Showing papers in "Cancer Journal in 2001"

Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.

Abstract: PURPOSE Zoledronic acid, a new and more potent bisphosphonate, was compared with pamidronate, the current standard treatment for patients with osteolytic or mixed bone metastases/lesions. PATIENTS AND METHODS A total of 1,648 patients with either Durie-Salmon stage III multiple myeloma or advanced breast cancer and at least one bone lesion were randomly assigned to treatment with either 4 or 8 mg of zoledronic acid via 15-minute intravenous infusion or 90 mg of pamidronate via 2-hour intravenous infusion every 3 to 4 weeks for 12 months. The primary efficacy endpoint was the proportion of patients experiencing at least one skeletal-related event over 13 months. RESULTS The proportion of patients with at least one skeletal-related event was similar in all treatment groups. Median time to the first skeletal-related eventwas approximately 1 year in each treatment group. The skeletal morbidity rate was slightly lower in patients treated with zoledronic acid than in those treated with pamidronate, and zoledronic acid (4 mg) significantly decreased the incidence and event rate for radiation therapy to bone, both overall and in breast cancer patients receiving hormonal therapy. Pain scores decreased in all treatment groups in the presence of stable or decreased analgesic use. Zoledronic acid (4 mg) and pamidronate were equally well tolerated; the most common adverse events were bone pain, nausea, fatigue, and fever and < 5% of serious adverse events were related to the study drug. The incidence of renal impairment among patients treated with 4 mg of zoledronic acid via 15-minute infusion was similar to that among patients treated with pamidronate. CONCLUSIONS Zoledronic acid (4 mg) via 15-minute intravenous infusion was as effective and well tolerated as 90 mg of pamidronate in the treatment of osteolytic and mixed bone metastases/lesions in patients with advanced breast cancer or multiple myeloma. (Can-

Tissue microarray: a new technology for amplification of tissue resources.

Abstract: Tissue microarrays are a method of harvesting small disks of tissue from a range of standard histologic sections and placing them in an array on a recipient paraffin block such that hundreds of cases can be analyzed simultaneously. This technique allows maximization of tissue resources by analysis of small-core biop sies of blocks, rather than complete sections. Using this technology, a carefully planned array can be constructed with cases from pathology tissue block archives, such that a 20-year survival analysis can be performed on a cohort of 600 or more patients by use of only a few microliters of antibody in a single experiment. The reflex criticism of this technique is that the tissue analyzed is not representative, especially in antigens with heterogeneous staining patterns. This review addresses this issue, as well as the issue of antigen preservation or durability, which validates construction of arrays from archives. Strategies and methods of construction and analysis of the arrays are discussed, as well as some other unusual array applications. This technique can provide a highly efficient, high-throughput mechanism for evaluation of protein expression in large cohorts. It has the potential to allow validation of new genes at a speed comparable to the rapid rate of gene discovery afforded by DNA microarrays.

Radiofrequency ablation of solid tumors.

Abstract: Radiofrequency ablation of solid tumors is produced by frictional heating caused when ions in the tissue attempt to follow the changing directions of a high-frequency alternating current The radiofrequency probe is typically placed under ultrasound guidance, and the ablation is performed with real-time ultrasound monitoring Radiofrequency ablation has been demonstrated to be effective in the treatment of unresectable hepatic tumors, and promising results have also been obtained in tumors of the lung, bone, brain, kidney, prostate gland, and pancreas Most recently, radiofrequency ablation has been tested in the treatment of invasive breast tumors A preliminary study reported that intraoperative radiofrequency ablation causes invasive breast cancer cell death in patients with locally advanced breast cancer An ongoing study is investigating the use of radiofrequency ablation for the treatment of breast tumors 2 cm or less in diameter

Cancer proteomics: from biomarker discovery to signal pathway profiling.

Abstract: In the post-genomic era of science, the field of proteomics promises the discovery of new molecular targets for therapy, biomarkers for early detection, and new endpoints for therapeutic efficacy and toxicity. Patient-specific targeted therapeutics with reduced toxicity and increased efficacy, the ultimate goal for rational drug development, can only be achieved if direct analyses of the tissue cells in the actual human malignancy are analyzed. To that end, technologies such as Laser Capture Microdissection (LCM), is providing unparalleled access to the purified diseased human cells directly from tissue specimens. However, limited availability of patient material is a challenge towards the development of new highly sensitive proteomic methodologies. Two-dimensional gel electrophoresis (2D-PAGE), still the mainstay of most proteomic analysis of disease, is being complemented, and in some instances replaced by new exciting approaches to multiparametric protein characterization. The use of rapid, high throughput mass spectrometric-based fingerprints of peptides and proteins may prove to be valuable for new molecular classification of human tumors and disease stages. Coupled with LCM, high-density protein arrays, antibody arrays, and small molecular arrays, could have a substantial impact on proteomic profiling of human malignancies. Finally, detailed real-time knowledge about the states of intracellular signaling circuitry and pathways in the normal and malignant cells before, during and after therapy will yield invaluable information about mechanism of action and efficacy of existing and novel therapeutics for the treatment of human cancer.

Human embryonic stem cells: culture, differentiation, and genetic modification for regenerative medicine applications.

Abstract: Human embryonic stem (hES) cells can proliferate extensively in culture and can differentiate into representatives of all three embryonic germ layers in vitro and in vivo. The undifferentiated hES cells have now been cultured for more than 50 passages in vitro, yet maintain a normal karyotype. The hES cells express a series of specific surface antigens, as well as OCT-4 and human telomerase, proteins associated with a pluripotent and immortal phenotype. On differentiation, OCT-4 and human telomerase expression decreases with the emergence of a maturing population of cells. During hES cell differentiation, modulation of the expression of many genes has been evaluated using microarray analysis. To improve the ease, reproducibility, and scalability of hES culture, methods have been developed to propagate the cells in the absence of mouse embryonic cell feeders. hES cells maintained in culture using extracellular matrix factors together with mouse embryonic cell conditioned medium proliferate indefinitely while maintaining a normal karyotype, proliferation rate, and complement of undifferentiated cell markers. hES cells cultured without feeder layers retain their capacity to differentiate into cells of all three germ layers in vitro and in teratomas. The hES cells can also be genetically modified transiently or stably using both plasmid and viral gene transfer agents. These analyses and technological developments will aid in the realization of the full potential of hES cells for both research and therapeutic applications.

Antiangiogenic scheduling of lower dose cancer chemotherapy.

Abstract: Cancer chemotherapy utilized at maximum tolerated, toxic doses, rarely results in sustained total tumor eradication, with patients ultimately failing a variety of chemotherapeutic regimens. If tumors respond, the constituent cancer cells acquire resistance to chemotherapeutic agents, largely due to tremendous genetic instability. Changing the target of these agents to the tumor's proliferating microvasculature, a more genetically stable cell, may provide important therapeutic advantages. Modifying the cyclic schedule and high doses of chemotherapeutic agents to a continuous, lower dose, "metronomic" regimen increases the efficacy of targeting the tumor microvasculature, and produces therapeutic activity with decreased toxicity. Preclinically, the antiangiogenic properties of continuous, lower-dose chemotherapy can be further enhanced by the concurrent administration of a selective angiogenesis inhibitor. Because the target is not exclusively the tumor cell, this antiangiogenic combination strategy provides the opportunity to delay or possibly avoid acquired resistance. Preclinical and clinical observations provide a basis for treating cancer as a chronic disease, using protracted, continuous dosing. Because appropriate chemotherapeutic agents and commercially available compounds that inhibit angiogenesis are readily available, it would be beneficial to initiate clinical trials to evaluate the antiangiogenic scheduling of chemotherapy expeditiously.

Staging and clinical prognostic factors for small-cell lung cancer.

Abstract: The two-stage system introduced by the Veterans' Affairs Lung Study Group continues to be widely utilized in small-cell lung cancer (SCLC), mainly because of its simplicity and clinical utility. Approximately one third of patients with SCLC present with limited-stage disease, which is defined as disease that can be encompassed in a tolerable radiation field. However, this definition is controversial when it is applied to the staging classification of patients with locoregionally advanced disease manifested as the presence of an ipsilateral pleural effusion, contralateral supraclavicular lymphadenopathy, or contralateral mediastinal lymphadenopathy. The more descriptive TNM system is useful for patients with disease limited to the lung, when surgical resection may be feasible; this occurs in far less than 10% of cases. As shown by clinical studies and autopsy data, metastatic disease frequently involves the liver, adrenals, bone, bone marrow, and brain. History and physical examination, complete blood count and chemistry studies, chest x-ray studies, computed tomography of the chest or upper abdomen, computed tomographic scanning or magnetic resonance imaging of the brain, and bone scans are recommended for the pretreatment evaluation of patients with SCLC. A bone marrow biopsy may be omitted for patients with normal blood counts, normal lactate dehydrogenase level, and negative result on bone scan. The use of new imaging modalities, such as magnetic resonance imaging of the bone marrow and positron emission tomographic scanning, may optimize staging evaluation. Multiple prognostic parameters have been identified for patients with SCLC, the most important of which are the stage or extent of disease, performance status, serum lactate dehydrogenase level, and male gender. Identification of risk factors for treatment-related mortality is important for the management of patients with SCLC.

Breast-conserving therapy in the setting of collagen vascular disease.

Abstract: Background It is unclear whether the presence of collagen vascular disease should be considered a contraindication to irradiation. This study was undertaken to determine whether women with pre-existing collagen vascular disease have an increased incidence of complications after breast-conserving therapy. Methods and materials A cohort of 36 patients with documented collagen vascular disease was conservatively treated for early-stage breast cancer between 1975 and 1998. All of these patients were treated with conventional radiation therapy to a total medium dose of 64 Gy. Seventeen had rheumatoid arthritis; four, scleroderma; four, Raynaud's phenomenon; five, lupus erythematosus; two, Sjogren's disease; and four, polymyositis. Each of these patients was matched to two control patients without a history of collagen vascular disease on the basis of age, radiation therapytechnique, chemotherapy or hormone therapy use, tumor histology, and date of treatment. Acute and late complications were assessed using a six-point scale from the toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer. The scoring system for both acute and late reactions ranged from 0 (no change over baseline) to 5 (radiation led to death). For the purpose of statistical analysis, patients were classified as having a significant complication if they had a score of 3 or greater. Results With a median clinical follow-up time of 12.5 years (range, 3.0-22.5 years), no significant difference was detected between the collagen vascular disease and control groups with respect to acute complications (14% vs 8%). With respect to late complications, a significant difference was observed (17% vs 3%) between the two groups. However, when patients in the collagen vascular disease group were analyzed by specific disease, this significance disappeared in all but the scleroderma group. Conclusions Patients with scleroderma have a statistically significant increased incidence of radiation therapy complications after breast-conserving surgery and radiation therapy. The presence of other collagen vascular diseases should not be considered a contraindication for this treatment modality.

Radiosurgery for brain metastases from primary lung carcinoma.

Abstract: Purpose Brain metastases are a common problem in patients with lung cancer. This retrospective review was performed to describe the efficacy and toxicity of stereotactic radiosurgery for brain metastases from lung carcinoma and to evaluate prognostic factors for survival. Patients and methods A retrospective review was performed of 113 patients with the diagnosis of lung carcinoma who underwent radiosurgery with or without whole-brain radiotherapy for management of newly diagnosed or recurrent, single, or multiple brain metastases from 1991 through 1998 at the University of California, San Francisco. Freedom from progression and survival were measured from the date of radiosurgery and estimated using the Kaplan-Meier method. Prognostic factors were evaluated with the log-rank test and Cox proportional hazards models. Results The median patient age at the time of radiosurgery was 59 years (range, 37-82 years), and the median Karnofsky performance score was 90 (range, 50-100). The median survival time from radiosurgery was 12.0 months overall, 13.9 months for 41 patients treated with radiosurgery alone initially, 14.5 months for 19 patients treated with radiosurgery and whole-brain radiotherapy initially, and 10.0 months for 53 patients with recurrent brain metastases. Among newly diagnosed patients, multivariate analysis showed that improved survival was associated with absence of extracranial metastases and fewer brain metastases. Among patients with recurrent brain metastases, improved survival was associated with higher Karnofsky performance score, control of the primary tumor, and fewer metastases. Measured by lesion, 1-year local freedom from progression probabilities were 81% for radiosurgery alone, 86% for radiosurgery and whole-brain radiotherapy, and 65% for radiosurgery performed after recurrence. In patients with newly diagnosed brain metastases, there was a significantly greater risk of developing subsequent brain metastases and of worse overall brain freedom from progression after radiosurgery alone versus radiosurgery and whole-brain radiotherapy. One-year brain freedom from progression probabilities were 13% without salvage therapy and 62% with salvage therapy in the 41 patients treated initially with radiosurgery alone, versus 67% without salvage therapy and 89% with salvage therapy in the 19 patients treated initially with radiosurgery plus whole-brain radiotherapy. Discussion Radiosurgery is an effective therapy for selected patients with newly diagnosed or recurrent brain metastases from lung carcinoma. Initial whole-brain radiotherapy with radiosurgery appears to improve brain control but not survival. Prospective, randomized trials are needed to further investigate the role of radiosurgery with and without whole-brain radiotherapy for brain metastases.

Variations in the use of adjuvant chemotherapy for node-positive colon cancer in the elderly: a population-based study.

Abstract: BACKGROUND: Since 1990, the recommended adjuvant therapy for patients with surgically resected node-positive colon cancer has been 5-fluorouracil (5-FU), usually in combination with leucovorin or levamisole. The purpose of this study is to assess the distribution of adjuvant 5-FU treatment in the elderly. METHODS: The Surveillance, Epidemiology and End Results-Medicare database provides population-based information on cancer patients, representing approximately 14% of the United States population, along with health care utilization data from Medicare claims files. We studied patients with node-positive colon cancer diagnosed between 1992 and 1996 who survived at least 120 days beyond diagnosis (N = 4998). RESULTS: About 50% of elderly patients received 5-FU within 4 months of diagnosis. The proportion of patients treated with 5-FU increased by about 10% from 1992 to 1996. In a multiple logistic regression model, 5-FU treatment was less likely to be given to older patients (compared with those aged 65-69 years, the odds ratio (OR) [95% CI] was 0.82 [0.67-1.00] for ages 70 to 74 years, 0.47 [0.39-0.57] for ages 75 to 79, 0.17 [0.13-0.20] for ages 80 to 84, and 0.04 [0.03-0.05] for ages 85 to 88 years. Non-Hispanic black patients were less likely to be treated than non-Hispanic white patients (OR 0.46 [0.36-0.59]); patients with more than three positive lymph nodes were more likely to be treated than those with three or less, and those with comorbid conditions were less likely to be treated than those without such conditions. CONCLUSIONS: Despite its proven efficacy in reducing colon cancer mortality, 5-FU-based chemotherapy is not widely used among apparently eligible patients over age 65. Efforts are needed to ensure that elderly and non-Hispanic black patients receive appropriate treatment.

Advances in the surgical management of pancreatic cancer.

Abstract: Pancreatic cancer continues to pose a major public health concern and clinical challenge. The incidence of the disease is nearly equivalent to the death rate associated with the diagnosis of pancreatic cancer. Thus, there exists a need for continued improvement in the diagnostic, therapeutic and palliative care of these patients. Surgeons play an integral role in the management of pancreatic cancer patients, with surgery providing the only potentially curative intervention for the disease. Specialized centers have reported improved hospital morbidity, mortality and survival after pancreaticoduodenectomy; however, disease-specific survival after surgical resection remains dismal. An emphasis therefore has been placed upon the accurate preoperative staging of patients in order to identify those patients who would benefit from a complete surgical resection. Surgical staging that incorporates the use of laparoscopic techniques now complements non-surgical methods of staging, including helical CT scans. While there is no defined preoperative staging approach, it is imperative that centers identify areas of expertise and experience with available modalities in any combination to effect accurate staging. Once patients have been accurately staged and deemed resectable, there exist various methods for resection of pancreas lesions, which include the standard "Whipple procedure," pylorus-preserving pancreaticoduodenectomy, regional pancreatectomy, total pancreatectomy, and en bloc vascular resection, where appropriate. Reconstructive techniques have been explored and include methods of pancreaticojejunostomy and pancreaticogastrostomy with or without pancreatic ductal stents and intraoperatively placed closed suction drains. Perioperative mortality following pancreaticoduodenectomy for cancer has a general reported incidence of 1% to 4% at high volume centers experienced with the operation. Morbidity however still remains high with that of delayed gastric emptying, pancreatic anastomotic leak or fistula, intraabdominal abscess, and hemorrhage as the leading reported complications. Researchers have investigated several agents and strategies to decrease or prevent the potential morbidity of these complications including the use of octreotide, drainage of the pancreatic bed and institution of early enteral feeding. Unfortunately, the majority of patients with pancreatic cancer present with either locally advanced or metastatic disease that precludes operative cure. The expected survival for these patients is usually less than six months from diagnosis. Therefore, a goal of therapy should be adequate palliation of symptoms of pain, biliary or duodenal obstruction and improvement of remaining quality of life with the least degree of morbidity possible.

Clinical applications of a novel sustained-release injectable drug delivery system: DepoFoam technology.

Abstract: The therapeutic effectiveness of drugs is often limited by the inability to sustain therapeutic levels at the target site. Encapsulation of drugs in multivesicular lipid-based particles for sustained release is a novel approach to improving the pharmacokinetics of drug therapy. This paper reviews the preclinical and clinical literature on the applications and potential therapeutic benefits of DepoFoam technology, a novel sustained-release, injectable drug delivery system. DepoFoam formulations of drugs, including anticancer agents (cytarabine, methotrexate, bleomycin, recombinant interferon alfa, 5-fluorouridine-5'-monophosphate, and others), anti-infective agents (dideoxycytidine, 2'-norcyclic guanosine monophosphate, cidofovir, tobramycin, gentamicin, amikacin), analgesics (morphine, bupivacaine), and macromolecules (insulin, interleukin-2), delivered intrathecally, subcutaneously, intraperitoneally, or intralesionally, provide sustained therapeutic levels of drug at the intended target site and reduce systemic exposure and toxicity. Pharmacokinetic studies have demonstrated that DepoFoam particle encapsulation effectively extends the half-life of drugs, thus prolonging the duration of therapeutic drug concentrations in local tissues or in body spaces into which the encapsulated drug is injected. In the case of cell-cycle phase-specific chemotherapeutic agents, such formulations can improve efficacy and therapeutic ratio. DepoFoam is a promising drug delivery system for sustained release of hydrophilic injectable drugs that has a wide range of potential applications in oncology, infectious disease, analgesia, and other therapeutic areas.

Approach to angiogenesis inhibition based on cyclooxygenase-2.

Abstract: Two cyclooxygenase (COX) isoforms have been identified: COX-1 and COX-2. COX-1 is the constitutively expressed form of the enzyme and is ubiquitous in its distribution. COX-2 is inducible and is present in inflammatory foci, tumors, and neovasculature. Expression of COX-2 appears to be important in tumor promotion, growth, and metastasis. It is up-regulated in a variety of premalignant disorders and malignancies. COX inhibitors have a major role in the treatment of inflammation and pain. Epidemiologic evidence in patients who take nonsteroidal anti-inflammatory drugs links COX inhibition with decreases in malignant esophageal, stomach, colon, lung, and breast tumors. Nonselective COX inhibitors have demonstrated efficacy in control of familial adenomatous polyposis, a disorder associated with the development of thousands of benign intestinal polyps. The selective COX-2 inhibitor celecoxib (Celebrex, Pharmacia) has been shown to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care. Celecoxib has recently been approved for this indication and offers the potential for equivalent or greater efficacy than that seen with nonselective COX inhibitors but without the gastrointestinal mucosal toxicity and the inhibition of platelet function associated with those agents. Angiogenesis is a feature of both benign and malignant disease. Because COX-2 is up-regulated in the neovasculature of the rheumatoid pannus and in malignant tumors and their surrounding stroma, selective COX-2 inhibitors may be able to modify the progression of these disorders through the control of angiogenesis.

Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation.

Abstract: BACKGROUND: Both EGF family ligands and ErbB family receptor kinases act upstream of RAS to induce mitogenesis of normal cells, such as NIH 3T3 fibroblasts. However, oncogenically mutated RAS, such as v-Ha-RAS is constitutively activated and therefore no longer requires these ligands or receptors for its activation. Nevertheless, it up-regulates the expression of these EGF family ligands. To understand the biologic significance of RAS-induced up-regulation of these ligands in both RAS-induced PAK activation and malignant transformation, we have conducted the following studies, based on the previous observations that (1) the N-terminal SH3 domain of PIX selectively binds a Pro-rich domain of 18 amino acids of PAKs, CDC42/Rac-dependent Ser/Thr kinase family, and (2) this specific interaction is essential for both PAK activation and membrane ruffling RESULTS: Using four distinct, cell-permeable, and highly specific inhibitors, namely WR-PAK18, which blocks the PAK-PIX interaction; AG 1478, which inhibits ErbB1 kinase activity; and AG 825 or AG 879, which inhibits ErbB2 kinase activity, we demonstrate that (1) the PAK-PIX interaction is essential for v-Ha-RAS-induced malignant transformation; (2) v-Ha-RAS requires not only ErbB1 but also ErbB2, which are activated through two independent autocrine pathways to induce both the PIX/Rac/CDC42-dependent PAK activation and malignant transformation in vitro; and (3) a combination of AG 879 and the Src family kinase-specific inhibitor PP1 suppresses almost completely the growth of RAS-induced sarcomas in nude mice. CONCLUSION: These findings not only change our conventional view on the role of these RAS-inducible ligands and ErbB family receptors (serving as RAS activators) but also suggest a new avenue for the treatment of RAS-associated cancers by a combination of inhibitors specific for ERbB, Src, or PAK family kinases.

The role of tissue microdissection in cancer research.

Abstract: Introduction ― Les cellules cancereuses du colon humain expriment le recepteur la gastrine et de ce fait il a ete postule que la gastrine joue un role dans la croissance du cancer du colon. La gastrine stimule, a la fois, la croissance du cancer du colon chez la souris et de lignes cellulaires de carcinome du colon. Dans cette etude, nous avons etudie les effets de la pentagastrine et des antagonistes des recepteurs a la gastrine (proglumide, benzotript, CR 2093) sur la croissance et le metabolisme des polyamines de cellules de carcinome de colon humain (Caco-2) qui, apres une phase de replication active, se differencient spontanement en entrocytes matures. Methodes ― Les cellules on ete cultivees dans du milieu DMEN + 10% FCS ou en milieu sans serum, contenant la pentagastrine et/ou la proglumide, du benzotript ou CR 2093

Mesenchymal stem cells: stealth and suppression.

Abstract: Human post-natal bone marrow contains mesenchymal stem cells (MSCs), which are capable of giving rise to multiple mesenchymal cell lineages. Large quantities of human MSCs can be readily obtained following a simple bone marrow aspiration procedure and subsequent expansion over a million-fold in culture. This extensive capacity for clinical scale expansion in vitro has facilitated the development of preclinical models as well as clinical studies designed to assess the safety, feasibility, and efficacy of transplanting allogeneic MSCs for a variety of indications. This review focuses on the rationale for performing clinical studies of MSC transplantation and will discuss the potential role that MSCs may have in the field of hematopoietic stem cell transplantation as well as for the repair or regeneration of bone, cartilage, and cardiac tissues.

Taxane-based chemotherapy for patients with carcinoma of unknown primary site.

Abstract: Background The purpose of this study was to determine the long-term follow-up on survival of patients with carcinoma of unknown primary site treated with taxane-based chemotherapy in a multicenter community-based setting. Patients and methods Patients were treated with three sequential phase II trials between 1995 and 1998 as follows: Study I: paclitaxel 200 mg/m2 intravenously (i.v.) Day 1, carboplatin AUC = 6 i.v. Day 1, and oral etoposide 50 mg daily alternating with 100 mg daily days 1-10 every 3 weeks; Study II: docetaxel 75 mg/m2 i.v. Day 1, cisplatin 75 mg/m2 i.v. Day 1, repeated every 3 weeks; Study III: docetaxel 65 mg/m2 i.v. Day 1, carboplatin AUC 6 i.v. Day 1, repeated every 3 weeks. A total of 144 patients (71 on Study I, 26 on Study II, 47 on Study III) were treated (45% had well differentiated carcinoma, 48% had poorly differentiated carcinomas, and 6% poorly differentiated neuroendocrine tumors). The majority of the patients had multiple sites of metastatic disease. Results Thirty-six percent of all evaluable patients responded to therapy (27% partial and 9% complete responses). The median survival was 10 months with 1-, 2-, 3-, and 4-year survivals of 42%, 22%, 17%, and 17%, respectively. Follow-up ranges from 11 to 50 months. Women survived significantly longer than men. Thirty-one patients remain alive and 14 are progression-free. The primary toxicity was leukopenia with the carboplatin regimens and nausea and vomiting with the cisplatin regimen. A review of the survival of several large previously reported series of patients was compared to results after taxane-based chemotherapy. A compelling argument is made that chemotherapy is superior to best supportive care alone and that taxane-based chemotherapy is superior to other forms of chemotherapy. However, prospective randomized trials will be necessary to definitively demonstrate the superiority of this treatment compared to other therapies for these patients. Conclusion Taxane-based chemotherapy for patients with carcinoma of unknown primary site appears to be clinically beneficial and is associated with long-term survival for a minority of patients at 2-, 3-, and 4-year follow-up.

Angiogenesis inhibition in solid tumors.

Abstract: Angiogenesis plays a central role in a variety of physiologic and pathologic disease states. Because the growth and metastasis of malignant neoplasms require the presence of an adequate blood supply, pharmacologic inhibition of tumor-induced angiogenesis represents a promising target for antineoplastic therapy. A number of approaches to such inhibition are therefore under active investigation. Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are among the best characterized of the various key elements in benign and neoplastic angiogenesis. In 1997, clinical trials were initiated to evaluate an anti-VEGF monoclonal antibody and a VEGFR-2 antagonist as therapy for patients with different types of solid tumors and hematologic neoplasms. Dose selection for these cytostatic agents requires translation from preclinical models, as these agents are likely to require chronic dosing at an optimal biological dose, rather than a maximally tolerated dose. For example, SU5416, a novel small-molecule inhibitor of VEGFR-2, administered at 145 mg/m2 intravenously twice weekly, is well tolerated and achieves the concentration levels required to inhibit endothelial cell proliferation in preclinical models. Because the mechanism of action of angiogenesis inhibitors is complementary to that of classic cytotoxic chemotherapy, preclinical models and subsequent clinical trials frequently explore combinations of these agents with cytotoxic chemotherapy, hoping to achieve additive or synergistic antitumor activity. It is hoped that the combination of angiogenesis inhibitors with cytotoxic chemotherapeutic agents will significantly improve survival and quality of life for cancer patients. As a result of favorable results from Phase 1 and 2 studies, randomized, multicenter clinical investigations of angiogenesis inhibitors are ongoing.

The diagnosis of pancreatic cancer.

Abstract: Despite increasing interest and research on pancreatic cancer, patients with this devastating disease have a very poor prognosis. The principal reason for this grim prognosis is the inability to diagnose the disease at an early, localized, and curable stage. This review is intended to present an overview of our current status on the diagnosis of pancreatic cancer and emphasize recent advances in imaging and tumor markers that are attempting to overcome the challenges of this dreaded disease. Clinical presentation and risk factors for pancreatic cancer are reviewed. Various imaging modalities-including endoscopic and transabdominal ultrasound, ERCP, CT, MRI and PET-are described, with emphasis on their limitations for diagnosing pancreatic cancer at a size that has a significant impact on survival rates. The most promising approach for the early diagnosis of pancreatic adenocarcinoma utilizes tumor markers. Many of the tumor markers investigated over the past 20 years as well as some promising markers under current investigation are reviewed. The combination of serum markers may improve sensitivity and specificity in making the diagnosis of pancreatic adenocarcinoma. We conclude that the current status of imaging and tumor markers does not permit the early diagnosis of an adenocarcinoma of the pancreas. The development of improved early detection methods for pancreatic cancer is essential; however, at the present time it should be limited to high-risk individuals to allow for a better opportunity for success.

Pancreatic cancer: current concepts in imaging for diagnosis and staging.

Abstract: Because of its late clinical presentation, pancreatic cancer remains the fourth most common cause of cancer death. Surgery is the only option for cure, and advancements in surgical technique and neoadjuvant therapy have the potential to increase the number of patients who could undergo surgery for potential cure. Accurate diagnosis and staging of pancreatic ductal carcinoma are therefore of great importance. This paper reviews the state of the art for such diagnostic modalities as computed tomography, magnetic resonance imaging, endoscopic ultrasound, positron emission tomography, and laparoscopic surgery and laparoscopic ultrasound for diagnosis and staging of pancreatic cancer. Currently, accurate diagnosis and staging probably require the use of a combination of techniques, including multiphase helical or multidetector computed tomography and/or dynamically enhanced magnetic resonance imaging with endoscopic ultrasound with fine-needle aspiration. The role of positron emission tomography still needs to be determined. The role of laparoscopic surgery and laparoscopic ultrasound may be limited in those institutions with state-of-the-art imaging techniques.

Integrins as targets of angiogenesis inhibition.

Abstract: Integrins area widely distributed family of cell surface alpha/beta heterodimers that bind cells to components of the extracellular matrix and mediate cell-cell interactions. Integrin alpha(v)beta3 interacts with RGD (Arg-Gly-Asp) sequence-containing proteins in the extracellular matrix. The distribution of alpha(v)beta3 is highly restricted, with expression on activated endothelium, activated vascular smooth muscle, tumors, and osteoclasts. Expression of alpha(v)beta3 may contribute to a malignant phenotype by supporting the growth and persistence of small blood vessels that nourish the primary and metastatic tumors and increasing invasive potential. Inhibition of alpha(v)beta3 can modulate tumor-induced angiogenesis and can increase apoptosis of tumor-associated small blood vessels. It might also help control humoral hypercalcemia of malignancy through direct or indirect activity on the osteoclast. Preclinical studies found that several RGD peptidomimetics and a monoclonal antibody to alpha(v)beta3 can inhibit tumor growth by blocking tumor-induced angiogenesis.

Detection of low level HER-2/neu gene amplification in prostate cancer by fluorescence in situ hybridization.

Abstract: PURPOSE: Although expression of the HER-2/neu oncogene has been correlated with tumor progression in prostate cancer, the biologic significance of detecting HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) or evidence for protein overexpression by immunohistochemistry (IHC) remains unclear. In this study, we directly compared HER-2/neu FISH and IHC to determine which may be more predictive of the response to trastuzumab. PATIENTS AND METHODS: Forty patients with prostate cancer were analyzed for gene amplification by FISH performed with HER-2/neu and chromosome 17 (CEP 17) DNA probes (Vysis). Protein expression was examined by immunofluorescence and by IHC using the DAKO HercepTest antibody protocol and a monoclonal antibody to Her-2/neu on archival paraffin sections. The patients included 30 men with primary tumors that were treated with radical prostatectomy. Of these, 15 demonstrated subsequent disease progression within 3 years. Five patients with prostatic intraepithelial neoplasia were tested, as were five with metastatic disease whose samples were obtained before androgen ablation therapy. RESULTS: None of the 30 primary prostate cancer specimens showed overexpression for HER-2/neu by immunofluorescence or by IHC with the DAKO protocol. One sample showed 3+ membrane expression with the monoclonal antibody. In contrast, low copy number gene amplifications (3-8 HER-2/neu signals/nucleus) were detected in 16 of 30 samples (53%) by FISH. Most amplified cells were diploid for CEP 17, demonstrating that amplification was not due to total cell aneuploidy. FISH and IHC determined that prostatic intraepithelial neoplasia samples were normal. Four of five (80%) metastatic samples were amplified for HER-2/neu by FISH. Nearly 70% of metastatic cancer cells among all five specimens demonstrated aneuploidy. A single lymph node metastasis showed 3+ membrane staining by IHC (DAKO). CONCLUSIONS: In contrast to breast cancer, FISH detects HER-2/neu amplification in a substantial proportion of prostate cancers that do not overexpress HER-2/neuby IHC. Although the biologic significance of this finding is uncertain, it has implications for the direction of current and planned clinical trials of trastuzumab in advanced prostate cancer, including determination of patient eligibility.

Cancer patients use unconventional medical therapies far more frequently than standard history and physical examination suggest.

Abstract: BACKGROUND: Studies with questionnaires have suggested that many cancer patients utilize unconventional medical therapies (UMT). There are few data evaluating directed questions about the use of UMT. This study was performed to determine if careful directed questioning about UMT reveals a higher rate of utilization compared to standard history and physical examination. MATERIALS AND METHODS: A prospective evaluation of 196 consecutive patients presenting for initial consultation at the University of Pennsylvania was performed. Each patient underwent standard history and physical examination, including questions regarding prescription and over-the-counter medications. At the completion of standard questioning, patients were asked an explicit set of directed questions regarding the utilization of UMT. The median age of the patient population was 61 years (range = 28-80 years). Cancer diagnoses included breast (19%), lung (28%), prostate (26%), and other (27%). Females constituted 32% of the patient population. RESULTS: Initially, only 13 patients (7%) revealed they were using UMT during a standard history and physical. Evaluation of the remaining 183 patients with directed questioning revealed an additional 66 patients (36%) were utilizing these therapies. Of the 79 patients taking UMT, 84% were identified by directed questioning and 16% by standard history and physical examination (P or = 2 of these therapies (mean = 2.5; range 1-17 therapies). A total of 48 different UMT were used by this patient population. Patients utilizing multivitamin supplementation were significantly more likely to be using an UMT than those who were not (68% vs. 31%; P < 0.0001). Females were more likely to use UMT than males (49% vs. 35%; P = 0.08). CONCLUSIONS: The addition of explicitly directed questioning to the standard history and physical examination significantly increases the oncologist's ability to identify cancer patients who utilize UMT. Some of these therapies may interact with conventional cancer treatments and/or cause significant side effects; consequently, it is important for oncologists to detect those patients utilizing these therapies.

Developmental aspects of early pancreatic cancer.

Abstract: The specific cell of origin responsible for generating pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma remains unknown. During development, epithelial stem cells within embryonic pancreatic epithelium give riseto mature acinar, ductal, and islet elements. Emerging evidence suggests that cells with precursor potential also exist within adult pancreas, resulting in significant developmental plasticity among both endocrine and exocrine cell types. In this review, the contribution of developmental plasticity in initiating pancreatic metaplasia and neoplasia is considered, and evidence supporting a role for epithelial stem cells in pancreatic cancer is discussed.

Management of craniopharyngioma.

Abstract: PURPOSE The management of craniopharyngioma does not have a consensus. Extensive surgery may be associated with major complications. The purpose of this study was to evaluate local tumor control and survival after limited surgery and postoperative radiotherapy. METHODS AND MATERIALS Thirty patients with craniopharyngioma were treated at SUNY Upstate Medical University in Syracuse, NY from 1967 to 2000. The group consisted of 13 males and 17 females, and the median age was 35 years. The median follow-up was 71 months. Only two patients underwent complete tumor resection. Eighteen patients underwent subtotal resection, and 10 underwent decompressive surgery (ventriculoperitoneal shunt or cyst aspiration). Most (20/ 28) patients who had less than total resection received immediate postoperative radiotherapy. Four patients received conventional radiotherapy for recurrence. Gamma knife radiosurgery was used as part of the primary treatment in two patients and at the time of local tumor recurrence in three patients. RESULTS The local control rate, including after salvage treatment, was 91% and 83% at 5 and 10 years, respectively. Salvage was radiotherapy, gamma knife or surgery. Ultimate local tumor control appeared better for patients who underwent subtotal resection (100% and 89% at 5 and 10 years, respectively) than for those who did not undergo resection (61% and 61% at 5 and 10 years, respectively). The overall survival was 93% and 83% at 5 and 10 years, respectively. Two patients underwent gross total resection, and one patient experienced recurrence 6 years after the surgery and was treated by gamma knife radiosurgery. Both patients are well without recurrence at 3 and 7 years after the initial surgery. Survival also appeared to be improved for the group who underwent subtotal resection (100% and 90% at 5 and 10 years, respectively) versus those who did not undergo surgery (73% and 73% at 5 and 10 years, respectively). The dose of radiotherapy > or = 50 Gy had no impact on local control or survival. Ten patients experienced surgery-related complications, and five had radiotherapy-related complications, including visual, cranial nerve, motor, and endocrine deficits. CONCLUSION The extent of surgery appears to be an important prognostic factor for predicting outcome, although this may represent selection bias. Long-term disease control is excellent after subtotal resection and postoperative radiotherapy. Encouraging initial results have been seen with gamma knife radiosurgery, and the potential for gamma knife radiosurgery to replace more extensive surgical resection should be further explored.

SU6668, a multitargeted angiogenesis inhibitor.

Abstract: Angiogenesis plays a critical role in the growth and metastasis of solid and hematologic malignancies. This complex and highly regulated process involves numerous different cell types and mediators. Vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor are among the soluble factors that stimulate this process. They are ligands for specific tyrosine kinase receptors that are important in transduction of intracellular signals and induction of angiogenesis. SU6668 is a novel molecule that competitively inhibits the tyrosine kinase of the receptors for vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, and c-kit. In vitro studies have confirmed that SU6668 inhibits growth factor-stimulated tyrosine phosphorylation. SU6668 also has significant antitumor activity against many types of tumor xenograft explants in athymic mice. SU6668 inhibits angiogenesis through several mechanisms, including the induction of apoptosis in vascular endothelial cells and tumor cells. Currently, Phase 1 studies are being initiated to evaluate the potential of SU6668 as an anticancer agent for humans.

Factors predictive of outcome in patients with breast cancer refractory to neoadjuvant chemotherapy.

Abstract: Purpose The purpose of this study was to determine the clinical, pathological, and treatment factors that are predictive of local-regional recurrence and overall survival for patients with breast cancer that is refractory to neoadjuvant chemotherapy Patients and methods This study analyzed the data of the 177 breast cancer patients treated on our institutional protocols who had less than a partial response to neoadjuvant chemotherapy The initial clinical stage of disease was II in 27%, III in 69%, and IV (supraclavicular lymph node involvement) in 4% Surgery was performed in 94% of the patients, and 77% of these patients also received adjuvant chemotherapy Results After a median follow-up of 52 years, 106 patients experienced disease recurrence, with 98 of these having distant metastases and 45 having local-regional recurrence The 5- and 10-year overall survivals for the entire group were 56% and 33%, respectively The factors that were independently associated with a statistically significant poorer overall survival in a Cox regression analysis were pathologically involved lymph nodes after surgery, estrogen receptor-negative disease, and progressive disease during neoadjuvant chemotherapy The 5-year overall survival for patients with pathologically negative lymph nodes ranged from 84% (estrogen receptor-positive disease) to 75% (estrogen re-ceptor-negative disease), compared with rates for patients with pathologically positive lymph nodes of 66% (estrogen receptor-positive disease) and 40% (estrogen receptor-negative disease) The 5-year survival of patients with progressive disease was only 19% The 5- and 10-year local-regional recurrence rates for the 177 patients were 27% and 34%, respectively Significant factors on Cox analysis that predicted for local-regional recurrence were four or more pathologically involved lymph nodes and estrogen receptor-negative disease For the 105 patients treated with surgery and postoperative radiation therapy, the 10-year local-regional recurrence rates for the subgroups with 0, 1, or 2 of these factors were 12%, 25%, and 44%, respectively Conclusions For patients with a poor response to neoadjuvant chemotherapy, conventional treatments achieve reasonable outcomes in those with lymph node-negative disease or estrogen receptor-positive disease However, more active systemic and local therapies are needed for patients with estrogen receptor-negative disease and positive lymph nodes and for those with clinical evidence of progressive disease during neoadjuvant chemotherapy

The genealogic approach to human genetics of disease.

Abstract: The goal of modern human genetics is to correlate genes with disease or, more specifically, relate genetic variation to phenotypic variation. Although this correlation is usually straightforward in the Mendelian disorders, it has proved to be much more difficult to find in the common diseases because they appear to be more complex, likely involving an interplay among multiple genes and between genes and the environment. Although the strategy of linkage mapping of families was very successful when it was applied to the rare monogenic diseases, few common diseases have been mapped to statistical significance. Many investigators are now abandoning linkage analysis altogether and are moving to a candidate gene case-control strategy. In this article, we describe a genealogic approach to mapping human disease genes and provide three examples of how we have used it to map common diseases to statistical significance. We focus on a simple population with little historic migration and use a computerized genealogy database to increase the number of patients who can be compared with other affected relatives through high-density microsatellite genotyping. The genealogy helps determine which phenotypic classification is inherited and therefore possible to map. It may represent a more efficient strategy than candidate gene case-control studies for determination of what alleles or haplotypes are shared by patients in a population. We suggest that the genetics community not give up on linkage analysis, nor should it assume that the common diseases are too complex to map.

DNA microarrays in pediatric cancer.

Abstract: Childhood cancer, like all cancer, is at heart a genetic disease. Consequently, fundamental understanding of the oncogenic process is likely to be beneficially addressed by genetic methodology. Current methods have largely focused on single-gene defects, like chimeric genes, which are present in many sarcomas and leukemias. Real understanding is more likely to derive from a genome-wide analysis of these malignancies. Recent technologic advances have made it possible to simultaneously assess the entire expressed gene profile, or transcriptome, of a given cancer. Foremost among these methods is gene expression profiling using DNA microarrays. Two basic approaches predominate: spotted arrays and photolithography arrays. Regardless of the method, the resulting information can be used to create disease profiles, but only if appropriate bioinformatic solutions are employed. Common analytic approaches include two-way expression comparisons, or scatter analyses; outlier gene analysis, to identify significantly dysregulated genes; dendrogram analyses, as pioneered by Eisen; cluster analyses to identify diagnostic or biologic groups; and various forms of functional analyses to identify relevant genes and biologic pathways. Studies of both adult and pediatric cancer have demonstrated the feasibility of such analyses to identify both diagnostic and prognostic groups of tumors. Acute childhood leukemias have been grouped into myelogenous and lymphoid, and even B- and T-cell subsets. Breast cancer prognostic groups have been identified on the basis of a small subset of expressed genes. In addition, preliminary data on childhood sarcomas appear to identify both diagnostic and prognostic subsets. Specifically, embryonal rhabdomyosarcoma could be distinguished from alveolar rhabdomyosarcoma, and even morphologically mixed embryonal and alveolar rhabdomyosarcoma showed similar gene expression profiles in both histologies. Further, collaborative studies using clustering analyses appear to identify prognostic groups of diverse sarcomas. Larger institutional and cooperative group studies are currently underway to validate these preliminary findings.