Objective: Epithelial Ovarian cancer (OvCa) commonly presents in advanced stages (stage IIIC and IV). Bowel involvement (BI) doesn't have a direct role in the current FIGO staging system, which uses peritoneal metastases size to subclassify stage III. A study was undertaken to identify the prognostic significance of BI and its surgical resection, on the recurrence rate and overall survival.

16536 Background: Epithelial Ovarian cancer (OvCa) often presents in advanced stages(stage IIIC and IV). Bowel involvement (BI) at the time of the diagnosis suggests bulky advanced disease and has been associated with poor prognosis. A retrospective analysis was done to assess the impact of BI at the time of diagnosis of OvCa on the recurrence and overall survival. Methods: A retrospective review of 154 consecutive patients (pts) with epithelial OvCa was undertaken, 86 pts had advanced stages(IIIC and IV). Data was obtained for age, stage of the disease, operative procedure, pathology, recurrence and survival. Results: Of the 86 pts with advanced OvCa, 48 pts, group A, had BI at the time of diagnosis while 38 pts, group B, did not have BI. In group A, 32 had large BI, 5 had small BI, 6 had both small and large BI and 5 had stomach involvement. All pts in group A underwent radical bowel resection to achieve optimal cytoreduction (OCR) followed by adjuvant chemotherapy. Bowel continuity without colostomy was maintained in 37 pts (77.1%). Twenty six (55%) pts in group A and 20 pts in group B (57%) had more extensive disease and received neoadjuvant chemotherapy (NAC). The median CA125 level for pts in group A was 499 as compared to 213 for pts in group B. OCR was achieved in 79% of pts in group A (92% of pts who received NAC vs 66% of pts who underwent primary debulking surgery) and in 68 % of pts in group B. Overall median survival in group A vs group B was similar (35 vs 36 months). Recurrent/Persistent disease developed in 56% of pts in group A as compared to 57% of pts in group B (p=.0.64). There was no difference in the median disease-free interval (DFS) of the two groups (16 vs 18 months, p=0.67). Conclusions: BI did not independently effect the overall survival, DFS or recurrence of pts with stage IIIC and IV EpOvCa if radical bowel resection and chemotherapy could be performed. NAC is associated with increased rates of OCR in pts with BI Table1: Comparison between pts with BI and with no BI at the time of diagnosis Variable Group A Group B P value Stage IIIC (# of pts) 43 30 0.22 IV (# of pts) 5 8 0.22 Age (years) 65 64 0.6 OCR (# of pts/percentage) 38/79% 26/68% 0.32 CA 125 at diagnosis 499 213 0.25 NAC (# of pts/percentage) 26/55% 20/57% 1.0 Recurrent/persistent disease (# of pts/percentage) 27/56% 22/57% 1.0 Follow up Median survival (months) 35 34 0.25 Median diease free survival (months) 16 18 0.1 Group A: 48 pts with BI Group B: 38 pts with no BI No significant financial relationships to disclose.

16596 Background: Primary debulking surgery (DS) has been used to achieve Optimal CytoReduction (OCR) in advanced epithelial ovarian cancer (OvCa). Survival has been directly related to the residual disease after surgery. The impact of neoadjuvant chemotherapy (NAC) is controversial, hence, a study was undertaken to evaluate impact of NAC on the surgical outcome, survival and recurrence of the disease compared to primary DS followed by adjuvant chemotherapy (AdjC). Methods: A retrospective analysis was undertaken in 86 consecutive patients (pts) diagnosed with advanced OvCa (stage IIIC and IV). Forty six pts had bulkier disease and were treated with NAC followed by DS and AdjC and 40 pts were treated with primary DS followed by AdjC. Carboplatin and Paclitaxel based chemotherapy was used in 89% of pts treated with NAC and in 79% of pts treated with primary DS. Data were collected regarding demographics, survival, recurrence and surgical outcome. Results: There was no difference in the percentage of stage IIIC and IV pts between the two groups (table 1). The median CA125 level at the time of diagnosis was 867 for pts treated with NAC vs 145 for pts treated with PDS (p=0.008). NAC was associated with decreased length of stay (8 vs 10 days) and less intra-operative blood loss (400 vs 700 cc, p=0.003). OCR was achieved in 93% of pts treated with NAC versus only 63% of pts treated with primary DS (p=0.001, table 1). Rates of recurrent/persistent disease were similar in both groups (63% vs 62%). There was improvement in the disease free survival (DFS) in both stage IIIC pts (22 vs 19 months) and stage IV pts (22 vs 16 months) treated with NAC as compared to pts treated with primary DS. Conclusions: NAC was associated with significantly higher rates of OCR, possibly leading to improved DFS despite having more extensive disease. Additionally, pts treated with NAC had less intra-operative blood loss and shorter length of stay Table 1: NAC versus PDS in advanced Epithelial Ovarian Cancer Variable NAC PDS P value Stage IIIC (# of pts/percentage) 38/82% 35/87% 0.56 IV (# of pts/percentage) 8/18% 5/13% 0.56 Surgery OCR (percentage) 93% 63% 0.001 LOS (days) 8 10 0.58 Blood loss (ml) 400 700 0.003 BR (# of pts/percentage) 26 (56%) 21 (53%) 0.82 CA 125 at diagnosis 867 145 0.008> Recurrence disease/Persistence disease (# of pts) 19/10 17/8 1 IIIC DFS (months) 22 19 0.25 IV DFS (months) 22 16 0.1 Recurrence sites Liver (# of pts) 5 2 Peritonium (# of pts) 8 9 Pelvic mass (# of pts) 5 4 Others (# of pts) 1 2 NAC, neoadjuvant chemotherapy; PDS, primary debulking surgery; LOS, length of stay; OCR, optimal cytoreduction; DFS, disease free survival; BR, bowel resection. No significant financial relationships to disclose.

Acute myelogenous leukemia (AML) is a heterogeneous disease consisting of a variety of different leukemic subtypes. While acute promyelocytic leukemia displays marked sensitivity to the differentiating effects of trans-retinoic acid (tRA), other subtypes of AML display resistance. We now describe a novel compound (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) that induces apoptosis in the tRA-resistant leukemia cell lines M07e, KG-1, and HL-60R, and in tRA-resistant patient leukemic blasts. The 3-Cl-AHPC totally inhibits leukemia colony formation at concentrations that inhibit committed human bone marrow stem cell proliferation, that is, granulocyte/macrophage colony-forming units (CFU-GMs) by only 30%. Exposure to 3-Cl-AHPC results in caspase activation and the cleavage of poly(adenosine diphosphate) (poly(ADP)) ribose polymerase. While activation of the extracellular signal-regulated kinase (ERK) and p38 pathways is not necessary for 3-Cl-AHPC-mediated apoptosis, maximal apoptosis requires c-Jun N-terminal kinase (JNK) activation. The 3-Cl-AHPC-mediated cleavage of the antiapoptotic B-cell leukemia XL (Bcl-XL) protein to a proapoptotic 18-kDa product is found in both the M07e cell line and patient leukemic blasts. The 3-Cl-AHPC treatment of mice bearing the AML 1498 cell line results in a 3.3-log kill in the leukemic blasts. While 3-Cl-AHPC does not activate retinoic nuclear receptors, it is a potent inducer of apoptosis in AML cells and may represent a novel therapy in the treatment of this disease.

Only a few blastic natural killer (NK) cell leukemias and lymphomas have been reported. As such, the clinicopathologic spectrum of this disease is incompletely understood. We report 7 cases of blastic NK cell lymphoma/leukemia. All patients were men, 5 white and 2 Arab American. All cases exhibited blastic morphologic features and were CD3- and CD56+ with germline T-cell receptor genes. Five cases were CD4+ and involved the skin. Both CD4- cases never involved the skin. Other markers of mature NK cells such as CD16, CD57, and TIA-1 were expressed infrequently. Three cases were CD33+. One CD33+ case had a clonal rearrangement of the immunoglobulin heavy chain gene. Skin and lymph nodes were involved most often, with frequent evolution to a leukemic phase. Initial responses to therapy were achieved in most patients, but the tumors invariably recurred.

CD56, a neural adhesion molecule, is a marker of natural killer (NK) lymphocytes as well as a subgroup of CD8+ T cells. Normal lymphocytes with a CD56/CD4 phenotype are scarce. Physiologic increases may occur in patients with immunosuppression, chronic inflammation, and autoimmune disorders. We report 4 cases of lymphomas/leukemias with the unusual CD56/CD4 phenotype. Two were of T-cell and 2 of true NK-cell origin. The T-cell lymphomas had large granular lymphocyte morphologic features and splenomegaly. One patients had a benign course; the other died within months of the leukemia diagnosis. The 2 NK cell lymphomas had blastic morphologic features, initially involved skin, and had a very aggressive clinical course; 1 patient died of acute leukemia, and 1 had recurrence after bone marrow transplantation. Cytogenetic analyses did not show a consistent pattern of abnormalities. The NK lymphoma with acute leukemia had a t(2;5) but was CD30- and anaplastic lymphoma kinase negative. Although CD56+/CD4+ lymphomas/leukemias are a heterogeneous group, there may be a distinct subgroup of NK lymphoblastoid lymphomas of the skin, judging from our cases, as well as those previously reported.

The purpose of this study was to evaluate the probability and extent of response to radiation therapy in patients with chemotherapy-resistant intermediate grade non-Hodgkin's lymphoma. Thirty-five patients with chemotherapy-resistant non-Hodgkin's lymphoma received local radiation therapy after initial treatment with at least six cycles of systemic chemotherapy. There were 17 men and 18 women in our study. Ages ranged from 15 to 68 years, median age was 42 years. Chemotherapy resistance was defined as relapse after initial chemotherapy (11 patients) or failure to achieve complete remission (partial response in 18 patients, stable disease in 1 patient, and disease progression in 5 patients). Radiation doses were between 1,980–5,040 cGy (median dose of 3,200 cGy). Treatment outcome was evaluated with respect to any subsequent relapse either within or outside the irradiated region. The 2-year actuarial survival was 65%. The cumulative incidence of isolated local failure and any local failure at 2 years were 33% and 54%, respectively. Tumors that responded to initial chemotherapy had a better local control probability than tumors that did not respond. The 2-year actuarial local failure rates for these two groups were 51% and 83%, respectively (P = 0.01). There was a trend for improved local control with radiation doses ≥3,960 cGy, suggesting the presence of a dose–control relationship. The rate of disease progression within an irradiated region in patients with intermediate grade non-Hodgkin's lymphoma that relapsed after or failed to respond completely to full course chemotherapy was substantially higher than the historical in-field failure rates when radiation therapy was used as the sole modality of treatment. Prior response to initial chemotherapy was a predicting factor for local control following radiation therapy. Radiat. Oncol. Invest. 7:186–191, 1999. © 1999 Wiley-Liss, Inc.

Significant advances have occurred in the diagnosis, treatment, and long-term outcome of patients with acute promyelocytic leukemia (APL). The purpose of this review is to describe the molecular genetics of this disease, the use of all-trans retinoic acid (ATRA) in clinical trials of APL, and the clinical and basic research questions for future investigation. Findings of clinical studies in mainland China using ATRA as induction therapy for patients with APL concurrent with laboratory characterization of the molecular changes in APL have led to worldwide clinical trials of ATRA in the treatment of patients with APL. Major advances in understanding the molecular biology and genetics of APL have occurred over the past 5 years. These findings have been translated into novel treatment strategies using all-trans retinoic acid as a differentiation agent in the induction phase of therapy resulting in improved long-term outcome, reduced morbidity, and lower costs for patients with APL. Advanced molecular techniques are being employed for diagnosis and for monitoring of patient response to treatment.

A reciprocal chromosomal translocation, t(15;17)(q22;q11.2‐12), is characteristic of acute promyelocytic leukemia (APL) of French‐American‐British (FAB) subtype M3, and is not associated with any other human malignancy. The non‐random pattern of the APL translocations suggests that specific genes on chromosomes 15 and 17 are somehow altered or deregulated as a consequence of the rearrangement. Translocation breakpoints in APL patients provide physical landmarks that suggest an approach to isolating the APL gene(s). Genetic and physical maps constructed for the APL breakpoint region on chromosome 17 have indicated that two fully‐linked DNA markers, defining loci for THRA1 and D17S80, map to opposite sides of an APL breakpoint yet reside on a common 350‐kb Cla1 fragment. Cosmid‐walking experiments to clone this APL breakpoint have revealed a 38‐kilobase deletion on chromosome 17. Studies in additional APL patients have shown that the breakpoint region on chromosome 17 spans at least 80 kilobases.