Alexander J. Crandon

Peritoneal cytology: impact on disease-free survival in clinical stage I endometrioid adenocarcinoma of the uterus

The prognostic significance of positive peritoneal cytology in endometrial carcinoma has led to the incorporation of peritoneal cytology into the current FIGO staging system. While cytology was shown to be prognostically relevant in patients with stage II and III disease, conflicting data exists about its significance in patients who would have been stage I but were classified as stage III solely and exclusively on the basis of positive peritoneal cytology (clinical stage I). Analysis was based on the data of 369 consecutive patients with clinical stage I endometrioid adenocarcinoma of the endometrium. Standard treatment consisted of an abdominal total hysterectomy, bilateral salpingo-oophorectomy with or without pelvic lymph node dissection. Peritoneal cytology was obtained at laparotomy by peritoneal washing of the pouch of Douglas and was considered positive if malignant cells could be detected regardless of the number of malignant cells present. Disease-free survival (DFS) was considered the primary statistical endpoint. In 13/369 (3.5%) patients, positive peritoneal cytology was found. The median follow-up was 29 months and 15 recurrences occurred. Peritoneal cytology was independent of the depth of myometrial invasion and the grade of tumour differentiation. Patients with negative washings had a DFS of 96% at 36 months compared with 67% for patients with positive washings (log-rank P<0.001). The presence of positive peritoneal cytology in patients with clinically stage I endometrioid adenocarcinoma of the endometrium is considered an adverse prognostic factor.

Microinvasive Adenocarcinoma of the Cervix

Summary: We evaluated the management of patients with microinvasive adenocarcinoma of the cervix (MIAC), in particular, to determine the place of conservative surgery, and determine if the FIGO classification for MIAC is valid and equivalent to the classification as it applies to microinvasive squamous cancer. A review was undertaken of the database of the Queensland Centre for Gynaecological Cancer (QCGC) from January, 1986 to October, 1998. The records of all patients recorded as having MIAC were retrieved. Microinvasion was defined according to the 1995 FIGO classification as a depth of invasion of no greater than 5 mm and a horizontal dimension of no greater than 7 mm. 30 patients were found to have been treated for MIAC. The vast majority (29) were asymptomatic, disease being discovered at the time of routine Papanicolaou smear. There was a 43% incidence of coexisting squamous intraepithelial neoplasia. Multifocal disease was found in 17% of patients and lymph‐vascular positivity in 7%. Eighteen patients were treated with radical surgery and 13 with conservative surgery. There were no recurrences over a follow‐up interval of 3–116 months. Of the 18 patients treated with radical surgery, none was found to have occult microscopic disease in the parametria or nodal metastases. A total of 27 ovaries were removed, all of which were free of disease. In this small study, MIAC appears to behave in a manner similar to the squamous equivalent. The results provide some justification for the FIGO classification of a microinvasive glandular neoplasm of the cervix. There is some support for a role for conservative surgery in managing this condition, but there is insufficient worldwide experience to make definitive recommendations.

EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface.

Many cancers are dependent on inappropriate activation of epidermal growth factor receptor (EGFR), and drugs targeting this receptor can improve patient survival, although benefits are generally short-lived. We reveal a novel mechanism linking EGFR and the membrane-spanning, cancer-promoting protein CDCP1 (CUB domain-containing protein 1). Under basal conditions, cell surface CDCP1 constitutively internalizes and undergoes palmitoylation-dependent degradation by a mechanism in which it is palmitoylated in at least one of its four cytoplasmic cysteines. This mechanism is functional in vivo as CDCP1 is elevated and palmitoylated in high-grade serous ovarian tumors. Interestingly, activation of the EGFR system with EGF inhibits proteasome-mediated, palmitoylation-dependent degradation of CDCP1, promoting recycling of CDCP1 to the cell surface where it is available to mediate its procancer effects. We also show that mechanisms inducing relocalization of CDCP1 to the cell surface, including disruption of its palmitoylation and EGF treatment, promote cell migration. Our data provide the first evidence that the EGFR system can function to increase the lifespan of a protein and also promote its recycling to the cell surface. This information may be useful for understanding mechanisms of resistance to EGFR therapies and assist in the design of treatments for EGFR-dependent cancers.

Dietary folate and related micronutrients, folate-metabolising genes, and ovarian cancer survival.

OBJECTIVEnFolate is essential for DNA synthesis and methylation and is implicated in tumour progression. Few studies have examined its role in ovarian cancer survival. Our objective was to determine relationships between intake of folate, related one-carbon nutrients, single nucleotide polymorphisms (SNPs) in folate-metabolising genes and survival following ovarian cancer diagnosis.nnnMETHODSnThis analysis included 1270 women with invasive epithelial ovarian cancer diagnosed in 2002-2006. Pre-diagnostic and some post-diagnostic lifestyle, dietary, and sociodemographic information was collected via self-administered questionnaires. DNA samples were genotyped for SNPs in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR) genes. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression.nnnRESULTSnMultivariate analyses did not identify associations between higher pre-diagnostic intake of folate, folic acid, vitamins B2, B6, and B12, methionine, betaine or choline and survival overall. In stratified analyses, higher folic acid and folate intake was associated with significantly worse survival among women with mucinous tumours (HRs per 100 μg 1.30 and 1.43, respectively) and smokers (HRs per 100 μg 1.23 and 1.16 respectively). There was also a suggestion that higher supplemental folic acid use post-diagnosis was associated with worse survival (HR per 100 μg 1.03, 95%CI 1.00-1.05). MTHFR SNP rs2066470 was significantly associated with survival (per allele HR 0.81, 95%CI 0.67-0.98).nnnCONCLUSIONSnOur data provide little evidence that folate intake affects ovarian cancer survival. However, combined effects with smoking, and findings within the mucinous subtype and for post-diagnosis folic acid, warrant further investigation.

Cell line and patient-derived xenograft models reveal elevated CDCP1 as a target in high-grade serous ovarian cancer

Background:Development of targeted therapies for high-grade serous ovarian cancer (HGSC) remains challenging, as contributing molecular pathways are poorly defined or expressed heterogeneously. CUB-domain containing protein 1 (CDCP1) is a cell-surface protein elevated in lung, colorectal, pancreas, renal and clear cell ovarian cancer.Methods:CUB-domain containing protein 1 was examined by immunohistochemistry in HGSC and fallopian tube. The impact of targeting CDCP1 on cell growth and migration in vitro, and intraperitoneal xenograft growth in mice was examined. Three patient-derived xenograft (PDX) mouse models were developed and characterised for CDCP1 expression. The effect of a monoclonal anti-CDCP1 antibody on PDX growth was examined. Src activation was assessed by western blot analysis.Results:Elevated CDCP1 was observed in 77% of HGSC cases. Silencing of CDCP1 reduced migration and non-adherent cell growth in vitro and tumour burden in vivo. Expression of CDCP1 in patient samples was maintained in PDX models. Antibody blockade of CDCP1 significantly reduced growth of an HGSC PDX. The CDCP1-mediated activation of Src was observed in cultured cells and mouse xenografts.Conclusions:CUB-domain containing protein 1 is over-expressed by the majority of HGSCs. In vitro and mouse model data indicate that CDCP1 has a role in HGSC and that it can be targeted to inhibit progression of this cancer.

Advanced cytoreductive surgery: Asia Pacific perspective.

The thoroughness of cytoreductive surgery is the largest contributor to survival for patients with advanced ovarian and primary peritoneal carcinoma. For many years the surgery undertaken by Gynaecologic Oncologists has been tailored to match their surgical training. Future surgical training of Gynaecologic Oncologists needs to be tailored to the surgery required to provide complete tumour removal to no residual disease. This means the better teaching of anatomy and an increased scope of surgery to include the general and upper abdominal procedures and management required. This paradigm shift will be a challenge for all and impossible for some. It will require a significant mind-shift not only from our craft group and the profession at large but especially from the speciality Colleges who will need to take these changes on board for future curriculum development. The development of Advanced Cytoreductive Surgical Units needs to be undertaken in a team environment. This requires a commitment from participants at all levels, from the lead oncology surgeon through the hospital administration to the support services involved. While advanced cytoreductive surgery is feasible, it is only in this team environment, limited to major multidisciplinary hospitals, that it can be safely achieved by meticulous attention to detail at all levels.

L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution

LINE-1 (L1) retrotransposons are a source of insertional mutagenesis in tumor cells. However, the clinical significance of L1 mobilization during tumorigenesis remains unclear. Here, we applied retrotransposon capture sequencing (RC-seq) to multiple single-cell clones isolated from five ovarian cancer cell lines and HeLa cells and detected endogenous L1 retrotransposition inxa0vitro. We then applied RC-seq to ovarian tumor and matched blood samples from 19 patients and identified 88 tumor-specific L1 insertions. In one tumor, an intronic de novo L1 insertion supplied a novel cis-enhancer to the putative chemoresistance gene STC1. Notably, the tumor subclone carrying the STC1 L1 mutation increased in prevalence after chemotherapy, further increasing STC1 expression. We also identified hypomethylated donor L1s responsible for new L1 insertions in tumors and cultivated cancer cells. These congruent inxa0vitro and inxa0vivo results highlight L1 insertional mutagenesis as a common component of ovarian tumorigenesis and cancer genome heterogeneity.

Surgical Management of Abnormally Invasive Placenta: A Retrospective Cohort Study Demonstrating the Benefits of a Standardized Operative Approach

Multiple reports have identified risk factors for retained placenta to include induction of labor, multiparty, a history of retained placenta, previous dilatation and curettage, preterm delivery, and small placental weight.1–3 This study comprised an extensive database review and found independent risk factors for retained placenta regardless of parity to be stillbirth, maternal age 30 years or above, delivery at 24 weeks to almost 28 weeks compared with 34 weeks or later, and delivery in a teaching hospital. In nulliparous women, additional risk factors included longer first-stage or second-stage labor duration, and nonHispanic black compared with non-Hispanic white race was found to be protective. Furthermore, the study found that women with retained placenta had a significantly higher rate of postpartum hemorrhage than women without a retained placenta. However, no significant difference was found in the rate of postpartum blood transfusion between the women with a retained placenta and women without a retained placenta. Reasons for older maternal age being a risk factor is with increasing age comes the greater likelihood of having more comorbidities and hence more placental stress.1,3 The authors state it is unknown whether the placental stress that occurs with advanced age is associated with a decreased quality of placentation, or a difference in angiogenesis, which may be responsible for the increased risk of having a retained placenta. Multiparty increases the likelihood of having had more operative procedures with subsequent uteroplacental pathologic deficits. Specifically, Horn et al4 found 62% of stillbirths were caused by placenta pathology, and more frequently detected histopathologic lesions. Early preterm delivery is associated with placental immaturity and increases the likelihood for retained placenta.1,3 Chorioamnionitis is a well-known etiology for preterm delivery. In nulliparity, longer labor length is associated with more delivery complications. Teaching hospitals frequently care for a greater proportion of high-risk patients who may have confounding risk factors for retained placenta accounting for why delivery in a university affiliated hospital is a significant risk factor. The authors’ state these factors are minimally modifiable. However, early risk factor identification can benefit the patient regarding medical counseling and expectations, and also allow the clinician to be better prepared and ready for retained placenta complications such as postpartum hemorrhage, as well as any additional surgical interventions that frequently may be needed.

EGF-induced recycling of the cancer promoting protein CDCP1

15th International Biennial Congress of the METASTASIS RESEARCH SOCIETY Heidelberg, Germany, June 28th–July 1st, 2014 Springer Science+Business Media Dordrecht 2015

The impact of positive peritoneal washings and serosal and adnexal involvement on survival in patients with stage IIIA uterine cancer

OBJECTIVEnThe aim of this study was to determine the prognostic significance of serosal involvement (SER), adnexal involvement (ADN), and positive peritoneal washings (PPW) in patients with Stage IIIA uterine cancer. We also sought to determine patterns of recurrence in patients with this disease.nnnMETHODSnThe records of 136 patients with Stage IIIA uterine cancer treated at the Queensland Centre for Gynecological Cancer between March 1983 and August 2001 were reviewed. One hundred thirty-six patients underwent surgery and 58 (42.6%) had full surgical staging. Seventy-five patients (55.2%) had external beam radiotherapy and/or brachytherapy postoperatively. Overall survival was the primary statistical endpoint. Statistical analysis included univariate and multivariate Cox models.nnnRESULTSnForty-six patients (33.8%) had adnexal involvement, 23 (16.9%) had serosal involvement, and 40 (29.4%) had positive peritoneal washings. Median follow-up was 55.1 months (95% confidence interval, 36.9 to 73.4 months) after which time 71 patients (52.2%) remained alive. For patients with endometrioid adenocarcinoma, ADN and SER were associated with impaired survival on multivariate analysis (odds ratio 2.8 and 3.2, respectively). In the subgroup of patients with high-risk tumors (including papillary serous carcinomas, clear cell carcinomas, and uterine sarcomas), neither ADN, nor SER, nor PPW influenced survival.nnnCONCLUSIONnPatients with Stage IIIA uterine cancer constitute a heterogeneous group. For patients with endometrioid adenocarcinoma, both ADN and SER, but not PPW, were associated with impaired prognosis. For patients with high-risk histological types, prognosis is poor for all three factors.