|
|
              
 |
Research Corner Abstracts by Bruce Shriver and Tom Swartz
In this issue's column:
You can download a PDF copy of the program of the 12th Annual CTOS Meeting which was held in Venice Italy on November 2-4, 2006. The copy contains abstracts of all of oral presentations and poster sessions. Click here to download the file (this is a large file, approximately 2.6 MB).
Image guided surgery: New technology for surgery of soft tissue and bone sarcomas K. Reijnders, M.H. Coppes, A.L.J. van Hulzen, J.P. Gravendeel, R.J. van Ginkel and H.J. Hoekstra European Journal of Surgical Oncology (Article in Press, Corrected Proof) Abstract: Aim: Providing the surgical oncologist with a new means of performing safe and radical sarcoma surgery with the help of image guidance technology. Method: Two patients with pelvic sarcomas were operated upon with the help of an intra-operative navigation system. The technology of image guided surgery is described in one patient with a retroperitoneal sarcoma invading the bony pelvis and another patient with a chondrosarcoma of the iliac crest. Results: We show that this new procedure enables optimal radical surgical resection with minimal treatment related morbidity or loss of function.Conclusion: Image guided surgery is a new technical tool in sarcoma surgery.
Walter Rhomberg Sarcoma. 2006; 2006: 87367 Relatively few results are available in the literature about the radiation response of unresectable sarcomas in relation to their histology. The author of this article therefore made an attempt to summarize the present situation. This report is based on a review of the literature and the author's own experience. Adult-type soft tissue sarcomas, chondrosarcomas, and chordomas were analyzed. Radioresponse was mainly associated with the degree of tumor shrinkage, that is, objective responses. Histopathologic responses, that is, the degree of necrosis, are only discussed in relation to radiation treatment reports of soft tissue sarcomas as a group. The results were as follows. Radiation therapy alone leads to major responses in about 50% of lipo-, fibro-, leiomyo-, or chondrosarcomas. The response rate is less than 50% in malignant fibrous histiocytomas, synovial, neurogenic, and other rare soft tissue sarcomas. The response rates may increase up to 75% through the addition of radiosensitizers such as halogenated pyrimidines or razoxane, or by the use of high-LET irradiation. Angiosarcomas become clearly more responsive if biologicals, angiomodulating, and/or tubulin affinic substances are given together with radiation therapy. Razoxane is able to increase the duration and quality of responses even in difficult-to-treat tumors like chondrosarcomas or chordomas. The author concludes that the available data demonstrate that the radioresponsiveness of sarcomas is very variable and dependent on histology, kind of radiation, and various concomitantly given drugs. The rate of complete sustained remissions by radiation therapy alone or in combination with drugs is still far from satisfactory although progress has been made through the use of sensitizing agents.
Alveolar soft-part sarcoma: a review and update
Journal of Clinical Pathology 2006;59:1127-1132 Alveolar soft-part sarcoma (ASPS) is a rare, distinctive sarcoma, typically occurring in young patients. Although it displays a relatively indolent clinical course, the ultimate prognosis is poor and is often characterized by late metastases. Recently, understanding of the genetic events underlying the pathogenesis of ASPS has greatly increased. The historical, histopathological, ultrastructural, immunohistochemical and genetic aspects of ASPS are reviewed in this article.
Liposarcoma in adult limbs treated by limb-sparing surgery and adjuvant radiotherapy
Journal of Bone and Joint Surgery - British Volume, Vol 88-B, Issue 12, 1647-1651 In this review article from a single institution data of liposarcoma patients were analyzed. Between December 1995 and March 2003, 38 adult patients with intermediate or high-grade liposarcoma in a limb were treated by limb-sparing surgery and post-operative radiotherapy. The ten-year local recurrence-free survival was 83%, the ten-year metastasis-free survival 61%, the ten-year disease-free survival 51% and the ten-year overall survival 67%. Analysis of failure and success showed no association with the age of the patients, gender, the location of the primary tumor, the type of liposarcoma and the quality of resection. The authors’ results indicate that liposarcoma may recur even ten years after the end of definitive therapy and may spread to unexpected sites as for soft-tissue sarcoma.
Molecular and Cellular Biology, published online ahead of print on 2006 Nov 13 Chromosomal translocations are frequently associated with soft tissue sarcomas. Fusion proteins generated by such translocations often play critical roles in tumorigenesis. Therefore, it is important to understand the function of the fusion protein to develop therapeutic interventions. The t(X;18)(p11.2;q11.2) translocation found in synovial sarcomas results in a fusion between the SYT gene on chromosome 18 and an SSX gene on the X chromosome. Although SYT-SSX fusion proteins appear to trigger synovial sarcoma development, little is known about the downstream targets of SYT-SSX. The investigators of this study found that the SYT-SSX fusion protein produces a dominant-negative function for the SYT, which is a transcriptional co-activator. Then, the investigators analyzed the gene expression profiles of SYT-SSX1-expressing HeLa cells using oligonucleotide microarrays, and found that the SYT-SSX1 fusion protein directly down-regulated the expression of COM1, a regulator of a cell proliferation. COM1 was found to be expressed at relatively low levels in synovial sarcoma tissues and cell lines. They then investigated the impact of conditional COM1 expression in the synovial sarcoma cell line. Increased COM1 expression resulted in induced apoptosis, and in reduced cell growth and colony formation activity. The investigators thus conclude that their results suggested that restoration of COM1 expression may be of therapeutic benefit in synovial sarcoma.
Combined Transcriptional and Translational Targeting of EWS/FLI-1 in Ewing's Sarcoma
Clinical Cancer Research Vol. 12, 6781-6790, November 15, 2006 The purpose of this preclinical study was to show the efficacy of targeting EWS/FLI-1 expression with a combination of specific antisense oligonucleotides and rapamycin for the control of Ewing's sarcoma (EWS) cell proliferation in vitro and the treatment of mouse tumor xenografts in vivo. The experimental design was as follows. EWS cells were simultaneously exposed to EWS/FLI-1–specific antisense oligonucleotides and rapamycin for various time periods. After treatment, the following end points were monitored and evaluated: expression levels of the EWS/FLI-1 protein, cell proliferation, cell cycle distribution, apoptotic cell death, caspase activation, and tumor growth in EWS xenografts implanted in nude mice. The authors report the following results. Simultaneous exposure of EWS cells in culture to an EWS/FLI-1–targeted suppression therapy using specific antisense oligonucleotides and rapamycin resulted in the activation of a caspase-dependent apoptotic process that involved the restoration of the transforming growth factor-ß–induced proapoptotic pathway. In vivo, individual administration of either antisense oligonucleotides or rapamycin significantly delayed tumor development, and the combined treatment with antisense oligonucleotides and rapamycin caused a considerably stronger inhibition of tumor growth. The authors thus conclude that concurrent administration of EWS/FLI-1 antisense oligonucleotides and rapamycin efficiently induced the apoptotic death of EWS cells in culture through a process involving transforming growth factor-ß. In vivo experiments conclusively showed that the combined treatment with antisense oligonucleotides and rapamycin caused a significant inhibition of tumor growth in mice. The authors state these results provide proof of principle for further exploration of the potential of this combined therapeutic modality as a novel strategy for the treatment of tumors of the Ewing's sarcoma family.
NR0B1 Is Required for the Oncogenic Phenotype Mediated by EWS/FLI in Ewing's Sarcoma
Molecular Cancer Research 4:851-859 (2006) A number of solid tumors, such as alveolar rhabdomyosarcoma, synovial sarcoma, and myxoid liposarcoma, are associated with recurrent translocation events that encode fusion proteins. Ewing's sarcoma is a pediatric tumor that serves as a prototype for this tumor class. Ewing's sarcomas usually harbor the (11;22)(q24;q12) translocation. The t(11;22) encodes the EWS/FLI fusion oncoprotein. EWS/FLI functions as an aberrant transcription factor, but the key target genes that are involved in oncogenesis are largely unknown. Although some target genes have been defined, many of these have been identified in heterologous model systems with uncertain relevance to the human disease. To understand the function of EWS/FLI and its targets in a more clinically relevant system, the investigators of this study used retroviral-mediated RNAi to "knock-down" the fusion protein in patient-derived Ewing's sarcoma cell lines. By combining transcriptional profiling data from three of these lines, the investigators identified a conserved transcriptional response to EWS/FLI. The gene that was most reproducibly up-regulated by EWS/FLI was NR0B1. NR0B1 is a developmentally important orphan nuclear receptor with no previously defined role in oncogenesis. The investigators validated NR0B1 as an EWS/FLI-dysregulated gene and confirmed its expression in primary human tumor samples. Functional studies revealed that ongoing NR0B1 expression is required for the transformed phenotype of Ewing's sarcoma. Thus, the investigators conclude that these studies define a new role for NR0B1 in oncogenic transformation and emphasize the utility of analyzing the function of EWS/FLI in Ewing's sarcoma cells.
Cancer Research. 2006 Oct 15;66(20):9937-47 Tumors of the Ewing's sarcoma family (ESFT), such as Ewing's sarcoma (EWS) and primitive neuroectodermal tumors (PNET), are highly aggressive malignancies predominantly affecting children and young adults. ESFT express chimeric transcription factors encoded by hybrid genes fusing the EWS gene with several ETS genes, most commonly FLI-1. EWS/FLI-1 proteins are responsible for the malignant phenotype of ESFT, but only few of their transcriptional targets are known. Using antisense and short hairpin RNA–mediated gene expression knockdown, array analyses, chromatin immunoprecipitation methods, and reexpression studies, the investigators of this study show that caveolin-1 (CAV1) is a new direct target of EWS/FLI-1 that is overexpressed in ESFT cell lines and tumor specimens and is necessary for ESFT tumorigenesis. CAV1 knockdown led to up-regulation of Snail and the concomitant loss of E-cadherin expression. Consistently, loss of CAV1 expression inhibited the anchorage-independent growth of EWS cells and markedly reduced the growth of EWS cell–derived tumors in nude mice xenografts, indicating that CAV1 promotes the malignant phenotype in EWS carcinogenesis. Reexpression of CAV1 or E-cadherin in CAV1 knockdown EWS cells rescued the oncogenic phenotype of the original EWS cells, showing that the CAV1/Snail/E-cadherin pathway plays a central role in the expression of the oncogenic transformation functions of EWS/FLI-1. Overall, these data identify CAV1 as a key determinant of the tumorigenicity of ESFT and imply that targeting CAV1 may allow the development of new molecular therapeutic strategies for ESFT patients.
Abigail S. Caudle, Joel E. Tepper, Benjamin F. Calvo, Michael O. Meyers, Lav K. Goyal, William G. Cance and Hong Jin Kim Annals of Surgical Oncology, 10.1245/s10434-006-9248-9, 2006 Retroperitoneal sarcomas (RPS) remain a therapeutic challenge due to high local recurrence rates. Preoperative Radiotherarpy offers theoretical advantages in the multidisciplinary care of RPS. The purpose of this study was to evaluate experience using preoperative radiotherapy (PRT) in the treatment of RPS. This was a single-institution review of patients with RPS treated with PRT from 1994 until 2004. Three radiation oncologists and four surgical oncologists were involved. Medical records, tumor registries, and death records were reviewed. Fourteen patients were included; nine were treated for primary presentation and five for recurrent disease. Histologic grade was grade I (n = 3), grade II (n = 3), and grade III (n = 8). Five patients received additional IORT. Radiotherapy complications were generally mild, including nausea (n = 3), diarrhea (n = 1), dehydration (n = 1), anemia (n = 1), and skin changes (n = 1); one required early cessation due to nausea. Thirteen patients had gross negative margins; while 7/13 had negative microscopic margins. Operative complications included anastomotic bleeding (n = 1), fluid collections (n = 2), ileus (n = 3), ascites (n = 2), temporary leg weakness (n = 1), and uncomplicated wound infections (n = 2). In patients with R0 or R1 resections, one and two year local control rates were 64 and 50%. Overall survival for all patients was 90% at 1 year and 74% at 2 years with median survival of 21 months. The authors conclude that PRT and IORT can be administered effectively in carefully selected patients with resectable RPS. The authors also state that larger multi-center studies are needed to delineate the role of PRT and IORT to improve local recurrence and survival rates in the treatment of RPS.
A review of vaccine clinical trials for non-small cell lung cancer J Nemunaitis & J Nemunaitis, Expert Opinion on Biological Therapy, January 2007, Vol. 7, No. 1, Pages 89-102 Recent evidence suggests that vaccines which enhance tumour antigen recognition may provide clinical benefit to subsets of non-small cell lung cancer patients. In this review, a variety of peptide-, gene- and cell-based clinical vaccine approaches targeting non-small cell lung cancer patients are reviewed. Results consistently demonstrate lack of toxicity. Examples of prolonged stable disease, tumour shrinkage response and survival benefit in comparison with historical and low-dose control groups have been demonstrated. Specific vaccines fulfilling justification for Phase III evaluation based on these results include LBLP25, TGF-β2 antisense gene vaccine and GVAX.
Staging of Primary Malignancies of Bone
CA: A Cancer Journal for Clinicians, 2006; 56:366-375 Staging is the process whereby patients are evaluated with regard to the histology, as well as the local and distant extent, of disease. This process helps to define the prognosis for patients and helps guide their treatment. Proper staging also allows for meaningful comparisons to be made among groups of patients. This is especially important when studies are performed in an attempt to develop new treatment strategies. The previous AJCC system for bone cancers closely reflected the more commonly used MSTS staging system. It still is unclear whether or not the recent changes in the system will better serve physicians who treat patients or others who perform research in the field of musculoskeletal oncology. The current AJCC staging system is based on tumor grade and size and the presence and location of metastases. It is a strictly anatomic system. New discoveries in the field of molecular biology will likely contribute greatly to future tumor classification systems and treatment protocols.
In this study, the Quality
of life (QoL) and posttraumatic stress symptoms (PTSS) were
studied in patients with soft tissue
sarcoma (STS) of the extremities treated
with isolated limb perfusion and delayed resection, with or
without adjuvant irradiation. Forty-one patients received a questionnaire
that included the RAND-36 and Impact of Event Scale. The results
were as follows. Thirty-nine STS survivors (16 [41%] male and 23 [59%]
female; median age, 59 years; range, 15–78 years) participated
in the questionnaire survey (response rate, 95%). The median
age at perfusion was 49 years (range, 14–72 years). No
significant differences were found in mean scores between STS
survivors and the reference group with the exception of a worse
physical functioning. Patients with amputations showed significantly
worse physical and social functioning and more role limitations
than patients whose limbs were saved. Eleven patients (28%)
had a PTSS score of 0, and eight patients (20.5%) had a score
Annals of Surgical Oncology
13:1123-1129 (2006)
Use of Distal Femoral Osteoarticular Allografts in Limb Salvage Surgery
The Journal of Bone and Joint Surgery (American), 2006;88:305-321. As diagnostic and therapeutic techniques improve, patients with a musculoskeletal sarcoma should expect longer survival, fewer complications and side effects, and an improved quality of life. Functional longevity of the reconstruction after resection of the tumor becomes a major concern, especially in young and physically active patients. The purpose of this study was to analyze the mid-term and long-term survival of reconstructions with a distal femoral osteoarticular allograft in a series of patients. The authors retrospectively reviewed the results of eighty reconstructions with a distal femoral osteoarticular allograft following resection of a bone tumor in seventy-six patients. The mean duration of follow-up was eighty-two months. The rates of survival of the allograft and the joint surface were estimated with use of the Kaplan-Meier method. Cox regression analysis was performed to determine whether age, gender, the percentage of the femur that had been resected, and the use of chemotherapy were independent prognostic factors. Functional and radiographic results were documented according to the Musculoskeletal Tumor Society scoring system at the time of the latest follow-up. The results were as follows. Five patients were lost to follow-up, leaving seventy-five allografts in seventy-one patients available for study. Thirteen patients (thirteen allografts) died of tumor-related causes without allograft failure before a two-year radiographic follow-up could be performed. Of the remaining sixty-two allografts, fourteen failed: six failed as a result of infection; four, because of local recurrence; one, because of massive resorption; and three, as a result of fracture. At the time of final follow-up, at a mean of 125 months, forty-eight allografts were still in place. The overall rate of allograft survival was 78% at both five and ten years, and the rate of allograft survival without the need for resurfacing with a knee prosthesis was 71% at both five and ten years. With the numbers available, age, gender, the percentage of the femur that had been resected, and the use of chemotherapy were not found to have a significant effect on the overall allograft survival rates. The patients who retained the original allograft had good or excellent functional and radiographic results. The authors thus found a high rate of survival of distal femoral allograft reconstructions at both five and ten years.
Wild-type p53 Inhibits Nuclear Factor-κB–Induced Matrix Metalloproteinase-9 Promoter Activation: Implications for Soft Tissue Sarcoma Growth and Metastasis
Molecular Cancer Research 4(11):803-810 (2006) Human soft tissue sarcoma (STS) is a highly lethal malignancy in which control of metastasis determines survival. Little is known about the molecular determinants of STS dissemination. Here, we show that human STS express high levels of matrix metalloproteinase-9 (MMP-9) and that MMP-9 expression levels correlate with sequence analysis–defined p53 mutational status. Reintroduction of wild-type p53 (wtp53) into mutant p53 STS cell lines decreased MMP-9 mRNA and protein levels, decreased zymography-assessed MMP-9 proteolytic activity, and decreased tumor cell invasiveness. Reintroduction of wtp53 into STS xenografts decreased tumor growth and MMP-9 protein expression. Luciferase reporter studies showed that reintroduction of wtp53 into mutant p53 STS cells decreased MMP-9 promoter activity. Deletion constructs of the MMP-9 promoter identified a region containing a p53-responsive element that lacked a p53 consensus binding site but did contain a nuclear factor-κB (NF-κB) site. Mutating this NF-κB binding site eliminated the wtp53-repressive effect. Electrophoretic mobility shift assays confirmed decreased NF-κB binding in STS cells in the presence of wtp53. Our findings suggest a role for MMP-9 in STS progression and expand the role of p53 in molecular control of STS growth and metastasis. Therapeutic interventions in human STS targeting MMP-9 activity directly or via reintroduction of wtp53 merit further investigation.
Osteoclasts Direct Bystander Killing of Bone Cancer
Cancer Research, 2006 Nov 15;66(22):10929-35 Primary and metastatic bone cancers are difficult to eradicate and novel approaches are needed to improve treatment and extend life. As bone cancer grows, osteoclasts, the principal bone-resorbing cells of the body, are recruited to and activated at sites of cancer. In this investigation, the authors determined if osteoclast lineage cells could function as a cell-based gene delivery system to bone cancers. They used the cytosine deaminase (CD) 5-fluorocytosine (5-FC) enzyme/prodrug system and studied bone marrow and bones from transgenic mice expressing a novel CD gene regulated by the osteoclast tartrate-resistant acid phosphatase (TRAP) gene promoter (Tg/NCD). DsRed2-labeled 2472 sarcoma cells were placed in Tg/NCD osteoclastogenic cultures and treated with 5-FC. 5-FC treatment resulted in profound bystander killing (90%; P < 0.05). The effect of 5-FC treatment on osteoclast lineage cells was most dramatic when administered at the beginning of the 7-day cultures, suggesting that mature osteoclasts are less sensitive to 5-FC. Evaluation of osteoclast-directed bystander killing in vivo revealed dramatic killing of bone cancer with only a modest effect on osteoclast number. Specifically, 5-FC treatment of tumor-bearing Tg/NCD mice or Tg/NCD bone marrow transplanted C3H mice (Tg/NCD-C3H) resulted in 92% and 44% reductions in tumor area, respectively (P < 0.05). Eight of ten 5-FC-treated Tg/NCD mice had complete bone tumor killing and five of six 5-FC-treated Tg/NCD-C3H mice had reduced tumor compared with controls. In addition, Tg/NCD osteoclasts were resistant to 5-FC treatment in vivo, a very important feature, as it identifies osteoclasts as an ideal CD gene delivery system.
Prognostic factors and expression of p53 and mdm-2 in uterine sarcomas S.H. Kim, J.W. Kim, Y.T. Kim, J.H. Kim, B.S. Yoon and H.S. Ryu International Journal of Gynecology & Obstetrics, Volume 95, Issue 3 , December 2006, Pages 272-277 Abstract" Objectives: To evaluate the clinicopathologic prognostic factors of uterine sarcoma, and determine whether overexpression of p53 and mdm-2 proteins correlate with overall survival and prognostic factors. Methods: Thirty specimens from 43 patients with uterine sarcoma were available for slide review and evaluated by immunohistochemistry at Yonsei and Ajou University Medical Centers for the expression of p53 and mdm-2. Results: Overall survival was found to correlate to histologic type of uterine sarcoma, surgical stage, tumor grade, and mitotic index. Whereas 63% of the sarcomas expressed p53, with a significant correlation to overall survival, 60% expressed mdm-2, with a significant correlation to the mitotic index but not to overall survival. Conclusion: Histologic type, surgical stage, tumor grade, mitotic index, and p53 expression were prognostic factors of the overall survival of patients with uterine sarcoma
World's Largest Clinical Trial Into Osteosarcoma Well Underway The world's largest study aimed at improving the treatment of a rare type of bone cancer that mainly affects children and young adults is well underway. The European and American Osteosarcoma Study Group (EURAMOS) clinical trial, which involves a collaboration across 11 European countries, as well as the US and Canada, is on course to recruit some 1400 patients over the next few years to improve treatment for osteosarcoma, the most common bone cancer in children. Doctors and scientists meeting at the Pan European Sarcoma Trials conference which was help in Stuttgart, Germany in early December week heard that recruitment for the trial was on track, with some 335 patients being treated within the trial. The EURAMOS study brings together three existing European collaborations that are examining treatments for sarcomas, and one North American group. EURAMOS is being funded through the European Science Foundation's EUROCORES (European Collaborative Research) program on pan-European Clinical Trials (ECT). People with osteosarcoma are usually first given chemotherapy before the tumor is surgically removed, followed by another course of chemotherapy. The effect of the initial course of chemotherapy can vary however; in some cases there is a good response and in others a poor response. This can have a bearing on the ultimate outcome of the treatment, with poor responders to the initial course of chemotherapy tending to have a worse chance of surviving the disease. The EURAMOS trial will examine a different treatment regime for 'poor responders' to see if survival rates can be improved. The Stuttgart conference, attended by nearly 200 delegates from across the world, heard that new regulations governing clinical trials, introduced by the European Union, had caused difficulties but in the case of EURAMOS these hurdles had successfully been cleared. The clinical trials directive introduced by the EU and aimed at harmonizing administrative provisions governing clinical trials across the Union and introducing greater protection for patients had unwittingly created a number of obstacles to establishing non-commercial clinical trials. "Unfortunately the type of trials that we undertake to improve therapies using existing drugs now fall under the same regulations as trials by the pharmaceutical industry investigating novel agents," said Professor Bielack. "This has created many legal and bureaucratic difficulties, especially in setting up trials across national boundaries. It has also made trials far more expensive than in the past." Dr. Kathy Pritchard-Jones, President-elect of SIOP Europe , the European branch of the Société Internationale d'Oncologie Pédiatrique (a.k.a. International Society of Paediatric Oncology), said, "The aims of the EU's clinical trials directive are entirely laudable, but there have been unforeseen consequences that have led to delays in establishing trials. And while there is no doubt that clinical trials are now better constructed under the new regime, we do need a more rational approach to a number of aspects of non-commercial clinical trials." Dr. Heribert Jurgens, immediate past-president of the German Society for Pediatric Oncology and Hematology, told the conference, "The EU regulations were designed to promote better research and protect the subjects. We have to accept and apply them, and establish centralized structures and standardized procedures." The issue of the use of medicines in pediatric clinical trials was also discussed. Professor Paolo Paolucci, chairman of the Therapeutic Expert Group in Oncology of the Taskforce in Europe for Drug Development for the Young (TEDDY), said, "The objectives of the EU directive are important to increase development of medicines in children." TEDDY's role is to promote the availability of safe and effective medicines for children in Europe by integrating existing expertise and good practice. As a 'network of excellence' it has more than 100 doctors and scientists with an interest in sarcomas, Professor Paolucci said. The conference also heard of many new advances in the diagnosis and treatment of sarcomas, from molecular genetic techniques to determine precisely which type of cancer was present, to the latest radiotherapy technologies and new methods for removing secondary tumors from the lung with lasers. The conference was also told how as survival rates for sarcomas continue to improve, issues of quality of life of patients are becoming increasingly important, while remaining challenging to quantify precisely and objectively. Dr. Mariana Resnicoff, co-ordinator of the ESF EUROCORES program in medical sciences, said that the conference had demonstrated the importance of pan-European collaborations in academic trials aimed at developing new modalities in the treatment of sarcoma. Dr. Resnicoff added, "EURAMOS has succeeded in overcoming the hurdles imposed by the implementation of the EU Clinical Trials Directive and the experience gathered throughout the launch of this trial can be used as a model to pave the way for further pan-European academic clinical trials in the future."
The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of examinations of surgical specimens. The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that these protocols might be used by hospitals, attorneys, payers, and others. Effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, the College believes it becomes even more important for pathologists to familiarize themselves with this document. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document. The College regards the reporting elements in the “Surgical Pathology Cancer Case Summary (Checklist)” portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.
Longer Infusion Times for Anthracyclines Reduce Cardiac Damage Zosia Chustecks Medscape Medical News November 29, 2006 — Using a longer infusion time for anthracycline administration may reduce the cardiotoxicity of these drugs, suggests a new Cochrane review. "An anthracycline infusion duration of 6 hours or longer reduces the risk of clinical heart failure, and it seems to reduce the risk of subclinical cardiac damage," the authors conclude. Anthracycline-induced cardiotoxicity appears to be related to the peak plasma drug concentration, while the antitumor activity depends on tissue concentration over time, lead researcher Elvira van Dalen, MD, from the Emma Children's Hospital, in Amsterdam, the Netherlands, explained to Medscape. Prolonging the infusion time reduces the peak anthracycline concentration, with potentially less cardiotoxicity, while maintaining the antitumor activity, she said. The authors conducted a meta-analysis of 6 randomized clinical trials, involving a total of 625 patients. The majority of patients were adults with different types of solid tumors, and the drugs used were doxorubicin, daunorubicin, and epirubicin. Results from 5 trials (n = 557) showed that patients who received an infusion over a 6-hour period or longer had a significantly lower rate of clinical heart failure than patients who received infusions of shorter duration (lasting 1 hour or less). The risk was around 75% lower in patients receiving the longer infusions compared with the shorter infusions (relative risk, 0.27; 95% CI 0.09 – 0.81). Results from 2 individual trials suggest that the longer infusion time also reduces the risk of subclinical cardiac damage — the various cardiac abnormalities diagnosed with, for example, echocardiography in asymptomatic patients. The duration of the infusion did not appear to affect either tumor response or overall survival, the researchers report. The prolonged infusion of 6 hours or more might be justified in patients who are at high risk of cardiac damage or patients who need a high cumulative dose of chemotherapy, the authors conclude. However, in comments to Medscape, Dr. van Dalen added: "Recommendations for clinical practice should be made by clinicians who should weigh all the available evidence, not only on cardiotoxicity but also on antitumor efficacy and other adverse effects." The researchers emphasize that most of the patients in these studies were adults with advanced solid tumors, and very few children were included. "Since there is only a small amount of data for children and because data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children," they comment. No adequate studies in children with solid tumors are available, Dr. van Dalen noted, although there are 2 trials in children with leukemia. In these 2 trials, no difference was seen in the cardiac damage with different infusion durations, and there was no information on antitumor efficacy, she said. A second Cochrane review by the same group of authors investigated whether the anthracycline derivatives differed in their potential for cardiotoxicity. There is some suggestion of a lower rate of clinical heart failure with epirubicin compared with doxorubicin, they comment, although the difference was not significant. This analysis was based on 5 trials involving 1036 patients. "We are not able to favor either epirubicin or doxorubicin when given at the same dose," they conclude. However, there is evidence to favor liposomal-encapsulated doxorubicin over conventional doxorubicin in adults with solid tumors, they note. In an analysis of 2 trials involving 521 patients, the liposomal-encapsulated drug was associated with a significantly lower rate of clinical heart failure than the conventional product (RR, 0.20; 95% CI, 0.05 – 0.75).
Electroporation Therapy in Soft Tissue Sarcoma: A Potentially Effective Novel Treatment Remco de Bree, BernardM. Tijink, Cees J. van Groeningen, and C. Ren´e LeemansSarcoma, Volume 2006, Article ID 85234, Pages 1–5 Electroporation therapy (EPT) is a novel local treatment modality that uses brief, high-intensity, pulsed electrical currents to enhance the uptake of cytotoxic drugs, vaccines, and genes into cells by producing a transient increase in cell wall permeability. The technique is potentially useful in primary and secondary tumors of different tumor types. EPT involves the use of a specially developed delivery device, the MedPulser (Genetronics Biomedical Corporation, San Diego, California, USA), which consists of a circular array of electrode needles. This needle array is inserted directly into the lesion. Experience has been achieved with various tumor types, but there is yet no report on soft tissue sarcoma. This paper is a case report of using EPT in a sarcoma patient. The patient was a 24-year-old male who underwent extensive resection and postoperative radiotherapy for a malignant peripheral nerve sheath tumor in the right infratemporal fossa with intracranial extension and invasion of the maxillary sinus and mandible who had a recurrence in the scar of his craniotomy for which he was initially treated with doxorubicin. After discontinuation of doxorubicin he developed a metastatic mass at the same site for which he was treated with electroporation therapy. The subcutaneous metastasis was infiltrated with bleomycin and electroporated. The authors report that gradually the tumor became increasingly necrotic and demarcated from surrounding tissue. After 10 weeks no tumor was seen anymore. The wound healed secondarily. Thus, the authors conclude that intralesional bleomycin followed by EPT is potentially effective, well tolerated, and easy to perform in well accessible soft tissue sarcoma sites.
NIH Director's Pioneer Award A unique aspect of the NIH Roadmap for Medical Research is the NIH Director’s Pioneer Award (NDPA) Program, a high-risk research initiative of Research Teams of the Future. First announced in Fiscal Year 2004, nine awards were made in September 2004, and 13 awards each were made in 2005 and 2006. The NDPA is designed to support individual scientists of exceptional creativity who propose pioneering approaches to major challenges in biomedical and behavioral research. The term “pioneering” is used to describe highly innovative – potentially transformative – approaches that have the potential to produce an unusually high impact, and the term “award” is used to mean a grant for conducting research, rather than a reward for past achievements. Biomedical and behavioral research is defined broadly in this announcement as encompassing scientific investigations in the biological, behavioral, clinical, social, physical, chemical, computational, engineering, and mathematical sciences. The NDPA is meant to support individuals who intend to pursue new research directions that are not already supported by other mechanisms. The program is not intended simply to expand the funding of persons already well supported for a particular project. A fourth NDPA competition for approximately 5–10 new awards of $500,000 in direct costs per year for five years that will be made in Fiscal Year 2007. Awardees are required to commit the major portion (at least 51%) of their research effort to activities supported by the NDPA.
NIH Announces Licensing Opportunities for Rare Disease Technologies The National Institutes of Health (NIH) launched a new website today offering technologies available for commercial licensing that are related to rare diseases or conditions. The listing currently consists of more than 500 such technologies, including drugs, biologics, and devices, available to be transferred from the NIH and the U.S. Food and Drug Administration (FDA) to the private sector for further research and development and potential commercialization. Technologies related to rare diseases or conditions available for commercial licensing are listed under the related disease or condition on the website. Non-profit institutions can have their technologies included in this list (click here).
Patients' Views on Financial Conflicts of Interest in Cancer Research Trials Lindsay A. Hampson, B.A., Manish Agrawal, M.D., Steven Joffe, M.D., M.P.H., Cary P. Gross, M.D., Joel Verter, Ph.D., and Ezekiel J. Emanuel, M.D., Ph.D. New England Journal of Medicine, Nov. 30, 2006, Vol. 355, No. 22, pp. 2330-2337 Background Financial ties between researchers or medical centers and companies whose drugs are being tested have come under increasing scrutiny. Methods We conducted in-person interviews with 253 patients in cancer-research trials (a 93% response rate) at five U.S. medical centers to determine their attitudes regarding potential financial conflicts of interest among researchers and medical centers. Results More than 90% of patients expressed little or no worry about financial ties that researchers or institutions might have with drug companies. Most patients said they would have enrolled in the trial even if the drug company had paid the researcher for speaking (82% of those interviewed) or consulting (75%) or if the researcher had received royalty payments (70%) or owned stock in the company (76%). Similarly, most patients would have enrolled in the trial if their cancer center had owned stock in the drug company (77%) or received royalty payments from the company (79%). Most patients believed it was ethical for researchers to receive speaking fees (81%) or consulting fees (82%) from the company. However, a substantial minority of patients wanted disclosure of the oversight system for researchers (40%) and of researchers' financial interests (31%); 17% thought no disclosure to patients was necessary. Conclusions Most patients in cancer-research trials were not worried about financial ties between researchers or medical centers and drug companies and would still have enrolled in the trial if they had known about such financial ties. A substantial minority wanted to be informed about the oversight system to protect against financial conflicts of interest and about researchers' financial interests.
V3N6 ESUN Copyright © 2006 Liddy Shriver Sarcoma Initiative. |
26, which suggested the need for psychological counseling. None
of these eight patients had lost a limb. Patients who indicated
that the choice of treatment was made by the surgeon rather than
collaboratively showed significantly decreased social functioning,
more role limitations, and intrusion. Greater treatment satisfaction
was significantly related to better social functioning, more
vitality, better general health perception, less intrusion,
avoidance, and total Impact of Event Scale scores. The authors conclude
that even though STS survivors’ QoL was different from that of a
reference group only in physical functioning, one fifth of the
patients had PTSS. An amputation, the physician’s decision rather
than the patient’s decision for the perfusion treatment and a low
satisfaction with the performed treatment negatively influenced
QoL.
