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Abstracts by Bruce Shriver and Tom Swartz
In this issue's column: The prognosis of rhabdomyosarcoma (RMS) in advanced stages is still sobering. Therapy is limited due to local tumor recurrence, development of metastases and multidrug resistance. The aim of this study was to investigate the development of multidrug resistance in cell lines and in xenografts of alveolar and embryonal RMS treated according to the German Soft Tissue Sarcoma Study (CWS). Alveolar and embryonal RMS cell lines were treated with Vincristine, Topotecan, Carboplatin, Actinomycin D, or Ifosfamide. Expression levels of resistance-associated genes were assessed using Real time-PCR. Nude mice (NMRI nu/nu, n = 10 per group) underwent xenotransplantation of human embryonal or alveolar RMS. Animals were treated with standard chemotherapeutic drugs Vincristine, Topotecan, Carboplatin, Actinomycin D, or Ifosfamide according to treatment schedules of the CWS-study. Tumor sizes were measured and relative tumor volumes were calculated. Animals were sacrificed after 20 days and standard histology, Real-time-PCR for MDR1-, MRP-, LRP- and MDM2-gene as well as immunhistochemistry for MDR1-, LRP-, and MRP-protein were performed. In the cell lines, an up-regulation of MDR-1 gene was found in alveolar rhabdomyosarcoma. In embryonal rhabdomyosarcoma, an up-regulation of LRP and MRP was found. Standard chemotherapy of alveolar rhabdomyosarcoma resulted in a significant reduction of tumor growth (P < 0.05) in all groups. In embryonal rhabdomyosarcoma strongest effects were found after treatment with Ifosfamide, Vincristine and Carboplatin (P < 0.05). RT-PCR revealed a MDR1-dependent mechanism in alveolar rhabdomyosarcoma. In embryonal rhabdomyosarcoma, MDR1 occurred to a lower degree. Immunhistochemistry revealed correlating expression levels of multidrug resistance-associated proteins. The use of established chemotherapy on human RMS in vivo had strong effects on xenografts compared to their controls. In all cases, there was only a reduction of tumor growth, but not a complete eradication of the tumors. Chemotherapy seemed to upregulate the expression of resistance-associated genes in vitro and in vivo. The mechanism of multidrug resistance depends on the tumor subtype. Thus, the investigators conclude that further investigations will be required to evaluate multidrug resistance in patients and to investigate new modalities for a reversal of multidrug resistance.
Royal College of Radiologists "Problem-Solving" Web Tool The Royal College of Radiologists has launched a web-based discussion board exclusively for the use of sarcoma clinical staff. The system allows doctors who want to consult wider expertise when facing diagnostic or case problems to do so. The system has 150 members signed up worldwide and the number is growing. Membership is free of charge and aimed at all clinical disciplines, not just radiologists.
The system allows any subscribing member to start a discussion thread and to post images (for example scans or pathology slides). Automated email notification that a new thread has started can alert other members and their opinions or experiences can then be added to the thread. The system will also hold a library of documents, images and past threads so that the knowledge bank steadily accumulates and everything remains accessible.
Clinical staff wishing to find out more should contact Peter Lumb.
Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a noninvasive thermal ablation technique, shown to be clinically effective in the treatment of uterine fibroids and is being evaluated as a method of thermal ablation of benign and malignant breast tumors. The purpose of this study was to evaluate the safety and initial efficacy of MRgFUS for the palliation of pain caused by bone metastases, in patients for whom other treatments were either not effective or not feasible. Thirteen patients suffering from symptomatic bone metastases underwent MRgFUS procedure. Treatment safety was evaluated by assessing the incidence and severity of device-related complications up to 6 months after treatment. Effectiveness of pain palliation was evaluated by a visual analog scale, pain questionnaires and changes in the patients' medication. The results were as follows. Fifteen procedures were carried out. Mean follow-up was 59 days. Twelve patients received adequate treatment and were available for follow-up. Two patients died due to disease progression during the first month after treatment. No severe adverse events were recorded. The remaining 10 patients reported prolonged improvement in pain score and/or reduced analgesic dosage. The researchers conclude that MRgFUS may provide a safe and effective noninvasive alternative for the palliation of pain, caused by bone metastases.
Long-term Survival May Be Achieved with Surgical Removal of Soft Tissue Sarcoma Spread to the Lung According to results recently published in the Archives of Surgery, long-term survival may be achieved with the surgical removal of cancer spread to the lung among patients with soft tissue sarcoma. Standard treatment for soft-tissue sarcomas typically consists of surgery, chemotherapy, and/or radiation therapy. Unfortunately, a significant portion of patients who undergo initial treatment experience a recurrence of their cancer, which can spread (metastasize) to vital organs, such as the lungs. Once the cancer has metastasized to distant sites in the body, long-term survival is reduced. Results from recent studies have indicated that the surgical removal of a metastatic site of cancer may improve outcomes for patients with various cancers. Research into this therapeutic approach continues to be studied. Researchers from Germany recently reviewed medical records of 61 patients with soft tissue sarcoma that had metastasized to the lung. These patients had their lung metastases surgically removed between 1991 and 2002. The researchers’ findings were as follows:
The researchers concluded that the surgical removal of lung metastasis is well tolerated and may result in long-term survival in one out of four patients diagnosed with soft tissue sarcoma. The researchers state that long-term survival is even possible when the lung metastases have recurred and are surgically removed among these patients. Patients diagnosed with soft tissue sarcoma whose cancer has spread to the lung may wish to speak with their physician regarding their individual risks and benefits of surgical removal of their cancer.
Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene–environment interactions in human carcinogenesis. The above linked commentary article emerged from a workshop entitled "Cancer Survivorship: Genetic Susceptibility and Second Primary Cancers," held November 8–9, 2004, in Rockville, Maryland. The goals of the workshop were to identify research issues, priorities, resources, and infrastructure requirements needed to advance the field of second primary cancers and genetic susceptibility and to make specific recommendations for implementation of new research strategies. The workshop focused mainly on survivors of adult cancers, given the lack of a comprehensive, organized approach in this research area to date. Workshop participants considered inherent genetic susceptibility factors to second primary cancers within the context of familial syndromes, genetic modifiers of specific radiation- and chemotherapy-related cancers, and available populations of cancer survivors to study late effects. The participants represented a transdisciplinary group of experts in epidemiology, statistics, molecular genetics, clinical genetics, pharmacogenomics, informatics, radiation biology, medical oncology, pediatric oncology, and radiation oncology, as well as the advocacy community. The workshop’s recommendations are given in the full article which is accessible by clicking the link above.
Management of locally recurrent soft-tissue sarcoma after prior surgery and radiation therapy The aim of this study was to evaluate outcome and treatment toxicity after wide local re-excision (WLE), with or without additional radiation therapy, for patients with isolated first local recurrence of soft-tissue sarcoma arising within a previously irradiated field. A retrospective review was performed of 62 consecutive patients. All patients underwent prior resection and external beam radiation. For recurrent disease, 25 patients were treated with WLE alone, and 37 patients were treated with WLE and additional radiation (45– 64 Gy). In 33 patients, the radiation was delivered via an afterloaded brachytherapy, single-plane implant. The results were as follows. The 5-year disease specific and distant metastasis-free survival rates were 65% and 73%, respectively. Local control at 5 years was 51%, and on multivariate analysis, a positive surgical resection margin (p< 0.001) was associated with a lower rate of local control. Reirradiation was not associated with improved local control; however complications requiring outpatient or surgical management were more common in patients who had undergone reirradiation (80% vs. 17%, p < 0.001). Amputation was also more common in the subgroup of patients who underwent extremity reirradiation (35% with radiation vs. 11% without, p = 0.05), although only one amputation was performed to resolve a treatment complication. The authors conclude: Conservative surgery alone results in local control in a minority of patients who have failed locally after previous excision and external beam radiation. Although selection biases and small patient numbers confound the analysis, local treatment intensification with additional radiation does not clearly improve outcome after surgical excision alone, and is associated with an increase in complications.
Review of the M.D. Anderson experience in the treatment of bladder sarcoma The objective of this review was to assess the histologic subtypes, clinical presentations, treatment approaches, and treatment-related outcomes of patients with bladder sarcoma. Between January 1985 and July 2004, 19 patients (12 men and 7 women) with primary bladder sarcoma were evaluated at the University of Texas M.D. Anderson Cancer Center. Median follow-up duration was 72 months (range 3–141). The findings were as follows. The median age of patients at presentation was 57 years (range 22–94). The histologic subtypes of bladder sarcoma were leiomyosarcoma (N = 14), angiosarcoma (N = 3), and unclassified sarcoma (N = 2). The clinical presentation consisted of gross, painless hematuria in 79% of patients, lower urinary tract symptoms in 16%, and microhematuria in 5%. The primary treatment modalities used were surgery in 16 (84%) patients, chemotherapy in 2 (11%), and palliation in 1 (5%). The rate of local and distal recurrence was 16% and 53%, respectively. The most common sites of distant metastases were the lungs, bone, brain, and liver. The 5-year disease-specific survival rate was 59%, with a median survival duration of 6 years. There was no statistically significant difference in disease-specific survival between patients with bladder leiomyosarcoma compared to other sarcoma subtypes (P = 0.149). Lymphovascular invasion (P = 0.03) and lymphatic metastasis (P = 0.03) were associated with disease-specific survival, and surgical margin status was associated with recurrence-free (P = 0.04), disease-specific (P = 0.03), and overall survival (P = 0.005). The authors conclude that bladder sarcoma is a highly aggressive malignancy, regardless of its histologic subtype, and that surgical margin status is an important determinant of survival.
Pulmonary Metastasectomy in Patients with Soft Tissue Sarcomas: Experiences in 50 Patients Pulmonary resection of metastatic soft tissue sarcomas is an accepted method of treatment. The purpose of this study was to determine the clinical course, outcome and prognostic factors after surgery. Between 1996 and 2001, 50 patients (27 men, 23 women) with pulmonary metastases from a soft tissue sarcoma underwent surgical resection at the University of Heidelberg, Germany. Inclusion criteria for the study were the absence of primary tumor recurrence and other extrapulmonary metastases. Complete resection (CR) was achieved in 31 patients. The results were as follows. The overall 5-year survival rate was 37.6 %. The 5-year survival rate after complete metastasectomy was 52.7 %, but none of the patients who underwent incomplete resection survived 3 years. Complete resection was found to be a significant prognostic factor for survival following metastasectomy (p < 0.0001). Of the prognostic factors analyzed, age, sex, repeat thoracotomy, thoracic lymph node involvement, number of metastases, disease-free interval, histology and histological grading did not influence survival. The authors conclude that pulmonary resection of metastatic soft tissue sarcomas is a safe and effective treatment, which offers an improved survival benefit, particularly with the complete surgical resection of all clinically detected metastases.
Chronic Health Conditions in Adult Survivors of Childhood Cancer Only a few small studies have assessed the long-term morbidity that follows the treatment of childhood cancer. The authors of this study determined the incidence and severity of chronic health conditions in adult survivors. This study - The Childhood Cancer Survivor Study- is a retrospective cohort study that tracks the health status of adults who received a diagnosis of childhood cancer between 1970 and 1986 and compares the results with those of siblings. The authors calculated the frequencies of chronic conditions in 10,397 survivors and 3034 siblings. A severity score (grades 1 through 4, ranging from mild to life-threatening or disabling) was assigned to each condition. Cox proportional-hazards models were used to estimate hazard ratios, reported as relative risks and 95% confidence intervals (CIs), for a chronic condition. The results were as follows. Survivors and siblings had mean ages of 26.6 years (range, 18.0 to 48.0) and 29.2 years (range, 18.0 to 56.0), respectively, at the time of the study. Among 10,397 survivors, 62.3% had at least one chronic condition; 27.5% had a severe or life-threatening condition (grade 3 or 4). The adjusted relative risk of a chronic condition in a survivor, as compared with siblings, was 3.3 (95% CI, 3.0 to 3.5); for a severe or life-threatening condition, the risk was 8.2 (95% CI, 6.9 to 9.7). Among survivors, the cumulative incidence of a chronic health condition reached 73.4% (95% CI, 69.0 to 77.9) 30 years after the cancer diagnosis, with a cumulative incidence of 42.4% (95% CI, 33.7 to 51.2) for severe, disabling, or life-threatening conditions or death due to a chronic condition. The authors thus conclude that survivors of childhood cancer have a high rate of illness owing to chronic health conditions.
Oral chemotherapy safety practices at US cancer centers: questionnaire survey The objective of this study was to characterize the current safety practices for the use of oral chemotherapy at comprehensive cancer centers in the United States. Written questionnaire surveys of pharmacy directors of cancer centers were employed to obtain results. Those results were as follows. Respondents from 42 (78%) of 54 eligible centers completed the survey, after consulting with 89 colleagues. Clinicians at 29 centers used handwritten prescriptions, two used preprinted paper prescriptions, and six used electronic systems for most oral chemotherapy prescribing. For six commonly used oral chemotherapies, on average 10 centers required a diagnosis on the prescription, 11 required the protocol number, four required the cycle number, nine required double checking by a second clinician, 14 required a calculation of body surface area, and 14 required a calculation of dose per square meter of body surface area. Only a third of the centers requested patients' written informed consent when oral chemotherapy was given off protocol. Nearly a quarter (10) of the centers had no formal process for monitoring patients' adherence. In the past year respondents at 10 centers reported at least one serious adverse drug event related to oral chemotherapy, and respondents at 13 centers reported a serious near miss. The authors conclude that few of the safeguards routinely used for infusion chemotherapy have been adopted for oral chemotherapy at US cancer centers and that there is currently no consensus at these centers about safe medication practices for oral chemotherapy.
Stress Hormones May Play New Role In Speeding Up Cancer Growth New research suggests that hormones produced during periods of stress may increase the growth rate of a particularly nasty kind of cancer. The study published in the journal Cancer Research (Cancer Res. 2006 66: 10357-10364) showed that an increase in norepinephrine, a stress hormone, can stimulate tumor cells to produce two compounds. These compounds can break down the tissue around the tumor cells and allow the cells to more easily move into the bloodstream. From there, they can travel to another location in the body to form additional tumors, a process called metastasis. The research also suggests the same hormone can also stimulate the tumor cells to release another compound that can aid in the growth of new blood vessels that feed cancer cells, hastening the growth and spread of the disease. “This opens up an entirely new way of looking at stress and cancer that's different from current interpretations,” explained Ronald Glaser, a professor of molecular virology, immunology and medical genetics, and director of the Institute for Behavioral Medicine Research at Ohio State University. Glaser and Eric Yang, a research scientist in the same institute, focused on the role of these three compounds. Two of them, both matrix metalloproteinases -- MMP-2 and MMP-9 -- play a role in breaking down the scaffolding that cells attach to in order to maintain their shape. The third compound, vascular endothelial growth factor (VEGF), is important in the growth of new blood vessels into tumor cells. Earlier work by researcher Anil Sood at the University of Texas had shown that the same stress hormones can stimulate ovarian tumor cells to produce these three compounds. The key to that discovery was that the two stress hormones – epinephrine and norepinephrine – would bind to places on the surface of ovarian cancer cells, called adrenergic receptors, and stimulate the release of MMP-2, MMP-9 and VEGF which might then foster cancer growth. The Ohio State team wanted to see if the same occurred with other cancer cells.
They turned to cell lines Glaser had developed decades ago to study nasopharyngeal carcinoma (NPC), a serious, incurable head and neck cancer that occurs most frequently among people of Chinese descent. They treated Glaser's cell line with norepinephrine and, as predicted, the cells all produced MMP-2, MMP-9 and VEGF. This showed that the receptors for this hormone were present on cells in Glaser's cell line, but that might have been just a laboratory aberration in the tissue cultures. “We needed to see how relevant this finding was to what happened with actual tumors,” he said. Glaser asked colleagues for samples of actual NPC tumors to look for the presence of similar receptors. They studied tumor samples which included different types of NPC tumors. All had the sought-after receptors. “From this we can say that there is likelihood that all NPC tumors will have these receptors as well,” he said. “MMP-2 and MMP-9 contribute to the aggressiveness of these tumors,” Yang said. “It isn't clear exactly how they are operating but they may work with VEGF to facilitate blood vessel growth in new tumors so that they can grow.” The target adrenergic receptors for these hormones are well-known to clinicians dealing with high-blood-pressure patients. Typically, such patients are given a class of drugs known as beta-blockers which lead to a lowering of blood pressure levels. Glaser and Yang wanted to see how these same drugs affected these tumor cells. They added propanol, a beta-blocker, to the tumor cells and then exposed them to both norepinepherine and epinephrine. With the drug present, the levels of MMP-2, MMP-9 and VEGF didn't increase. “This suggests a new approach to possibly fight some cancers – the prescribing of beta-blocker-type drugs that would block these receptors and perhaps slow the progression of the disease,” Glaser said. “Using this approach may not cure this cancer but perhaps we could slow down its growth, making the tumor more sensitive to anti-cancer therapy, and therefore extending the patient's lifespan and improve their quality of life.”
Effective and generally applicable methods for generating cancer vaccines in children have not been defined. Dendritic cells (DCs) are the most potent professional antigen-presenting cells capable of activating primary cytolytic T cells. The investigators of this study tested the ability of DCs generated from pediatric patients' peripheral blood monocytes and pulsed with a necrotic tumor to activate autologous tumor-specific cytolytic T cells. Tumor and peripheral blood cells were obtained from pediatric patients undergoing biopsy or resection for advanced solid tumors. To generate DCs, the investigators treated peripheral blood monocytes with granulocyte-macrophage colony stimulating factor and interleukin (IL)-4. Maturation was induced with a cytokine cocktail (CC) containing tumor necrosis factor–α, IL-6, IL-1β, and prostaglandin E2. The DC phenotype was assayed using flow cytometry. Tumor necrosis was induced by exposure to UV-B irradiation (1000 mJ). Dendritic cells pulsed with a UV-B–treated primary tumor and matured with CC were used to stimulate autologous peripheral blood lymphocytes weekly. Tumor-specific cytolytic activity was assayed using 4-hour 51Cr release. The results were as follows. Peripheral blood monocytes isolated from pediatric patients differentiated into immature DCs (CD14−, MHCII+ [major histocompatibility complex], CD80low, CD86low) in the presence of granulocyte-macrophage colony stimulating factor and IL-4. Cytokine cocktail induced maturation of DCs, as characterized by increased expressions of MHCII, CD83, CD80, and CD86. Patients' peripheral blood lymphocytes stimulated in vitro with DCs loaded with a necrotic primary tumor and matured with CC specifically lysed autologous neuroblastoma in 7 of 9 patients. The investigators conclude dendritic cells generated from the peripheral blood of children with advanced solid tumors and pulsed with a necrotic primary tumor undergo maturation and effectively stimulate autologous tumor-specific cytolytic T cells in vitro. The investigators describe a simple method for generating a vaccine capable of activating cytotoxic T cells against pediatric solid tumors that does not require the genetic identification of tumor-associated antigens.
At Press Time
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