Prophylactic 3-hour graduated infusion schedule minimizes risk of carboplatin hypersensitivity reactions - A prospective study.

OBJECTIVE: Aim of this study was observation of hypersensitivity reaction (HSR) frequency by using a 3-hour graduated infusion protocol with appropriate premedication as a prophylactic measure in patients with gynecological cancer receiving carboplatin retreatment in second line or above. None of the patients had experienced HSRs to platinum previously. METHOD: All the patients in this study received premedication with corticosteroids and anti-histamines followed by carboplatin as 3-hour graduated infusion. Carboplatin was administered either as monotherapy or in combination with other chemotherapeutic agents. RESULTS: Ninety-nine patients with ovarian (n=71), fallopian tube (n=9), peritoneal (n=9) and other gynecological cancers (5 uterine cancer, 5 abdominal cancer of gynecological origin) were retreated by a total of 611cycles of carboplatin administered as monotherapy (210cycles) or combination regime (401cycles). HSRs were recorded in only 11cycles (1.8%) in a total of 11 patients. While 8 of these patients had grade 1or 2 reactions (8.1%), only 3 patients had grade 3 reactions (3%). After pause in the infusion and complete resolution of HSR symptoms, an attempt of retreatment using this infusion protocol with extra premedication was successful in 6 of these patients without any reoccurrence of HSRs. CONCLUSION: In this prospective study, we report that prophylactic 3-hour graduated infusion rate with appropriate premedication is associated with low frequency of HSRs in gynecological cancer patients requiring carboplatin retreatment in second line or above.

TP53 protein expression analysis by luminometric immunoassay in comparison with gene mutation status and prognostic factors in early stage endometrial cancer.

Mutations in the TP53 tumor suppressor gene have been shown to significantly correlate with poor prognosis in endometrial cancer. In the present study we have evaluated a luminometric immunoassay (LIA) for quantitative estimation of TP53 protein expression in 65 cytosol preparations from endometrial cancer, previously analyzed for mutations in TP53 exons 4-10. LIA showed high (> or = 0.6 ng/mg protein) expression of TP53 protein in all eight tumors with missense mutation, but high protein levels were also detected in 15 tumors with normal TP53 sequence. All four tumors with nonsense or frameshift mutations had low or no TP53 protein expression. LIA was further evaluated in a retrospective study of 201 cytosol samples from endometrial cancer. TP53 overexpression (> = 0.6 ng/mg protein) was observed in 22% of the tumors and correlated with nonendometrioid histology types (P = 0.005), poorly differentiated tumors (P = 0.001), higher FIGO grade (P = 0.001), DNA nondiploidy (P = 0.002), and high S-phase fraction (P = 0.03). After a median follow-up time of 6.8 years (range 0.7-9.9 years), 22 (13%) progressions were observed in the 175 patients with early stage (I-II) disease. TP53 overexpression (P = 0.04), FIGO grade 3 vs. 1 + 2 (P = 0.01), higher age (P = 0.02), and DNA nondiploidy (P < 0.001) showed significant correlation to shorter progression-free survival in these patients. We conclude that TP53 protein analysis by LIA provides an incomplete correlation to mutation status and cannot substitute for mutation analysis in assessment of prognosis in endometrial carcinoma. In comparison to TP53 overexpression and higher FIGO grades, DNA nonploidy status seems to be a better prognostic indicator to define a subset of early stage endometrial cancer patients who may benefit by adjuvant chemotherapy/radiotherapy.

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis.

BACKGROUND: Endometrial carcinomas seem to carry a different prognosis depending on the presence or absence of concomitant complex atypical hyperplasia (hyperplasia). The molecular genetic profile of these two pathogenetic types, based on the genes reportedly mutated in these cancers, remains to be defined. Although microsatellite inability is reported in approximately 25% of endometrial carcinomas, its relation with the 2 pathogenetic types is not investigated. METHODS: To elucidate their underlying genetic changes, we analyzed 53 sporadic endometrial tumors, including 19 with and 34 without hyperplasia, for microsatellite instability (MSI), DNA ploidy (by flow cytometry), and for mutations in different genes. RESULTS: Microsatellite instability was present in 21%, DNA nondiploidy in 15%, and mutations in the PTEN, KRAS, CTNNB1/beta-catenin, TP53, and CDKN2A genes were detected in 32, 11, 13, 17, and 0% of the tumors, respectively. Microsatellite instability and mutations in these genes were present in tumors both with and without complex atypical hyperplasia. All cases with complex atypical hyperplasia were early stage (I-II) endometrioid tumors and associated with long progression free disease (P = 0.0004). Furthermore, most tumors with hyperplasia had low World Health Organization or International Federation of Gynecology and Obstetrics grade, had less myometrial invasion, and showed expression of estrogen receptors. All MSI tumors were diploid and had a significantly higher rate of PTEN mutations, but similar rates of KRAS, beta-catenin, and TP53 mutations compared with microsatellite stable tumors. TP53 mutations more often were found in nondiploid tumors but never in tumors with PTEN, KRAS, or beta-catenin mutations, and all PTEN mutations occurred in diploid tumors. CONCLUSIONS: Thus, PTEN, KRAS, beta-catenin, and TP53 mutations occurred in tumors both with and without hyperplasia, but PTEN and TP53 mutations were more common in tumors without hyperplasia. However, none of these genes seems to clearly distinguish tumors with and without hyperplasia, suggesting that other factors may be involved. Conversely, alterations in the PTEN and TP53 genes seem to define distinct subgroups of endometrial carcinoma, the former associated with diploidy and MSI, the latter with macroscopic chromosomal instability.