Association of common maternal infections with birth outcomes: a multinational cohort study.

PURPOSE: It is unclear whether common maternal infections during pregnancy are risk factors for adverse birth outcomes. We assessed the association between self-reported infections during pregnancy with preterm birth and small-for-gestational-age (SGA) in an international cohort consortium. METHODS: Data on 120,507 pregnant women were obtained from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA. Self-reported common infections during pregnancy included influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections, cystitis, urinary tract infection, and the symptoms fever and diarrhoea. Birth outcomes included preterm birth, low birth weight and SGA. Associations between maternal infections and birth outcomes were first assessed using Poisson regression in each cohort and then pooled using random-effect meta-analysis. Risk ratios (RR) and 95% confidence intervals (CI) were calculated, adjusted for potential confounders. RESULTS: Vaginal infections (pooled RR, 1.10; 95% CI, 1.02-1.20) and urinary tract infections (pooled RR, 1.17; 95% CI, 1.09-1.26) during pregnancy were associated with higher risk of preterm birth. Similar associations with low birth weight were also observed for these two infections. Fever during pregnancy was associated with higher risk of SGA (pooled RR, 1.07; 95% CI, 1.02-1.12). No other significant associations were observed between maternal infections/symptoms and birth outcomes. CONCLUSION: Vaginal infections and urinary infections during pregnancy were associated with a small increased risk of preterm birth and low birth weight, whereas fever was associated with SGA. These findings require confirmation in future studies with laboratory-confirmed infection diagnosis.

Effects of Compliance With the Early Management Bundle (SEP-1) on Mortality Changes Among Medicare Beneficiaries With Sepsis: A Propensity Score Matched Cohort Study.

BACKGROUND: US hospitals have reported compliance with the SEP-1 quality measure to Medicare since 2015. Finding an association between compliance and outcomes is essential to gauge measure effectiveness. RESEARCH QUESTION: What is the association between compliance with SEP-1 and 30-day mortality among Medicare beneficiaries? STUDY DESIGN AND METHODS: Studying patient-level data reported to Medicare by 3,241 hospitals from October 1, 2015, to March 31, 2017, we used propensity score matching and a hierarchical general linear model (HGLM) to estimate the treatment effects associated with compliance with SEP-1. Compliance was defined as completion of all qualifying SEP-1 elements including lactate measurements, blood culture collection, broad-spectrum antibiotic administration, 30 mL/kg crystalloid fluid administration, application of vasopressors, and patient reassessment. The primary outcome was a change in 30-day mortality. Secondary outcomes included changes in length of stay. RESULTS: We completed two matches to evaluate population-level treatment effects. In standard match, 122,870 patients whose care was compliant were matched with the same number whose care was noncompliant. Compliance was associated with a reduction in 30-day mortality (21.81% vs 27.48%, respectively), yielding an absolute risk reduction (ARR) of 5.67% (95% CI, 5.33-6.00; P < .001). In stringent match, 107,016 patients whose care was compliant were matched with the same number whose care was noncompliant. Compliance was associated with a reduction in 30-day mortality (22.22% vs 26.28%, respectively), yielding an ARR of 4.06% (95% CI, 3.70-4.41; P < .001). At the subject level, our HGLM found compliance associated with lower 30-day risk-adjusted mortality (adjusted conditional OR, 0.829; 95% CI, 0.812-0.846; P < .001). Multiple elements correlated with lower mortality. Median length of stay was shorter among cases whose care was compliant (5 vs 6 days; interquartile range, 3-9 vs 4-10, respectively; P < .001). INTERPRETATION: Compliance with SEP-1 was associated with lower 30-day mortality. Rendering SEP-1 compliant care may reduce the incidence of avoidable deaths.

Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts.

BACKGROUND: Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. METHODS: Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. RESULTS: Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10-2.58)] and subtypes ALL [1.49 (0.87-2.56)] and AML [2.70 ([0.93-7.86)], but not with any cancer [1.13 (0.85-1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06-2.34)], ALL [1.43 (0.94-2.19)], AML [2.37 (1.10-5.12)] and any cancer [1.33 (1.09-1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. CONCLUSIONS: Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C).

The "delayed infection hypothesis" states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 106 person-years of follow-up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77-0.99) and 0.85: (0.73-0.99), respectively. Being later-born was associated with similarly reduced hazards of CL and ALL compared to being first-born; HRs = 0.78: 95% CI: 0.58-1.05 and 0.73: 0.52-1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later-born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06-0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures.

The International Childhood Cancer Cohort Consortium (I4C): A research platform of prospective cohorts for studying the aetiology of childhood cancers.

BACKGROUND: Childhood cancer is a rare but leading cause of morbidity and mortality. Established risk factors, accounting for <10% of incidence, have been identified primarily from case-control studies. However, recall, selection and other potential biases impact interpretations particularly, for modest associations. A consortium of pregnancy and birth cohorts (I4C) was established to utilise prospective, pre-diagnostic exposure assessments and biological samples. METHODS: Eligibility criteria, follow-up methods and identification of paediatric cancer cases are described for cohorts currently participating or planning future participation. Also described are exposure assessments, harmonisation methods, biological samples potentially available for I4C research, the role of the I4C data and biospecimen coordinating centres and statistical approaches used in the pooled analyses. RESULTS: Currently, six cohorts recruited over six decades (1950s-2000s) contribute data on 388 120 mother-child pairs. Nine new cohorts from seven countries are anticipated to contribute data on 627 500 additional projected mother-child pairs within 5 years. Harmonised data currently includes over 20 "core" variables, with notable variability in mother/child characteristics within and across cohorts, reflecting in part, secular changes in pregnancy and birth characteristics over the decades. CONCLUSIONS: The I4C is the first cohort consortium to have published findings on paediatric cancer using harmonised variables across six pregnancy/birth cohorts. Projected increases in sample size, expanding sources of exposure data (eg, linkages to environmental and administrative databases), incorporation of biological measures to clarify exposures and underlying molecular mechanisms and forthcoming joint efforts to complement case-control studies offer the potential for breakthroughs in paediatric cancer aetiologic research.

Does the Renal Parenchyma Adjacent to the Tumor Contribute to Kidney Function? A Critical Analysis of Glomerular Viability in Partial Nephrectomy Specimens.

OBJECTIVE: To evaluate the viability of glomeruli in the peritumor parenchyma of partial nephrectomy specimens removed for renal cell carcinoma (RCC) and relate it to kidney function, to better understand the contribution of peritumor parenchyma to renal function. MATERIALS AND METHODS: A retrospective analysis of 53 partial nephrectomies containing RCC was performed. Glomeruli within 0.25-cm increments from the tumor were quantified and histologically assessed for viability. Tumor size, minimum and maximum margin size, and pre- and postoperative estimated glomerular filtration rate (eGFR) were obtained. RESULTS: Glomerular viability positively correlated with distance from tumor with mean viable glomeruli in successive 0.25-cm increments of 0-0.25 cm, 58%; 0.25-0.5 cm, 80%; 0.5-0.75 cm, 90%; and 0.75-1.0 cm, 92%. Glomerular viability near the tumor did not correlate with preoperative eGFR, whereas decreased viability further from the tumor did correlate with worse preoperative eGFR. Tumor size showed a nonstatistically significant positive trend with minimum (median 0.15 cm) and maximum margin (median 0.7 cm) sizes. Percent change of glomerular filtration rate did not correlate with margin size (P = .190). CONCLUSION: Renal parenchyma immediately adjacent to RCC contains fewer viable glomeruli compared with the parenchyma further from the tumor. Based on this information, attempts to preserve all non-neoplastic renal parenchyma via a surgical margin approaching zero may not necessarily result in clinically relevant differences in the amount of viable glomeruli remaining or the renal function preserved.

Burnout and associated factors among members of the Society of Gynecologic Oncology.

OBJECTIVE: Burnout is specific to the work domain and in physicians is indicative of emotional exhaustion, depersonalization in relationships with coworkers and detachment from patients, and a sense of inadequacy or low personal accomplishment. The purpose of this study was to determine the burnout rate among gynecologic oncologists and evaluate other personal, professional, and psychosocial factors associated with this condition. STUDY DESIGN: This study used a cross-sectional design. Current members of the Society of Gynecologic Oncology were sent an anonymous email survey including 76 items measuring burnout, psychosocial distress, career satisfaction, and quality of life. RESULTS: A total of 1086 members were invited, 436 (40.1%) responded, and 369 (84.6%) of those completed the survey. Of physicians, 30% scored high for emotional exhaustion, 10% high for depersonalization, and 11% low for personal accomplishment. Overall, 32% of physicians scored above clinical cutoffs indicating burnout. In all, 33% screened positive for depression, 13% endorsed a history of suicidal ideation, 15% screened positive for alcohol abuse, and 34% reported impaired quality of life. Nonetheless, 70% reported high levels of personal accomplishment, and results suggested most were satisfied with their careers, as 89% would enter medicine again and 61% would encourage their child to enter medicine. Respondents with high burnout scores were less likely to report they would become a physician again (P = .002) or encourage a child to enter medicine (P < .001), and more likely to screen positive for depression (P < .001), alcohol abuse (P = .006), history of suicidal ideation (P < .001), and impaired quality of life (P < .001). CONCLUSION: Burnout is a significant problem associated with psychosocial distress and lower levels of career satisfaction in gynecologic oncologists. Burnout in obstetrics-gynecology and gynecologic oncology is of particular concern as young age and female gender are often identified as risk factors for this significant problem. Interventions targeted at improving quality of life, treatment of depression, or alcohol abuse may have an impact on burnout. However, significant barriers may exist as 44.5% of respondents in this study reported that they would be reluctant to seek medical care for depression, substance use, or other mental health issues due to concerns about their medical license.

Stromal Caveolin-1 Is Associated With Response and Survival in a Phase II Trial of nab-Paclitaxel With Carboplatin for Advanced NSCLC Patients.

UNLABELLED: In this phase II trial, carboplatin with nanoparticle albumin-bound (nab)-paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC) was evaluated. Most patients had squamous cell histology. Tumor-associated stromal caveolin-1 (Cav-1) expression was correlated with improved response rate and survival in NSCLC patients who received nab-paclitaxel in this phase II trial. These results suggest Cav-1 might serve as a potential biomarker in this patient population. BACKGROUND: The combination of bevacizumab with platinum-based chemotherapy results in greater response rate (RR) and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Bevacizumab is contraindicated in patients with squamous histology or hemoptysis. Nanoparticle albumin-bound (nab)-paclitaxel is a novel formulation of paclitaxel with greater dose tolerance and improved efficacy. We hypothesized that nab-paclitaxel and carboplatin would be superior to alternative doublets in advanced NSCLC patients ineligible for bevacizumab. PATIENTS AND METHODS: We conducted a single-arm phase II trial (NCT00729612) with carboplatin and nab-paclitaxel on day 1 of a 21-day cycle to evaluate RR (primary end point), safety, toxicity, and OS. Eligibility included: squamous histology, hemoptysis, or ongoing anticoagulation. Correlative studies included immunohistochemistry for secreted protein acid rich in cysteine (SPARC) and caveolin-1 (Cav-1). RESULTS: Sixty-three patients were enrolled. Most patients had squamous cell carcinoma (n = 48); other reasons for eligibility included hemoptysis (n = 11) and anticoagulation (n = 2). Toxicity Grade ≥ 3/4 included neuropathy, cytopenias, and fatigue. RR was 38% (24 partial response/0 complete response); 20 patients had stable disease (32%). Median progression-free survival was 5 months and median OS was 9.7 months. Immunohistochemistry for SPARC and Cav-1 was performed in 38 and 37 patients respectively. Although no association was found for SPARC expression in tumor or stroma with RR or OS, we found that higher Cav-1 levels in tumor-associated stroma was associated with improved RR and OS. CONCLUSION: Carboplatin and nab-paclitaxel every 21 days demonstrated promising efficacy with tolerable toxicity in NSCLC patients ineligible for bevacizumab therapy. Further analysis and validation of Cav-1 and SPARC expression in tumor and stromal compartments as prognostic and/or predictive biomarkers of NSCLC or nab-paclitaxel treatment is warranted.

Mediastinal and Hilar Lymph Node Measurements. Comparison of Multidetector-Row Computed Tomography and Endobronchial Ultrasound.

RATIONALE: Multidetector-row chest computed tomography scan is a common initial imaging modality and endobronchial ultrasound is a minimally invasive diagnostic tool used to evaluate enlarged lymph nodes, but comparisons of imaging results are lacking. OBJECTIVES: To determine the size of thoracic lymph nodes and the strength of agreement between each measurement from coronal plane computed tomography and static endobronchial ultrasound images. METHODS: A retrospective review of consecutive patients who underwent endobronchial ultrasound-transbronchial needle aspiration of their lymph nodes because of clinical suspicion of benign or malignant thoracic disease. MEASUREMENTS AND MAIN RESULTS: One hundred and twenty-four lymph nodes from the mediastinal (74.2%) and hilar (25.8%) stations were measured in 59 patients (mean age, 64.5 yr; 33 males). The mean (standard deviation) short-axis diameter on computed tomography was 14.1 (6.7) mm compared with 12.6 (6.6) mm on endobronchial ultrasound. Benign lymph nodes (n = 42) were larger on computed tomography than on endobronchial ultrasound (14.1 [6.2] vs. 11.5 [6.2] mm). Malignant lymph nodes (n = 35) were larger on endobronchial ultrasound than on computed tomography (17.3 [6.4] vs. 16.2 [6.7] mm). Sixty-five percent of the lymph nodes that were initially interpreted as not enlarged on axial computed tomography images measured greater than 10 mm on each imaging modality (12.5 [5.9] mm on computed tomography and 10.5 [5.6] mm on endobronchial ultrasound) and 24% of the sampled lymph nodes from this group contained malignant cells. Random-effects maximal likelihood linear regression showed a statistically significant difference between endobronchial ultrasound and the computed tomography method for measuring short-axis diameter in all 124 lymph nodes. There was a weak agreement (intraclass correlation, rho: 0.44 [95% confidence interval, 0.31-0.59]) between short-axis diameter measurements from each imaging modality. CONCLUSIONS: Our single-center study shows that there was poor correlation between computed tomography and endobronchial ultrasound for the measurement of mediastinal and hilar lymph nodes. Malignant cells were recovered by ultrasound-guided needle aspiration from a substantial fraction of lymph nodes that were initially interpreted as normal in size. If these findings are confirmed, new criteria may be needed for lymph node measurement on computed tomography that will guide selection of lymph nodes for endobronchial ultrasound-transbronchial needle aspiration.

Trends in psychotropic polypharmacy among youths enrolled in Ohio Medicaid, 2002-2008.

OBJECTIVE: This study examined polypharmacy patterns and rates over time among Medicaid-enrolled youths by comparing three enrollment groups (youths in foster care, with a disability, or from a family with low income). METHODS: Serial cross-sectional trend analyses of Medicaid claims data were conducted for youths age 17 and younger who were continuously enrolled in Ohio Medicaid for a one-year period and prescribed one or more psychotropic medications during fiscal years 2002 (N=26,252) through 2008 (N=50,311). Outcome measures were any polypharmacy (three or more psychotropic medications from any drug class) and multiclass polypharmacy (three or more psychotropic medications from different drug classes). RESULTS: Both types of polypharmacy increased across all three eligibility groups. Any polypharmacy increased from 8.8% to 11.5% for low-income youths (adjusted odds ratio [AOR]=1.12, 99% confidence interval [CI]=1.10-1.13), from 18.0% to 24.9% for youths with a disability (AOR=1.11, CI=1.09-1.13), and from 19.8% to 27.3% for youths in foster care (AOR=1.09, CI=1.07-1.11). Combinations associated with positive increases were two or more antipsychotics, two or more stimulants, and antipsychotics with stimulants. CONCLUSIONS: Polypharmacy increased across all enrollment groups, with the highest absolute rates for youths in foster care. Both the overall prevalence and increases in prescriptions for drug combinations with limited evidence of safety and efficacy, such as the prescription of two or more antipsychotics, underscore the need for targeted quality improvement efforts. System oversight and monitoring of psychotropic medication use appears to be warranted, especially for higher-risk groups, such as youths in foster care and those from low-income households who were prescribed multiple antipsychotics.

Clinicopathologic characteristics and overall survival in patients with bladder cancer involving the gastrointestinal tract.

Involvement of the gastrointestinal (GI) tract by bladder cancer is rare and documented in only a few case reports with no prognostic information available. The aim of this study was to clinicopathologically characterize patients with pathologically proven bladder cancer in the GI tract. We reviewed pathology reports from cystectomy patients at our institution from 2006 to 2011, identifying those with GI involvement at or after cystectomy. Overall survival (OS) was analyzed using Kaplan-Meier curves and Cox proportional hazard regression models. Twelve patients had surgical pathology specimens with GI involvement (anus, rectum, colon, and small bowel) at (n = 11) or within 4 months (n = 1) of cystectomy. These patients were noted to be pathologically staged inconsistently. GI involvement was a negative predictor of survival, with a 1.5-year OS of 25 versus 62 % without GI involvement (P < 0.001), similar to our pT4 patients (OS 26 %). In node-negative patients, there was a significantly worse 1.5-year OS with GI involvement compared to those without tumor in the GI tract (P = 0.005). We provide the first case series of patients with bladder cancer in the GI tract. GI involvement is a strong negative predictor of survival and behaves comparable to pT4 patients. However, we recommend that pathologists adhere to the current pT staging guidelines, in which GI involvement is not a criterion, until further research is conducted illustrating if and how it should be incorporated.

A multifaceted intervention to improve compliance with process measures for ICU clinician communication with ICU patients and families.

RATIONALE: Despite recommendations supporting the importance of clinician-family communication in the ICU, this communication is often rated as suboptimal in frequency and quality. We employed a multifaceted behavioral-change intervention to improve communication between families and clinicians in a statewide collaboration of ICUs. OBJECTIVES: Our primary objective was to examine whether the intervention resulted in increased compliance with process measures that targeted clinician-family communication. As secondary objectives, we examined the ICU-level characteristics that might be associated with increased compliance (open vs closed, teaching vs nonteaching, and medical vs medical-surgical vs surgical) and patient-specific outcomes (mortality, length of stay). METHODS: The intervention was a multifaceted quality improvement approach targeting process measures adapted from the Institute of Health Improvement and combined into two "bundles" to be completed either 24 or 72 hours after ICU admission. MEASUREMENTS AND MAIN RESULTS: Significant increases were seen in full compliance for both day 1 and day 3 process measures. Day 1 compliance improved from 10.7% to 83.8% after 21 months of intervention (p<0.001). Day 3 compliance improved from 1.6% to 28.8% (p<0.001). Improvements in compliance varied across ICU type with less improvement in open, nonteaching, and mixed medical-surgical ICUs. Patient-specific outcome measures were unchanged, although there was a small increase in patients discharged from ICU to inpatient hospice (p=0.002). CONCLUSIONS: We found that a multifaceted intervention in a statewide ICU collaborative improved compliance with specific process measures targeting communication with family members. The effect of the intervention varied by ICU type.

Pilot study on the efficacy of an ondansetron- versus palonosetron-containing antiemetic regimen prior to highly emetogenic chemotherapy.

PURPOSE: Nausea and vomiting are among the most feared complications of chemotherapy reported by patients. The objective of this study was to establish the overall complete response (CR; no emesis or use of rescue medication 0-120 h after chemotherapy) with either ondansetron- or palonosetron-containing antiemetic regimens in patients receiving highly emetogenic chemotherapy (HEC). METHODS: This was a prospective, open-label, randomized, single-center, pilot study that enrolled patients receiving their first cycle of HEC. Patients were randomized to receive either palonosetron 0.25 mg IV (PAD) or ondansetron 24 mg orally (OAD) on day 1 prior to HEC. All patients received oral aprepitant 125 mg on day 1, then 80 mg on days 2 and 3, and oral dexamethasone 12 mg on day 1, then 8 mg on days 2, 3, and 4. Descriptive statistics were used to summarize the data. RESULTS: A total of 40 patients were enrolled, 20 in each arm. All patients were female, and 39 received doxorubicin/cyclophosphamide chemotherapy for breast cancer. For the primary endpoint, 65 % (95 % CI, 40.8-84.6 %) of patients in the PAD arm and 40 % (95 % CI, 19.1-63.9 %) of patients in the OAD arm achieved an overall CR. CONCLUSIONS: While CR rates for aprepitant and dexamethasone plus palonosetron or ondansetron-containing regimens have been published previously, this is the first documentation of CR rates with these regimens in the same patient population. These results may be used to design a larger, adequately powered, prospective study comparing these regimens.

Early versus delayed autologous stem cell transplant in patients receiving novel therapies for multiple myeloma.

Autologous stem cell transplant (ASCT) is an effective treatment for multiple myeloma (MM). However, the timing of ASCT in the era of novel agents (lenalidomide, thalidomide, bortezomib) is unknown. We retrospectively reviewed the outcome of patients with MM who received novel agent-based induction treatment and received first ASCT within 12 months of diagnosis (early ASCT, n = 102) or at a later date (late ASCT, n = 65). Median time to ASCT was 7.9 months vs. 17.7 months in early vs. late ASCT. The 3- and 5-year overall survival (OS) from diagnosis was 90 and 63% vs. 82 and 63% in early and late ASCT, respectively (p = 0.45). Forty-one and 36 patients in the early and late ASCT groups have relapsed or progressed, with median time to relapse of 28 and 23 months (p = 0.055). On multivariable analysis, factors predictive of increased risk for progression were International Scoring System (ISS) stage III (p = 0.007), and less than a very good partial response (< VGPR) post-ASCT (p < 0.001). A factor predictive of worst outcome for OS was being on hemodialysis (p = 0.037). No superiority of one agent was seen. In summary, early or late ASCT is a viable option for patients with MM receiving induction treatment with novel targeted therapies.

The impact of close surgical margins after radical hysterectomy for early-stage cervical cancer.

OBJECTIVE: While it is known that positive surgical margins increase the risk of cervical cancer recurrence, little is known about the effect of close surgical margins (CSM). Therefore, we set out to determine the impact of margin status on recurrence and survival in patients with early-stage cervical cancer. METHODS: A retrospective review was conducted of patients undergoing radical hysterectomy from 2000 to 2010 with Stage IA2-IIA cervical cancer. CSM were defined as ≤5mm; association with other clinicopathologic factors as well as recurrence and survival was evaluated. RESULTS: Of the 119 patients, 75 (63%) with CSM had a recurrence rate of 24% compared to 9% without CSM. Though not independently associated with recurrence, CSM were significantly associated with positive lymph nodes (44% vs. 18%), positive parametria (33.3% vs. 2.3%), larger tumors (3.5 vs. 2.5cm), greater depth of stromal invasion (DOI) (84% vs. 33%), and lymphovascular space invasion (LVSI) (61.3% vs. 34.1%). We failed to find an association between adjuvant therapy and recurrence in those with CSM. Exploratory analysis revealed that a surgical margin of ≤2mm was significantly associated with an increased risk of overall recurrence (36% vs. 9%, p=0.009) as well as loco-regional recurrence (22% vs. 4%, p=0.0034). CONCLUSIONS: Surgical margins of ≤5mm on radical hysterectomy specimens are often associated with other high or intermediate risk factors for recurrence. While not a proven independent risk factor, the distance to surgical margin may warrant further investigation as an intermediate risk factor along with tumor size, DOI and LVSI.

Improving symptom communication through personal digital assistants: the CHAT (Communicating Health Assisted by Technology) project.

BACKGROUND: Communication problems impede effective symptom management during chemotherapy. The primary aim of this pilot randomized controlled trial was to test the effects of a personal digital assistant-delivered communication intervention on pain, depression, and fatigue symptoms among breast cancer patients undergoing chemotherapy. Secondary aims included assessment of 1) study feasibility, 2) patient and clinician responses to study participation, and 3) intervention effects on health-related quality of life (HRQoL) and communication self-efficacy. METHODS: Intervention group participants (n = 27) completed symptom inventories at baseline, once per week during treatment, and at posttreatment. Depending on symptom severity, they viewed race-concordant videos on how to communicate about pain, depression and/or fatigue, using the personal digital assistant. Symptom records were tracked and shared with clinicians. Control group participants (n = 23) received usual care. Longitudinal random effects modeling assessed the changes in average symptom scores over time. Descriptive statistics assessed study feasibility and intervention effects on HRQoL and communication self-efficacy. Postintervention focus groups, interviews, and surveys assessed responses to study participation. RESULTS: Mean age of the participants was 51.0 years; 42 participants (84%) were white. In comparison with control, intervention group participants reported lower average pain severity over time (P = .015). Mean pain interference scores over time were marginally different between groups (P = .07); mean depression and fatigue scores over time were statistically nonsignificant. Feasibility outcomes and perspectives about study participation were positive. Mean pre-post decreases in HRQoL were generally higher among intervention group participants; pre-post changes in communication self-efficacy were equivalent. CONCLUSION: Mixed findings of the study indicate the need for future research.

Stabilization of HIF-2α induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model.

Macrophage secretion of vascular endothelial growth factor (VEGF) in response to hypoxia contributes to tumor growth and angiogenesis. In addition to VEGF, hypoxic macrophages stimulated with GM-CSF secrete high levels of a soluble form of the VEGF receptor (sVEGFR-1), which neutralizes VEGF and inhibits its biological activity. Using mice with a monocyte/macrophage-selective deletion of hypoxia-inducible factor (HIF)-1α or HIF-2α, we recently demonstrated that the antitumor response to GM-CSF was dependent on HIF-2α-driven sVEGFR-1 production by tumor-associated macrophages, whereas HIF-1α specifically regulated VEGF production. We therefore hypothesized that chemical stabilization of HIF-2α using an inhibitor of prolyl hydroxylase domain 3 (an upstream inhibitor of HIF-2α activation) would increase sVEGFR-1 production from GM-CSF-stimulated macrophages. Treatment of macrophages with the prolyl hydroxylase domain 3 inhibitor AKB-6899 stabilized HIF-2α and increased sVEGFR-1 production from GM-CSF-treated macrophages, with no effect on HIF-1α accumulation or VEGF production. Treatment of B16F10 melanoma-bearing mice with GM-CSF and AKB-6899 significantly reduced tumor growth compared with either drug alone. Increased levels of sVEGFR-1 mRNA, but not VEGF mRNA, were detected within the tumors of GM-CSF- and AKB-6899-treated mice, correlating with decreased tumor vascularity. Finally, the antitumor and antiangiogenic effects of AKB-6899 were abrogated when mice were simultaneously treated with a sVEGFR-1 neutralizing Ab. These results demonstrate that AKB-6899 decreases tumor growth and angiogenesis in response to GM-CSF by increasing sVEGFR-1 production from tumor-associated macrophages. Specific activation of HIF-2α can therefore decrease tumor growth and angiogenesis.

Pulmonary rehabilitation for bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

Bronchiolitis obliterans syndrome (BOS) is a progressive, insidious lung disease affecting allogeneic hematopoietic stem cell transplantation recipients. Unfortunately, there is no standardized approach for treatment of BOS in post-hematopoietic stem cell transplantation patients. Pulmonary rehabilitation is a standard treatment in emphysema, an irreversible obstructive lung disease secondary to tobacco abuse. The National Emphysema Treatment Trial (NETT) demonstrated improved exercise tolerance, decrease dyspnea, and increase of quality of life in patients with severe emphysema after pulmonary rehabilitation. We hypothesized that pulmonary rehabilitation may benefit patients with BOS. Patients with BOS were identified retrospectively from January 2005 to the present. Patients who enrolled in pulmonary rehabilitation were included in the study. We obtained summaries via chart review of each patient's progress after pulmonary rehabilitation enrollment from his or her respective rehabilitation centers. Six-minute walk distances, spirometry, and pulmonary symptoms were compared before and after the completion of pulmonary rehabilitation. We identified 11 patients with BOS documented from their pulmonologist's clinical notes who were enrolled into pulmonary rehabilitation. Ten of the 11 patients completed pulmonary rehabilitation. All patients had improvement in their 6-minute walk distances after the completion of pulmonary rehabilitation, with an average improvement in distance of 307 feet (P value = .005). Six of the 10 patients completed Short Form-36 (SF-36) questionnaires before and after rehabilitation. There was a significant improvement in the physical functioning score (P value = 0.029). Pulmonary rehabilitation seems to improve 6-minute walk distance, subjective symptoms of dyspnea, and exercise tolerance in patients with BOS. This may be an important adjunctive therapy for a debilitating disease with limited treatment options.

Feasibility of stopping paclitaxel premedication after two doses in patients not experiencing a previous infusion hypersensitivity reaction.

PURPOSE: Paclitaxel-based chemotherapy continues to be an integral component in the treatment of many solid tumors. Prolonged use of paclitaxel may result in repeated doses of premedications and potential unwanted side effects. Infusion hypersensitivity reactions occurring beyond the second dose are infrequent and not well characterized. We hypothesized that patients whose paclitaxel premedications were discontinued after two doses were unlikely to experience infusion hypersensitivity reactions with subsequent paclitaxel doses. METHODS: Patients receiving paclitaxel-based chemotherapy who did not experience an infusion hypersensitivity reaction with their first or second dose had their paclitaxel premedications discontinued. The primary endpoint was to estimate the incidence of rescue medication for the treatment of paclitaxel infusion hypersensitivity during doses 3 to 6 for patients whose paclitaxel premedications had been discontinued. RESULTS: After receiving the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction (any grade), 55 breast cancer patients had their premedications discontinued for all remaining paclitaxel doses. None of these patients required rescue medication to treat an infusion hypersensitivity reaction with subsequent doses. CONCLUSIONS: In patients who have not experienced an infusion hypersensitivity reaction with the first two doses of paclitaxel, discontinuation of paclitaxel premedications may be considered an option without an increased risk of infusion hypersensitivity requiring rescue medication.