Germline and somatic testing for ovarian Cancer: An SGO clinical practice statement.

Germline and somatic genetic testing have become critical components of care for people with ovarian cancer. The identification of germline and somatic pathogenic variants as well as homologous recombination deficiency can contribute to the prediction of treatment response, prognostic outcome, and suitability for targeted agents (e.g. poly (ADP-ribose) polymerase (PARP) inhibitors). Furthermore, identifying germline pathogenic variants can prompt cascade genetic testing for at-risk relatives. Despite the clinical benefits and consensus recommendations from several organizations calling for universal genetic testing in ovarian cancer, only about one third of patients complete germline or somatic genetic testing. The members of the Society of Gynecologic Oncology (SGO) Clinical Practice Committee have composed this statement to provide an overview of germline and somatic genetic testing for patients with epithelial ovarian cancer, focusing on available testing modalities and options for care delivery.

Creating work environments where people of all genders in gynecologic oncology can thrive: An SGO evidence-based review.

Equality, equity, and parity in the workplace are necessary to optimize patient care across all aspects of medicine. Gender-based inequities remain an obstacle to quality of care, including within the now majority women subspecialty of gynecologic oncology. The results of the 2020 SGO State of the Society Survey prompted this evidence-based review. Evidence related to relevant aspects of the clinical care model by which women with malignancies are cared for is summarized. Recommendations are made that include ways to create work environments where all members of a gynecologic oncology clinical care team, regardless of gender, can thrive. These recommendations aim to improve equality and equity within the specialty and, in doing so, elevate the care that our patients receive.

The importance of hyperosmolarity in diabetic ketoacidosis.

AIM: Diabetic ketoacidosis is a hyperglycaemic emergency that is often treated in intensive care units (ICUs) despite having a low mortality and good prognosis. Current risk stratification is based primarily on acidosis, but it has been suggested that hyperosmolarity may also be an important marker of increased severity. Our aim was to evaluate the relationship between raised serum osmolarity and adverse clinical outcomes in ICU admissions for ketoacidosis. METHODS: Retrospective review of prospectively collected data for adult admissions with ketoacidosis in the Australian and New Zealand Intensive Care Society Adult Patient Database over a 15-year period (2004-2018). Exclusions were readmissions and records with critical missing data. Serum hyperosmolarity was defined as > 320 mosm/l. The primary outcome was hospital mortality; secondary outcomes were ICU mortality and other adverse clinical events. RESULTS: Some 17 379 admissions were included in the study population. People with hyperosmolarity had fourfold increased mortality, a higher incidence of renal failure and need for mechanical ventilation, and prolonged ICU and hospital length of stay. The relationship with mortality remained highly significant even after adjusting for severity of acidosis, hospital type, year of admission, time to ICU, and a modified Australia and New Zealand Risk of Death propensity score. CONCLUSIONS: Although adults with ketoacidosis have a good prognosis overall, hyperosmolarity was independently associated with a significantly higher incidence of multiple adverse outcomes including mortality. Whether or not this is directly causal, it may have practical applications to improve risk stratification and identify individuals at risk of adverse outcomes.

IL-4 receptor α blockade prevents sensitization and alters acute and long-lasting effects of allergen-specific immunotherapy of murine allergic asthma.

BACKGROUND: Allergen-specific immunotherapy (AIT) is the only causal treatment for allergy. However, success rates vary depending on the type of allergy and disease background of the patient. Hence, strategies targeting an increased therapeutic efficacy are urgently needed. Here, the effects of blockade of IL-4 and IL-13 signaling on different phases of AIT were addressed. METHODS: The impact of the recombinantly produced IL-4 and IL-13 antagonist IL-4 mutein (IL-4M) on allergic sensitization and AIT outcome in experimental allergic asthma were analyzed in a murine model. The effects of IL-4M administration were assessed prior/during sensitization, immediately after AIT under allergen challenge, and two weeks post-treatment. RESULTS: Intervention with IL-4M prior/during sensitization led to strong induction of IgG1, IgG2a, IgG2b, and IgG3, decrease of specific and total IgE, as well as of IL-5 in serum. Similar effects on the serum immunoglobulin levels were observed immediately after IL4M-supplemented AIT during allergen challenge. Additionally, IL4M markedly suppressed type-2 cytokine secretion of splenocytes beyond the effect of AIT alone. These effects were equaled to those of AIT alone two weeks post-treatment. Intriguingly, here, IL-4M induced a sustained decrease of Th2-biased Tregs (ST2+ FOXP3+ GATA3intermediate ). CONCLUSIONS: IL-4 and IL-13 blockade during experimental AIT demonstrates beneficial effects on immunological key parameters such as immunoglobulin and cytokine secretion immediately after AIT. Although two weeks later these effects were dropped to those of AIT alone, the number of potentially disease-triggering Th2-biased Tregs was further significantly decreased by IL-4M treatment. Hence, IL-4/IL13-targeting therapies prime the immune memory in therapy success-favoring manner.

A novel pretherapeutic gene expression-based risk score for treatment guidance in gastric cancer.

Background: Perioperative chemotherapy is an established treatment of advanced gastric cancer patients. Treatment selection is based on clinical staging (cT). We aimed to establish and validate a prognostic score including clinical and molecular factors, to optimize treatment decisions for these patients. Patients and methods: We analyzed 626 carcinomas of the stomach and of the gastro-esophageal junction from two academic centers including primarily resected and pre-/perioperatively treated patients. Patients were divided into a training (N = 269) and validation (N = 357) set. Expression of 11 target genes was measured by quantitative PCR in resected tumors. A risk score to predict overall survival (OS) was generated and validated. Intra-tumoral heterogeneity was assessed by analyzing 50 tumor areas from 10 patients. Results: A risk score including the expression of CCL5, CTNNB1, EXOSC3 and LZTR1 and the clinical parameters cT, tumor localization and histopathologic type suggested two groups with a significant difference in OS [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.17-0.52]. The risk score was successfully validated in an independent cohort (HR 0.32; 95% CI 0.21-0.51; P < 0.001) as well as in subgroups of primarily resected (HR 0.30; 95% CI 0.17-0.54; P < 0.001) and pre-/perioperatively treated patients (HR 0.37; 95% CI 0.17-0.81; P = 0.009). A significant difference in OS of high- and low-risk patients was also found in primarily resected patients with intestinal (HR 0.45; 95% CI 0.23-0.90; P = 0.020) and nonintestinal-type carcinomas (HR 0.1; 95% CI 0.02-0.42; P < 0.001). Intra-tumor heterogeneity analysis indicated a classification reliability of 95% for a supposed analysis of three biopsies. Conclusion: The identified risk score could substantially contribute to an improved management of gastric cancer patients in the context of perioperative chemotherapy.

Component-resolved diagnostics to direct in venom immunotherapy: Important steps towards precision medicine.

Stings of Hymenoptera can induce IgE-mediated systemic and even fatal allergic reactions. Venom-specific immunotherapy (VIT) is the only disease-modifying and curative treatment of venom allergy. However, choosing the correct venom for VIT represents a necessary prerequisite for efficient protection against further anaphylactic sting reactions after VIT. In the past, therapeutic decisions based on the measurement of specific IgE (sIgE) levels to whole venom extracts were not always straightforward, especially when the patient was not able to identify the culprit insect. In the last years, the increasing knowledge about the molecular structure and relevance of important venom allergens and their availability as recombinant allergens, devoid of cross-reactive carbohydrate determinants, resulted in the development of an advanced component-resolved diagnostics (CRD) approach in venom allergy. Already to date, CRD has increased the sensitivity of sIgE detection and enabled the discrimination between primary sensitization and cross-reactivity, particularly in patients with sensitization to both honeybee and vespid venom. Hence, CRD in many patients improves the selection of the appropriate immunotherapeutic intervention. Moreover, the detailed knowledge about sensitization profiles on a molecular level might open new options to identify patients who are at increased risk of side-effects or not to respond to immunotherapy. Therefore, increasing potential of CRD becomes evident, to direct therapeutic decisions in a personalized and patient-tailored manner. Reviewed here are the state of the art options, recent developments and future perspectives of CRD of Hymenoptera venom allergy.

Optimizing the impact of alcohol and drug screening and early intervention in a high-risk population receiving services in New York City sexual health clinics: A process and outcome evaluation of Project Renew.

Unhealthy substance use is associated with increased rates of STDs, including HIV. Within three high-risk New York City (NYC) sexual health clinics between 2008 and 2012 (n = 146,657), 17% of patients screened positive for a current SUD but only 5.3% ever received prior treatment. The goal of Project Renew was to expand the reach of substance use early intervention services within and across sexual health clinics citywide and decrease substance use, poor mental health, and risky sexual behavior. To accomplish this goal, Screening, Brief Intervention, and Referral to Treatment (SBIRT), an evidence-based substance use early intervention model, was implemented in all eight NYC sexual health clinics February 2012-January 2015. Clinic patients were screened for substance misuse using the AUDIT/DAST-10, and those who screened positive were eligible for on-site brief intervention. Overall, 130,597 substance misuse screenings were conducted (66,989, or 51%, positive), and 17,474 on-site brief interventions and 1238 referrals were provided (not unique to individual patients). A 10% sample of 14,709 unique patients who screened positive were interviewed using a federal data collection tool at baseline and six months later to assess changes in substance use, sexual risk behaviors, mental health, and health status (n = 1328). At six-month follow-up, patients reported reduced substance use, less sexual activity, improved overall health, and fewer days of depression and anxiety compared to measures at baseline (p < 0.05). Based on positive results, Project Renew SBIRT services have been sustained, ensuring essential care which may help prevent acquisition of HIV/STDs among a large population of high-risk New Yorkers.

Application of recombinant antigen 5 allergens from seven allergy-relevant Hymenoptera species in diagnostics.

BACKGROUND: Hymenoptera stings can cause severe anaphylaxis in untreated venom-allergic patients. A correct diagnosis regarding the relevant species for immunotherapy is often hampered by clinically irrelevant cross-reactivity. In vespid venom allergy, cross-reactivity between venoms of different species can be a diagnostic challenge. To address immunological IgE cross-reactivity on molecular level, seven recombinant antigens 5 of the most important Vespoidea groups were assessed by different diagnostic setups. METHODS: The antigens 5 of yellow jackets, hornets, European and American paper wasps, fire ants, white-faced hornets, and Polybia wasps were recombinantly produced in insect cells, immunologically and structurally characterized, and their sIgE reactivity assessed by ImmunoCAP, ELISA, cross-inhibition, and basophil activation test (BAT) in patients with yellow jacket or Polistes venom allergy of two European geographical areas. RESULTS: All recombinant allergens were correctly folded and structural models and patient reactivity profiles suggested the presence of conserved and unique B-cell epitopes. All antigens 5 showed extensive cross-reactivity in sIgE analyses, inhibition assays, and BAT. This cross-reactivity was more pronounced in ImmunoCAP measurements with venom extracts than in sIgE analyses with recombinant antigens 5. Dose-response curves with the allergens in BAT allowed a differentiated individual dissection of relevant sensitization. CONCLUSIONS: Due to extensive cross-reactivity in various diagnostic settings, antigens 5 are inappropriate markers for differential sIgE diagnostics in vespid venom allergy. However, the newly available antigens 5 from further vespid species and the combination of recombinant allergen-based sIgE measurements with BAT represents a practicable way to diagnose clinically relevant sensitization in vespid venom allergy.

Added sensitivity of component-resolved diagnosis in hymenoptera venom-allergic patients with elevated serum tryptase and/or mastocytosis.

BACKGROUND: Anaphylaxis caused by hymenoptera venom allergy is associated with elevation of baseline serum tryptase (sBT) and/or mastocytosis in about 5% of patients. Up to now, no information has become available on single venom allergen sIgE reactivity and the usefulness of component-resolved approaches to diagnose this high-risk patient group. To address the component-resolved sIgE sensitization pattern and diagnostic sensitivity in hymenoptera venom-allergic patients with elevated sBT levels and/or mastocytosis, a panel of yellow jacket and honeybee venom allergens was applied on a widely used IgE immunoassay platform. METHODS: Fifty-three patients with mastocytosis and/or elevated sBT tryptase level and systemic reactions to hymenoptera venoms were analyzed for their IgE reactivity to recombinant yellow jacket and honeybee venom allergens by Immulite3 g. RESULTS: sIgE reactivity to Ves v 1, Ves v 5, Api m 1 to Api m 4 and Api m 10 was found at a similar frequency in hymenoptera venom-allergic patients with and without elevated sBT levels and/or mastocytosis. However, the use of the recombinant allergens and a diagnostic cutoff of 0.1 kUA /L allowed the diagnosis of patients with otherwise undetectable IgE to venom extract. The diagnostic sensitivity of yellow jacket venom allergy using the combination of Ves v 1 and Ves v 5 was 100%. CONCLUSIONS: In high-risk patients with elevated sBT levels and/or mastocytosis, the use of molecular components and decreasing the threshold sIgE level to 0.1 kUA /L may be needed to avoid otherwise undetectable IgE to hymenoptera venom extracts in about 8% of such patients.

EAACI Molecular Allergology User's Guide.

The availability of allergen molecules ('components') from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled 'component-resolved diagnosis' (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology User's Guide (MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low-abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross-reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE-mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross-reactive panallergens from plant (lipid transfer proteins, polcalcins, PR-10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE-mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients.

Decline of Ves v 5-specific blocking capacity in wasp venom-allergic patients after stopping allergen immunotherapy.

While allergen-specific immunotherapy (AIT) is very efficient in hymenoptera venom (HV)-allergic patients, long-term outcome after finishing AIT is not well investigated, especially regarding mechanisms that are suggested to contribute to allergen-specific tolerance. Here, we analyse the Ves v 5-inhibitory activity of sera from wasp venom-allergic patients using the novel cell-free enzyme-linked immunosorbent facilitated antigen binding (ELIFAB) assay. Compared to pre-AIT, sera from patients undergoing AIT displayed an increased ability to inhibit Ves v 5 binding by IgE antibodies. In contrast, this inhibitory activity was reduced in patients having finished AIT 5-12 years ago. Allergen-blocking capacity correlated with serum concentrations of Ves v 5-specific IgG4 which rose during AIT but almost reached pretreatment levels in patients who had stopped AIT more than 5 years ago. These data raise questions about how long allergen tolerance is maintained in AIT-treated HV-allergic patients and suggest that the ELIFAB assay might be an easy-to-use tool assessing long-term tolerance in patients treated with HV-AIT.

[The use and benefit of the 'children with special health care needs screener' in the paediatric school entrance examinations 2004/2005 in Cologne]. / Einsatz und Nutzen des "Children with Special Health Care Needs-Screener" im Rahmen der Schuleingangsuntersuchung 2004/2005 in Köln.

The aim of this study was to provide an assessment of the usefulness of the questionnaire "Children with Special Health Care Needs Screener" (CSHCN Screener) as a screening instrument to identify children with special needs in the context of paediatric school entrance examinations (SEE).In a retrospective cross-sectional study of the years 2004 and 2005 in Cologne, Germany, the sum variables were derived from the results of the SEE in accordance to the 7 questions of the CSHCN Screener. The correlations of the SEE sum variables and the CSHCN Screener results were analysed and tested for correlations with sociodemographic factors.Of the 18 402 children of the cohorts 2004/2005, corresponding SEE findings and results of the CSHCN Screener were available for 13 076 children. The prevalence of children with special needs was only 6% according to the results of the CSHCN Screener. According to the SEE, however, 26% of the children showed diseases or developmental problems. Out of this group, only one in 8 children was identified by the CSHCN Screener (sensitivity 13%). The sensitivity of the screener was also 13% for children who had been diagnosed to be in need of special support by school physicians. In the case of girls and of children with migration family backgrounds, the sensitivity of the screener was even lower. The CSHCN Screener also could not detect the higher rate of special needs determined by school physicians in children from areas with high quotas of state family support payments.The results of the CSHCN Screener are not convincing, due to his low sensitivity. This is true with regard to its use as a diagnostic tool for the individual child at the beginning of school age as well for its use as an instrument to assess an increased need for support in cohorts of school entry students.

Prognostic value of histopathological regression in 850 neoadjuvantly treated oesophagogastric adenocarcinomas.

BACKGROUND: Recently, histopathological tumour regression, prevalence of signet ring cells, and localisation were reported as prognostic factors in neoadjuvantly treated oesophagogastric (junctional and gastric) cancer. This exploratory retrospective study analyses independent prognostic factors within a large patient cohort after preoperative chemotherapy including clinical and histopathological factors. METHODS: In all, 850 patients presenting with oesophagogastric cancer staged cT3/4 Nany cM0/x were treated with neoadjuvant chemotherapy followed by resection in two academic centres. Patient data were documented in a prospective database and retrospectively analysed. RESULTS: Of all factors prognostic on univariate analysis, only clinical response, complications, ypTNM stage, and R category were independently prognostic (P<0.01) on multivariate analysis. Tumour localisation and signet ring cells were independently prognostic only when investigator-dependent clinical response evaluation was excluded from the multivariate model. Histopathological tumour regression correlates with tumour grading, Laurén classification, clinical response, ypT, ypN, and R categories but was not identified as an independent prognostic factor. Within R0-resected patients only surgical complications and ypTNM stage were independent prognostic factors. CONCLUSIONS: Only established prognostic factors like ypTNM stage, R category, and complications were identified as independent prognostic factors in resected patients after neoadjuvant chemotherapy. In contrast, histopathological tumour regression was not found as an independent prognostic marker.

Impact of liver fibrosis on prognosis following liver resection for hepatitis B-associated hepatocellular carcinoma.

BACKGROUND: This study aims to evaluate the impact of liver fibrosis severity on prognosis following liver resection among HBV-HCC patients. METHODS: Data were extracted from a prospective database of 189 HBV-HCC patients treated at Mount Sinai between 1995 and 2008. Fibrosis staging of each surgical resection specimen using the modified Ishak method was performed by a single liver pathologist. RESULTS: A wide range of Ishak fibrosis stage was observed among this patient population, with 29% having established cirrhosis (Ishak stage 6). Ishak stage 6 was independently associated with poor overall and recurrence-free survival. In patients with Ishak stage 1-5, Ishak stage did not affect survival; rather, tumour size was associated with poor overall survival, and tumour size, histologic activity index and serum AFP>20 ng ml(-1) were associated with poor recurrence-free survival. In patients with Ishak stage 6, poorly differentiated histology and tumour size were associated with poor overall survival, and tumour size was associated with poor recurrence-free survival. CONCLUSION: HBV-HCC develops with varying degrees of underlying liver fibrosis; however, progressive liver fibrosis does not affect the outcomes following resection until cirrhosis is reached. Established cirrhosis, as defined histologically by Ishak stage 6, is an independent predictor of poor overall and recurrence-free survival among these patients.

Extending the honey bee venome with the antimicrobial peptide apidaecin and a protein resembling wasp antigen 5.

Honey bee venom is a complex mixture of toxic proteins and peptides. In the present study we tried to extend our knowledge of the venom composition using two different approaches. First, worker venom was analysed by liquid chromatography-mass spectrometry and this revealed the antimicrobial peptide apidaecin for the first time in such samples. Its expression in the venom gland was confirmed by reverse transcription PCR and by a peptidomic analysis of the venom apparatus tissue. Second, genome mining revealed a list of proteins with resemblance to known insect allergens or venom toxins, one of which showed homology to proteins of the antigen 5 (Ag5)/Sol i 3 cluster. It was demonstrated that the honey bee Ag5-like gene is expressed by venom gland tissue of winter bees but not of summer bees. Besides this seasonal variation, it shows an interesting spatial expression pattern with additional production in the hypopharyngeal glands, the brains and the midgut. Finally, our immunoblot study revealed that both synthetic apidaecin and the Ag5-like recombinant from bacteria evoke no humoral activity in beekeepers. Also, no IgG4-based cross-reactivity was detected between the honey bee Ag5-like protein and its yellow jacket paralogue Ves v 5.

Preoperative therapy of esophagogastric cancer: the problem of nonresponding patients.

INTRODUCTION: Preoperative treatment is nowadays standard for locally advanced esophagogastric cancer in Europe. Surprisingly, little attention has been paid to nonresponders so far. The aim of our retrospective exploratory study was the comparison of responder, nonresponder, and primary resected patients in respect of outcome considering the tumor entity. PATIENTS AND METHODS: From 2001-2011, 607 patients with locally advanced esophagogastric carcinoma (adenocarcinoma of the esophagogastric junction (AEG), n = 293; squamous cell cancer (SCC), n = 111; gastric cancer, n = 203) after preoperative treatment (n = 281) or primary resection (n = 326) were included. Histopathological response evaluation (Becker criteria) was available for 263. RESULTS: A total of 76/263 (28.9 %) were responders (<10 % residual tumor). There was an association of response with increased R0 resections (p < 0.001) but also with a higher complication rate (p = 0.008) compared to nonresponse and primary surgery. Mortality was not influenced. Increased R0 resections after response were confirmed in every tumor entity (AEG, p = 0.010; SCC, p = 0.023; gastric cancer, p = 0.006). Median survival was best for responders with 43.5 months [95 % confidence interval (CI), 27.9-59.1], followed by nonresponders with 24.3 months (95 % CI, 21.6-27.0) and primary resected patients with 20.8 months (95 % CI, 17.7-23.9; p = 0.002). AEG (p = 0.012) and gastric cancer (p = 0.017) revealed identical results, but in the subgroup of SCC, the survival of nonresponders (median, 11.6 months; 95 % CI, 6.9-16.3) was even worse than for primary resected patients (median, 23.8 months; 95 % CI, 1.7-46.0; p = 0.012). CONCLUSION: The histopathological response rate was low. Generally, nonresponding patients with AEG or gastric cancer seem not to have a disadvantage compared to primary resected patients, but nonresponders with SCC have a worse prognosis, which strengthens the demand for a critical patient selection in surgery for this tumor entity.

[Pediatrics. Sharing of the medical letter with the patient]. / Pédiatrie. 5. Le partage de l'information médicate en 2012.

Some paediatrics centres routinely send the medical consultation letter not only to the primary or referring physician but to the patient and his/her family as well. This way of sharing medical information is appreciated not only by the patients themselves but also by a majority of physicians.

[Cholecystolithiasis and intestinal bypass procedures]. / Cholezystolithiasis und intestinale Bypassverfahren.

With the increasing number of surgical interventions for obesity, the numbers of associated complications, such as gallstones after bariatric surgery are also increasing. The incidence of postbariatric symptomatic cholecystolithiasis is 5-10%; however, the numbers of severe complications due to gallstones and the probability of a necessary extraction of gallstones are low. For this reason, a simultaneous or preoperative cholecystectomy should only be carried out in symptomatic patients. Treatment with ursodeoxycholic acid reduced the risk of gallstone formation in randomized trials but not the risk of complications related to gallstones in cases of pre-existing gallstones. The most frequently used access route to bile ducts after intestinal bypass procedures is the laparoscopic approach via the stomach remnants. Other possible access routes are the enteroscopic approach as well as the endosonography-guided puncture of the stomach remnants.

Phase II study of bevacizumab with liposomal doxorubicin for patients with platinum- and taxane-resistant ovarian cancer.

BACKGROUND: Suppression of neoangiogenesis and pegylated liposomal doxorubicin (PLD) each contribute to the management of platinum-resistant/refractory ovarian cancer. The aim of this study is to test the combination of bevacizumab and PLD in women with resistant or refractory ovarian cancer. METHODS: Eligibility criteria were no more than two prior treatments with platinum-containing regimens and one additional regimen, without anthracyclines. Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m(2)). The primary end point was progression-free survival (PFS) at 6 months; the secondary end points included side-effects, overall response rates (ORR) and survival (OS). RESULTS: Forty-six patients were enrolled. The average number of courses administered was 7. The median PFS was 6.6 months (range 1-24.6 months) according to Gynecologic Cancer Intergroup Committee (GCIC) criteria and 7.8 months (range 2-13.3 months) according to Response Evaluation Criteria in Solid Tumors (RECIST). The median OS was 33.2 months (range 3-37.5+ months). The ORR was 30.2% [95% confidence interval (CI) 17.2-46.1] and the clinical benefit rate (CBR) was 86.1% (95% CI 72.1-94.7). Adverse events included mucosal and dermal erosions (30% grade 3) and asymptomatic cardiac dysfunction. Additional toxic effects included hypertension, headache, renal dysfunction and proteinuria, wound healing delay, and one episode each of central nervous system (CNS) ischemia and hemolytic uremic syndrome. CONCLUSION: PLD with bevacizumab has improved activity in recurrent ovarian cancer with increased toxicity.