Showing papers in "Cancer Journal in 2003"
TL;DR: The available evidence indicates that the HPV-cervical cancer association satisfies all relevant causal criteria for public health action and is the first instance in which a necessary cause has been demonstrated in cancer epidemiology--a realization that has obvious implications for primary and secondary prevention of this neoplastic disease.
Abstract: Cervical cancer is one of the most common neoplastic diseases affecting women, with a combined worldwide incidence of almost half a million new cases annually, second only to breast cancer. Basic and epidemiologic research conducted during the past 15-20 years have provided overwhelming evidence for an etiologic role for infection with certain types of sexually-transmitted human papillomavirus (HPV) as the primary cause of cervical cancer. The relative risks of cervical cancer following HPV infection as ascertained in case-control and cohort studies are among the highest in cancer epidemiology. The available evidence indicates that the HPV-cervical cancer association satisfies all relevant causal criteria for public health action. Other cervical cancer risk factors, such as smoking, parity, use of oral contraceptives, diet, other infections, and host susceptibility traits must be understood in the context of mediation of acquisition of HPV infection or in influencing events of the natural history of cervical neoplasia that occur following the establishment of a persistent HPV infection. Virtually all cervical carcinoma specimens contain HPV DNA, which suggests that HPV infection is a necessary cause of cervical neoplasia. This is the first instance in which a necessary cause has been demonstrated in cancer epidemiology--a realization that has obvious implications for primary and secondary prevention of this neoplastic disease.
213 citations
TL;DR: The progression-free survival of 19 months achieved with embolization in this study is encouraging, given that most patients had extensive liver involvement and had shown disease progression while receiving systemic treatment, and the survival probability was 93% at 1 year, 62% at 2 years, and 24% at 5 years.
Abstract: Background Carcinoid tumors have a predilection for metastasizing to the liver. The presence of liver metastases is associated with poor prognosis and also results in significant deterioration of patient's quality of life. Several reports suggest that hepatic artery embolization or chemoembolization can be used for control of liver disease in these patients. We retrospectively reviewed our experience with the use of hepatic arterial embolization or chemoembolization in patients with liver-dominant metastatic carcinoid disease, evaluating the clinical and radiologic response rates, duration of response, and progression-free and overall survival rates of these patients. Materials and methods The medical records of all patients with carcinoid tumors metastatic to the liver who underwent hepatic artery embolization or chemoembolization between January 1992 and December 2000 were reviewed. For the purposes of this study, we compared the follow-up computed tomography or magnetic resonance imaging with the baseline imaging to determine each patient's objective tumor response. The interval between the dates of response and disease progression was considered the response duration. Progression-free survival duration was calculated from the date of initial treatment to the date disease progression was recorded or the date of death. Survival durations were calculated using the Kaplan-Meier method. Results Eighty-one patients (48 men and 33 women; age range, 38-79 years) were included in this study. The mean duration of disease from the initial discovery of liver metastases until embolization was 24.5 months. Fifty patients were treated with bland hepatic artery embolization, and 31 underwent chemoembolization. Of the 69 patients in whom radiologic response could be evaluated, partial response was observed in 46 patients (67%), minimal response (MR) in six (8.7%), stable disease in 11 (16%), and progressive disease in six (8.7%). The median duration of response in the 42 patients with partial response was 17 months (range, 4-51 months). Sixty-three percent of patients had a reduction in their tumor-related symptoms. The median progression-free survival duration was 19 months (95% confidence interval, 17-21 months); the probability of progression-free survival was 75%, 35%, and 11% at 1, 2, and 3 years, respectively. The median overall survival time was 31 months (95% confidence interval, 23-38 months); the survival probability was 93% at 1 year, 62% at 2 years, and 24% at 5 years. Conclusions Hepatic arterial occlusive therapy using hepatic artery embolization or chemoembolization results in symptomatic and radiologic response in most patients with carcinoid metastases in the liver. The progression-free survival of 19 months achieved with embolization in our study is encouraging, given that most patients had extensive liver involvement and had shown disease progression while receiving systemic treatment.
184 citations
TL;DR: The data suggest that apoptosis may play an important role in determining breast cancer response to chemotherapy and that the level of treatment-induced apoptotic levels may have some value as a predictive marker.
Abstract: Purpose The relevance of apoptosis to breast cancer response to chemotherapy is unclear. We investigated whether changes in tumor cell apoptosis and Bcl-2 expression immediately after chemotherapy correlated with response to breast cancer treatment. Patients and methods Serial core biopsies of 25 breast cancer primary tumors were performed at either two or three time points: before treatment (N = 24) and approximately 24 hours (N = 22) and/or 48 hours (N = 19) after the initiation of the first cycle of chemotherapy. Apoptosis levels were quantified by use of a fluorescent terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) stain, and Bcl-2 and Bax were measured by semiquantitative immunohistochemical assays. All calculated P values were two sided. Results The apoptosis level at 48 hours was significantly higher in the tumors with pathological complete response or 1 cm residual disease (median, 7%; range, 1%-36%); Mann-Whitney test. This difference was also present in the subgroup of 16 tumors treated with docetaxel/doxorubicin chemotherapy (25% vs 4%, respectively). A decrease in Bcl2 expression after chemotherapy relative to the expression from the pretreatment sample also correlated with disease response. Specifically, three of the nine tumors with a decrease in Bcl-2 had a pathological complete response, compared with 0 of the 15 tumors with stable levels of Bcl-2 (Fisher's exact test). There was no relationship between serial measurements of Bax and response. Discussion These data suggest that apoptosis may play an important role in determining breast cancer response to chemotherapy and that the level of treatment-induced apoptosis may have some value as a predictive marker.
142 citations
TL;DR: Intensity-modulated radiotherapy after extrapleural pneumonectomy is tolerable and seems effective, at least at this early point, and it may be appropriate to add novel agents to further improve the therapeutic ratio.
Abstract: PURPOSE Malignant pleural mesothelioma often recurs locally in spite of aggressive resection by extrapleural pneumonectomy and conventional radiotherapy. This may be due to failure to recognize the extent of clinical target volume (CTV) or suboptimal dose delivery to a target that abuts the heart, esophagus, liver, lung, kidney, and spinal cord. We report how these geometric/dosimetric constraints were overcome by exploiting intensity-modulated radiotherapy in the first cohort patient. MATERIALS AND METHODS Twenty-eight patients who had undergone extrapleural pneumonectomy were treated with intensity-modulated radiotherapy. The CTV included the surgically violated inner chest wall, insertion of diaphragm, pleural reflections, and deep margin of the incision. CTV delineation was facilitated by intraoperative radio-opaque marking. Motion was assessed. CTV doses were 45-50 Gy with boosts taken to 60 Gy. RESULTS Despite the large, irregular CTV (median, 4151 cc; range, 2667-7286 cc), an average of 97% of the CTV was covered to the target dose (range, 92%-100%). Respiratory motion was minimal because of immobility of the prosthetic diaphragm. Normal tissue dose constraints were met. The commonest effects were nausea/vomiting (89%) and dyspnea (80%). Esophagitis was absent (59% of patients) or mild (34% grade 1/2). At median follow-up of 9 months (range, 5-27 months), local control within the contoured target was 100%. One-year survival, disease-specific survival, and disease-free survival are 65%, 91%, and 88%, respectively. CONCLUSIONS Intensity-modulated radiotherapy after extrapleural pneumonectomy is tolerable and seems effective, at least at this early point. As local control improves, systemic metastases become more common, and it may be appropriate to add novel agents to further improve the therapeutic ratio.
122 citations
TL;DR: The data obtained from patients with glioblastoma multiforme have already demonstrated that these new magnetic resonance techniques are able to contribute to diagnosis, characterization of malignant potential, treatment planning and assessment of response to therapy.
Abstract: Glioblastoma multiforme are infiltrative lesions that have a high degree of heterogeneity, both within and between different patients Imaging is critical for all phases in the evaluation and treatment of these lesions, but has been limited in providing information that is reliable enough to stratify patients into groups with uniform behavior and to predict outcome Although magnetic resonance imaging is the method of choice for visualizing anatomic features of the lesion, its results are ambiguous in terms of defining the functional characteristics of the lesion and distinguishing tumor from treatment induced necrosis Recent advances in magnetic resonance have made possible the routine acquisition of physiological data such as perfusion- and diffusion-weighted images and of metabolic data such as water suppressed proton spectroscopic images These provide quantitative measurements that are more closely related to the biological properties of the tumor and reflect changes in tumor vascularity, cellularity and proliferation that are associated with tumor progression As the molecular properties that influence invasion and neoplastic transformation are elucidated, it is critical that noninvasive imaging techniques are available for investigating new therapies and tailoring treatment to individual patient characteristics The data obtained from patients with glioblastoma multiforme have already demonstrated that these new magnetic resonance techniques are able to contribute to diagnosis, characterization of malignant potential, treatment planning and assessment of response to therapy
116 citations
TL;DR: This novel combined-modality regimen is highly active in the treatment of locoregional esophageal cancer, producing an actuarial 3-year survival of 41%.
Abstract: Purpose This phase II study was designed to determine the feasibility, toxicity, and therapeutic efficacy of a novel outpatient combined-modality preoperative regimen in patients with localized esophageal cancer. Patients and methods One hundred twenty-nine eligible patients with previously untreated, potentially resectable, clinical stage I-III carcinoma of the esophagus were treated between July 1995 and July 1999. Combined-modality treatment included: paclitaxel, 200 mg/m2, 1-hour i.v. infusion, days 1 and 22; carboplatin, an area under the concentration time curve 6.0 i.v., days 1 and 22; 5-fluorouracil, 225 mg/m2/day, continuous i.v. infusion, days 1-42; and radiation therapy, 45 Gy, 1.8-Gy single daily fractions 5 days weekly, beginning day 1. All patients underwent surgical resection 4-8 weeks after completion of the preoperative therapy. Results One hundred twenty-three patients (95%) completed preoperative therapy, 105 patients (81%) underwent attempted resection, and 96 patients (74%) had definitive resection. A pathological complete response was achieved in 47 of 123 evaluable patients (38%); an additional 30 patients (24%) had only microscopic residual tumor. With a median follow-up of 45 months, the median survival is 22 months (95% CI = 15-32 months), with actuarial 1-, 2-, and 3-year survivals of 71%, 47%, and 41%, respectively. The most frequent grade 3/4 toxicities of the neoadjuvant program were leukopenia (73%) and esophagitis (43%). Although 73 patients (57%) required brief hospitalizations during preoperative therapy, there were no treatment-related deaths, and 94% of patients remained candidates for resection after the completion of treatment. Six patients (6%) died after surgery. Conclusions This novel combined-modality regimen is highly active in the treatment of locoregional esophageal cancer, producing an actuarial 3-year survival of 41%. Although this preoperative regimen produced moderate acute toxicity, there were no treatment-related deaths and the large majority of patients were able to undergo subsequent esophageal resection. These results, obtained in a community-based setting and involving multiple surgeons, radiation oncologists, and medical oncologists, compare favorably with those of previous single-center and multicenter results. Further evaluation of novel combined-modality programs is warranted, as is the incorporation of epidermal growth factor receptor antagonists or other targeted agents.
106 citations
TL;DR: Failure to express Smad2, pSmad 2, or Smad4 was associated with advanced stage disease, the presence of lymph node metastases, and a significantly shorter overall survival (median survival: 35 vs 58 months).
Abstract: Purpose Based largely on in vitro investigations and animal studies, investigators believe that disruptions of transforming growth factor-beta (TGF-beta) signaling contribute to the development and progression of human colorectal cancer. The purpose of this study was to directly assess the status of the TGF-beta signaling pathway in colorectal cancer and determine the effects of its disruption on clinical behavior and outcome. Materials and methods Smad proteins are the principal intracellular components of the TGF-beta signaling pathway. We conducted a high-throughput analysis of the expression patterns of Smad2, phosphorylated (activated) Smad2 (pSmad2), and Smad4 in more than 600 human colorectal cancer specimens assembled in tissue microarrays. Results The vast majority (93.8%; 95% CI: 92%-96%) of colorectal cancers expressed phosphorylated Smad2, indicating the ability of the tumors to survive and proliferate within a microenvironment that contains bioactive TGF-beta. Twelve of 633 (1.9%; 95% CI: 1%-3%) cases failed to express Smad2, and 15 of 641 (2.3%; 95% CI: 1%-4%) cases failed to express Smad4. Moreover, 29 of 615 (4.7%; 95% CI: 3%-7%) of cases expressed Smad2 but not its activated form (pSmad2), suggesting the presence of a TGF-beta receptor defect. Based on an analysis of 577 cases for which clinical outcome information was available, failure to express Smad2, pSmad2, or Smad4 was associated with advanced-stage disease, the presence of lymph node metastases, and a significantly shorter overall survival (median survival: 35 vs 58 months). Discussion Loss of Smad activation and/or expression occurs in approximately 10% of colorectal cancers. This subset has a poor prognosis because of its association with advanced disease and the presence of lymph node metastases at diagnosis.
106 citations
TL;DR: Despite the overall poor prognosis of patients with glioblastoma multiforme, multimodality treatment and chemotherapy in particular improve outcome, and chemotherapeutic options are beginning to have an increased impact.
Abstract: INTRODUCTION Glioblastoma multiforme continues to be associated with a dismal prognosis, despite aggressive therapy. What limited therapeutic impact that has been made has come via multimodality treatment in which chemotherapy plays an important role. In this manuscript, we review current chemotherapy options for glioblastomas. METHODS The current literature concerning glioblastoma multiforme chemotherapy was reviewed. In addition to a review of landmark references, a MEDLINE search of the literature published from January 2000 to November 2002 was performed using the key words “chemotherapy AND malignant glioma” and limiting responses to clinical trials. RESULTS Several cytotoxic chemotherapeutic agents that are efficacious in treating glioblastoma are in common clinical use. These can be classified as first-line or second-line agents, depending on their efficacy. In addition, cytostatic chemotherapy agents are beginning to play a role in glioblastoma treatment. Finally, new methods to deliver high chemotherapy doses to brain tumors hold promise for future therapies. CONCLUSIONS Despite the overall poor prognosis of patients with glioblastoma multiforme, multimodality treatment and chemotherapy in particular improve outcome, and chemotherapeutic options are beginning to have an increased impact. Strategies currently in clinical trials may improve this impact more in the future.
96 citations
TL;DR: The available data suggests that increased levels of FAK protein and activity may contribute to an increased ERK activity and cell proliferation in vivo in these tumors.
Abstract: Focal adhesion kinase (FAK) is a non-receptor cytoplasmic-tyrosine kinase that is activated by several different cell surface receptors shown to be upregulated on glioblastoma cells (integrins alpha(v)beta3 and alpha(v)beta5, and the epidermal growth factor receptor). Activated FAK can signal through several different signaling pathways, which are reviewed here. Published data are summarized that have demonstrated 1) elevated FAK expression in anaplastic astrocytoma and glioblastoma tumor biopsy samples, 2) a role for FAK in the promotion of glioblastoma cell proliferation, survival and migration in vitro, and 3) a role for FAK in the promotion of glioblastoma cell proliferation in vivo in an animal model. The available data suggests that increased levels of FAK protein and activity may contribute to an increased ERK activity and cell proliferation in vivo in these tumors.
94 citations
TL;DR: Aggressive attempts at salvage therapy for locoregional failures are warranted and frequently produce long-term disease control, particularly in patients with close or positive surgical margins.
Abstract: PURPOSE The purpose of this study was to review treatment results for primary soft tissue sarcomas of the head and neck in order to determine prognostic factors. PATIENTS AND METHODS From 1970 to 2000, 44 adult patients were diagnosed with a biopsy-proven, nonmetastatic primary soft tissue sarcoma in a head and neck subsite; were treated with curative intent; and had adequate follow-up and records for our review. Patients with extraosseous Ewing's sarcoma, Kaposi's sarcoma, rhabdomyosarcoma, dermatofibrosarcoma protuberans, and desmoid tumor were excluded. The most common tumor histologies included malignant fibrous histiocytoma (15 patients), angiosarcoma (nine patients), fibrosarcoma (six patients), and leiomyosarcoma (six patients). RESULTS The median overall survival for all patients was 79 months. The actuarial 5-year local control for all patients was 55% and was highly correlated with the extent of surgical excision: 25% for subtotal resection/debulking, 65% for wide local excision, and 100% for radical excision. Local control at 5 years was 60% for patients treated with both surgery and radiotherapy, 54% for those treated with surgery alone, and 43% for those treated with radiotherapy alone. Adjuvant radiotherapy significantly improved the local control rates (from 25% to 54%) for patients with close (<2 mm) or positive surgical margins. Of 14 patients with locoregional failure in whom salvage was attempted, nine (64%) were rendered disease free. CONCLUSIONS Multimodality therapy with both surgery and radiotherapy improves local control, particularly in patients with close or positive surgical margins. Aggressive attempts at salvage therapy for locoregional failures are warranted and frequently produce long-term disease control.
79 citations
TL;DR: Insight into tumor genesis by means of genomic assays may aid in predicting the clinical behavior of glioblastoma and in providing individualized potential targets for therapeutic agents.
Abstract: Recent advances in cytogenetic and molecular methodologies have elucidated certain principal characteristics of oncogenesis in glioblastoma multiforme. The earliest clues implicate gene sequence alterations, such as gene amplification and numerical gain or loss of function in specific chromosomes. Genetic classification and expression patterns have thus been constructed, conferring the likelihood of two types of glioblastoma, primary (de novo) as opposed to secondary (evolving from a pre-existing low-grade glioma). The former group of tumors exhibits more frequent occurrences of EGFR gene amplification, whereas the latter group relies strongly on TP53 gene inactivation. Many other tumor suppressor genes and oncogenes have been discovered. Most gene alterations induce cell cycle dysfunction on a complex molecular level. Further insight into tumor genesis by means of genomic assays may aid in predicting the clinical behavior of glioblastoma and in providing individualized potential targets for therapeutic agents.
TL;DR: It is recommended that a “gross total” resection of the enhancing portion of a GBM be performed whenever possible and the mortality rate is 3% and the rate of major neurologic morbidity is less than 10%.
Abstract: Surgical resection is a critical aspect of the management of a patient with a glioblastoma (GBM). An intimate knowledge of the anatomy of a GBM, as well as familiarity with particular surgical techniques and adjunctive technologies is required for safe surgical resection. The goals of resection include diagnosis, relief of mass effect, and cytoreduction. A recent study showed that resection of 98% or more of the tumor mass can result in a statistically significant survival advantage. Even in functionally critical areas, "gross total" resections are possible if proper techniques are employed. It is recommended that a "gross total" resection of the enhancing portion of a GBM be performed whenever possible. With this philosophy, the mortality rate is 3% and the rate of major neurologic morbidity is less than 10%.
TL;DR: In the comparison between the patients with CVD and the matched-control patients, there was no significant difference in the incidence of acute or late complication, but there was a higher incidence of radiation complications in patients with scleroderma.
Abstract: Background Controversy surrounds the potential complication rate of patients with collagen vascular diseases (CVD) after radiation. We assess the acute and late complications (based on Radiation Therapy Oncology Group criteria) by a matched-control retrospective study. PATIRNTS/METHODS: The charts of 12,000 patients treated with radiation therapy at the University of Louisville from 1982 to 2001 were reviewed for CVD. A total of 38 patients with documented CVD were compared with a matched-control group of 38 patients without CVD. Median follow-up for patients with CVD was 35 months. The patients were matched on the basis of site treated, age, dose, date of treatment, sex, treatment goal, follow-up, tumor site and histology, therapeutic technique, and general treatment method. The patients with CVD included 21 patients with systemic lupus erythematosus (55%), two with scleroderma (5%), four with Raynaud's phenomena (11%), three with fibromyalgia (8%), three with polymyalgia rheumatica (8%), three with Sjogren's syndrome (8%), and two with polymyositis-dermatomyositis (5%). Twenty-nine patients received curative doses, and nine patients received palliative doses. Results No difference was observed in the incidence of acute or late complications between the two groups. For CVD and matched-control patients receiving curative doses, the incidence of acute reaction for grade II was 49% versus 58% and for grade III was 7% versus 7%, respectively. The incidence of late reactions for patients with CVD and the matched control patients for grade I was 3% versus 7%, for grade II was 7% versus 3%, and for grade III was 7% versus 7%, respectively. The patients treated with palliation had a similar incidence of acute reaction in the CVD and the matched-control groups. No patients in the CVD or matched-control group had fatal complications. Only patients with scleroderma had a slight increase in acute and late complications. Conclusion This is the largest matched-control study thus far in the literature. In the comparison between the patients with CVD and the matched-control patients, there was no significant difference in the incidence of acute or late complication. However, there was a higher incidence of radiation complications in patients with scleroderma. Importantly, no fatal complication was noted in any of the patients with CVD.
TL;DR: The unique ability of NSCs to "home in" on tumor cells followed by the delivery of a desired gene product makes the NSC a very promising agent in brain tumor therapy.
Abstract: Neural stem cells (NSCs) are capable of tremendous migratory potential to areas of pathology in the central nervous system. When implanted into a diseased or injured nervous system, NSCs can travel through great distances to and engraft within areas of discrete as well as diffuse abnormalities. Engraftment is often followed by integration into the local neural milieu, accompanied by stable gene expression from the NSCs. In addition, the pluripotency of NSCs endows them with the capability to replace diseased tissues in an appropriate manner. Recent evidence has also suggested that engrafted exogenous NSCs may have effects on the surrounding microenvironment, such as promoting protection and/or regeneration of host neural pathways. These characteristics of NSCs would seem to make them ideal agents for the treatment of various central nervous system pathologies, especially brain tumors. Brain tumors are generally difficult to treat because of the unique location of the lesions. In primary gliomas, the extensive infiltrative nature of the tumor cells presents a challenge for their effective and total eradication, hence the high rate of treatment failure and disease recurrence. In addition, normal brain structures are distorted and are often destroyed by the growing neoplasm. Even with effective therapy to surgically resect and destroy the neoplastic tissues, the brain is still injured, which often leaves the patient in a debilitated state. The unique ability of NSCs to "home in" on tumor cells followed by the delivery of a desired gene product makes the NSC a very promising agent in brain tumor therapy. Cytolytic viruses and genes coding for anti-tumor cytokines, pro-drug converting enzymes, and various neurotrophic factors have all been engineered into engraftable NSCs for delivery to tumors. When they are specially tagged, such injected NSCs can be visualized with the use of novel imaging techniques and tracked in vivo within living animals over real time. If the NSCs were also capable of participating in the subsequent repair and regeneration of the tumor-afflicted brain-at present a potential but as-yet-unproven aspect of this intervention-then its role in abetting anti-tumor therapy would be complete. It is important to emphasize, however, that the use of NSCs is adjunctive and is not a replacement for other therapies that should be used in parallel.
TL;DR: The 6-mg/m2 dose of CI-994 was defined as the maximum tolerated dose that could safely be administered in combination with gemcitabine during a 28-day cycle.
Abstract: PURPOSE The purpose of this study was to determine the maximum tolerated dose, pharmacokinetic profile, and evidence of antitumor activity of CI-994 used in combination with gemcitabine. METHODS This was a dose escalation trial in which gemcitabine (1000 mg/ m 2 ) was given as a 30-minute infusion on days 1, 8, and 15 of a 28-day cycle. CI-994 was taken orally on consecutive days 1-21 at escalating doses of 2, 4, 6, and 8 mg/m 2 per cohort (three patients/cohort). Plasma samples were collected on days 1 and 15 of course 1 and analyzed for CI-994 pharmacokinetic assessment. RESULTS Twenty patients with advanced cancer received a total of 76 courses of treatment. Dose-limiting toxicity occurred at the 8-mg/ m 2 dose. Four of seven patients experienced thrombocytopenia during the first cycle. Grade 4 thrombocytopenia was observed in three of 10 (30%) courses at 8 mg/m 2 . In contrast, only two of 28 (7%) courses at 6 mg/m 2 were associated with grade 4 thrombocytopenia. Pharmacokinetic analysis indicated that absorption of CI-994 was rapid, with peak plasma concentrations occurring at the first sample 2 hours after dosing. Two patients achieved a minor response, 12 had stable disease (median duration, 105 days), four had progressive disease, and two were not evaluable. CONCLUSIONS The 6-mg/m 2 dose of CI-994 (p.o. x 21 days) was defined as the maximum tolerated dose that could safely be administered in combination with gemcitabine (1000 mg/m 2 i.v. on days 1, 8, and 15) during a 28-day cycle.
TL;DR: The failure of most clinical gene therapy protocols to produce a significant and unequivocal benefit to brain tumor patients seems to be mainly due to the low tumor cell transduction rates observed in vivo, but it may also depend on the respective physical delivery strategy of the vector.
Abstract: PURPOSE Brain tumors were the first human malignancy to be targeted by therapeutic transfer of nucleic acids into somatic cells, a process also known as gene therapy. Malignant brain tumor cells in the adult brain have some unique biologic features, such as high mitotic activity on an essentially postmitotic background and virtually no tumor spread outside of the central nervous system. Brain tumors seem therefore to offer major advantages in the design of tumor-selective gene therapy strategies, and the role of gene therapy in malignant glioma has been investigated since the late 1980s, initially in numerous laboratory studies and later on in clinical trials. DESIGN Retrovirus has been one of the earliest recombinant virus vectors used in brain tumors. Experiments in cell culture and in animal models have demonstrated the feasibility of retrovirus-mediated transduction and subsequent killing of glioma cells by toxic transgenes. Phase I and II clinical studies in patients with recurrent malignant glioma have shown a favorable safety profile and some efficacy of retrovirus-mediated gene therapy. However, the only prospective, randomized, phase III clinical study of retrovirus gene therapy in primary malignant glioma failed to demonstrate significant extension of progression-free or overall survival. Adenovirus- and herpes simplex virus type 1-based vectors have been actively investigated along with retrovirus, but their clinical use is still limited, mostly because of safety concerns. To increase efficacy, novel generations of therapeutic adenovirus and herpes simplex virus type 1 rely more on genetically engineered and tumor-selective lytic properties and less on the actual transfer of therapeutic genes. CONCLUSIONS The failure of most clinical gene therapy protocols to produce a significant and unequivocal benefitto brain tumor patients seems to be mainly due to the low tumor cell transduction rates observed in vivo, but it may also depend on the respective physical delivery strategy of the vector. Standard radiologic criteria for assessing the efficacy of clinical treatments may also not be fully applicable to the specific metabolic changes and blood-brain barrier permeability phenomena caused in brain tumors by virus-mediated gene therapy. Clinical trials in malignant glioma have nevertheless produced a substantial amount of data and have contributed to the continuous improvement of vector systems, delivery methods, and clinical protocols.
TL;DR: The molecular characteristics of glioblastoma multiforme are summarized and special attention is paid to molecular predictors of survival outcome, an area of research that is still in its infancy.
Abstract: Unlike most patients with glioblastoma multiforme who survive less than a year, approximately 2% have an unusually long survival after diagnosis and contemporary treatment (> or = 3 or more years); rarely, the disease appears to be "cured." Understanding these rare patients may tell us something important about the biology of glioblastoma multiforme. Patients who are young, have good performance status, and receive multimodalitytherapy (i.e., surgical resection, radiotherapy, and adjuvant chemotherapy) are more likely to have a long survival than older patients with poor performance status who are treated identically. However, the aforementioned clinical characteristics of long-term survivors do not explain why most patients with glioblastoma multiforme who have this same constellation of favorable features succumb to the disease relatively quickly. "Glioblastoma multiforme" is a group of diseases, one subtype of which behaves in a more indolent fashion, or responds well to current therapies, or both. In this review, we summarize the molecular characteristics of glioblastoma multiforme and pay special attention to molecular predictors of survival outcome, an area of research that is still in its infancy. We conclude by suggesting a translational research strategy that is aimed at uncovering the molecular signatures of long survivorship.
TL;DR: Randomized trials have supported a role for radiation therapy in the initial management of Glioblastoma Multiforme for over twenty-five years, but recently completed randomized trials of brachytherapy and radiosurgery do not support these modalities.
Abstract: Randomized trials have supported a role for radiation therapy in the initial management of Glioblastoma Multiforme (GBM) for over twenty-five years. Although technological advances in imaging and three-dimensional treatment planning have reduced the toxicity for patients and have allowed safe radiation dose escalation, unfortunately they have not produced a correspondingly dramatic improvement in overall survival. The dose of 60 Gy partial brain RT remains the standard of care for patients with newly diagnosed GBM. Recently completed randomized trials of brachytherapy and radiosurgery do not support these modalities in the initial management of GBM, but these and other focal RT techniques such as intensity modulated radiation therapy enable safe retreatment in selected patients. Future studies will need to explore radiation biologic response modification and radiosensitization through targeted therapies.
TL;DR: Cervical cancer remains a clinically staged malignancy according to the FIGO staging system and surgical-pathologic staging would not be feasible for advanced-stage disease or in early-stage patients treated primarily with radiation, especially in nations that do not routinely offer surgical extirpation due to different or limited health care resources.
Abstract: The "International Classification of the Stages of Carcinoma of the Uterine Cervix" dates back to 1950; since then, seven changes have been made to the staging system for cervical cancer (almost all were made to Stage I), the most recent being in 1995. The FIGO system of classification of cervical cancer is originally based on the results of clinical examination, essentially of the anatomical extent of disease, and is determined at the time of primary diagnosis. Only if the rules for clinical staging are strictly observed is it possible to compare results using different modalities of treatment. Cervical cancer remains a clinically staged malignancy according to the FIGO staging system. Surgical-pathologic staging would not be feasible for advanced-stage disease or in early-stage patients treated primarily with radiation, especially in nations that do not routinely offer surgical extirpation due to different or limited health care resources. However, surgical and pathological data are important for precise analysis of survival and prognostic risk factors.
TL;DR: The role of chemotherapy is examined, particularly in those patients with disseminated disease and those with locally advanced disease in the pelvis who are at high risk of developing cervical cancer.
Abstract: Carcinoma of the cervix remains the most common form of cancer to affect women worldwide despite effective screening techniques. Advances in treatment, particularly systemic therapies, have improved outcomes for cervical cancer. This article examines the role of chemotherapy, particularly in those patients with disseminated disease and those with locally advanced disease in the pelvis.
TL;DR: The epidemiology and pathogenesis of the squamous cell carcinoma, its clinical and histologic features, including microinvasive carcinomas, its histologic grade, and variant tumors, and the prognostic impact are discussed.
Abstract: Squamous cell carcinoma is the most common malignant cervical tumor, but the incidence of adenocarcinomas has been rising during the past few decades. This article discusses the epidemiology and pathogenesis of the squamous cell carcinoma, its clinical and histologic features, including microinvasive carcinoma, its histologic grade, and variant tumors. The prognostic impact of these features and the differential diagnosis are also covered. The second portion of this article is devoted to the glandular tumors of the cervix, including adenocarcinoma in situ and invasive adenocarcinoma and its variants. The differential diagnosis of these tumors with tumor like glandular lesions is given special attention. Finally, less common malignant cervical tumors are covered, with an emphasis being placed on their significance.
TL;DR: The overwhelming majority of clinical studies point one to conclude that methodologies that will increase tumor infection/transduction will lead to enhanced therapeutic results.
Abstract: Malignant gliomas remain amongst the most difficult cancer to treat. Viral-based gene therapies have been employed for the last decade in preclinical and clinical modes as a novel treatment modality. In this review, such therapies are summarized. The overwhelming majority of clinical studies point one to conclude that methodologies that will increase tumor infection/transduction will lead to enhanced therapeutic results.
TL;DR: New insights are discussed into the parallels between glial differentiation and glioma formation as well as the potential application of differentiation-inducing therapy.
Abstract: Gliomas are the most common primary malignancy in human central nervous system. Many similarities in cell morphology and expression of markers exist between cancerous cells and normal undifferentiated progenitor cells. At the molecular level, many important gene products are causally implicated in both the glial differentiation process and glial neoplasm formation. These observations raise the question of to what degree cell differentiation state influences glioma formation. In this review, we discuss new insights into the parallels between glial differentiation and glioma formation as well as the potential application of differentiation-inducing therapy.
TL;DR: The acute radiation reaction and preliminary tumor response of prostate cancer to hypofractionated intensity-modulated radiation therapy assisted with real-time tumortracking radiation therapy were investigated in this study.
Abstract: PURPOSE The positioning of the prostate is improved with the use of the fluoroscopic real-time tumor-tracking radiation therapy system for prostate cancer. The acute radiation reaction and preliminary tumor response of prostate cancer to hypofractionated intensity-modulated radiation therapy assisted with real-time tumor-tracking radiation therapy were investigated in this study. METHODS Patients were classified into prognostic risk groups on the basis of the presence of the pretreatment prostate-specific antigen, clinical stage, and histologic differentiation. Neoadjuvant hormonal therapy was administered to patients in the high-risk group for 6 months before radiation therapy commenced. The intensity-modulated radiation therapy employed a segmental multileaf collimator, which generated a field made up of two or more shaped subfields using forward planning. Real-time tumor-tracking radiation therapy was used for the precise positioning of the prostate to minimize geometric uncertainties, while the dose was escalated in increments of 5 Gy from 65 Gy using a daily dose of 2.5 Gy (65 Gy/2.5 Gy), following the dose-escalation rules. Acute and late gastrointestinal and genitourinary morbidities due to radiation therapy were scored according to the toxicity criteria of Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer. RESULTS Thirty-one patients were enrolled in this study between 1998 and 2001. Eighteen patients were classified as being members of the high-risk group. Total dose was escalated, with 65 Gy/2.5 Gy being administered to 12 patients and 70 Gy/2.5 Gy to 19 patients. The median follow-up period was 37 months (range, 30-43 months), and 19 months (range, 10-27 months), for the 65-Gy and 70-Gy arms, respectively. Patients experienced no acute toxicity and grade 1 late gastrointestinal toxicity (8.3%) in the 65-Gy/2.5-Gy arm. Patients in the 70-Gy/2.5-Gy arm experienced grade 1 acute gastrointestinal toxicity (5.3%) and grade 1 and 2 acute genitourinarytoxicities (15.8%). No patients experienced dose-limiting toxicity (defined as a grade 3 or higher acute toxicity) or a grade 2 or higher late complication in this study period. One and two prostate-specific antigen relapses were observed in the 65-Gy and 70-Gy arms, respectively. CONCLUSION Up to 70 Gy/2.5 Gy, equivalent to 80 Gy with a daily dose of 2.0 Gy, assuming alpha/beta ratio of 1.5, intensity-modulated radiation therapy assisted with real-time tumor-tracking radiation therapy was administered safely with a reasonable biochemical control rate. A further dose-escalation study using this system is justifiable.
TL;DR: There was a wide range in the dose of radiation and the age at exposure, suggesting that exposure to head and neck radiation at any age and dose may increase the risk for salivary gland tumors (SGT).
Abstract: PURPOSE The purpose of this study was to examine the relationship between radiation exposure and subsequent development of salivary gland tumors (SGTs) MATERIALS AND METHODS Eighteen patients with SGTs as second cancers after head and neck irradiation were identified from chart review of institutional databases of 3025 patients with SGTs evaluated between 1986 and 2001 RESULTS The median age at the time of initial radiation therapy was 22 years (range, 5-74 years) The median age of the group at the time of their diagnosis of a SGT was 54 years (range, 21-79 years) The median interval between radiation exposure and diagnosis of the SGT was 21 years (range, 4-64 years) The most common initial diagnosis for which patients received radiation therapy was Hodgkin's disease Histology of the secondary SGT was varied, but most were malignant (N = 15), and mucoepidermoid carcinoma was the most common histology (N = 9) CONCLUSION There is an association between radiation exposure and the risk of developing an SGT There was a wide range in the dose of radiation and the age at exposure, suggesting that exposure to head and neck radiation at any age and dose may increase the risk for SGT This series also suggests an increased risk for developing malignant (versus benign) SGT after radiation exposure
TL;DR: It is clear that much remains to be discovered to better elucidate the causes of GBM, but the increasing recognition of molecular subtypes may help advance this field.
Abstract: Glioblastoma (GBM) is the most important primary brain tumor, both in terms of its incidence and its devastating impact on the unfortunate patients who have it. Although several well-defined hereditary syndromes predispose to malignant gliomas, most cases occur in the absence of a such a syndrome. The role of environmental factors, based on the known associations to date, also appears limited when compared with the total number of patients affected. It is clear that much remains to be discovered to better elucidate the causes of GBM, but the increasing recognition of molecular subtypes may help advance this field. This review highlights current insights into the molecular epidemiology of GBM.
TL;DR: Some of the practical aspects of using imaging to more meaningfully follow tumor progression and response to treatment are discussed, particularly relevant to the use of therapies that target blood flow directly, which is fundamental to modern imaging modalities.
Abstract: Gliomas are characterized by very high levels of neo-vascularization holding out the hope that therapies aimed at angiogenesis will have a significant impact on this intractable family of tumors. Intense research into the molecular mechanisms that drive the formation of new blood vessels in response to tumor growth has revealed a great deal of complexity, at the heart of which are competing pro- and anti-angiogenic influences. The relevant signaling pathways, and how they might be manipulated to interfere in the promotion of vessel growth are discussed. Several types of anti-angiogenic lead compounds are already in clinical trials, but assessing their impact on brain tumors is not straightforward. We discuss in depth some of the practical aspects of using imaging to more meaningfully follow tumor progression and response to treatment, which is particularly relevant to the use of therapies that target blood flow directly, which is fundamental to modern imaging modalities.
TL;DR: This is the largest series in the literature thus far that quantitatively assesses radial extracapsular extension and its radial distance and it is concluded that coverage of sub-clinical disease must be addressed carefully before successful implementation of intensity-modulated radiation therapy, brachytherapy, or prostatectomy in order to avoid geographical miss.
Abstract: Purpose Tightly constricted isodose lines are generated using brachytherapy or intensity-modulated radiation therapy (IMRT) treatment planning systems for prostate cancer. Definition of margins that encompass subclinical disease extension is important to maximize dose escalation while attemptingto adhere to normal tissue dose tolerances. In this study, we attempted to find predictors of extracapsular extension (ECE) and its radial distance. Materials and methods Pathological assessment of ECE and its radial distance was performed on 712 radical prostatectomy specimens. Preoperative data (initial prostate-specific antigen, clinical stage, ultrasound volume, and biopsy Gleason score) were evaluated for their ability to predict the presence of ECE and its radial distance. Results Measurable disease was noted outside the prostatic capsule in 185 of 712 (26.0%) specimens. All preoperative parameters except ultrasound volume were able to predict the presence of ECE. However, none of them was predictive of the radial ECE distance. In this group, the median and the range of the maximum depth of invasion (radial extension from the capsule) were 2.00 and 0.5-12.00 mm, respectively. The mean radial distance from the capsule was 2.93 mm, SD +/- 2.286 mm. All subgroups had some patients with radial extension ranging from 0-2 mm, 2-5 mm, to > 5 mm. Only patients with a prostate-specific antigen of 0-4 ng/mL had no extension > 5 mm. Conclusions This is the largest series in the literature thus far that quantitatively assesses radial extracapsular extension. Coverage of subclinical disease must be addressed carefully before successful implementation of intensity-modulated radiation therapy, brachytherapy, or prostatectomy in order to avoid geographical miss.
TL;DR: A review of pelvic exenteration in gynecologic oncology is provided, emphasizing preoperative evaluation, surgical techniques and their postoperative management.
Abstract: For the past six decades, pelvic extenteration has been utilized in the treatment of localized central pelvic recurrences after chemo/radiotherapy. The radicality of the procedure that includes resection of the bladder, vulva/vagina, and rectum, although with curative intent, results in comprehensive changes for the patient. For this reason, all patients should undergo extensive psychosocial counseling to prepare them for the changes in body image and lifestyle. Extirpation of the pelvic viscera has undergone a number of modifications since Brunschwig first described it in 1948 to maximize survivability and minimized anatomical distortion. Most of the advancements have been focused on the reconstructive phase after pelvic exenteration. A few select patients can be free of any external appliances such as a colostomy bag with utilization of a low colorectal anastomosis, and can maintain sexual intimacy with creation of a neovagina. In addition, reconstruction of the pelvic floor with omental flaps, dura mater grafts and myocutaneous flaps have decreased postoperative morbidity. In this article, we provide a review of pelvic exenteration in gynecologic oncology, emphasizing preoperative evaluation, surgical techniques and their postoperative management.
TL;DR: The Bethesda System for reporting cervical cytology was developed to provide a uniform system of terminology that would promote clear management guidelines, and major changes include specimen adequacy designation and criteria, general categorization, and terminology for atypical epithelial cells.
Abstract: Cervical cancer screening represents one of the great success stories in cancer prevention Cervical cytology results were reported by use of various terminologies during the first 40 years of widespread screening These terms did not correspond to current knowledge of cervical carcinogenesis The Bethesda System for reporting cervical cytology was developed to provide a uniform system of terminology that would promote clear management guidelines The Bethesda System has been widely adopted since the first workshop was convened by the National Cancer Institute in 1988 Two additional workshops were held in 1991 and 2001 in order to address scientific advances and controversial areas The 2001 workshop was attended by more than 400 participants and was preceded by Internet discussion groups Major changes include specimen adequacy designation and criteria, general categorization, and terminology for atypical epithelial cells The “within normal limits” and “benign cellular changes” categories have been combined into a single category called “negative for intraepithelial lesion or malignancy” The “favor reactive” descriptors have been removed from the atypical epithelial categories, and new terms correlate better with management guidelines Other changes are discussed, and a brief update of cancer screening guidelines is also provided