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INTRODUCTION Few studies have examined the real-world impact of haemophilia on daily activities and work productivity in people with severe haemophilia A (PWSHA). AIM To determine clinical attributes and treatment characteristics associated with impairment in daily activities and work among PWSHA using the patient-reported Work Productivity and Activity Impairment-General Health Questionnaire (WPAI-GH). METHODS PWSHA were asked to complete the WPAI-GH as part of the Cost of Haemophilia in Europe: A Socioeconomic Survey (CHESS) study. Outcomes were determined for activity impairment (AI), absenteeism, presenteeism and overall work productivity loss (WPL). Descriptive statistics and regression analyses were used to evaluate the association between these outcomes and clinical and treatment attributes. RESULTS Overall, 376 participants completed the AI element of WPAI-GH; 175 were employed and thus also reported on work impact. Mean ± standard deviation scores were as follows: AI = 34.2% ± 25.8%; absenteeism = 0.06% ±0.2%; presenteeism = 26.8% ± 22.4%; WPL = 28.6% ± 24.0%. Increased AI and WPL were associated with high haemophilia-related morbidity, measured both as chronic pain (p

Background Host gene expression has emerged as a complementary strategy to pathogen detection tests for the discrimination of bacterial and viral infection. The impact of immunocompromise on host-response tests remains unknown. We evaluated a host-response test discriminating bacterial, viral, and noninfectious conditions in immunocompromised subjects. Methods An 81-gene signature was measured using real-time–polymerase chain reaction in subjects with immunocompromise (chemotherapy, solid-organ transplant, immunomodulatory agents, AIDS) with bacterial infection, viral infection, or noninfectious illness. A regularized logistic regression model trained in immunocompetent subjects was used to estimate the likelihood of each class in immunocompromised subjects. Results Accuracy in the 136-subject immunocompetent training cohort was 84.6% for bacterial versus nonbacterial discrimination and 80.8% for viral versus nonviral discrimination. Model validation in 134 immunocompromised subjects showed overall accuracy of 73.9% for bacterial infection (P = .04 relative to immunocompetent subjects) and 75.4% for viral infection (P = .30). A scheme reporting results by quartile improved test utility. The highest probability quartile ruled-in bacterial and viral infection with 91.4% and 84.0% specificity, respectively. The lowest probability quartile ruled-out infection with 90.1% and 96.4% sensitivity for bacterial and viral infection, respectively. Performance was independent of the type or number of immunocompromising conditions. Conclusions A host gene expression test discriminated bacterial, viral, and noninfectious etiologies at a lower overall accuracy in immunocompromised patients compared with immunocompetent patients, although this difference was only significant for bacterial infection classification. With modified interpretive criteria, a host-response strategy may offer clinically useful diagnostic information for patients with immunocompromise.

OBJECTIVES Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test. DESIGN Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results. SETTING Four U.S. emergency departments. PATIENTS Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis. INTERVENTIONS Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes. MEASUREMENTS AND MAIN RESULTS Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance. CONCLUSIONS The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.

Viruses cause a wide spectrum of clinical disease, the majority being acute respiratory infections (ARI). In most cases, ARI symptoms are similar for different viruses although severity can be variable. The objective of this study was to understand the shared and unique elements of the host transcriptional response to different viral pathogens. We identified 162 subjects in the US and Sri Lanka with infections due to influenza, enterovirus/rhinovirus, human metapneumovirus, dengue virus, cytomegalovirus, Epstein Barr Virus, or adenovirus. Our dataset allowed us to identify common pathways at the molecular level as well as virus-specific differences in the host immune response. Conserved elements of the host response to these viral infections highlighted the importance of interferon pathway activation. However, the magnitude of the responses varied between pathogens. We also identified virus-specific responses to influenza, enterovirus/rhinovirus, and dengue infections. Influenza-specific differentially expressed genes (DEG) revealed up-regulation of pathways related to viral defense and down-regulation of pathways related to T cell and neutrophil responses. Functional analysis of entero/rhinovirus-specific DEGs revealed up-regulation of pathways for neutrophil activation, negative regulation of immune response, and p38MAPK cascade and down-regulation of virus defenses and complement activation. Functional analysis of dengue-specific up-regulated DEGs showed enrichment of pathways for DNA replication and cell division whereas down-regulated DEGs were mainly associated with erythrocyte and myeloid cell homeostasis, reactive oxygen and peroxide metabolic processes. In conclusion, our study will contribute to a better understanding of molecular mechanisms to viral infections in humans and the identification of biomarkers to distinguish different types of viral infections.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA) is detected in the bloodstream of some patients with coronavirus disease 2019 (COVID-19), but it is not clear whether this RNAemia reflects viremia (ie, virus particles) and how it relates to host immune responses and outcomes. Methods SARS-CoV-2 vRNA was quantified in plasma samples from observational cohorts of 51 COVID-19 patients including 9 outpatients, 19 hospitalized (non–intensive care unit [ICU]), and 23 ICU patients. vRNA levels were compared with cross-sectional indices of COVID-19 severity and prospective clinical outcomes. We used multiple imaging methods to visualize virions in plasma. Results SARS-CoV-2 vRNA was detected in plasma of 100%, 52.6%, and 11.1% of ICU, non-ICU, and outpatients, respectively. Virions were detected in plasma pellets using electron tomography and immunostaining. Plasma vRNA levels were significantly higher in ICU > non-ICU > outpatients (P 6000 copies/mL was strongly associated with mortality (hazard ratio, 10.7). Levels of vRNA were significantly associated with several inflammatory biomarkers (P Conclusions Visualization of virus particles in plasma indicates that SARS-CoV-2 RNAemia is due, at least in part, to viremia. The levels of SARS-CoV-2 RNAemia correlate strongly with disease severity, patient outcome, and specific inflammatory biomarkers but not with neutralizing antibody titers.

Introduction: Hemophilia A (HA) is a congenital bleeding disorder caused by a deficiency in clotting factor VIII (FVIII). There are currently limited data on the impact of HA on daily life. Here we examine the impact of HA on the daily life of adult persons with HA (PwHA) without current FVIII inhibitors according to disease severity. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey II (CHESS II) is a retrospective, burden-of-illness study in adults with mild, moderate, and severe HA or hemophilia B (defined by endogenous FVIII/IX [IU/dL] relative to normal; mild, 5- Results: Of 258 PwHA completing questionnaires, 15.9% (n=41), 27.9% (n=72), and 56.2% (n=145) had mild, moderate, and severe HA, respectively. Of those with severe HA, 60.0% were currently receiving FVIII prophylaxis (standard of care for severe HA); in comparison, 4.9% and 6.9% of those with mild and moderate HA were receiving prophylaxis (Table 1). Treatment adaptation in anticipation of physical or social activity was reported by 19.5%, 23.6%, and 38.6% of those with mild, moderate, and severe HA, respectively. Over a third of participants with mild (36.6%) and moderate (44.4%) HA, and 64.8% of those with severe HA (58.6% with severe HA receiving on-demand treatment and 69.0% receiving prophylaxis) agreed or strongly agreed that HA had reduced their physical activity (Figure 1). Overall, 38.9% of those with moderate HA and 58.6% of those with severe HA (63.8% with severe HA receiving on-demand treatment and 55.2% receiving prophylaxis) agreed or strongly agreed that their HA had reduced their social activity; this was less pronounced in mild HA (9.8%). Additionally, 31.7%, 36.1%, and 64.1% of those with mild, moderate, and severe HA (62.1% with severe HA receiving on-demand treatment and 65.5% receiving prophylaxis) agreed or strongly agreed that their HA had caused them to miss opportunities. Correspondingly, frustration due to HA was felt by 19.5%, 34.7% and 57.9% (56.9% with severe HA receiving on-demand treatment and 58.6% receiving prophylaxis) of people, respectively. When asked whether they believed their daily life was compromised due to their hemophilia, 24.4%, 37.5%, and 63.4% of those with mild, moderate, and severe HA, respectively, agreed. Pain, as reported by the physician, was noted in 36.6% of people with mild HA (100% was reported as 'mild'); in people with moderate HA, pain was reported as 'mild', 'moderate', and 'severe' in 44.4%, 20.8%, and 1.4% of PwHA, respectively. In people with severe HA, pain was reported as 'mild', 'moderate', and 'severe' in 39.7%, 27.6%, and 8.6% for those receiving on-demand treatment, and 37.9%, 32.2%, and 8.0% for those receiving prophylaxis, respectively. Conclusions: In all disease severity groups, there was a notable group of PwHA that felt that they have had to reduce their physical and social activity, have had fewer opportunities and are frustrated due to their disease. While the impact on daily life is most pronounced in people with severe HA (including those receiving on-demand treatment and those receiving prophylaxis), it is also apparent in mild and moderate HA, indicating that there may be an unmet medical need in these groups. Disclosures Noone: Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; Research Investigator PROBE: Research Funding; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees. Nissen:F. Hoffmann-La Roche Ltd: Current Employment; Actelion: Consultancy; Novartis: Research Funding; GSK: Research Funding. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Burke:University of Chester: Current Employment; HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Asghar:HCD Economics: Current Employment. Dhillon:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; HCD Economics: Current Employment. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Khair:Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Haemnet: Membership on an entity's Board of Directors or advisory committees.

Background: Distinguishing bacterial and viral respiratory infections is challenging. Novel diagnostics based on differential host gene expression patterns are promising but have not been translated to a clinical platform nor extensively tested. Here, we validate a microarray-derived host response signature and explore performance in microbiology-negative and coinfection cases. Methods: Subjects with acute respiratory illness were enrolled in participating emergency departments. Reference standard was an adjudicated diagnosis of bacterial infection, viral infection, both, or neither. An 87-transcript signature for distinguishing bacterial, viral, and noninfectious illness was measured from peripheral blood using RT-PCR. Performance characteristics were evaluated in subjects with confirmed bacterial, viral, or noninfectious illness. Subjects with bacterial-viral coinfection and microbiologically-negative suspected bacterial infection were also evaluated. Performance was compared to procalcitonin. Findings: 151 subjects with microbiologically confirmed, single-etiology illness were tested, yielding AUROCs 0•85–0•89 for bacterial, viral, and noninfectious illness. Accuracy was similar to procalcitonin (88% vs 83%, p = 0•23) for bacterial vs. non-bacterial infection. Whereas procalcitonin cannot distinguish viral from non-infectious illness, the RT-PCR test had 81% accuracy in making this determination. Bacterial-viral coinfection was subdivided. Among 19 subjects with bacterial superinfection, the RT-PCR test identified 95% as bacterial, compared to 68% with procalcitonin (p = 0•13). Among 12 subjects with bacterial infection superimposed on chronic viral infection, the RT-PCR test identified 83% as bacterial, identical to procalcitonin. 39 subjects had suspected bacterial infection; the RT-PCR test identified bacterial infection more frequently than procalcitonin (82% vs 64%, p = 0•02). Interpretation: The RT-PCR test offered similar diagnostic performance to procalcitonin in some subgroups but offered better discrimination in others such as viral vs. non-infectious illness and bacterial/viral coinfection. Gene expression-based tests could impact decision-making for acute respiratory illness as well as a growing number of other infectious and non-infectious diseases. Keywords: Biomarkers, Gene expression, Respiratory tract infections, Coinfection, Diagnosis, Precision medicine

Background Antibiotic resistance is rising at disturbing rates and contributes to the deaths of millions of people yearly. Antibiotic resistant infections disproportionately affect those with immunocompromising conditions, chronic colonization, and frequent antibiotic use such as transplant patients or those with cystic fibrosis. However, clinicians lack the diagnostic tools to confidently diagnose and treat infections, leading to widespread use of empiric broad spectrum antimicrobials, often for prolonged duration. Case presentation A 22 year-old Caucasian female with cystic fibrosis received a bilateral orthotopic lung transplantation 5 months prior to the index hospitalization. She underwent routine surveillance bronchoscopy and was admitted for post-procedure fever. A clear cause of infection was not identified by routine methods. Imaging and bronchoscopic lung biopsy did not identify an infectious agent or rejection. She was treated with a prolonged course of antimicrobials targeting known colonizing organisms from prior bronchoalveolar lavage cultures (Pseudomonas, Staphylococcus aureus, and Aspergillus). However, we identified Stenotrophomonas maltophilia in two independent whole blood samples using direct-pathogen sequencing, which was not identified by other methods. Conclusions This case represents a common clinical conundrum: identification of infection in a high-risk, complex patient. Here, direct-pathogen sequencing identified a pathogen that would not otherwise have been identified by common techniques. Had results been clinically available, treatment could have been customized, avoiding a prolonged course of broad spectrum antimicrobials that would only exacerbate resistance. Direct-pathogen sequencing is poised to fill a diagnostic gap for pathogen identification, allowing early identification and customization of treatment in a culture-independent, pathogen-agnostic manner.

SARS-CoV-2 infection has been shown to trigger a wide spectrum of immune responses and clinical manifestations in human hosts. Here, we sought to elucidate novel aspects of the host response to SARS-CoV-2 infection through RNA sequencing of peripheral blood samples from 46 subjects with COVID-19 and directly comparing them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a powerful transcriptomic response in peripheral blood with conserved components that are heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, which persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95 [95% CI 0.92–0.98]). The transcriptome in peripheral blood reveals both diverse and conserved components of the immune response in COVID-19 and provides for potential biomarker-based approaches to diagnosis.

In order to elucidate novel aspects of the host response to SARS-CoV-2 we performed RNA sequencing on peripheral blood samples across 77 timepoints from 46 subjects with COVID-19 and compared them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a conserved transcriptomic response in peripheral blood that is heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, that persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95). The transcriptome in peripheral blood reveals unique aspects of the immune response in COVID-19 and provides for novel biomarker-based approaches to diagnosis.

Background Pathogen-based diagnostics for acute respiratory infection (ARI) have limited ability to detect etiology of illness. We previously showed that peripheral blood-based host gene expression classifiers accurately identify bacterial and viral ARI in cohorts of European and African descent. We determined classifier performance in a South Asian cohort. Methods Patients ≥15 years with fever and respiratory symptoms were enrolled in Sri Lanka. Comprehensive pathogen-based testing was performed. Peripheral blood ribonucleic acid was sequenced and previously developed signatures were applied: a pan-viral classifier (viral vs nonviral) and an ARI classifier (bacterial vs viral vs noninfectious). Results Ribonucleic acid sequencing was performed in 79 subjects: 58 viral infections (36 influenza, 22 dengue) and 21 bacterial infections (10 leptospirosis, 11 scrub typhus). The pan-viral classifier had an overall classification accuracy of 95%. The ARI classifier had an overall classification accuracy of 94%, with sensitivity and specificity of 91% and 95%, respectively, for bacterial infection. The sensitivity and specificity of C-reactive protein (>10 mg/L) and procalcitonin (>0.25 ng/mL) for bacterial infection were 100% and 34%, and 100% and 41%, respectively. Conclusions Previously derived gene expression classifiers had high predictive accuracy at distinguishing viral and bacterial infection in South Asian patients with ARI caused by typical and atypical pathogens., Host biomarkers can identify bacterial versus viral acute respiratory infection (ARI). Previously, we derived host gene expression classifiers that accurately identify bacterial versus viral ARI. Here, we show that our classifiers had high predictive accuracy in a South Asian cohort.

Key Points Question Can noninvasive, wrist-worn wearable devices detect acute viral respiratory infection and predict infection severity before symptom onset? Findings In a cohort study of 31 participants inoculated with H1N1 and 18 participants with rhinovirus, infection detection and severity prediction models trained using data on wearable devices were able to distinguish between infection and noninfection with 92% accuracy for H1N1 and 88% accuracy for rhinovirus and were able to distinguish between mild and moderate infection 24 hours prior to symptom onset with 90% accuracy for H1N1 and 89% accuracy for rhinovirus. Meaning This study suggests that the use of wearable devices to identify individuals with presymptomatic acute viral respiratory infection is feasible; because wearable devices are common in the general population, using them for infection screening may help limit the spread of contagion., Importance Currently, there are no presymptomatic screening methods to identify individuals infected with a respiratory virus to prevent disease spread and to predict their trajectory for resource allocation. Objective To evaluate the feasibility of using noninvasive, wrist-worn wearable biometric monitoring sensors to detect presymptomatic viral infection after exposure and predict infection severity in patients exposed to H1N1 influenza or human rhinovirus. Design, Setting, and Participants The cohort H1N1 viral challenge study was conducted during 2018; data were collected from September 11, 2017, to May 4, 2018. The cohort rhinovirus challenge study was conducted during 2015; data were collected from September 14 to 21, 2015. A total of 39 adult participants were recruited for the H1N1 challenge study, and 24 adult participants were recruited for the rhinovirus challenge study. Exclusion criteria for both challenges included chronic respiratory illness and high levels of serum antibodies. Participants in the H1N1 challenge study were isolated in a clinic for a minimum of 8 days after inoculation. The rhinovirus challenge took place on a college campus, and participants were not isolated. Exposures Participants in the H1N1 challenge study were inoculated via intranasal drops of diluted influenza A/California/03/09 (H1N1) virus with a mean count of 106 using the median tissue culture infectious dose (TCID50) assay. Participants in the rhinovirus challenge study were inoculated via intranasal drops of diluted human rhinovirus strain type 16 with a count of 100 using the TCID50 assay. Main Outcomes and Measures The primary outcome measures included cross-validated performance metrics of random forest models to screen for presymptomatic infection and predict infection severity, including accuracy, precision, sensitivity, specificity, F1 score, and area under the receiver operating characteristic curve (AUC). Results A total of 31 participants with H1N1 (24 men [77.4%]; mean [SD] age, 34.7 [12.3] years) and 18 participants with rhinovirus (11 men [61.1%]; mean [SD] age, 21.7 [3.1] years) were included in the analysis after data preprocessing. Separate H1N1 and rhinovirus detection models, using only data on wearble devices as input, were able to distinguish between infection and noninfection with accuracies of up to 92% for H1N1 (90% precision, 90% sensitivity, 93% specificity, and 90% F1 score, 0.85 [95% CI, 0.70-1.00] AUC) and 88% for rhinovirus (100% precision, 78% sensitivity, 100% specificity, 88% F1 score, and 0.96 [95% CI, 0.85-1.00] AUC). The infection severity prediction model was able to distinguish between mild and moderate infection 24 hours prior to symptom onset with an accuracy of 90% for H1N1 (88% precision, 88% sensitivity, 92% specificity, 88% F1 score, and 0.88 [95% CI, 0.72-1.00] AUC) and 89% for rhinovirus (100% precision, 75% sensitivity, 100% specificity, 86% F1 score, and 0.95 [95% CI, 0.79-1.00] AUC). Conclusions and Relevance This cohort study suggests that the use of a noninvasive, wrist-worn wearable device to predict an individual’s response to viral exposure prior to symptoms is feasible. Harnessing this technology would support early interventions to limit presymptomatic spread of viral respiratory infections, which is timely in the era of COVID-19., This cohort study evaluates the feasibility of using noninvasive, wrist-worn wearable devices to detect presymptomatic viral infection after exposure and predict infection severity in patients exposed to H1N1 influenza or human rhinovirus.

Introduction Severe hemophilia A (SHA) is characterized by spontaneous (non-trauma related) bleeding episodes into the joint space and muscle tissue, leading to progressive joint deterioration and chronic pain. Chronic joint damage is most often associated with severe hemophilia, however more recent research has illustrated that people with moderate hemophilia A (MHA) also experience hemophilic arthropathy and functional impairment. The need to measure joint health in children as well as adults, is underscored by findings from the Joint Outcome Continuation Study, which found that FVIII prophylaxis was insufficient to protect joints from damage, from childhood through adolescence in severe HA (Warren et al., 2020). The objective of this analysis is to gain a more patient-centric understanding of the clinical, economic and humanistic burden associated with 'Problem Joints', a measure of joint morbidity developed in consultation with an expert panel to overcome limitations with existing measures, in people with MHA and SHA. Methods A descriptive cohort analysis was conducted, utilizing retrospective, cross-sectional real-world data from the 'Cost of Haemophilia in Europe: a Socioeconomic Survey' (CHESS Paeds and CHESS II), studies of adult and pediatric persons with hemophilia. The analysis population is comprised of children (17 and below) with MHA or SHA in CHESS Paeds, and adults aged 20 and over with MHA or SHA in CHESS II. To account for the possibility that persons aged 18 or 19 in CHESS II may have participated in CHESS Paeds, these individuals were excluded from the analysis. Physician-reported clinical outcome data and patient/caregiver-reported quality of life were analyzed. A problem joint (PJ) is defined as having chronic joint pain and/or limited range of movement due to compromised joint integrity (i.e. chronic synovitis and/or hemophilic arthropathy). Analyses were stratified by number of PJs: none, 1 PJ, and 2+ PJs. We report retrospective data of the 12 months prior to study enrollment, on annualized bleeding rate (ABR), prevalence of target joints (TJ), as defined by the International Society on Thrombosis and Haemostasis, and EQ-5D-/5L/Y/Proxy score. Results are presented as mean (standard deviation) or N (%). Results Among 785 participants (N = 464 SHA; N = 321 MHA) in CHESS Paeds, mean age and BMI were 10.33 (4.63) and 22.50 (17.07), respectively. Of 493 participants (aged 20 and above) in CHESS II (N = 298 SHA; N = 195 MHA), the mean age and BMI were 38.61 (14.06) and 24.55 (2.92), respectively. Current inhibitor to FVIII replacement was more prevalent in children than in adults (10% vs. 5%). In CHESS II, approximately 40% of people with MHA and 49% with SHA had one or more PJs, respectively [1 PJ (23% vs. 28%); 2+ PJs (16% vs. 21%)]. In CHESS Paeds, approximately 14% of children with MHA and 18% with SHA had at least one PJ, respectively [1 PJ (9% vs. 14%); 2+ PJs (5% vs. 3%)]. TJs were less prevalent with MHA in comparison to SHA, in both adults (24% vs. 45%) and children (13% vs. 22%). Clinical burden was higher among both children and adults with PJs compared to those with no PJs. ABR correlates with the number of PJs, in those with MHA and SHA in CHESS II (Figure 1). Similarly, PJs were associated with higher ABR across MHA and SHA in CHESS Paeds (Figure 2). Hemophilia-related hospitalizations were higher in both adult and pediatric participants with PJs. In CHESS II, MHA with no PJs had fewer [0.73 (1.23)] hospitalizations compared to having those with 1 PJ [1.38 (1.11)] or 2+ PJs [1.28 (1.25)]. Similarly, children with MHA with 2+ PJs had 1.60 (1.92) hemophilia-related hospitalizations, compared to 1.38 (1.92) with 1 PJ and 0.71 (1.14) with no PJs. PJs were associated with impaired quality of life. In CHESS II, MHA and SHA EQ-5D-5L values in persons with no PJs were 0.81 (0.19) and 0.79 (0.18), respectively, compared to 0.65 (0.16) and 0.62 (0.23) with 1 PJ, and 0.65 (0.14) and 0.51 (0.33) in with 2+ PJs. A similar trend was observed in EQ-5D-Y and EQ-5D-proxy scores in CHESS Paeds. Conclusions Data from CHESS Paeds and CHESS II demonstrate an association between chronic joint damage, as measured by the 'problem joint' definition, and worsening clinical and quality of life outcomes, across both MHA and SHA. Further analyses will seek to expand upon the initial results presented here, to investigate the wider elements of burden associated with compromised long-term joint health. Disclosures McLaughlin: BioMarin: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Roche/Chugai: Speakers Bureau; Takeda: Speakers Bureau. Hermans:Novo Nordisk: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; CAF-DCF: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; WFH: Other; EAHAD: Other; Octapharma: Consultancy, Speakers Bureau; Kedrion: Speakers Bureau; LFB: Consultancy, Speakers Bureau. Asghar:HCD Economics: Current Employment. Burke:HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Nissen:GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Dhillon:HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. . O'Hara:F. Hoffmann-La Roche Ltd: Consultancy; HCD Economics: Current Employment, Current equity holder in private company.

Objective Distinguishing bacterial, viral, or other etiologies of acute illness is diagnostically challenging with significant implications for appropriate antimicrobial use. Host gene expression offers a promising approach, although no clinically useful test has been developed yet to accomplish this. Here, Qvella’s FAST HR (Richmond Hill, Ontario, Canada) process was developed to quantify previously identified host gene expression signatures in whole blood in Method Whole blood was collected from 128 human subjects (mean age 47, range 18–88) with clinically adjudicated, microbiologically confirmed viral infection, bacterial infection, noninfectious illness, or healthy controls. Stabilized mRNA was released from cleaned and stabilized RNA-surfactant complexes using e-lysis, an electrical process providing a quantitative real-time reverse transcription polymerase chain reaction-ready sample. Threshold cycle values (CT) for 10 host response targets were normalized to hypoxanthine phosphoribosyltransferase 1 expression, a control mRNA. The transcripts in the signature were specifically chosen to discriminate viral from nonviral infection (bacterial, noninfectious illness, or healthy). Classification accuracy was determined using cross-validated sparse logistic regression. Results Reproducibility of mRNA quantification was within 1 cycle as compared to the difference seen between subjects with viral versus nonviral infection (up to 5.0 normalized CT difference). Classification of 128 subjects into viral or nonviral etiologies demonstrated 90.6% overall accuracy compared to 82.0% for procalcitonin (P = .06). FAST HR achieved rapid and accurate measurement of the host response to viral infection in less than 45 minutes. Conclusions These results demonstrate the ability to translate host gene expression signatures to clinical platforms for use in patients with suspected infection. Clinical Trials Registration NCT00258869.

RationaleAsthma exacerbations often occur due to infectious triggers, but determining whether infection is present and whether it is bacterial or viral remains clinically challenging. A diagnostic strategy that clarifies these uncertainties could enable personalized asthma treatment and mitigate antibiotic overuse.ObjectivesTo explore the performance of validated peripheral blood gene expression signatures in discriminating bacterial, viral, and noninfectious triggers in subjects with asthma exacerbations.MethodsSubjects with suspected asthma exacerbations of various etiologies were retrospectively selected for peripheral blood gene expression analysis from a pool of subjects previously enrolled in emergency departments with acute respiratory illness. RT-PCR quantified 87 gene targets, selected from microarray-based studies, followed by logistic regression modeling to define bacterial, viral, or noninfectious class. The model-predicted class was compared to clinical adjudication and procalcitonin.ResultsOf 46 subjects enrolled, 7 were clinically adjudicated as bacterial, 18 as viral, and 21 as noninfectious. Model prediction was congruent with clinical adjudication in 15/18 viral and 13/21 noninfectious cases, but only 1/7 bacterial cases. None of the adjudicated bacterial cases had confirmatory microbiology; the precise etiology in this group was uncertain. Procalcitonin classified only one subject in the cohort as bacterial. 47.8% of subjects received antibiotics.ConclusionsOur model classified asthma exacerbations by the underlying bacterial, viral, and noninfectious host response. Compared to clinical adjudication, the majority of discordances occurred in the bacterial group, due to either imperfect adjudication or model misclassification. Bacterial infection was identified infrequently by all classification schemes, but nearly half of subjects were prescribed antibiotics. A gene expression-based approach may offer useful diagnostic information in this population and guide appropriate antibiotic use.

Background: Acute respiratory infections (ARIs) are the leading indication for antibacterial prescriptions despite a viral etiology in the majority of cases. The lack of available diagnostics to discriminate viral and bacterial etiologies contributes to this discordance. Recent efforts have focused on the host response as a source for novel diagnostic targets although none have explored the ability of host-derived microRNAs (miRNA) to discriminate between these etiologies. Methods: In this study, we compared host-derived miRNAs and mRNAs from human H3N2 influenza challenge subjects to those from patients with Streptococcus pneumoniae pneumonia. Sparse logistic regression models were used to generate miRNA signatures diagnostic of ARI etiologies. Generalized linear modeling of mRNAs to identify differentially expressed (DE) genes allowed analysis of potential miRNA:mRNA relationships. High likelihood miRNA:mRNA interactions were examined using binding target prediction and negative correlation to further explore potential changes in pathway regulation in response to infection. Results: The resultant miRNA signatures were highly accurate in discriminating ARI etiologies. Mean accuracy was 100% [88.8–100; 95% Confidence Interval (CI)] in discriminating the healthy state from S. pneumoniae pneumonia and 91.3% (72.0–98.9; 95% CI) in discriminating S. pneumoniae pneumonia from influenza infection. Subsequent differential mRNA gene expression analysis revealed alterations in regulatory networks consistent with known biology including immune cell activation and host response to viral infection. Negative correlation network analysis of miRNA:mRNA interactions revealed connections to pathways with known immunobiology such as interferon regulation and MAP kinase signaling. Conclusion: We have developed novel human host-response miRNA signatures for bacterial and viral ARI etiologies. miRNA host response signatures reveal accurate discrimination between S. pneumoniae pneumonia and influenza etiologies for ARI and integrated analyses of the host-pathogen interface are consistent with expected biology. These results highlight the differential miRNA host response to bacterial and viral etiologies of ARI, offering new opportunities to distinguish these entities.

Background: Sickle Cell Disease (SCD) describes a group of inherited hemolytic disorders caused by structurally abnormal variants of hemoglobin, which result in the sickle-shaped red blood cells (RBCs) that are characteristic of the disease. In patients with SCD, overexpression of adhesion molecules such as P-selectin bind sickled RBCs to endothelial cells; this contributes to hemolytic anemia and vaso-occlusive crises (VOCs), which are associated with severe acute and chronic pain. Patients with sickle cell disease often experience disease-related complications, affecting a diverse range of organs, thought to be due to the systemic impact of chronically inflamed vasculature, ongoing hemolysis and ischemic damage as a result of vaso-occlusive events. Many of these SCD-related complications are associated with significant morbidity and poor quality of life. The relationship between VOC frequency and the incidence of these complications is still being assessed. This study aimed to assess the relationship between the number of VOC experienced in the previous year and the occurrence of complications using real world evidence from the UK, specifically the Hospital Episode Statistics (HES) database. OBJECTIVE: To examine the relationship between the number of VOCs reported in the previous 12 months and the presence of SCD-related complications using a mixed modelling approach. METHODS: All patients reported with a diagnosis of SCD between 2008 and 2017 in the NHS England's HES database were identified. Detailed follow-up data on the number of vaso-occlusive crisis events and occurrence of complications was evaluated using ICD-10 diagnosis codes. Assuming no unmeasured confounding, the causal effect of VOCs, categorized into 3 groups (0, 1-2, 3+), was estimated using marginal structural models (MSM) for the complications reported in the dataset. To obtain inverse probability of treatment and censoring weights (IPTW and IPCW), the probability of being in each VOC category was estimated with a multinomial logistic model, and subsequently, the probability of being censored was estimated with a binary logistic model. The two models were adjusted for age, gender, ethnicity, and the occurrence in the previous 12 months of the 20 most common SCD complications and comorbidities in the dataset. Pooled logistic regressions were used to approximate the IPW-MSM Cox model. E-values were used to assess the minimum strength of association that an unmeasured confounder would have to have with both exposure (VOC) and outcome in order to fully explain away the observed relationship. Uncertainty in the magnitude of the E-value required to explain observed associations was explored by calculating values for both the point estimate and the lower bound of the confidence interval. RESULTS: A total of 15,076 patients were identified with a diagnosis of SCD in the HES database for this analysis. Patients had a median age of 30 and a female-male ratio of 1.7:1. A broad range of SCD related-complications were experienced by patients in the UK as shown in Table 1. Rates of some complications were observed less frequently than expected, in particular, leg ulcers, pulmonary hypertension, osteomyelitis, priapism and acute kidney injury, reported at E-values (Table 1) suggest that most outcomes are robust to considerable unmeasured confounding, although large confidence intervals resulted in small lower-bound E-values for some outcomes (e.g. leg ulcers: 3.62 lower-bound: 1.00). Large E-values (>= 3 based on similar research in SCD) suggest results are robust to considerable unmeasured confounding, while small values imply greater fragility. CONCLUSIONS: This analysis shows that vaso-occlusive crises are related to the occurrence of important complications of sickle cell disease. Reducing the annual incidence of VOC may significantly lessen the ongoing organ damage and morbidity but may also improve the patient's quality of life with respect to these conditions. Disclosures Bailey: Novartis: Employment. Abioye:Novartis: Employment. Morgan:HCD Economics: Employment. Burke:HCD Economics: Employment. Disher:Cornerstone Research Group: Employment. Brown:Cornerstone Research Group: Employment. Bonner:Cornerstone Research Group: Employment. Herquelot:HEVA: Employment. Lamarsalle:HEVA: Employment. Raguideau:HEVA: Employment.

Background Severe haemophilia is associated with major psychological and economic burden for patients, caregivers, and the wider health care system. This burden has been quantified and documented for a number of European countries in recent years. However, few studies have taken a standardised methodology across multiple countries simultaneously, and sought to amalgamate all three levels of burden for severe disease. The overall aim of the ‘Cost of Haemophilia in Europe: a Socioeconomic Survey’ (CHESS) study was to capture the annualised economic and psychosocial burden of severe haemophilia in five European countries. A cross-section of haemophilia specialists (surveyed between January and April 2015) provided demographic and clinical information and 12-month ambulatory and secondary care activity for patients via an online survey. In turn, patients provided corresponding direct and indirect non-medical cost information, including work loss and out-of-pocket expenses, as well as information on quality of life and adherence. The direct and indirect costs for the patient sample were calculated and extrapolated to population level. Results Clinical reports for a total of 1,285 patients were received. Five hundred and fifty-two patients (43% of the sample) provided information on indirect costs and health-related quality of life via the PSC. The total annual cost of severe haemophilia across the five countries for 2014 was estimated at EUR 1.4 billion, or just under EUR 200,000 per patient. The highest per-patient costs were in Germany (mean EUR 319,024) and the lowest were in the United Kingdom (mean EUR 129,365), with a study average of EUR 199,541. As expected, consumption of clotting factor replacement therapy represented the vast majority of costs (up to 99%). Indirect costs are driven by patient and caregiver work loss. Conclusions The results of the CHESS study reflect previous research findings suggesting that costs of factor replacement therapy account for the vast majority of the cost burden in severe haemophilia. However, the importance of the indirect impact of haemophilia on the patient and family should not be overlooked. The CHESS study highlights the benefits of observational study methodologies in capturing a ‘snapshot’ of information for patients with rare diseases.

Background: BAY 81-8973 (Kovaltry®, Bayer) is an unmodified full-length recombinant FVIII launched in 2016 in Europe and the US for the prophylaxis and treatment of bleeds in patients with hemophilia A. BAY 81-8973 has been extensively studied in clinical trials, which have demonstrated consistent efficacy and safety in both children and adults in the LEOPOLD trials, and since launch, 6750 patient-years of experience have been accumulated. Pharmacokinetic analyses have demonstrated an increased half-life for BAY 81-8973 compared with standard factor VIII products (rFVIII-FS and rFVIII [rAHF-PFM]). Real world evidence demonstrating the effectiveness and safety of BAY 81-8973 across age groups is being collected, though aggregated international data have yet to be published. The primary objective of this analysis was to describe the effectiveness of BAY 81-8973 in the real world setting in children and adults from Europe and the US, as captured in the Cost of Haemophilia: a Socioeconomic Survey (CHESS) study. Methods: The CHESS 2018 program investigated the economic and psychological burden of moderate and severe hemophilia (FVIII < 5%) in Europe and the USA. The pediatric cohort (CHESS Pediatric) included 1050 males aged 1-17 years, with moderate or severe hemophilia, while CHESS US included 568 adults with severe hemophilia aged > 18 years. Clinical and patient reported data were obtained via medical chart abstraction and cross-sectional surveys sent to both physicians and patients. Data were collected between December 2017 and April 2018, and captured 12 months of clinical retrospective data. The current study is a descriptive analysis of patients treated with BAY 81-8973 from the CHESS pediatric and adult cohorts. Results: At the data cut off (May 2018), 49 patients were being treated with BAY 81-8973. The majority of pediatric patients were aged 6-11 years (51.7%, n=15), while 17.2% (n=5) were aged 0-5 years and 31% (n=9) were aged 12-17 years. In the adult US cohort, most (60%, n=12) were aged 18-35 years, 35% (n=7) were aged 36-59 years, and 5% (n=1) were aged > 60 years. The vast majority of patients across cohorts had severe disease (93.1% of children and 100% of adults); however, 89.7% (26/29) of children and 80% (16/20) of adults had no target joints. In this population, 75.9% (22/29) of children and 55.0% (11/20) of adults were receiving regular prophylaxis with BAY 81-8973. Children and adults on prophylaxis both had a mean (± SD) of 2 (± 1) infusions/week, with median (Q1; Q3) weekly doses of 84 (67; 110) and 62 (29; 144) IU/kg, respectively. Overall, 20.7% (6/29) of children and 35% (7/20) of adults treated with BAY 81-8973 had zero bleeds and mean annualized bleed rate (ABR) was 2.66 (± 2.06) in children and 1.45 (± 1) in adults; 68.9% (20/29) of children and 95.0% (19/20) of adults had experienced ≤ 3 bleeds in the previous year. There were no reports of inhibitor development in either the pediatric or adult cohorts while on BAY 81-8973. Conclusions: These observations suggest that BAY 81-8973 is an effective and well-tolerated treatment for adults and children with moderate and severe hemophilia A, with ABR < 3 in children and < 2 in adults and with many patients free from bleeds despite only 67% of patients studied receiving regular prophylaxis. These data confirm the observations from the LEOPOLD trials, suggest BAY 81-8973 provides good protection from bleeding across a range of patient types in routine clinical practice and illustrate how the established pharmacokinetic profile of BAY 81-8973 translates to clinical benefits for patients with hemophilia A. Study supported by Bayer Disclosures Hirst: Bayer: Employment. Rauchensteiner:Bayer: Employment.

Background The health care industry, including consumers, providers, and payers of health care, recognize the importance of developing meaningful, patient-centered measures. This article describes our experience using an existing electronic medical record largely based on free text formats without structured documentation, in conjunction with tumor registry abstraction techniques, to obtain and analyze data for use in clinical improvement and public reporting. Methods We performed a retrospective analysis of 2467 previously untreated patients treated with curative intent who presented with laryngeal, pharyngeal, or oral cavity cancer in order to develop a system to monitor and report meaningful outcome metrics of head and neck cancer treatment. Patients treated between 1995 and 2006 were analyzed for the primary outcomes of survival at 1 and 2 years, the ability to speak at 1 year posttreatment, and the ability to swallow at 1 year posttreatment. Results We encountered significant limitations in clinical documentation because of the lack of standardization of meaningful measures, as well limitations with data abstraction using a retrospective approach to reporting measures. Almost 5000 person-hours were required for data abstraction, quality review, and reporting, at a cost of approximately $134,000. Our multidisciplinary teams document extensive patient information; however, data is not stored in easily accessible formats for measurement, comparison, and reporting. Conclusion We recommend identifying measures meaningful to patients, providers, and payers to be documented throughout the patients' entire treatment cycle, and significant investment in the improvements to electronic medical records and tumor registry reporting in order to provide meaningful quality measures for the future. © 2013 Wiley Periodicals, Inc. Head Neck 36: 226–230, 2014

Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational, cohort study determined whether host gene expression patterns discriminate non-infectious from infectious illness, and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or non-infectious illness as well as 44 healthy controls was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a non-infectious cause of illness (26 probes). Overall accuracy was 87% (238/273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, p

Changes in the management of cancers such as colorectal cancer (CRC) are urgently needed, as such cancers continue to be one of the most commonly diagnosed cancers; CRC accounts for 21% of all cancers and is responsible for mortalities second only to lung cancer in the United States. A comprehensive science-driven approach towards markedly improved early detection/screening to efficacious targeted therapeutics with clear diagnostic and prognostic markers is essential. In addition, further changes addressing rising costs, stemming from recent health care reform measures, will be brought about in part by changes in how care is reimbursed. For oncology, the advances in genomics and biomarkers have the potential to define subsets of patients who have a prognosis or response to a particular type of therapy that differs from the mean. Better definition of a cancer’s behavior will facilitate developing care plans tailored to the patient. One method under study is episode-based payment or bundling, where one payment is made to a provider organization to cover all expenses associated with a discrete illness episode. Payments will be based on the average cost of care, with providers taking on a risk for overutilization and outliers. For providers to thrive in this environment, they will need to know what care a patient will require and the costs of that care. A science-driven “personalized approach” to cancer care has the potential to produce better outcomes with reductions in the use of ineffectual therapies and costs. This promising scenario is still in the future, but progress is being made, and the shape of things to come for cancer care in the age of genomics is becoming clearer.

Historically, quality measures for cancer have followed a different route than overall quality measures in the health care system. Many specialized cancer treatment centers were exempt from standard reporting on quality measures because of the complexity of cancer. Additionally, it has been difficult to create meaningful quality measures for cancer because the disease can strike so many different organs; is discovered at and progresses through different stages; and is treated using different modalities, such as surgery, radiation, and chemotherapy. Over the past decade the National Quality Forum, a nonprofit organization dedicated to bettering the quality of US health care, has endorsed measures of quality for cancer providers and patients. The Affordable Care Act of 2010, which has sections specific to cancer reporting, will also further the development and public reporting of cancer quality measures-important steps in improving the delivery of cancer care.

This study reviews the experience at the University of Texas M.D. Anderson Cancer Center with elderly patients treated for advanced epithelial ovarian cancer with cisplatin-based combination chemotherapy.From 1978 through 1988, 215 patients with Stage III or IV, Grade 2 or 3 epithelial ovarian cancer were entered onto one of three consecutive trials involving cisplatin-based combination chemotherapy. The treatment plans were as follows: Trial 1: 12 cycles of cisplatin-melphalan (75 patients); Trial 2: 12 cycles of cisplatin-cyclophosphamide (49 patients); and Trial 3: 6 cycles of cisplatin-cyclophosphamide (91 patients). End-points of analysis included the effect of age on other prognostic factors, clinical response rate, surgical response rate, toxicity, progression-free survival, and survival.Of the entire study group, 57 patients (27%) were 65 years of age and older at diagnosis. There was no effect of age on FIGO stage or histologic grade distribution, but 61% of patients younger than 65 years of age had residual tumors less than or equal to 2 cm compared with only 33% of patients 65 years of age and older (P = 0.00027). There were no differences between the two age groups with respect to response rates, recurrence rate after negative second-look surgery, toxicity, or progression-free survival. Patients in the younger than 65 years of age group, however, had a significantly longer median survival time than those 65 years of age and older (30 versus 19 months, respectively) (P = 0.0038).This analysis suggests that elderly patients are more likely to begin chemotherapy with bulky residual disease and to have a significantly shorter survival time than their younger counterparts.

BACKGROUND: The objective of this study was to determine the efficacy of mifepristone (RU-486) in women with advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma (LGESS). METHODS: Mifepristone (RU-486; 200 mg orally) was given daily to patients with progesterone receptor-positive advanced or recurrent endometrioid adenocarcinoma or LGESS. Patients were evaluated every 4 weeks for toxicity and response. Quality-of-life data were obtained using the Memorial Symptom Assessment Scale and Functional Assessment for Cancer Therapy. RESULTS: Twelve of 13 enrolled patients were evaluable in the first phase of accrual. Stable disease was noted in 3 of 12 patients (at 8 weeks, 12 weeks, and ≥77 weeks, respectively), and the median time to disease progression was 48 days. Among the patients who had stable disease, 2 women had endometrioid endometrial cancer, and 1 woman had LGESS. No partial or complete responses were observed. The most frequent grade 1 and 2 toxicities were anorexia, fatigue, and mood alterations observed in 50%, 50%, and 58% of patients, respectively. The most common grade 3 toxicities were fatigue and dyspnea observed in 25% and 17% of patients, respectively. One patient experienced grade 4 dyspnea. Thirty-three percent of patients had asymptomatic elevations of corticotropin. No serious treatment-related adverse events occurred. There were no significant changes in quality of life. CONCLUSIONS: Single-agent mifepristone used in the treatment of recurrent endometrioid adenocarcinoma or LGESS resulted in a stable disease rate of 25%. One patient who had a biopsy-positive disease recurrence remained stable at 77 weeks. Although mifepristone was tolerated well, as a single agent, it provided limited response as a single agent in women with progesterone receptor-positive uterine tumors. Recently, was been recognized that biologic agents used as single agents may result only in stable disease unless they are combined with cytotoxic agents. The authors concluded that further research into the best mode of application for mifepristone in the treatment of endometrial cancer is needed. Cancer 2009. © 2009 American Cancer Society.

Objective. To determine the outcomes of patients with intermediate-risk Stages IC and II uterine corpus cancer treated with surgery alone or surgery followed by radiation therapy. Methods. Patients with uterine corpus cancer diagnosed in 1995 were identified from hospitals in the United States with tumor registry databases. Data were collected on histology, surgical treatment, radiation therapy, recurrence, and survival. Survival analysis was performed using life-table computational method. Results. 713 hospitals submitted data on 10,726 patients with uterine corpus cancer. 9977 patients (93.0%) underwent surgery, and 2624 patients (26.3%) received radiation therapy. Patients with clinical Stages IC and IIA disease who underwent surgery followed by radiation therapy compared to surgery alone had a trend toward improved 5-year relative survival (RS) (81.2% vs. 92.5%; 74.3% vs. 96.0%, respectively). The 5-year RS of patients with surgical Stage IC disease was not statistically different between the surgery alone group and the radiation group (93.9% vs. 91.7%). Patients with surgical Stage IIA and IIB disease did not benefit from radiation therapy compared to surgery alone (5-year RS; 83.7% vs. 98.0% and 82.3% vs. 81.8%, respectively). Conclusion. There is a trend toward improved survival in patients with clinical Stages IC and IIA uterine corpus cancer when radiation therapy is utilized following surgery. The survival of patients with surgical Stages IC and II uterine corpus cancer is not improved with adjuvant radiation therapy.

Background. Conservative treatment with progestins is a reasonable treatment option for endometrial complex atypical hyperplasia and, in the experimental setting, for some women with grade 1 endometrial endometrioid adenocarcinoma. The risk of progression to a high-stage endometrial cancer is quite low, with only two previously reported cases in the English literature. Case. A 40-year-old woman with endometrial complex atypical hyperplasia diagnosed by dilatation and curettage was managed conservatively with progestin therapy (initially, megesterol acetate; then, a combination oral contraceptive). More than 2 years after her original diagnosis, she developed endometrial endometrioid adenocarcinoma, FIGO grade 2, with lymph node metastasis. The tumor was microsatellite instability-high due to methylation of MLH1 and loss of MLH1 protein. Conclusion. Currently, there are no good criteria for predicting which patients with complex atypical hyperplasia/grade 1 endometrioid adenocarcinoma will optimally respond to progestin therapy. There is some evidence that endometrial complex hyperplasia demonstrating loss of MLH1 protein by immunohistochemistry is strongly related to subsequent or concurrent endometrial cancer, especially tumors of higher grade and stage. In a woman with a biopsy diagnosis of endometrial hyperplasia, evaluation of MLH1 protein status by immunohistochemistry may provide useful information when medical management is being considered.

Objective. The purpose of surgical staging is to better determine prognosis and treatment. The International Federation of Gynecology and Obstetrics (FIGO) stage IIIA endometrial cancer is a heterogenous disease, and adjuvant therapy is not well-defined. The aim of this study was to survey the Society of Gynecologic Oncologists (SGO) members and fellows about their approach to the treatment of patients with stage IIIA endometrial cancer. Methods. All 850 members of the SGO were mailed surveys that asked how they would manage various case scenarios of stage IIIA endometrial cancer. Data were collected using an Internet survey database. Frequency distributions were determined, and nonparametric tests were performed. Results. Fifty-three percent of SGO members and fellows responded. For the treatment of stage IIIA disease with malignant cytology only, adjuvant therapy was recommended 46%, 62%, and 98% of the time for women with grades 1, 2, and UPSC, respectively. Sixty-six percent of respondents would not remove malignant cytology from the current staging criteria. Ninety-nine percent of respondents recommended adjuvant therapy for patients with adnexal or serosal involvement. Eighty-six percent indicated that a hysteroscopy for diagnosis would not alter their treatment recommendations. Conclusions. While most gynecologic oncologists in our survey recommend adjuvant therapy for stage IIIA endometrial carcinoma, our results showed that patients with malignant cytology only would receive different treatments than patients with adenxal or serosal involvement. Histology and grade of the tumor are predictors of therapy recommendations over malignant cytology. Most respondents agreed that patients with malignant cytology should remain in stage IIIA.

Objective We compared the efficacy and side effects of taxanes, with or without platinum, to bleomycin, etoposide, and cisplatin (BEP) in treating sex cord-stromal ovarian tumors. Methods We conducted a retrospective review of all patients with sex cord-stromal ovarian tumors seen at our institution from 1985 to 2002. Eligible patients were those who underwent pathologic confirmation, clinical evaluation, and treatment with a taxane or BEP for initial or recurrent disease. Results Of 222 patients identified, 21 received BEP for new ( n = 11) or recurrent disease ( n = 10); 44 received a taxane during 48 treatment episodes (four patients on two occasions each) for new ( n = 11) or recurrent disease ( n = 37). Newly diagnosed patients treated with BEP vs. taxanes had no significant difference in response rate (Fisher's exact test, P = 1), progression-free survival (PFS) (log-rank test, P = 0.213), or overall survival (log-rank test, P = 0.994). Among patients treated for recurrent measurable disease, the response rate was higher for BEP-treated (71%) than for taxane-treated patients (37%), but this was not statistically significant. In all patients treated for recurrent disease, there was no significant difference in failure to progress at chemotherapy completion between BEP- (70%) and taxane-treated patients (62%) or in median PFS (11.2 vs. 7.2 months). The presence of platinum in taxane-containing regimens correlated with response. Taxane-related side effects included neutropenia ( n = 6), anemia ( n = 1), thrombocytopenia ( n = 1), myelodysplasia ( n = 1), and hypersensitivity ( n = 1). BEP-related side effects included pulmonary fibrosis ( n = 3) and neutropenia ( n = 2). Conclusions Taxanes demonstrated activity against sex cord-stromal tumors of the ovary and may be less toxic than BEP. Taxane and platinum combination chemotherapy warrants further investigation in this disease.

Endometrial cancer is the most common gynecologic malignancy in the United States. The mean age at diagnosis is 61 years; however, 5-30% of women are aged younger than 50 years at the time of diagnosis. The objective of this study was to conduct a clinical and pathologic review of endometrial cancers diagnosed in premenopausal women aged younger than 50 years, to better identify the risk factors for this subgroup of women.We conducted a retrospective cohort study of patients with histologically confirmed endometrial cancer treated at the University of Texas, M. D. Anderson Cancer Center from 1989 to 2003. Clinical characteristics including age, body mass index (BMI), parity, diabetes, and personal or family history of cancer were obtained from the medical record. Pathologic information was obtained from pathology reports.Twelve percent (188/1531) of all patients with endometrial adenocarcinoma were aged younger than 50 years. The mean age at diagnosis was 41 years (range 21-49 years). Mean BMI was 34 kg/m(2) (range 18-68); 58% of patients had a BMI of 30 or greater. Fifty-five percent were nulliparous and 39% reported irregular menstrual cycles. The incidence of both diabetes and hypertension was 23%. Thirty-six patients (19%) had synchronous ovarian cancers.We found that the majority of patients diagnosed with endometrial cancer at a young age were obese and nulliparous. In addition, we found a high incidence of synchronous primary ovarian cancers in this cohort of young, premenopausal women.

Purpose To determine the efficacy and side effects of taxanes, with or without platinum, for the treatment of sex cord-stromal tumors of the ovary. Patients and Methods We conducted a retrospective review of all patients seen from 1985 to 2002 at The University of Texas M.D. Anderson Cancer Center with ovarian sex cord-stromal tumors. Eligible patients underwent pathology confirmation and clinical evaluation at M.D. Anderson and received a taxane for initial or recurrent disease. Results Of 222 patients identified, 44 were eligible for analysis. For nine patients treated in the first-line adjuvant setting, median progression-free survival (PFS) was not reached at 51 months. Of two patients treated for measurable disease in the first-line setting, one had a complete response. Median PFS was 34.3 months; median overall survival (OS) was not reached. Median follow-up was 90.3 months (range, 39.4 to 140.5 months). Response rate for 30 patients treated with a taxane ± platinum for recurrent, measurable disease was 42%. Median PFS was 19.6 months; median OS was not reached. Median follow-up was 100.7 months (range, 8.1 to 361.3 months). The presence of platinum correlated with response in the recurrent, measurable disease setting. The number of patients was insufficient to detect relative efficacy of paclitaxel and docetaxel. Adverse effects of paclitaxel included neutropenia (n = 6), anemia (n = 1), thrombocytopenia (n = 1), myelodysplasia (n = 1), and hypersensitivity (n = 1). Conclusion Taxanes seem to be active agents in the treatment of patients with sex cord-stromal tumors of the ovary. The combination of taxanes with platinum in the treatment of this disease deserves additional investigation.

Purpose Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer characterized by early metastasis, resistance to therapy, and a high mortality rate. Little is known about the biology of these tumors. Smaller studies suggest that Her-2/neu may be involved in the tumorigenesis of this disease. The purpose of this study was to evaluate the protein expression and gene amplification of Her-2/neu in UPSC and to determine its prognostic value. Patients and Methods Tumor tissue from 68 patients with UPSC treated at The University of Texas M.D. Anderson Cancer Center from 1989 to 2002 was available. Her-2/neu expression was evaluated by immunohistochemistry (IHC). Overexpression was defined as complete membrane staining in greater than 10% of the cells. In tumors with overexpression of Her-2/neu by IHC, fluorescence in situ hybridization (FISH) was performed to assess gene amplification. Clinical and pathologic information was obtained from medical records. Results Twelve (18%) of 68 tumors demonstrated Her-2/neu overexpression. Of these, only two showed gene amplification. When evaluating all 68 patients, Her-2/neu overexpression was associated with a poorer overall survival (OS; P = .008). In our multivariate Cox proportional hazards models, Her-2/neu IHC overexpression, lymph node status, and stage were each associated with OS (P ≤ .05). Conclusion Positive IHC overexpression of Her-2/neu was seen in 18% of UPSCs but was rarely correlated with Her-2/neu gene amplification. Overexpression of Her-2/neu was associated with a worse overall prognosis. The use of trastuzumab (Herceptin; Genentech, South San Francisco, CA) in women with UPSC should be further evaluated in a clinical trial setting.

Purpose Patients with completely resected high-risk endometrial cancer have a risk of disease recurrence even with the addition of adjuvant pelvic radiotherapy (RT). A Phase II study was completed by the Radiation Therapy Oncology Group to assess the safety and toxicity of chemotherapy when combined with pelvic RT for these patients. Methods and materials Eligibility requirements included a total abdominal hysterectomy and bilateral salpingo-oophorectomy with Grade 2 or 3 endometrial adenocarcinoma with >50% myometrial invasion, stromal invasion of the cervix, or pelvic-confined extrauterine disease. This study was designed to administer 4500 cGy in 25 fractions to the pelvis, along with cisplatin (50 mg/m2) on Days 1 and 28. Vaginal brachytherapy with a low-dose-rate applicator (1 × 20 Gy to the surface) or high-dose-rate applicator (3 × 6 Gy to the surface) was performed after external beam RT. Four courses of cisplatin (50 mg/m2) and paclitaxel (175 mg/m2) were given at 4-week intervals after RT completion. Results Forty-six patients were entered between October 1997 and April 1999. Two patients were ineligible (one with previous bladder cancer and one who had undergone surgery >8 weeks before the start of RT). Follow-up ranged from 6.9 to 48.8 months (median, 28.7 months). The disease was Stage III, II, and I in 66%, 16%, and 18% of patients, respectively. Two patients were not assessable because of incomplete treatment data. The protocol completion rate was 98% (41 of 42 assessable patients). Acute toxicity during RT/chemotherapy was Grade 1 in 27%, Grade 2 in 43%, Grade 3 in 27%, and Grade 4 in 2%. During adjuvant chemotherapy, the toxicity was Grade 1 in 7%, Grade 2 in 7%, Grade 3 in 21%, and Grade 4 in 62%. Severe toxicity was primarily hematologic. Chronic toxicity was Grade 1 in 20%, Grade 2 in 39%, Grade 3 in 16%, and Grade 4 in 2%, including 1 patient with a Grade 4 small bowel complication. At 24 months, the pelvic recurrence, regional recurrence, distant recurrence, disease-free survival, and overall survival rate was 2%, 3%, 17%, 83%, and 90%, respectively. Conclusion This treatment protocol demonstrated an excellent treatment completion rate and expected toxicity. Longer follow-up is needed to assess the outcome. To assess the efficacy of this adjuvant treatment program, a Phase III trial (Radiation Therapy Oncology Group 9905) was designed with high-risk uterine-confined disease to be randomized between pelvic RT alone and pelvic RT with chemotherapy.

Objective . To evaluate patients with vulvar cancer who experienced a recurrence after undergoing lymphatic mapping and sentinel lymph node (SLN) biopsy. Methods . We reviewed the records of 52 patients who underwent vulvectomy and lymphatic mapping with blue dye for treatment of vulvar cancer at our institution from 1993 to 1999 and identified patients who experienced recurrent disease. Results . Fourteen (27%) of 52 patients experienced a recurrence. The patients' median age was 60 years (range 35–84 years). Nine patients had squamous lesions, four patients had melanoma, and one patient had Paget's disease with stromal invasion. Four tumors were stage T1, seven were T2, and three were T3. Eight lesions were located at the midline and six were lateral. Thirteen patients underwent superficial inguinal lymphadenectomy while one patient underwent SLN biopsy only. Postoperatively, seven patients underwent no further treatment, six underwent radiation therapy, and one patient underwent chemotherapy. The median follow-up was 46 months and the median disease-free interval was 21 months. Primary recurrence was in the vulva in eight patients (57%), in the groin in three patients (21%), and distant in three patients (21%). Nine of 32 (22%) squamous lesions recurred, four (57%) of seven melanomas recurred, and the sole patient with invasive Paget's recurred. Patient weight was found to be significantly different between patients who experienced a recurrence and those who did not ( P = 0.05). At least one SLN was identified in 46 (88%) of the 52 patients. One (17%) of six patients in whom no SLN was identified experienced a recurrence, and 13 (28%) of 46 patients in whom a SLN was identified experienced a recurrence ( P = 0.5). In the 41 patients with negative SLNs and negative non-SLNs, the recurrence rate was 24%; in the six patients with positive SLNs and negative non-SLNs, the recurrence rate was 40%; and in the five patients with positive SLNs and positive non-SLNs, the recurrence rate was 40% ( P = 0.6). No patients had a negative SLN and positive non-SLN. Of the three patients who experienced a recurrence in the groin, one had a negative SLN and negative non-SLN, one had a positive SLN and positive non-SLN, and one had no SLN identified and a negative non-SLN. Conclusions . This heterogeneous group of patients who underwent lymphatic mapping with blue dye had similar patterns of recurrence to reported series of patients who did not undergo lymphatic mapping. Groin relapse following a negative SLN biopsy is of concern and suggests that long-term follow-up data are required before lymphatic mapping and SLN biopsy alone can be considered standard treatment for patients with vulvar cancer.

The objective of this study was to investigate the cause of groin recurrence in patients with vulvar cancer who had negative nodes in their superficial inguinal lymphadenectomy (SIL) specimens.The records of patients with vulvar cancer treated at M. D. Anderson Cancer Center between 1986 and 1997 were reviewed to identify patients with squamous histology, clinical and surgical stage I or II, depth of invasion greater than 1 mm, and primary treatment consisting of radical wide excision and SIL. One hundred four patients met these criteria. Among these, nine experienced recurrent disease that involved one or both of the groins. All of the original hematoxylin and eosin (HE)-stained slides were reviewed by one pathologist (AM). Then, each paraffin block containing nodal tissue was recut at 40 microm intervals to obtain five sections for HE staining and two unstained sections to be used for cytokeratin immunostaining if necessary.The median age at diagnosis and primary surgery was 65 years and the median depth of invasion was 4 mm. Seven patients underwent bilateral, and two underwent unilateral, groin dissections. The median number of lymph nodes removed per groin was seven. The median time to recurrence was 22 months. A total of 785 additional HE-stained slides were prepared and examined at 100x and 400x magnification. No micrometastases were identified, and there were no other suspicious findings. Therefore, immunohistochemical staining was not performed. At recurrence, one patient had a biopsy only, and eight had attempted surgical resection. In two patients, tumor was identified in fibroadipose tissue only; no lymph nodes were identified. Among the other six patients, the median number of lymph nodes resected at the time of the recurrence was five (range 1 to 10). At last report, six patients had died and three were alive and free of disease. Median follow-up for survivors was 63 months (range 42 to 71).These data strongly suggest that groin relapse in patients with negative nodes on SIL is caused by metastatic disease in unresected inguinal nodes. SIL as performed on the patients in this study did not eliminate all sites of nodal metastasis.

Objective The aim of this study was to determine the efficacy of cisplatin, ifosfamide, and mesna in uterine malignant mixed mullerian tumor (MMMT) and to evaluate the expression of clinically relevant molecular markers. Methods Women with advanced or recurrent MMMT were treated every 28 days with cisplatin (75 mg/m 2 ), ifosfamide (1.2 gm/m 2 ), and mesna (240 mg/m 2 ). Treatment continued until disease progression or for six courses in the case of nonmeasurable disease. Immunohistochemical analysis for estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, C-kit, Abl, and PDGFR-β expression were performed. Results Sixteen patients received 1–10 cycles; 2 died of disease progression after 1 cycle; 3 stopped after 1 cycle because of toxicity. Of 6 with measurable disease, 2 had a partial response, 1 had stable disease (SD), and 3 had progression (RR 33%). Partial response durations were 6 and 9 months; SD duration was 6 months. Of 5 patients without measurable disease, 4 received 6 cycles; 1 received 4 cycles. Four died of recurrent disease and 1 was without disease 6.5 years after treatment. Thirty-six percent experienced at least one neutropenic G3 or G4 event. All experienced G1 gastrointestinal toxicity. Four required dose reductions. At 7.5 months, only 1 with measurable disease was still living. Immunohistochemical analyses revealed that 24% expressed ER or PR, 19% expressed HER-2/neu , and none expressed C-kit . However, 45% expressed Abl and 100% expressed PDGFR-β. Conclusions Although the combination of cisplatin, ifosfamide, and mesna in patients with MMMT had moderate activity, the high toxicity and short response duration in this uncommon, aggressive malignancy suggest that this regiment continues to be a disappointing treatment choice for uterine MMMT. HER-2/Neu , Abl , or PDGFR-β expression may be of value in order to investigate novel multimodality treatment strategies.

To determine the outcome of patients after radical radiotherapy (RT) for isolated vaginal recurrence of endometrial carcinoma and to determine the clinical and pathologic predictors of outcome.We reviewed the records of 91 patients treated at our institution between 1960 and 1997 with radical RT for vaginal recurrence after definitive surgery for endometrial carcinoma. Thirty-one percent of the patients received external beam RT (EBRT) alone, 12% received brachytherapy alone, and 57% received a combination. The median dose of radiation was 75 Gy (range 34-122). All end points were measured from the time of the first recurrence. The median duration of follow-up after recurrence was 58 months (range 1-289).The 2- and 5-year local control (LC) rate and overall survival rate was 82% and 75% and 69% and 43%, respectively. The median time from initial diagnosis of endometrial cancer to death from disease was 38 months. On univariate analysis, a dose to the relapse site ofor =80 Gy and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved LC. On multivariate analysis, only the type of treatment correlated significantly with LC (p = 0.03). On univariate analysis, Grade 1 or 2 vs. Grade 3 tumor and EBRT plus brachytherapy vs. single-modality therapy were significant predictors of improved overall survival.RT provides excellent LC of isolated vaginal recurrences of endometrial carcinoma, particularly when high doses are given using a combination of EBRT and brachytherapy. However, distant metastases frequently develop despite local disease control, contributing to a 5-year overall survival rate of50%. For patients who have an isolated vaginal recurrence, the time from initial diagnosis of endometrial cancer to death from disease is usually3 years. For this reason, in studies of adjuvant RT, long-term follow-up is required to permit evaluation of the impact of treatment on survival.

Uterine tumors resembling ovarian sex-cord tumors (UTROSCTs) are unusual neoplasms with histologic features that resemble those within ovarian Sertoli and granulosa cell tumors. We report the case of a 24-year-old woman with a UTROSCT presenting as a cervical mass, which on initial evaluation was thought to represent cervical adenocarcinoma. The patient's cervical biopsy specimen contained epithelioid cells arranged in tubules and anastomosing cords, without significant cellular atypia or mitotic activity. Because this morphology elicited a broad differential diagnosis, immunohistochemical studies were performed. The tumor was found to be diffusely positive for cytokeratin cocktail, calretinin, and desmin, focally positive for CK7 and SMA, and negative for EMA, CEA, inhibin, CD10, CK20, chromogranin, and synaptophysin. Ultrastructural examination revealed occasional gland-like lumens with cells joined by desmosomes and a continuous basal lamina. UTROSCTs have features that may cause them to be confused with more common tumors, especially in limited biopsy samples, and should be included in the differential diagnosis when a gland-forming neoplasm with an unusual appearance is identified in a cervical or endometrial biopsy specimen.

Our objective was to assess the value of lymphangiography in selecting patients for surgical staging of locally advanced cervical cancer. We reviewed our computerized database to identify patients with cervical cancer who had abnormal findings on lymphangiography and underwent retroperitoneal lymph node dissection between September 1991 and January 1996. The records of these patients were retrospectively reviewed, and the following data were retrieved: clinical tumor stage and findings on lymphangiography at surgery, and on pathologic examination of resected lymph nodes. The lymphangiograms were reviewed and reinterpreted in blinded fashion by two of the authors. The positive and negative predictive values of lymphangiography for the presence of lymph node metastases were calculated, with findings on pathologic examination of lymph nodes used as the gold standard. The positive and negative predictive values of surgeons' clinical assessments at surgery were also calculated. Fifty patients met the selection criteria and constituted the study population. Fourteen patients (28%) had histologically negative nodes, and 36 patients (72%) had lymph node metastases. Thirty-three patients had metastases to pelvic nodes, 1515 patients had metastases to common iliac nodes, and 1616 patients had metastases to para-aortic nodes. The positive predictive value of lymphangiography for lymph node metastases was 74% for pelvic nodes, 73% for common iliac nodes, and 88% for para-aortic nodes. The negative predictive value of lymphangiography for lymph node metastasis was 76% for common iliac nodes and 77% for para-aortic nodes. Overall, 46% of the patients selected for surgical exploration had histologic findings of either common iliac or para-aortic lymph node metastases; these findings led clinicians to extend radiation fields to cover the para-aortic lymph nodes. Lymphangiography is helpful in selecting patients with cervical cancer who have a high risk of common iliac or para-aortic lymph node metastasis. However, more accurate and more readily available noninvasive methods of evaluating cervical patients for the presence of regional disease continue to be needed.

This is a report of 52 patients with vulvar cancer who were injected with isosulfan blue dye at the time of their primary surgical treatment. The intent was to identify the sentinel nodes, which are the first nodes to receive metastases from the primary tumor, All patients who had their primary surgical treatment for vulvar cancer at the authors' institutions between 1993 and 1999 were included in the study (N = 52; median age = 58 years, range = 18-92). After preparation for surgery and before the skin incision was made, 1 to 4 ml of isosulfan blue dye were injected into the dermis at the edge of the tumor closest to the groin. Bilateral injections were made when the tumor was located with 2 cm of the midline, Injection sites were massaged for 5 minutes, a deep groin incision was made, and the afferent lymphatic channel was identified. This channel was followed until one or more blue nodes were found. These sentinel nodes were excised and sent for gross histological examination. If the findings were suspicious, a frozen section analysis was done. All nonsentinel nodes were excised and examined separately. The blue dye disappeared within 45 minutes of injection. In 22 of the 52 patients (42%), tumor was diagnosed in the labium. Fourteen patients (27%) had disease in the clitoris. Other tumor sites included the perineum, fourchette, and Bartholin's gland. Squamous cell (67%) and adenocarcinoma (17%) were the most frequent tumor types. Melanoma and Paget's disease were also diagnosed (13 and 2%, respectively). Most patients (81%) underwent superficial inguinal lymphadenectomy. The others had inguinal femoral lymphadenectomy (12%) or sentinel lymph node biopsy (8%). Unilateral groin dissection was performed in the 25 women with lateral tumors and in 3 of the 27 women with a midline tumor. The other 24 patients had bilateral dissection. The blue dye was well tolerated by all patients. Forty-six patients (88%) had at least one sentinel node diagnosed. In all, 76 groin dissections were performed, and the sentinel node was identified in 57 of the dissected groins (75%). When incisional or excisional biopsy preceded the node mapping, the sentinel node could not be identified in 44% of the groin dissections. When only a punch biopsy was performed, the percentage of patients in whom no sentinel node was found was significantly lower (16%, P =.007). The tumor location also had a significant effect on the identification of sentinel nodes. Successful identification was made in 22 of the 25 of women with lateral tumors (88%) and 35 of the 51 women with midline tumors (65%) (P =.067). Sentinel nodes were less likely to be identified in the early years of the study (P =.034). In all, 556 nodes were removed from the 52 women (median = 7 per groin). A total of 83 sentinel nodes were identified (median = 1 in each groin, range = 1-4). Tumor metastases were found in the lymph nodes of 11 patients, 10 with involvement on one side and 1 with a midline tumor. No sentinel node was found in 2 of the 12 groins with metastases, both in patients enrolled during the first 2 years of the study. No false-positive nodes were seen. Since 1995, a successful sentinel node identification has been made in 100% of the patients with T 1 or T 2 primary vulvar squamous cell cancer who had clinically nonsuspicious nodes.

Objective. The aim of this study was to determine the effectiveness and toxicity of monthly treatment with intravenous paclitaxel for women with advanced or recurrent uterine papillary serous carcinoma (UPSC). Methods. Consenting women with histologically confirmed advanced (FIGO stage III or IV) or recurrent UPSC were treated on an Institutional Review Board approved protocol of a 24-h intravenous infusion of 200 mg/m 2 of paclitaxel every 3 weeks. Both measurable and nonmeasurable disease cases were enrolled. Treatment was continued until disease progression, patient intolerance, or (in women with nonmeasurable disease) completion of six courses. Results. Twenty patients received from 1 to 11 cycles of therapy. Two women died of disease after 1 cycle of therapy and were not evaluable for response. Among 13 women with measurable tumor receiving 2 or more cycles of therapy, 4 had a complete clinical response and 6 had a partial response (objective response rate, 77%). The median time to progression was 7.3 months (range, 2–21 months). All 3 remaining patients with measurable disease had stable disease for a median of 6 months. The 5 patients without evaluable disease received 5 to 6 cycles of adjuvant paclitaxel. Three developed recurrence (range, 4–10 months; median, 7.2 months). Neutropenia was the major toxicity. Eleven of the 20 patients required G-CSF support, and 9 were hospitalized for neutropenic fever. One woman had reversible cardiac symptoms, which might have been related to paclitaxel treatment. At the time of analysis (mean follow-up, 23 months; range, 4.3–59.9 months), 13 women had died of disease, 4 were alive with disease, and 2 were disease free. All 3 disease-free patients had been treated for nonmeasurable advanced stage disease. Conclusion. Paclitaxel appears to have excellent activity in the treatment of advanced or recurrent UPSC, an uncommon but aggressive malignancy. Longer survival appears to be more common among women with small-volume disease.

Author(s): Lee, Larissa J; Ratner, Elena; Uduman, Mohamed; Winter, Kathryn; Boeke, Marta; Greven, Kathryn M; King, Stephanie; Burke, Thomas W; Underhill, Kelly; Kim, Harold; Boulware, Raleigh J; Yu, Herbert; Parkash, Vinita; Lu, Lingeng; Gaffney, David; Dicker, Adam P; Weidhaas, Joanne | Abstract: ObjectiveTo explore the association of a functional germline variant in the 3'-UTR of KRAS with endometrial cancer risk, as well as the association of microRNA (miRNA) signatures and the KRAS-variant with clinical characteristics and survival outcomes in two prospective RTOG endometrial cancer trials.Methods/materialsThe association of the KRAS-variant with endometrial cancer risk was evaluated by case-control analysis of 467 women with type 1 or 2 endometrial cancer and 582 age-matched controls. miRNA and DNA were isolated for expression profiling and genotyping from tumor specimens of 46 women with type 1 endometrial cancer enrolled in RTOG trials 9708 and 9905. miRNA expression levels and KRAS-variant genotype were correlated with patient and tumor characteristics, and survival outcomes were evaluated by variant allele type.ResultsThe KRAS-variant was not significantly associated with overall endometrial cancer risk (14% controls and 17% type 1 cancers), although was enriched in type 2 endometrial cancers (24%, p = 0.2). In the combined analysis of RTOG 9708/9905, miRNA expression differed by age, presence of lymphovascular invasion and KRAS-variant status. Overall survival rates at 3 years for patients with the variant and wild-type alleles were 100% and 77% (HR 0.3, p = 0.24), respectively, favoring the variant.ConclusionsThe KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.

mg/m 2 . In the second stage of the study, the doses of cisplatin and melphalan were fixed at 75 mg/m 2 and the MTD level, respectively, and the dose of paclitaxel was escalated. The planned dose escalation levels of paclitaxel were 150 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 225 mg/m 2 , and 250 mg/m 2 . G-CSF was administered for 12‐19 days with each cycle, and cycles were repeated every 4 weeks for a total of 6 cycles. Other end points included clinical or surgical response, progression free survival, and survival. RESULTS. Between January 1993 and May 1996, 34 women with untreated advanced stage epithelial ovarian carcinoma or primary peritoneal carcinoma were treated with 192 cycles of therapy. The MTD of melphalan was 10 mg/m 2 , with the dose-limiting toxicity being thrombocytopenia. Paclitaxel was escalated to a dose level of 200 mg/m 2 with a toxicity rate of , 33%. The clinical response rate was 80% in 29 patients with measurable disease. Of 11 patients who underwent second-look surgery, 5 (45%) had a surgical pathologic complete response. The median progression free survival was 16.8 months and the median survival was 32.8 months. CONCLUSIONS. The combination of intravenous melphalan, paclitaxel, and cisplatin was found to have acceptable toxicity and good activity. A Phase II study of this combination appears to be warranted. Cancer 1999;86:2291‐300. © 1999 American Cancer Society.

BACKGROUND The purpose of the current study was to evaluate the current practice of surgical staging of ovarian serous borderline tumors. METHODS Women with a diagnosis of ovarian serous borderline tumors whose pathology slides were sent to the M. D. Anderson Cancer Center for second-opinion diagnostic consultation between 1990–1996 were identified. The original pathology reports and M. D. Anderson Cancer Center consultation reports of 255 cases were reviewed for the frequencies of frozen-section analyses and staging biopsies, biopsy results, the specialty of the surgeon, and hospital type. RESULTS The majority (78%) of ovarian borderline tumors primarily were encountered and staged by general obstetrician-gynecologists. Overall, 66% of patients had at least 1 staging biopsy performed. Approximately 12% of subjects underwent complete surgical staging, defined as having biopsy samples taken from pelvic and abdominal peritoneum, omentum, and retroperitoneal lymph nodes. Gynecologic oncologists performed complete staging in 50% of cases, obstetrician-gynecologists performed complete staging in 9% of cases, and general surgeons performed complete staging in 0% cases. The overall frequency of a positive staging biopsy was 37%. Approximately 47% (80 of 169) of patients who underwent biopsies were upstaged as a result of positive biopsies, - with 41% (70 of 169) having extrapelvic spread. CONCLUSIONS Currently, surgical staging for women with ovarian serous borderline tumors remains inadequate, although a significant proportion of patients who undergo staging are noted to have extrapelvic spread. Cancer 1999;85:905–11. © 1999 American Cancer Society.

Objectives. To evaluate the efficacy of radiation therapy and potential prognostic factors in patients treated for pelvic recurrence of cervical carcinoma after radical hysterectomy. Materials. The records of 50 patients treated between 1964 and 1994 for an isolated pelvic recurrence of cervical carcinoma a median of 10.5 months after initial radical hysterectomy were retrospectively reviewed. Patients were categorized according to the extent of disease on clinical examination as group 1, mucosal involvement only (5); group 2, paravaginal extension (11); group 3, central recurrence with pelvic wall extension (13); and group 4, recurrences limited to the pelvic sidewall (21). Seven patients with group 3 or 4 disease who had a poor performance status were treated with palliative intent using hypofractionated radiotherapy. The remaining 43 patients were treated with curative intent, 33 with radiotherapy only and 10 with a combination of cisplatin-based chemotherapy and radiotherapy. Survival rates were calculated from the date of initial recurrence. Median follow-up of surviving patients was 109 months. Results. The overall 5-year survival rate was 33% for all 50 patients (median survival, 18 months), 39% for the 43 patients treated with curative intent, and 25% for patients with isolated sidewall recurrences treated with curative intent. The survival rate was 69% for patients with group 1 and 2 disease and 18% for those treated with curative intent for group 3 disease ( P = 0.07). The survival rate was better for patients with recurrent squamous carcinomas (51%) than for those with adenocarcinomas (14%) ( P = 0.05). Three group 4 patients who survived more than 5 years were treated with external-beam radiation alone. Eight-one percent of patients who had a second recurrence had evidence of disease progression. Three patients experienced late treatment complications. Conclusions. Patients who experience an isolated recurrence of cervical cancer after initial radical hysterectomy have an excellent prognosis if disease does not involve the pelvic wall. Occasional long-term survivors of recurrent disease involving the pelvic wall justify an aggressive treatment approach.

Background The objective of the current study was to update the authors' experience with patients with ovarian serous borderline tumors with invasive peritoneal implants to gain additional insight into the biologic behavior of these tumors and a better understanding of the effect of postoperative treatment. Methods Thirty-nine patients with ovarian serous borderline tumors with invasive peritoneal implants were identified through a retrospective review. Major endpoints selected for analysis were surgicopathologic response, time to recurrence, type of recurrence, progression free survival, and overall survival. Univariate and multivariate regression analyses also were performed. Results Median follow-up time was 111 months. Four of 7 evaluable patients who had second-look surgery (57%) had a response to chemotherapy. Twelve of 39 patients (31%) either developed progressive disease or had a recurrence. The median time from date of diagnosis to recurrence was 24 months. In 10 of these 12 patients with a recurrence, tissue was available; 9 had invasive low grade serous carcinoma and 1 had a recurrent borderline tumor. Macroscopic residual disease was the only factor studied that had a significant effect on survival; patients with no macroscopic residual tumor had a significantly better survival than those with any macroscopic residual tumor (P Conclusions Greater than 30% of patients with ovarian serous borderline tumors with invasive peritoneal implants will develop progressive or recurrent tumor, most commonly serous carcinoma. The presence of macroscopic residual disease appears to be the major predictor of recurrence and survival. However, in this study, the authors were unable to elucidate the role of postoperative therapy or the criteria for selection of patients for such therapy.

To evaluate the effectiveness of an outcomes-management program designed to provide high-quality patient care, generate data for outcomes research, and decrease costs in a managed-care environment.An outcomes-management program was launched in June 1994, based on the elimination of wasteful or ineffective therapies through the systematic development of practice guidelines and collaborative care paths, with concomitant definition of desired outcomes. Over 3 months, care paths were developed for our most common surgical procedures. A matched control outcomes study was undertaken for the most commonly performed gynecologic oncology procedure: total abdominal hysterectomy and oophorectomy with pelvic and para-aortic node sampling for endometrial cancer. Thirty consecutive women treated on the care path were compared with 29 matched controls accrued during the period of care-path planning and with 73 controls from the period preceding care-path planning. Patient satisfaction with care-path treatment was assessed by a survey sent 2 weeks after discharge.Median length of hospital stay decreased significantly, from 6 days before care-path planning to 4 days after care-path implementation (P.001). Median laboratory costs decreased by 74% (P.001), medication costs by 35% (P.001), room costs by 29% (P.001), and total hospital costs by 20% (P.002). Incremental improvements were observed during care-path planning. There were no readmissions for complications in the care-path group. According to the survey results, patient satisfaction with care was very high among care-path patients.A physician-driven outcomes-management program in an academic setting permits the delivery of high-quality care and supports outcomes research while decreasing costs.