New Generation Of Clinical Trials Research Articles

Abstract C026: Single-cell multi-omics in pancreatic cancer reveals differential immune evasion mechanisms between prognostic groups

Abstract Pancreatic cancer has the worst survival of any human cancer with a 5 year survival of less than 10% with minimal treatment options. We have previously made the observation that patients with a T cell infiltrate in their primary tumor have a better prognosis then those that do not. To understand the nature of the immune infiltrate, we have in 12 patients performed 10X sequencing on CD45 cells from the tumor as well as single cell TCR-seq, BCR-seq and cite-seq and have performed the same experiment on the matching PBMCs. We have generated a dataset of approximately 185000 cells with half coming from the tumor. This unravels a complex immune infiltrate with the predominant immune cell types consisting of T cells. Our data shows that within the tumor infiltrate, patients either have high or low myeloid infiltration. We see a highly active Treg population that has multiple checkpoints activated. Using TCR data, we saw the biggest clonal expansions in CD8 EM, CD8 senescent cells and Tregs. Circulating TIL CD4 T cells are dominated by activated Tregs, Tfh, and Th2 and circulating TIL CD8 T cells are dominated by CD8 EM T cells. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma. Citation Format: Shivan Sivakumar, Ashwin Jainarayanan, Edward Arbe-Barnes, Enas Abu-Shah, Rachael Bashford-Rogers. Single-cell multi-omics in pancreatic cancer reveals differential immune evasion mechanisms between prognostic groups [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C026.

Investigating the tryptophan‐metabolizing enzyme AFMID (arylformamidase) in colon cancer

Tryptophan is an essential amino acid which is metabolized into catabolites necessary for physiological homeostasis. Of the various catabolic fates of tryptophan, the kynurenine pathway is of both basic and clinical interests due to its signature catabolite kynurenine which contributes to immune privilege, is a precursor of NAD +, and acts as an activating ligand of the transcription factor aryl hydrocarbon receptor (AHR.) Through elevated expression of tryptophan transporters and tryptophan‐catabolizing enzymes, cancer cells promote the production of kynurenine and downstream catabolites. Oncogene‐mediated upregulation of tryptophan transporters and tryptophan catabolizing enzymes IDO1, TDO2, and arylformamidase (AFMID) occur in several cancer types including breast, esophageal, liver, and colon cancers with correlation to poor prognosis. Targeting of the kynurenine pathway has therefore been a clinical focus; however, all initial clinical trials aiming to inhibit IDO1 failed. A new generation of clinical trials targeting IDO1, TDO2, and tryptophan transporters are underway, yet no preclinical evaluation of the enzyme (AFMID) has ever been conducted. AFMID acts immediately downstream of IDO1, IDO2, and TDO2 to catalyze the reaction that produces kynurenine itself. Unlike IDO1/2 and TDO2 which are functionally redundant, AFMID features a unique function. Despite its importance, no studies have comprehensively evaluated AFMID’s direct roles in metabolic reprogramming, cell‐autonomous proliferation, or microenvironment remodeling. We aim to investigate the cell autonomous and immune modulatory functions of AFMID in colon cancer and to define novel approaches to inhibit AFMID activity as strategy to block the kynurenine pathway.

Glioblastoma: Emerging Treatments and Novel Trial Designs.

Simple SummaryNowadays, very few systemic agents have shown clinical activity in patients with glioblastoma, making the research of novel therapeutic approaches a critical issue. Fortunately, the availability of novel compounds is increasing thanks to better biological knowledge of the disease. In this review we want to investigate more promising ongoing clinical trials in both primary and recurrent GBM. Furthermore, a great interest of the present work is focused on novel trial design strategies.Management of glioblastoma is a clinical challenge since very few systemic treatments have shown clinical efficacy in recurrent disease. Thanks to an increased knowledge of the biological and molecular mechanisms related to disease progression and growth, promising novel treatment strategies are emerging. The expanding availability of innovative compounds requires the design of a new generation of clinical trials, testing experimental compounds in a short time and tailoring the sample cohort based on molecular and clinical behaviors. In this review, we focused our attention on the assessment of promising novel treatment approaches, discussing novel trial design and possible future fields of development in this setting.

Activated Regulatory T-Cells, Dysfunctional and Senescent T-Cells Hinder the Immunity in Pancreatic Cancer.

Simple SummaryPancreatic cancer has the worst survival of any human cancer. Checkpoint blockade has not yielded much benefit in pancreatic cancer. We explored immune cell phenotypes with this disease to identify new targets for checkpoint blockade therapy. We created a checkpoint-focused panel to analyse immune cells from eight pancreatic cancer patients. This showed us the majority of T-cells are senescent. Further T-cell investigation demonstrated the majority of cytotoxic T-cells have intermediate to low PD1 expression suggesting why PD1 may not work as a pancreatic cancer therapy strategy. Our data has also highlighted a regulatory T-cell population which is highly activated and can mediate immunosuppression. The checkpoints that are highly expressed on these cells are TIGIT, ICOS and CD39, suggesting inhibition of these may be a viable therapeutic strategy. Furthermore, we showed that Tregs were retained amongst the fibroblast stroma of the tumour. Our work suggests there are key checkpoints on Tregs that may help guide therapeutic strategies in pancreatic cancer.Pancreatic cancer has one of the worst prognoses of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify better therapeutic strategies. In this study, we analysed 32 human pancreatic cancer patients from two independent cohorts. A multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight patients. Single-cell RNA sequencing dataset analysis was performed on a cohort of 24 patients. Multiplex immunohistochemistry imaging and spatial analysis were performed to map immune infiltration into the tumour microenvironment. Regulatory T-cell populations demonstrated highly immunosuppressive states with high TIGIT, ICOS and CD39 expression. CD8+ T-cells were found to be either in senescence or an exhausted state. The exhausted CD8 T-cells had low PD-1 expression but high TIGIT and CD39 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset. These data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.

Rumo a uma nova geração de ensaios clínicos: Pesquisa-ação Participativa em Saúde

A Pesquisa-ação Participativa em Saúde (PaPS) é uma abordagem que inclui as pessoas no processo. Não é feita "nas" pessoas como sujeitos passivos que fornecem "dados", mas "com" elas para fornecer informações relevantes no sentido de melhorar as suas vidas e produzir soluções. O processo de pesquisa é visto como uma parceria com as pessoas cuja vida ou trabalho é o tema da pesquisa. A PaPS é uma proposta promissora para uma nova geração de ensaios clínicos, sobretudo em estudos de base comunitária pois produz evidência para fazer face a diversos desafios atuais como o uso de tecnologias emergentes de saúde e estratégias de envolvimento de pacientes/comunidade para cocriarem soluções úteis assim como a gestão dos dados e a emergência da epidemiologia participativa.

Personalized treatment in metastatic triple-negative breast cancer: The outlook in 2020.

Compared with other breast cancer subtypes, patients with triple-negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This-in return-has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti-PD-L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key-practice changing-clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.

Community and academic partnerships: Moving a new generation of clinical trials in NCI Community Oncology Research Program (NCORP) into community oncology practices.

2551 Background: NCORP is a model program that bridges academic and community oncology practices and research. Over the past decade, community cancer investigators have adopted new technology, encountered new treatment sequalae, and faced rising cost of care with its financial toxicity imposed upon individuals seeking care. Opportunities are abundant for community investigators to assess feasibility and uptake of research advances into community practice settings, yet these opportunities are met with the challenges of dynamic changes in types of organizations delivering cancer care and diversity of populations within their catchment areas. Little information is shared about how and to what extent the health environment influences this partnership and the implementation of a broad cancer research portfolio. Methods: This abstract reports on the continued interest and participation of community oncologists in research which is demonstrated by 987 practices with over 4000 investigators in NCORP. Since 2014, over 30,000 individuals enrolled in symptom management, screening, surveillance, quality of life, and treatment trials. An additional 4500 patients and clinicians have enrolled in care delivery studies. Results: NCORP has been central in evaluating the most effective strategies for investigators to effectively communicate to patients the science of genomically-driven trials. It has also provided ways of bringing the pediatric and AYA patients access to the most up-to-date treatment strategies and new therapies in their community. This creates the least disruption on family structure/dynamics, diminished traveling requirements/costs, and reduced the financial burden. NCORP promotes involvement of treating oncologists in research activities. This also improves care for patients not enrolled in clinical trials. Therefore, NCORP serves as a laboratory to determine the most effective strategies for co-management of cancer patients and survivors. Conclusions: Several questions however remain to be addressed using this clinical trial model. These include: how to continue to reduce disparities in cancer care and clinical trial participation; and, what are the best strategies for fostering implementation of cancer care models in community practice.

Network science in clinical trials: A patient-centered approach.

There has been a paradigm shift in translational oncology with the advent of novel molecular diagnostic tools in the clinic. However, several challenges are associated with the integration of these sophisticated tools into clinical oncology and daily practice. High-throughput profiling at the DNA, RNA and protein levels (omics) generate a massive amount of data. The analysis and interpretation of these is non-trivial but will allow a more thorough understanding of cancer. Linear modelling of the data as it is often used today is likely to limit our understanding of cancer as a complex disease, and at times under-performs to capture a phenotype of interest. Network science and systems biology-based approaches, using machine learning and network science principles, that integrate multiple data sources, can uncover complex changes in a biological system. This approach will integrate a large number of potential biomarkers in preclinical studies to better inform therapeutic decisions and ultimately make substantial progress towards precision medicine. It will however require development of a new generation of clinical trials. Beyond discussing the challenges of high-throughput technologies, this review will develop a framework on how to implement a network science approach in new clinical trial designs in order to advance cancer care.

Tailoring Medulloblastoma Treatment Through Genomics: Making a Change, One Subgroup at a Time.

After more than a decade of genomic studies in medulloblastoma, the time has come to capitalize on the knowledge gained and use it to directly improve patient care. Although metastatic and relapsed disease remain poorly understood, much has changed in how we define medulloblastoma, and it has become evident that with conventional therapies, specific groups of patients are currently under- or overtreated. In this review, we summarize the latest insights into medulloblastoma biology, focusing on how genomics is affecting patient stratification, informing preclinical studies of targeted therapies, and shaping the new generation of clinical trials.

SC15.01 The American Perspective

The treatment of lung cancer has changed dramatically in the past few years. From a time when treatment decisions were made without regard to histology or genotype, an era of personalized therapy, at least for a subset of patients with lung cancer, is a reality. The treatment of EGFR mutation-positive patients with EGFR inhibitors has resulted in significant improvements in outcomes over standard chemotherapy. Similarly, for patients with ALK- and ROS1-positive non-small cell lung cancer (NSCLC), targeted therapies have proven to be superior. However, for patients with KRAS mutations, which are seen in approximately 25-30% of lung adenocarcinomas, there is no effective targeted therapy option. For nearly 70% of patients with NSCLC, systemic chemotherapy remains the standard approach. The emergence of immune-checkpoint inhibitors has resulted in considerable change in the treatment algorithm for advanced NSCLC. These agents are now preferred salvage therapy after progression following platinum-based chemotherapy. As immunotherapy moves to the first-line therapy setting for advanced NSCLC, it is anticipated that at least 25-30% of the patients without a driver mutation will be treated with immune-checkpoint inhibitors. All of these exciting developments call for careful evaluation of ongoing and planned clinical trials, so that appropriate new priorities are established. The newly established NCI National Clinical Trials Network (NCTN) includes all the adult cancer cooperative groups (ALLIANCE, ECOG-ACRIN, SWOG, & NRG Oncology) is actively engaged in conducting the new generation of clinical trials for lung cancer. Despite, the success with targeted agents in advanced stage NSCLC, patients do not achieve a cure. Using these agents in early stage NSCLC provides the best chance for a cure. The ALCHEMIST study has been launched by the NCTN to evaluate personalized adjuvant therapy for early stage NSCLC. In this study, patients with early-stage lung cancer (stages IB, II and IIIA) are treated with systemic chemotherapy after surgical resection, as per standard of care. Subsequently, their tumor is subjected to molecular testing. Patients with ALK-positive disease are randomized to treatment with crizotinib or placebo. Patients with EGFR mutations are randomized to erlotinib or placebo. Patients who are negative for EGFR and ALK, are randomized to nivolumab or observation. These studies will evaluate the effect of the personalized adjuvant therapy on overall survival and disease-free survival. Another ongoing effort is to understand the therapeutic value of targeted strategies in patients with advanced stage squamous cell lung cancer. The lung-MAP study enrolls patients with advanced stage squamous NSCLC. Following next-gen sequencing, patients with selected targets are treated with an appropriate targeted agent. The study includes a phase 2 component, which can be rapidly adapted to phase 3 if an agent demonstrates the pre-defined level of efficacy. This trial is also designed to accelerate the development of treatments leading to full approval by the FDA by shortening timelines. These individualized treatment approaches based on genotype are likely to answer important questions in a definitive manner. As immunotherapy becomes integrated in the standard treatment paradigms, considerable changes are also warranted for patients without driver mutations. For a subset of patients, as immunotherapy becomes the first line treatment in the advanced stage disease setting, the role of platinum-based chemotherapy in the second line needs to be investigated. It is also important to evaluate the need for continued immunotherapy after disease progression when patients are switched to chemotherapy. Another key question relates to the duration of therapy for patients receiving immune checkpoint inhibitors. Appropriately designed trials to understand the optimum duration of therapy will optimize benefits, reduce toxicity, and decrease cost. Combination strategies using immune checkpoint inhibitors with chemotherapy and other targeted agents is also an important area of priority. The role of biomarkers to select therapy is another critical research priority. We should also make efforts to improve the percentage of patients enrolled to clinical trials. A major reason for this is the stringent eligibility criteria that excludes a significant proportion of patients in order to select the ‘fittest’ candidates for clinical trials. While this is certainly appropriate in early phase drug development, if patients enrolled in clinical trials do not represent the ‘real-world’ patient population, the applicability of the results are limited. The next wave of clinical trials should also take into consideration the impact of new treatments on the overall cost of care and the clinical significance of improvements in efficacy. The national Cooperative groups in the United States are committed to a collaborative approach to address key research questions and improve outcomes for lung cancer. NSCLC, Adjuvant therapy, ALCHEMIST, immunotherapy

Anaemia in the Premature Infant and Red Blood Cell Transfusion: New Approaches to an Age-Old Problem

Red blood cell (RBC) transfusion is a common intervention in very preterm infants with variable utilisation between centres and individual clinicians. This variation likely reflects uncertainty about who, when and how much to transfuse. Most RBC transfusions are given in small volumes as “top-up” for anaemia or cumulative phlebotomy loss. Whilst the newly born infant may have a low haemoglobin (Hb) value, it is uncertain if this is of clinical or physiologic significance except at extreme values. Little attention has been given to the potentially favourable effect of RBC transfusion on oxygen kinetics, particularly in the interval after birth when the risk of hypoxic ischaemia is high. Later anaemia, at the time of likely Hb nadir, more typifies anaemia of prematurity. In this article, we will firstly review the conventional model of RBC transfusion based on haemoglobin [Hb] thresholds and secondly, we will propose an alternate, individualised, practice based on the oxygen physiology. This effectively reframes the potential role of RBC transfusion in the very preterm infant and demands a new generation of clinical trials.

From pathobiology to the targeting of pericytes for the treatment of diabetic retinopathy.

Pericytes, the mural cells that constitute the capillaries along with endothelial cells, have been associated with the pathobiology of diabetic retinopathy; however, therapeutic implications of this association remain largely unexplored. Pericytes appear to be highly susceptible to the metabolic challenges associated with a diabetic environment, and there is substantial evidence that their loss may contribute to microvascular instability leading to the formation of microaneurysms, microhemorrhages, acellular capillaries, and capillary nonperfusion. Since pericytes are strategically located at the interface between the vascular and neural components of the retina, they offer extraordinary opportunities for therapeutic interventions in diabetic retinopathy. Moreover, the availability of novel imaging methodologies now allows for the in vivo visualization of pericytes, enabling a new generation of clinical trials that use pericyte tracking as clinical endpoints. The recognition of multiple signaling mechanisms involved in pericyte development and survival should allow for a renewed interest in pericytes as a therapeutic target for diabetic retinopathy.

Cancer stem cells: are they responsible for treatment failure?

Overcoming resistance to standard anticancer treatments represents a significant challenge. The interest regarding cancer stem cells, a cellular population that has the ability to self-renew and to propagate the tumor, was prompted by experimental evidence delineating the molecular mechanisms that are selectively activated in this cellular subset in order to survive chemotherapy. This has also stimulated combination strategies aimed at rendering cancer stem cells vulnerable to anticancer agents. Moreover, cancer stem cells offer a unique opportunity for modeling human cancers in mice, thus emerging as a powerful tool for testing novel drugs and combinations in a simulation of human disease. These novel animal models may lay the foundation for a new generation of clinical trials aimed at anticipating the benefit to patients of anticancer therapies.

Evolving Panorama of Treatment for Metastatic Pancreas Adenocarcinoma

Evolving Panorama of Treatment for Metastatic Pancreas Adenocarcinoma

Methodological and practical challenges for personalized cancer therapies

Many experts agree that personalized cancer medicine, defined here as treatment based on the molecular characteristics of a tumor from an individual patient, has great potential in the therapy of many types of cancer. Although targeted therapy agents are increasingly available for clinical applications, many of these promising drugs have produced disappointing results when tested in clinical trials, indicating that there are many challenges that must be addressed to advance this field. We propose that a new generation of clinical trials requiring biopsies to obtain relevant tumor specimens, as well as novel statistical designs, will be essential to improve treatment outcomes. However, these novel clinical trials will only be successful if appropriate biomarkers are identified to help guide the selection of the most beneficial treatments for the participating patients. Although biomarkers based on single gene mutations are the most commonly used in clinical applications today, gene-expression or protein-expression 'signatures' and new imaging technologies have the potential to play important roles as biomarkers in the future. Therefore, it is of crucial importance that we identify and resolve existing challenges that may impede the rapid identification and translation of validated biomarkers with acceptable sensitivity and specificity from the laboratory to the clinic. These challenges include limitations of current biomarker development methodologies and regulatory and reimbursement policies and practices.

The search for optimal response prediction in cancer leads to a personalized approach

There is a clear need for better response prediction in the management of patients with cancer. Important progress has indeed been made in understanding the underlying mechanisms of tumor growth and targeting important new targets with novel drugs blocking receptors or interfering with one of the important pathways. A long list of new, targeted agents has been developed or is under development. With this comes also the need of new methods and new molecular markers for response prediction. The area of response prediction is booming: functional imaging is becoming a very important tool and aid and the knowledge on molecular markers is growing very rapidly. Functional imaging with positron emission tomography (PET) scan, dynamic contrast-enhanced ultrasonography (DCE-US) and magnetic resonance imaging (MRI) is coming into the research arena and is likely to be implemented in the future in clinical practice. Better validation of the clinical utility of functional imaging techniques is, however, still needed in many clinical situations. A major clinical problem for the use of novel molecular targeted agents is to determine their activity by the use of classic imaging evaluation methods such as computed tomography (CT) and by the use of standard tumor size assessment with Response Evaluation Criteria in Solid Tumors (RECIST). Therefore, functional imaging techniques that could be performed in the evaluation of the early activity and also in the determination of the optimal dose of the new targeted agents are necessary. Dynamic contrast-enhanced (DCE)-MRI and DCE-US, diffusion and perfusion MRI and PET-CT, using new tracers for proliferation, will probably be integrated gradually in the new generation of clinical trials and eventually also in clinical practice. Molecular markers clearly have the potential to help to select cancer patients that are suitable for treatment with a molecular targeted, agent if they are able to predict the activity or the lack of activity of these agents. Among examples of predictive biomarkers for response and clinical activity, there are cKIT mutations for imatinib therapy in gastrointestinal stromal tumors (GIST), epidermal growth factor receptor (EGFR) mutations for erlotinib and gefitinib treatment in nonsmall cell lung cancer (NSCLC), HER-2 gene amplification for the use of trastuzumab in breast cancer, as well as recently HER-2 overexpression in gastric cancer, KRAS mutations as predictors of lack of activity of cetuximab and panitumumab in colorectal cancer and, finally, BRAF mutations for treatment with selective BRAF inhibitors in melanoma. This list is not completed and will certainly be expanded in the near future. Further, some of these biomarkers are not only predictive for response to a given treatment, but they could have also a prognostic role. As an example, BRAF mutations correlate with poor prognosis, lack of cetuximab and panitumumab efficacy and poor response to chemotherapy in metastatic colorectal cancer. The discovery of whole gene signatures, if they would be confirmed predictive and/or prognostic, will for E. Van Cutsem (*) University Hospital Gasthuisberg, Leuven, Belgium e-mail: eric.vancutsem@uz.kuleuven.ac.be

New directions in MS therapeutics: vehicles of hope

Basic immunological research has greatly expanded our understanding of the suspected immunopathology of multiple sclerosis (MS) and, more importantly, spawned a new generation of clinical trials evaluating dozens of immune-based therapies. Adhesion molecules are the furthest into development, although patient acceptance and neutralizing antibodies both support the development of small, orally available molecules. Progressive MS probably has a significant neurodegenerative component, so progress with neuroprotective strategies will require appropriate animal models, as well as more advanced clinical imaging techniques, such as brain atrophy and diffusion tensor. Dozens of therapies are in various stages of clinical development and results from these clinical studies will provide important tests of immune and inflammatory mechanisms of MS disease.

Oesophageal cancer: new developments in systemic therapy

Oesophageal cancer is a rare but highly virulent malignancy in the United States and Western countries, and adenocarcinoma of the oesophagus has had the most rapid rate of increase of any solid tumour malignancy. Systemic metastatic disease is present in 50% of patients at diagnosis, and in the remaining 50% of patients presenting initially with loco-regional disease, systemic metastatic disease will develop in the vast majority of these patients. Combined chemotherapy and radiotherapy is the standard of care in the nonsurgical management of oesophageal cancer. Preoperative chemoradiotherapy followed by surgery continues to be actively studied in the surgical management of locally advanced oesophageal cancer. Pathologic complete responses are seen in 20–40% of patients, with five-year survival achieved in 25–35% of patients. The limited efficacy and substantial toxicity of conventional 5-FU–cisplatin-based chemotherapy combined with radiation, or used to treat advanced disease, has prompted the evaluation of newer agents, including the taxanes and irinotecan. These trials have indicated promising antitumour activity and therapy tolerance in both advanced disease and in combined modality therapy trials, depending on the dose and schedule of therapy administered. The advent of newer, targeted therapies, including agents directed against growth factor receptor pathways, tumour angiogenesis, and tumour invasion and metastasis, is leading to a new generation of clinical trials combining these agents with conventional cytotoxic chemotherapy and radiation.

New developments in the treatment of esophageal cancer.

Esophageal cancer is a rare but highly virulent malignancy in the United States and Western Europe, and adenocarcinoma of the esophagus has had the most rapid rate of increase of any solid tumor malignancy. Combined chemoradiotherapy is the standard of care in the nonsurgical management of esophageal cancer. Trials of preoperative chemotherapy followed by surgery have not shown a consistent benefit. Preoperative chemoradiotherapy followed by surgery continues to be actively studied in the surgical management of locally advanced esophageal cancer. Pathologic complete responses are seen in 20% to 40% of patients, with 5-year survival achieved in 30% to 35%. Newer agents, such as the taxanes and irinotecan, have been evaluated in combined chemoradiotherapy trials. These trials have shown promising antitumor activity and therapy tolerance, depending on the dose and schedule of therapy administered. Increasing the dose of radiotherapy, or adding a brachytherapy boost to chemoradiotherapy, has not improved the outcome of treatment in clinical trials. The advent of newer targeted therapies, including agents directed against growth factor receptor pathways, tumor angiogenesis, and tumor invasion and metastasis, is leading to a new generation of clinical trials combining these agents with conventional cytotoxic chemotherapy and radiation.

Beyond Lithium in the Treatment of Bipolar Illness

Dramatic changes have recently occurred in the availability of treatment options for bipolar illness. Second generation mood stabilizing anticonvulsants carbamazepine and valproate are now widely used as alternatives or adjuncts to lithium. High potency benzodiazepines are also used as alternatives to typical neuroleptics, and now atypical neuroleptics are demonstrating efficacy and better side-effects profiles than the typicals. Thyroid augmentation strategies and dihydropyridine L-type calcium channel blockers require further clinical trials to define their role. Putative third generation mood stabilizing anticonvulsants lamotrigine, gabapentin, and topiramate have unique mechanisms of action and deserve further systematic study, as does the potential role for nonconvulsive brain stimulation with repeated transcranial magnetic stimulation (rTMS). These and a host of other potential treatment options now require a new generation of clinical trials to help identify clinical and biological markers of response and optimal use alone and in complex combination therapeutic regimens.