Endoscopic assessment of radiological stage IVA cervical cancer: A bivariate meta-analysis supporting an evidence-based staging algorithm proposal.

OBJECTIVE: To optimize the use of confirmatory endoscopic exams (cystoscopy/proctoscopy) in the staging of locally advanced cervical cancer (LACC), the present study evaluates the predictive value of radiological exams (CT and MRI) to detect bladder/rectum invasion. METHODS: A systematic search of databases (PubMed and EMBASE) was performed (CRD42021270329). The inclusion criteria were: a) cervix cancer diagnosis; b) staging CT and/or MRI (index test); c) staging cystoscopy and/or proctoscopy (standard test); and d) numbers of true positives (TP), true negatives (TN), false positives (FP), and false negatives (FN) provided. A random-effects bivariate meta-analysis of positive predictive value (PPV) and negative predictive value (NPV) was performed with moderator analyses by imaging modality (CT and MRI) and prevalence. RESULTS: Nineteen studies met the inclusion criteria, totaling 3480 and 1641 patients for bladder and rectum analyses, respectively. For bladder invasion (prevalence ranged from 0.9% to 34.5%), the overall PPV was 45% (95% confidence interval, 33%-57%, based on 19 studies). Per subgroup, the PPV was 31% for MRI/prevalence ≤6%, 33% for CT/prevalence ≤6%, and 69% for CT/prevalence >6%. For rectal invasion (prevalence ranged from 0.4% to 20.0%), the overall PPV was 30% (95% confidence interval, 17%-47%, based on 8 studies). Per subgroup, the PPV was 36% for MRI/prevalence ≤1%, 17% for MRI/prevalence >1%, and 38% for CT/prevalence >1%. The overall NPV for bladder invasion and rectal invasion were 98% (95% confidence interval, 97%-99%) and 100% (95% confidence interval, 99%-100%), respectively. Considering prevalence and radiological modality, the point estimate of NPV varied from 95% to 100% for bladder invasion and from 99% to 100% for rectum invasion. CONCLUSIONS: Due to low PPV (<50%) of radiological staging, endoscopic exams may be necessary to correctly assess radiological stage IVA LACC. However, they are not necessary after negative radiological exam (NPV ≥95%).

A practical guide for the safe implementation of early phase drug development and immunotherapy program in gynecologic oncology practice.

The success of targeted and immune therapies in other malignancies has led to an exponential increase in the number of active and pending clinical trials using these therapeutic approaches in patients with gynecologic cancers. These novel investigational agents are associated with unique and potentially life-threatening toxicities and many require special multidisciplinary logistical considerations. The objective of this review is to describe a practical approach for the safe implementation of targeted and immune therapies in academic gynecologic oncology practices based on our experience at M.D. Anderson Cancer Center.

Potential immunotherapy targets in recurrent cervical cancer.

OBJECTIVE: Our objective was to characterize the intra and peritumoral immune profile in recurrent cervical cancers to identify rational immunotherapy targets. METHODS: Archival pelvic exenteration specimens were examined using a validated multiplex immuno-fluorescent panel of antibodies against cluster of differentiation 8 (CD8), cluster of differentiation 68 (CD68), forkhead box P3 (FoxP3), programmed cell death protein 1 (PD1), and programmed death-ligand 1 (PD-L1, N=28). Clinical data were abstracted from the electronic medical record. RESULTS: Cytotoxic T cells, macrophages, and regulatory T cells were found in higher densities in peritumoral stroma (CD8+ density 497.7 vs 83.5, p<0.0001, CD68+ density 345.0 vs 196.7, p=0.04, FoxP3+ density 214.5 vs 35.6, p<0.0001). Antigen experienced T cells (PD1+) were higher in peritumoral compared to tumor tissue (median normalized fluorescence intensity 0.05 vs 0.0085, p<0.001). Although there was a higher median density of intratumoral cytotoxic T cells and macrophages compared to regulatory T cells (median density CD8+ 83.5 vs 35.6, p<0.05, median density 196.7 vs 35.6, p<0.05), the presence of macrophages correlated with the presence of regulatory T cells in tumors (r=0.58, p=0.001). CONCLUSIONS: While cytotoxic T cells are present in tumor tissue to varying degrees, their density is lower than in peritumoral stroma, suggesting intratumoral exclusion or destruction of T cells. Higher densities of intratumoral macrophages compared to regulatory T cells suggest macrophages may be important contributors to the immunosuppressive tumor environment. Future directions for combination therapy include altering T cell trafficking and targeting tumor associated macrophages (TAMs) to enhance intratumoral activated T cell density and effect a more robust immune response.

Overall survival after pelvic exenteration for gynecologic malignancy.

BACKGROUND: Five-Year survival after pelvic exenteration for gynecologic malignancies has been reported as high as 60%. The objective of this study was to determine overall survival (OS) after pelvic exenteration and evaluate factors impacting outcome. METHODS: A retrospective review of all women who underwent pelvic exenteration at our institution between February 1993 and December 2010 was performed. OS was defined as time from exenteration to date of death or last contact. Survival analysis was performed using the Kaplan Meyer method. Multivariate analysis was performed to determine the impact of clinical and pathologic factors on survival outcomes. RESULTS: One hundred sixty patients with gynecologic malignancy underwent pelvic exenteration. Five-year recurrence free survival (RFS) was 33% (95%CI 0.25-0.40). Factors which negatively impacted RFS included shorter treatment-free interval (p=.050), vulvar primary (p=.032), positive margins (p<.001), lymphovascular space invasion (LVSI, p<.001), positive lymph nodes (p<.001) and perineural invasion (p=0.030). In multivariate analysis, positive margins (p=.040), positive nodes (p<.001) and lymphovascular space invasion (LVSI, p=.003) retained a significant impact on RFS. Five-year OS was 40% (95% CI 0.32-0.48). Factors which negatively impacted OS included vulvar primary (p=.04), positive margins (p<.001), LVSI (p<.001), positive lymph nodes (p<.001) and perineural invasion (p=.008). In multivariate analysis, positive nodes (p=.001) and LVSI (p=.001) retained a significant impact on OS. CONCLUSION: Five-year OS after pelvic exenteration was 40%. Survival outcomes have not significantly improved despite improvements in technique and patient selection. Multiple non-modifiable factors at the time of exenteration are associated with poor survival.

Comparing long-term sexual dysfunction across different uterine cancer treatment modalities.

INTRODUCTION: The objective of this study was to assess differences in long-term sexual and menopausal side effects after uterine cancer treatment among treatment modalities. METHODS AND MATERIALS: This is a cross-sectional study that examined women treated for uterine cancer from 2006-2018. Eligible women included those who underwent a hysterectomy/bilateral salpino-oophorectemy alone (HS), with brachytherapy (BT), or with external beam radiation therapy (EBRT). A noncancer cohort of women who underwent a hysterectomy/BSO for benign indications were also identified (non-CA). To compare outcomes, we utilized a shortened form of the female sexual function index (FSFI) and the menopause survey, which consists of 3 subscales: hot flashes, vaginal symptoms, and urinary symptoms. Demographic, comorbidity, and other treatment variables were collected. Survey totals were compared across cohorts using ANOVA tests and logistic regression. RESULTS: A total of 284 women completed the Menopause Survey (Non-CA 64, HS 60, BT 69, EBRT 91); 116 women reported sexual activity in the last 4 weeks and completed the FSFI (NC 32, HS 21, BT 31, EBRT 32). The mean FSFI score for the entire cohort was 11.4 (SD 4.16), which indicates poor sexual function. There was no significant difference between any cohort in the overall FSFI score (p = 0.708) or in any of the FSFI subscales (all p > 0.05). On univariate analysis, BT was associated with fewer menopausal hot flashes and vaginal symptoms compared to the non-CA cohort (p < 0.05), which did not persist on multivariable analysis. CONCLUSION: There was no significant difference in sexual dysfunction or menopausal symptoms in those treated for uterine cancer with or without adjuvant radiation. Most patients reported poor sexual function.

Predictors of Oncologic Outcome in Patients Receiving Phase I Investigational Therapy for Recurrent or Metastatic Cervical Cancer.

Introduction: We aimed to identify clinical, pathologic, and treatment factors that are predictive of response and survival in patients with cervical cancer referred to phase I clinical trials. Methods: Patients with cervical cancer who received at least one dose of a phase I investigational agent at our institution between 2014 and 2022 were included. The log-rank test was used to analyze differences in progression-free survival (PFS) and overall survival (OS), and multivariable regression analysis was performed. Results: We included 65 patients with a median age of 41 years (range, 20-74), 3 prior therapies (range, 1-7), and 67.7% squamous carcinoma. The rate of distant metastasis at trial entry was 84.6%. The most common molecular alterations included PIK3CA (46.5%), PD-L1+ (46.2%), EPH (30.0%), and CREBBP (23.1%); 23.1% had received a prior checkpoint inhibitor. Phase I trials were for immunotherapy (58.5%) or targeted therapy (41.5%). The rate of biomarker matching was 21.5%. For all patients, median PFS was 3.6 months (95% CI, 2.0-5.2) and OS was 9.3 months (95% CI, 7.0-10.6). Factors at study entry associated with worse survival were presence of bone metastasis (PFS 1.6 vs 4.4 months: hazard ratio [HR], 2.8; p = 0.001; OS 3.8 vs 10.0 months: HR, 3.9; p < 0.0001) and absolute lymphocyte count below 1000/µL (PFS 1.8 vs 5.2 months: HR, 2.9; p = 0.0004; OS 7.0 vs 10.6 months: HR, 3.2; p = 0.0009). Factors associated only with worse OS were absolute neutrophil count above 4700/µL, hemoglobin below 10.5 g/dL, and smoking status. Grade 3+ treatment-related adverse events were seen in 16.9% of cases. Conclusion: Bone metastasis and absolute lymphocyte count below normal range at phase I study entry portend poor survival in patients with recurrent or metastatic cervical cancer.

Proceedings from the Melanoma Research Foundation Mucosal Melanoma Meeting (December 16, 2022, New York, USA).

Mucosal melanoma remains a rare cancer with high mortality and a paucity of therapeutic options. This is due in significant part to its low incidence leading to limited patient access to expert care and downstream clinical/basic science data for research interrogation. Clinical challenges such as delayed and at times inaccurate diagnoses, and lack of consensus tumor staging have added to the suboptimal outcomes for these patients. Clinical trials, while promising, have been difficult to activate and accrue. While individual institutions and investigators have attempted to seek solutions to such problems, international, national, and local partnership may provide the keys to more efficient and innovative paths forward. Furthermore, a mucosal melanoma coalition would provide a potential network for patients and caregivers to seek expert opinion and advice. The Melanoma Research Foundation Mucosal Melanoma Meeting (December 16, 2022, New York, USA) highlighted the current clinical challenges faced by patients, providers, and scientists, identified current and future clinical trial investigations in this rare disease space, and aimed to increase national and international collaboration among the mucosal melanoma community in an effort to improve patient outcomes. The included proceedings highlight the clinical challenges of mucosal melanoma, global clinical trial experience, basic science advances in mucosal melanoma, and future directions, including the creation of shared rare tumor registries and enhanced collaborations.

Fertility sparing surgery for treatment of early-stage cervical cancer: open vs. robotic radical trachelectomy.

OBJECTIVE: To compare the open versus robotic surgical approaches and provide surgical outcome data on patients who have undergone radical trachelectomy (RT). METHODS: We identified patients who underwent open (ORT) or robotic radical trachelectomy (RRT) between September 2005 and June 2011. Tumor characteristics, perioperative, operative and obstetrical outcomes were analyzed. RESULTS: Thirty-seven patients with early stage cervical cancer that desired future fertility underwent attempted radical trachelectomy, and 32 patients (20 with 1B1, 11 with 1A2, and 5 with 1A1 with LVSI/poorly differentiated histology) had successful completion of RT. Five (1 open/4 robotic) underwent conversion to radical hysterectomy secondary to close (<5mm) endocervical margin (p=0.08). The median age at diagnosis was 28.9 years (range; 21.4-37.2), 70% were nulliparous, and 9 had a visible lesion. Twenty-five patients (68%) underwent ORT and 12 (32%) underwent RRT. RRT was associated with less blood loss (62.5 mL vs. 300 mL, p=0.0001) and decreased length of postoperative stay (1 vs. 4 days, p<0.001), with no difference in operative time or histopathologic outcomes. Twenty-three patients (62%) had no residual cervical disease on final pathology. Common long-term morbidities were irregular menstrual bleeding or amenorrhea (25%), cerclage erosion (13%), or cervical stenosis (9%). Although there was a higher rate of conversion to hysterectomy in the robotic surgery cohort, rates of serious morbidities among the cohorts were comparable (robotic: 33% vs. open: 24%, p=0.70). Eleven (36%) patients are actively attempting pregnancy and three have achieved pregnancy. The median time of follow up is 17.0 months (range 0.30-64.9 months). There are no documented recurrences. CONCLUSIONS: RRT results in less blood loss and decreased length of hospital stay with no compromise in histopathologic outcomes.

Volumetric assessment of apparent diffusion coefficient predicts outcome following chemoradiation for cervical cancer.

OBJECTIVE: To determine the utility of volumetric diffusion weighted imaging (DWI) compared to other clinical factors for predicting recurrence and survival in cervical cancer patients treated with definitive chemoradiation. METHODS AND MATERIALS: We retrospectively studied cervical cancer patients treated with definitive chemoradiation between 2009-2013 at a single institution with a baseline MRI with DWI and 18F-FDG positron emission tomography/computed tomography (FDG-PET) scan. To identify clinical and imaging metrics correlated with survival and recurrence endpoints, variable importance values were calculated from random forest models. To provide clinically relevant threshold values, recursive partitioning analysis dichotomized patients into potential risk groups based on selected metrics. Cox's proportional hazard models assessed the effect of clinical and imaging factors on survival endpoints. RESULTS: Ninety-three patients were included in the analysis (median age 50 years). At a median follow-up of 35.6 months, 32 patients (34%) had disease recurrence. In the best multivariate model including clinical and imaging parameters, 90th percentile ADC < 1.917 was the only significantly associated factor with worse progression free survival (PFS). Overall survival, PFS, and distant metastasis free survival (DMFS) were significantly different between patient groups divided on 90th percentile ADC with threshold of 1.917 × 10-3 mm2/s and MRI volume with threshold of 18.9 cc (P = 0.037, P = 0.0002, P = 0.001). High MRI volume and low ADC were associated with worse clinical outcomes. CONCLUSIONS: Volumetric 90th percentile ADC value of the primary tumor on pretreatment MRI was a significant predictor of PFS and DMFS in cervical cancer patients, independent of established clinical factors and SUV on FDG-PET.

Survivors of gynecologic malignancies: impact of treatment on health and well-being.

PURPOSE: While overall survival from gynecologic malignancies has greatly improved over the last three decades, required treatments can lead to multiple health issues for survivors. Our objective was to identify health concerns that gynecologic cancer survivors face. METHODS: A systematic, stratified sample of women with gynecologic malignancies was surveyed for 18 health issues occurring before, during, or after treatment. The impact of clinical features and treatment modality on health issues was assessed through multivariate logistic regression models. RESULTS: Of 2,546 surveys mailed, 622 were not received by eligible subjects secondary to invalid address, incorrect diagnosis, or death. Thus, 1924 survivors potentially received surveys. Of the 1,029 surveys (53.5%) completed, median age was 59 years; diagnoses included 29% cervical, 26% endometrial, 26% ovarian/primary peritoneal/fallopian tube, 12.1% vulvar, and 5.4% vaginal cancers. The most frequently reported health issues included fatigue (60.6%), sleep disturbance (54.9%), urinary difficulties (50.9%), sexual dysfunction (48.4%), neurologic issues (45.4%), bowel complaints (42.0%), depression (41.3%), and memory problems (41.2%). These rankings were consistent with patients' self-reported rankings of "highest impact" personal issues. After controlling for demographic and clinical variables, multivariate analyses revealed that treatment modality impacted the odds of experiencing a given health issue. CONCLUSIONS: Our study demonstrates that gynecologic cancer survivors experience a high frequency of health conditions and highlights the association between treatment modality and specific health concerns. IMPLICATIONS FOR CANCER SURVIVORS: The study findings highlight the multiple health concerns experienced by gynecologic cancer survivors and suggest the potential for developing interventions to mitigate these concerns in survivorship.

Thomas Eakins' Agnew Clinic. a study of medicine through art.

In 1889, Thomas Eakins was commissioned to paint a portrait of Dr. David Hayes Agnew to commemorate his exemplary career as a physician and teacher at The University of Pennsylvania. What was originally proposed as a three-quarters portrait of the retiring professor quickly became an enormous painting depicting an operating theater with Dr. Agnew assuming his role as both surgeon and educator. When comparing this piece with an earlier Eakins' painting, The Gross Clinic, one can trace the rapid evolution of surgical techniques that accompanied medicine's advancement in the late 19th century. Eakins obviously embraced this progress, but was the public ready to do so too?

Risk of thromboembolic disease in patients undergoing laparoscopic gynecologic surgery.

OBJECTIVE: To estimate the incidence of venous thromboembolism among patients undergoing gynecologic laparoscopy and characterize the risk of venous thromboembolism among patients with gynecologic malignancy. METHODS: Data were collected for patients who underwent laparoscopic gynecologic surgery from January 2000 to January 2009. Incidence of deep vein thrombosis (DVT) or pulmonary embolism diagnosed within 6 weeks of surgery was estimated. Fisher's exact test was used to estimate the association between the presence of perioperative venous thromboembolism and categorical variables. RESULTS: Six (of 849) patients developed symptomatic venous thromboembolism (0.7%, 95% confidence interval: 0.024-1.44%). The median time to diagnosis of venous thromboembolism was postoperative day 15.5 (range, 1-41 days), median body mass index was 25.4 kg/m (range, 18.4-50 kg/m), median operative time was 176 minutes (range, 53-358 minutes), and median estimated blood loss was 125 mL (range, 10-250 mL). Five of 430 (1.2%) patients with a history of gynecologic malignancy developed postoperative thromboembolic events. Venous thromboembolism was diagnosed in three of 662 (0.5%) patients undergoing intermediate complexity procedures and three of 106 (2.8%) patients undergoing high-complexity procedures. Three patients with venous thromboembolism (50%) had a history of at least one previous modality of cancer treatment before laparoscopy. One patient (17%) had DVT only, four (67%) had pulmonary emboli without an identified DVT, and one (17%) had both. There were no associated mortalities. CONCLUSION: The incidence of thromboembolism in patients undergoing low- and intermediate-complexity, minimally invasive surgery was low, even among patients with a gynecologic malignancy. Patients undergoing high-complexity, minimally invasive procedures may benefit from postoperative anticoagulation. LEVEL OF EVIDENCE: II.