11;354 (19):2006-13.
Endoprosthetic Reconstruction in 250 Patients with Sarcoma The authors of this study assessed the clinical results and complications associated with an endoprosthetic replacement system called Mutars® used in 250 patients with a malignant bone or soft tissue tumor. The key features of the Mutars® system are its cementless, hexagonal-shaped stem (titanium alloy), the possibility of torsion adjustments in 5° increments, and the Trevira® tube for soft tissue attachment. The mean age of the patients was 30.7 years, and the mean follow up was 45 months. Prosthetic survival at 5 years was 89.7% for the upper extremity and 68.5% for the lower extremity. Prosthetic survival without any reoperation was 73.4% at 3 years postoperatively and 60.4% at 5 years postoperatively. Prosthetic failure was caused by deep infection in 12% (30 patients) of patients and aseptic loosening in 8% (20 patients) of patients. Stem fracture occurred in only 1.6% (four patients) of patients. Dislocation rates were reduced by using the Trevira® tube. Limb survival was achieved in 82.6% to 93.1% of patients depending on the endoprosthetic replacement site, and functional results ranged between 63% to 83% according to the Tumor Society score. The authors conclude that these results suggest limb salvage with the Mutars® endoprosthesis is successful with good functional results. The full text of the above article is available by subscription.
Clinical Results of Surgery for Retroperitoneal Sarcoma with Major Blood Vessel Involvement This study was conducted to evaluate the clinical results of resection for retroperitoneal soft tissue sarcomas (STS) with vascular involvement. The peritoneum is the smooth transparent serous membrane that lines the cavity of the abdomen and is folded inward over the abdominal and pelvic viscera. Thus, a retroperitoneal sarcoma is one which is situated behind the peritoneum (see the article, Abdominal anatomy for GIST: the peritoneum and retroperitoneum for a discussion of and images of the abdominal anatomy). The study group consisted of consecutive patients (mean age, 52 years) who underwent surgery for retroperitoneal STS with vascular involvement. The procedures were performed between 1988 and 2004. Vessel involvement by STS was classified as type I, artery and vein; type II, only artery; type III, only vein; and type IV, neither artery nor vein (excluded from the analysis). Patient data were prospectively gathered in a computerized database and retrospectively analyzed. Of 141 patients with retroperitoneal STS, 25 (17.7%) underwent surgery for tumors with vascular involvement. The most common vascular involvement pattern was vein only (type III) at 64%. Arterial and vein (type I) and arterial only (type II) involvement were observed in 16% and 20% of the cases, respectively. STS originating from the vessel wall (primary vessel involvement) was seen in eight patients, and 17 patients had secondary vascular involvement. Resection and vascular repair were done in 22 patients (no vascular repair in three patients due to ligation of the external iliac vein in one patient, and debulking procedures in two). All patients with arterial involvement (type I and II) had arterial reconstruction consisting of aortic replacement (Dacron, n = 3; and expanded polytetrafluoroethylene [ePTFE], n = 2), iliac repair (Dacron, n = 3), and truncal reimplantation (n = 1). The inferior vena cava (6 ePTFE tube grafts, 3 ePTFE patches, 2 venoplasties), iliac vein (1 ePTFE bypass, 1 Dacron bypass, 1 venous patch), and superior mesenteric vein (1 anastomosis, 1 Dacron bypass) were restored in 80% of the patients (n = 16) with either arterial and venous or only venous involvement (type I and type III setting). Morbidity was 36% (hemorrhage, others), and mortality was 4%. At a median follow-up of 19.3 months (interquartile range, 12.8 to 49.9 months) the arterial patency rate was 88.9%, and the venous patency rate was 93.8% (primary and secondary). Thrombosis developed in one arterial and venous (type I) iliac reconstruction due to a perforated sigmoid diverticulitis 12 months after surgery. The local control rate was 82.4%. The 2-year and 5-year survival rates were 90% and 66.7% after complete resection with tumor-free resection margins (n = 10 patients, median survival not reached at latest follow-up). The median survival was 21 months in patients with complete resection but positive resection margins (n = 7) and 8 months in patients with incomplete tumor clearance (n = 8, persistent local disease or metastasis). The authors of the study conclude (1) that patency rates and an acceptable surgical risk underline the value of en bloc resection of retroperitoneal STS together with involvement of blood vessels; (2) the oncologic outcome is positive, especially after complete resection with tumor-free resection margins; and (3) a classification of vascular involvement can be used to plan resection and vascular replacement as well as to compare results among reports in a standardized fashion.
Oncogene Mutation Detection in Human Cancers by Mass Spectrometry-Based Genotyping Researchers have devised a new method to detect a spectrum of known gene mutations in a variety of cancer genes that they say is both sensitive and cost-effective. They say that if validated, this method of genotyping might ultimately be used in “real time” to match patients to available targeted therapies. Results were presented at the first meeting on Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research. The technique, developed at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT, may also offer aid in the testing and development of tailored treatments, according to researcher Levi A. Garraway, M.D., Ph.D., an assistant professor in the Dana-Farber Department of Medical Oncology. “It may help clinical testing of new targeted therapies, because patients can, in principle, be screened in advance for activating mutations in the protein the agent is directed against,” he said. It could also help eliminate a “significant bottleneck” in the development of drugs, which is the ability to test for multiple types of cancer genetic alterations simultaneously in the clinic. “Tests that use DNA sequencing to look for mutations in a single gene can cost a couple thousand dollars,” Dr. Garraway said. “We ran a whole panel of genes for about $60 each, and the price could drop below that with more updated methods.” The method uses high-throughput mass spectrometry-based genotyping, which is a sensitive and accurate method to detect single nucleotide polymorphisms (SNPs) in DNA. But while this tool is mostly used to understand how single letter (or nucleotide) changes in genes might correlate with disease risk in normal individuals, the researchers adapted it to look for known point mutations in genes that make them oncogenic. They chose oncogenes known to contain “dominant activating mutations in many tumor types. In a lot of cases, the entire biology of the tumor is conditioned around such mutations, so if you eliminate the oncogene, the tumor shrinks,” Dr. Garraway said. Examples include the c-kit tyrosine kinase that drives development of gastrointestinal stromal tumors (GISTs), and certain EGFR mutations that are responsible for one form of lung cancer. These cancers can be treated with the targeted therapies Gleevec and Tarceva, respectively, which shut down the affected oncogenes. The test involves taking a sample of fresh or frozen tumor, amplifying its DNA, and then searching for 250 known mutations in 17 oncogenes. (These include members of the ras, EGFR, pi3 and c-kit kinase families, among others.) To check performance of the genotyping, the research team tested over 1,000 tumors, representing 15 different cancer types, and then independently verified over half of the mutations they identified using traditional DNA sequencing or other methods. They found that over 92 percent of mutations identified by the mass spectrometry method were validated in this manner, and believe that much of the difference is due not to the mass spectrometry method but to limitations of the laborious sequencing test “which is not always sensitive in tumor specimens,” Dr. Garraway said. He added that the mass spectrometry test offers information that is distinct from the cancer microarray gene expression tests now being developed. “Those tests depend on gene expression while this one looks directly at problems in the genome,” Dr. Garraway said.
Uncommon sarcomas of the uterine cervix: a review of selected entities Sarcomas constitute less than 1% of all cervical malignancies. With over 150 reported cases, rhabdomyosarcomas represent the most commonly reported sarcoma at this location. In this report, a select group of the more uncommon sarcomas of the uterine cervix are briefly reviewed, including all previously reported examples of leiomyosarcoma, liposarcoma, alveolar soft part sarcoma, Ewing sarcoma/primitive neuroectodermal tumor, undifferentiated endocervical sarcoma, and malignant peripheral nerve sheath tumor (MPNST). Emphasis in the report is placed on any distinctive clinicopathologic features of these entities at this unusual location. Each of these entities appear to have a distinctive clinicopathologic profile. Management options should be based on the outcomes of the previously reported examples of the entity in question. Indiscriminate direct extrapolations from their soft tissue counterparts may not be appropriate, at least for all entities.
Eag1 is Aberrantly Expressed in over 70% of Sarcomas A provisional PDF copy a paper that will appear in and upcoming issue of Molecular Cancer, "Ether a go-go potassium channel expression in soft tissue sarcoma patients", is now available. Researchers from the Instituto Nacional Câncer in Rio de Janeiro, Brazil and the Max Plank Institute für Experimentelll Medizin in Göttingen, Germany conclude that "Eag1 is aberrantly expressed in over 70% sarcomas. In sarcoma cell lines, inhibition of Eag1 expression and/or function leads to reduced proliferation. The high frequency of expression of Eag1 in primary tumours and the restriction of normal expression of the channel to the brain, suggests the application of this protein for diagnostic or therapeutic purposes." In a companion paper, "Overexpression of Eag1 potassium channels in clinical tumours". the conclusion states, "Inhibition of Eag1 expression in tumour cell lines reduced cell proliferation. Eag1 may therefore represent a promising target for the tailored treatment of human tumours. Furthermore, as normal cells expressing Eag1 are either protected by the blood-brain barrier or represent the terminal stage of normal differentiation, Eag1 based therapies could produce only minor side effects".
Radiation induced angiosarcomas (RIA) can affect breast cancer patients who have had radiotherapy following conservative breast surgery. Their diagnosis is often delayed due to their benign appearance and difficulty in differentiation from radiation induced skin changes. Therefore it is very important that clinicians are aware of their existence. In this article the authors report on a case of RIA followed by a discussion and review of the literature. This literature indicates the following. The incidence of RIA following radiotherapy to the breast varies from 0.05 to 0.2 % with an average latency period reported as 12.5 years. Also, there is general consensus in the literature that the only logical treatment of RIA regardless of histologic type is wide surgical resection i.e. mastectomy usually with a latissimus dorsi flap reconstruction. Conservative treatment even with negative margins exposes the patient to early recurrences and metastatic spread, and adjuvant chemotherapy in RIA has so far produced disappointing results. Median survival in RIA is reported from 1.5 to 2.5 years, and recurrence rates approach 70% with 2-year disease free survival ranging from 0–35 % in various series. The authors conclude that a high index of suspicion for RIA and generous tissue biopsy can lead to early diagnosis. Also, an aggressive surgical approach can lead to a better prognosis. The authors also note that while chemotherapy has not achieved a role in the treatment of these tumors there have been some encouraging results with the use of hyperfractionated radiotherapy.
Isolated limb infusion (ILI) is a minimally invasive technique of delivering regional chemotherapy in patients with advanced melanoma or soft tissue sarcoma of the limb. Reports from Australia of efficacy similar to that of isolated limb perfusion prompted the investigators here to conduct a phase II trial to evaluate the efficacy and safety of ILI. Eligible patients had American Joint Committee on Cancer stage IIIB or IIIC melanoma or unresectable soft tissue sarcoma of the limb. Angiographic catheters were positioned just above the knee or elbow of the extremity. General anesthesia was performed, a proximal tourniquet was inflated, and a normothermic, low-flow, hypoxic infusion of melphalan and dactinomycin was circulated through the involved limb for 20 minutes. The tumor response was assessed by using standard criteria at 3 months. Morbidity was determined in the hospital and at 2, 6, and 12 weeks. The results were as follows. Twenty-five patients were accrued to the trial, and 32 ILIs were performed (8 patients had 2 ILIs); 1 patient was not treated. Of the 22 assessable patients, 11 (50%) had a significant response at 3 months: 23% of patients had a complete response, and 27% of patients had a partial response. The median duration of complete response was 1 year (range, 6–32 months). Morbidity was acceptable. Peak morbidity occurred at 2 weeks and was considered moderate in most patients. Limb edema and erythema were common. No patient developed compartment syndrome or required amputation. The investigators thus conclude that isolated limb infusion is well tolerated, and that half of the patients experienced a complete or partial response.
In his article, Delivering on Nano's Promise, which is the cover story of the current issue of Drug Discovery & Development, Matrick McGee states, "Nanotechnology has been the subject of a great deal of hype, and the pharmaceutical and biotechnology industries are no exception. However, there is a good deal of hard science to back the hype. Nanoparticles such as liposomes, dendrimers, gold nanoshells, quantum dots, and fullerenes have a number of potential advantages over classical drug delivery methods, proponents say. These include greatly altering the absorption, distribution, and length of time drugs stay in the body, as well as allowing for targeted delivery of drugs to diseased sites. A great deal of work is being done exploring its application to cancer therapeutics in an effort to make them more targeted and avoid toxic systemic effects, but scientists are exploring applications in several other areas as well, such as cardiology and infectious diseases. But the field is not without its challenges. Some cite concerns with toxicity and many are skittish when it comes to nanoparticles, arguing that there could be liability concerns. Still another challenge is taking these types of particles from the lab to scaling them up for clinical studies and commercial production." He gives several interesting examples in the article and discusses the need for regulatory guidelines. [Editor's Note: See also An Overview of Some Recent Cancer-Related Nanotechnology Research.]
Incidence of sarcoma in patients treated with fast neutrons The authors of this article, which appears in the November issue of the International Journal of Radiation Oncology Biology Physics (V. 66, I 3, pp 842-844) conclude that, "The long-term incidence of sarcomas in patients previously treated with fast neutrons is significant." This study, which took place at Edinburgh Cancer Center in Scotland, reviewed the case histories of 620 patients treated between 1977 to 1984. The results showed that, "Three cases of sarcoma, developing within the treatment volume, were observed in a small group of patients treated some years earlier using fast neutrons. This incidence was 111 times what would have been expected in the normal population and 15 times the incidence in a comparable photon-treated group of patients."
The E-Cell Project is an international research project aiming to model and reconstruct biological phenomena in silico, and developing necessary theoretical supports, technologies and software platforms to allow precise whole cell simulation. The E-Cell Project’s grand aim is to allow for precise whole cell simulation at the molecular level. Some of the research focuses of the Project include:
The E-Cell System software is an object-oriented software suite for modeling, simulation, and analysis of large scale complex systems such as biological cells, and consists of the following three major parts:
The E-Cell Project is open to anyone who shares the view that development of cell simulation technology may have a multitude of eminent scientific, medical and engineering impacts on our society. E-Cell is an Open Source project. Any contribution is welcome.
With the public’s increased use of the Internet, the use of email as a means of communication between patients and physicians will likely increase. Yet, despite evidence of increased interest by patients, email use by physicians for clinical care has been slow. The authors of this paper sought to examine the factors associated with physician-patient email, and report on the physicians’ adherence to recognized guidelines for email communication. They conducted a cross-sectional survey (March–May, 2005) of all primary care physicians (n = 10253), and a 25% stratified, random sample of all ambulatory clinical specialists (n = 3954) in the state of Florida. Physicians were surveyed on email use with patients, adherence to recognized guidelines, and demographics. The results were as follows. 4203 physicians completed the questionnaire (a 28.2% participation rate). Of these, 689 (16.6%) had personally used email to communicate with patients. Only 120 (2.9%) used email with patients frequently. In univariate analysis, email use correlated with physician age (decreased use: age > 61; P = .014), race (decreased use: Asian background; P < .001), medical training (increased use: family medicine, P = .001; or surgical specialty, P = .007; but not internal medicine, P = .112), practice size (> 50 physicians, P < .001), and geographic location (urban 17.2% vs. rural, 7.9%; P < .001). Multivariate modeling showed that only practice size greater than 50 (OR = 1.94; 95% CI = 1.01-3.79) and Asian-American race (OR = 0.26; 95% CI = 0.14-0.49) were related to email use with patients. Remarkably, only 46 physicians (6.7%) adhered to at least half of the 13 selected guidelines for email communication. The authors conclude that this large survey of physicians, practicing in ambulatory settings, shows only modest advances in the adoption of email communication, and little adherence to recognized guidelines for email correspondence. They argue that further efforts are required to educate both patients and physicians on the advantages and limitations of email communication, and to remove fiscal and legal barriers to its adoption.
Synthetic Molecule Causes Cancer Cells To Self-Destruct Scientists have found a way to trick cancer cells into committing suicide. The novel technique potentially offers an effective method of providing personalized anti-cancer therapy. Most living cells contain a protein called procaspase-3, which, when activated, changes into the executioner enzyme caspase-3 and initiates programmed cell death, called apoptosis. In cancer cells, however, the signaling pathway to procaspase-3 is broken. As a result, cancer cells escape destruction and grow into tumors. "We have identified a small, synthetic compound that directly activates procaspase-3 and induces apoptosis," said Paul J. Hergenrother, a professor of chemistry at the University of Illinois at Urbana-Champaign and corresponding author of a paper published in the journal Nature Chemical Biology. "By bypassing the broken pathway, we can use the cells' own machinery to destroy themselves." To find the compound, called procaspase activating compound one (PAC-1), Hergenrother, with colleagues at the U. of I., Seoul National University, and the National Center for Toxicological Research, screened more than 20,000 structurally diverse compounds for the ability to change procaspase-3 into caspase-3. The researchers tested the compound's efficacy in cell cultures and in three mouse models of cancer. The testing was performed in collaboration with William Helferich, a professor of food science and human nutrition at the U. of I., and Myung-Haing Cho at Seoul National University. The researchers also showed that PAC-1 killed cancer cells in 23 tumors obtained from a local hospital. Cell death was correlated with the level of procaspase-3 present in the cells, with more procaspase-3 resulting in cell death at lower concentrations of PAC-1. "This is the first in what could be a host of organic compounds with the ability to directly activate executioner enzymes," said Hergenrother, who is also an affiliate of the Institute for Genomic Biology at the U. of I. "The potential effectiveness of compounds such as PAC-1 could be predicted in advance, and patients could be selected for treatment based on the amount of procaspase-3 found in their tumor cells." Such personalized medicine strategies are preferential to therapies that rely on general cytotoxins, the researchers say, and could be the future of anti-cancer therapy. Click here to access the abstract of research article in Nature Chemical Biology.
EMBOSS - Molecular Biology Open Software Suite EMBOSS is "The European Molecular Biology Open Software Suite". EMBOSS is a free Open Source software analysis package specially developed for the needs of the molecular biology (e.g. EMBnet) user community. The software automatically copes with data in a variety of formats and allows transparent retrieval of sequence data from the web. Also, as extensive libraries are provided with the package, it is a platform to allow other scientists to develop and release software in true open source spirit. EMBOSS also integrates a range of currently available packages and tools for sequence analysis into a seamless whole. EMBOSS breaks the historical trend towards commercial software packages. Within EMBOSS you will find hundreds of programs (applications) covering areas such as:
EMBOSS has several important features/advantages:
A major new version of EMBOSS is released each year, which is downloadable from the above link, and is licensed for use by everyone under the GPL and LGPL licenses.
Cancer's Molecular Sweet Tooth and the Warburg Effect More than 80 years ago, the renowned biochemist Otto Warburg described how cancer cells avidly consume glucose and produce lactic acid under aerobic conditions. Recent studies arguing that cancer cells benefit from this phenomenon, termed the Warburg effect, have renewed discussions about its exact role as cause, correlate, or facilitator of cancer. Molecular advances in this area may reveal tactics to exploit the cancer cell's "sweet tooth" for cancer therapy. This article reviews these recent studies. The full text of the article is available by subscription. Cancer Research 66, 8927-8930, September 15, 2006.
Dr. Juang state, "Values of preoperative serum CA125 were significantly higher in the uterine leiomyosarcoma group than those in the uterine leiomyoma group. There was significant overlapping of preoperative serum CA125 between the uterine leiomyoma group and early-stage uterine leiomyosarcoma. For both the premenopausal and postmenopausal group, there was a significant difference in the distribution of preoperative serum CA125 in early-stage and advanced-stage uterine leiomyosarcoma. The optimal cutoff values of serum CA125 for the premenopausal group and postmenopausal group was 162 U/mL and 75 U/mL, respectively." Based on this he and his co-workers conclude, "These findings demonstrated that preoperative serum CA125 had a potential role in the differential diagnosis between early-stage and advanced-stage uterine leiomyosarcoma. Further investigation with a larger sample size at adequate power is necessary to verify the current study." [Eur J Gynaecol Oncol. 2006;27(4):370-4]
Tumor Necrosis Has no Prognostic Value in Neoadjuvant Chemotherapy for Soft Tissue Sarcoma From the abstract, "Neoadjuvant chemotherapy for treatment of soft tissue sarcomas is controversial, and the correlation between local recurrence and survival is unclear. Histologic necrosis is a well-documented predictor of survival in patients with malignant bone tumors; however, the association is unknown in patients with soft tissue sarcomas. We assessed the prognostic significance of tumor necrosis for treatment of soft tissue sarcomas. We retrospectively collected data from 82 patients who received neoadjuvant chemotherapy for treatment of soft tissue sarcomas of the extremities. Patients had wide resections if tumors were high-grade, deep to the investing fascia, and had clear margins. We quantified the amount of necrosis and analyzed the relationship with local recurrence and overall survival. At an average followup of 65 months (range, 24-154 months), the 5-year local recurrence rates for patients with less than 95% and 95% or greater necrosis were 20% and 33%, respectively. The overall 5-year survivorship rates for patients with less than 95% necrosis and 95% or greater necrosis were 82% and 78%, respectively. There was no difference in recurrence-free survival or overall patient survival based on the amount of histologic necrosis. Tissue necrosis from neoadjuvant chemotherapy does not seem to predict outcome in soft tissue sarcomas." [Clin Orthop Relat Res 2006 Sep 28]
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