DNA Methylation and P53 Immunohistochemistry as Prognostic Biomarkers for Vulvar Lichen Sclerosus.

Vulvar lichen sclerosus (LS) is an inflammatory dermatosis which can progress to human papillomavirus (HPV-)independent vulvar intraepithelial neoplasia (HPVi VIN) and vulvar squamous cell carcinoma (VSCC). Although LS has a much lower cancer risk compared to HPVi VIN (5% versus 50%, respectively), its incidence is significantly higher. Therefore, there is a clinical need to identify LS patients with an increased cancer risk. Our objective was to study the value of DNA methylation and p53 immunohistochemistry (IHC) as prognostic biomarkers for progression to cancer in patients with LS. Vulvar tissues from 236 patients were selected, including 75 LS and 68 HPVi VIN, both with and without cancer development, 32 VSCC and 61 healthy vulvar controls. Samples were subjected to p53 IHC and DNA methylation analysis of a three-gene marker panel containing ZNF582, SST and miR124-2. Methylation levels and p53 IHC status (mutant or wild-type) were assessed and compared among all disease categories. Odds ratios (ORs) were determined to identify whether the biomarkers were associated with progression to cancer in patients with LS. Highest methylation levels were found in HPVi VIN and VSCC, followed by LS and healthy vulvar controls. The largest heterogeneity in methylation levels was observed in LS cases. In fact, the three-marker panel tested positive in 70% of LS which progressed to VSCC versus only 17% of LS in patients without cancer development (p=0.002). Also, mutant p53 IHC was observed more frequently in LS with progression to VSCC as compared to non-progressive LS cases (42% versus 3%, respectively, p=0.001). Multivariable analysis identified a mutant p53 status as the only independent risk factor for cancer development in LS (OR 34.0, 95% CI: 1.4 - 807.4). In conclusion, DNA methylation testing and p53 IHC show strong potential as prognostic biomarkers for the identification of LS patients at high risk of progression to cancer.

Selective Removal of Only Clinically Suspicious Positive Lymph Nodes Instead of a Complete Inguino-Femoral Lymph Node Dissection in Squamous Cell Carcinoma of the Vulva.

BACKGROUND: The oncological safety of only removing bulky, positive groin lymph nodes followed by radiotherapy without performing a complete inguino-femoral node dissection (IFL) in squamous cell cancer of the vulva is based on two small studies. The aim of this study was to confirm the oncological safety of this treatment policy. METHODS: The survival of consecutive patients with clinically suspicious and pathologically positive groin nodes treated with the selective removal of these nodes followed by radiotherapy was compared with the survival in historical controls matched for the variables extranodal spread and diameter of the metastasis > 15 mm and treated with a complete IFL. RESULTS: There was no difference in disease-specific survival between patients treated with debulking (n = 40) versus complete IFL (n = 37) (43.1% vs. 44.8%, p = 0.336, respectively). Overall, survival and groin recurrence-free survival did not differ between the groups either. CONCLUSION: This retrospective study in a cohort of women with vulvar cancer corroborates previous smaller studies that have shown that the selective removal of suspicious inguinal nodes yields similar oncological outcomes compared with patients matched for important prognostic variables and treated with a complete IFL when both are followed by radiotherapy.

Role of adjuvant therapy in intermediate-risk cervical cancer patients - Subanalyses of the SCCAN study.

OBJECTIVE: The "intermediate-risk" (IR) group of early-stage cervical cancer patients is characterized by negative pelvic lymph nodes and a combination of tumor-related prognostic risk factors such as tumor size ≥2 cm, lymphovascular space invasion (LVSI), and deep stromal invasion. However, the role of adjuvant treatment in these patients remains controversial. We investigated whether adjuvant (chemo)radiation is associated with a survival benefit after radical surgery in patients with IR cervical cancer. METHODS: We analyzed data from patients with IR cervical cancer (tumor size 2-4 cm plus LVSI OR tumor size >4 cm; N0; no parametrial invasion; clear surgical margins) who underwent primary curative-intent surgery between 2007 and 2016 and were retrospectively registered in the international multicenter Surveillance in Cervical CANcer (SCCAN) study. RESULTS: Of 692 analyzed patients, 274 (39.6%) received no adjuvant treatment (AT-) and 418 (60.4%) received radiotherapy or chemoradiotherapy (AT+). The 5-year disease-free survival (83.2% and 80.3%; PDFS = 0.365) and overall survival (88.7% and 89.0%; POS = 0.281) were not significantly different between the AT- and AT+ groups, respectively. Adjuvant (chemo)radiotherapy was not associated with a survival benefit after adjusting for confounding factors by case-control propensity score matching or in subgroup analyses of patients with tumor size ≥4 cm and <4 cm. In univariable analysis, adjuvant (chemo)radiotherapy was not identified as a prognostic factor in any of the subgroups (full cohort: PDFS = 0.365; POS = 0.282). CONCLUSION: Among patients with IR early-stage cervical cancer, radical surgery alone achieved equal disease-free and overall survival rates to those achieved by combining radical surgery with adjuvant (chemo)radiotherapy.

Sentinel lymph node procedure in patients with recurrent vulvar squamous cell carcinoma: a proposed protocol for a multicentre observational study.

BACKGROUND: Standard groin treatment in recurrent vulvar cancer consists of uni- or bilateral inguinofemoral lymphadenectomy (IFL), whereas in the primary setting women with selected unifocal tumours will undergo a sentinel lymph node (SLN) procedure. The SLN procedure results in fewer short and long-term sequelae compared to IFL, but some concerns must first be considered. Lymph drainage of the vulvar region can be affected by a previous surgery, which might reduce the number of detectable SLN nodes (feasibility) but increase the chance of encountering aberrant lymph drainage patterns such as bilateral SLNs in lateral tumours or SLNs at unexpected locations. Therefore, the SLN procedure potentially carries a higher risk of groin recurrence if a tumour positive node is not retrieved, but may also improve outcomes for women with aberrant drainage patterns. Since the relative benefits and drawbacks of the SLN procedure are still unclear we will investigate the safety of the SLN procedure in women with a first recurrent vulvar cancer. In a simultaneously started registration study we prospectively gather information on women with a first recurrence of vulvar cancer ineligible for the SLN procedure. METHOD: In this prospective multicentre observational study all women with a first recurrence of vulvar cancer will be asked to consent to the collection of information on their diagnostics, treatment and outcome, and to complete quality of life and lymph oedema questionnaires. Women with unifocal tumours smaller than 4 cm and unsuspicious groin nodes will be offered the SLN procedure, with follow-up every 3 months together with imaging at 6 and 12 months when the SLN is tumour negative. The primary outcome is groin recurrence within 2 years of initial surgery. A total of 150 women with negative SLNs will be required to demonstrate safety, a stopping rule will apply and an extensive statistical analysis has been designed. DISCUSSION: Should the SLN procedure prove feasible and safe in recurrent vulvar cancer, it will be available for implementation in clinics worldwide. The inclusion of women ineligible for the SLN procedure in the current prospective study will help to bridge knowledge gaps and define future research questions. TRIAL REGISTRATION: Medical Ethical Committee approval number NL70149.078.19 (trial protocol version 2.0, date March 2nd, 2020). Affiliation: Erasmus Medical Centre. Dutch trial register NL8467 . Date of registration 19.03.2020.

Biomarker Expression in Multifocal Vulvar High-Grade Squamous Intraepithelial Lesions.

In patients with high-grade squamous intraepithelial lesion (HSIL) of the vulva, the presence of multiple lesions, called multifocal HSIL, is common. The aim of this exploratory study was to investigate biomarker expression profiles in multifocal HSIL. In total, 27 lesions from 12 patients with high-risk human papillomavirus (HPV)-positive multifocal HSIL were tested for HPV genotype, expression of p16INK4a and Ki-67, and DNA methylation of six genes. HPV16 was found most commonly in 21 (77.8%) HSILs. In two (16.4%) patients, HPV genotype differed between the lesions. All lesions demonstrated diffuse p16INK4a staining, of which three (11.1%) were combined with patchy staining. One patient (8.3%) demonstrated markedly different DNA methylation levels between lesions. Generally, heterogeneity in methylation profiles was observed between different patients, even when other biomarkers showed similar expression. In conclusion, this study is the first to demonstrate heterogeneity of individual lesions in patients with multifocal HSIL. The studied biomarkers have the potential to refine prognostic and predictive diagnostics. Future prospective, longitudinal studies are needed to further explore the potential of a biomarker profile for management of patients with multifocal HSIL.

Immune landscape in vulvar cancer-draining lymph nodes indicates distinct immune escape mechanisms in support of metastatic spread and growth.

BACKGROUND: Therapeutic immune intervention is highly dependent on the T-cell priming and boosting capacity of tumor-draining lymph nodes (TDLN). In vulvar cancer, in-depth studies on the immune status of (pre)metastatic TDLN is lacking. METHODS: We have phenotyped and enumerated various T-cell and myeloid subsets in tumor-free (LN-, n=27) and metastatic TDLN (LN+, n=11) using flow cytometry. Additionally, we studied chemokine and cytokine release profiles and assessed expression of indoleamine 2,3-dioxygenase (IDO) in relation to plasmacytoid dendritic cell (pDC) or myeloid subsets. RESULTS: Metastatic involvement of TDLN was accompanied by an inflamed microenvironment with immune suppressive features, marked by hampered activation of migratory DC, increased cytokine/chemokine release, and closely correlated elevations of pDC and LN-resident conventional DC (LNR-cDC) activation state and frequencies, as well as of terminal CD8+ effector-memory T-cell (TemRA) differentiation, regulatory T-cell (Treg) rates, T-cell activation, and expression of cytotoxic T-lymphocyte protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) immune checkpoints. In addition, high indoleamine 2,3-dioxygenase (IDO) expression and increased frequencies of monocytic myeloid-derived suppressor cells (mMDSC) were observed. Correlation analyses with primary and metastatic tumor burden suggested respective roles for Tregs and suppression of inducible T cell costimulator (ICOS)+ T helper cells in early metastatic niche formation and for CD14+ LNR-cDC and terminal T-cell differentiation in later stages of metastatic growth. CONCLUSIONS: Metastatic spread in vulvar TDLN is marked by an inflamed microenvironment with activated effector T cells, which are likely kept in check by an interplay of suppressive feedback mechanisms. Our data support (neoadjuvant) TDLN-targeted therapeutic interventions based on CTLA-4 and PD-1 blockade, to reinvigorate memory T cells and curb early metastatic spread and growth.

Radiotherapy is not indicated in patients with vulvar squamous cell carcinoma and only one occult intracapsular groin node metastasis.

OBJECTIVE: Most guidelines advise no adjuvant radiotherapy in vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis. However, several recent studies have questioned the validity of this recommendation. The aim of this study was to analyze the groin recurrence rate in patients with a single intracapsular positive lymph node treated without adjuvant radiotherapy. METHODS: Patients with a single clinically occult intracapsular lymph node metastasis, treated without adjuvant radiotherapy, formed the basis for this study. Groin recurrences, and the risk of death, were analyzed in relation to the size of the metastasis in the lymph node and the lymph node ratio. Data were analyzed using SPSS, version 26.0 for Windows. RESULTS: After a median follow-up of 64 months, one of 96 patients (1%) was diagnosed with an isolated groin recurrence and another two (2.1%) were diagnosed with a combination of a local and a groin recurrence. The only isolated groin recurrence occurred in a contralateral lymph node negative groin. Size of the metastasis and lymph node ratio had no impact on the groin recurrence risk, nor on survival. The 5-year actuarial disease-specific and overall survivals were 79% and 62.5% respectively. The 5-year actuarial groin recurrence-free survival was 97%. CONCLUSION: Because of the low risk of groin recurrence and the excellent groin recurrence-free survival, we recommend that adjuvant radiotherapy to the groin in patients with vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis can be safely omitted to prevent unnecessary toxicity and morbidity.

Analysis of isolated loco-regional recurrence rate in intermediate risk early cervical cancer after a type C2 radical hysterectomy without adjuvant radiotherapy.

BACKGROUND: The efficacy of adjuvant radiotherapy in patients with intermediate risk early cervical cancer after radical hysterectomy is still under debate. Most guidelines recommend adjuvant radiotherapy, whereas others consider observation a viable option. OBJECTIVE: To investigate if patients with intermediate risk factors for cervical cancer who underwent radical hysterectomy may benefit from adjuvant radiotherapy. METHODS: Consecutive patients with tumor confined to the cervix and intermediate risk factors (according to Sedlis), treated between January 1982 and December 2014 who were observed after a type C2 radical hysterectomy formed the basis for this study. The frequency of recurrences, specifically isolated loco-regional recurrences, and the risk of death from recurrences, were analyzed. Data were analyzed using SPSS, version 23.0 for Windows RESULTS: A total of 161 patients were included in the analysis. Median age was 40 (range 20-76). Stages IB1 and IB2 were seen in 87 (54%) and 74 patients (46%), respectively. Squamous cell and non-squamous histology was seen in 114 (70.8%) and 47 patients (29.2%), respectively. Of the 161 patients, 25 (15.5%) had recurrent disease, of whom nine had an isolated loco-regional recurrence (5.6%). Median time to recurrence for isolated loco-regional recurrences was 28 months (range 9-151). Treatment for an isolated loco-regional recurrence was radiotherapy (n = 4) and chemoradiotherapy (n = 5). Four patients (2.5%) died from disease as a result of an isolated loco-regional recurrence. Actuarial disease- specific survival was 93.0% for the total group. No variables were found that predicted an isolated loco-regional recurrence. DISCUSSION: The mortality from isolated loco-regional recurrence in patients with intermediate risk factors for cervical cancer who underwent only radical hysterectomy type C2 was 2.5%. Further studies should compare outcomes between patients who undergo a type C2 radical hysterectomy without adjuvant radiotherapy with those undergoing a less radical hysterectomy but with adjuvant radiotherapy.

Vulvar Paget disease: A national retrospective cohort study.

BACKGROUND: Vulvar Paget disease (VPD) is a rare skin disorder that is considered premalignant. OBJECTIVE: To assess the clinical course, treatment schedules, and effect of invasion and treatment on recurrence and survival in patients with VPD. METHODS: Data on women with VPD were retrieved from the medical files and pathology reports in all Dutch tertiary university medical centers. Disease-free survival and 5-year disease-specific survival were estimated by using Kaplan-Meier curves. RESULTS: Data on 113 patients whose VPD was diagnosed between 1991 and 2016 were analyzed; 77% had noninvasive VPD. Most of the women (65%) underwent a surgical procedure. Recurrences were reported in 40%. Of the women with noninvasive VPD, 8% developed invasion. There were no disease-specific deaths reported in the women with noninvasive VPD. The 5-year disease-specific survival rate was greater than 98% in noninvasive and microinvasive VPD, but significantly worse in invasive VPD (50% [P < .0005]). LIMITATIONS: The main limitations of this study are its retrospective character and the fact that original pathology samples were not available for reassessment. CONCLUSIONS: VPD is extremely rare, and the recurrence rates are high. Most patients have noninvasive VPD, which does not affect survival and should be considered a chronic disorder with limited invasive potential. In cases of invasive disease, survival decreases significantly.

Laparoscopy to Predict the Result of Primary Cytoreductive Surgery in Patients With Advanced Ovarian Cancer: A Randomized Controlled Trial.

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.

Effectiveness of a hospital-based work support intervention for female cancer patients - a multi-centre randomised controlled trial.

OBJECTIVE: One key aspect of cancer survivorship is return-to-work. Unfortunately, many cancer survivors face problems upon their return-to-work. For that reason, we developed a hospital-based work support intervention aimed at enhancing return-to-work. We studied effectiveness of the intervention compared to usual care for female cancer patients in a multi-centre randomised controlled trial. METHODS: Breast and gynaecological cancer patients who were treated with curative intent and had paid work were randomised to the intervention group (n = 65) or control group (n = 68). The intervention involved patient education and support at the hospital and improvement of communication between treating and occupational physicians. In addition, we asked patient's occupational physician to organise a meeting with the patient and the supervisor to make a concrete gradual return-to-work plan. Outcomes at 12 months of follow-up included rate and time until return-to-work (full or partial), quality of life, work ability, work functioning, and lost productivity costs. Time until return-to-work was analyzed with Kaplan-Meier survival analysis. RESULTS: Return-to-work rates were 86% and 83% (p = 0.6) for the intervention group and control group when excluding 8 patients who died or with a life expectancy of months at follow-up. Median time from initial sick leave to partial return-to-work was 194 days (range 14-435) versus 192 days (range 82-465) (p = 0.90) with a hazard ratio of 1.03 (95% CI 0.64-1.6). Quality of life and work ability improved statistically over time but did not differ statistically between groups. Work functioning and costs did not differ statistically between groups. CONCLUSION: The intervention was easily implemented into usual psycho-oncological care and showed high return-to-work rates. We failed to show any differences between groups on return-to-work outcomes and quality of life scores. Further research is needed to study which aspects of the intervention are useful and which elements need improvement. TRIAL REGISTRATION: Nederlands Trial Register (NTR) 1658.

Long-term sexual function in survivors of vulvar cancer: a cross-sectional study.

OBJECTIVES: To assess sexual function of vulvar cancer survivors who received extensive and less extensive treatment. To explore associations between sexual function and patient, disease, treatment, and psychological variables. METHODS: Sexual function (Female Sexual Function Index, FSFI), mental and physical well-being (SF36 Health Survey), body image (Body Image Scale), and optimism (Life Orientation Test) were assessed in vulvar cancer survivors treated in the period January 1997-January 2007. Demographic, disease and treatment characteristics were collected from medical files. Radical local excision with inguinal lymph node dissection and radical vulvectomy were considered extensive treatments; radical local excision, with or without sentinel node dissection, was considered less extensive treatment. Univariate and multivariate linear regression analyses were performed. RESULTS: Of 120 eligible patients, 76 (63%) responded. Eighteen women with a male partner (43%) reported having sexual intercourse. FSFI domain scores did not differ between extensively and less extensively treated women. Age was negatively associated with "Arousal" and "Desire", having a partner was positively associated with "Satisfaction", and optimism and physical well-being were positively associated with "Desire" and "Orgasm". Adjuvant inguinal radiotherapy was negatively associated with "Orgasm". One woman reported having better sexual function after than before treatment, 50% reported a similar sexual function, and 42% a worse sexual function. CONCLUSIONS: 43% of women who survived vulvar cancer and who had a male partner were sexually active. Treatment-related variables had a limited influence on long-term sexual function in these patients. Having a partner, good physical well-being, and being optimistic were positively associated with sexual function.

Primary groin irradiation versus primary groin surgery for early vulvar cancer.

BACKGROUND: Despite changes in technique, morbidity after surgery for vulvar cancer is high and mainly related to the groin dissection. Primary radiotherapy to the groin is expected to result in lower morbidity. However, studies on the efficacy of primary radiotherapy to the groin in terms of groin recurrences and survival show conflicting results. OBJECTIVES: To determine whether the effectiveness and safety of primary radiotherapy to the inguinofemoral lymph nodes in early vulvar cancer is comparable with surgery. SEARCH STRATEGY: We searched The Cochrane Gynaecological Cancer Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE from 1966 to July 2010. SELECTION CRITERIA: We selected randomised clinical trials (RCTs) comparing inguinofemoral lymph node dissection and primary radiotherapy of the inguinofemoral lymph nodes for patients with early squamous cell cancer of the vulva. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study quality and extracted results. Primary outcome measures were the incidence of groin recurrences, patient survival and morbidity. MAIN RESULTS: No new RCTs were identified by the updated search. Out of twelve identified papers only one met the selection criteria. From this one small RCT of 52 women, there was a trend towards increased groin recurrence rates (relative risk (RR) 10.21, 95% confidence interval (CI) 0.59 to 175.78), lower disease-specific survival rates (RR 3.70, 95% CI 0.87 to 15.80), less lymphoedema (RR 0.06, 95% CI 0.00 to 1.03) and fewer life-threatening cardiovascular complications (RR 0.08, 95% CI 0.00 to 1.45) in the radiotherapy group. Primary surgery was associated with a longer hospital stay than primary groin irradiation (RR 0.28, 95% CI 0.13 to 0.58). AUTHORS' CONCLUSIONS: Primary radiotherapy to the groin results in less morbidity but may be associated with a higher risk of groin recurrence and decreased survival when compared with surgery. Due to the small numbers in this trial and criticisms regarding the depth of radiotherapy applied, corroboration of these findings by larger RCTs using a standardised radiotherapy method, is desirable. However, until better evidence is available, surgery should be considered the first choice treatment for the groin nodes in women with vulvar cancer. Individual patients not physically able to withstand surgery may be treated with primary radiotherapy.

Prognostic value of bilateral positive nodes in squamous cell cancer of the vulva.

OBJECTIVES: The aim of the current study was, first, to determine whether laterality of lymph node metastases has prognostic significance, independent of the number of lymph node metastases. Second was to determine the prognostic significance of extracapsular spread irrespective of the number of lymph node metastases. METHODS: Data on 134 patients with stage III/IVA vulva cancer from 1982 till 2004 and treated with curative intent in either the Academic Medical Centre in Amsterdam or the Mercy Hospital for Women in Melbourne were reviewed. The impact of the number of lymph node metastases, extracapsular spread, and bilateral existence of lymph node metastases on survival was determined. RESULTS: The bilateral presence of lymph node metastases is not a significant predictor for survival if a correction is made for the number of lymph node metastases (hazards ratio, 1.31; 95% confidence interval, 0.68-2.51; P = 0.420). If extracapsular spread is put into the model as well, this is the only parameter of prognostic significance in multivariate analysis (hazards ratio, 5.27; 95% confidence interval, 2.60-10.67; P < 0.001). The five-year survival of patients with extracapsular spread is only 31%, which is considerably lower than the 80% survival of patients with only intracapsular metastases. CONCLUSIONS: In conclusion, there is growing evidence that bilateral existence of lymph node metastases is not a sufficient variable to qualify stage. Extracapsular spread, however, seems to be the most valuable lymph node-associated prognostic factor for survival.

The therapeutic management of a twin pregnancy complicated by the presence of cervical cancer, following laparoscopic staging and chemotherapy, with an emphasis on cisplatin concentrations in the fetomaternal compartments amnion fluid, umbilical cord, and maternal serum.

OBJECTIVE: To evaluate the feasibility, toxicity, and pharmacokinetics in the maternal and fetal compartments during chemotherapy in a pregnant patient with cervical cancer. DESIGN: Case report. SETTING: University Hospital. PATIENT: A 35-year-old woman was diagnosed with an adenocarcinoma FIGO stage IB1 of the cervix uteri at 14 weeks' gestation with twin pregnancy. INTERVENTION(S): A laparoscopic transperitoneal pelvic lymphadenectomy was performed at 15 weeks' gestation There was no evidence of lymph node metastases (0/19). The patient decided to continue her pregnancy. Three cycles of neoadjuvant chemotherapy consisting of cisplatin during the second and third trimester were given and well tolerated. Amniocentesis was performed at the time of the second cisplatin cycle. MAIN OUTCOME MEASURE(S) AND RESULT(S): The concentration in the amniotic fluid samples reached 10% of the maternal blood levels at this time. At 32 weeks' gestation, a Caesarean section followed by radical hysterectomy was performed. The twins developed normally and displayed no chemotherapically related side effects. At the time of delivery, the corresponding concentration in the amniotic fluid was approximately one-third of the umbilical cord levels. CONCLUSION(S): To our knowledge, this is the first report quantifying the amount of transplacental transport of cisplatin during pregnancy in vivo. One-tenth of the maternal serum concentration was detected in the amniotic fluid; the concentration of cisplatin in the umbilical cord was three times higher than in the amniotic fluid.

Assessment of promising protein markers for vulva cancer.

OBJECTIVES: To validate the results of a previous study with the tissue microarray technology showing that cyclooxygenase 2 (COX-2) overexpression and absent caspase 3 expression are associated with poor disease-specific survival in univariate analysis. METHODS: The study group comprised 80 consecutive patients with vulva cancer treated in the period from 1999 to 2003 in a university hospital. A tissue microarray with 3 tumor tissue cores per patient was constructed and stained with antibodies against COX-2, caspase 3, epidermal growth factor receptor, p16 INK4, cyclin D1, and Ki-67. The impact of the expression of these protein markers and selected clinicopathologic variables on disease-specific as well as disease-free survival was measured. Cox proportional hazard model was used for both univariate and multivariate analyses. RESULTS: In multivariate analysis, lymph node metastases and strong COX-2 expression were related to disease-free (hazard ratio [HR], 8.33, 95% confidence interval [CI], 2.97-23.36; P < 0.001; and HR, 6.42; 95% CI, 2.33-17.72; P < 0.001) and disease-specific survival (HR, 6.04; 95% CI, 2.12-17.19; P = 0.001; and HR, 5.11; 95% CI, 1.82-14.36; P = 0.002). In the present series, no association was found between caspase 3 expression and survival. CONCLUSION: The prognostic significance of COX-2 overexpression was confirmed. In contrast, in the present series, no relation was found between caspase 3 expression and survival.

The efficacy of hormonal treatment for residual or recurrent low-grade endometrial stromal sarcoma. A retrospective study.

OBJECTIVE: Low-grade endometrial stromal sarcoma (EES) is a rare tumour with a high recurrence rate but a very good prognosis. Responses to hormonal treatment of these recurrences have been published in case reports. The aim of this study was to determine the objective response rate and response duration of hormonal treatment for recurrent or residual low-grade ESS in a consecutive series of patients. STUDY DESIGN: Thirteen consecutive patients with residual or recurrent disease were retrieved from the files. Eleven patients with measurable disease were treated with hormones and form the basis of this study. The following data were collected: age, date of primary diagnosis, type of primary treatment, the presence and localization of residual or recurrent disease, type of treatment, response, duration of response and survival. RESULTS: After hormonal treatment 9 (82%) patients showed an objective response (4 complete response; 5 partial response), one showed stable disease (26+ months) and one progressive disease. Response duration was from 4+ to 252+ months (median 48+ months). CONCLUSION: Hormonal treatment for measurable residual or recurrent low-grade ESS has a high response rate and should be considered as the treatment of choice for patients in which recurrent disease cannot easily be resected.