Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe.

OBJECTIVE: Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN. METHODS: We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up. RESULTS: Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence. CONCLUSION: The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.

"Locus minoris resistentiae" and connective tissue weakness in older women: a case report and literature review on pelvic organ prolapse with inguinal bladder hernia.

BACKGROUND: Conditions such as genital prolapse and hernia are known to be related to connective tissue dysfunction. In this report on cases of the rare simultaneous finding of large genital prolapse and post-prolapse repair female inguinal bladder hernia, we aim to contribute to the discussion of a possible clinical definition of connective tissue weakness, for its clinical assessment and preoperative patient counselling. CASE PRESENTATION: Three cases of medial third-grade (MIII, Aachen classification) inguinal bladder hernia developing or enlarging after successful stage-IV pelvic organ prolapse (POP) repair at a university pelvic floor centre are presented. All patients were aged ≥ 80 years with long-standing postmenopausal status. One patient was followed for 5 years and two patients were followed for 6 months. In all patients, ultrasound revealed that the hernia sac contained the urinary bladder, which had herniated through the inguinal hernia orifice. A literature search revealed only one case report of direct female inguinal bladder hernia and few investigations of the simultaneous occurrence of POP and hernia in general. CONCLUSION: The simultaneous occurrence of inguinal hernia and female POP can lead to bladder herniation following prolapse surgery in the sense of a "locus minoris resistentiae". Clinical examination for simultaneous signs of connective tissue weakness and counselling prior to pelvic reconstructive surgery could help to increase patients' compliance with further surgical treatment for hernia.

Ten-year results of intense dose-dense chemotherapy show superior survival compared with a conventional schedule in high-risk primary breast cancer: final results of AGO phase III iddEPC trial.

Background: Primary breast cancer (BC) patients with extensive axillary lymph-node involvement have a limited prognosis. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) trial compared intense dose-dense (idd) adjuvant chemotherapy with conventionally scheduled chemotherapy in high-risk BC patients. Here we report the final, 10-year follow-up analysis. Patients and methods: Enrolment took place between December 1998 and April 2003. A total of 1284 patients with 4 or more involved axillary lymph nodes were randomly assigned to receive 3 courses each of idd sequential epirubicin, paclitaxel and cyclophosphamide (iddEPC) q2w or standard epirubicin/cyclophosphamide followed by paclitaxel (EC â†’ P) q3w. Event-free survival (EFS) was the primary end point. Results: A total of 658 patients were assigned to receive iddEPC and 626 patients were assigned to receive EC â†’ P. The median duration of follow-up was 122 months. EFS was 47% (95% CI 43% to 52%) in the standard group and 56% (95% CI 52% to 60%) in the iddEPC group [hazard ratio (HR) 0.74, 95% CI 0.63-0.87; log-rank P = 0.00014, one-sided]. This benefit was independent of menopausal, hormone receptor or HER2 status. Ten-year overall survival (OS) was 59% (95% CI 55% to 63%) for patients in the standard group and 69% (95% CI 65% to 73%) for patients in the iddEPC group (HR = 0.72, 95% CI 0.60-0.87; log-rank P = 0.0007, two-sided). Nine versus two cases of secondary myeloid leukemia/myelodysplastic syndrome were observed in the iddEPC and the EC â†’ P arm, respectively. Conclusion: The previously reported OS benefit of iddEPC in comparison to conventionally dosed EC â†’ P has been further increased and achieved an absolute difference of 10% after 10 years of follow-up.

Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I.

OBJECTIVE: In 2008 GROINSS-V-I, the largest validation trial on the sentinel node (SN) procedure in vulvar cancer, showed that application of the SN-procedure in patients with early-stage vulvar cancer is safe. The current study aimed to evaluate long-term follow-up of these patients regarding recurrences and survival. METHODS: From 2000 until 2006 GROINSS-V-I included 377 patients with unifocal squamous cell carcinoma of the vulva (T1, <4 cm), who underwent the SN-procedure. Only in case of SN metastases an inguinofemoral lymphadenectomy was performed. For the present study follow-up was completed until March 2015. RESULTS: Themedian follow-up was 105 months (range 0­179). The overall local recurrence ratewas 27.2% at 5 years and 39.5% at 10 years after primary treatment, while for SN-negative patients 24.6% and 36.4%, and for SN-positive patients 33.2% and 46.4% respectively (p = 0.03). In 39/253 SN-negative patients (15.4%) an inguinofemoral lymphadenectomy was performed, because of a local recurrence. Isolated groin recurrence rate was 2.5% for SN-negative patients and 8.0% for SN-positive patients at 5 years. Disease-specific 10-year survival was 91% for SN-negative patients compared to 65% for SN-positive patients (p b .0001). For all patients, 10-year disease-specific survival decreased from 90% for patients without to 69% for patients with a local recurrence (p b .0001).

Risk index for pelvic organ prolapse based on established individual risk factors.

PURPOSE: To identify known risk factors for pelvic organ prolapse (POP) in a hospital cohort and to develop a prolapse risk index (PRI). METHODS: Risk factors for POP were recorded in women who underwent surgery with symptomatic POP (n = 500) or non-POP gynaecological conditions (n = 236). Descriptive statistics were determined by Chi-squared and Mann-Whitney U tests. Stepwise multivariate regression analysis was performed for all patients and subgroups by age (<60 and ≥60 years). Primary outcome measures were variables with the strongest impact on prolapse and PRI development. Secondary: specificity, sensitivity, positive and negative predictive values (PPV and NPV, respectively), and Cohen's kappa statistic (κ). RESULTS: Stepwise multivariate regression analysis (n = 736) showed difficult obstetric history [odds ratio (OR) 10.04], family history of POP (OR 7.28), and ≥10 years since menopause (OR 4.53) were independent risk factors for prolapse (P < 0.001). When one of the three variables with the strongest influence on POP development was present, the PRI for all women showed a PPV of 82%, NPV of 68%, and κ of 0.47 for predicting symptomatic POP requiring treatment. In women under 60 years (n = 349), logistic regression revealed difficult obstetric history (OR 9.108), positive family history (OR 8.016), and body mass index (OR 2.274) as independent risk factors. CONCLUSIONS: Eighty-seven percent of our patient cohort with symptomatic POP requiring therapy could be identified by the PRI, which may be useful for counselling and education.

Sonographic discrimination between benign and malignant adnexal masses in premenopause.

PURPOSE: The aim of this study was to assess the diagnostic value of sonographic pattern recognition by experts, a standardized morphological scoring system, the risk malignancy index (RMI) and CA 125 assay for the preoperative assessment of ovarian lesions in premenopausal patients. MATERIAL AND METHODS: Diagnostic work-up of 1320 patients who underwent surgical exploration due to an adnexal mass at a tertiary referral center were included. We assessed the discriminative value of pattern recognition, a sonographic morphological scoring system, RMI and CA 125 by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Cohen's kappa for each diagnostic approach while using histopathology as the reference standard. RESULTS: Pattern recognition showed the highest discriminative power with an observed kappa of 0.53. Sensitivity and specificity yielded 0.76 and 0.97 respectively. Combining pattern recognition with CA 125 serum measurement in the context of a triage system diminished the diagnostic value (kappa: 0.24; sensitivity: 0.29 specificity: 0.97). For the RMI we observed a sensitivity of 0.54 and a specificity of 0.96 and estimated kappa value yielded 0.37. Omitting the CA 125 assay and using a morphological sonographic assessment system increased the kappa value to 0.45 with sensitivity and specificity observed at 0.61 and 0.97 respectively. CONCLUSION: Expert pattern recognition was found to be the method with the highest discriminative power in assessing an adnexal mass during premenopause. Additional assessment of serum CA 125 diminished the diagnostic accuracy. Standardized morphological sonographic assessment resulted in a moderate diagnostic accuracy. Supplementing the morphological sonographic assessment with CA 125 by using the RMI algorithm did not improve the diagnostic value.

Laparoscopic lymphocele fenestration in gynaecological cancer patients after retroperitoneal lymph node dissection as a first-line treatment option.

OBJECTIVE: To evaluate laparoscopic lymphocele fenestration (LLF) as a first-line treatment in gynaecological cancer patients with a history of retroperitoneal lymph node dissection (LND). DESIGN: Retrospective cohort study. SETTING: A tertiary referral centre. POPULATION: Patients who underwent LLF between January 2001 and December 2010 for a symptomatic lymphocele following retroperitoneal LND. METHODS: Surgical outcomes of 102 patients who underwent LLF at our hospital between January 2001 and December 2010 were analysed. Patients were identified using hospital database search software, and hand-written and electronic charts were reviewed. MAIN OUTCOME MEASURES: Outcomes included operating time, blood loss, conversion rate, intra- and postoperative complication rates, hospital stay and relapse rate. RESULTS: A total of 132 lymphoceles were fenestrated in 102 patients. The mean duration of surgery was 115.6 minutes and the average intraoperative blood loss per patient was 146 ml. The overall conversion rate to laparotomy was 7.8%. Intra- and postoperative complication rates were estimated at 9.8 and 5.9%, respectively. The rate of intraoperative and postoperative complications was significantly higher in patients after pelvic plus paraaortic LND (23.8%), compared with those after pelvic LND only (3.6%; P > 0.01). The mean follow-up time was 60.4 months and a total of seven symptomatic recurrences of lymphoceles were observed (a recurrence rate of 6.9%). CONCLUSIONS: For the treatment of symptomatic lymphoceles, LLF has previously been established as an efficient first-line treatment option in a post-transplant context. Our data suggest that these favourable results for LLF may be transferable to gynaecological cancer patients.

Ovarian cancer prevention by opportunistic salpingectomy is a new de facto standard in Germany.

PURPOSE: The most prevalent and aggressive subtype of epithelial ovarian carcinoma (EOC), high-grade serous carcinoma (HGSC), originates in many cases from the fallopian tubes. Because of poor prognosis and lack of effective screening for early detection, opportunistic salpingectomy (OS) for prevention of EOC is being implemented into clinical routine in several countries worldwide. Taking the opportunity of a gynecological surgery in women at average cancer risk, extramural fallopian tubes are completely resected preserving the ovaries with their infundibulopelvic blood supply. Until recently, only 13 of the 130 national partner societies of the International Federation of Obstetrics and Gynecology (FIGO) have published a statement on OS. This study aimed to analyze the acceptance of OS in Germany. METHODS: (1) Survey of German gynecologists in 2015 and 2022 by the Department of Gynecology of the Jena University Hospital in co-operation with the Department of Gynecology at Charité-University Medicine Berlin with support of NOGGO e. V. and AGO e. V. (2) Salpingectomy numbers in Germany for years 2005-2020 as retrieved from the Federal Statistical Office of Germany (Destatis). RESULTS: (1) Survey: Number of participants was 203 in 2015 and 166 in 2022, respectively. Nearly all respondents (2015: 92%, 2022: 98%) have already performed bilateral salpingectomy without oophorectomy in combination with benign hysterectomy with the intention to reduce the risk for malignant (2015: 96%, 2022: 97%) and benign (2015: 47%, 2022: 38%) disorders. Compared to 2015 (56.6%), considerably more survey participants performed OS in > 50% or in all cases in 2022 (89.0%). Recommendation of OS for all women with completed family planning at benign pelvic surgery was approved by 68% in 2015 and 74% in 2022. (2) Case number analysis: In 2020, four times more cases of salpingectomy were reported by German public hospitals compared to 2005 (n = 50,398 vs. n = 12,286). Of all inpatient hysterectomies in German hospitals in 2020, 45% were combined with salpingectomy, and more than 65% in women at the age of 35 to 49 years. CONCLUSION: Mounting scientific plausibility regarding involvement of fallopian tubes in the pathogenesis of EOC led to change of clinical acceptance of OS in many countries including in Germany. Case number data and widespread expert judgment demonstrate that OS has become a routine procedure in Germany and a de facto standard for primary prevention of EOC.

A randomized phase III adjuvant study in high-risk cervical cancer: simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): a NOGGO-AGO Intergroup Study.

BACKGROUND: Simultaneous adjuvant platinum-based radiochemotherapy in high-risk cervical cancer (CC) is an established treatment strategy. Sequential paclitaxel (Taxol) and platinum followed by radiotherapy may offer further advantages regarding toxicity. PATIENTS AND METHODS: An open-labeled randomized phase III trial was conducted to compare paclitaxel (175 mg/m(2)) plus carboplatin (AUC5) followed by radiation (50.4 Gy) (experimental arm-A) versus simultaneous radiochemotherapy with cisplatin (40 mg/m(2)/week) (arm-B) in patients with stage IB-IIB CC after surgery. Primary objective was progression-free survival (PFS). RESULTS: Overall, 271 patients were randomized and 263 were eligible for evaluation; 132 in arm-A and 131 in arm-B appropriately balanced. The estimated 2-year PFS was 81.8% [95% confidence interval (CI) 74.4-89.1] in arm-B versus 87.2% (95% CI 81.2-93.3) in arm-A (P = 0.235) and the corresponding 5-year survival rates were 85.8% in arm-A and 78.9% in arm-B (P = 0.25). Hematological grade 3/4 toxicity was higher in arm-B. Alopecia (87.9% versus 4.1%; P < 0.001) and neurotoxicity (65.9% versus 15.6%; P < 0.001) were significantly higher in arm-A. Early treatment termination was significantly more frequent in arm-B than in arm-A (32.1% versus 12.9%; P = 0.001). CONCLUSIONS: Sequential chemotherapy and radiation in high-risk CC could not show any significant survival benefit; however, a different toxicity profile appeared. This sequential regime may constitute an alternative option when contraindications for immediate postoperative radiation are present.

[Space-occupying tumor of the temporal region with facial nerve palsy, vestibular dysfunction and hearing loss]. / Raumforderung der Regio temporalis bei Fazialisparese, vestibulärem Ausfall und Hörminderung.

A 73-year-old female patient complained of right-sided facial pain, progressive loss of hearing, giddiness when changing position, a pre-auricular swelling and lack of facial expression. Clinically there was a right-sided indolent and immovable swelling approximately 7 cm in size and an incomplete ipsilateral acute peripheral facial paralysis. Magnetic resonance tomography revealed a space-occupying lesion approximately 75 mm in diameter right temporal and multilocular metastases in the pelvis, spinal column, clavicle and skull. Histology showed this to be a well to moderately differentiated adenocarcinoma with centers of positive immune response to GCDFP-24 (gross cystic disease fluid protein). The subsequent computed tomography of the thorax and mammography located the approximately 25 mm in size primary tumor in the left breast. After surgery and radiation therapy the TNM classification was a tubular adenocarcinoma of the left breast grade 2, T2N0M1 (OSS multiple osseous, BRA brain) stage IV.

Inverse correlation between urethral length and continence before and after native tissue pelvic floor reconstruction.

Urethral length was evaluated retrospectively in patients with prolapse undergoing anterior native-tissue repair. Effects of age, prolapse stage, defect pattern, urodynamic and clinical stress test findings, and tension-free vaginal tape (TVT) surgery indication were analyzed using Mann-Whitney and Wilcoxon tests and linear and logistic regression. Of 394 patients, 61% had stage II/III and 39% had stage IV prolapse; 90% of defects were central (10% were lateral). Median pre- and postoperative urethral lengths were 14 and 22 mm (p < 0.01). Preoperative urethral length was greater with lateral defects [p < 0.01, B 6.38, 95% confidence interval (CI) 4.67-8.08] and increased stress incontinence risk (p < 0.01, odds ratio 1.07, 95% CI 1.03-1.12). Postoperative urethral length depended on prolapse stage (p < 0.01, B 1.61, 95% CI 0.85-2.38) and defect type (p = 0.02, B - 1.42, 95% CI - 2.65 to - 0.2). Postoperatively, TVT surgery was indicated in 5.1% of patients (median 9 months), who had longer urethras than those without this indication (p = 0.043). Native-tissue prolapse repair including Kelly plication increased urethral length, reflecting re-urethralization, particularly with central defects. The functional impact of urethral length in the context of connective tissue aging should be examined further.

Treatment of endometriosis of uterosacral ligament and rectum through the vagina: description of a modified technique.

BACKGROUND: Endometriosis is common in women of childbearing age, whereas involvement of the rectosigmoid requiring resection is rare. Laparoscopy has become a standard procedure in the management of endometriosis. The optimum way to diagnose endometriosis is by direct visualization of the implants. Usually for the removal of the specimen, an additional larger abdominal incision is needed. METHODS: Here we report on cases of four patients with a uterosacral ligament and rectal endometriosis who were successfully treated with combined laparovaginal resection, using a modification of an existing technique. They had been complaining of rectal bleeding and lower abdominal pain in relation to their menstrual cycle. The aim of this technique is to achieve a careful and margin-free resection of the area involved. This can be done without any large incisions of the abdominal wall. The hypogastric nerves remain preserved on both sides. RESULTS: The intra- and post-operative courses were uneventful. No blood transfusions were needed. Haemoglobin decrease was usually < or =1 mmol/l. The average tumour diameter was 3.5 cm. CONCLUSIONS: Our technique circumvents a larger abdominal incision. This combined laparoscopic-transvaginal approach, avoiding the extension of port-site incisions, represents a viable option for the treatment of bowel endometriosis.

Sentinel lymph node biopsy in vulvar cancer: a pilot study.

BACKGROUND: The aim of the pilot study was to assess the feasibility, efficacy, and accuracy of the sentinel lymph node biopsy (SLNB) procedure in vulvar cancer. PATIENTS AND METHODS: From February 2003 to March 2007, 17 patients with vulvar cancer, clinical Stages I and II, underwent SLN (sentinel lymph node) detection, followed by a complete inguinal-femoral lymphadenectomy. Demographic, surgical, and pathologic data on all patients were reviewed. RESULTS: 17 patients underwent the SLNB procedure. Sixteen had vulvar carcinoma and one patient suffered from melanoma of the vulva. Midline localisation was done in 11 patients (64.7%). A total of 371 lymph nodes were resected. The median number of removed lymph nodes was 15 (range 2 to 81). Nineteen lymph nodes were positive with a maximum of six in one patient. Overall the detection rate for the sentinel lymph node was 88.2% (15 out of 17). One of the two patients with a non detectable sentinel node had positive lymph nodes. Eighty lymph nodes were detected as the sentinel node. The median number of sentinel nodes was five (range 0 to 11). Seventeen sentinel nodes were involved. The sentinel node was negative in nine patients; one of these had involved lymph nodes. CONCLUSIONS: SLNB is feasible and safe to perform in vulvar cancer. Further evaluation is needed until new guidelines allow the use in early-stage vulvar cancer.

Ablative dual-phase Erbium:YAG laser treatment of atrophy-related vaginal symptoms in post-menopausal breast cancer survivors omitting hormonal treatment.

PURPOSE: First evaluation of dual-phase vaginal Er:YAG laser to omit hormonal treatment for atrophy-related symptoms in post-menopausal breast cancer survivors following prolapse surgery. METHODS: Patients with a history of breast cancer at the time of surgery for pelvic organ prolapse were offered non-hormonal vaginal Er:YAG laser treatment when complaining of atrophy-related genitourinary syndrome of menopause. A single 10-min course of dual-phase protocol of pulsed Er:YAG laser (2940 nm, fractional ablative and thermal mode, fluence according to tissue thickness). Follow-up included subjective satisfaction, vaginal pH, vaginal health index (VHI), and complications after 6 weeks. RESULTS: A total of 16 breast cancer survivors (age 71 years, SD 7) had been seeking treatment for pelvic floor symptoms related to vaginal atrophy at follow-up visits after prolapse surgery. All ablative vaginal Er:YAG laser outpatient procedures were successfully completed, all patients returned to daily activities without a need for analgetic medication. Evaluation was performed after 8.3 (SD 2.5) weeks. Pre-laser VHI scored 16 (SD 4.6) and post-laser VHI 20 (SD 3) with p = 0.01. Patients were satisfied in 94% (n = 15) regarding symptom relief. CONCLUSIONS: Breast cancer survivors with atrophy-related complaints after pelvic floor surgery may benefit from vaginal application of this innovative dual protocol of Er:YAG laser technology as a non-hormonal treatment approach.

Progesterone receptor gene polymorphism is associated with decreased risk for breast cancer by age 50.

In a population-based case-control study for breast cancer before the age of 51 years, 554 cases and 559 age-matched controls were genotyped for the polymorphic progesterone receptor allele PROGINS. Breast cancer risk was decreased in women carrying the PROGINS allele. The odds ratio adjusted for age and study region was 0.76 [95% confidence interval (CI), 0.58-1.00]. Compared with wild-type A1/A1 homozygotes, the odds ratio for A1/A2 heterozygotes and A2/A2 homozygotes was 0.82 (95% CI, 0.62-1.08) and 0.27 (95% CI, 0.10-0.74), respectively, suggesting a gene dosage effect of the A2 allele. There was suggestive evidence for a differential effect by menopausal status (P = 0.07) and by family history of breast cancer (P = 0.15).

Gynaecological Prolapse Surgery in Very Old Female Patients: A Case-Control Study on Co-Morbidity and Surgical Complications.

BACKGROUND: The aim of this study is to compare very elderly female patients with a younger control group after prolapse surgery with regard to co-morbidity and complications. METHOD: In a case-control design, the consecutive data of patients after prolapse surgery at the age of over 80 years and those of a control group were analysed by means of the Clavien-Dindo (CD) classification of surgical complications, the Charlson Comorbidity Index and the Cumulative Illness Rating Scale Geriatrics (CIRS-G). Statistics: Student's t, Fisher's exact and Mann-Whitney U tests. RESULTS: The analysis comprised n = 57 vs. n = 60 operations. In the very elderly patients there was often a grade IV prolapse (p < 0.001), apical fixations were more frequent (p < 0.001), but the operating times were not different. In the very elderly patients 21 % CD II+III complications were observed, in the control group 6.6 % (p = 0.031). No CD IV and V complications occurred in either group, the duration of inpatient stay amounted to 5 (± 1) vs. 4.1 (± 0.8; p < 0.001) days, the very elderly patients needed an inpatient follow-up more frequently (p < 0.001). The co-morbidities of the very elderly patients differed from those of the control group in number (median 2.0 vs. 1.5; p < 0.001), in CIRS-G (4.1 ± 2.2 vs. 2.4 ± 1.7; p < 0.01) and in Charlson Index (1.6 ± 1.6 vs. 0.5 ± 0.7; p < 0.001). CONCLUSIONS: A prolapse in very elderly women can be safely managed by surgery. In no case did the complications require intensive care treatment nor were they life-threatening, but they did lead to a longer duration of hospital stay and more frequently to further treatment geriatric or inpatient internal medicine facilities.

Altered WAF1 genes do not play a role in abnormal cell cycle regulation in breast cancers lacking p53 mutations.

Seventy-five to 80% of breast cancers are negative for p53 gene mutations. We have investigated the possibility that altered WAF1 genes provide an alternative mode of cell cycle disruption in these tumors. DNA from a total of 85 primary breast tumors and cell lines from both the United States and Australia were examined for WAF1 and p53 mutations. With the exception of one primary tumor containing the polymorphic codon 31 (AGC-->AGA), no missense mutations in the WAF1 gene were found in 33 primary tumors or in the 19 cell lines from the United States. By contrast, 2 of 33 tumors from Australia contained tumor-specific missense mutations in the WAF1 gene, while an additional six cases contained the AGC-->AGA polymorphic 31st codon in the WAF1 gene. The p53 mutation frequency in the Australian cohort (18%) was found to be similar to that reported by us (Glebov et al., Cancer Res., 54: 3703-3709, 1994; Runnebaum et al., Proc. Natl. Acad. Sci. USA, 88: 10657-10661, 1991) in the tumors of United States patients (13%) with sporadic breast cancer. Thus, mutations in the WAF1 gene are rare in tumors with or without p53 mutations, suggesting that except in a minor population of breast cancer patients of Caucasian origin, cell cycle dysregulation by mutated p53 or WAF1 genes may not contribute to breast tumor initiation or progression.

Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer.

PURPOSE: The p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in ovarian cancer patients. EXPERIMENTAL DESIGN: One hundred seventy-eight ovarian carcinomas, snap frozen and stored at -80 degrees C, were analyzed for mutations of the p53 gene (exons 2-11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry (monoclonal antibody DO7). RESULTS: p53 mutations were found in 56% (99 of 178) of the tumors, and 62% of these were located in evolutionary highly conserved domains of the gene. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared with wild-type p53 (P = 0.029 and P = 0.014) and patients with mutations in highly conserved domains as opposed to nonconserved domains or wild-type p53 (P = 0.010 and P = 0.007). p53 protein overexpression (>10% positively stained nuclei) was found in 62% (110 of 178). Time to progression and overall survival were shorter in cases with p53 overexpression (cutpoint, 10%: P = 0.071 and P = 0.056) but only marginally significant. Resistance to adjuvant cisplatin or carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (P = 0.001) or p53 missense mutations (P = 0.008) than patients with normal p53. CONCLUSIONS: p53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor.

Adenoviral transduction efficiency of ovarian cancer cells can be limited by loss of integrin beta3 subunit expression and increased by reconstitution of integrin alphavbeta3.

Recombinant adenoviruses expressing a therapeutic gene are currently used in clinical studies for treatment of advanced ovarian cancer. We therefore tested whether the expression level of primary (CAR) and secondary adenovirus receptors (integrins) was predictive of the efficacy of adenoviral gene transfer in ovarian cancer cells. Adenoviral transduction efficiency (ATE) was determined with an E1-deleted adenovirus type 5 expressing beta-galactosidase under a CMV promoter (AdGal). ATE was studied in relationship to the expression level of both CAR (coxsackie and adenovirus receptor) and integrins. A representative sample of 25 permanent human cell lines established from advanced ovarian cancer in our laboratory and the OV-2774 cell line were tested. Overall, ATE increased with increasing titers of AdGal. At a given titer of 50 infectious units per cell, transduction efficiency varied from 6 to 94% among the individual cell lines. All cell lines expressed CAR and integrin alpha(v)beta(5), but no relation between ATE and expression level of CAR or alpha(v)beta(5) integrin was observed. In contrast, cell lines with poor ATE, despite expressing high levels of CAR, lacked expression of integrins alpha(v)beta(3) and alpha(5)beta(1). Reconstitution of alpha(v)beta(3) integrin by reexpressing the beta(3) subunit significantly enhanced ATE of ovarian cancer cells. In ovarian cancer, neither integrins nor CAR alone appear to be potentially useful predictive markers for ATE by serotype 5 adenovirus in clinical gene therapy. A minimum level of CAR necessary for binding of adenoviruses was observed in all tested ovarian cancer cell lines. Loss of alpha(v)beta(3) integrin is frequently associated with advanced stages of ovarian cancer and can significantly reduce ATE.

Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives.

Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth.