Urological outcomes following pelvic exenteration for non-urological malignancies.

Background: Pelvic exenteration (PE) is a major surgical procedure used as a salvage therapy for patients with locally advanced or recurrent pelvic malignancies. Urinary reconstruction is a major part of PE and is often associated with high rates of post-operative complications. In the current study we evaluate the short and long-term urological outcomes following PE for Colo-Rectal (CR) and gyneco-oncological (GO) malignancies. Methods: Study included 22 patients who underwent PE for recurrent or locally advanced CR and GO malignancies in our institution between the years 2010-2018. The endpoint was post-operative freedom from urological complications. Results: Of 22 patients included, 13 (59 %) and 9 (41 %) underwent PE for CR and GO malignancies respectively. The mean age of the patients was 54 years. The median follow-up was 19 months. Seven (78 %) patients with GO malignancy and 11 (85 %) with CR malignancy underwent PE for local recurrence. Hydronephrosis prior to surgery existed in 8 (36.3 %) patients, of which, 5 patients required kidney drainage via nephrostomy tube. Two patients underwent posterior pelvic exenteration (PPE) with bladder preservation whereas the remaining 20 underwent cystectomy with urinary diversion by ileal conduit. Hydronephrosis post PE developed in 13 patients (59 %). eight (36 %) patients needed kidney drainage by nephrostomy tubes post PE, of these, 6 (75 %) had disease recurrence. The 2 years freedom from kidney drainage was 68 %, however the median time for kidney drainage was 0.5 months. The median overall survival was 12.5 months. Conclusion: The rate of urological complications following PE is relatively high and associated with disease recurrence.

Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial.

BACKGROUND: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. PATIENTS AND METHODS: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. RESULTS: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). CONCLUSIONS: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.

An antibody to amphiregulin, an abundant growth factor in patients' fluids, inhibits ovarian tumors.

Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progression and, accordingly, antibodies that intercept a cognate receptor, epidermal growth factor receptor (EGFR)/ERBB1, or a co-receptor, HER2, have been approved for cancer therapy. Although they might improve safety and delay onset of chemoresistance, no anti-ligand antibodies have been clinically approved. To identify suitable ligands, we surveyed fluids from ovarian and lung cancer patients and found that amphiregulin (AREG) is the most abundant and generalized ligand secreted by advanced tumors. AREG is a low affinity EGFR ligand, which is upregulated following treatment with chemotherapeutic drugs. Because AREG depletion retarded growth of xenografted ovarian tumors in mice, we generated a neutralizing monoclonal anti-AREG antibody. The antibody inhibited growth of ovarian cancer xenografts and strongly enhanced chemotherapy efficacy. Taken together, these results raise the possibility that AREG and other low- or high-affinity binders of EGFR might serve as potential targets for cancer therapy.

FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis.

Serous ovarian carcinoma is the most lethal gynecological malignancy in Western countries. The molecular events that underlie the development of the disease have been elusive for many years. The recent identification of the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin for most cases of this disease has led to studies aimed at elucidating new candidate therapeutic pathways through profiling of normal FTSECs and serous carcinomas. Here we describe the results of transcriptional profiles that identify the loss of the tumor suppressive transcription factor FOXO3a in a vast majority of high-grade serous ovarian carcinomas. We show that FOXO3a loss is a hallmark of the earliest stages of serous carcinogenesis and occurs both at the DNA, RNA and protein levels. We describe several mechanisms responsible for FOXO3a inactivity, including chromosomal deletion (chromosome 6q21), upregulation of miRNA-182 and destabilization by activated PI3K and MEK. The identification of pathways involved in the pathogenesis of ovarian cancer can advance the management of this disease from being dependant on surgery and cytotoxic chemotherapy alone to the era of targeted therapy. Our data strongly suggest FOXO3a as a possible target for clinical intervention.

Exposure of fallopian tube epithelium to follicular fluid mimics carcinogenic changes in precursor lesions of serous papillary carcinoma.

OBJECTIVES: Ovulation-related inflammation is suspected to have a causal role in ovarian carcinogenesis, but there are no human models to study the molecular pathways. Our aim is to develop such an ex-vivo model based on human fallopian tube (FT) epithelium exposed to human follicular fluid (FF). METHODS: FT epithelium was dissociated from normal surgical specimens. FF was obtained from donors undergoing in-vitro fertilization. The cells were cultured on collagen-coated Transwells and incubated with FF for various periods of time. The transcriptomic changes resulting from FF treatment were profiled using Affymetrix expression arrays. Specific characteristics of the FT pre-cancerous lesions were studied using immunohistochemistry, immunofluorescence, RT-PCR and XTT assay. RESULTS: We show that FF exposure causes up-regulation of inflammatory and DNA repair pathways. Double stranded DNA breaks are induced. There is a minor increase in cell proliferation. TP53, which is the hallmark of the precursor lesion in-vivo, is accumulated. Levels of expression and secretion of Interleukin-8 are significantly increased. CONCLUSIONS: Our model addresses the main non-genetic risk factor for ovarian cancer, namely the impact of ovulation. This study demonstrates the biological implications of in-vitro exposure of human FT epithelial cells to FF. The model replicates elements characterizing the precursor lesions of ovarian cancer, and warrants further investigation of the linkage between repeated exposure to ovulation-related damage and accumulation of neoplastic changes.

Bowel obstruction in recurrent gynecologic malignancies: defining who will benefit from surgical intervention.

AIM: To define factors that could help select, in a cohort of gynecologic cancer patients with malignant gastro-intestinal obstruction, those most likely to benefit from palliative surgery. METHODS: In this retrospective study of patients with malignant gastro-intestinal obstruction who underwent palliative surgery in our institute over 7 years, outcome measures were oral intake, chemotherapy, and 30-day, 60-day and overall survival. Based on Cox proportional-hazards regression models and Kaplan-Meier curves with log-rank tests, a prognostic score was developed to identify those most likely to benefit from surgery. RESULTS: Sixty-eight palliative surgeries were performed in 62 patients with ovarian (69.1%), primary-peritoneal (8.8%), cervical (11.8%) or uterine (10.3%) malignancies. Procedures were colostomy (26.5%), ileostomy (39.7%), colonic stent (1.5%), gastrostomy (7.3%), gastroenterostomy (5.9%) and bypass/resection and anastomosis (19.1%). Eighteen patients died prior to discharge, within 3-81 days (median 25 days). The 30-day and 60-day mortality rates were 14.7% and 29.4%, respectively. Postoperative oral-intake and chemotherapy rates were 65% and 53%, respectively, with albumin level identified on multivariate analysis as the only significant predictor of both. Median postoperative survival was 106 days (3-1342). Bypass/resection and anastomosis was associated with improved survival. Ascites below 2 L, younger age, ovarian primary tumor, and higher blood albumin correlated with longer postoperative survival. A prognostic index based on these factors was found to identify patients with increased 30-day and 60-day mortality. CONCLUSIONS: Our proposed prognostic index, based on age, primary tumor, albumin and ascites, might help select those gynecological cancer patients most likely to benefit from palliative surgery.

Human immunodeficiency virus-associated thrombotic microangiopathies: clinical characteristics and outcome according to ADAMTS13 activity.

Human immunodeficiency virus (HIV) infection is a risk factor for thrombotic microangiopathy (TMA). We sought whether a severe deficiency in ADAMTS13, the enzyme specifically involved in the cleavage of von Willebrand factor, was associated with specific presenting features and outcome in HIV-associated TMA. In this prospective, multicentre, case-control study, 29 patients of 236 in the French Network on TMA had an HIV-associated TMA. Seventeen patients with severe ADAMTS13 deficiency (ADAMTS13 <5% HIV(+) group) were compared to 12 patients with a detectable ADAMTS13 activity (ADAMTS13 >or=5% HIV(+) group). HIV(+) patients were also compared to 62 patients with idiopathic TMA, either with (45 patients, ADAMTS13 <5% idiopathic group) or without (17 patients, ADAMTS13 >or=5% idiopathic group) severe ADAMTS13 deficiency. ADAMTS13 <5% HIV(+) patients had less AIDS-related complications than ADAMTS13 >or=5% HIV(+) patients (23.5% versus 91.6%, respectively, P = 0.0005) and their median CD4(+) T cell count was higher (P = 0.05). TMA-associated death rate was higher in ADAMTS13 >or=5% HIV(+) patients than in ADAMTS13 <5% HIV(+) patients (50% versus 11.7%, respectively, P = 0.04). In ADAMTS13 <5% patients, TMA-associated death rate was comparable between HIV(+) and idiopathic patients (15.5% in idiopathic patients, P-value was non-significant). By contrast, TMA-associated death rate in ADAMTS13 >or=5% HIV(+) patients was higher than in idiopathic patients (11.7% in idiopathic patients, P = 0.04). In conclusion, HIV-associated TMA with severe ADAMTS13 deficiency have less AIDS-related complications and a higher CD4(+) T cell count. TMA prognosis is better and comparable to this of idiopathic forms.

MRgFUS for pain relief as palliative treatment in recurrent cervical carcinoma: a case report.

INTRODUCTION: Focused ultrasound under real-time MR guidance and control (MRgFUS) can be used for the thermal ablation of tissue. Currently this technique is used clinically for the noninvasive treatment of uterine leiomyomas and is in clinical evaluation for breast cancer, adenomyosis and other indications. MRgFUS is being tested for pain relief in patients suffering from bone metastases. This is the first case to report on MRgFUS for pain relief in patients suffering from recurrent cervical carcinoma. CASE REPORT: A 29-year-old patient with recurrent squamous cell carcinoma of cervix following radical hysterectomy, chemotherapy and radiation was treated by MRgFUS due to pelvic mass unresponsive to conventional treatment that caused intractable pain. Following two treatments the patient experienced a marked reduction in pain and increase in Karnovsky Performance Status (KPS) from 50% to 80%. DISCUSSION: Palliative treatment of pain with noninvasive MRgFUS in cases of recurrent cervical carcinoma may be a safe and efficient alternative to other invasive techniques.

What are the indications for plasma exchanges in autoimmune diseases?: The registry of the Société Française d'Hémaphérèse.

The use of plasma exchange (PE) in the autoimmune diseases is encouraged in France. Since 1990, the national registry of PE allows an analysis of the evolution of the coverage of these pathologies. The variation of the number of patients treated by PE is correlated in respect to the results of the therapeutic studies. After a decrease of PE activity in these indications during the 90s, one observes a new increase of the patients treated because of the validation of new indications. Autoimmune diseases represent the third cause of morbidity in developed countries, with a global prevalence of 5%, and concerns four groups of pathologies of organs or systems (neurology, haematology, nephrology and vasculitis). In 1976, Lockwood demonstrated the place of plasma exchanges (PE) in Goodpasture's syndrome [Lockwood CM, Rees AJ, Pearson TA, Evans DJ, Peters DK, Wilson CB. Immunosuppression and plasma exchange in the treatment of Goopasture's syndrome. Lancet 1976;1(7962):723-6. [1]], with a significant decrease of antibodies during large volume exchanges. In the 80s, several prospective studies began to estimate the efficiency of PE in other autoimmune diseases. The national registry of the Société Française d' Hémaphérèse, has collected the epidemiological and technical data of PE since 1985. This work analyses the evolution of the validated indications, between 1990 and 2005 in France.

Vulvar cancer metastatic to the breast.

BACKGROUND: Vulvar cancer rarely sends metastases to distant sites. CASE: A 49-year-old female presented with a vulvar mass. The histologic examination revealed an infiltrating lesion with free surgical margins and no evidence of lymph node involvement. Four months following surgery, due to a bloody breast discharge and a palpable breast lump an excisional biopsy was performed. The histological evaluation revealed morphological features suggestive of metastatic squamous cell carcinoma. The morphological, immunohistochemical and in situ hybridization findings were consistent with a breast metastatic nodule of squamous cell carcinoma arising from the primary vulvar cancer. CONCLUSION: We conclude that the specimens are from the same origin therefore making the breast lesion a metastasis from the vulva.

Importance of accurate preoperative diagnosis in the management of aggressive angiomyxoma: report of three cases and review of the literature.

BACKGROUND: Aggressive angiomyxoma is a benign but locally aggressive tumor that occurs mostly in young women. Because excision is often incomplete, the risk of local recurrence is high. This report describes differences in presentation and the importance of accurate preoperative diagnosis of this rare neoplasm. METHODS AND RESULTS: We describe three cases with different presentations. Two were initially misdiagnosed, and local recurrence necessitated reoperation. Accurate diagnosis in the third case was followed by complete excision, with no recurrence. CONCLUSION: Aggressive angiomyxoma should be considered in the differential diagnosis of young women who present with a well-defined mass in the pelvic tissue. Accurate preoperative diagnosis should alert the surgeon to the need for wide excision, which is essential for prevention of local recurrence.

Indications for plasma exchange in systemic lupus erythematosus in 2005.

Plasma exchange can remove putative pathogenic autoantibodies and circulating immune complexes from the blood of patients with systemic lupus erythematosus (SLE). However, their efficacy has only been supported by noncontrolled and/or retrospective studies. Nonetheless, PE may still be of relevance in some selected SLE patients and as adjunctive therapy, in combination with corticosteroids (CS) and other immunosuppressant(s). We review herein the principal historical steps of the use of plasma exchange to treat SLE, based upon the main trials and case reports that have highlighted its most pertinent indications. Acute life-threatening manifestations and severe therapy-resistant manifestations, like refractory SLE renal disease, diffuse alveolar hemorrhage, neuropsychiatric SLE, thrombotic thrombocytopenic purpura, catastrophic antiphospholipid syndrome, hyperviscosity syndrome and cryoglobulinemia, are the indications for which plasma exchange might have a beneficial therapeutic role. Although few SLE patients undergo plasma exchange each year nowadays (10-20 per year in France), adverse events are very rare and recent advances in plasma exchange technologies, like immunoadsorption, might, in the future, counterbalance their cost and broaden their place in the therapeutic armamentarium for SLE.

Transvaginal ultrasound and diagnostic hysteroscopy as a predictor of endometrial polyps: risk factors for premalignancy and malignancy.

The aim of this study is to assess accuracy of transvaginal ultrasound (TVUS) and diagnostic hysteroscopy in diagnosing endometrial polyps and to determine premalignancy and malignancy rates in asymptomatic women. The study was designed to retrospectively analyze 438 women who underwent operative hysteroscopy in a day-care unit when endometrial polyp was suspected after TVUS and diagnostic hysteroscopy. Multivariate logistic regression modeling showed effects of age, previous breast cancer with tamoxifen treatment, and menopause with or without bleeding on pathologic results. The results indicate that positive predictive value of TVUS with diagnostic hysteroscopy was 79.9%. Premalignancy or malignancy occurred in 3.2% and was significantly related to menopause with abnormal bleeding (P < 0.001), which carried a 20-fold higher risk of pathology than any other group. Age was also a risk factor. It was concluded that TVUS with diagnostic hysteroscopy reliably evaluates endometrial polyps. The low incidence of endometrial tumors in asymptomatic (especially premenopausal) women suggests that their operative evaluation may not be cost effective. Larger studies are needed to support this tentative conclusion.

World apheresis association--world apheresis registry.

In 2002 WAA decided to start a world-wide apheresis registry to gain insight into the extent of treatment, adverse events, and to facilitate contacts among centers when treatment indications are rare and experience limited. Stem cell and other blood products collections intended for therapeutic application can also be entered. The WAA planned to use the French Registry. Its translation into English has not been accomplished and the fiscal obligations for that registry has not, as yet, been determined or considered and approved by the WAA Board. From Dec 2002 the proposed registry (a merged version of the French, Canadian and Swedish registries) can be immediately implemented. We now cordially invite all centers to join that registry. Please, also inform colleagues at other centers in your country to join. E-mail and address lists of colleagues in your country who have not registered will be welcomed. The site is at: Go to World Apheresis Registry; Login code to test the Registry is: al61tms. Then apply for a specific login code for your center. We welcome you to this registry for your input of data. You will not be charged any registration fee. The registry includes a randomization system that can be used for local or multi center studies (randomization by in-center basis allows you to make your own studies). It includes a formula that increases the chance to get a more even distribution between groups also for smaller sample sizes.

Plasma exchange in France: Epidemiology 2001.

The French plasma exchange registry created in 1985 lists the indications, techniques and complications of the French therapeutic haemapheresis. In 2001 it contains the data of more than 16,700 patients for a total of 153,641 sessions. The indications concern five groups of pathologies (neurology, haematology, nephrology, vasculitis, and endocrinology). Until 2000, the neurology represented the most important group but the use of the high dose IgIV for Guillain-Barre and myasthenia gravis decreased the indications. The haematology became most important group treated because of the increase of the TTP and HUS number treated. The endocrinology (familial hypercholesterolemia) represents at present 10% of the patients treated for 18.7% of the sessions. The vascular access little changed since 1985, the peripheral venous access being the most used. The plasma substitution initially based on the albumin alone was gradually replaced by an association albumin macromolecules, in particular hydroxyethylstarch since 1990. After the observation of the side effects due to starches we observed an increase of the albumin alone use. The immediate complications decreased in half in 15 years. The French plasma exchange registry is the largest world database of haemapheresis with the cooperation of about 80 centres, allowing numerous scientific studies.