Using our own developed stent in the palliative treatment of obstruction in the left half of the colon due to ovarian cancer.

OBJECTIVES: An assessment of implantation efficacy and safety of self-developed self-expanding stent in patients with an ovarian cancer induced by intestinal obstruction. MATERIAL AND METHODS: The study of the stenting efficacy and safety was realized prospectively. The group consisted of 13 patients with left half colon obstruction due to an inoperable metastatic ovarian carcinoma. All the patients had a histopathologically diagnosed ovarian carcinoma and were treated in the past both surgically and systemically. Stenting was preceded by a Computed Tomography (CT) scan confirming and locating the obstruction. Patients with a multilevel intestinal obstruction were disqualified. RESULTS: Nine stents were implanted in the rectosigmoid; 4 stents were implanted in an externally compressed rectum. One migration of implanted stent was observed. In one case 2 stents were implanted due to an insufficient coverage of the stricture. The decompression of the obstruction of the gastrointestinal tract was achieved in 11 patients (85%). CONCLUSIONS: 1) The implantation of our own developed, self-expanding stent is effective and safe. 2) The implantation of the stent in patients with an inoperable ovarian cancer causing an obstruction of the gastrointestinal tract is an effective procedure limiting postoperative complications and improving life comfort by avoiding stoma.

Prognosis of patients with BRCA1-associated ovarian carcinomas depends on TP53 accumulation status in tumor cells.

OBJECTIVE: TP53 mutation is the most frequent molecular event in BRCA1-associated ovarian carcinomas. TP53 status may be a confounding factor in the evaluation of clinical importance of other proteins. We aimed to evaluate the clinical significance of BRCA1 mutations with respect to the TP53 accumulation status in 159 high-grade ovarian carcinomas. METHODS: Statistical analyses were done with the Kaplan-Meier method, log-rank test, the Cox's and logistic regression models for all patients, and in subgroups with and without TP53 accumulation (TP53+ and TP53-, respectively). RESULTS: Forty of 159 ovarian carcinomas (25.2%) were diagnosed in patients with BRCA1 germline mutations; 102 tumors (64.2%) were TP53+ and 57 (37.8%) were TP53-. Among patients with TP53+ carcinomas, BRCA1 carriers had increased odds of recurrence compared with sporadic cases (HR 2.25, P=0.003; median disease-free survival time 7.7 vs. 18.4months, respectively). In the smaller TP53- subgroup, BRCA1 mutation reduced the risk of death by 46% (HR 0.54, P=0.099, median overall survival time 42.7 vs. 28.1months), but beyond the border of significance. When the TP53 status was not taken into account, BRCA1 mutations did not show any significance, however, there was a trend toward increased odds of complete remission for women with BRCA1 mutations compared to non-carriers (OR 2.47, P=0.064). Taxane-platinum therapy showed advantage over the platinum-cyclophosphamide one in the entire group of patients and in the TP53+ subgroup. CONCLUSIONS: Our results suggest that the TP53 accumulation status determines the prognosis of BRCA1 mutation carriers with high-grade ovarian carcinomas.

Evaluation of urgent multivisceral resections due to complications resulting from an advanced ovarian cancer.

BACKGROUND: Unlike other solid tumors (i.e. pancreas, gallbladder, stomach), an ovarian cancer is responsive to a systemic treatment with platinum derivates in 80% of patients. This apparent chemosensitivity justifies a broader surgical approach. A cytoreductive, "tumor-debulking" surgery is defined as an attempt to remove in a maximum degree all visible and detect-able lesions. Despite treatment, the advancement of the disease very often leads to complications defined as "surgical" and life-threatening. OBJECTIVES: The aim was to evaluate the efficacy and safety of palliative surgery in advanced ovarian cancer implicating acute surgical diseases of the abdominal cavity. MATERIAL AND METHODS: Between years 2005 and 2014 were operated 118 patients with an advanced ovarian cancer (FIGO III-IV) implicating acute and directly life-threatening diseases of the abdominal cavity, involving 132 surgical operations. The causes of these operations were: obstruction of the gastrointestinal tract - 91 patients; perforation of the gastrointestinal tract - 15; gastrointestinal bleeding - 9; intussusceptions - 3. RESULTS: Retrospective data for the 118 patients were analyzed. Safety and the perioperative mortality rate were assessed. Serious postoperative complications were recorded in 31 patients (anastomotic stoma - 9; bleeding requiring repeated surgery -3; recurring gastrointestinal obstruction - 16; liver failure after partial hepatic resection - 3). Systemic compli-cations in the form of respiratory failure and cardiovascular disorders requiring cardiological treatment - 21. All patients required clinical nutrition, both parenteral and enteral. Deaths recorded - 3. 39 patients were rehospitalized within 30 days of surgery. 7 deaths were recorded in this group. CONCLUSIONS: Combining lifesaving surgery with cytoreduction allows further adjuvant treatment. Early rehospitalization occurring within less than 30 days is linked to increased mortality.

The significance of c.690G>T polymorphism (rs34529039) and expression of the CEBPA gene in ovarian cancer outcome.

The CEBPA gene is known to be mutated or abnormally expressed in several cancers. This is the first study assessing the clinical impact of CEBPA gene status and expression on the ovarian cancer outcome. The CEBPA gene sequence was analyzed in 118 ovarian cancer patients (44 platinum/cyclophosphamide (PC)-treated and 74 taxane/platinum (TP)-treated), both in tumors and blood samples, and in blood from 236 healthy women, using PCR-Sanger sequencing and Real-Time quantitative PCR (qPCR)-based genotyping methods, respectively. The CEBPA mRNA level was examined with Reverse Transcription quantitative PCR (RT-qPCR). The results were correlated to different clinicopathological parameters. Thirty of 118 (25.4%) tumors harbored the CEBPA synonymous c.690G>T polymorphism (rs34529039), that we showed to be related to up-regulation of CEBPA mRNA levels (p=0.0059). The presence of the polymorphism was significantly associated with poor prognosis (p=0.005) and poor response to the PC chemotherapy regimen (p=0.024). In accordance, elevated CEBPA mRNA levels negatively affected patient survival (p<0.001) and tumor response to the PC therapy (p=0.014). The rs34529039 SNP did not affect the risk of developing ovarian cancer. This is the first study providing evidence that the c.690G>T, p.(Thr230Thr) (rs34529039) polymorphism of the CEBPA gene, together with up-regulation of its mRNA expression, are negative factors worsening ovarian cancer outcome. Their adverse clinical effect depends on a therapeutic regimen used, which might make them potential prognostic and predictive biomarkers for response to DNA-damaging chemotherapy.

Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.

SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻5) and rs828054 (OR = 1.06; p = 1 × 10⁻4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006). CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Androgen, progesterone, and FSH receptor polymorphisms in ovarian cancer risk and outcome.

Genes encoding hormone receptors are among candidate genes modulating the risk of ovarian cancer. We aimed to assess a frequency of PGRG+331A, FSHRAla307Thr, and FSHRSer680Asn polymorphic variants, and the length of (CAG)n and (GGN)n repeat tracts in the androgen receptor gene (AR) with respect to ovarian cancer risk and outcome. We genotyped 215 ovarian cancer patients and 352 unaffected control subjects. Statistical analysis was performed with the logistic regression model with adjustment for age. Clinical importance of the polymorphic variants was evaluated in multivariate models on 69 patients treated with taxane-platinum chemotherapy, with respect to TP53 status. Longer AR (GGN)n and (CAG)n repeat tracts decreased the risk of ovarian cancer. For (GGN)n, each additional repeat decreased the risk by 17% (P=0.011) or 27% (P=0.002), while the presence of at least 23 repeats decreased the risk by 41% (P=0.032) or 68% (P=0.008), for the shorter or longer allele respectively. The risk of disease was also decreased by 11% with each additional (CAG)n repeat (P=0.006 for the longer allele). FSHRAla307Ala or FSHRSer680Ser polymorphisms increased ovarian cancer risk by 1.8 times (P=0.042). In all 69 patients, longer AR (CAG)n repeats decreased the risk of recurrence (P=0.031). In the group with TP53 accumulation, longer AR (CAG)n repeats decreased the risk of recurrence (P=0.003) and death (P=0.03), while the FSHRSer680Ser polymorphism increased the risk of recurrence (P=0.037). Progesterone receptor polymorphisms analyzed did not show any associations. Our results support both the androgen and gonadotropin hypotheses of ovarian cancer development.

PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients.

PI3K/AKT signalling pathway controls important cellular processes such as the cell proliferation and apoptosis. PIK3CA gene encoding a catalytic subunit of the PI3K is mutated and/or amplified in various neoplasms, including ovarian cancer. We aimed to evaluate PIK3CA alterations and their clinical importance in ovarian cancer patients. Molecular analysis was performed on 117 ovarian carcinomas with the use of qPCR, SSCP and sequencing. In a group of 98 patients with complete clinical data, 62 patients were treated with standard taxane-platinum regimens and 36 patients with platinum-cyclophosphamide regimens. A multivariate analysis was performed by the Cox's and logistic regression models. PIK3CA mutations occurred in 5/117 (4.3%) carcinomas, exclusively in the endometrioid and clear cell types (p = 0.0002); they were also associated with low FIGO stage (p = 0.0003), low tumor grade (p = 0.045) and early patient's age at diagnosis (p = 0.0005). The PIK3CA amplification (predominantly a low-level) was found in 28/117 (24%) ovarian carcinomas. It was more frequent in TP53 mutant tumors (p = 0.012) and tended to associate with high pAKT expression (p = 0.061). The PIK3CA amplification strongly diminished odds of complete remission (OR = 0.25, p = 0.033) and platinum sensitive response (PS, OR = 0.12, p = 0.004) in the taxane-platinum treated patients. The odds of PS were also much lower in all patients with the PIK3CA amplification evaluated together, regardless of the treatment applied (OR = 0.18, p = 0.001). Our results suggest that PIK3CA amplification may be a marker predicting ovarian cancer response to chemotherapy.

TP53, BCL-2 and BAX analysis in 199 ovarian cancer patients treated with taxane-platinum regimens.

OBJECTIVE: In cell line studies, BCL-2 and BAX proteins interfere with cancer response to taxanes. This issue has not received much attention with regard to taxane-platinum (TP)-treated ovarian cancer patients. METHODS: We evaluated prognostic/predictive significance of BCL-2 and BAX with regard to TP53 status. Immunohistochemical analysis was performed on 199 ovarian carcinomas FIGO stage IIB-IV treated with TP; the results were analyzed by the Cox and logistic regression models. RESULTS: Clinicopathological parameters (residual tumor size, FIGO stage and/or tumor grade, but not patient's age) were the only or the strongest predictors of patient's outcome. Platinum highly sensitive response showed a positive association with TP53 accumulation (p=0.045). As in our previously published analysis on platinum-cyclophosphamide-treated group, complete remission showed a borderline negative (paradoxic) association with high BAX expression in the whole group (p=0.058) and with BCL-2 expression in the TP53(-) group (p=0.058). CONCLUSION: Our results suggest that TP53, BCL-2 and BAX proteins carry some predictive potential in taxane-platinum-treated ovarian cancer patients, auxiliary to clinicopathological factors. We have confirmed on another patient group that clinical importance of BCL-2 may depend on TP53 status.

TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: a non-randomized retrospective study.

BACKGROUND: Taxane-platinum therapy (TP) has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy) in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC. METHODS: We compared the effectiveness of PC/PAC (n = 253) and TP (n = 199) with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Cox's and logistic regression models was performed in all patients and in subgroups with [TP53(+)] and without TP53 accumulation [TP53(-)]. RESULTS: The advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+), and not in the TP53(-) group. In the TP53(+) group taxane-platinum therapy enhanced the probability of complete remission (p = .018), platinum sensitivity (p = .014), platinum highly sensitive response (p = .038) and longer survival (OS, p = .008). Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+) group. In the TP53(-) group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010). However, in the TP53(-) group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077). Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation. CONCLUSION: Our results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+) tumors or older than 53 years. In the group of patients < or =53 yrs and with TP53(-) tumors platinum-based therapy is possibly equally efficient. We provide hints for planning randomized trials to verify these observations.

Technetium-99m MIBI imaging in diagnosis of pelvic and abdominal masses in patients with suspected gynaecological malignancy.

BACKGROUND: The aim of this study was to determine the diagnostic value of (99m)Tc MIBI planar dynamic scintigraphy in the diagnosis of gynaecological malignancies and to determine if it has a greater diagnostic accuracy than conventional ultrasound technique (US). MATERIAL AND METHODS: A prospective trial was performed to assess the accuracy of (99m)Tc MIBI scintigraphy and ultrasound in 93 female patients (mean age 50, SD 16; range 17-82 years). Three readers assessed all the imaging independently and this was compared with histological examination in 89 cases and by clinical follow-up and correlative imaging for a minimum of 6 months in 4 patients. RESULTS: There were 37 patients with cancer of gynaecological origin. There were in addition 56 benign lesions within the pelvis. (99m)Tc MIBI identified correctly 29 of the 37 malignant tumours localised within the pelvis and also correctly identified 21 of 23 metastases within the abdomen. Conventional US identified correctly 35 of the 37 tumours in the pelvis and 16 sites of metastases within the abdomen. The sensitivity and specificity of tumour detection within the pelvis for (99m)Tc MIBI were as follows: 78% and 70%; and for metastases within the abdomen 91% and 90%. The results of ultrasound for tumour detection within the pelvis: the sensitivity and specificity were 95% and 79% and for abdominal metastases 70% and 97%. Analysis of the index area under a receiver operator characteristic (ROC) curve in scintigraphy did not show a significant difference between both techniques in the diagnosis of pelvic lesions. There was however a significant increase in the sensitivity of scintigraphy (99m)Tc MIBI over US in metastases detection within the abdomen. CONCLUSIONS: (99m)Tc MIBI cannot be recommended for the imaging of pelvic cancer alone, but it may be helpful in the identification of intra-abdominal spread of ovarian carcinoma and appears to offer significant advantages over ultrasound.