Faculty Bibliography

Background/Purpose: Treatment with a combination of immune checkpoint inhibitors (ICI) has promising outcomes in many tumor types but carries higher adverse event risk than ICI monotherapy. Also, patients with pre-existing autoimmune disease (AID) have largely been excluded from ICI clinical trials due to concern for pre-existing AID flare or immune-related adverse events (irAEs). This is the first study to analyze safety and effectiveness of ICI combination versus monotherapy for this at-risk population.
Method(s): We conducted a multi-center retrospective study in patients with pre-existing AIDs receiving ICIs (i.e., antiprogrammed cell death protein 1 (PD-1) single-agent (monotherapy) or ICI combination). Primary endpoints included the time to occurrence of any-type ICI AE (irAE or AID flare), time to irAEs and time to AID flares in the presence of the competing risk of death with progression free survival (PFS, time to progression or death) and overall survival (OS) as secondary endpoints. We used Fine-Gray models and Cox regression models to investigate the factors associated with these endpoints.
Result(s): 133 patients with pre-existing AID who received ICIs were identified: 69 (52%) monotherapy and 64 (48%) combination (Table 1). About half the patients had melanoma (44%) and 25% had lung cancer. Rheumatic (34%) or dermatologic (22%) pre-existing AIDs were the most common. Most patients (95%) had controlled autoimmune disease at ICI start. Six of 7 patients with active AID at baseline experienced some AE. Patients receiving baseline DMARD(s) were more likely to experience an AE (95%CI 1.079-2.996, p=0.024). The cumulative incidence of irAEs was higher for ICI combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.28, 95%CI 1.36-3.84), adjusting for age at malignancy, but there was no significant difference between rate of high-grade toxicity for patients treated with ICI combination versus monotherapy (See Figure 1). On subgroup analysis for patients with melanoma or lung cancer, the cumulative incidence of irAEs or AID flares were not statistically different between treatment groups. PFS was longer (but not statistically significant) for combination therapy for any tumor type compared to single agent (median 12.3mo, 95%CI 5.0-23.2 versus 7.3mo, 95%CI 5.2-11.3, p=0.116). Similar trend was noted for PFS for melanoma (median 23.2mo combination vs. 14.0mo monotherapy, p=0.4237), while the opposite relation was noted for lung cancer subgroup (4.4mo combination vs. 7.1mo monotherapy, p=0.2933).
Conclusion(s): Efficacy of ICI combination versus monotherapy was not statistically significant and so still remains unclear in this patient population, but there was no significant difference in rates of high-grade toxicity between the two cohorts. Our data supports the notion that patients with pre-existing AIDs should not be indiscriminately precluded from getting ICI combination. Our results provide guidance for future prospective clinical trials studying combination therapy for subgroups of this at-risk population. No statistically significant difference appreciated in high grade adverse events between patients with pre-existing autoimmune disease treated with ICI combination versus monotherapy. Grading determined by the Common Terminology Criteria for Adverse Events rubric with grade 3 or higher considered "high grade."

OBJECTIVE:To investigate the protective effects of betelnut polyphenols on the vital organs against high-altitude hypoxia in rats. OBJECTIVE:We compared low-, medium-, and high- dose betelnut polyphenols (400, 800, and 1600 mg/kg, respectively) and rhodiola the effects of against high-altitude hypoxia in Wistar rats. The rats were kept in normal condition and given the drugs daily for 3 days before transfer to a facility at the altitude of 4010 m, where the rats were kept for 5 consecutive days for hypoxic exposure. The rats were then euthanized for measuring arterial blood gas and assessing liver, lung, brain and cardiac pathologies with HE staining. SOD activity, MDA content and GSH content in the organs were measured, and serum levels of inflammatory factors were detected using a protein microarray. OBJECTIVE:< 0.05). OBJECTIVE:Betelnut polyphenols provides protection of the vital organs against acute high-altitude hypoxia in rats by enhancing the antioxidant capacity and reducing inflammatory response.

Purpose: Appropriateness criteria (AC) are important tools that could help inform decision making for elective surgical procedures. Available AC for elective total knee replacement (TKR) focus on pre-operative factors only. With recent availability of longitudinal outcome data on thousands of patients from patient registries and administrative databases, we aimed to develop new AC that also included predicted outcomes.
Method(s): To update the AC, we expanded these 16 hypothetical scenarios of the validated modified Escobar AC to include 3 predicted outcome factors: risk of serious complications (0%, 1-2%, 3-5%), time to revision (<5, 5-15, >15 years), and improvement in pain and function 2 years after surgery (little, some, a lot). The modified Escobar AC are based on 5 clinical factors: age, osteoarthritis radiographic severity, knee stability, symptoms severity, and number of knee compartments with osteoarthritis). A panel of clinician experts (3 orthopedic surgeons, 2 rheumatologists, 2 internists, 1 physical therapist, 1 experienced nurse practitioner) rated 432 written clinical scenarios for appropriateness on a 1-9 scale (1 being least appropriate and 9 being most appropriate), and the median score for each scenario was classified into one of 3 categories: inappropriate 1-3, maybe appropriate 4-6, and appropriate 7-9. Classification and Regression Tree (CART) analysis was applied to the TKR AC appropriateness categories to determine the contribution of the predicted outcomes variables to appropriateness classification.
Result(s): After orthopedic surgeons ruled out clinically implausible scenarios, the remaining 279 scenarios were classified as 71 inappropriate, 112 maybe appropriate, and 96 appropriate. Figure below shows the results of the CART analyses classification tree with the branches labeled with the key variables that discriminated among the classifications. The terminal nodes of each branch (highlighted in grey) indicate the final distribution of the ratings of appropriate (App), may be appropriate ( Maybe App) and inappropriate (Inapp). CART analyses showed that all 3 predicted outcome factors and 2 of the clinical presentation factors (knee symptom severity and X-ray findings) were the variables that discriminated among the classifications.
Conclusion(s): Our Results showed that predicted outcomes were utilized by clinicians when determining appropriateness for TKR. How these data influence the decision making of patients contemplating TKR should be investigated further. [Formula presented]
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Extraneural ependymomas are rare tumors that occur in sacrococcygeal, pelvic and extra pelvic regions. While sacrococcygeal extraneural ependymomas are equally distributed among males and females, pelvic and extra pelvic ependymomas have been exclusively reported in women, mainly of child bearing age. We present a case of extraneural, pelvic ependymoma that showed clinical response to GnRH therapy with its immunohistochemical and electron microscopic analysis, and an overview of primary extraneural ependymomas based on a review of all such cases published in English literature.

RATIONALE: Phenytoin (Dilantin((R)); DPH) is used to treat epilepsy but causes estrogen agonist-antagonist-like side effects. We investigated the interaction of phenytoin with estrogen receptors (ERs) alpha and beta by computational molecular docking, ER competition binding, transcriptional assays, and biological actions, comparing outcomes with estradiol (E2), estrone (E1), and tamoxifen (TMX). EXPERIMENTAL: (1) The DPH docking to 3-dimensional crystal structures of the ERalpha ligand-binding domain (LBD) showed a high degree of structural complementarity (-57.15 calculated energy units, approximating kcal/mol) with the ligand-binding pocket, including a contact at leucine (L540) in helix 12. Estrogen receptor beta showed slightly less favorable interactions (-54.27 kcal/mol), without contacting L450. Estradiol, E1, and TMX contact points with ERalpha and ERbeta do not include L450. (2) Cellular actions: Incubation of cells transfected with ERalpha or ERbeta and a luciferase promoter phenytoin was several orders weaker than E2 as an agonist through ERalpha and had no effect through ERbeta. However, phenytoin at clinical concentrations (10(-11) to 10(-6) mol/L) powerfully antagonized action of E2 on ERalpha-expressing cells. Similarly, phenytoin at clinically effective concentrations marginally induced alkaline phosphatase by ERalpha- and ERbeta-expressing endometrial cancer cells but at doses well below clinical effectiveness blocked E2-induced alkaline phosphatase. (3) ER competition: In Scatchard plots comparing phenytoin with 17beta-estradiol against endometrial cancer cell cytosol E2-alone more effectively displaced labeled E2 than phenytoin, but phenytoin was approximately equimolar effective to E2 in inhibiting E2's displacement of the radiolabel, further confirming that phenytoin is a strong E2 antagonist. CONCLUSIONS: At clinically effective concentrations, phenytoin is a strong ERalpha cell antagonist but a many-fold weaker agonist. Although it interacts with ERbeta LBD residues, phenytoin has no effects on ERbeta-only expressing cells. Docking studies indicate phenytoin interacts with the ERalpha LBD at the hinge of helix 12 and could thereby interfere with the entry of other ER ligands or with the mobility of helix 12, either of which actions could explain phenytoin's antagonism of ER-mediated E2 actions. Our results suggest an explanation for the broad profile of phenytoin's actions and raise possibilities for the use of phenytoin or congeners in the clinical management of ERalpha-dependent conditions.

Study Objective: To evaluate the clinical value of office endometrial Pipelle biopsy (Embx) for detection of premalignant and malignant lesions in the presence of an endometrial polyp. Design: A retrospective study. Setting: A tertiary care academic hospital. Patients: 335 patients with a preoperative Embx and subsequent hysteroscopy (HSC), dilation and curettage (D&C), with or without polypectomy. Intervention: The accuracy of Embx was compared between the study group (with visible polyps on hysteroscopy) and control group (without visible polyps on hysteroscopy). Measurements and Main Results: Using final pathology (D&C +/- polypectomy specimen) as the gold standard, the accuracy of Embx was compared between the study (n = 217) and control groups (n = 118). After excluding all patients with an insufficient sample, results suggest improved sensitivity of Embx in detecting premalignant and malignant lesions in the absence of an endometrial polyp (control group 57% vs study group 36%, p = 0.314). Specificity, positive predictive value, and negative predictive value were comparable for both groups (96% vs 98%, 67% vs 69%, 94% vs 91%, respectively, p value not significant). Notably, discordance between Embx and final pathology was 13% for both groups and, of these cases, 71% in the control group and 84% in the study group had upgraded lesions on final pathology. Insufficient sampling by either Embx or D&C occurred significantly more frequently in postmenopausal women. Finally, Embx detected only 40% of premalignant and malignant lesions confined to polyps. Conclusion: The presence of an endometrial polyp may decrease the detection of premalignant and malignant endometrial lesions with Pipelle biopsy; further studies with a larger sample size are necessary to demonstrate statistical significance. Given the rates of discordance and upgraded lesions, endometrial Pipelle biopsy should not be used solely for counseling patients who desire conservative management

Abdominal myomectomies can be associated with a large amount of blood loss due to the vascular nature of fibroids. Laparoscopic management of fibroids is a difficult task in minimally invasive surgery given the extensive amount of suturing typically involved. The advantages of robotic surgery, including increased precision and fine motor coordination as well as excellent suturing capabilities, have led to its increased use in myomectomies. In comparision to conventional laparotomy, studies have shown reduced blood loss, complication rates, and length of stay with robotic myomectomies. This video demonstrates the improved precision in the enucleation of a myoma with attention to preserving fertility and the advantage of using monopolar and bipolar energy together to decrease blood loss. The ease of laparoscopic suturing shown in this robotic myomectomy due to increased fine motor coordination demonstrates a key advantage in robotic surgery in comparision to conventional laparoscopy

Minimally invasive surgery has been shown to decrease length of hospital stay, time to recovery, and postoperative pain scores. There has been a tremendous rise in the use of robotic surgery for high-precision surgeries, including gynecologic surgery for benign disease. It has been reported that one in nine women will eventually have a hysterectomy for benign indications, including symptomatic fibroids, adenomyosis, lower pelvic pain, and abnormal bleeding. Several studies have suggested advantages of robotic surgery over conventional laparotomy and laparoscopy regarding visualization, improved ergonomics, and fine motor coordination, although long-term patient outcomes have yet to be determined. This video explores the feasibility of robotic hysterectomy and the advantage of using monopolar and bipolar energy together with increased precision during dissection. In addition, we will show several conditions, including extensive pelvic adhesions and large uterine size, that can make a robotic hysterectomy more challenging

OBJECTIVE: Surgical experience in the operating room is an essential component of the education and training of residents in Obstetrics and Gyne- cology. With the revolution in minimally invasive technologies, the medical management of conditions that were previously surgically managed, and the introduction of the 80-hour work week, the time available to residents for the development of surgical skills has become more limited. The aim of our study is to quantify the changes over time in the operative experiences of graduating residents in Obstetrics and Gynecology. DESIGN: The Accreditation Council for Graduate Medical Education (ACGME) Resident Statistics Summary reports from the academic year 2002-2003 till the present were retrospectively reviewed. MATERIALS AND METHODS: The mean number of cases performed during the chief year as the primary surgeon for both abdominal hysterectomy and vaginal hysterectomy were analyzed. Statistical analysis was carried out using unpaired t tests and the analysis of variance (ANOVA). All statistical tests were performed using SAS 9.2 (SAS Institute, Cary, NC) and statistical significance was set at P<0.05. RESULTS: The mean number of abdominal hysterectomies performed by a graduating resident was 89.1 in 2002-2003 as compared to 68.6 in 20092010 (P< 0.001). The mean number of vaginal hysterectomies performed by a graduating resident was 34.9 in 2002-2003 as compared to 19.7 in 2009-2010 (P< 0.001). In addition, there was a statistically significant decrease in the operative experience of graduating chief residents during the study period (P<0.001). CONCLUSION: Current graduating residents are more likely to be performing fewer abdominal and vaginal hysterectomies than previous generations. To develop the technical skills required to be a competent and independently practicing gynecologic surgeon, graduating residents should consider additional fellowship training

The McCall culdoplasty was performed for mild/moderate pelvic organ prolapse along with total laparoscopic hysterectomy for the indication of adenomyosis. Bipolar electrocoagulator was a simple and efficacious instrument for total laparoscopic hysterectomy procedure. Procedure could be done briefely with minor hemorrhage. It is crucial to identify bladder, ureter and other adjacent organs prior to vaginal vault suspension by modified McCall's method to minimize urinary complications. It is a major part of culdoplasty to obliterate culdesac with delayed absorbable and non-absorbable suture materials. Video guided culdoplasty has an advantage of lower risk of ureteral damage than vaginal procedure. McCall's culdoplasty is a safe and efficacious way to manage the range of minor to moderate pelvic relaxation combined with other minimally invasive procedures