To Örebro University

In a series of 131 primary cervical carcinomas in FIGO stages I-IV suitable for combined external pelvic and intraluminal cervical-vaginal brachytherapy predictive and prognostic factors were analyzed with regard to locoregional tumor control, recurrences and survival data. Patients with prior surgery or patients treated with external beam therapy alone were excluded from this series. Concomitant chemotherapy was given to 47 patients (36%). The external beam therapy was given with a four-field technique (50-60 Gy) and brachytherapy with high dose-rate (Ir-192) using a ring applicator set. The dose (18-30 Gy) was specified according to the rules in ICRU 38 (a minimum dose to the surface of the target volume). Three or five fractions were given once a week in parallel with external beam irradiation. A CT-based 3-D dose-planning system (TMS) was used for the external beam therapy and for the brachytherapy planning (PLATO). The mean age of the patients was 65 years. One hundred and seven tumors were squamous cell carcinomas (82%) and 24 adenocarcinomas or adenosquamous carcinomas. One hundred and eight tumors were in FIGO stages I-II and 23 tumors in stages III-IV. The mean tumor diameter was 44 mm. Most tumors (92%) were moderately well or poorly differentiated. The primary cure rate of the complete series was 92% and 98% after chemoradiotherapy. Squamous cell carcinomas had complete remission in 96% and adenocarcinomas in 81% (Pearson Chi-square; P=0.00002). Tumor size was also highly significantly associated with local tumor control. The brachytherapy dose, the combined external and brachytherapy dose and the number of days of interruption (delay) of external irradiation were all significant predictive factors of local tumor control. In the complete series 39 recurrences (30%) were recorded. A lower FIGO stage, chemoradiotherapy, squamous cell histology, diploid DNA-profile, a higher brachytherapy dose, more brachytherapy fractions and a higher total combined irradiation dose were favorable factors with regard to the risk of tumor recurrences. The overall survival rate was 50% and the cancer-specific survival rate 65%. Tumor size was the strongest individual prognostic factor in multivariate analysis. Chemoradiotherapy therapy versus radiotherapy alone and squamous cell carcinomas versus adenocarcinomas were associated with improved survival rates. Early radiation reactions were recorded in 58% (mostly grade 1) and serious late radiation reactions (grade 3-4) in 11%.

BACKGROUND/AIM: To discover candidate protein biomarkers in the serum of patients with cervical cancer that differentiate between patients with relapse from those who are tumor-free after primary treatment with (platinum-based chemo-) radiation.

PATIENTS AND METHODS: Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) with cation exchange (CM10) and hydrophobic/reverse-phase (H50) was used to examine 44 serum samples from patients with advanced cervical cancer, primarily treated with (platinum-based chemo-) radiation.

RESULTS: Ten candidate biomarkers were identified in the serum of 34 patients. Six candidate markers were elevated in patients with no relapse and four were elevated in patients with relapse [p=0.007-0.11; area under the curve (AUC)=0.70-0.75]. Masses of candidate biomarkers ranged from 2,022 to 116,165 Da.

CONCLUSION: Patients with relapse from primary advanced cervical cancer exhibit different serum protein expression profiles from those with no relapse.

Objective: Hedgehog signaling proteins were assessed in patients with cervical carcinoma receiving chemoradiation. Associations between five Hedgehog proteins and prognosis were studied.

Methods: In all, 131 cases of cervical carcinomas (FIGO stages I-IV) were immunohistochemically (IHC) analyzed for Patched (PTCH), Smoothened (SMO), and GLI1, GLI2 and GLI3 protein expression. Associations between Hedgehog protein expressions, clinicopathological factors, and clinical outcome data were examined.

Results: Positive IHC staining for the five Hedgehog proteins was recorded in 8% to 37% of the tumor cells. The highest frequency was noted for SMO and the lowest for all. There was a significant association between low SMO- and GLI2-expression and KRAS-mutation. Tumors with overexpressed SMO had a higher frequency of residual tumor or local recurrences than tumors with low SMO expression. Patients with tumors expressing PTCH in more than 75% of the cells had significantly (P = 0.023) better recurrence-free survival than patients with tumors with low expression. The opposite situation was true for SMO. For GLI2, there was a statistically significant difference with regard to overall (P = 0.004) and distant (P = 0.015) relapse rate for groups with expression of GLI2 in the range of 5-25% compared to higher rates.

Conclusions: A predictive and prognostic value was found for PTCH, SMO, and GLI2 with regard to residual carcinoma, local recurrences, and for GLI2 distant relapses. The Hedgehog signaling pathway also seems to play an important role in cervical carcinogenesis together with HPV16-infection and KRAS-mutation.

Wnt signaling proteins were assessed in patients with primary cervical carcinomas who received chemoradiation. The associations between three Wnt signaling proteins and prognosis were assessed. Specimens from 122 patients with cervical carcinomas (FIGO stage I-IV) were immunohistochemically (IHC) analyzed for β-catenin, APC and axin protein expression. Associations between these Wnt-protein expressions, clinicopathological factors, and clinical outcome data were examined.Positive IHC staining for the β-catenin protein (cell-membranes, cytoplasm and nuclei) was recorded in 88%, 58% and 5%, respectively. There was a strong association between β-catenin staining of the cell-membranes and prediction of recurrences and prognosis (p = 0. 002). Tumors with > 5% of nuclear β-catenin staining were associated with inferior cancer-specific survival (p = 0.048) compared with no staining. The overall recurrence rate was significantly higher in the group with increased nuclear staining (67%) compared with the group with no staining (33%). Nuclear APC staining of high intensity was associated with a significantly worse cancer-specific survival and increased overall recurrence rate compared to tumors with weak staining. Distant recurrences were recorded in 29% of cases with intense staining and in 14% of cases with low staining.The Wnt signaling pathway seems to be of importance in the process of cervical oncogenesis. A predictive and prognostic value was found for β-catenin, where strong cell-membrane staining was favorable, and > 5% positive nuclear staining was associated with poorer cancer-specific survival and overall recurrence rate. Nuclear APC staining intensity was also associated with a less favorable prognosis.