Major Disease Sites Research Articles

The biliary atresia susceptibility gene, EFEMP1, regulates extrahepatic bile duct elastic fiber formation and mechanics

IntroductionEGF-Containing Fibulin Extracellular Matrix Protein 1 (EFEMP1, also called fibulin-3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibrotic disease of the neonatal extrahepatic bile duct. Fibulin-3 is deposited in most tissues and Efemp1 null mice have decreased elastic fibers in visceral fascia; however, fibulin-3 does not have a role in the development of large elastic fibers and its overall function in the extrahepatic bile ducts remains unclear. MethodsWe used staining and histology to define the amount and organization of key extracellular matrix components in the extrahepatic bile ducts. We also repurposed pressure myography, a technique heretofore applied to the vasculature, to determine the contribution of elastin and fibulin-3 to extrahepatic bile duct mechanics. We examined extrahepatic bile duct structure and mechanics in three models: neonatal vs. adult rat ducts (n=6 each), elastase-treated adult rat ducts (n=6-7 each), and Efemp1+/- vs. wild type mouse ducts (n=6 each). ResultsWe demonstrated that fibulin-3 is expressed in the submucosa of both neonatal and adult mouse, rat and human extrahepatic bile ducts and that, in adult Efemp1+/- mouse ducts, elastin organization into fibers is decreased by approximately half. Pressure myography showed that Efemp1+/- ducts have altered mechanics compared to control ducts, with Efemp1+/- ducts displaying significant stretch compared to controls (p=0.0376); these changes in stretch are similar to those observed in elastase-treated compared to normal ducts (p<0.0001) and in neonatal ducts compared to adult ducts (p< 0.0001). ConclusionFibulin-3 has an important role in the formation of elastic fibers and the mechanical properties of the extrahepatic bile duct. This provides functional relevance for the biliary atresia susceptibility gene EFEMP1. Impact and ImplicationsThe gene EFEMP1 was found via a genome wide association study to be a susceptibility gene for the neonatal disease biliary atresia. EFEMP1 encodes the protein fibulin-3, which regulates elastic fiber organization in the extrahepatic bile duct (EHBD), the major site of disease in biliary atresia. We showed that neonatal EHBDs as well as mice heterozygous for Efemp1 have decreased numbers of elastic fibers, and that this alters EHBD mechanics. This work is important for understanding the mechanism of biliary atresia, in particular susceptibility to obstruction.

The ABS brachytherapy schools

The American Brachytherapy Society brachytherapy schools have been pivotal in teaching and evolving the art of brachytherapy over the past decades. Founded in 1995, the schools have consistently provided content for the major disease sites including gynecologic, prostate, and breast with ocular, vascular, head and neck, pediatric, intraluminal, systemic, and intraoperative approaches more selectively addressed. In addition, Physics schools, either coupled with clinical schools or as stand-alone venues, have provided an essential educational component for practicing physicists, a pivotal part of the brachytherapy team. Celebrating 25 years in existence, this historical overview of the American Brachytherapy Society brachytherapy schools is a tribute to the many teachers who have shared their expertise, to the many students who have been enthusiastic and interactive participants, and the staff who have made it all possible, with the reward of perpetuating the important and timely art of brachytherapy.

Radiation Fractionation Schedules Published During the COVID-19 Pandemic: A Systematic Review of the Quality of Evidence and Recommendations for Future Development

PurposeNumerous publications during the COVID-19 pandemic recommended the use of hypofractionated radiation therapy. This project assessed aggregate changes in the quality of the evidence supporting these schedules to establish a comprehensive evidence base for future reference and highlight aspects for future study.Methods and MaterialsBased on a systematic review of published recommendations related to dose fractionation during the COVID-19 pandemic, 20 expert panelists assigned to 14 disease groups named and graded the highest quality of evidence schedule(s) used routinely for each condition and also graded all COVID-era recommended schedules. The American Society for Radiation Oncology quality of evidence criteria were used to rank the schedules. Process-related statistics and changes in distributions of quality ratings of the highest-rated versus recommended COVID-19 era schedules were described by disease groups and for specific clinical scenarios.ResultsFrom January to May 2020 there were 54 relevant publications, including 233 recommended COVID-19–adapted dose fractionations. For site-specific curative and site-specific palliative schedules, there was a significant shift from established higher-quality evidence to lower-quality evidence and expert opinions for the recommended schedules (P = .022 and P < .001, respectively). For curative-intent schedules, the distribution of quality scores was essentially reversed (highest levels of evidence "pre-COVID" vs "in-COVID": high quality, 51.4% vs 4.8%; expert opinion, 5.6% vs 49.3%), although there was variation in the magnitude of shifts between disease sites and among specific indications.ConclusionsA large number of publications recommended hypofractionated radiation therapy schedules across numerous major disease sites during the COVID-19 pandemic, which were supported by a lower quality of evidence than the highest-quality routinely used dose fractionation schedules. This work provides an evidence-based assessment of these potentially practice-changing recommendations and informs individualized decision-making and counseling of patients. These data could also be used to support radiation therapy practices in the event of second waves or surges of the pandemic in new regions of the world.

The environment is a first order issue for lung health

In this issue of the Journal we publish the first of a series of State of the Art articles on environmental health. This is a topic that is front and centre for those concerned about lung health.Not only are the airways and lungs the major portal of entry for airborne pollutants, they are also a major site of disease caused by air pollutants, including asthma-like syndromes, chronic obstructive pulmo-nary disease, pneumonitis, pneumoconiosis and lungmalignancy. Of all the environmental causes of ill-health, air pollutants are, by far, the major contributor to death and burden of disease. Furthermore, the burden of this exposure falls particularly on those living in low- and middle-income countries, where the capacity to reduce exposure and mitigate the effects is weakest. This series is thus a timely reminder of the importance of the environment to lung health

Radiotherapy in the age of cancer immunology: Current concepts and future developments.

Major advances in the knowledge of cancer biology and its interactions with tumor immune environment led to the emergence, in the last five years of new immunotherapy-based treatment strategies in cancer patients. At the same time, improvement in radiation technique and progress in radiobiology allowed in the last decade to expand the applications of radiotherapy in a growing number of settings. At present, there are strong theoretical basis to propose immune-enhanced radiation therapy that may represent in the future a new paradigm of treatment, combining the intrinsic power of radiotherapy to elicit a specific, systemic, tumor-directed immune response with modern highly conformal and precise dose delivery, in order to maximize response at the major site of disease and obtain durable disease control. The aim of this review is to describe the principal mechanisms of immune modulation of response to radiation and investigational strategies to harness the potential of radiation-inducible immune response: radiation therapy is expected to be not just a local treatment but the cornerstone of a multimodal strategy that might achieve long-lasting tumor remission at the primary site and systemic efficacy metastatic lesions.

Quantitative analysis of treatment process time and throughput capacity for spot scanning proton therapy.

To determine the patient throughput and the overall efficiency of the spot scanning system by analyzing treatment time, equipment availability, and maximum daily capacity for the current spot scanning port at Proton Therapy Center Houston and to assess the daily throughput capacity for a hypothetical spot scanning proton therapy center. At their proton therapy center, the authors have been recording in an electronic medical record system all treatment data, including disease site, number of fields, number of fractions, delivered dose, energy, range, number of spots, and number of layers for every treatment field. The authors analyzed delivery system downtimes that had been recorded for every equipment failure and associated incidents. These data were used to evaluate the patient census, patient distribution as a function of the number of fields and total target volume, and equipment clinical availability. The duration of each treatment session from patient walk-in to patient walk-out of the spot scanning treatment room was measured for 64 patients with head and neck, central nervous system, thoracic, and genitourinary cancers. The authors retrieved data for total target volume and the numbers of layers and spots for all fields from treatment plans for a total of 271 patients (including the above 64 patients). A sensitivity analysis of daily throughput capacity was performed by varying seven parameters in a throughput capacity model. The mean monthly equipment clinical availability for the spot scanning port in April 2012-March 2015 was 98.5%. Approximately 1500 patients had received spot scanning proton therapy as of March 2015. The major disease sites treated in September 2012-August 2014 were the genitourinary system (34%), head and neck (30%), central nervous system (21%), and thorax (14%), with other sites accounting for the remaining 1%. Spot scanning beam delivery time increased with total target volume and accounted for approximately 30%-40% of total treatment time for the total target volumes exceeding 200 cm(3), which was the case for more than 80% of the patients in this study. When total treatment time was modeled as a function of the number of fields and total target volume, the model overestimated total treatment time by 12% on average, with a standard deviation of 32%. A sensitivity analysis of throughput capacity for a hypothetical four-room spot scanning proton therapy center identified several priority items for improvements in throughput capacity, including operation time, beam delivery time, and patient immobilization and setup time. The spot scanning port at our proton therapy center has operated at a high performance level and has been used to treat a large number of complex cases. Further improvements in efficiency may be feasible in the areas of facility operation, beam delivery, patient immobilization and setup, and optimization of treatment scheduling.

Single-Breath Washout Tests to Assess Small Airway Disease in COPD

Current functional assessments do not allow a reliable assessment of small airways, which are a major site of disease in COPD. Single-breath washout (SBW) tests are feasible and reproducible methods for evaluating small airway disease. Their relevance in COPD remains unknown. We performed a cross-sectional study in 65 patients with moderate to severe COPD. Phase III slope of nitrogen (SIIIN2) and double tracer gas (SIIIDTG) SBW tests were used as a measure of ventilation inhomogeneity. The association of both markers with established physiological and clinical features of COPD was assessed. Ventilation inhomogeneity as measured by SIIIN2 and SIIIDTG was increased in patients with COPD compared with healthy subjects (P< .001 and P< .001, respectively). SIIIN2 was associated with FEV1 predicted, residual volume (RV)/total lung capacity (TLC) and diffusing capacity of the lung for carbon monoxide (Dlco) (all P< .001). Furthermore, SIIIN2 was related to dyspnea, exercise-induced desaturation, and exercise capacity (P= .001, P< .001, and P= .047, respectively). SIIIDTG was associated with TLC, Dlco, and cough (P< .001, P= .001, and P= .009, respectively). In multivariate regression models, we demonstrated that these associations are largely independent of FEV1 and mostly stronger than associations with FEV1. In contrast, FEV1 was superior in predicting emphysema severity. SIIIN2 and SIIIDTG, two fast and clinically applicable measures of small airway disease, reflect different physiological and clinical aspects of COPD, largely independent of spirometry. ISRCTN99586989, Ethics committee Beider Basel (approval number 295/07).

Actualités ≪ environnement et pollution ≫

Current functional assessments do not allow a reliable assessment of small airways, which are a major site of disease in COPD. Single-breath washout (SBW) tests are feasible and reproducible methods for evaluating small airway disease. Their relevance in COPD remains unknown.We performed a cross-sectional study in 65 patients with moderate to severe COPD. Phase III slope of nitrogen (SIIIN2) and double tracer gas (SIIIDTG) SBW tests were used as a measure of ventilation inhomogeneity. The association of both markers with established physiological and clinical features of COPD was assessed.Ventilation inhomogeneity as measured by SIIIN2 and SIIIDTG was increased in patients with COPD compared with healthy subjects (P < .001 and P < .001, respectively). SIIIN2 was associated with FEV1 predicted, residual volume (RV)/total lung capacity (TLC) and diffusing capacity of the lung for carbon monoxide (Dlco) (all P < .001). Furthermore, SIIIN2 was related to dyspnea, exercise-induced desaturation, and exercise capacity (P = .001, P < .001, and P = .047, respectively). SIIIDTG was associated with TLC, Dlco, and cough (P < .001, P = .001, and P = .009, respectively). In multivariate regression models, we demonstrated that these associations are largely independent of FEV1 and mostly stronger than associations with FEV1. In contrast, FEV1 was superior in predicting emphysema severity.SIIIN2 and SIIIDTG, two fast and clinically applicable measures of small airway disease, reflect different physiological and clinical aspects of COPD, largely independent of spirometry.ISRCTN99586989, Ethics committee Beider Basel (approval number 295/07)

Identifying Distinct Patterns of Metastatic Progression Over Time in Patients Who Have Received Definitive Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

Identifying Distinct Patterns of Metastatic Progression Over Time in Patients Who Have Received Definitive Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

Recent advances in radiation oncology: intensity-modulated radiotherapy, a clinical perspective.

Radiotherapy plays an important role in the treatment of various malignancies, and intensity-modulated radiotherapy (IMRT) is an attractive option because it can deliver precise conformal radiation doses to the target while minimizing the dose to adjacent normal tissues. IMRT provides a highly conformal dose distribution by modulating the intensity of the radiation beam. A number of malignancies have been targeted by IMRT; this work reviews published data on the major disease sites treated with IMRT. The dosimetric advantage of IMRT has resulted in the significant reduction of adverse effects in some tumors. However, there are few clinical trials comparing IMRT and three-dimensional conformal radiotherapy (3D-CRT), and no definite increase in survival or the loco-regional control rate by IMRT has been demonstrated in many malignancies. IMRT also requires greater time and resources to complete compared to 3D-CRT. In addition, the cost-effectiveness of IMRT versus 3D-CRT has not yet been established.

Patients as partners in defining outcomes.

148 Background: The aim of this project was to develop an understanding of how patients conceptualize the term “outcomes” as it relates to their cancer experience and to determine patient preference for receiving and using outcomes-related information. When asked to rank cancer outcomes, most health care professionals suggest survival is the most significant outcome metric. We sought to determine if patients felt the same way. Methods: Focus group methodology was used in cancer patients with one of five major disease sites: breast, colon, lung, prostate, and head and neck. Participants were diverse with respect to age, ethnicity, income level, education level, and gender. Participants received semi-structured questions intended to elicit the patient’s personal conceptualization and use of outcomes information during their cancer continuum. Results: Patients identified a range of phenomena as their preferred definition of outcome and were sometimes confused by the term. Participants reported finding it difficult to interpret survival data without a basis for comparison or medical knowledge. Results of the focus groups will be presented and will address the wide variety of outcome definitions defined by patient participants. Conclusions: We found a large disconnect between what providers consider important and what patients consider important. We are continuing to evaluate patient perceptions of outcomes information by conducting further focus groups, and these qualitative findings will be used to develop a rigorous survey tool that can be administered to a greater number and wider variety of patients. Ultimately, the finding from these focus groups will allow for the creation of useful tools that educate patients and empower them to be full partners in their care.

Intraperitoneal Treatment in Ovarian Cancer: The Gynecologic Oncology Group Perspective in 2012

The peritoneal cavity is the major site of disease in ovarian cancer. The peritoneal predominance of disease provides a rationale for administration of chemotherapy within the peritoneal cavity. Intraperitoneal (IP) chemotherapy for ovarian cancer has been studied rigorously for more than 30 years and has been reproducibly shown to improve the survival of patients with ovarian cancer. Three large randomized trials of IP compared with intravenous (IV) therapy have demonstrated statistically significant improvement in clinical outcome measures. Despite this, the IP approach has not gained widespread acceptance in the treatment of ovarian cancer. Here, we review reported, recently completed, and ongoing trials of IP therapy in ovarian cancer including attempts to improve the tolerability and acceptance of this proven approach.

Sown the seeds: An analysis of published trials in clinical oncology.

6068 Background: Competition in the pharmaceutical marketplace has resulted in “seeding trials” which appear to serve little scientific purpose other than to gain a financial hold in the marketplace. Hallmarks of “seeding” clinical trials [Kessler, et al N Eng J Med 1994] include trial design that does not support stated research goals, industry sponsorship without novel findings or poor scientific rationale, and drugs introduced into an already crowded therapeutic class, i.e. “me too” drugs. We evaluated clinical trials published in high impact oncology journals to ascertain the prevalence of trials bearing the characteristics of a seeding trial. Methods: We conducted a PubMed search using “clinical trial”, “oncology”, published 2/2005 – 2/2010, in Ann Oncol, J Clin Oncol, Lancet, Lancet Oncol, or the N Engl J Med. All phase I/II, II and III studies were included. Phase I, hematology, radiation oncology, and pediatric studies were excluded. Data collected included disease site, phase, funding source, journal, and whether the trial fit criteria for “seeding” as previously defined. Results: 1781 articles have been evaluated to date. 528 met criteria for analysis. 130 were considered seed studies. Seed studies per journal were Ann Oncol 26 of 128, J Clin Oncol 88 of 340, Lancet 8 of 22, Lancet Oncol 5 of 16, and N Engl J Med 3 of 22. Studies published per disease site and percent seed studies were melanoma 19 and 31.6%, breast 106 and 30.2%, GI 126 and 20.6%, lung 101 and 29.7%, GU 65 and 24.6%, gynecology 40 and 30%, head and neck 24 and 12.5%, CNS 24 and 12.5%, sarcoma 11 and 18.2%, and advanced cancer 12 with zero seeds. Overall phase totals were phase I/II 16, phase II 272, and phase III 240. Seed studies per phase were phase II 28.7%, phase III 21.7% and zero for phase I/II. 210 studies were solely industry sponsored, and of these, 37.1% were seed studies. Funding was not listed for 73 studies. Conclusions: The integrity of clinical trials is challenged in the race to claim major market share. Our analysis of clinical trials published in high impact oncology journals found seeding trials account for 24.6% of publications. 37.1% of industry sponsored trials are seed studies. Seed studies are more common among the major disease sites or sites for which targeted therapies exist.

Primary Follicular Lymphoma of the Gastrointestinal Tract

Follicular lymphoma (FL), a common nodal lymphoma, is rare in the gastrointestinal (GI) tract. We report our experience with primary FL of the GI tract. The surgical pathology computer files at the Massachusetts General Hospital were searched for cases of FL involving the GI tract. Patients were included if on staging, the major site of disease was the GI tract. Thirty-nine cases were identified. Clinical data were collected from electronic medical records. The 27 women and 12 men ranged in age from 29 to 79 years (median, 59 y). Thirty tumors involved the small bowel (19 the duodenum); 8 involved the colon; and 1 involved the stomach. Eight of 10 tumors that were resected involved the small bowel (jejunum and/or ileum without duodenum) of which 5 presented with intestinal obstruction. All tumors were grade 1 or 2. Immunostains showed consistent expression of CD20 (100%), CD10 (97%), and Bcl-2 (97%). Among the 34 cases with Ann Arbor staging information, 22 were stage I, 10 were stage II, and 2 were (6%) stage IV. Of 36 cases with follow-up (median, 4.5 y), 27 patients are alive without disease, 7 are alive with disease, and 2 died of other causes. No lymphoma-related deaths were recorded. Primary FL of the GI tract occurs most often in middle-aged adults with a 2:1 female preponderance. The most frequent site of involvement is the duodenum, followed by the ileum and colon. Distal small bowel involvement is more likely to present as bowel obstruction requiring resection. The disease is localized in the bowel and regional lymph nodes in the vast majority of cases. The prognosis is favorable even when the disease is disseminated.

Quantitative analysis of beam delivery parameters and treatment process time for proton beam therapy

To evaluate patient census, equipment clinical availability, maximum daily treatment capacity, use factor for major beam delivery parameters, and treatment process time for actual treatments delivered by proton therapy systems. The authors have been recording all beam delivery parameters, including delivered dose, energy, range, spread-out Bragg peak widths, gantry angles, and couch angles for every treatment field in an electronic medical record system. We analyzed delivery system downtimes that had been recorded for every equipment failure and associated incidents. These data were used to evaluate the use factor of beam delivery parameters, the size of the patient census, and the equipment clinical availability of the facility. The duration of each treatment session from patient walk-in and to patient walk-out of the treatment room was measured for 82 patients with cancers at various sites. The yearly average equipment clinical availability in the last 3 yrs (June 2007-August 2010) was 97%, which exceeded the target of 95%. Approximately 2200 patients had been treated as of August 2010. The major disease sites were genitourinary (49%), thoracic (25%), central nervous system (22%), and gastrointestinal (2%). Beams have been delivered in approximately 8300 treatment fields. The use factor for six beam delivery parameters was also evaluated. Analysis of the treatment process times indicated that approximately 80% of this time was spent for patient and equipment setup. The other 20% was spent waiting for beam delivery and beam on. The total treatment process time can be expressed by a quadratic polynomial of the number of fields per session. The maximum daily treatment capacity of our facility using the current treatment processes was estimated to be 133 +/- 35 patients. This analysis shows that the facility has operated at a high performance level and has treated a large number of patients with a variety of diseases. The use factor of beam delivery parameters varies by disease site. Further improvements in efficiency may be realized in the equipment- and patient-related processes of treatment.

Human immunodeficiency virus-associated gastrointestinal disease: common endoscopic biopsy diagnoses.

The gastrointestinal (GI) tract is a major site of disease in HIV infection: almost half of HIV-infected patients present with GI symptoms, and almost all patients develop GI complications. GI symptoms such as anorexia, weight loss, dysphagia, odynophagia, abdominal pain, and diarrhea are frequent and usually nonspecific among these patients. Endoscopy is the diagnostic test of choice for most HIV-associated GI diseases, as endoscopic and histopathologic evaluation can render diagnoses in patients with non-specific symptoms. In the past three decades, studies have elucidated a variety of HIV-associated inflammatory, infectious, and neoplastic GI diseases, often with specific predilection for various sites. HIV-associated esophageal disease, for example, commonly includes candidiasis, cytomegalovirus (CMV) and herpes simplex virus (HSV) infection, Kaposi's sarcoma (KS), and idiopathic ulceration. Gastric disease, though less common than esophageal disease, frequently involves CMV, Mycobacterium avium-intracellulare (MAI), and neoplasia (KS, lymphoma). Small bowel biopsies and intestinal aspirates from HIV-infected patients often show HIV enteropathy, MAI, protozoa (Giardia, Isospora, Cryptosporidia, amebae, Microsporidia), and helminths (Strongyloides stercoralis). Colorectal biopsies demonstrate viral (CMV, HSV), bacterial (Clostridia, Salmonella, Shigella, Campylobacter), fungal (cryptococcosis, histoplasmosis), and neoplastic (KS, lymphoma) processes. Herein, we review HIV-associated GI pathology, with emphasis on common endoscopic biopsy diagnoses.

Integration between primary care providers and the cancer system: Gaps and opportunities

6584 Background: A number of reports suggest that family physicians (FPs) are poorly integrated with the cancer care system. The specific gaps in care integration are poorly understood. In this study we examine specific processes of care associated with integration between FPs and regional cancer programs. Methods: Cross sectional survey of all identified primary care providers within a representative health region in Ontario, Canada. The survey instrument was created specifically for this study with items generated from published literature and expert input and pilot tested in a representative sample. A modified dilman method was used. Results: 500 physicians responded (response rate 60%). Overall 90% of respondants reported confidence in the workup of a new cancer case for the major disease sites but only half (54%) knew the process of referring to the regional cancer program. Only 57% felt investigations necessary could be done in a timely manner and 44% indicated that coordination of care needs to be improved. Most indicated preferance for an active navigation structure for newly diagnosed patients. Despite over 80% of respondents indicating use of the internet only 10% reported accessing cancer program web portals for information on the regional cancer program (such as waiting times). The majority of respondants (75%) indicated ongoing involvement in care during the active treatment phase, mostly for non cancer related medical issues but 20% indicated that they were not properly infomed of patients’ health status by the oncology program and only 57% indicated that they felt their role was valued by the cancer program during this phase in the care trajectory. In the follow up phase, 35% were unclear of their role specific to monitoring and surveillance. 60% felt their current compensation model was inadequate to support care of cancer patients. This did not vary by compensation model reported. Factors associated with better integration included attendance at educational sessions and years in practice. Conclusions: Cancer systems need to be more responsive to the needs of FPs to better integrate them and support optimal quality of care for cancer patients. Policies to clarify and support roles and responsibilites are necessary to ensure that FPs are integrated team members. No significant financial relationships to disclose.

Phase II study of weekly topotecan in recurrent or metastatic cervical cancer: a GEICO study

5591 Background: Single-agent topotecan has demonstrated activity against persistent, metastatic and recurrent cancer of the uterine cervix. In combination with cisplatin has been shown to prolong survival in this setting although the benefit of combination therapy is scarce. Topotecan administered on a weekly basis has been reported to possess antineoplastic activities with lower toxicities than the standard 5-day regimen every 3 weeks in other tumors like ovarian or small cell lung cancers.Up to now there is no established second line treatment in cervical cancer. Methods: We studied in a multi-centre phase II trial the activity of weekly of Topotecan (3mg/m2/days 1, 8 and 15 on a 28-day cycle.) in recurrent or metastatic cervical cancer patients (pts) after failure to primary treatment with cisplatin chemotherapy. The primary objective was response rate evaluated by RECIST criteria. Secondary objectives were toxicity, PFS and OS (using Kaplan-Meier method). Results: Thirty three patients were included. Information is available currently for 30. Median age 55 years (range 33–76); Histology: squamous 66.7%, adenocarcinoma 26.7%, others 6.6%. Major sites of disease: local relapse (30%), nodes (20%) and lung (10%). Median number of cycles administered was 3.6 (1–11). Only five pts (16.7%) reported grade 3 toxicity (asthenia: 1, gastrointestinal: 1, neutropenia: 2, anemia: 2). Eight pts (26.7%) showed stable disease and 20 pts (66.6%) progression, 2 pts( 6.7%) were not evaluated for response. Median progression free survival was 4.17 months (95%CI: 3.19–5.15) and median survival was 14 months (95% CI: 10.16–18.11). Conclusions: These preliminary data show that weekly topotecan is an easy and well tolerated schedule but it has no activity at this dose in this population with recurrent cervical cancer previously treated with cisplatin based chemotherapy. No significant financial relationships to disclose.

WE-B-BRA-01: Advanced MRI Techniques: Current and Future Applications in Radiation Therapy

Newer radiation therapy (RT) modalities and devices are able to deliver radiation more precisely and accurately to irregular three-dimensional target volumes and have generated renewed interest in optimized targeting and dosing with the goal to increase radiation effectiveness while reducing side effects. These RT approaches offer great potential in redefining the value of RT in certain disease sites. However, the more conformal and precise the RT delivery the more important becomes the definition of target volumes, placing a premium on definition of the tumor's spatial location, its extent, heterogeneity and possible spread in order to direct more or less dose to appropriate areas while sparing as much normal tissue as possible. CT and MRI have provided the morphological information used for target definition and treatment planning for several decades. They describe the anatomic relationship of the tumor and surrounding structures well but fail to provide biologic information. In addition, they have oftentimes proven nonspecific in assessing treatment related changes. Recently introduced advanced MR-based techniques have shown promise as a means of providing information on the tumor's biological characteristics. Three-dimensional Proton Magnetic Resonance Spectroscopy Imaging (MRSI) provides information on cellular metabolism, energetics and hypoxia through its ability to distinguish signals from cellular metabolites allowing the detection of tumor suggestive metabolism relative to surrounding same organ tissues. Diffusion Weighted Imaging (DWI) provides additional information on cellularity, cell membrane permeability, intra- and extracellular diffusion, and tissue architecture and integrity. Perfusion Weighted Imaging (PWI) provides insight into overall blood volume, tissue microvasculature and angiogenesis as well as vessel permeability. These imaging modalities complement each other greatly as they provide metabolic, physiologic and functional information relative to the underlying anatomy. Two major disease sites have been studied at UCSF with respect to the potential and actual incorporation of advanced MR imaging into the treatment planning process for RT: prostate cancer and brain gliomas. Brain gliomas have traditionally proved difficult to image using standard means due to their literally “non-visible” infiltrative behavior and heterogeneous composition. The extent and location of prostate cancer are similarly difficult to determine without the aid of particularly MRSI because although MRI has good sensitivity it has relatively low specificity. The combination of these metabolic and physiologic modalities with standard anatomic MR modalities will enhance our current understanding of tumor biology, heterogeneity and extent and will provide guidance as to how to optimize current treatment approaches. In addition to assisting in image guidance for RT, these imaging tools show promise for assessing and predicting therapeutic response and to help distinguish treatment effect from tumor progression. The latter becomes even more important in light of the increasing use of combined radiation and chemotherapeutic or molecularly targeted treatment approaches. Educational objectives are to become familiar with the application of advanced Magnetic Resonance Imaging (MRI) techniques to Radiation therapy of brain and prostate cancer patients. Specifically, to understand the current technology, molecular information attainable, and to become familiar with current and future clinical applications.

Associations Between Socioeconomic Status and Cancer Survival: Choice of SES Indicator May Affect Results

Two previous studies, by Gorey et al. and Boyd et al., compared associations between socioeconomic status (SES) and cancer survival in Canada and the United States. Both studies used SES information from population censuses linked to cancer registries. This study investigates why two similar studies led to apparently conflicting results. We conducted analyses following analytic details provided by the previously published studies to describe cancer survival in Toronto, Canada, and Detroit, MI. We examined the effects of choice of census indicators and census levels on the observed SES-related gradients in cancer survival. Significant associations between SES and cancer survival were observed in Toronto for several major disease sites when median household income was used as an SES indicator. Associations were weaker when a poverty indicator was used. In Detroit, similar SES gradients were observed by using both income and poverty as SES indicators. When SES quintiles were represented by income ranks, SES-associated survival gradients were much steeper in Detroit than Toronto. When SES was described by the median income in each quintile, gradients were similar in the two cities. The apparent contradiction in results of two previous studies is related to the choice of SES indicators. Poverty may not be an indicator of choice for such an intercountry comparison.