Role of lymphadenectomy in management of adenocarcinoma of the endometrium

PURPOSE: To review the role of lymphadenectomy (LND) for patients with endometrial adenocarcinoma. METHODS: A review was undertaken of the English Language literature dealing with the role of LND for patients with endometrial adenocarcinoma (EC). RESULTS: The prognostic value of node status for EC patients has been recognized. LND performed by experienced surgeons has acceptable morbidity. Multiple series have suggested that significantly less external beam radiation is given to patients with known negative nodes. The decreased use of postop whole pelvic radiation has potential cost savings. However a survival advantage for LND has not yet been proven in a randomized clinical trials. United Kingdom investigators have begun a trial to determine if there is a demonstrable survival advantage for EC patients who undergo LND. CONCLUSION: Although the morbidity, potential cost savings, and prognostic impact of node status are well accepted, it remains controversial as to whether LND provides a survival advantage. Trials are underway.     

The use of zebrafish to understand immunity

For decades immunologists have relied heavily on the mouse model for their experimental designs. With the realization of the important role innate immunity plays in orchestrating immune responses, invertebrates such as worms and flies have been added to the repertoire. Here, we discuss the advent of the zebrafish as a powerful vertebrate model organism that promises to positively impact immunologic research.     

Phase II study of ifosfamide plus daily oral etoposide in previously treated ovarian cancer: a Hoosier Oncology Group (HOG) study

Advanced epithelial ovarian carcinoma is a chemosensitive tumor to platinum plus paclitaxel combination chemotherapy. However, most patients develop recurrences following their initial platinum-based regimen and are candidates for subsequent chemotherapy. Several chemotherapeutic drugs have been tested as single therapeutic agents or in combination for relapsed epithelial ovarian carcinoma. The response rate has been modest with no obvious advantage to combination chemotherapy versus single agents. Both oral etoposide and ifosfamide have shown activity as single agents in pretreated patients. We completed a phase II study at the Hoosier Oncology Group utilizing oral etoposide plus ifosfamide in patients with relapsed ovarian epithelial carcinoma. Fourteen patients entered the study. Ifosfamide was given intravenously (IV) at a dose of 1.2 g/m2/d on days 1 to 4 with mesna 300 mg/m2 IV 15 minutes prior to and 4 and 8 hours after ifosfamide infusion. Etoposide was administered as 37.5 mg/m2/d orally on days 1 to 14. This regimen was repeated every 28 days until disease progression or for a maximum of 6 cycles. Grade III to IV granulocytopenia occurred in 9 patients (64%), with 2 neutropenic infections, but with no therapy-related deaths. Grade III to IV thrombocytopenia occurred in 3 patients (21%), and grade III to IV nausea and vomiting in 1 patient. No renal, pulmonary, hepatic, cardiac, or serious neurotoxicity was observed. Two patients (14%) achieved partial response, and additional 5 (35%) patients had stable disease. The 1-year survival probability using Kaplan-Meier analysis was 0.8. In this small sample-size trial, we did not demonstrate an advantage to this combination regimen compared to these or other single agents.     

The prognostic value of polymorphonuclear leukocyte elastase in patients with primary breast cancer

A variety of serine proteases, including urokinase-type plasminogen activator (uPA), plasmin,and polymorphonuclear leukocyte elastase (PMN-E), have been implicated in the processes of tumor cell invasion and metastasis. Besides degrading of matrix proteins, PMN-E has been shown to be able to cleave and inactivate plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of uPA, and alpha2-antiplasmin, the natural inhibitor of plasmin, thus enabling an uncontrolled matrix degradation by the fibrinolytic enzymes. Because only limited data are available on a relationship between the tumor level of PMN-E and prognosis in primary breast cancer patients, in the present study we have measured with an ELISA the levels of PMN-E (in complex with alpha1-proteinase inhibitor) in cytosolic extracts of 1143 primary breast tumors. Levels of complexed PMN-E have been correlated with the lengths of metastasis-free survival (MFS), relapse-free survival, and overall survival, and a comparison was made with data previously obtained for uPA and PAI-1. Our results show that patients with a high PMN-E level in their primary tumor had a rapid relapse and an early death compared with patients with a low tumor level of PMN-E. This held true for node-negative and node-positive subgroups of patients as well. The relationship of PMN-E with a poor prognosis was especially obvious during short-term follow-up (0-60 months). In Cox multivariate regression analysis, corrected for the traditional prognostic factors, PMN-E was an independent prognostic factor, and high levels of PMN-E were associated with a poor MFS [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.23-2.16; P < 0.001], relapse-free survival (HR, 1.45; 95% CI, 1.10-1.89; P = 0.01), and overall survival (HR, 1.64; 95% CI, 1.20-2.23; P = 0.003). Furthermore, in all three multivariate models, PMN-E still added significantly to the model after the additional inclusion of the uPA. PMN-E was an independent prognostic factor for MFS even in the multivariate analysis including the traditional clinical prognostic factors and the strong established biochemical prognostic factors uPA and PAI-1. Our present study suggests that PMN-E is associated with breast cancer metastasis, and knowledge of the tumor PMN-E status might be helpful in selecting the appropriate individualized (adjuvant) treatment for patients with breast cancer.     

Synthesis and discovery of macrocyclic polyoxygenated bis-7-azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-3beta inhibitors

Attempts to design the macrocyclic maleimides as selective protein kinase C gamma inhibitors led to the unexpected discovery of a novel series of potent and highly selective glycogen synthase kinase-3beta (GSK-3beta) inhibitors. Palladium-catalyzed cross-coupling reactions were used to synthesize the key intermediates 17 and 22 that resulted in the synthesis of novel macrocycles. All three macrocyclic series (bisindolyl-, mixed 7-azaindoleindolyl-, and bis-7-azaindolylmaleimides) were found to have submicromolar inhibitory potency at GSK-3beta with various degrees of selectivity toward other protein kinases. To gain the inhibitory potency at GSK-3beta, the ring sizes of these macrocycles may play a major role. To achieve the selectivity at GSK-3beta, the additional nitrogen atoms in the indole rings may contribute to a significant degree. Overall, the bis-7-azaindolylmaleimides 28 and 29 exhibited little or no inhibitions to a panel of 50 protein kinases. Compound 29 almost behaved as a GSK-3beta specific inhibitor. Both 28 and 29 displayed good potency in GS cell-based assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3beta selectivity of azaindolylmaleimides.     

Biological aspects of neuroblastomas identified by mass screening in Quebec

BACKGROUND: Neuroblastoma has several characteristics that suggest that preclinical diagnosis might improve outcome. Therefore, the Quebec Neuroblastoma Screening Project was undertaken from 1989 to 1994 to examine infants at 3 weeks and 6 months by measuring urinary catecholamine metabolites. PROCEDURE: Over the 5-yr period, 45 tumors were detected by screening, 20 were identified clinically prior to the third week, and 64 were identified clinically at a later time. We analyzed available tumors for Shimada histopathology, tumor ploidy, MYCN copy number and serum ferritin. RESULTS: Of the tumors detected by screening, only 2 of 45 tested had unfavorable histology, 2 of 45 had diploid or tetraploid DNA content, 0 of 43 had MYCN amplification, and 4 of 44 had elevated serum ferritin. All of these patients are alive and well. The 20 patients detected prior to the 3-week screen had similar biological characteristics. In contrast, of the patients detected clinically after 3 weeks of age, 19 of 51 testedhad unfavorable histology, 25 of 66 had diploid or tetraploid tumors, 12 of 56 had MYCN amplification, and 14 of 54 had elevated ferritin. CONCLUSIONS: The difference between the screened and clinically detected cases was highly significant for each biological variable. Preliminary data on other biological variables, such as neurotrophin expression and allelic loss on 1 p in these patients are consistent with the above findings. These data suggest that mass screening for neuroblastoma at or before 6 months of age detects almost exclusively tumors that have favorable biological characteristics, many of which might have regressed spontaneously. Thus, continued mass screening for neuroblastoma at 6 months is unlikely to accomplish its intended goal, and should probably be discontinued.     

Teniposide plus cytarabine improves outcome in childhood acute lymphoblastic leukemia presenting with a leukocyte count greater than or equal to 100 x 10(9)/L

Childhood acute lymphoblastic leukemia with an initial leukocyte count greater than or equal to 100 X 10(9)/L responds poorly to conventional chemotherapy. To extend event-free survival (EFS) in this disease, we devised a protocol that specifies intensive 2-week courses of teniposide (VM-26, 165 mg/m2) plus cytarabine (ara-C, 300 mg/m2), before and immediately after standard 4-week remission induction therapy with prednisone, vincristine, and L-asparaginase. The VM-26 and ara-C combination was also administered intermittently for the first year of continuation treatment with oral 6-mercaptopurine and methotrexate. CNS prophylaxis consisted of periodic intrathecal (IT) injections of methotrexate and delayed cranial irradiation. At a median follow-up of 4 years, the estimated EFS rate for 57 consecutive patients with leukocyte counts of 100 to 1,000 X 10(9)/L was 44%, compared with 10% for matched controls (P less than .001). Remission induction rates in the two groups were similar (82% v 72%, P = .16). Twenty-five patients in the VM-26/ara-C group have survived without adverse events for 2.7 to 6.8 years, whereas only nine of the controls achieved more than a year of EFS. The most common complications during early treatment were acute hyperkalemia from rapid tumor cell lysis and infections due to prolonged marrow aplasia. Continuation chemotherapy was well tolerated. We conclude that VM-26 plus ara-C, added to each phase of an otherwise basic regimen of chemotherapy, will substantially improve prognosis in this high-risk form of childhood leukemia.     

Changes in body temperature and urinary cortisol after routine immunization in babies with intrauterine growth retardation

Aim : To investigate whether infants with intrauterine growth retardation (IUGR) experience different changes in temperature and cortisol excretion after routine immunization compared with normal healthy infants. Methods : Overnight deep body temperature and urinary cortisol to creatinine ratios were measured on the night after immunization and a control night in normal and IUGR infants. Results : In 60 normal infants, first vaccination at about 10 wk of age led to a significant increase in minumum overnight temperature compared to the control night, mean rise 0.25°C (95% CI, 0.12 to 0.38). In 35 IUGR infants the mean rise in temperature between immunization night and control night was 0.35°C (95% CI, 0.15 to 0.55). The increases in minimum temperature did not differ significantly between the normal and IUGR infants ( p = 0.11). Cortisol to creatinine ratios measured from overnight urine samples showed that 23 IUGR infants had consistently higher levels than 39 normal infants; control night medians 34 and 15 ( p = 0.01) and immunization night medians 56 and 26 ( p= 0.02), respectively. However, the percentage increase did not differ significantly between the IUGR infants and the normal infants. A smaller number of second immunizations were studied, but no significant differences were found.

Conclusion : These results suggest that although the impact of immunization is the same for IUGR and normal infants, because IUGR infants are less mature and at greater stress before immunization, the absolute levels that they experience after immunization are higher than those for normal infants.