Velocity Time Integral: A Novel Method for Assessing Fetal Anemia.

The velocity time integral (VTI) is a clinical Doppler ultrasound measurement of blood flow, measured by the area under the wave curve and equivalent to the distance traveled by the blood. This retrospective study assessed the middle cerebral artery (MCA) VTI of fetuses in pregnancies complicated by maternal alloimmunization. Doppler indices of the MCA were retrieved from electronic medical records. Systolic deceleration-diastolic time, systolic acceleration time, VTI, and peak systolic velocity (PSV) were measured at 16-40 weeks gestation. Cases with PSV indicating fetal anemia (cutoff 1.5 MoM) and normal PSV were compared. The study included 255 Doppler ultrasound examinations. Of these, 41 were at 16-24 weeks (group A), 100 were at 25-32 weeks (group B), and 114 were at 33-40 weeks (group C). VTI increased throughout gestation (5.5 cm, 8.6 cm, and 12.1 cm in groups A, B, and C, respectively, p = 0.003). VTI was higher in waveforms calculated to have MCA-PSV ≥ 1.5 MoM compared to those with MCA-PSV < 1.5 MoM (9.1 cm vs. 14.1 cm, respectively, p < 0.001), as was VTI/s (22.04 cm/s vs. 33.75 cm/s, respectively; p < 0.001). The results indicate that the MCA VTI increases significantly among fetuses with suspected anemia, indicating higher perfusion of hemodiluted blood to the brain. This feasible measurement might provide a novel additional marker for the development of fetal anemia.

The Effect of External Cephalic Version on Fetal Circulation: A Prospective Cohort Study.

External cephalic version (ECV) is a cost-effective and safe treatment option for breech presentation at term. Following ECV, fetal well-being is assessed via a non-stress test (NST). An alternative option to identify signs of fetal compromise is via the Doppler indices of the umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV). Inclusion criteria were an uncomplicated pregnancy with breech presentation at term. Doppler velocimetry of the UA, MCA and DV were performed up to 1 h before and up to 2 h after ECV. The study included 56 patients who underwent elective ECV with a success rate of 75%. After ECV, the UA S/D ratio, UA pulsatility index (PI) and UA resistance index (RI) were increased compared to before the ECV (p = 0.021, p = 0.042, and p = 0.022, respectively). There were no differences in the Doppler MCA and DV before or after ECV. All patients were discharged after the procedure. ECV is associated with changes in the UA Doppler indices that might reflect interference in placental perfusion. These changes are probably short-term and have no detrimental effects on the outcomes of uncomplicated pregnancies. ECV is safe; yet it is a stimulus or stress that can affect placental circulation. Therefore, careful case selection for ECV is important.

Analysis of two topotecan treatment schedules in patients with recurrent ovarian cancer.

Two topotecan treatment schedules in patients with recurrent epithelial ovarian cancer were evaluated. Protocol A (21 days) was 1.5 mg/m(2)/day topotecan on days 1 through 5 of a 21-day cycle; Protocol B (weekly) 4 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Efficacy was determined by clinical exam, CT scan, and CA125 levels. Forty-three patients on Protocol A and 21 on Protocol B were evaluated. As second-line treatment, Protocol A response was 9/20 (45%). Response to Protocol B was 4/17 (23.5%; NS). As third line or more, the response on Protocols A and B together was only 3/27 (11%). High-grade haematological toxicity was reported in 12/43 (27.9%) on Protocol A and 1/21 (4.8%) on Protocol B (p = 0.04). There was no difference in progression-free-intervals between schedules in second-line treatment. The weekly protocol had lower severe haematological toxicity. Clinical response in third line or more was very low.

High Efficacy and Low Toxicity of the Modified Docetaxel and Carboplatin Protocol in Patients with Recurrent Ovarian Cancer-A Phase 2 Cohort Study.

OBJECTIVE: Most patients with epithelial ovarian cancer will experience a recurrence; currently, there is no cure. In patients with platinum-sensitive disease (platinum-free interval >6 months), a combination similar to that used as frontline therapy (carboplatin and paclitaxel) is recommended. However, it is associated with a high incidence (20%) of neurotoxicity. This study evaluated the efficacy and toxicity of combination docetaxel/carboplatin therapy in patients with platinum-sensitive recurrent ovarian cancer. METHODS: Forty patients with recurrent, histologically proven ovarian, fallopian tube, or primary peritoneal cancer were enrolled in this phase 2 trial. The study protocol included combination therapy with docetaxel, 30 mg/m, on days 1 and 8, and carboplatin, area under the curve 5, on day 1, every 21 days. Twenty received the classical paclitaxel/carboplatin regimen (control group), and another 20 received the modified docetaxel/carboplatin protocol (study group). RESULTS: Median follow-up was 78 months for the study group and 62 months for the control group. The study group had a higher overall response rate compared to controls: 80% and 30%, respectively (P = 0.004; relative risk, 9.3; 95% confidence interval, 2.18-39.96). Complete response was achieved in 60% and 25%, respectively (P = 0.054). The study group patients showed a superior 2-year survival rate of 75% compared with the 35% of the controls (P = 0.011; relative risk, 5.57; 95% confidence interval, 1.47-21.56). Hematological and neurological toxicity rates did not differ between the groups (P = 0.451 and P = 0.605, respectively). CONCLUSIONS: Patients with recurrent ovarian cancer who received the modified docetaxel/carboplatin regimen had higher overall response and survival rates compared to those who had the paclitaxel/carboplatin regimen, with no difference in toxicity. Future larger studies should focus on strategies to compare this regimen to the current standard, with an emphasis on quality of life.

Preoperative clinical and radiological features of metastatic ovarian tumors.

PURPOSE: To investigate the clinical characteristics and pre-operative imaging features of non-genital metastatic ovarian tumors. METHODS: A retrospective case series study that compared 18 patients with histologically confirmed non-genital metastatic ovarian tumors (the study group) with 25 patients who were diagnosed with a primary ovarian cancer (control group). RESULTS: The most common primary disease was breast cancer (n = 10; 55 %), followed by colon cancer, gastric cancer, lymphoma, and unknown primary malignancy. The diagnosis of the previous primary neoplasm preceded the ovarian tumor diagnosis by 1-20 years (mean 7 years). No differences were found in the presenting signs and symptoms between the two groups. Statistically significant differences were noted between the two groups in the composition of the adnexal mass on sonography (p < 0.0005) and the CA-125 levels (p = 0.007). The presence of a complex adnexal mass with papillary projections and CA-125 >170 U/ml predicted primary ovarian cancer in 95.7 % of patients. Pre-operative CT scan revealed a greater tendency toward omental involvement and ascites in the control group (p = 0.058). The median risk of malignancy index (RMI) 2 score was significantly higher in the control group compared to the study group (8,000 and 1,120 respectively, p = 0.001). Using a RMI 2 cut-off level of 3,800 for diagnosing primary ovarian cancer versus metastatic ovarian cancer, the sensitivity was 70 %, with a positive predictive value of 87.5 %. CONCLUSION: Pre-operative sonography findings, CA-125 levels and RMI 2 scores can be highly accurate in differentiating between primary and metastatic ovarian tumors.

Brain metastases from endometrial carcinoma.

This paper will focus on knowledge related to brain metastases from endometrial carcinoma. To date, 115 cases were documented in the literature with an incidence of 0.6% among endometrial carcinoma patients. The endometrial carcinoma was usually an advanced-stage and high-grade tumor. In most patients (~90%), brain metastasis was detected after diagnosis of endometrial carcinoma with a median interval from diagnosis of endometrial carcinoma to diagnosis of brain metastases of 17 months. Brain metastasis from endometrial carcinoma was either an isolated disease limited to the brain only (~50%) or part of a disseminated disease involving also other parts of the body (~50%). Most often, brain metastasis from endometrial carcinoma affected the cerebrum (~75%) and was solitary (~60%). The median survival after diagnosis of brain metastases from endometrial carcinoma was 5 months; however, a significantly better survival was achieved with multimodal therapy including surgical resection or stereotactic radiosurgery followed by whole brain radiotherapy (WBRT) and/or chemotherapy compared to WBRT alone. It is suggested that brain imaging studies should be considered in the routine follow up of patients with endometrial carcinoma and that the search for a primary source in females with brain metastases of unknown primary should include endometrial biopsy.

Brain metastases from ovarian carcinoma.

This paper will focus on knowledge related to brain metastases from ovarian carcinoma. So far, less than 600 cases were documented in the literature with an incidence among ovarian carcinoma patients ranging from 0.29% to 11.6%. The ovarian carcinoma was usually an advanced-stage epithelial serous carcinoma, and the median interval between diagnosis of ovarian carcinoma and brain metastases was 2 years. Most often, brain metastases, affected the cerebrum, were multiple and part of a disseminated disease. Treatment of brain metastasis has evolved over the years from whole brain radiotherapy (WBRT) only to multimodal therapy including surgical resection or stereotactic radiosurgery followed by WBRT and/or chemotherapy. The median survival after diagnosis of brain metastases was 6 months; nevertheless, a significantly better survival was achieved with multimodal therapy compared to WBRT only. It is suggested that brain imaging studies should be included in the followup of patients after treatment for ovarian carcinoma.

Randomized trial of tamoxifen versus combined tamoxifen and octreotide LAR Therapy in the adjuvant treatment of early-stage breast cancer in postmenopausal women: NCIC CTG MA.14.

PURPOSE: Somatostatin analogs act directly on breast cancer cells and indirectly on insulin and insulin-like growth factor 1 (IGF-1) levels. This trial was undertaken to assess whether octreotide would lower insulin and IGF-1 levels and reduce risk of breast cancer recurrence. PATIENTS AND METHODS: The NCIC CTG MA.14 (NCIC Clinical Trials Group MA.14) trial randomly assigned postmenopausal women to 5 years of tamoxifen 20 mg daily (TAM) or TAM plus 2 years of octreotide 90 mg depot intramuscular injections monthly (TAM-OCT) as adjuvant therapy. The primary end point was event-free survival (EFS). Secondary end points were relapse-free survival (RFS), overall survival (OS), toxicity, and effects of treatment on IGF physiology. RESULTS: Among 667 women with a median follow-up of 7.9 years, 220 events occurred-108 with TAM-OCT and 112 with TAM. Adjusted hazard ratios (HRs; TAM-OCT to TAM) were 0.93 for EFS (95% CI, 0.71 to 1.22; P = .62), 0.84 for RFS (95% CI, 0.59 to 1.18; P = .31), and 0.97 for OS (95% CI, 0.69 to 1.37; P = .86). Among patients with normal baseline gallbladder imaging, cholecystectomy was required in 23.0% of those receiving TAM-OCT but in only 1.4% of those receiving TAM (P < .001). At 4 months, TAM-OCT had significantly (P < .001) lowered IGF-1, IGF binding protein 3, and C-peptide levels. Older age (P = .02), tumor size (P = .001), nodal status (P = .01), high C-peptide levels (P < .001), and higher body mass index (BMI) in models excluding C-peptide (P < .001) were associated with poorer EFS in multivariate analysis. CONCLUSION: Octreotide-related changes in circulating IGF-1 and C-peptide levels were statistically significant. Octreotide did not add significant clinical benefit. High C-peptide levels (surrogate for insulin secretion rate) and high BMI were associated with poor outcome.

Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins.

OBJECTIVE: The aims of the study were to evaluate the ability of metformin to induce apoptosis in epithelial ovarian cancer cell lines and to identify the pathways involved in this effect. METHODS: After treatment with metformin and/or cisplatin, OVCAR-3 and OVCAR-4 cellular apoptosis was assessed by flow cytometry and caspase 3/7 activity. Cell cycle analysis was also performed by flow cytometry as well. Modulation of protein expression of the Bcl-2 family after treatment with metformin and/or cisplatin was determined by Western blotting. RESULTS: Metformin induced apoptosis in OVCAR-3 and OVCAR-4 cell lines in an AMPK-independent manner and provoked a cell cycle arrest in the S and G2/M phase. Moreover, we established that metformin can induce apoptosis in OVCAR-3 and OVCAR-4 cells by activating caspases 3/7, down-regulating Bcl-2 and Bcl-xL expression, and up-regulating Bax and Bad expression. The induction of apoptosis by metformin was also enhanced by cisplatin and combination of these drugs did not modulate the expression of Bcl-2 family proteins in OVCAR-3 cell line, whereas the effect was enhanced in OVCAR-4 cell line. CONCLUSION: Bcl-xL and Bcl-2 targeted strategies were suggested to constitute an effective therapeutic tool for the treatment of chemoresistant ovarian carcinoma, in conjunction with conventional chemotherapy. These data are relevant to ongoing translational research efforts and clinical trials exploring a possible protective effect of metformin against ovarian cancer, including Bcl-2 inhibition.

Autoantibodies to tailor-made panels of tumor-associated antigens in breast carcinoma.

Autoantibodies (AAbs) to tumor-associated antigens (TAAs) have been identified in the sera of cancer patients. In a previous review published in this journal, we have focused on recent knowledge related to circulating AAbs to individual TAAs in breast carcinoma. This review will focus on recent knowledge related to AAb assays to tailor-made panels of TAAs in breast carcinoma. So far, AAb assays to the following tailor-made panels of TAAs have been assessed in breast carcinoma: (1) p53, c-myc, HER2, NY-ESO-1, BRCA2, and MUC1, (2) IMP1, p62, Koc, p53, c-MYC, cyclin B1, and survivin, (3) PPIA, PRDX2, FKBP52, HSP-60, and MUC1, (4) MUC1, HER2, p53, and IGFBP2, (5) p53, HER2, IGFBP-2, and TOPO2α, (6) survivin and livin, (7) ASB-9, SERAC1, and RELT, and (8) p16, p53, and c-myc. Assessment of serum AAbs to a tailor-made panel of TAAs provides better sensitivity to diagnosis of breast carcinoma than measuring serum AAbs to a single TAA. Nevertheless, measurement of serum AAbs to a panel of TAAs for screening and early diagnosis of breast carcinoma is still investigational and should be carried out along with traditional diagnostic studies.

Autoantibodies to tumor-associated antigens in breast carcinoma.

Autoantibodies (AAbs) to tumor-associated antigens (TAAs) have been identified in the circulation of patients with cancer. This paper will focus on recent knowledge related to circulating AAbs to TAAs in breast carcinoma. So far, the following TAAs have been identified to elicit circulating AAbs in breast carcinoma: p53, MUC-1, heat shock proteins (HSP-27, HSP-60, and HSP-90), HER2/neu/c-erb B2, GIPC-1, c-myc, c-myb, cancer-testis antigens (NY-ESO-1), BRCA1, BRCA2, endostatin, lipophilin B, cyclin B1, cyclin D1, fibulin, insulin-like growth factor binding protein 2 (IGFBP-2), topoisomerase II alpha (TOPO2α), and cathepsin D. Measurement of serum AAbs to one specific TAA only is of little value for screening and early diagnosis of breast carcinoma; however, assessment of AAbs to a panel of TAAs may have promising diagnostic potential.

[Splenic metastases from female genital tract malignancies].

Splenic metastases are rare. Usually, they are part of a disseminated disease and located on the splenic capsule. Common sources are breast cancer, lung cancer and malignant melanoma. SoLitary splenic metastases are rare, usuaLLy located in the splenic parenchyma and metastasizing via the hematogenous route. Splenic metastases from ovarian carcinoma are usuaLly part of a disseminated disease, located on the splenic capsule and metastasize via the peritoneum. Splenic metastases from endometriaL carcinoma are usuaLLy solitary, Located in the splenic parenchyma and metastasize via the hematogenous route. Splenic metastases from cervical carcinoma are divided equally between metastases as part of a disseminated disease and soLitary metastases. Less than 100 cases of solitary splenic metastases have been reported with half of them being metastases from female genital tract malignancies: 30--ovarian carcinoma; 11--endometriaL carcinoma; 8--cervical carcinoma; and 1--tubal carcinoma. Few cases have been reported of splenic rupture because of metastases from choriocarcinoma. Splenic metastases as part of a disseminated disease are associated with poor prognosis, and splenectomy--apart from cases in which it might assist in achieving optimaL debulking--is not effective. Solitary splenic metastases represent a more moderate disease and the treatment of choice is splenectomy. SoLitary splenic metastases may be detected after an interval from the diagnosis of the primary disease. Hence, patients who had been treated for female genital tract malignancy, even if they are asymptomatic, need a long-term follow-up, including serial imaging studies of the spleen.

Autoantibodies to tumor-associated antigens in epithelial ovarian carcinoma.

This review will focus on recent knowledge related to circulating autoantibodies (AAbs) to tumor-associated antigens (TAAs) in epithelial ovarian carcinoma. So far, the following TAAs have been identified to elicit circulating AAbs in epithelial ovarian carcinoma: p53, homeobox proteins (HOXA7, HOXB7), heat shock proteins (HSP-27, HSP-90), cathepsin D, cancer-testis antigens (NY-ESO-1/LAGE-1), MUC1, GIPC-1, IL-8, Ep-CAM, and S100A7. Since AAbs to TAAs have been identified in the circulation of patients with early-stage cancer, it has been speculated that the assessment of a panel of AAbs specific for epithelial ovarian carcinoma TAAs might hold great potential as a novel tool for early diagnosis of epithelial ovarian carcinoma.