Improvements in progression-free and overall survival due to the use of anti-angiogenic agents in gynecologic cancers.

OPINION STATEMENT: In ovarian cancer (OC), the best established anti-angiogenic drug, bevacizumab, has demonstrated only modest prolonged progression free survival (PFS) and no increased overall survival (OS). The unanswered question is in which clinical situation bevacizumab might benefit ovarian cancer patients most. The cost-benefit analysis in the primary treatment was found not to be favorable but the use in the recurrent OC setting might be more compelling. Multi-targeted anti-angiogenic tyrosine kinase inhibitors (TKI) such as cediranib and pazopanib have shown some therapeutic benefits with improvements of PFS and OS in patients with platinum-sensitive as well as resistant OC, in whom there is a major need for novel therapies. Very promising is also the observed improvement of PFS in recurrent OC in patients when combining cediranib with the PARP inhibitor olaparib without giving additional chemotherapy. The anti-angiogenic agent trebananib has achieved similar results like TKI, but has a favorable toxicity profile which does not overlap with those of VEGF inhibitors. In cervical cancer the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent or metastatic chemotherapy-naive disease results in a significant increase in OS. Considering the lack of therapeutic options in this difficult clinical setting, the inclusion of bevacizumab most likely will become a new standard for recurrent cervical cancer. In uterine sarcomas as very aggressive malignancies with a substantial need for better therapies the observed improved PFS with sorafenib warrants further investigation. No data showing a convincing improvement of survival in endometrial cancer have been presented yet. In view of the limited PFS and OS benefit observed with anti-angiogenics in gynecologic oncology, increased morbidity due to side effects of this treatment resulting in loss of quality of life and also substantial costs have to be taken into consideration. Thorough case selection based on molecular subgrouping of gynecologic cancers will therefore be a prerequisite for future anti-angiogenic therapy. This will require the integration of molecular diagnostics which still have to be developed and standardized.

Macrosomic and low birth weight neonates in Pacific Islanders from Samoa: a case-control study.

BACKGROUND: To assess the perinatal morbidity and mortality of macrosomic (>4500 g) and low birth weight (LBW) (<2500 g) neonates in a Pacific Islander population (PIP) from Samoa compared to a Caucasian population (CP). METHODS: Case-control study. Clinical data were extracted by chart review. RESULTS: In 3166 (PIP) and 2101 (CP) deliveries, macrosomia was more prevalent and LBW less prevalent in the PIP [76/3166 (2.4 %) vs. 21/2101 (0.9 %); p < 0.0001 and 149/3166 (4.7 %) vs. 163/2101 (7.7 %); p < 0.0001, respectively]. Among macrosomic neonates, perinatal mortality and composite severe neonatal morbidity (CNM) were higher in the PIP compared to the CP [2/76 (3 %) vs. 0/21 (0 %) and 6/76 (7 %) vs. 1/21 (4 %), respectively]. Among LBW neonates, mortality, but not CNM, was significantly higher in the PIP [16/149 (7 %) vs. 2/163 (1 %), p < 0.0001 and 10/149 (6 %) vs. 5/163 (3 %), p = 0.2, respectively]. The proportion of macrosomic neonates transferred to the Neonatal Intensive Care Unit was significantly higher in the PIP [50/76 (65 %) vs. 0/21 (0 %), p < 0.0001]. Age, body mass index, and delivery mode did not independently predict CNM. CONCLUSION: Samoan women have higher rates of macrosomia and lower rates of LBW compared to Caucasians, suggesting an anthropomorphic basis of this phenomenon.

A Preparatory Virtual Reality Experience Reduces Anxiety before Surgery in Gynecologic Oncology Patients: A Randomized Controlled Trial.

Perioperative anxiety is common among patients undergoing surgery, potentially leading to negative outcomes. Immersive virtual reality (VR) has shown promise in reducing anxiety in various clinical settings. This study aimed to evaluate the effectiveness of VR in reducing perioperative anxiety in patients undergoing gynecological oncology surgery and was conducted as a single-center, double-arm, single-blinded randomized controlled trial at the Gold Coast University Hospital, Queensland, Australia. Participants were randomized into the VR intervention + care as usual (CAU) group (n = 39) and the CAU group (n = 41). Anxiety scores were assessed using a six-tier visual facial anxiety scale at baseline, after the intervention/CAU on the same day, and, several days up to weeks later, immediately before surgery. There was no significant difference in baseline anxiety scores, type of operation, or suspected cancer between the two groups. The VR intervention significantly reduced anxiety scores from baseline to preoperative assessment (p < 0.001). The median anxiety score in the VR intervention group decreased from 3 (interquartile range 2 to 5) at baseline to 2 (2 to 3) prior to surgery, while the control group's scores were 4 (2 to 5) and 4 (3 to 5), respectively. Multivariate analysis showed that group assignment was the sole outcome predictor, not age, type of procedure, or the time elapsed until surgery. Thus, VR exposure was effective in reducing perioperative anxiety in patients undergoing gynecological oncology surgery. The use of VR as a preparation tool may improve patient experience and contribute to better surgical outcomes, warranting further research into exploring the potential benefits of VR in other surgical specialties and its long-term impact on patient recovery.

Uterine packing with chitosan-covered gauze for control of postpartum hemorrhage.

OBJECTIVE: To describe the use of gauze covered with chitosan, a potent hemostatic agent derived from chitin, in the treatment of postpartum hemorrhage (PPH). STUDY DESIGN: Patients suffering from postpartum hemorrhage were treated by uterine packing with chitosan-covered gauze, either through the hysterotomy in case of cesarean delivery or transvaginally, for up to 24 hours. RESULTS: Chitosan-covered gauze was used in 19 cases of postpartum hemorrhage due to uterine atony, placenta accreta/increta, or anticoagulation, including 5 severe cases where a hysterectomy seemed inevitable otherwise. In all but one case, the bleeding stopped and further interventions were avoided. Over comparable periods of time (18 months) and births (3822 vs 4077) before and after the introduction of the chitosan gauze in our clinic, the rate of peripartum hysterectomies was reduced by 75% (8 vs 2; odds ratio, 4.27; P = .044). CONCLUSION: Chitosan-covered gauze is a viable option in the treatment of (severe) postpartum hemorrhage. It is easy to use and requires no special training. It can be used after both vaginal and cesarean deliveries, and there are no adverse side effects. Furthermore, it is very inexpensive compared with other treatment options, making it suitable for use also in low resource-countries, where the death toll due to postpartum hemorrhage is especially high.

Postpartum hemorrhage: use of hemostatic combat gauze.

Cheap and simple interventions that are intended to minimize postpartum hemorrhage are of major public health concern. We report a case of postpartum hemorrhage in which conservative interventions had failed. The use of a chitosan-covered gauze that originally was developed for combat trauma allowed us to achieve hemostasis, and a seemingly inevitable hysterectomy was avoided.

Two case studies of cardiac arrest occurring in medically fit patients undergoing radical hysterectomy for cervical cancer.

We report case histories of two young women who had an intraoperative cardiac arrest, potentially caused by preoperative emotional stress, while undergoing open radical hysterectomy for cervical cancer. Neither had any history of heart disease or other comorbidities. Takotsubo cardiomyopathy, a form of stress cardiomyopathy characterized by acute reversible ventricular dysfunction that can occur in the perioperative period, was the cause in one patient. A vasovagal episode during the exploration of the abdomen was the cause in the other. Successful resuscitation and stabilisation of both patients made it possible to continue the surgery and successfully complete both procedures. Takotsubo cardiomyopathy should be considered in any patient showing significant preoperative stress who has a cardiac arrest, even if there is no preoperative morbidity. It is difficult to differentiate from a vasovagal episode intraoperatively. Surgical and anaesthetic teams should be aware of importance of countering severe preoperative stress.

Forced coughing versus local anesthesia and pain associated with cervical biopsy: a randomized trial.

OBJECTIVE: Cervical biopsy often causes discomfort and pain. To compare local anesthesia (1% lidocaine) with forced coughing as pain relief, we quantified the actual pain experienced during cervical punch biopsies. STUDY DESIGN: For a prospective trial conducted at the Medical University of Vienna, 68 women undergoing cervical punch biopsies for assessment of abnormal cervical smears were randomized in 2 pain relief treatment groups. Patients' discomfort was assessed immediately after taking the biopsy using at 10-cm visual analog scale. RESULTS: No statistically significant difference was found between pain scores recorded for the 2 groups (P = .47, 95% confidence interval [CI], -0.4 to 1.3 cm). However, when local anesthesia was applied, the examination was significantly prolonged by a median of 2.11 min (P < .001; 95% CI, 1.6-2.8). CONCLUSION: Forced coughing during cervical biopsies reduces patients' discomfort to the same extent as local anesthesia, but is associated with a significantly reduced examination time.

Examining word association networks: A cross-country comparison of women's perceptions of HPV testing and vaccination.

In this study, we examined the perceptual associations women hold with regard to cervical cancer testing and vaccination across two countries, the U.S. and Australia. In a large-scale online survey, we presented participants with 'trigger' words, and asked them to state sequentially other words that came to mind. We used this data to construct detailed term co-occurrence network graphs, which we analyzed using basic topological ranking techniques. The results showed that women hold divergent perceptual associations regarding trigger words relating to cervical cancer screening tools, i.e. human papillomavirus (HPV) testing and vaccination, which indicate health knowledge deficiencies with non-HPV related associations emerging from the data. This result was found to be consistent across the country groups studied. Our findings are critical in optimizing consumer education and public service announcements to minimize misperceptions relating to HPV testing and vaccination in order to maximize adoption of cervical cancer prevention tools.

Evaluation of MUC1 splice variants as prognostic markers in patients with ductal carcinoma in situ of the breast.

Despite intense research in the field of breast cancer it still remains the most common cancer in women in the Western world. A decreasing trend in mortality was mainly achieved by improved early detection which led to an increased incidence of ductal carcinoma in situ (DCIS) of the breast. For the patient's prognosis and the administration of a patient-tailored therapy strategy it is crucial to identify diagnostic and prognostic markers for high-risk DCIS patients. MUC1 is associated with tumour aggressiveness in human breast cancer. Recent studies used MUC1 splice variant A to identify malignant thyroid cancer. In the present study we have examined the usefulness of MUC1 splice variants as prognostic markers in DCIS. We used laser capture microdissection of paraffin-embedded tissue to isolate RNA from isolated tumour cells and determined the MUC1 splice variant distribution by RT-PCR. In the majority of cases variant B was more highly expressed than variant A. This was true for pure DCIS (66%) as well as for DCIS with adjacent invasive cancer (66%). In 7 out of 18 cases (38%) of pure DCIS variant A was not expressed at all. In DCIS with adjacent invasive cancer only 2 samples out of 12 showed this expression pattern (16%). The situation that variant A was more highly expressed than B, or that variant B was not expressed at all, was similar for pure DCIS (27%) and for DCIS with adjacent invasive cancer (33%). The present study describes the differences of MUC1 splice variant expression in pure DCIS compared to DCIS with adjacent invasive cancer. A discriminating pattern of MUC1 splice variants could not be demonstrated.

New perspectives in ovarian cancer treatment.

Ovarian cancer (OC) is increasingly understood as a heterogeneous disease comprising distinct subtypes of different origin that vary significantly with regard to molecular biology and clinical behaviour. Despite some limited progress in its treatment over the last decade, currently there are few therapeutic options and overall survival remains poor. Increasing knowledge about the molecular biology of ovarian cancer has led to the development of targeted therapies which promise to be more effective and to provide the basis for personalized treatment. The most successful strategies so far are employing anti-angiogenics (VEGF antibodies, tyrosine kinase inhibitors and angiopoietin antagonists) and polyadenosine diphosphate-ribose polymerase (PARP) inhibitors. Other approaches target aberrant OC signalling such as the PI3K/Akt/mTOR network, the epidermal growth factor receptor, the WEE1 tyrosine kinase and the folate receptor alpha. Immunotherapy is another promising new approach against ovarian cancer. In this area, immunotherapeutic modulation by administering autologous immune cells, such as dendritic cells (DCs), to stimulate antitumour host responses is of special interest. Finally, there is now growing evidence from clinical studies showing a survival advantage for intraperitoneal (IP) chemotherapy when compared to conventional intravenous treatment in the adjuvant setting. New strategies such as pressurized IP aerosol chemotherapy might further improve the efficacy of this approach.

Management of nonpregnant women with elevated human chorionic gonadotropin.

Human chorionic gonadotropin (hCG) is useful in evaluating and monitoring early pregnancy as well as trophoblastic disease. Here we describe the management of women with elevated serum human chorionic gonadotropin in a case of a 51-year-old female who was unsuccessfully treated for ectopic pregnancy. She was subsequently diagnosed with pituitary hCG production, which should be considered as differential diagnosis before treatment is initiated.

The neuronal guidance cue Slit2 induces targeted migration and may play a role in brain metastasis of breast cancer cells.

Cell migration is essential in many diverse processes ranging from embryonic development to wound healing and immune response. Cancer cells have recently been shown to utilize chemoattraction mechanisms mediated by chemokines and their respective receptors, e.g., the CXCL12/CXCR4 pathway normally found in leukocytes. Here we show that Slit2, a secreted protein signaling through the Roundabout (Robo) receptor as a chemorepellent in axon guidance and neuronal migration, acts as a potent chemoattractant for breast cancer cells. Comparing cell lines specifically metastasizing to either brain or bone, we found significant differences in their responses to CXCL12 and Slit2 treatments, suggesting a role for Slit/Robo signaling in brain metastasis.

CXCR4 is expressed in ductal carcinoma in situ of the breast and in atypical ductal hyperplasia.

Recent evidence attributed important influence of chemokines and their receptors on motility, homing, and proliferation of cancer cells at specific metastatic sites. Here we report that the CXCL12 (SDF-1alpha) chemokine receptor CXCR4 is expressed in human ductal carcinoma in situ (DCIS) as well as in atypical ductal hyperplasia. CXCR4 was expressed in pure DCIS and DCIS with concurrent invasive disease. In 66% of the samples, atypical ductal hyperplasia was present, and > 92% exhibited positive CXCR4-staining. Expression of CXCR4 at this very early step of tumor development indicates a role of this receptor in providing a selective advantage to such cells on their way to metastasizing carcinomas. These results strengthen the ideas to target chemokine networks involved in tumor progression and metastatis as a therapeutic approach in malignant disease or as a chemoprevention strategy, blocking the transition from premalignancy to malignancy.

Expression of MUC1 splice variants in benign and malignant ovarian tumours.

MUC1 is expressed on the surface of ovarian cancer cells. Nine different splice variants of MUC1 have been described, but no study has reported on the expression of MUC1 isoforms in human ovarian cancer. Our study compares patterns of expression of MUC1 splice variants of malignant and benign ovarian tumours. Ovarian tissue samples were taken from patients with benign ovarian tumours (n = 34) and from patients who had surgery for primary (n = 47) or recurrent (n = 8) ovarian cancer. RT-PCR for MUC1 splice variants A, B, C, D, X, Y, Z, REP and SEC was performed and their expression compared to clinical and histopathologic parameters. Variants A, D, X, Y and Z were more frequently expressed in malignant than in benign tumours. All primary ovarian cancer cases were positive for variant REP but negative for variant SEC. No significant association of the expression of MUC1 splice variants with the response to chemotherapy or patient survival could be demonstrated. Expression of MUC1 splice variants A, D, X, Y, Z and REP is associated with the presence of malignancy, whereas expression of MUC1/SEC is associated with the absence of malignancy.

Expression of MUCI splice variants correlates with invasive growth of breast cancer cell lines.

On the basis of alternative splicing the human breast cancer associated MUCI gene codes for different protein products. MUCI splice variants A and B have been shown to be determined by a single A/G nucleotide polymorphism (SNP) in exon 2 of the MUCI gene. We now describe two new splice variants C and D and show by that in human breast cancer cell lines there is selective co-expression of these variants, namely co-expression of variants A and D. We have found that the expression of variants C and D is also determined by the same SNP in exon 2. Since the overexpression of MUCI proteins has been associated with increased invasive behavior of cancer cell lines, we quantitatively determined the mRNA expression levels of the splice variants A, B, C, and D in breast cancer cell lines and correlated them with the in vitro invasiveness of these cell lines. We revealed a significant correlation between the lack of MUCI splice variants B and C and the invasiveness of the cell lines tested. Furthermore, we showed that concomitant expression of variants A and D is associated with a GG in the genotype. These findings suggest that the invasive behavior of breast cell lines may depend on different expression patterns of the MUCI gene determined by a genetic polymorphism.