Section on Oncology. (Abstracts of Scientific Posters).

ONC1-A. NEUTROPENIC ENTEROCOLITIS WITH COMPLETE BOWEL NECROSIS COMPLICATING INDUCTION CHEMOTHERAPY IN A CHILD WITH ACUTE INFANTILE LEUKEMIA. Paulina Rojas, Aarati Rao, Raj P. Warner, Kenneth Ward, and Maria C. Velez. Hematology/Oncology, Department of Pediatrics, LSUHSC and Children's Hospital, New Orleans, LA.

A 4-month-old infant presented with two-week history of abdominal distention and hematochezia. Physical examination revealed pallor, marked organomegaly, ecchymosis, and petechiae. Laboratory data included WBC count of 53,000/mm3 with 87% blasts, platelet count of 12,000/mm3, Hgb of 4.1 gm/dL, and LDH of 3,327 U/dL.

Bone marrow examination confirmed the diagnosis of infantile leukemia (IALL), acute lymphocytic, L1 morphology, CALLA negative, and low DNA index. Cytogenetic analysis detected translocation (4,11) with 11q23, the MLL rearrangement. Spinal fluid was negative for blasts. Chemotherapy with decadron, vincristine, daunomycin, cyclophosphamide, asparaginase, and intrathecal was begun. The clinical course was complicated by tumor lysis syndrome requiring acute hemodialysis, profound pancytopenia, mucositis, septic shockdue to alpha-hemolytic streptococcus, and severe abdominal distention with cholestatic jaundice. Despite treatment with broad-spectrum antibiotics and antifungals, and aggressive supportive care, he subsequently developed perforation secondary to complete bowel necrosis. Because of catastrophic side effects, chemotherapy was discontinued and the child continues on TPN as his only source of intake. The child remains in hematologic and cytogenetic remission of his leukemia without further therapy after 40 months. Neutropenic enterocolitis (NE) is a life threatening inflammation of the cecum with a reported mortality rate of 50% to 100%. It is more commonly seen in hematologic malignancies. IALL carries a poor prognosis and high relapse rate with conventional chemotherapy. This child is doing well with normal development for his age after two weeks of chemotherapy for IALL with devastating side effects (complete bowel necrosis on TPN). This case exemplifies the remarkable improvements in supportive care, but at the same time highlights the need for further research in the pathophysiology of these entities with better understanding of the triggering events.

ONC2-A. PAROTID GLAND METASTASIS AS THE INITIAL MANIFESTATION OF NON-SMALL CELL LUNG CANCER. Nathan H. Fowler, MD, Derrick W. Spell, MD, and James T. Lin, MD. Division of Hematology/Oncology, Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX.

A 68-year-old man with a medical history of hypertension and heavy tobacco use presented with a six-week history of an enlarging right-sided facial mass. The patient also reported occasional right-sided facial pains, but denied any other complaints. Physical examination revealed a fixed mass in the right parotid region that measured 5 X 5 cm. MRI of the head and neck revealed a 4.7 X 3.8 X 4.3 cm mass in the superficial lobe of the right parotid gland that enhanced with gadolinium contrast. The mass extended into the facial nerve and the deep lobe of the parotid; however no other abnormalities were noted. CT of the thorax revealed a mass in the left upper lobe measuring 8 X 5 X 8 cm and enlarged subcarinal lymph nodes. Bronchial washings from the left upper lobe and a biopsy of the right parotid gland both confirmed poorly differentiated squamous cell carcinoma. The patient was initially treated with paclitaxel and carboplatin. After four cycles of chemotherapy, the patient had no measurable disease in his pa rotid gland. CT of thorax was repeated and revealed resolution of the subcarinal lymphadenopathy and a decrease in the size of the lung mass to 4 cm in greatest diameter. Two more cycles of paclitaxel and carboplatin were given. The patient was subsequently treated with docetaxel due to disease progression. After four cycles of docetaxel, the patient was referred to hospice. He died eleven months after his initial presentation. Malignant neoplasms account for approximately 20% of parotid gland tumors. The overwhelming majority of parotid malignancies represent either primary parotid tumors, direct spread from tumors in contiguous areas, or metastatic disease from other areas of the head and neck. Metastatic disease from infraclavicular tumors is an extremely rare event. To our knowledge, this is the first case report of non-small cell lung cancer presenting with a right parotid gland metastasis.

ONC3-A. AN ASSESSMENT OF THE EFFICACY OF CHEMOTHERAPY FOR AFRICAN AMERICAN PATIENTS DIAGNOSED WITH STAGE III COLON CANCER Trina Cofield, BSc, Fritzroy Dawkins, MD, K. Kim, PhD, and William Matory, MD. Washington, DC.

In the United States, colon cancer is the third most common cause of cancer after prostate and lung cancer in men and breast and lung cancer in women. Furthermore, colon cancer is the third leading cause of mortality in deaths caused by cancer. However, in the past twenty years the incidence and mortality rates of persons diagnosed with colorectal cancer have decreased. This decline may be related to improved public health education, changes in lifestyle and early detection using highly specialized procedures such as colonoscopy and sigmoidoscopy. There is a decrease in the incidences of all sites and stages of cancer of the colon. There are a number of etiologic factors that contribute to the pathogenesis of colorectal cancer. Predisposing factors to colon cancer include nutritional, environmental, genetic, and certain diseases of the bowel, including ulcerative colitis and Crohn's disease. The incidence of colorectal cancer in the United States is twice that of less developed countries. Epidemiologic studie s have shown that this difference is mainly due to environmental factors, such as diet. American diets consist of a large portion of lipids and iron. Hyperimmune responses may contribute to the development of colorectal cancer. High concentrations of fatty acids from the n-6 series and dietary iron may enhance tumorigenesis in the colon by pronounced stimulation of the immune responses. There are many hereditary syndromes that present a risk for the development of colon cancer including familial adenomatous polyposis (FAP) coli, hereditary nonpolyposis colorectal cancer (HNPCC), Peutz-Jeghers syndrome, Gardner's syndrome, and others. The inflammatory bowel diseases, ulcerative colitis and Crohn's disease, increase the risk of developing colorectal cancer by thirty times. Other factors that contribute to the pathogenesis of colon cancer include a sedentary lifestyle, no parity or low parity, and a diet deficient in vegetables and grains. The incidence of colon cancer varies according to age and sex. Generally, the incidence of colorectal cancer is identical in men and women; however, the location of lesions differ between the two groups. The incidence of tumors in the colon is higher in women whereas the incidence of tumors in the rectum is higher in men. The incidence of colon cancer is rare before the age of 40 years, accounting for only 3% of cases. Persons between the ages of 41 and 55 years account for 12% of all cases, and the remainder of cases of colon cancer occur in persons aged 55 years and older. The mean age at diagnosis is 60 to 65 years. There is a disparity between the survival rates of African Americans and Caucasians in the United States. Studies have shown that blacks have lower survival rates for colon cancer than whites. The more advanced stage at diagnosis for black patients accounts for the 50% to 60% excess mortality. Other factors that contribute to the lower survival rates of blacks with colon cancer is lower socioeconomic status and inadequate treatment. The locations of the tumors do no t contribute to the disparity in survival rates. The later stage at diagnosis, socioeconomic factors, and inadequate treatment do not entirely account for the lower survival rates of blacks. The difference in survival for black patients may be due to environmental exposure, host susceptibility, tumor biology, or other factors. These factors could indicate the need for a different treatment strategy for African American patients. There have been few studies done to determine if changes in treatment strategy can improve survival rates of blacks with colorectal cancer. The purpose of this study is to determine if African American patients diagnosed with stage III colorectal cancer receiving chemotherapy have a survival advantage over those patients who are not receiving chemotherapy.

ONC4-A. CD8+ TC1- AND TC2-MEDIATED GVT RESPONSES: T CELL AND BREAST CANCER CELL AUTOCRINE AND PARACRINE REGULATION BY TGF-b. Karen Abdool, William A. Matory, MD, and Georgia Dunston, PhD, Department of Microbiology, Washington, DC

Allogeneic bone marrow transplantation (alloBMT) is a potentially curative therapy for leukemias and lymphomas. The primary therapeutic component of alloBMT appears to be initiated by donor T cells contained in the allograft. This allogeneic anti-leukemia effect has been termed the graft-vs-leukemia (GVL) effect, and recently, the graft-vs-tumor (GVT) effect when allogeneic transplantation results in reduction of solid tumors. Donor CD8+ cytotoxic T lymphocytes (CTL), which mediate antitumor effects, can be characterized by their functional properties into the Tc1 and Tc2 subsets. Previous studies in our laboratory have shown that both subsets can mediate a GVT effect against metastatic breast cancer. TGF-b, a known regulator of apoptosis and suppressant of T cell immunity, is produced by many breast tumors. These tumors escape the apoptotic signaling of TGF-b. This study has explored the effect of TGF-b on the ability of CD8+ cell to mediate a GVT effect against breast cancer cells. Tumor cell lines were gen erously donated by Dr. Ronald Cress. TS/A- is a spontaneously occurring mammary adenocarcinoma from a DBA/Z mouse (H-2d). This line secretes high levels of TGF-b. Splenic cells of CB6F1 (H2b/d) mice were harvested and cultured in complete media (CM). The cytokines rmGM-CSF 1000 u/ml, + rm IL-4 1000 u/ml were added to promote dendritic cell maturation. Flow cytometry was done to confirm the presence of dendritic cells. These cells were used for APC stimulation of T cells. Alloreactive Tc1 and Tc2 cells, harvested from C57BL/B6 (B6, H-2b), were suspended in CM and stimulated with either APC or CD3/CD28 beads. Cells were grown with a specific cytokine cocktail to drive differentiation into Tc1 or Tc2 subtypes. Cytotoxic activity of Tc1 and Tc2 was assessed by chromium 51 assay. Cytokine production was assessed by biotin/extravadin ELISA. Flow cytometry was used for assessment of Fas-receptor on tumor cells. Fas up-regulation in vivo was assessed by transplant of PKH-stained tumor cells by intraperitoneal injecti on into CB6F1 mice and flow cytometric assessment of Fas receptor after harvesting of cells by gastric lavage. Laser scanning cytometry was used for assessment of caspase activity in tumor cells. Statistical analysis utilized Wilcoxon's test of nonparametric data. In vitro data was obtained from tissue culture of tumor cells, and splenic T cells fro C57B1 and CB6F1 mice. In vivo data was obtained from CB6F1 mice. In Cr51 assays, we found that abrogation of breast cancer cell TGF-b production through an anti-sense (TS/A-AS) transfection approach increased Tc1 and Tc2 cell lysis of tumor cells relative to sham transfected (TS/A-CAT) or wild-type (TS/A) tumor cells that produced high levels of TGF-b. We also determined that the enhanced Tc1 and Tc2 mediated lysis of TGF-b anti-sense tumor cells was generated through enhancement of both major pathways of T cell lysis, the perforin/granzyme and Fas pathways. In marked contrast to this TGF-b inhibition of lytic function, we found no evidence of TGF-b mediated modul ation of Tc1 or Tc2 cytokine secretion. We hypothesized therefore that TGF-b regulation of cytotoxic function might be associated with an autocrine down-regulatory effect on breast cancer cell apoptotic signaling (rather than a tumor cell/T cell down-regulation). To this extent, we measured caspase-3 activation in each tumor cell line when subjected to Tc1 and Tc2 CTL. We found significantly greater expression of activated caspase-3 in the TS/A-AS cells relative to the wild type TS/A (P = .046). We also found increased expression of activated caspase-3 in the TS/A-AS relative to the TS/A-CAT, although this difference did not reach statistical significance (P = .075). We next hypothesized that one mechanism whereby autocrine TGF-b might down-regulate tumor cells is through inhibition of the Fas death receptor (CD95). We assessed Fas receptor (FasR) expression on the different cell lines. Consistent with this hypothesis, tumor cell CD95 expression was reduced in the TS/A relative to the TS/A-AS (p=0.075) and wa s reduced in the TS/A-CAT relative to the TS/A-AS (P = .028). In additional studies where breast cancer cells were administered to syngeneic mice, we also found that the TS/A-AS cells had increased Fas receptor in vivo relative to the wild-type TS/A (P = .018) or the TS/A-CAT (P = .043). These results indicate that Fas receptor down-regulation represents an autocrine effect of tumor-derived TGF-b that allows tumor cell escape from Tc1 and Tc2 cell lysis. In light of this apparent role of tumor cell autocrine TGF-b in regulating T cell immunity, we next hypothesized that Tc1 and Tc2 cell autocrine TGF-b may regulate GVT effects. To this extent, we generated Tc1 and Tc2 cells from both 2C mice and from dominant negative TGF- receptor II (DRNII) transgenic mice not capable of responding to TGF-b on the basis of their expression of a nonsigualing TGF- receptor (2c/DNRII). Tc1 and Tc2 cells not capable of responding to TGF-b had 50-100% lytic function against breast cancer cells. This increased lysis was primarily due to enhanced CTL exocytosis function. Interestingly, TGF-b DNRII Te1 and Tc2 cells had reduced Fas-mediated lytic function and cytokine secretion. These results, therefore, indicate that T cell autocrine TGF- production may differentially regulate cytolytic and cytokine effector mechanisms. Our studies indicate that TGF-b of Tc1- and Tc2-mediated GVT has effects against breast cancer cells. This downregulation appears to occur, at least in part, through autocrine effects of TGF-b at the cellular level of both the T cell and the tumor cell. Further studies are focused on evaluating potential mechanisms of this TGF-b mediated down-regulation of immunity, with an emphasis on the role of TGF-b signaling events in T cells and breast cancer cells. AlloBMT represents a curative treatment option for patients with leukemia and lymphoma. The curative component of alloBMT is thought to be derived from a donor T-cell-mediated GVL effect. This potent antitumor therapy has effected prolonged disease-free states in many patients. Early clinical trial results indicate that such an allogeneic GVT effect may also exist in the setting of solid tumors such as renal cell carcinoma. The role of alloBMT in the treatment of metastatic breast cancer has been evaluated on a very limited basis with some evidence of a clinically significant GVT effect. Recent results in our lab and in the lab of our collaborator, demonstrate that an allogeneic GVT effect exists in murine models of metastatic breast cancer. Because alloBMT has the immune-mediated GVL or GVT effect as its primary therapeutic component, it is possible that this form of transplantation may represent a new approach to the treatment of breast cancer. TGF-b is a member of the TGF-b superfamily of proteins, which regulate cell growth and differentiation. In the adult mammary gland, TGF-b is a critical regulator of the cell death and restructuring that occurs before, during and after lactation by regulating ductal and alveola development in non-pregnant women while suppressing d uctal development but allowing alveola development to occur in pregnant women. TGF-b plays a major role in cell cycle arrest and transcriptional regulation in epithelial cells. Several studies indicate that TGF-b down-regulates T cell function. We therefore hypothesize, that Tc1 and Tc2 mediated GVT effects are down-regulated in TGF-b producing breast tumor cells. This down-regulation is largely a result of tumor cell modifications resulting in resistance to the transcriptional regulation and apoptotic effects of TGF-b as mediated through different mechanisms of programmed cell death. We also believe that TGF-b independently exerts an important down-regulatory effect on CD8+ cell activation and function. If the effects of TGF-b can be inhibited, it may be possible to create a more efficient CD8 cells and thus increase the GVT effect during allotransplant in breast cancer.

ONC5-A. MALIGNANT METASTATIC PHEOCHROMOCYTOMA. Ravi R Kurella, MD, Paresh R Jadav, MD, and Michael Weisz, MD, FACP. Tulsa, OK.

Pheochromocytoma is usually a benign tumor of the chromaffin tissue of the adrenal medulla or sympathetic paraganglia. A malignant pheochromocytoma is rare. A malignant metastatic pheochromocytoma is extremely rare. It typically presents one year after the diagnosis of the primary tumor. We report an unusual presentation of malignant metastatic pheochromocytoma. An apparently healthy 53-year-old woman presented with a fracture of the proximal right humerus. She sustained this fracture without trauma. An x-ray film revealed a moth-eaten radiolucent appearance at the site of the displaced fracture. Our initial diagnosis based on the x-ray film findings was a pathologic fracture secondary to a metastatic disease, though a primary bone tumor could not be excluded. The patient was taken to surgery for internal fixation. A biopsy of the bone at the fractured site revealed pheochromocytoma. A search for the primary tumor was made. CT scan of the abdomen revealed a left adrenal mass. A subsequent CT-guided biopsy con firmed that this was a pheochromocytoma. The patient did not have any symptoms suggestive of a pheochromocytoma in the past. A malignant metastatic pheochromocytoma presenting one year after the diagnosis of the primary, though extremely rare, has been previously described in the literature. Pheochromocytoma with an initial presentation as a pathologic fracture and with no prior symptoms suggestive of a primary pheochromocytoma has never been reported in the literature, to the best of our knowledge. Thus, a malignant metastatic pheochromocytoma should be considered in the differential diagnosis of pathologic fractures.

ONC6-A. DIFFUSE LARGE B-CELL LYMPHOMA 64 MONTHS AFTER SPLENECTOMY FOR SPLENIC MARGINAL ZONE LYMPHOMA--PROGRESSION IN A STEPWISE FASHION. Ebele C. Chira, MD, Ali R. Rahimi, MD, FACP, AGSF, and L. E. Robertson, MD. Savannah Hematology Oncology Associates, Savannah, GA.

Splenic marginal zone lymphoma (SMZL) is a B-cell lymphoma of the spleen, and accounts for < 5% of all NHLs. The course of SMZL is indolent, with survival rates in excess of 70% at 10 years. It does, however, have the potential to transform into a higher grade lymphoma, as has been described in sporadic cases. Diffuse large B-cell lymphoma (LBCL) is an aggressive B-cell non-Hodgkin's lymphoma, and accounts for approximately 30% of all NHLs. We report the case of a 74-year-old woman who presented 64 months after splenectomy followed by adjuvant chemotherapy for SMZL. Three years after the initial episode, she had had a recurrence of lymphoma in the mediastinum and retroperitoneum, which was highly responsive to chemotherapy. She had another recurrence 8 months later, and a third recurrence 12 months after the second one. Both also responded well to chemotherapy. These recurrences were progressively more aggressive. She now presented with diffuse large B-cell lymphoma involving the lumbar spine and left anterio r chest wall. She seemed to respond initially to radiotherapy, but soon afterward developed a rapidly progressive disease. As with other low-grade lymphomas, SMZL can undergo large-cell transformation. For SMZL, this phenomenon appears to be uncommon, but the frequency is largely unknown. There appears to be a subset of cases with underlying molecular abnormalities that may predispose them to this. In our patient, formal evidence of a relationship between the primary SMZL and the transformed LBCL, such as by comparing them using techniques to establish clonal identity, was not obtained; thus, de novo LBCL cannot be completely excluded, although we feel that transformation is most likely the case. She had had two previous recurrences, each time with histologic findings suggesting a somewhat progressive nature. Until the subset of cases that are likely to transform can be reliably identified, any case of SMZL that presents with one recurrence after therapy should probably be considered for management as aggress ive as one would use in high-grade lymphomas.

ONC7-A. ASYMPTOMATIC ADVANCED HEPATOCELLULAR CARCINOMA REVEALED BY SPINAL CORD COMPRESSION. Ricardo Castillo, MD, and Alejandro Saranglao, Jr., MD. SUNYHSC, Brooklyn, NY.

A 49-year-old man, former alcohol abuser, was admitted to the hospital for a 1-day history of inability to walk. He complained of increasing lower back pain over the past 2 weeks, radiating to the abdomen and aggravated by trunk movement. Low back pain was associated with progressive weakness of both lower extremities. He denied any history of weight loss or abdominal pain. Pertinent neurologic examination at the time of admission revealed 4/5 motor power in both lower extremities with sensory deficits to light touch from T-7 to T-12, bilaterally. Otherwise, physical examination was unremarkable. No jaundice, abdominal tenderness, organomegaly, or markers of chronic liver disease were noted. Laboratory data on admission revealed mild leukocytosis (13,480 cells/mm3) and slight elevation of alkaline phosphatase level (206 U/L). Liver function tests (LFTs) and coagulation profile were within normal limits. Emergent spinal MRI done showed a pathologic fracture at T-9 level with associated spinal cord compression. Treatment with high-dose corticosteroids and radiation therapy were immediately instituted. A search for a possible occult malignancy causing the above-mentioned signs and symptoms was done. Abdominal CT scan revealed "innumerable nodules of low attenuation throughout the liver." Subsequent alpha-fetoprotein (AFP) and hepatitis profile proved noncontributory. Pathologic finding of a CT-guided biopsy of one of the liver nodules was consistent with hepatocellular carcinoma (HCC) stage III. The patient's hospital course was complicated by total paraplegia of both lower extremities, despite aggressive treatment of spinal cord compressian. He also had an episode of gastrointestinal bleeding on hospital day 23, and on hospital day 26 he died due to respiratory complications. Hepatocellular carcinoma is the 4th most common cancer in the world, and its incidence is increasing. Common sites of metastases include the lung, lymph nodes, and the portal vein. Bone metastases of HCC are relatively rare, and when they do o ccur, the disease is usually far advanced and is associated with deranged LFTs and elevated AFP levels. This case report presents a patient with asymptomatic advanced HCC with normal LFTs and AFP values, presenting with spinal cord compression. With the increasing incidence of HCC worldwide, rare presentations, such as spinal cord compression, become more likely. Thus, HCC should be part of the work-up of a patient presenting with spinal cord compression, especially if there is a history predisposing to chronic liver damage, such as hepatitis or chronic alcohol abuse.