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Abstracts by Tom Swartz and Bruce Shriver
In this issue: Specialist Centers Should Deal With All Soft Tissue Sarcomas Soft tissue sarcomas should be treated at the few centers which see most cases, in order to give patients the best chance of good outcomes, concludes an analysis of sarcoma management in Florida, published in the Annals of Surgery last month. "STS [soft tissue sarcomas] are rare. This paucity leaves most health care institutions with low case volumes and outdated or inadequate resources, which impede the ability to offer optimal treatment of these rare and often complicated tumors," the authors explain.
Using an analysis of a large population-based state cancer registry in Florida, Juan Gutierrez and colleagues tested the hypothesis that soft tissue sarcomas are better treated at institutions with higher volumes of cases. They used the Florida cancer data system, a prospective database of all cancer cases in the state of Florida since 1981, to identify all records of soft tissue sarcomas up to 2001. A total of 6259 cases were extracted and, after duplicates were removed, the researchers arrived at a total of 5564 unique cases. A final study sample of 4205 cases was created by excluding individuals who had non-surgical treatments.
Next, the researchers looked at the medical facilities where each person's treatment was done. A total of 256 institutions in Florida performed at least one resection of a soft tissue sarcoma between 1981 and 2001; these were grouped into percentile ranges by surgical procedure volume. Of 4673 surgical procedures recorded (including repeat procedures, which were excluded from the main analysis), 7 institutions performed 1504 cases (32.2%) and were classified as high volume centers. The remaining two thirds of institutions did 3169 cases (67.8% of the total) and were classed as low volume. "Our analysis of 20 years' surgical management of STS in Florida…[showed that] volumes in 213 facilities amounted to less than 1 case per year and less than 2 cases per year were managed at an additional 79 health care institutions," reported the authors.
Patients at high volume centers were generally younger, with a higher proportion of women, were more likely to have high-grade tumors and were more likely to receive radiation therapy and chemotherapy. When the authors looked at outcomes, they found that 30-day mortality rates were twice as high in low volume centers than in high volume institutions; there was a similar disparity with the 90-day mortality rate. Median 5-year and 10-year survival was significantly better for patients treated at high volume centers (40 months versus 37 months); however, survival of patients with extremity tumors was equal among the two groups of institutions. There was a slight selection bias in favor of the low volume centers because tumors managed at high volume places were higher grade and larger in size but despite this, higher volume centers achieved superior outcomes in patients with high grade lesions and those with tumors over 10 cm in size.
In an additional analysis, the researchers examined outcomes from treatment of extremity tumors alone to establish whether the volume of surgeries done at a center affected the likelihood of patients keeping their limbs. A total of 1937 extremity tumors were analyzed. At high volume centers, 90.6% of procedures for these tumors were limb sparing operations compared with 86.2% at low volume centers, suggesting that physicians at low-volume centers were more likely to resort to amputation to protect the patient's survival chances.
"This analysis reveals a direct correlation between hospital surgical volume and both short-term and long-term treatment outcomes for STS. While the observations reported here require confirmation with additional independent data sets they argue persuasively for exclusive referral of patients with STS to high volume specialized centers for optimal treatment, survival, and functional outcomes," conclude the authors.
The Cancer Therapy & Research Center Institute for Drug Development, in collaboration with Oncolytics Biotech Inc., a biotechnology company, has enrolled the first two patients in a new Phase II clinical study for patients with various types of sarcomas that have metastasized to the lung. CTRC is one of only three sites in the United States, and the only in Texas, enrolling patients. The novel anti-cancer therapy, REOLYSIN(R), is a living virus, not a chemotherapy drug, which is toxic to cancer cells but not harmful to normal cells. This novel therapy, using a living virus, is the first of its kind available at CTRC. According to Monica Mita, MD, principal investigator at the CTRC Institute for Drug Development, REOLYSIN(R)'s name was derived from the human reovirus, a mild virus that occurs naturally in the environment.
"This novel therapy has shown success because the reovirus replicates in and destroys the cancer cells within the patient's body," said Mita. "Cancer cells have several molecular and genetic abnormalities. In normal, healthy cells, the reovirus is unable to reproduce because of an enzyme named PKR. The enzyme is suppressed in cancer cells, and therefore the reovirus can replicate in the cancer cell and kill it." "REOLYSIN(R) typifies the true targeted therapy approach that seeks to use fundamental differences between cancer and normal cells as the basis for effective anti-cancer approaches and we are thus very excited about the this study," said Francis Giles, MD, director of the CTRC Institute for Drug Development.
Eligible patients are those who have a bone or soft tissue sarcoma that has spread to the lung and who are deemed by their physician to be unresponsive to or untreatable by standard therapies. These include patients with osteosarcoma, Ewing sarcoma family tumors, malignant fibrous histiocytoma, synovial sarcoma, fibrosarcoma and leiomyosarcoma.
REOLYSIN(R) has demonstrated success against tumors during earlier phases of scientific testing. This study (REO 014) is a Phase II, open-label, single agent study with the primary objective of measuring tumor responses and the duration of those responses, and of describing any evidence of anti-tumor activity. REOLYSIN(R) will be given intravenously to patients for five consecutive days. Patients may receive additional five-day cycles of therapy every four weeks for a maximum of eight cycles. Up to 52 patients will be enrolled in the study.
Located in San Antonio, Texas, the Cancer Therapy and Research Center (CTRC) is one of the nation's leading academic research and treatment centers. CTRC, through its research partnership with the University of Texas Health Science Center at San Antonio (UTHSCSA), created the San Antonio Cancer Institute (SACI), one of a few elite cancer centers in the country to be named a National Cancer Institute (NCI) Designated Cancer Center. CTRC handles more than 120,000 patient visits each year and is a world leader in developing new drugs to treat cancer. The CTRC Institute for Drug Development (IDD) is internationally recognized for conducting the largest oncology Phase I clinical drug trials program in the world. Sixteen of the cancer drugs most recently approved by the Food & Drug Administration underwent development or testing at the IDD. For more information visit CTRC's website.
Oncolytics is a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of Phase I and Phase II human trials using REOLYSIN(R), its proprietary formulation of the human reovirus, alone and in combination with radiation or chemotherapy. For further information about Oncolytics, please visit their website.
Child Cancer Patients Find Hope For Future Fertility Israeli scientists have successfully extracted and frozen eggs from the ovarian tissue of five-year-old female cancer patients in the hope of securing successful fertility treatment in the future. Dr Ariel Revel, head of the Department of Obstetrics and Gynecology at Hadassah University Hospital in Jerusalem, announced the breakthrough at the 23rd Annual Conference of the European Society for Human Reproduction and Embryology (ESHRE), in Lyon, France. While survival rates of childhood cancer continue to improve and have reached 70 to 90 percent, the aggressive chemotherapy needed to fight the cancers severely damages the patient's fertility.
In male patients, sperm samples can be taken and frozen before treatment for future use. Up until this breakthrough, it was believed that female patients before puberty did not have a similar option, since freezing the ovarian cortex, which contains the egg-producing follicles, would destroy the tissue. The more successful way to harvest eggs is to retrieve individual eggs from the follicles, which are more resistant to extreme cold. Dr Revel's team was astonished to discover that this was possible in girls as young as five to 10 years old, well before puberty. "We were able to extract oocytes (cells that later produce eggs) using needle aspiration from very young girls," said Dr Revel.
"For example, we found seven eggs in a girl of five years old with Wilm's tumor, eight in an eight year old with Ewing's sarcoma, and 17 in a 10 year old, also with Ewing's sarcoma. We were then able to mature the eggs in vitro and freeze them for use in the future," he explained. The researchers were able to mature 41 of 130 eggs in vitro which were then frozen.
Despite the success, it is still too early to determine whether the study was successful, as none of the eggs have been thawed since the patients are still too young for fertilization. Revel and his team said that the final results of this study would not be apparent until at least the next 10 years, when the girls decided to attempt to get pregnant. "But we are encouraged by our results so far, particularly the young ages of the patients from which we have been able to collect eggs. We believe that no younger patients have ever undergone egg collection, in vitro maturation, and egg freezing," said Dr Revel. "We are hopeful that the mature eggs can offer these girls a realistic possibility of preserving their fertility," he concluded.
Depression In Terminal Illness: The Need For Primary Care-Specific Research Palliative care research highlights depression as a common, treatable condition in patients with terminal cancer. Guidance from the European Association for Palliative Care calls for proactive screening and treatment of the disease. However, prevalence of depression among primary care patients with advanced cancer is unknown and it remains uncertain whether existing guidance is appropriate for use by GPs. The objective of this study was to estimate the prevalence of depression in a primary care population with terminal cancer. A two-stage community prevalence survey was thus conducted in primary care practices in Merseyside, UK. Adult patients with advanced metastatic cancer were invited to join the study. In phase 1, a depression screening tool (the Edinburgh Depression Scale [EDS]) was used to categorize patients as being high or low risk of depression. In phase 2, samples from each group underwent a diagnostic assessment using the revised Clinical Interview Schedule. Weighted prevalence estimates were calculated. The Results were as follows: In a final sample of 70 (response rate 47.9%), the prevalence of depression was 4.1% (95% confidence interval 0–8.8%). The sensitivity and specificity of the EDS were poorer than predicted. The authors conclude: The prevalence of depression in our sample was lower than expected given findings from previous studies. Screening tools also performed differently in this population. The limitations in our study are discussed; however, our findings raise questions about whether depression guidance from palliative care studies can be directly applied to a primary care setting. We propose the need for development of a primary palliative care evidence base to underpin appropriate clinical care.
Knowledge of and Barriers to Pain Management in Caregivers of Cancer Patients Receiving Homecare Cancer treatment is increasingly being provided in outpatient settings, requiring many of the responsibilities for patient care to be undertaken by family caregivers. Pain is one of the most frequent and distressing symptoms experienced by cancer patients and is a primary concern for the family caregiver. Caregivers struggle with many issues that lead to inadequate management of cancer pain. The purpose of this study was to determine pain management knowledge and examine concerns about reporting pain and using analgesics in a sample of primary family caregivers of cancer patients receiving homecare. The Barriers Questionnaire and the Family Pain Questionnaire were administered to 46 primary caregivers. Between 46% and 94% of the caregivers reported having at least some agreement with the various concerns that are barriers to reporting pain and using analgesics, and up to 15% reported having strong agreement. The areas of greatest concern were about opioid-related side effects, fears of addiction, and the belief that pain meant disease progression. Results showed that caregivers with higher pain management knowledge had significantly fewer barriers to cancer pain management, supporting the importance of increasing caregiver’s knowledge of management of cancer pain.
Sensitivity To Diverse Range Of Chemotherapeutic Drugs Linked To Common Pathway Using a functional genomic screen, scientists have defined elements that impact the responsiveness of cancer cells to drugs commonly used as anticancer therapeutics. The research, published in the June issue of the journal Cancer Cell, published by Cell Press, identifies individual genes that are associated with resistance to chemotherapeutic drugs and sets the stage for future studies that may significantly enhance the ability to predict whether or not a particular tumor will respond to treatment.
Resistance to chemotherapeutic drugs is the primary cause of treatment failure in patients with metastatic cancer. Dr. Julian Downward from the Cancer Research UK London Research Institute and colleagues used RNA interference to directly examine the contribution of over 800 candidate proteins to the sensitivity or resistance of cancer cells to several drugs that are commonly used to treat cancer.
Using this technique, the researchers found that resistance to the chemotherapeutic agent paclitaxel, a member of the taxane family, as expected, involves genes that impair drug-induced mitotic arrest following knockdown. Silencing of these genes in many cases also induces polyploidy and multinucleation in the absence of drug treatment. The researchers conclude that specific disruption of the mitotic checkpoint promotes paclitaxel resistance and that chromosomal numerical heterogeneity may be a useful predictor of paclitaxel resistance in some cancers.
Ceramide metabolism was identified as a critical regulator of sensitivity to a wide range of chemotherapeutic drugs. Although ceramide has been associated with apoptosis for some time, the mechanisms have not been well understood. In this study, decreased expression of a ceramide transport protein, COL4A3BP, sensitized cancer cells to multiple cytotoxic agents. Further, expression of COL4A3BP was increased in drug-resistant tumor cells and in a small cohort of ovarian cancers following paclitaxel treatment.
The researchers suggest that paclitaxel-induced prolonged mitotic arrest may result in ceramide accumulation and initiation of apoptosis, while inhibition of this arrest, characterized by polyploidy, may suppress ceramide generation and promote cell survival. "These data suggest that the taxane class of drugs may lack efficacy in tumors with high levels of chromosomal instability characterized by chromosomal numerical heterogeneity and provide a rational basis for identification of patients likely to benefit from these drugs," explains Dr. Downward.
With modern therapies and supportive care, survival of childhood cancer has increased considerably. Patients who have survived cancers involving the central nervous system or who have received therapy toxic to the developing brain are at risk of long-term neurocognitive sequelae. Negative outcomes are observed most frequently in survivors of acute lymphoblastic leukemia and brain tumors. The Children’s Oncology Group Long-term Follow-up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer has generated risk-based, exposure-related guidelines designed to direct the follow-up care of survivors of pediatric malignancies based on a comprehensive literature review and expert opinion. This article expands on these guidelines by reviewing the risk factors for the development of neurocognitive sequelae and describing the expected pattern of these disabilities. The authors of this article present recommendations for the screening and management of neurocognitive late effects and outline important areas of school and legal advocacy for survivors with disabilities. Finally, they list resources that can guide patients, their parents, and their medical caregivers as they face the long-term neurocognitive consequences of cancer therapy.
There is evidence that some cancer survivors suffer cognitive impairment after chemotherapy. Determining if a patient has cognitive impairment is challenging, especially because impairment is usually subtle. The authors of this article assessed the design of studies evaluating cognitive function during or after chemotherapy in adult patients with solid tumors. They also reviewed methods used to evaluate cognitive function in subjects with other diseases and make recommendations for future studies. The Results were as follows: The authors identified 22 studies that met their criteria: 82% included women with breast cancer. Eight studies were longitudinal, 12 were cross-sectional, and two were follow-ups of cross-sectional studies. Sixteen studies used a battery of neuropsychological (NP) tests to assess subjects, and 13 included a control group. Ten studies (45%) had no explicit definition of cognitive impairment; most others used z scores or T scores and defined impairment based on standard deviations below the mean, but there was no consistency in for the cutoff point used or the number of tests required. The Authors Conclude: There is no consistency in defining cognitive impairment, in the NP batteries used, or in statistical methods in studies of cognitive function of cancer patients. They suggest guidelines to define criteria for cognitive impairment. Use of summary scores and control groups is recommended. Practice effect should be adjusted for in longitudinal studies. A balance is needed between comprehensive batteries and briefer tests, which still need to be sensitive to mild impairment.
Early Results Find Activity In Drug That Turns on Tumor "Death" Receptors The first clinical trial to evaluate a new type of drug that activates "death" receptors on cancer cells has found it to be both safe and suggestive of potential benefit, say researchers from The University of Texas M. D. Anderson Cancer Center. The drug, human Apo2L/TRAIL (Apo2L), produced only minimal side effects in the 58 patients being tested in the ongoing Phase I study, reports Roy Herbst, M.D., Ph.D., professor and chief, Section of Thoracic Medical Oncology.
Herbst also says that the agent shrunk tumors in one patient with sarcoma, and seemed to stabilize cancer growth in about 56 percent of the 58 patients, but added that it is too early to adequately assess the benefit of Apo2L, especially since the maximum dose that can treat patients and still be well tolerated has not yet been reached. "This is an interesting new class of targeted agents, and Apo2L may well prove to be promising as we study it further," says Herbst, who presented safety data on the Phase I clinical trial at the 42nd annual meeting of the American Society of Clinical Oncology.
Patients with a variety of advanced cancers are participating in the clinical trial, which is being conducted at five centers around the country. In preclinical studies, Apo2L selectively induced programmed cell death (also known as apoptosis, or cell suicide) in cancer cells while sparing normal cells. It showed activity in animal models of leukemia, non-small cell lung cancer, melanoma and cancers of the colon, prostate and breast. The drug is designed to activate pathways inside tumor cells that lead to destruction of these cells.
"Normally, the p53 gene regulates cell suicide in the presence of cell damage, such as that induced by chemotherapy and radiotherapy, but this gene is mutated - and therefore inactivated - in more than half of all cancers. We expect this agent to work even in those patients with mutated p53," Herbst says. Herbst and his team have been trying to exploit a different and natural way to induce cell suicide, through so-called death receptors that are located on the outside of all cells. These receptors, which are believed to be especially numerous on cancer cells, work in tandem with the tumor-necrosis factor receptor (TNFR) super-family, which can signal cell destruction from outside the cell (unlike p53, which activates suicide from inside the cell.) Drugs aimed at treating autoimmune disease have been developed that block specific death receptors; now oncology researchers have designed agents that will selectively activate death receptors 4 and 5 (DR4, DR5) known to be present on cancer cells.
The first TNFR agents developed to induce apoptosis resulted in liver toxicity, so researchers looked for the natural "ligand," or protein, that bound on to DR4 and DR5. The biotechnology firms Genentech and Amgen found and cloned the Apo2L/TRAIL gene, and used its protein product to create a recombinant protein that closely resembles this natural ligand. According to Herbst, Apo2L is the only agent of its kind that can directly activate both DR4 and DR5, which then mounts an immune response that can attack the tumor cells. Herbst suspects that Apo2L and other death receptor agents being developed for cancer treatment will work best when used with chemotherapy and/or radiation, and says Apo2L will be tested in combination therapy after this dose escalation study ends.
Positive ZIO-201 Interim Phase II Sarcoma Data Presented at European Society for Medical Oncology ZIOPHARM Oncology, Inc. has announced that positive interim data from an ongoing phase II trial of ZIO-201 (isophosphoramide mustard - IPM) to treat advanced sarcoma patients was presented at the European Society of Medical Oncology (ESMO) meeting held July 5-8, 2007 in Lugano, Switzerland. The abstract entitled, "Phase-I/II Study of IPM (ZIO-201) In Advanced Sarcoma," was presented by Rashmi Chugh, MD, a Principal Investigator from the University of Michigan, Ann Arbor, Michigan.
The trial has now enrolled 39 patients and this presentation reports on the first 10 evaluable patients. Of these 10 heavily pretreated patients (median 4 prior regimens), 1 had a partial response (21 weeks and ongoing) and 4 had stable disease. Of these 5 patients, 2 had progressed through prior ifosfamide (IFOS) treatment. ZIO-201 was shown to be well tolerated at the phase II dose with no significant bone marrow suppression, alopecia (hair loss) or neurotoxicity reported. Based on this encouraging data, enrollment has been expanded to include additional patients.
"Ifosfamide is one of the few effective standard therapies available for most sarcomas," commented Dr. Chugh. "Having a novel drug that could offer the benefits of high-dose ifosfamide without the debilitating side effects, particularly the bone marrow suppression and neurotoxicity, would be of great benefit in the treatment of this disease. We are enthusiastic about these early results and we look forward to further elucidating the overall impact of ZIO-201 in this setting."
ZIO-201, the active moiety of IFOS, is a bi-functional alkylator that causes irreparable inter-strand DNA cross-linking resulting in cell death. ZIO-201 is equal to or more active than IFOS in diverse cancer models. Unlike IFOS, which is a pro-drug, ZIO-201 is directly active against cancer cells. Also, unlike IFOS, ZIO-201 is not metabolized to acrolein or chloroacetaldehyde which cause bladder or central nervous system toxicities. ZIO-201 continues in a phase I trial in diverse cancers exploring maximum tolerated dose at alternate schedules. A phase II trial in advanced sarcoma continues to enroll patients. Trials in lymphoma and pediatric cancers are in the advanced planning stage. An oral form of ZIO-201 is in advanced preclinical development. The Company expects to report more complete data at upcoming medical meetings, including the 14th European Cancer Conference (ECCO) taking place in Barcelona from September 23-27, 2007.
Ariad Gets $75 Million Up Front In Merck Deal On mTOR Inhibitor With its lead candidate AP23573 poised to begin Phase III trials in metastatic sarcoma, Ariad Pharmaceuticals Inc. signed a global development and commercialization partnership for the small-molecule mTOR inhibitor with Merck and Co. Inc. The deal includes $75 million up front to Ariad and $652 million in potential milestones, as well as additional development support, royalties and co-promotion clauses. The companies will evenly split the costs of global development with the exception of ex-U.S. development designed to support ex-U.S. commercialization, for which Merck will pick up the tab. Merck also will contribute at least $200 million to the cost of global development and, once Ariad has spent $150 million, Merck will fork over another $200 million in interest-bearing repayable development-cost advances. An interesting aspect to the cost sharing is that both partners may choose to opt out of conducting and funding certain late-stage clinical trials of AP23573. During a conference call, Ariad Chairman and CEO Harvey Berger explained that the clause is intended to provide either party with the freedom to explore new directions for the drug, even if the direction in question is not of interest to both partners.
In the U.S., Ariad and Merck would co-promote AP23573 for all cancer indications. Ariad will take the lead on advancing the sarcoma indication, given its prior history and experience, while the partners will share development responsibility for all future indications. Ariad will handle distribution and book all sales, with both companies evenly splitting that income. Outside the U.S., Merck would distribute, sell, promote and book all sales of AP23573. Merck also will have primary responsibility for ex-U.S. development in all cancer indications. Ariad will manufacture the active pharmaceutical ingredient to support global sales, while Merck will manage formulation of the finished product.
Ariad has called the protein mTOR, or mammalian target of rapamycin, a "master switch" in cancer cells. Blocking mTOR, it said, creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism and angiogenesis. Given the extensive amount of collaboration involved, Ariad Vice President and Chief Commercial Officer Richard Pascoe said the companies have established joint development, manufacturing, commercialization and steering committees to "ensure open and consensus-driven decision making."
Moving forward, the first Phase III trial in metastatic sarcoma is expected to begin shortly. In April, the company announced that a meeting with the FDA had resulted in a change in the primary endpoint for that trial from progression-free survival, which Ariad had demonstrated in a Phase II trial, to overall survival. Berger said the final trial design would be made available prior to the trial's initiation and will reflect input from the FDA, the European Agency for the Evaluation of Medicinal Products and Merck. He added that he anticipates a "single successful Phase III trial will be sufficient for approval in the U.S., Europe and most of the world. Berger declined to specify a timeline to the initiation of additional trials, although he did say that the partners will run multiple trials in multiple indications in parallel, and that there will be "a lot of activity in the first three years" of the partnership. He also said that one of Ariad's goals is to be in a position to initiate a second registration trial within the next 12 months.
Spectrum Pharmaceuticals Completes New Drug Application Filing for ISO-Vorin(TM) On July 2nd, Spectrum Pharmaceuticals, Inc. announced that it has completed its filing with the U.S. Food and Drug Administration (FDA) with the filing of an amendment to the New Drug Application (NDA) for ISO-Vorin(TM) (levofolinic acid, or LFA) for the treatment of osteogenic sarcoma. ISO-Vorin(TM) is the pure active isomer of calcium leucovorin. Calcium leucovorin is used after the administration of high-dose methotrexate in treating osteogenic sarcoma and is also a component of "standard of care" 5-fluorouracil (5-FU) containing regimens for the treatment of colorectal and other malignancies.
"The completion of this NDA continues to validate our risk-reduced business model of identifying promising drug candidates and advancing them through the regulatory process," said Luigi Lenaz, M.D., Chief Scientific Officer of Spectrum Pharmaceuticals. "We had acquired the rights to market ISO-Vorin(TM) in 2006. We also plan to file a supplemental NDA for the additional indication of colorectal cancer and to file an oral formulation of ISO-Vorin(TM) with the FDA. We believe that ISO-Vorin(TM) has the potential to be an effective treatment option for these indications."
The FDA's Oncology Drug Advisory Committee had already recommended ISO-Vorin(TM) for approval, based upon clinical data demonstrating the efficacy, safety and bioequivalency in comparison to the racemic leucovorin form. During a review of the NDA application that was on file with the FDA, the FDA raised questions surrounding the chemistry manufacturing and control section of the NDA. The amendment to the NDA filed on July 2nd provides manufacturing information and six months stability data on commercial batches, required by the FDA to complete its review of ISO-Vorin(TM) NDA.
V4N4 ESUN Copyright © 2007 Liddy Shriver Sarcoma Initiative. |
Golfers
Against Cancer has raised over $150,000 in Shannon’s memory
and in the memory of the many children and young adults who
have lost their lives to this bone cancer and to honor of
all those still fighting this battle, Pat stated that,
"Every cent of our proceeds goes directly to the
researchers. There is no middle organization. We have no
salaries or overhead. Every service and item for fund
raising is donated or performed by our many dedicated
volunteers. The exception is the Golf Courses that we have
played. (So far, we have not been able to get them to donate
their facilities)."
