The Peritoneal Cancer Index is a Strong Predictor of Incomplete Cytoreductive Surgery in Ovarian Cancer.

BACKGROUND: Extent of tumor load is an important factor in the selection of ovarian cancer patients for cytoreductive surgery (CRS). The Peritoneal Cancer Index (PCI) gives exact information on tumor load but still is not standard in ovarian cancer surgery. The aim of this study was to find a PCI cutoff for incomplete CRS. The secondary aims were to identify reasons for open-close surgery and to compare surgical complications in relation to tumor burden. METHODS: The study included 167 women with stage III or IV ovarian cancer scheduled for CRS. Possible predictors of incomplete surgery were evaluated with receiver operator curves, and a PCI cutoff was identified. Surgical complications were analyzed by one-way analysis of variance and Chi square tests. RESULTS: The median PCI score for all the patients was 22 (range 3-37) but 33 (range 25-37) for the patients with incomplete surgery (n = 19). The PCI predicted incomplete CRS, with an area under the curve of 0.94 (95% confidence interval [CI], 0.91-0.98). Complete CRS was obtained for 67.2% of the patients with a PCI higher than 24, who experienced an increased rate of complications (p = 0.008). Overall major complications were found in 16.9% of the cases. Only 28.6% of the patients with a PCI higher than 33 achieved complete CRS. The reason for open-close surgery (n = 14) was massive carcinomatosis on the small bowel in all cases. CONCLUSION: The study found PCI to be an excellent predictor of incomplete CRS. Due to a lower surgical success rate, the authors suggest that neoadjuvant chemotherapy could be considered if the PCI is higher than 24. Preoperative radiologic assessment should focus on total tumor burden and not necessarily on specific regions.

Validation of 18F-FDG PET/MRI and diffusion-weighted MRI for estimating the extent of peritoneal carcinomatosis in ovarian and endometrial cancer -a pilot study.

BACKGROUND: The extent of peritoneal carcinomatosis is difficult to estimate preoperatively, but a valid measure would be important in identifying operable patients. The present study set out to validate the usefulness of integrated 18F-FDG PET/MRI, in comparison with diffusion-weighted MRI (DW-MRI), for estimation of the extent of peritoneal carcinomatosis in patients with gynaecological cancer. METHODS: Whole-body PET/MRI was performed on 34 patients with presumed carcinomatosis of gynaecological origin, all scheduled for surgery. Two radiologists evaluated the peritoneal cancer index (PCI) on PET/MRI and DW-MRI scans in consensus. The surgeon estimated PCI intraoperatively, which was used as the gold standard. RESULTS: Median total PCI for PET/MRI (21.5) was closer to surgical PCI (24.5) (p = 0.6), than DW-MRI (median PCI 20.0, p = 0.007). However, both methods were highly correlated with the surgical PCI (PET/MRI: ß = 0.94 p < 0.01, DW-MRI: ß = 0.86, p < 0.01). PET/MRI was more accurate (p = 0.3) than DW-MRI (p = 0.001) when evaluating patients at primary diagnosis but no difference was noted in patients treated with chemotherapy. PET/MRI was superior in evaluating high tumour burden in inoperable patients. In the small bowel regions, there was a tendency of higher sensitivity but lower specificity in PET/MRI compared to DW-MRI. CONCLUSIONS: Our results suggest that FDG PET/MRI is superior to DW-MRI in estimating total spread of carcinomatosis in gynaecological cancer. Further, the greatest advantage of PET/MRI seems to be in patients at primary diagnosis and with high tumour burden, which suggest that it could be a useful tool when deciding about operability in gynaecological cancer.

Peritoneal cancer index predicts severe complications after ovarian cancer surgery.

INTRODUCTION: prediction and importance of severe postoperative complications after ovarian cancer surgery is a strong issue in patient selection and evaluation. Pre- and early peroperative predictors of severe 30-days postoperative complications (Clavien-Dindo class ≥3) after surgery for primary ovarian cancer are not fully established, neither their impact on patients' survival. MATERIALS AND METHODS: A prospective observational study included 256 patients with primary ovarian cancer FIGO stages IIB-IV, operated during 2009-2018 in a primary or interval debulking surgery setting. Patient variables were analysed in relation to severe postoperative complications (Clavien-Dindo class ≥3) and overall survival. RESULTS: High-grade postoperative complications occurred in 24.2% patients. Class 3a complications were observed in 12.5% cases. High-grade complications class ≥3 were observed in 31.6% after primary debulking surgery compared to 12.2% after interval debulking surgery (p = 0.0004). Peritoneal cancer index ≥21 and preoperative albumin concentration ≤33 g/L were independent predictors of high-grade complications. Peritoneal cancer index correlated with the surgical complexity score and completeness of cytoreduction. Increased peritoneal cancer index was a negative predictor of overall survival, but high-grade complications did not influence survival negatively. CONCLUSIONS: Peritoneal cancer index ≥21 was an independent predictor of high-grade complications after ovarian cancer surgery. Increased peritoneal cancer index also impacted overall survival negatively, but high-grade complications did not influence overall survival.

DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets.

BACKGROUND: The epigenetics of ovarian carcinogenesis remains poorly described. We have in the present study investigated the promoter methylation status of 13 genes in primary ovarian carcinomas (n = 52) and their in vitro models (n = 4; ES-2, OV-90, OVCAR-3, and SKOV-3) by methylation-specific polymerase chain reaction (MSP). Direct bisulphite sequencing analysis was used to confirm the methylation status of individual genes. The MSP results were compared with clinico- pathological features. RESULTS: Eight out of the 13 genes were hypermethylated among the ovarian carcinomas, and altogether 40 of 52 tumours were methylated in one or more genes. Promoter hypermethylation of HOXA9, RASSF1A, APC, CDH13, HOXB5, SCGB3A1 (HIN-1), CRABP1, and MLH1 was found in 51% (26/51), 49% (23/47), 24% (12/51), 20% (10/51), 12% (6/52), 10% (5/52), 4% (2/48), and 2% (1/51) of the carcinomas, respectively, whereas ADAMTS1, MGMT, NR3C1, p14ARF, and p16INK4a were unmethylated in all samples. The methylation frequencies of HOXA9 and SCGB3A1 were higher among relatively early-stage carcinomas (FIGO I-II) than among carcinomas of later stages (FIGO III-IV; P = 0.002, P = 0.020, respectively). The majority of the early-stage carcinomas were of the endometrioid histotype. Additionally, HOXA9 hypermethylation was more common in tumours from patients older than 60 years of age (15/21) than among those of younger age (11/30; P = 0.023). Finally, there was a significant difference in HOXA9 methylation frequency among the histological types (P = 0.007). CONCLUSION: DNA hypermethylation of tumour suppressor genes seems to play an important role in ovarian carcinogenesis and HOXA9, HOXB5, SCGB3A1, and CRABP1 are identified as novel hypermethylated target genes in this tumour type.

NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma.

We studied the clinical role of leukocyte infiltration and chemokine receptor expression in ovarian carcinoma effusions. Expression of leukocyte markers (CD3, CD4, CD8, CD4/CD8 ratio, CD16, CD19, and CD14) and chemokine receptors (CXCR1, CXCR4, CCR2, CCR5, and CCR7) was studied in 73 effusions by using flow cytometry. CXCR4, CCR5, and CCR7 were expressed abundantly on leukocytes, but all receptors were expressed rarely on cancer cells. The presence of natural killer cells (P = .042) and International Federation of Gynecology and Obstetrics (FIGO) stage IV disease (P = .024) predicted worse overall survival (OS). A higher percentage of CD19+ cells (P = .015) and stage IV disease (P = .008) predicted poor survival for patients with postchemotherapy effusions. Only FIGO stage retained significance as a predictor of OS (P = .035) in multivariate analysis. Chemokine receptors are expressed widely on leukocytes but rarely on carcinoma cells in ovarian carcinoma effusions, arguing against an autocrine chemokine pathway in this malignancy. Immune response parameters in ovarian cancer effusions are weak predictors of outcome.

Expression of E-cadherin transcriptional regulators in ovarian carcinoma.

Unlike most epithelial cancers, E-cadherin expression is upregulated in ovarian carcinoma effusions compared with corresponding primary tumors. In the present study, we analyzed the anatomic site-specific expression of transcription factors that negatively regulate E-cadherin in ovarian carcinoma. Using reverse-transcription polymerase chain reaction, mRNA in situ hybridization, and Western blotting, we analyzed the expression and localization of the Snail, Slug, and SIP1 transcription factors and E-cadherin in 78 effusions, 41 primary carcinomas, and 15 solid metastases. Slug mRNA and protein expression was highest in metastases (p=0.042 and p<0.001, respectively). Snail mRNA was comparable at all anatomic sites, but higher protein expression was found in primary tumors and solid metastases compared with effusions (p<0.001). SIP1 mRNA expression was higher in effusions (p<0.001) compared to other sites. Confocal microscopy analysis of fresh and cultured cells from effusion specimens revealed cytoplasmic localization of the Snail protein in primary tumor cells, with a nuclear shift following culturing of these cells. In conclusion, E-cadherin and its negative regulators show site-dependent expression in ovarian carcinoma. In solid tumors, E-cadherin is negatively regulated by Snail and Slug. In effusions, SIP1 may be the main regulator of E-cadherin, but with a lesser level of suppression compared with primary tumors and solid metastases.

Death receptor expression is associated with poor response to chemotherapy and shorter survival in metastatic ovarian carcinoma.

BACKGROUND: Death receptors mediate both apoptosis and survival in cancer cells. The authors analyzed death receptor expression in metastatic ovarian carcinoma. METHODS: Viable tumor cells in ovarian carcinoma effusions (n = 95) were analyzed for DR4, DR5, Fas, TNFR1, and TNFR2 expression using flow cytometry. Results were analyzed for association with clinicopathologic parameters, chemotherapy response, and survival. RESULTS: DR4, DR5, and Fas were expressed by the majority of specimens, with less frequent expression of TNFR1 and TNFR2. DR4 (P = .005) and TNFR2 (P = .041) expression was higher in FIGO stage IV compared with stage III tumors. Effusions from patients who responded poorly to chemotherapy administered at disease recurrence had significantly higher DR4 (P = .006), DR5 (P = .01), and Fas (P = .001) expression. In univariate survival analysis, higher DR4 expression in viable cells correlated with poor overall (P = .0352) and progression-free (P = .0411) survival. DR4 expression was found to be an independent predictor of overall (P = .008) and progression-free (P = .003) survival. CONCLUSIONS: The authors have presented the first evidence of death receptor coexpression in ovarian carcinoma effusions. The association of death receptor expression in effusions with advanced stage, poor response to chemotherapy, and shorter survival suggests that these molecules are linked to an aggressive clinical course in metastatic ovarian carcinoma.

Low-molecular weight forms of cyclin E differentiate ovarian carcinoma from cells of mesothelial origin and are associated with poor survival in ovarian carcinoma.

BACKGROUND: The authors recently reported on the role of cyclin E in differentiating ovarian/primary peritoneal carcinoma from malignant peritoneal mesothelioma using gene expression arrays. In the current study, they analyzed the expression of low-molecular weight (LMW) forms of cyclin E in ovarian carcinoma, malignant mesothelioma, and benign reactive effusions. METHODS: Cyclin E protein expression was analyzed in 98 effusions (72 ovarian carcinomas, 14 malignant mesotheliomas, and 12 reactive specimens) using immunoblotting. Sixty-two ovarian carcinoma effusions were studied further for cyclin E expression using immunohistochemistry. The correlations between cyclin E expression in ovarian carcinoma and clinical parameters, including chemotherapy response, were analyzed. RESULTS: LMW forms of cyclin E were identified in 54 of 72 ovarian carcinoma effusions (75%) compared with 1 of 14 malignant mesothelioma effusions (7%) and 1 of 12 reactive effusions (8%) (P < .001). Their presence in ovarian carcinoma was associated with a higher percentage of cyclin E-positive cells (P = .001) and increased staining intensity (P < .001) using immunohistochemistry. The presence of LMW forms of cyclin E was correlated with shorter overall survival (P = .021) and progression-free survival (P = .020). The presence of a higher percentage of cyclin E-positive cells using immunohistochemistry was correlated with shorter progression-free survival (P = .026). No association with chemotherapy response was observed. CONCLUSIONS: LMW forms of cyclin E differentiated ovarian carcinoma from benign and malignant mesothelial cells and were associated with increased protein expression using immunohistochemistry. The expression of LMW cyclin E forms was not associated with chemotherapy response, although it may be a marker of aggressive disease in patients with metastatic ovarian carcinoma.

Nuclear expression of survivin is associated with improved survival in metastatic ovarian carcinoma.

BACKGROUND: Inhibitor of apoptosis proteins (IAPs) mediate cancer cell survival and chemoresistance. The expression of XIAP, Survivin, and Livin in ovarian carcinoma was analyzed. METHODS: Effusions (106) were analyzed for XIAP, Survivin, and Livin expression using immunoblotting. Effusions (220), corresponding primary tumors (60), and solid metastases (103) were further immunohistochemically analyzed for XIAP and Survivin expression. The results were analyzed for association with anatomic site, clinicopathologic parameters, and survival. RESULTS: Immunoblotting showed frequent expression of XIAP and Survivin, and no expression of Livin. Immunohistochemistry showed cytoplasmic XIAP expression in 208 of 220 (94%) effusions, 50 of 60 (83%) primary tumors, and 87 of 103 (84%) solid metastases, with a significantly higher staining extent in effusions (P < .001). Cytoplasmic Survivin was found in 194 of 220 (88%) effusions, 55 of 60 (92%) primary tumors, and 102 of 103 (99%) solid metastases, with a significantly higher cytoplasmic staining extent in solid metastases (P = .018 and P = .006 compared with primary tumors and effusions, respectively). Nuclear Survivin was expressed in 159 of 220 (72%) effusions, 54 of 60 (90%) primary carcinomas, and 96 of 103 (93%) solid metastases (P > .05). For patients with prechemotherapy effusions, higher nuclear Survivin expression correlated with better progression-free (P = .0003) and overall (P = .002) survival in univariate survival analysis. Nuclear Survivin expression was found to be an independent predictor of progression-free survival (P = .004). CONCLUSIONS: XIAP and Survivin, but not Livin, are frequently expressed in ovarian carcinoma. XIAP and cytoplasmic Survivin are up-regulated in effusions and solid metastases, respectively, possibly mediating survival at these sites. Nuclear Survivin expression predicts better outcome in prechemotherapy patients.

The EPH receptor Bs (EPHBs) promoters are unmethylated in colon and ovarian cancers.

Aberrant expression of EPH receptors and their ligands, ephrins, has been reported in a large variety of human cancers, including epithelial cancers from the colon and ovary. Due to the recently reported decrease or loss of EPHBs expression in colorectal carcinomas and the abundance of CpG sites in their promoters, we analyzed the promoter methylation status of three members of the EPHB family, EPHB2, EPHB3 and EPHB4, in a series of 22 colon cancer cell lines, as well as in four ovarian cancer cell lines and 56 ovarian tumor samples. The promoters of the three receptor genes were unmethylated in the vast majority of samples as assessed by methylation-specific polymerase chain reaction (MSP). These results were confirmed by direct bisulphite sequencing. Furthermore, from RT-PCR analyzes and Northern blotting, EPHB2 showed only small variation in RNA expression across ovarian cancer cell lines and clinical samples. We conclude that promoter hypermethylation of EPHB2, EPHB3 and EPHB4 is not a common event in colon and ovarian cancers and therefore plays no major role in these tumors.

Colposcopic and histopathologic evaluation of women participating in population-based screening for human papillomavirus deoxyribonucleic acid persistence.

OBJECTIVE: Evaluation of colposcopic and histopathological findings in women screened for cervical human papillomavirus deoxyribonucleic acid persistence. STUDY DESIGN: A total of 12 527 women, aged 32 to 38 years old, attending the population-based cervical cancer screening program in Sweden were randomized 1:1 to mock testing or human papillomavirus deoxyribonucleic acid testing by general primer 5+/6+ polymerase chain reaction and subsequent typing. Human papillomavirus deoxyribonucleic acid-positive women with a normal Papanicolaou smear (n=341) and an equal number from the control group were human papillomavirus tested on average 19 months later. One hundred nineteen women with type-specific human papillomavirus persistence and 111 controls were referred to colposcopy, and 84.8% attended. RESULTS: Histopathology from colposcopically directed biopsies confirmed cervical intraepithelial neoplasia grade 2 or 3 in 28 of 100 of the women with human papillomavirus deoxyribonucleic acid persistence and in 2 of 95 among controls. CONCLUSION: Among women with normal Papanicolaou smear attending population-based screening, the positive predictive value of human papillomavirus deoxyribonucleic acid persistence for detection of biopsy-confirmed cervical intraepithelial neoplasia 2 or 3 was 29%.

Chlamydia trachomatis infection and persistence of human papillomavirus.

Human papillomavirus (HPV) persistence is the major cause of cervical cancer, but most HPV infections will not persist and risk factors for HPV persistence are not well known. Chlamydia (C.) trachomatis infection seems to also be associated with cervical cancer. We investigated whether C. trachomatis infection is a risk factor for HPV persistence. In a cohort of 12,527 women participating in a population-based HPV screening trial in Sweden, 6,418 women completed testing for HPV DNA by general primer PCR and typing by reverse dot blot hybridization. On average 19 months later, 303 women that had been HPV-positive and had normal cytology at enrollment completed a new HPV test. Environmental exposures were assessed by an 87-item questionnaire. Previous sexually transmitted infections were also investigated by serology. At follow-up, 44% of the women were positive for the same type of HPV DNA as at enrollment. Persistence correlated with length of follow-up (p < 0.01) and condom use seemed to protect against HPV persistence (p < 0.05). The most significant risk factor for persistent presence of HPV DNA was self-reported history of previous C. trachomatis infection (relative risk in multivariate model = 2.09; 95% confidence interval = 1.05-4.18). We conclude that persistence of oncogenic HPV infections is more likely among women with a previous C. trachomatis infection.

Clustering of seropositivities for sexually transmitted infections.

BACKGROUND: Serology for different sexually transmitted infections (STIs) is useful for epidemiologic studies on the spread of STIs in different populations. Studying whether seropositivities for different STIs cluster could be useful, both for development of improved serologic markers of sexual behavior in populations and for understanding how STIs may differ in terms of the dynamics of their spread. GOAL: To evaluate the degree of clustering of different STIs in relation to sexual history. STUDY DESIGN: An age- and sexual history-stratified subsample of 275 women from a survey of healthy Swedish women seeking contraceptive advice was tested for human papillomavirus (HPV) types 6, 11, 16, 18, and 33; Chlamydia trachomatis; herpes simplex virus 2 (HSV-2); and human herpesvirus 8. RESULTS: Significant clustering was observed only for HPV types 6 and 11; for HPV types 16, 18, and 33; and for C trachomatis and HSV-2. The serologic marker that correlated best with lifetime number of sex partners was HPV type 16 (odds ratio [OR], 10.2; 95% CI, 3.8-27.6). The combined serologic marker that correlated most highly with sexual history was joint positivity for HPV types 16 and 33 (OR, 25.5; 95% CI, 5.4-120.4). CONCLUSIONS: The degree of clustering between different STIs varies from nonexistent to strong, implying that different STIs commonly have very different transmission dynamics. Certain combinations of STI serologic tests may be useful in epidemiologic studies for predicting sexual behavior in groups.

Serological evidence for protection by human papillomavirus (HPV) type 6 infection against HPV type 16 cervical carcinogenesis.

Human papillomavirus (HPV) exists as more than 100 genotypes. It is not well-established whether the different HPV types interfere with infection or pathogenesis by each other. Possible interactions in cervical carcinogenesis between infection with the most common HPV types (6, 11, 16, 18 and 33) were studied in a seroepidemiological case- control study of 218 women with primary untreated cervical cancer and 219 healthy age-matched control women. As previously shown, HPV-16 seropositivity was associated with cervical cancer risk [odds ratio (OR), 2.39], but HPV-16 was not associated with cervical cancer risk among HPV-6 seropositive women (OR, 1.0). The relative excess risk due to interaction between HPV-6 and -16 was -2. 35 (95% confidence interval, -0.04 to -4.65), indicating significant antagonism. The results suggest that infection with HPV-6 may interfere with HPV-16-associated cervical carcinogenesis.

Evaluation of antibodies to human papillomavirus as prognostic markers in cervical cancer patients.

OBJECTIVES: We wished to evaluate whether the presence of antibodies to HPV or to the HPV oncoproteins E6 and E7 or type of HPV DNA is related to prognosis among cervical cancer patients. METHODS: Blood samples were drawn from 313 patients with incident, untreated cervical cancer on admission to two hospitals in Sweden. Patients were followed from enrollment in 1984-1991 until death or up to June 1999. Clinical information was obtained from a review of medical records. Survival and cause of death were ascertained from both medical records and population-based cancer registries. The correlation of survival with antibodies to HPV16, to oncoproteins E6 and E7, and to type of HPV DNA was evaluated using multivariate Cox regression analysis, including stage, age, histology, and hospital in the model. RESULTS: Stage was the only significant prognostic factor influencing cervical cancer patient survival (OR = 3.62, 95% CI = 2.71-4.83). Age over 50 was associated with increased death rate among stage I-IIa patients (OR = 2.29, 95% CI = 1.12-4.68). Presence of antibodies to the oncoproteins E6 and E7 or to the HPV16 capsid or type of HPV DNA did not associate significantly with disease prognosis. CONCLUSIONS: Antibodies to HPV16 capsids and to oncoproteins E6 and E7 or type of HPV DNA do not appear to be useful as indicators of cervical cancer prognosis.

A population-based study of cervical carcinoma and HPV infection in Latvia.

OBJECTIVES: We wished to quantify the population-based importance of cervical carcinoma risk factors in Latvia. METHODS: Totally, 223 of 224 eligible cases of incident invasive cervical carcinoma were enrolled during July 1998-February 2001 in Latvia. An age-matched sample of 300 healthy control women was selected from the Latvian population registry and 239 of these women (79%) were enrolled. A demographic and life-style questionnaire was completed, cervical brush samples were analyzed for human papillomavirus (HPV) DNA by PCR and serum samples for HPV antibodies. RESULTS: Risk factors for cervical cancer in multivariate analysis were HPV type 16 or 18 DNA positivity (OR = 32.4; CI 95% 16.5-63.6) and living in the capital (OR = 2.4; CI 95% 1.2-4.7). Oral contraceptive use was not a risk factor (OR = 0.4; CI 95% 0.2-1.1). A strong protective effect was found for having had more than three Pap smears in the last 5 years (OR = 0.07 CI 95% 0.03-0.19). CONCLUSIONS: Inadequate population coverage of Pap smears, in spite of excessive smear usage, caused 28.4% of cervical cancers in age groups eligible for screening. HPV type 16 infection was the most important risk factor for cervical cancer in Latvia, with a population-attributable risk percent for all ages of 58.5%.