Survival differences by race and surgical approach in early-stage operable cervical Cancer.

OBJECTIVE: To evaluate if the higher rate of open radical hysterectomy in Black patients, prior to the widespread return to open surgical techniques, mitigated survival disparities and to identify other actionable factors to target for systemic change. METHODS: This is a retrospective cohort study including patients from the National Cancer Database with cervical cancer who underwent radical hysterectomy from 2010 to 2018. Patient demographics, clinical characteristics and survival were compared by race and surgical route. Kaplan-Meier plots were constructed. Cox proportional hazards modeling was used to adjust for covariates. RESULTS: 7201 patients were eligible for inclusion, 687 (9.5%) Black and 4870 (68%) White. We found that 51% of Black patients and 39% of White patients underwent open surgery. Black patients were 10% less likely to receive Guideline Concordant Care (GCC). Those with publicly-funded insurance had a 40% higher hazard of death compared to private insurance (CI 1.19-1.73 p < 0.001). Black patients who had open surgery had similar 5-year survival compared to White patients who had MIS surgery (0.90 vs 0.91, NS). After adjusting for potential confounders including age, insurance, nodal status, and lymphovascular space invasion, Black patients who had surgery had a 40% higher hazard for death (HR 1.40 95% CI 1.10-1.79, p = 0.007) compared to White patients. CONCLUSIONS: A lower 5 and 10-year survival was seen in Black patients, regardless of surgical approach. Adjustment for significant covariates did not resolve this disparity, confirming that these factors do not fully account racial disparities.

Take me to your leader: Reporting structures and equity in academic gynecologic oncology.

OBJECTIVE: Gynecologic oncology includes increasing percentages of women. This study characterizes representation of faculty by gender and subspecialty in academic department leadership roles relevant to the specialty. METHODS: The American Association of Medical Colleges accredited schools of medicine were identified. Observational data was obtained through institutional websites in 2019. RESULTS: 144 accredited medical schools contained a department of obstetrics and gynecology with a chair; 101 a gynecologic oncology division with a director; 98 a clinical cancer center with a director. Women were overrepresented in academic faculty roles compared to the US workforce (66 vs 57%, p < 0.01) but underrepresented in all leadership roles (p < 0.01). Departments with women chairs were more likely to have >50% women faculty (90.2 vs 9.8%, p < 0.01); and have larger faculties (80.4 vs 19.6% >20 faculty, p = 0.02). The cancer center director gender did not correlate to departmental characteristics. A surgically focused chair was also associated with >50% women faculty (85.7 vs 68.3%, p = 0.03); faculty size >20 (85.7 vs 61.4%, p < 0.01); and a woman gynecologic oncology division director (57.6 vs 29.4%, p < 0.01; 68.4 vs 31.7%, p < 0.01) and gynecologic oncology fellowship (50 vs 30.4%, p < 0.01; 59.1 vs 32%, p < 0.01). Gynecologic oncology leadership within cancer centers was below expected when incidence and mortality to leadership ratios were examined (p < 0.01, p < 0.01). CONCLUSION: Within academic medical schools, women remain under-represented in obstetrics and gynecology departmental and cancer center leadership. Potential benefits to gynecologic oncology divisions of inclusion women and surgically focused leadership were identified.

The effect of preexisting anti-carrier immunity on subsequent responses to CRM197 or Qb-VLP conjugate vaccines.

CONTEXT: Certain antigens, such as haptens (small molecules), short peptides, and carbohydrates (e.g. bacterial polysaccharides) are non- or poorly immunogenic unless conjugated to a carrier molecule that provides a structural scaffold for antigen presentation as well as T cell help required for B-cell activation and maturation. However, the carriers themselves are immunogenic and resulting carrier-specific immune responses may impact the immunogenicity of other conjugate vaccines using the same carrier that are administered subsequently. OBJECTIVE: Herein, using two different carriers (cross-reactive material 197, CRM and Qb-VLP), we examined in mice the impact that preexisting anti-carrier antibodies (Ab) had on subsequent immune responses to conjugates with either the same or a different carrier. METHOD: For this purpose, we used two nicotine hapten conjugates (NIC7-CRM or NIC-Qb), two IgE peptide conjugates (Y-CRM or Y-Qb), and a pneumococcal polysaccharide conjugate (Prevnar 13(®)). RESULTS: Prior exposure to CRM or Qb-VLP significantly reduced subsequent responses to the conjugated antigen having the homologous carrier, with the exception of Prevnar 13® where anti-polysaccharide responses were similar to those in animals without preexisting anti-carrier Ab. CONCLUSION: Collectively, the data suggest that the relative sizes of the antigen and carrier, as well as the conjugation density for a given conjugate impact the extent of anti-carrier suppression. All animals developed anti-carrier responses with repeat vaccination and the differences in Ab titer between groups with and without preexisting anti-carrier responses became less apparent; however, anti-carrier effects were more durable for Ab function.

Gynecologic Oncology and Inclusion of Women Into the Surgical Workforce: The Canary in This Coal Mine.

Objective: Women make up a majority of the gynecologic oncology workforce. Increasing the numbers of women in leadership has been proposed as a path towards professional gender equity. This study examined whether leadership gender and departmental infrastructure impact the work environment for women gynecologic oncologists. Methods: Members of a 472-member private Facebook group "Women of Gynecologic Oncology" (WGO) who self-identified as women gynecologic oncologists provided demographics, practice infrastructure, personal experience with workplace bullying, gender discrimination, microaggressions using a REDcap survey platform. Results: Of 250 (53%) respondents to this survey, most were younger than age 50 years (93.6%); White (82.2%) and non-Hispanic (94.3%); married (84.7%); and parenting (75.2%). Practice environments included academic (n=152, 61.0%), hospital employed (n=57, 22.9%), and private practice (n=31, 12.4%), and 89.9% supervised trainees. A significant percent of respondents had experienced bullying (52.8%), gender discrimination (57%) and microaggressions (83%). Age, race, ethnicity, practice setting, or mentorship were not statistically significantly associated with these experiences. Reported perpetrators were varied and included colleagues (84%), patients (44%), staff (41%), administrators (18%), and trainees (16%). Prevalence of bullying (55.0 vs 47.7%, p=0.33), gender discrimination (59.1 vs 52.3%, p=0.33) and microaggressions (83.3 vs 83.0%, p=1.00) were similar irrespective of departmental leadership gender. Conclusions: Women gynecologic oncologists report a high prevalence of workplace bullying, gender discrimination and microaggressions regardless of the gender of their immediate leadership. Proactive and deliberate structural interventions to improve the work environment for surgeons who are women are urgently needed.

Modeled trace element concentrations and partitioning in the San Francisco estuary, based on suspended solids concentration.

Although trace element (Ag, As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Se, and Zn) and methylmercury (MeHg) concentrations have been systematically sampled 1-3 times per year throughout the San Francisco Bay estuary for more than two decades, those collections do not capture episodic events that may govern the biogeochemical cycles of these elements in the Bay and adjacent Pacific coastal waters. Analyses of the partitioning of in situ elemental concentrations between particulate and total dissolved (<0.45 microm) phases coupled with optically based measurements of suspended solids concentration (SSC) showed highly significant (p<0.001) associations between all elemental concentrations and SSC in the Bay. Predictive models were developed to estimate the distribution ratio (D), or partition coefficient (Kd), and total concentration of each element in the water column based solely on SSC measurements. Modeled predictions of total element concentrations and distribution ratios were then coupled with measured SSC to predict the concentrations of dissolved trace elements in the water column. These predicted total and dissolved concentrations of trace elements can provide both better diagnostics of biogeochemical cycling within the estuary and better estimates of fluxes to adjacent coastal waters, overcoming the limitations of the long-running but limited direct measurements of trace elements from existing sampling programs.

Sample entropy analysis of cervical neoplasia gene-expression signatures.

BACKGROUND: We introduce Approximate Entropy as a mathematical method of analysis for microarray data. Approximate entropy is applied here as a method to classify the complex gene expression patterns resultant of a clinical sample set. Since Entropy is a measure of disorder in a system, we believe that by choosing genes which display minimum entropy in normal controls and maximum entropy in the cancerous sample set we will be able to distinguish those genes which display the greatest variability in the cancerous set. Here we describe a method of utilizing Approximate Sample Entropy (ApSE) analysis to identify genes of interest with the highest probability of producing an accurate, predictive, classification model from our data set. RESULTS: In the development of a diagnostic gene-expression profile for cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma of the cervix, we identified 208 genes which are unchanging in all normal tissue samples, yet exhibit a random pattern indicative of the genetic instability and heterogeneity of malignant cells. This may be measured in terms of the ApSE when compared to normal tissue. We have validated 10 of these genes on 10 Normal and 20 cancer and CIN3 samples. We report that the predictive value of the sample entropy calculation for these 10 genes of interest is promising (75% sensitivity, 80% specificity for prediction of cervical cancer over CIN3). CONCLUSION: The success of the Approximate Sample Entropy approach in discerning alterations in complexity from biological system with such relatively small sample set, and extracting biologically relevant genes of interest hold great promise.

Computer-enhanced robotic surgery in gynecologic oncology.

BACKGROUND: This study aimed to report the computer-enhanced robotic surgery experience of the authors' gynecologic oncology division. METHODS: From January 2001 to August 2006, 41 patients underwent laparoscopic surgery by our gynecologic oncology service using a computer-enhanced surgical robot. This report describes a retrospective review of these patients. RESULTS: The patients ranged in age from 27 to 77 years (mean, 44.2 years), in weight from 44 to 131 kg (mean, 72.1 kg), in operative time from 1 h and 50 min to 9 h (mean, 5 h and 2 min), and in estimated blood loss from 50 to 1,500 ml (mean, 253 ml). Of the 20 patients with gynecologic malignancies, 14 had cervical cancer. A total of 21 patients had benign indications for surgery. Complications included shoulder palsy, robot failure, colotomy, bradycardia, and intraabdominal bleeding requiring minilaparotomy and ligation of a bleeding pedicle. CONCLUSION: This case series is one of the first to report the use of a computer-enhanced surgical robot in gynecologic oncology. This approach proved to be feasible and well tolerated in this series of patients and deserves further study for clarification of its indications, benefits, and safety.

Recurrent mature cystic ovarian teratoma in adolescence: atypical case of the growing teratoma syndrome.

BACKGROUND: A primary mature cystic ovarian teratoma was diagnosed in an adolescent female. She was followed up after initial exploration with computed tomography, pelvic ultrasonography, and serum tumor markers. Recurrent tumor, consisting solely of mature teratomatous elements, was confirmed with 2 subsequent laparotomies. CASE: This is a report of the growing teratoma syndrome in a young woman with a primary diagnosis of a mature cystic ovarian teratoma not treated with adjuvant chemotherapy. CONCLUSION: The growing teratoma syndrome is an uncommon condition. Surgical resection of recurrent lesions is necessary to reduce potential complications of abdominopelvic organ compression and obstruction and to evaluate for the presence of malignant degeneration.

Anti-nicotine vaccines: Comparison of adjuvanted CRM197 and Qb-VLP conjugate formulations for immunogenicity and function in non-human primates.

Anti-nicotine vaccines comprise nicotine-like haptens conjugated to a carrier protein plus adjuvant(s). Unfortunately, those tested clinically have failed to improve overall long term quit rates. We had shown in mice that carrier, hapten, linker, hapten load (number of haptens per carrier molecule), aggregation and adducts, as well as adjuvants influence the function of antibodies (Ab) induced. Herein, we tested an optimized antigen, NIC7-CRM, comprised of 5-aminoethoxy-nicotine (NIC7) conjugated to genetically detoxified diphtheria toxin (CRM197), with hapten load of ~16, no aggregation (~100% monomer) and minimal adducts. NIC7-CRM was tested in non-human primates (NHP) and compared to NIC-VLP, which has the same hapten and carrier as the clinical-stage CYT002-NicQb but a slightly different linker and lower hapten load. With alum as sole adjuvant, NIC7-CRM was superior to NIC-VLP for Ab titer, avidity and ex vivo function (83% and 27% nicotine binding at 40ng/mL respectively), but equivalent for in vivo function after intravenous [IV] nicotine challenge (brain levels reduced ~10%). CpG adjuvant added to NIC7-CRM/alum further enhanced the Ab responses and both ex vivo function (100% bound) and in vivo function (~80% reduction in brain). Thus, both optimal antigen design and CpG adjuvant were required to achieve a highly functional vaccine. The compelling NHP data with NIC7-CRM with alum/CpG supported human testing, currently underway.

Palivizumab prophylaxis of respiratory syncytial virus disease in 2000-2001: results from The Palivizumab Outcomes Registry.

The objective of the Registry was to characterize the population of infants receiving prophylaxis for respiratory syncytial virus (RSV) disease by describing the patterns and scope of usage of palivizumab in a cross section of US infants. RSV hospitalization outcomes were also described. The Palivizumab (Synagis, MedImmune, Inc., 25 West Watkins Mill Road, Gaithersburg, MD 20878) Outcomes Registry was a prospective multicenter survey conducted at 63 sites. Demographics, injection history, and RSV hospitalization outcomes were collected on 2,116 infants receiving palivizumab. Infants were enrolled in the Registry between September 1, 2000-March 1, 2001, at the time of their first injection. Infants born at less than 32 weeks of gestation accounted for 47% of infants enrolled, and those between 32-35 weeks accounted for 45%; approximately 8% were greater than 35 weeks of gestation. Lower RSV hospitalization rates were observed in infants who had greater adherence to regularly scheduled injections. Nearly one-half of all hospitalizations occurred within the first and second injection intervals, suggesting the importance of early RSV protection. The confirmed RSV hospitalization rate of all infants in the Registry was 2.9%; the rate was 5.8% in infants with chronic lung disease of infancy, and 2.1% in premature infants without chronic lung disease. In conclusion, these data support the continued effectiveness of palivizumab prophylaxis for severe RSV lower respiratory tract disease in a large cohort of high-risk infants from geographically diverse pediatric offices and clinics. The Palivizumab Outcomes Registry provides an opportunity to assess palivizumab utilization and clinical effectiveness in the US.

131I therapy using rhTSH stimulation and dosimetry in metastatic malignant struma ovarii.

A 38-year-old woman with metastatic malignant struma ovarii, including massive liver metastases and retroperitoneal lymphadenopathy, underwent ovarian resection and retroperitoneal lymph nodes excision, partial hepatectomy, and radiofrequency ablation for liver metastases. She underwent thyroidectomy and received three I treatments using recombinant human thyrotropin stimulation and radioiodine dosimetry. posttherapy I imaging, anatomic images, and thyroglobulin levels showed significant diminution in the tumor burdens and remarkable decline in thyroglobulin levels. This case provided valuable information on recombinant human thyrotropin-assisted I ablation in conjunction with dosimetry in an unusual presentation of iodine-avid malignant struma ovarii with bulky metastases.

Enhancing immunogenicity of a 3'aminomethylnicotine-DT-conjugate anti-nicotine vaccine with CpG adjuvant in mice and non-human primates.

Tobacco smoking is one of the most preventable causes of morbidity and mortality, but current smoking cessation treatments have relatively poor long term efficacy. Anti-nicotine vaccines offer a novel mechanism of action whereby anti-nicotine antibodies (Ab) in circulation prevent nicotine from entering the brain, thus avoiding the reward mechanisms that underpin nicotine addiction. Since antibody responses are typically long lasting, such vaccines could potentially lead to better long-term smoking cessation outcomes. Clinical trials of anti-nicotine vaccines to date have not succeeded, although there was evidence that very high anti-nicotine Ab titers could lead to improved smoking cessation outcomes, suggesting that achieving higher titers in more subjects might result in better efficacy overall. In this study, we evaluated CpG (TLR9 agonist) and aluminum hydroxide (Al(OH)3) adjuvants with a model anti-nicotine antigen comprising trans-3'aminomethylnicotine (3'AmNic) conjugated to diphtheria toxoid (DT). Anti-nicotine Ab titers were significantly higher in both mice and non-human primates (NHP) when 3'AmNic-DT was administered with CpG/Al(OH)3 than with Al(OH)3 alone, and affinity was enhanced in mice. CpG also improved functional responses, as measured by nicotine brain levels in mice after intravenous administration of radiolabeled nicotine (30% versus 3% without CpG), or by nicotine binding capacity of NHP antisera (15-fold higher with CpG). Further improvement should focus on maximizing Ab function, which takes into account both titer and avidity, and this may require improved conjugate design in addition to adjuvants.

Selection of a novel anti-nicotine vaccine: influence of antigen design on antibody function in mice.

Anti-nicotine vaccines may aid smoking cessation via the induction of anti-nicotine antibodies (Ab) which reduce nicotine entering the brain, and hence the associated reward. Ab function depends on both the quantity (titer) and the quality (affinity) of the Ab. Anti-nicotine vaccines tested previously in clinical studies had poor efficacy despite high Ab titer, and this may be due to inadequate function if Ab of low affinity were induced. In this study, we designed and synthesized a series of novel nicotine-like haptens which were all linked to diphtheria toxoid (DT) as carrier, but which differed in the site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. The resulting hapten conjugates were evaluated in a mouse model, using CpG (a TLR9 agonist) and aluminum hydroxide (Al(OH)3) as adjuvants, whereby Ab titers, affinity and function were evaluated using a radiolabeled nicotine challenge model. A series of additional linkers varying in length, rigidity and polarity were used with a single hapten to generate additional DT-conjugates, which were also tested in mice. Conjugates made with different haptens resulted in various titers of anti-nicotine Ab. Several haptens gave similarly high Ab titers, but among these, Ab affinity and hence function varied considerably. Linker also influenced Ab titer, affinity and function. These results demonstrate that immune responses induced in mice by nicotine-conjugate antigens are greatly influenced by hapten design including site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. While both Ab titer and affinity contributed to function, affinity was more sensitive to antigen differences.

Human papillomavirus vaccine: progress and the future.

A vaccine to prevent infection by human papillomavirus is available in the US. This article reviews the biology of human papillomavirus that allows for the development of both therapeutic and prophylactic vaccines. Issues that may delay the acceptance of the vaccine are discussed.

Primary gastrointestinal cancers presenting as gynecologic malignancies.

OBJECTIVE: The goal of this study was to characterize presenting symptoms, prognostic factors, and treatment outcome in patients diagnosed with primary gastrointestinal (GI) cancers initially presumed to be of gynecologic origin. METHODS: A retrospective review of all admissions to the gynecologic oncology service at Saint Luke's Hospital in Kansas City, Missouri, was performed between 1993 and 2003. Twenty-six patients with primary GI cancers who presented with presumed gynecologic malignancies were identified. Clinical and pathologic features were reviewed, methods of diagnosis were recorded, and survival was analyzed by the Kaplan-Meier method. RESULTS: One percent of all gynecologic cancer referrals had a tumor of nongynecologic gastrointestinal origin. Seven subtypes of GI cancers were identified, most at stage 4 disease. Colon cancer was identified most commonly (26.9%). Abdominal pain was the most frequent symptom (57.6%), and an adnexal mass was diagnosed in the majority of patients (65.4%). Preoperative endoscopic evaluation provided a definitive diagnosis in only 3.8%. The median survival was 15 months with a 5-year survival of 35%. Ninety-six percent of patients had their GI tumor definitively diagnosed by exploratory laparotomy. Optimal cytoreduction provided a 7-month survival advantage. CONCLUSION: Most patients required a major surgical procedure to establish the primary diagnosis of gastrointestinal cancer. The cancers encountered were almost always at advanced stage disease and were referred to the gynecologic oncologist due to the presence of an adnexal mass and a failed preoperative work-up. Surgical management should include removal of the primary or recurrent GI tumor and cytoreduction of all bulky disease, including adnexal metastases.