Robotic blue-dye sentinel lymph node detection for endometrial cancer - Factors predicting successful mapping.

OBJECTIVE: Sentinel lymph node (SLN) mapping has emerged as a viable option for the treatment of patients with endometrial cancer. We report our initial experience with SLN mapping algorithm, and examine the factors predicting successful SLN mapping. METHODS: We analyzed all data recorded in our institute on robotic blue-dye SLN detection mapping from the time it was first introduced to our department in January 2012-December 2014. Data included patient demographics, SLN allocation, operating room times, and pathology results. RESULTS: During the study period, 74 patients had robotic assisted surgery for endometrial cancer with attempted SLN mapping. SLN was found overall in 46 patients (62.1%). At first, SLN was detected in only 50% of cases, but after performing 30 cases, detection rates rose to 84.6% (OR = 3.34, CI 1.28-8.71; p = 0.003). Univariate analysis showed a higher detection rate with methylene blue than patent blue dye, 74.3% vs. 52.3% (OR = 2.744, 95% CI 1.026-7.344; p = 0.042). In multivariate analysis, high body mass index (BMI) was associated with failed mapping (OR = 0.899; 95% CI 0.808-1.00), as was the presence of lymph-vascular space invasion (LVSI) (OR = 0.126; 95% CI 0.24-0.658) and few cases per surgeon (OR = 1.083, 95% CI 1.032-1.118). Factors related to uterine pathology itself, including tumor histology, grade, method of diagnosis, the presence of an endometrial polyp, and lower uterine segment involvement were not found to be associated with successful mapping. CONCLUSIONS: Surgeon experience, BMI and LVSI may affect the success rate of SLN mapping for endometrial cancer. These factors should be investigated further in future studies.

Disrupted abdominal laparotomy wounds in gynaecologic oncology patients: benefits of active surgical re-closure.

OBJECTIVE: To assess the outcome of active management of disrupted wounds through surgical approximation and re-closure. METHOD: A prospective, non-comparative study, on all consecutive patients with disrupted laparotomy wounds treated at a tertiary medical centre, from November 2009 to December 2011. Data on patient demographics, diagnosis, type of abdominal incision, initial closure technique, infections and results of secondary re-closure were collected from the medical files. All patients underwent bedside closure with an en bloc mass suture mattress technique, performed by two attending gynaecologic oncologists. RESULTS: Of 197 patients who underwent abdominal laparotomy during the study period, 31 (16%) had a disrupted wound. Following surgical re-closure, 26 wounds (84%) were completely healed or needed only minor additional care by follow up on day 10. Five wounds (16%) failed primary management and required re-suturing; all subsequently healed. There were no long-term complications. CONCLUSION: Active surgical re-closure of disrupted abdominal laparotomy wounds is safe and effective in patients after treatment surgically for Müllerian malignancies.

Can parametrectomy be avoided in early cervical cancer? An algorithm for the identification of patients at low risk for parametrial involvement.

AIMS: To assess the rate of parametrial involvement in a large cohort of patients who underwent radical hysterectomy for cervical cancer and to suggest an algorithm for the triage of patients to simple hysterectomy or simple trachelectomy. METHODS: Multicenter retrospective study of patients with cervical cancer stage I through IIA who underwent radical hysterectomy and pelvic lymphadenectomy. The patients were divided into 2 groups according to whether or not the parametrium was involved. The two groups were compared with regard to the clinical and histopathological variables. Logistic regression of the variables potentially assessable prior to definitive hysterectomy such as age, tumor size, lymph-vascular space invasion (LVSI) and nodal involvement was performed. RESULTS: Five hundred and thirty patients had specific histological data on parametrial involvement and in 58 (10.9%) patients, parametria was involved. Parametrial involvement was significantly associated with older age, tumors larger than 2 cm, deeper invasion, LVSI, involved surgical margins, and the presence of nodal metastasis. By triaging patients with a tumor ≤ 2 cm and no LVSI, the parametrial involvement rate was 1.8% (2/112 patients). With further triage of patients with negative nodes, the rate of parametrial involvement was 0% (0/107 patients). CONCLUSION: Using a pre-operative triage algorithm, patients with early small lesions, no LVSI and no nodal involvement may be spared radical surgical procedures and parametrectomy. Further prospective data are urgently needed.

Long-term glutamate supplementation failed to protect against peripheral neurotoxicity of paclitaxel.

Toxic peripheral neuropathy is still a significant limiting factor for chemotherapy with paclitaxel (PAC), although glutamate and its closely related amino acid glutamine were claimed to ameliorate PAC neurotoxicity. This pilot trial aimed to evaluate the role of glutamate supplementation for preventing PAC-induced peripheral neuropathy in a randomized, placebo-controlled, double-blinded clinical and electro-diagnostic study. Forty-three ovarian cancer patients were available for analysis following six cycles of the same PAC-containing regimen: 23 had been supplemented by glutamate all along the treatment period, at a daily dose of three times 500 mg (group G), and 20 had received a placebo (group P). Patients were evaluated by neurological examinations, questionnaires and sensory-motor nerve conduction studies. There was no significant difference in the frequency of signs or symptoms between the two groups although neurotoxicity symptoms presented mostly with lower scores of severity in group G. However, this difference reached statistical significance only with regard to reported pain sensation (P = 0.011). Also the frequency of abnormal electro-diagnostic findings showed similarity between the two groups (G: 7/23 = 30.4%; P: 6/20 = 30%). This pilot study leads to the conclusion that glutamate supplementation at the chosen regimen fails to protect against peripheral neurotoxicity of PAC.

Sclerosing peritonitis associated with bilateral luteinized thecoma, linked to anticonvulsant therapy.

OBJECTIVE: To present a new case of sclerosing peritonitis associated with bilateral luteinized thecoma of the ovaries, linked to anticonvulsant therapy. CASE: A 22-year-old patient, receiving carbamazepine for seizures and anxiety attacks presented with shortness of breath, abdominal pain, nausea and vomiting. Clinical and imaging examinations revealed bilateral ovarian masses with massive ascites. At emergency surgery, bilateral ovarian luteinized thecoma with sclerosing peritonitis was found. Due to recurrent, postoperative episodes of small bowel obstruction she was treated with nasogastric suction, intravenous fluids and electrolyte replacement. Total parenteral nutrition was introduced. Since only partial improvement was achieved tamoxifen was administered with resolution of the bowel obstruction. CONCLUSIONS: This is the 19th case of sclerosing peritonitis associated with luteinized thecoma of the ovaries and the 3rd to be associated with anticonvulsant therapy. Treatment should be aimed at relief of bowel obstruction symptoms, preferably with conservative methods. Tamoxifen for downregulation of TGF-beta production should be considered as a treatment modality, as it proved to be very helpful in the presented patient.

Screening for cervical cancer--an evidence-based approach.

INTRODUCTION: The Papanicolau (Pap) smear is widely accepted by both the public and health authorities as a useful tool for detection of cervical cancer and its precursors. In Israel only opportunistic screening exists and still the incidence of invasive cervical cancer is among the lowest in the world. OBJECTIVES: To examine the existing evidence for the effectiveness of cervical cancer screening by Pap smears; to apply the findings to Israeli data, and to assess the implications for the current cervical cancer screening policy. METHODS: Search of Medline (1966-June 2003) and the Cochrane Library for relevant systematic reviews, controlled trials and cohort studies. RESULTS: There have been no trials of screening for cervical cancer and its precursors and therefore, no direct evidence that screening improves outcomes. A single retrospective cohort study estimated the age-adjusted RR for invasive cervical cancer in women with at least one Pap smear, whether normal or abnormal, compared to women with no smear at 0.4 (95% CI 0.2-0.9). In Israel some 27,800 (range: 20,800-167,000) women need to be screened in order to prevent one case of cervical cancer. The cost of preventing a single case of invasive cervical is approximately 1.288 million NIS (range: 1.643-13.193 million NIS). CONCLUSIONS: An evidence-based approach to the question of the effectiveness of cervical cancer screening using Pap smears has yielded weak evidence. Based on this weak evidence and rough estimations of the effectiveness and cost of mass screening for cervical cancer in Israel, we conclude that the current policy should be maintained.

A multicenter study of CA 125 level as a predictor of non-optimal primary cytoreduction of advanced epithelial ovarian cancer.

AIMS: To provide a large database of pre-operative CA 125 levels which may predict inappropriate cytoreductive surgery in patients with advanced epithelial ovarian cancer. METHODS: A multicenter review of the records of 424 patients with FIGO stage III and IV epithelial ovarian cancer of patients who underwent primary cytoreductive surgery was performed. The validity of pre-operative CA 125 level measurement as a single predictor of the possibility to achieve only suboptimal cytoreduction was evaluated by calculating the sensitivity and the specificity of various cut-off values. The relative importance of different cut-off values in achieving the best predictive validity was assessed by a receiver operating characteristics (ROC) curve. RESULTS: Optimal cytoreduction (largest diameter of residual tumour < or =1 cm) was achieved in 242 patients. The median CA 125 level in optimally cytoreduced patients was lower than in those patients suboptimally debulked (304 vs 863 U/mL; p<0.001). The area under the ROC curve was 0.65 (95% confidence interval, 0.60-0.71) and the CA 125 threshold derived from the ROC was 400 U/mL. The accuracy of the test at this level was 62%. CONCLUSIONS: The clinical applicability of the ROC derived CA 125 threshold is limited. The data accrued in the study provides a basis for decision-making regarding the place of primary surgery various CA 125 levels.

BRCA susceptibility genes--a review of current conservative management of BRCA mutation carriers.

Three options for the management of a patient carrying a deleterious mutation in the BRCA gene exist: close surveillance, chemoprevention and prophylactic surgical procedures. We aimed at reviewing the current knowledge on the conservative management of patients who are found to be carriers of the BRCA susceptibility genes. Recent literature in the English language was reviewed for publications containing the conservative management of BRCA mutation-carriers. Close surveillance for the breasts includes breast self-examination, clinical examination by a specialist and breast imaging techniques--mammography and magnetic resonance imaging. Ovarian surveillance includes pelvic examination, transvaginal ultrasonography and blood CA-125 measurements. Age at beginning of examinations and their frequency are discussed. Chemoprevention includes tamoxifen and oral contraceptives for breast and ovarian cancer prevention, respectively.

Failure of sentinel node identification following neo-adjuvant chemo-radiotherapy for locally advanced squamous cell carcinoma of the vulva.

A case of a 70-year-old patient with advanced local vulvar cancer is presented. Treatment with neo-adjuvant chemo-radiotherapy for two courses was administered and two weeks after completion of treatment the patient underwent wide local excision with bilateral inguino-femoral lymph node dissection through three separate incisions. Two methods for the evaluation of sentinel nodes--lymphoscintigraphy and intraoperative gamma hand-held probe and blue dye injection, did not detect any sentinel node on either side. Groin-node dissection revealed 23 negative nodes. It is our hypothesis that the non-visualization of sentinel nodes in this patient was due to post-irradiation damage to the lymph channels.

A mobile aerosol cryotherapy device (Histofreezer) for treatment of cervical contact bleeding: a pilot study.

This study aims to evaluate the efficacy of the Histofreezer (a mobile aerosol cryotherapy device) treatment for women with cervical contact bleeding. Ten healthy women aged 22-50 years referred to our outpatient colposcopy clinic for recurrent postcoital or contact bleeding, and who suffered from mild to wide ectropion with bleeding on contact were studied. All women had a normal pelvic examination and ultrasound and a normal colposcopy and PAP smear. They were treated with the Histofreezer, which freezes the tissue to a temperature of -55 degrees C. A picture of the cervix was taken by a cervical camera before, after the procedure and during follow-up visits 4 and 8 weeks afterwards. There was a complete resolution of bleeding ectropion with a good healing of squamous metaplasia in seven patients. Two women showed partial improvement. Based on this initial study, this short and simple ambulatory treatment shows good results, both subjectively and on follow-up colposcopy.

Frequency of BRCA mutations in primary peritoneal carcinoma in Israeli Jewish women.

OBJECTIVE: The aim of the present study was to compare demographic and clinical characteristics of primary peritoneal carcinoma (PPC) to ovarian carcinoma (OvC) with regard to BRCA mutation frequencies. METHODS: Incident cases of histologically confirmed cancer of the ovary or peritoneum diagnosed in Israeli Jewish women between March 1, 1994, and June 30, 1999, were identified within the framework of an ongoing nationwide epidemiological study of these neoplasms in Israel. The present study comprises 609 (81.5% of 747) Jewish women with epithelial stage III-IV OvC and 68 (77.3% of 88) Jewish women with PPC who were genetically tested for the BRCA mutations. Data from each patient were collected by the aid of a prestructured questionnaire and medical records. Blood samples or tumor tissue was tested for the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutations in BRCA2. RESULTS: A carrier rate of 28% of any BRCA 1/2 mutation was observed among the PPC group and of 30% among the invasive stage III-IV OvC. No differences were found between PPC and OvC neither in the overall distribution of BRCA1/2 mutation carrier rates nor according to type of mutation, age, ethnic origin, and histologic subtype. Among women with a positive family history, a higher rate of mutation carriers was observed in the PPC group compared to the OvC group (72.7 vs 43.8%, respectively, P = 0.07). CONCLUSIONS: The similar frequency distribution of BRCA1/2 mutations in PPC and OvC observed in the present study indicates that these mutations may predispose to PPC as well and that this neoplasm is part of the hereditary breast-ovarian cancer syndrome.

Effect of BRCA mutations on the length of survival in epithelial ovarian tumors.

PURPOSE: To study the role of BRCA mutations in ovarian cancer survival. PATIENTS AND METHODS: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG, 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. RESULTS: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and noncarriers among the women with invasive ovarian cancer (median survival, 53.4 months v. 37.8 months; 3-year survival, 65.8% v. 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. CONCLUSION: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis.

A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers.

RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers. We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations. We discovered two single nucleotide polymorphisms (SNPs) at positions 135 g-->c and 172 g-->t of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 g-->c, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 g-->c with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4-40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 g-->c SNP. Analysis of the RAD51:135 g-->c SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele. We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown.

The polymorphic CAG repeat in the androgen receptor gene in Jewish Israeli women with endometrial carcinoma.

BACKGROUND: Endometrial carcinoma is considered a hormonal-dependent tumor; estrogen induces endometrial cellular proliferation, whereas progestins display an antiproliferative effect on endometrial tissue. The role that androgen and its receptor (androgen receptor [AR]) play in the pathogenesis of endometrial carcinoma is less clear. Although androgen has an in vitro inhibitory effect on endometrial cell proliferation, up to 75% of endometrial carcinoma express AR somatically. A polymorphic CAG repeat within exon 1 of the AR encodes for a polyglutamine tract, with length range of 8 to 33 repeats, which is inversely correlated with the transcriptional activity of the AR. METHODS: To gain insight into the role of AR in endometrial carcinoma, the authors analyzed the polymorphic CAG repeat in 79 Jewish Israeli patients with endometrial carcinoma as compared with 44 healthy Jewish women serving as controls. Analysis was conducted using germline DNA as template and using polymerase chain reaction primers flanking the CAG repeat with subsequent fluorescent determination of allele sizes. RESULTS: Allele size range of the longer of the two alleles in the patients was 11-33 (mean, 19.8 +/- 2.7) and in the controls 10-22 (mean, 17.9 +/- 1.9), a statistically significant difference (P < 0.01). Allele size variation within the patient group did not correlate with disease stage, grade, reproductive history, or age at diagnosis. CONCLUSIONS: The authors conclude that AR-CAG repeat length differs in Jewish patients with endometrial carcinoma as compared with healthy individuals in Israel, and this finding increases the possibility that the AR is involved in the predisposition to this neoplasm.

Connective tissue activating peptide III expression disappears progressively with increased dysplasia in human cervical epithelium.

OBJECTIVE: The aim of this study was to explore the possible involvement of CTAP-III in the development of cervical cancer as it progresses through several cervical intraepithelial neoplasia (CIN) stages. MATERIAL AND METHODS: Twenty-four cervical specimens were obtained by direct punch biopsy, conization, or hysterectomy. Diagnosis of CIN I to CIN III was based on standard morphological criteria in 12 specimens. Tissue specimens were also obtained from 4 normal uteri and 8 cases of invasive squamous cell cervical carcinoma. RT-PCR, using CTAP-III-specific primers, was used to identify CTAP-III mRNA and polyclonal antibodies, directed against the N-terminus of CTAP-III, for immunostaining of the CTAP-III protein. RESULTS: RT-PCR yielded amplified fragments in RNA derived from normal cervical tissue, while no PCR product was detected in the invasive cervical carcinoma tissue. The PCR product corresponded to a CTAP-III plasmid PCR product. Both tissues expressed the same amounts of GAPDH mRNA as the control for the integrity and equal amounts of the isolated RNA. In each of the 16 specimens of normal cervices and of CIN tissues, epithelial cells were stained with the anti-CTAP-III antibodies. In normal epithelium, CTAP-III staining was homogeneously distributed in all epithelial layers, except in the highly active and proliferating basal cells. CTAP-III was localized at the epithelial cell membrane or between adjacent epithelial cells in a granular, chain-like pattern of staining. In the CIN specimens, CTAP-III staining was no longer seen in the deep epithelial layers, consistent with the dysplastic appearance of the cells, and remained in the seemingly normal superficial epithelial layers. Cells of invasive cervical carcinoma did not stain for CTAP-III and were detected in endothelial cells of capillary blood vessels. CONCLUSION: The specific localization of CTAP-III between adjacent epithelial cells suggests a possible role of this chemokine in maintaining the normal architecture of epithelial tissues. Its progressive disappearance in increasingly severe CIN may be applied to distinguish between specific stages in the progression of cervical carcinoma.

The biology of ovarian cancer of epithelial origin.

Ovarian cancer of epithelial origin is associated with the highest mortality rate of all gynecologic malignancies. Since no symptoms or signs are manifested at the early stages of the disease, it is no surprise that in 75% of patients peritoneal metastases are found during primary surgery. Despite advances in conservative treatment methods (invasive and noninvasive), screening for early detection of the disease is not yet available, and the overall survival rate is as low as 5-15%. Recent studies in molecular biology have drawn attention to different research directions in ovarian cancer and have contributed much to our understanding of this disease and its underlying pathologic mechanisms. This review is intended to highlight some of the new aspects of this research, specifically: hereditary ovarian cancer, genetic background in terms of chromosomal changes, DNA anomalies, oncogenes, tumor-suppressor genes, peptide growth factors and cytokines, invasiveness and metastasis, and finally, drug resistance. No breakthrough has as yet occurred in any of the subjects screened in this review, but results are promising. The clinical application of the steadily increasing knowledge in the biology of ovarian cancer may assist in the development of new treatment modalities that will improve survival.

Conservative management of postmenopausal pelvic echo-free findings--preliminary results.

OBJECTIVES: To develop a conservative protocol for the treatment of echo-free findings in the pelvis, diagnosed by sonography in post-menopausal women, in order to avoid unnecessary surgical intervention. METHODS: A prospective study where each post-menopausal-patient underwent sonographic evaluation of the pelvic mass, serum Ca-125 levels, ambulatory aspiration of the cyst, and operative laparoscopy if necessary. RESULTS: One hundred and eighty-two women were included in the 3 years of the study. Only two cases of malignancy were diagnosed. There were no false-negative results. CONCLUSION: Although the results of our protocol of conservative management look promising, we cannot draw final conclusions because of the small sample size. Perhaps as our knowledge increases, physicians will feel more confident in handling adnexal findings conservatively.