Abstract

Presentation: Surveillance in Barrett'S Esophagus: A Failed Premise

John M. Inadomi

Background: It is recommended that patients in whom Barrett'S esophagus is diagnosed undergo surveillance endoscopy. However, multiple issues regarding the efficacy and feasibility of surveillance remain.
Methods: Quantitative techniques were used to examine surveillance in patients with Barrett'S esophagus. A retrospective case-control study was performed to determine whether surveillance endoscopy prolonged survival in a cohort of U.S. veterans diagnosed with esophageal adenocarcinoma. Cost-effectiveness analysis was employed to compare competing strategies of management for patients with Barrett'S esophagus, to determine whether surveillance strategies using alternative biomarkers could out-perform dysplasia based surveillance, and whether new techniques for eradicating Barrett'S metaplasia would constitute cost-effective strategies.
Results: Surveillance did not improve long-term survival among veterans diagnosed with esophageal adenocarcinoma. Lead-time bias has confounded previous reports claiming the efficacy of endoscopic surveillance. Cost-effectiveness analysis revealed that while screening 50-year old Caucasian males with heartburn may be cost-effective, surveillance even at 5 year intervals among patients with Barrett'S esophagus without dysplasia exceeded the threshold of cost-effective care. If a biomarker were developed whose sensitivity and specificity to predict cancer development exceeded 80%, this could represent a more viable strategy than dysplasia-based surveillance. Finally, techniques that reduce cancer incidence such as endoscopic mucosal resection or ablation will likely be more cost-effective than current surveillance strategies that rely on early detection of cancer.
Conclusions: Current recommendations for the management of patients with Barrett'S esophagus are flawed. Future guidelines should include alternative markers of cancer risk and focus on strategies that reduce cancer incidence instead of cancer detection.

Adoptive Cell Immunotherapy for Human Cancer

Daniel J. Powell Jr.

The Surgery Branch of the National Cancer Institute, USA, is investigating adoptive cell transfer (ACT) therapy for the treatment of patients with melanoma and other solid tumors. Tumor infiltrating lymphocyte (TIL) can be activated and expanded in vitro, circumventing normal immune regulatory mechanisms and avoiding the immunosuppressive tumor environment that has hampered previous cancer vaccine therapies. Administration of TIL with interleukin-2 to the autologous patients following non-myeloablative lymphodepleting chemotherapy caused the regression of bulky metastatic disease and objective clinical responses in fifty percent of treated patients. Some patients receiving ACT therapy exhibited the stable engraftment and persistence of the transferred T cells in the peripheral blood, leading to tumor regression and autoimmune melanocyte destruction. In ongoing clinical efforts to improve these treatments, increased intensity of the lymphodepleting conditioning is being performed. We are also investigating the retargeting of lymphocytes using T cell receptors genes. In our first trial, four of 31 patients who were treated with ACT therapy using autologous peripheral blood lymphocytes genetically engineered to recognize the MART-1 antigen had dramatic tumor regressions. A new MART-1 specific TCR with higher affinity is now under clinical investigation. Ongoing and future efforts include the use of novel T cell receptor genes that may allow the translation of these finding to patients with common epithelial cancers. These data demonstrate that adoptive cell immunotherapy can mediate the objective clinical responses in patients with refractory solid tumor.

About Lymphatic Vessel System in the Human Skin.
Basics and Special Dermatological Issues

W.Ch. Marsch

The lymphatic vessel system is largely a wide-spread one-way drainage system to clear the interstitial connective tissue of most organs- including the largest one, the skin - from a surplus of water and proteins, both of which are locally delivered through the microcirculation of the two-way supporting blood vessel system. This is the so-called ultrafiltrate, 10 percent of which is subsequently absorbed in the initial lymphatic capillaries, which are located in the upper dermis just beneath the epidermis. Their specific ultrastructural details offer a combined view on functional needs, namely to enable lymph resorption and inital passive lymph transport. To date, immunohistochemistry provides several specific lymphatic markers to distinguish endothelial cells from blood and lymphatic vessels (LYVE-1, Prox-1, Podoplanin).
Four phenomena of physiological and disturbed functions are selected to provide new insights in the biology and pathology of the cutaneous lymphatic system:
1. Fibrin thrombus formation ("Sclerosing lymphangitis of the penis", "Mondor'S phlebitis").
2. eNOS is detectable in lymphatic endothelial cells. However, the inducible isoform (iNOS) does not play a major role indicating a reduced dynamic potential in regulatory function on this cellular level.
3. Erythrocytes in lymphatic vessel lumina. Their fate and significance ( Lymphangioma circumscriptum superficiale, Psoriasis vulgaris)
4. Lymphangiogenesis ( The dermal papillae in Psoriasis vulgaris: are lymphatic vessels involved? )
The evolutionary task of the cutaneous lymphatic vessel system is prevention of longstanding edema, swelling und ultimate induration. However, below this clinical aspect, a more detailed spectrum of functions is apparent offering a broad field of scientific activities.

Walking Influences
The Initiation and Progression of Knee Osteoarthritis

Thomas Andriacchi

Current research on the mechanical environment of the knee during walking in patients with osteoarthritis supports the development of a framework for the initiation and progression of osteoarthritis at the knee. The initiation of osteoarthritis is associated with a kinematic change at the knee in the patterns of ambulation of sufficient magnitude (injury, increased laxity, neuromuscular changes, obesity) to shift load to regions of the cartilage at the knee that are not conditioned to chronic ambulatory loading. Thus, the Initiation Phase begins with healthy cartilage (pre-clinical) where some condition (traumatic or chronic) causes kinematic changes at the knee to reach a threshold where there is a substantial spatial shift in the load bearing contact location of the joint to a zone not conditioned to frequent load bearing causing the initiation of degenerative changes to the cartilage. The Initiation Phase was associated with kinematic changes reported in patients with ACL deficient knees and helps to explain the premature osteoarthritis in this group. The Progression Phase begins when degenerative changes to cartilage exceed a threshold where the tissue is vulnerable to high loads. At some point cartilage can no longer adapt to the altered chronic ambulatory loading and begins to degrade. Once cartilage starts to degrade it responds negatively to load and the rate of progression of OA increases with loading. Thus a reduction in loading at the knee during walking can slow the rate of progression in patients with knee OA. Individual variations in the range of loading and kinematics at the knee during walking can have a profound influence on the initiation and progression of osteoarthritis at the knee.